@article {pmid41831526,
year = {2026},
author = {Kelliher, JC and Engeland, CG and Graham-Engeland, JE and Katz, M and Kessler, C and Shearer, GC},
title = {Oxylipin composition of high-density lipoprotein is altered in men and Hispanic adults with mild cognitive impairment.},
journal = {Journal of lipid research},
volume = {67},
number = {4},
pages = {101021},
doi = {10.1016/j.jlr.2026.101021},
pmid = {41831526},
issn = {1539-7262},
abstract = {High-density lipoprotein (HDL) oxylipins are potent inflammatory mediators. HDL dyshomeostasis and inflammation increase mild cognitive impairment (MCI) and dementia risk, which vary by gender and race/ethnicity. It is unknown whether and how HDL oxylipin profiles differ between non-MCI and MCI individuals, or if potential differences are gender- and/or race/ethnicity dependent. In this targeted lipidomics study, we profiled plasma HDL oxylipins in older (70+) adults (N = 222) with or without MCI to determine how HDL oxylipin composition relates to cognitive impairment status. HDL oxylipin concentrations were analyzed by cognitive status, gender, and race/ethnicity (non-Hispanic Black, Hispanic, and non-Hispanic white). We found a gender- and race/ethnicity-specific association between MCI and lower HDL oxylipin content, which was independent of overall HDL-c concentrations. The HDL of MCI men contained lower amounts of anti-inflammatory and vasodilatory omega (ω)3 EPA C20:5ω3-derived hydroxyeicosapentaenoic acids (HEPEs) and DHA C22:6ω3-derived hydroxydocosahexaenoic acids than that of non-MCI men. Similarly, Hispanic participants with MCI had lower HDL concentrations of EPA C20:5ω3-derived HEPEs and DHA C22:6ω3-derived hydroxydocosahexaenoic acids than non-MCI Hispanic participants. Higher HDL concentrations of EPA C20:5ω3-derived HEPEs appeared protective against MCI in both men and Hispanic individuals. Further, higher oxylipin concentrations within HDL correlated with better cognition in non-Hispanic white women. This work identifying altered HDL oxylipin composition in MCI highlights a novel dysregulated lipid signaling pathway in cognitive decline. Reduced anti-inflammatory and vasodilatory ω3 oxylipins within HDL in MCI men and Hispanic individuals provide molecular evidence linking together HDL functionality, inflammation, and dementia risk.},
}

@article {pmid41964066,
year = {2026},
author = {Zehra, S and Rai, S and Rani, K and Choudhury, SD and Rai, H and Bhowmik, S and Mohan, N and Gupta, A and Chatterjee, P and Reddy, TJ and Rani, N and Modi, GP and Nikolajeff, F and Kumar, S},
title = {Stress-induced alteration of small extracellular vesicles drives amyloid-beta sequestration and exacerbates Alzheimer's disease pathogenesis.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02028-1},
pmid = {41964066},
issn = {1758-9193},
}

@article {pmid41964075,
year = {2026},
author = {Andreozzi, E and Yagi, T and Wildsmith, K and Rawal, S and Horie, K and Boyd, P and Takahashi, E and Barthélemy, NR and Aluri, J and Charil, A and Reilhac, A and Gordon, BA and Flores, S and Verbel, D and Sauter, N and Benzinger, TLS and McDade, E and Mummery, C and , and , and Zhou, J and Bateman, RJ and Reyderman, L},
title = {Etalanetug (E2814) in dominantly inherited Alzheimer's disease: an open-label phase 1b/2 study to assess safety and target engagement in participants with mild to moderate cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02047-y},
pmid = {41964075},
issn = {1758-9193},
abstract = {INTRODUCTION: Etalanetug (E2814) is designed to delay the clinical progression of Alzheimer's disease (AD) by binding to the microtubule binding region (MTBR) of tau implicated in seeding and spreading of tau pathology. Dominantly inherited Alzheimer's disease (DIAD) is a rare form of the disease (< 1%), having similar changes in the tau distribution and pathology to sporadic AD. Herein, we report the safety, pharmacology and biomarker results of the etalanetug Study 103 in DIAD patients.

METHODS: Study 103 enrolled participants with mild-to-moderate cognitive impairment due to DIAD who received etalanetug intravenously every 4 weeks escalating from 750 mg, 1500 mg, 3000 mg, to 4500 mg. After ascending to 4500 mg, patients received 4500 mg for up to 108 weeks. Tau pathology biomarkers, ptau217 and MTBR-tau243 were measured in CSF. Additional assessments included tau PET ([[18]F]MK-6240) and MRI. Pharmacodynamic effects of etalanetug on biomarkers were evaluated. Untreated participants from the DIAN Observational and DIAN-TU studies trial served as natural history controls.

RESULTS: Overall, 8 participants enrolled in Study 103. Etalanetug reduced concentrations of ptau217 30.4% after 12 weeks (n = 7), 48.6% at 36 weeks (n = 5), and 57.9% at 108 weeks (n = 2). Etalanetug treatment reduced concentrations of MTBR-tau243 by 50.6% in DIAD participants (n = 7) after 12 weeks of treatment. Maximal reduction in MTBR-tau243 levels (71.6%) was observed at week 36 (n = 4) and was sustained to 108 weeks (n = 2). In healthy volunteers who lack tau pathology, etalanetug had no effect on MTBR-tau243 or ptau217 after 12 weeks of treatment. Three DIAD patients had tau PET acquired at week 60 and week 108. The data indicate that the tau PET SUVr signal remains stable overall, with a trend towards decrease over time. At 108 weeks, no tau accumulation was observed via tau PET in any of the 3 patients. Three participants experienced treatment-related adverse events (AEs) with the 3000 mg dose; additionally, 5 serious AEs total were reported in 3 participants.

DISCUSSION: Etalanetug treatment in these symptomatic participants with DIAD was tolerated across dose levels, and immunogenicity was found to be minimal. Etalanetug demonstrated effects on both hyperphosphorylated tau and tau tangle pathology. Taken together, the data support continued evaluation of etalanetug as an AD disease-modifying therapy.

TRIAL REGISTRATION: NCT04971733 (registration date: 2021-07-20).},
}

@article {pmid41964371,
year = {2026},
author = {Lin, JY and Huang, ZB and Fang, EF and Lu, G},
title = {STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2026.2658848},
pmid = {41964371},
issn = {1554-8635},
abstract = {PINK1 serves as the central regulator of PINK1-PRKN-mediated mitophagy, and its precise regulation is critical for efficient mitochondrial clearance. Although the cleavage of PINK1 and its subsequent degradation via the N-end rule pathway under basal conditions are well understood, how full-length PINK1 stability is regulated following mitochondrial damage has remained elusive. In our recent study, we identified the STUB1-VCP/p97 axis as a mechanism that fine-tunes full-length PINK1 levels during mitophagy. We demonstrate that STUB1 functions as an E3 ubiquitin ligase that catalyzes K48-linked polyubiquitination of full-length PINK1, which is subsequently recognized and extracted by VCP/p97 for proteasomal degradation. Disruption of this axis results in excessive accumulation of full-length PINK1, accelerated turnover of PRKN, and impaired mitophagy. Moreover, we find that this regulatory mechanism is compromised in the brains of patients with Alzheimer disease (AD), and its disruption leads to neuronal mitophagy defects and impaired associated learning capability in C. elegans. These findings demonstrate that the STUB1-VCP/p97 complex fine-tunes PINK1 levels to ensure efficient mitophagy and preserve mitochondrial homeostasis.Abbreviations: AD, Alzheimer disease; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; MPP, mitochondrial processing peptidase; MQC, mitochondrial quality control; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; SILAC, stable isotope labeling by amino acids in cell culture; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.},
}

@article {pmid41964394,
year = {2026},
author = {Abdullah, LB and Zhang, F and Petersen, M and Hall, J and Handen, BL and Mapstone, M and Christian, B and Head, E and Harley, S and Andrews, H and Lee, JH and Tudorascu, D and Hom, C and Zaman, S and Brickman, AM and Rosas, D and Cohen, A and Harp, JP and Schmitt, F and Ptomey, L and Burns, JM and Lott, IT and Lai, F and Laymon, C and Cruchaga, C and O'Bryant, S and Ances, BM},
title = {The association between APOE 𝜀4 carrierships and the detection of amyloid positivity using an Alzheimer's disease proteomic blood test in asymptomatic Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71338},
pmid = {41964394},
issn = {1552-5279},
support = {U01 AG051406/AG/NIA NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; //Investigation of Co-occurring conditions across the Lifespan to Understand Down syndrome (NIH INCLUDE Project)/ ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {Humans ; Male ; *Down Syndrome/genetics/blood/diagnostic imaging ; Female ; *Apolipoprotein E4/genetics ; Proteomics ; Middle Aged ; Adult ; Cross-Sectional Studies ; Biomarkers/blood ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/blood/genetics ; tau Proteins/blood ; Positron-Emission Tomography ; Neurofilament Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; Peptide Fragments/blood ; Heterozygote ; Aniline Compounds ; },
abstract = {INTRODUCTION: This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance.

METHODS: Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates.

RESULTS: Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4.

DISCUSSION: These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status.},
}

Humans
Male
*Down Syndrome/genetics/blood/diagnostic imaging
Female
*Apolipoprotein E4/genetics
Proteomics
Middle Aged
Adult
Cross-Sectional Studies
Biomarkers/blood
*Amyloid beta-Peptides/blood
*Alzheimer Disease/blood/genetics
tau Proteins/blood
Positron-Emission Tomography
Neurofilament Proteins/blood
Glial Fibrillary Acidic Protein/blood
Peptide Fragments/blood
Heterozygote
Aniline Compounds

@article {pmid41964654,
year = {2026},
author = {Stögmann, E and König, T},
title = {Response to Amalia.},
journal = {Genetics in medicine : official journal of the American College of Medical Genetics},
volume = {28},
number = {4},
pages = {101689},
doi = {10.1016/j.gim.2026.101689},
pmid = {41964654},
issn = {1530-0366},
}

@article {pmid41964656,
year = {2026},
author = {Amalia, R},
title = {Correspondence on "Assessing family history and approaches for identifying patients with dementia with diagnostically significant genetic findings" by König et al.},
journal = {Genetics in medicine : official journal of the American College of Medical Genetics},
volume = {28},
number = {4},
pages = {101688},
doi = {10.1016/j.gim.2026.101688},
pmid = {41964656},
issn = {1530-0366},
}

@article {pmid41964788,
year = {2026},
author = {Zhang, R and Dong, X and Pei, G and Huang, S},
title = {Engineered Alzheimer Organoids Validate the Link Between Intracellular and Soluble p-Tau Biomarkers and Highlight the Contribution of Astrocytic Tau.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41964788},
issn = {1995-8218},
abstract = {Soluble phosphorylated tau has become a key biomarker for Alzheimer's disease pathology, yet further mechanistic studies are needed beyond observational investigations to clarify the relationship between soluble p-tau species and intracellular tau pathology. Here, we utilized chimeric human cerebral organoids (chCOs) to generate a series of organoids in which the endogenous MAPT gene was CRISPR/Cas9 edited in different cell types to create phosphorylation-deficient mutants at the AD-associated sites. We found that the APPswe mutation increased tau phosphorylation in both neurons and astrocytes. Notably, astrocyte-specific phosphorylation-deficient mutations of tau in organoids reduced soluble p-tau181 and p-tau217 levels, as detected by single-molecule array. These findings indicate that astrocytic tau plays a substantial role in contributing to the pool of extracellular phosphorylated tau and suggest it may be an overlooked source of AD biomarkers. Moreover, our engineered chCOs offer a versatile platform for exploring how cell-type-specific pathologies correlate with changes in biomarker profiles.},
}

@article {pmid41964801,
year = {2026},
author = {Shteinfer-Kuzmine, A and Nivedita, AK and Santhanam, M and Trishna, S and Swerdlow, RW and Pan, J and Shoshan-Barmatz, V},
title = {Targeting VDAC1 to protect against mitochondria-linked cell death pathways: apoptosis, pyroptosis, ferroptosis, and associated diseases.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {4},
pages = {},
pmid = {41964801},
issn = {1573-675X},
mesh = {*Voltage-Dependent Anion Channel 1/metabolism/genetics/antagonists & inhibitors ; *Ferroptosis/drug effects ; *Pyroptosis/drug effects ; Animals ; *Mitochondria/metabolism/drug effects ; *Apoptosis/drug effects ; Humans ; Mice ; Reactive Oxygen Species/metabolism ; *Alzheimer Disease/metabolism/genetics/drug therapy/pathology ; Inflammatory Bowel Diseases/metabolism/drug therapy/genetics/pathology ; Mice, Inbred C57BL ; Inflammasomes/metabolism ; },
abstract = {The pathways of programmed cell death (PCD), including apoptosis, pyroptosis, and ferroptosis, are interconnected. They can be activated simultaneously within tissues or cell lines and are often associated with various diseases. Thus, identifying a common player and inhibitor targeting several PCD types is essential. Here, we show that overexpression and oligomerization of the mitochondrial gatekeeper voltage-dependent anion channel 1 (VDAC1) is involved in apoptosis, pyroptosis, and ferroptosis, and specific VDAC1 oligomerization inhibitors, VBIT-4 and VBIT-12, prevented multiple forms of PCD triggered by various stimuli. In addition, they mitigated mitochondrial dysfunction, reduced reactive oxygen species production and intracellular Ca[2][+] levels, preserved mitochondrial-associated hexokinase, and inhibited assembly/activation of the NLRP3 inflammasome. In Alzheimer's disease and inflammatory bowel disease mouse models, VBIT-4 and VBIT-12, respectively, protected against apoptosis, pyroptosis, ferroptosis, and disease-associated pathologies. Thus, we show that VDAC1 oligomerization represents a prime target for VBIT-4 and VBIT-12 that can simultaneously inhibit various PCD forms and diseases associated with enhanced PCD and/or inflammation.},
}

*Voltage-Dependent Anion Channel 1/metabolism/genetics/antagonists & inhibitors
*Ferroptosis/drug effects
*Pyroptosis/drug effects
Animals
*Mitochondria/metabolism/drug effects
*Apoptosis/drug effects
Humans
Mice
Reactive Oxygen Species/metabolism
*Alzheimer Disease/metabolism/genetics/drug therapy/pathology
Inflammatory Bowel Diseases/metabolism/drug therapy/genetics/pathology
Mice, Inbred C57BL
Inflammasomes/metabolism

@article {pmid41964823,
year = {2026},
author = {Ibrahim, KN and Wasim, R and Rahman, E},
title = {HMGB1-mediated neuroinflammation: molecular mechanisms and emerging therapeutic approaches.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41964823},
issn = {1568-5608},
abstract = {High mobility group box 1 (HMGB1) has emerged as a central inflammatory mediator linking cellular stress and tissue injury to sustained neuroinflammation in the central nervous system. Although originally characterized as a nuclear chromatin-binding protein, HMGB1 acquires potent pro-inflammatory activity following cytoplasmic translocation and extracellular release, where it functions as a damage-associated molecular pattern. The inflammatory actions of HMGB1 are regulated by its redox state and post-translational modifications, which determine receptor engagement and downstream signaling. Extracellular HMGB1 interacts with pattern-recognition receptors including TLR4/MD-2, the receptor for advanced glycation end products (RAGE), CXCR4, and nucleic acid-sensing Toll-like receptors, leading to activation of NF-κB, MAPK, JAK/STAT, and inflammasome pathways. These cascades amplify cytokine production, glial activation, oxidative stress, blood-brain barrier disruption, and neuronal dysfunction. Dysregulated HMGB1 signaling has been implicated in acute and chronic neurological disorders, including ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and epilepsy. From a pharmacological perspective, HMGB1 has emerged as a potential therapeutic target, although most supporting evidence currently comes from preclinical studies and further clinical validation is required. Several strategies aimed at attenuating HMGB1-driven inflammation-such as neutralizing antibodies, direct HMGB1 inhibitors including glycyrrhizin, TLR4 and RAGE antagonists, natural anti-inflammatory compounds, and nanotechnology-based delivery systems-have demonstrated beneficial effects in experimental and preclinical models, but clinical validation remains limited. However, clinical translation remains limited by poor blood-brain barrier penetration, insufficient redox specificity, receptor redundancy, and a lack of well-designed human trials. This review summarizes current knowledge on HMGB1 biology, disease relevance, and therapeutic targeting, and highlights key challenges and future directions for HMGB1-based anti-inflammatory therapies in neuroinflammatory disorders.},
}

@article {pmid41964835,
year = {2026},
author = {Bekena, S and Singh, RK and Zhu, Y and Trani, JF and Ances, BM and Babulal, GM},
title = {Grip strength modifies the association between blood-based alzheimer's biomarkers and cognitive function.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41964835},
issn = {2509-2723},
support = {R01 AG074302/AG/NIA NIH HHS/United States ; R01 AG068183/AG/NIA NIH HHS/United States ; R01 AG067428/AG/NIA NIH HHS/United States ; U19AG073585-01/AG/NIA NIH HHS/United States ; },
abstract = {Blood-based biomarkers are increasingly used to characterize Alzheimer's disease (AD)-related pathology, yet substantial heterogeneity exists in how biomarker burden relates to cognitive performance. Grip strength, a marker of frailty and functional reserve, may modify this relationship. We conducted a cross-sectional analysis of 348 participants from the Aging Adult Brain Connectome (AABC) study. Global cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Plasma biomarkers included phosphorylated tau-217 (pTau217), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and total tau (tTau). Multiple linear regression models tested biomarker × grip strength interactions, adjusting for demographic factors, APOE ε4 status, cardiometabolic risk factors, body mass index, and creatinine. Sensitivity analyses included age-based propensity score matching and age-stratified models. Participants with low PACC were older, had lower grip strength, and higher plasma biomarker levels than those with normal cognition (all p < 0.001). In adjusted models, significant interactions between low grip strength and biomarkers were observed for pTau217 (β = - 0.046, p < 0.01), NfL (β = - 0.002, p < 0.001), and GFAP (β = - 0.005, p < 0.05). Age-matched showed attenuation of some interaction effects except for low grip strength and NfL. Age-stratified analyses showed a significant interaction for NfL among adults ≥ 65 years and for GFAP among those < 65 years. Grip strength moderated the association between plasma AD-related biomarkers and cognitive performance, supporting physical strength as an indicator of vulnerability. Integrating simple strength measures with blood biomarkers may improve cognitive risk stratification in community-dwelling adults.},
}

@article {pmid41964857,
year = {2026},
author = {Ramírez-Olvera, A and Almazán, JL and Pérez-Martínez, L and Pedraza-Alva, G},
title = {BDNF Protects Against Neuronal Damage Induced by TNF and β-Amyloid Peptides by Targeting JNK Activation.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41964857},
issn = {1573-6903},
support = {477677//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; 773657//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; IFC2016-2282//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; CF/2019-40792//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; IN217822//Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México/ ; IN213119//Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México/ ; },
}

@article {pmid41964873,
year = {2026},
author = {Hong, M and Lee, SER},
title = {Internal Structure and Reliability of the Public Stigma of Alzheimer's Disease Scale (PSAD-K) Among Korean Americans.},
journal = {Journal of cross-cultural gerontology},
volume = {41},
number = {2},
pages = {},
pmid = {41964873},
issn = {1573-0719},
}

@article {pmid41964934,
year = {2026},
author = {Ghosh, N and Pathak, S and Bera, R and Sharma, A and Kakkar, D and Kurmi, BD and Srivasatava, P and Ghosh, M and Karwasra, R and Ansori, ANM and Das, S and Sharma, N},
title = {Biomimetic nanocarriers as advanced drug delivery strategies in neurological disorders.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2026.2659924},
pmid = {41964934},
issn = {1744-7593},
abstract = {INTRODUCTION: Neurological disorders represent a major and growing global health challenge due to complex central nervous system pathology and limited drug penetration across the blood - brain barrier. Conventional therapies are largely symptomatic and often fail to achieve sufficient brain bioavailability or disease modification. Biomimetic nanocarriers have emerged as a promising strategy to improve brain targeting and therapeutic efficacy.

AREAS COVERED: This review discusses recent advances in biomimetic nanocarriers for the treatment and diagnosis of neurological disorders. We summarize the pathological mechanisms underlying central nervous system diseases and discuss how cell membrane-coated nanocarriers derived from red blood cells, platelets, immune cells, stem cells, and cancer cells can enhance BBB penetration, immune evasion, and targeted delivery. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to evaluate therapeutic and diagnostic applications in Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, ischemic stroke, and glioblastoma.

EXPERT OPINION: Biomimetic nanocarriers offer a promising strategy to overcome biological barriers and improve central nervous system drug delivery. However, clinical translation remains challenged by membrane source standardization, scalability, and safety concerns. Future research should focus on reproducible manufacturing, regulatory frameworks, and long-term toxicity evaluation to accelerate clinical adoption.},
}

@article {pmid41964958,
year = {2026},
author = {Fukui, M and Kaise, T and Masaki, T and Sakamoto, T and Kageyama, R},
title = {Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer's disease model mice.},
journal = {Cell reports},
volume = {45},
number = {4},
pages = {117250},
doi = {10.1016/j.celrep.2026.117250},
pmid = {41964958},
issn = {2211-1247},
abstract = {Adult hippocampal neurogenesis declines with aging and in neurological disorders, leading to cognitive impairment. We previously showed that inducing Plagl2 and antagonizing Dyrk1a (iPaD) rejuvenates aged neural stem cells (NSCs), enhancing neurogenesis and cognition in aged mice. Here, we found that NSC-specific iPaD treatment activates neurogenesis, reduces amyloid-β deposition, and improves cognition in Alzheimer's disease model mice. Transcriptomic analysis revealed widespread changes in gene expression in the hippocampus after iPaD treatment. The upregulated genes include those associated with astrocyte and microglial activation involved in amyloid-β clearance, while several genes upregulated in Alzheimer's disease are downregulated. Among the latter genes, knockdown of Prkag2 in the hippocampus most effectively enhances neurogenesis and reduces amyloid-β accumulation. Notably, both iPaD treatment and Prkag2 knockdown activate AMP-activated protein kinase signaling, upregulating genes involved in autophagy and cellular homeostasis. These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41965189,
year = {2026},
author = {Gouvea, RG and Bezerra, ES and Amaral, LG and da Conceição, RA and Pauli, FP and Coutinho, MS and Amaral, AP and de Oliveira, PCO and da Silva, FC and Teles de Souza, AM and de Moraes, MC and Forezi, LDSM},
title = {Dual inhibition of AChE and BuChE by coumarin-benzothiazole hybrids: potent candidates unveiled through innovative screening and docking studies.},
journal = {Bioorganic chemistry},
volume = {176},
number = {},
pages = {109838},
doi = {10.1016/j.bioorg.2026.109838},
pmid = {41965189},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is closely associated with cholinergic dysfunction, and dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) represents a promising therapeutic strategy. However, current screening methods for cholinesterase inhibitors, particularly Ellman-based assays, are prone to spectral interferences and limited analytical specificity, which may compromise accurate identification and kinetic characterization of potent inhibitors. In addition, highly potent dual AChE/BuChE inhibitors with well-defined structure-activity relationships remain limited. To address these limitations, this study combines rational molecular design with the development of a selective chromatographic screening platform based on magnetic particle-immobilized enzymes and post-column derivatization, enabling improved analytical specificity and reliable quantification of enzymatic activity. In this work, a series of novel coumarin-benzothiazole hybrids were designed, synthesized, and evaluated as potential dual ChE inhibitors. The target compounds were obtained through a multistep synthetic strategy involving formation of coumarin-benzothiazole 10 (90% yield), O-alkylation (81-89% yield), and nucleophilic substitution with nitrogen heterocycles to afford hybrids 13a-p in yields ranging from 19 to 92%. The compounds were first screened using a newly developed semi-automated chromatographic platform, which combines magnetic particle-immobilized enzymes with post-column derivatization, overcoming limitations of conventional Ellman-based assays. Donepezil was used as a proof-of-concept reference inhibitor, confirming the accuracy of the method. The analytical method demonstrated excellent linearity (R[2] = 0.9983-0.9992), precision (CV ≤ 7.8%), and accuracy within accepted validation limits. Biological evaluation revealed highly potent inhibitors, particularly 13a and 13m, which exhibited IC50 values of 1.0 ± 0.1 nM and 0.6 ± 0.1 nM against AChE, respectively, compared with 64.9 ± 16.0 nM for donepezil. For BuChE, 13m showed an IC50 of 109.2 ± 14.7 nM, while 13a displayed 1212.5 ± 144.0 nM, both lower than donepezil (2202 ± 326 nM). Kinetic studies confirmed a competitive mechanism of inhibition, with Kᵢ values as low as 0.12 ± 0.02 nM for AChE and 47.76 ± 15.14 nM for BuChE (13m). Molecular docking studies supported these findings, demonstrating key interactions within the catalytic sites of both enzymes. Additionally, in silico evaluations indicated that these derivatives have favorable druglikeness. Together, the results highlight coumarin-benzothiazole derivatives as promising dual-target ChEIs and establish the developed analytical method as a versatile tool for the discovery and characterization of new anti-AD candidates.},
}

@article {pmid41965454,
year = {2026},
author = {Wagle, MM and Liu, C and Liu, Z and Wang, Y and Kellis, M and Patrick, E and Yang, P},
title = {Interpretable deep generative ensemble learning for single-cell omics with Hydra.},
journal = {Molecular systems biology},
volume = {},
number = {},
pages = {},
pmid = {41965454},
issn = {1744-4292},
support = {1173469//DHAC | National Health and Medical Research Council (NHMRC)/ ; },
abstract = {Single-cell omics enable the dissection of cellular heterogeneity, yet the high dimensionality, inherent noise, and sparsity present significant challenges. These challenges are amplified for rare cell populations, which are often difficult to annotate reliably but can be central to development and disease. As single-cell assays increasingly capture multiple molecular layers, the integrative analysis of such multimodal data further increases complexity. Here, we propose Hydra, a deep generative framework based on an ensemble of variational autoencoders for effective learning of unimodal and multimodal single-cell omics data. Hydra implements interpretable modules for capturing cell-type-specific molecular signatures. The ensemble of such interpretable modules enables reproducible feature selection and robust cell-type annotation, with particular effectiveness for rare populations. We benchmarked Hydra on a repertoire of 21 datasets, including unimodal and multimodal single-cell omics data. Our results demonstrate that Hydra offers comparable to superior performance to several state-of-the-art methods. Finally, we highlight the utility of Hydra in robustly annotating brain cellular subtypes and preserving disease-relevant signatures using our previously published dataset that profiles Alzheimer's disease.},
}

@article {pmid41965547,
year = {2026},
author = {Shi, Y and Fang, Z and Chen, Y and Lin, R and Huang, C and Li, H and Yan, Y},
title = {Prevalence and risk factors of loneliness in older adults with preclinical and prodromal Alzheimer's disease: the impact of depression, frailty-weight loss and quality of life.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07432-8},
pmid = {41965547},
issn = {1471-2318},
support = {2020Y9021//Innovation of Science and Technology of Fujian Province/ ; 2023J05224//Natural Science Foundation of Fujian Province/ ; },
}

@article {pmid41965602,
year = {2026},
author = {Meléndez, JC and Escudero, J and Satorres, E and Pitarque, A and Marti-Hoyos, I and Gonzalez-Moreno, J},
title = {Combined home-delivered transcranial direct current stimulation and cognitive training in older adults with mild cognitive impairment due to Alzheimer's disease: a randomized, single-blind, sham-controlled trial.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07481-z},
pmid = {41965602},
issn = {1471-2318},
support = {PID2022-136798OB-I00//Ministerio de Ciencia e Innovación/ ; },
}

@article {pmid41965633,
year = {2026},
author = {Mansel, CO and Ghisays, V and Mahnken, JD and Swerdlow, RH and Reiman, EM and Karnes, JH and Denny, JC and Veatch, OJ},
title = {Downward bias in the association between APOE and Alzheimer's disease using prevalent and by-proxy disease sampling in the All of Us research program.},
journal = {BMC medical genomics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12920-026-02362-1},
pmid = {41965633},
issn = {1755-8794},
support = {P30 AG072973/NH/NIH HHS/United States ; P30 AG072973/NH/NIH HHS/United States ; P30 AG035982/NH/NIH HHS/United States ; 1OT2OD026549/NH/NIH HHS/United States ; ZIA HG200417/NH/NIH HHS/United States ; P30 AG035982/NH/NIH HHS/United States ; },
}

@article {pmid41965638,
year = {2026},
author = {Khan, AJ and Rahman, I and Beg, HA and Akter, S and Haque, R and Monsur, DT and Rani, H and Dom, TNM},
title = {Association of periodontitis and tooth loss with cognitive decline in the older adults - a systematic review.},
journal = {BMC oral health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12903-026-08310-w},
pmid = {41965638},
issn = {1472-6831},
abstract = {BACKGROUND: The increasing global burden of dementia highlights the importance of identifying factors that may contribute to cognitive decline in later life. Growing evidence suggests that chronic oral conditions, particularly periodontitis (PD) and tooth loss, may be associated with Alzheimer's disease (AD) and related dementias. This study synthesizes current observational evidence on the association between PD, tooth loss, and cognitive impairment (CI) among older adults.

METHODS: A comprehensive literature search was conducted in PubMed, the Cochrane Library, Embase, Scopus, and Google Scholar for English-language studies published between 2010 and 2025. Cross-sectional and longitudinal cohort studies examining associations between PD, tooth loss, and CI were included. Study selection, data extraction, and quality assessment were performed in accordance with PRISMA 2020 guidelines.

RESULTS: Thirteen studies met the inclusion criteria, with sample sizes ranging from 40 participants to over 500,000 individuals in large population-based cohorts. Most studies focused on adults aged ≥ 50 years, particularly those aged 60 years and above. Periodontal status, tooth loss, and cognitive outcomes were assessed using heterogeneous diagnostic methods. Most studies reported significant associations between PD or tooth loss and CI, dementia, or AD. Periodontal treatment appeared protective in several studies, although some associations weakened after adjustment for confounders.

CONCLUSIONS: The findings support PD and tooth loss are consistently associated with adverse cognitive outcomes, although causal relationships cannot be established due to methodological heterogeneity and residual confounding. Integrating oral health care into geriatric and dementia-prevention strategies may help preserve cognitive function and improve quality of life among older adults.},
}

@article {pmid41965687,
year = {2026},
author = {Hamed, FM and Mady, MS and Elgayed, SH and Mansour, YE and Mahgoub, S and Lai, KH and Lin, CY and Elsayed, HE and Moharram, FA},
title = {Carpoxylon macrospermum leaf extract and its phenolic compounds: a multi-targeted therapeutic remedy for Alzheimer's disease.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-026-05365-8},
pmid = {41965687},
issn = {2662-7671},
support = {MOST 111-2320-B-038-040-MY3, 113-2628-B-038-009-MY3, and 113-2321-B-255-001//National Science and Technology Council of Taiwan/ ; },
}

@article {pmid41965693,
year = {2026},
author = {Liu, J and Liu, J and Fan, Y and Liu, C and Cao, J and Ma, H and Hou, Y and Gao, S and Wang, P},
title = {Targeting the astrocyte-microglia EFEMP1-GALNT10 axis: a spatially programmable therapeutic strategy for hippocampal vulnerability in Alzheimer's disease.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-08098-x},
pmid = {41965693},
issn = {1479-5876},
support = {82030064//The State Key Program of the National Natural Science Foundation of China grants/ ; L246009//Natural Science Foundation of Beijing Municipality/ ; },
}

@article {pmid41965838,
year = {2026},
author = {Yoo, JK and Kim, JH},
title = {Genome-wide investigation of synthetic rescue interactions in Alzheimer's disease implicates glial lipid and sterol metabolism.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02009-4},
pmid = {41965838},
issn = {1758-9193},
support = {RS-2023-NR077290//National Research Foundation of Korea/ ; RS-2023-NR077290//National Research Foundation of Korea/ ; Education and Research Encouragement Fund//Seoul National University Hospital/ ; Education and Research Encouragement Fund//Seoul National University Hospital/ ; },
}

@article {pmid41965896,
year = {2026},
author = {Wang, J and Chen, L and Wang, Z and Chen, XY and Zhang, S and Ding, D and Zhou, Y and Rager-Aguiar, R and Lin, G and Zhang, H and Boda, VK and Ortyl, TC and Nelson, PT and Bezprozvanny, I and Zhou, FM and Du, J and Wu, Z and Li, W and Liao, FF},
title = {Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease models.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41965896},
issn = {1476-5578},
abstract = {Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegenerative diseases, such as Alzheimer's disease (AD), remain elusive. We found that TRPC3 expression is upregulated in excitatory neurons of brains with AD. We tested a selective inhibitor (JW-65) for TRPC3 over TRPC6 to investigate the potentially distinct role of TRPC3 in AD. JW-65 treatment significantly restored impaired synaptic plasticity and learning memory in acute and chronic experimental AD models. JW-65 treatment of late symptomatic 5XFAD transgenic mice reversed the impaired LTP, correlating with their significantly corrected synaptic gene expression based on hippocampal RNA-seq data analysis. JW-65 also provided synaptic protection in primary rat hippocampal neurons against soluble β-amyloid oligomers (AβOs), primarily via restoring the AβOs-impaired Ca[2+]/calmodulin-mediated signaling pathways. JW-65 treatment also significantly prevented Ca[2+] overload induced by AβOs. These findings suggest that aberrantly upregulated TRPC3, as a novel non-selective ion channel, significantly contributes to Ca[2+] dyshomeostasis in AD. Our work identifies TRPC3 as a potential therapeutic target for treating or preventing synaptic dysfunction of AD.},
}

@article {pmid41966037,
year = {2026},
author = {Qudoos, MA and Elliott, DP},
title = {Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges.},
journal = {The Senior care pharmacist},
volume = {41},
number = {3},
pages = {98-108},
doi = {10.4140/TCP.n.2026.98},
pmid = {41966037},
issn = {2639-9636},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and functional impairment, primarily driven by the accumulation of amyloid-beta (Aβ) plaques and tau tangles. Historically, treatments have focused on symptomatic relief; however, recent therapeutic advances have focused on disease-modifying monoclonal antibodies (mAbs), notably lecanemab and donanemab, which target Aβ pathology in early-stage AD. This review explores the clinical efficacy, safety profile, and limitations of lecanemab and donanemab, emphasizing key findings from the CLARITY-AD and TRAILBLAZER-ALZ 2 trials. In these studies, lecanemab was shown to slow cognitive decline by 27% over 18 months, while donanemab achieved a 28.9% reduction over 76 weeks, with the greatest benefits observed in patients presenting with lower baseline tau pathology.Despite these promising outcomes, challenges remain, including possible reduced efficacy in women based on subgroup analyses of trial data, racial disparities in trial representation, adverse effects such as amyloid-related imaging abnormalities (ARIA), and substantial cost and accessibility barriers. This review underscores the need for more inclusive research, personalized treatment strategies, and continued exploration of AD's complex pathology beyond amyloid clearance.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
*Antibodies, Monoclonal/therapeutic use/adverse effects
Amyloid beta-Peptides/metabolism

@article {pmid41966233,
year = {2026},
author = {Rusinek, H and Bokacheva, L and Chen, H and Masurkar, A and Osorio, R and Betensky, R and Vedvyas, A and Chodosh, J and Shao, Y and Shepherd, T and Marsh, K and Wisniewski, T},
title = {Test-retest Reliability of FreeSurfer Measures of Neurodegeneration.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121920},
doi = {10.1016/j.neuroimage.2026.121920},
pmid = {41966233},
issn = {1095-9572},
abstract = {Reliable structural brain measurements are essential for studying neurodegeneration and for designing adequately powered aging and Alzheimer's disease (AD) research. We evaluated the test-retest reliability of FreeSurfer 7.1 morphometric measures in 100 older adults (mean age 73.5 years) ranging from cognitively unimpaired to dementia. Each participant underwent two T1-weighted 3T MRI scans on the same scanner within a short interval (mean 5.5 weeks), minimizing biological change. Segmentation was performed in both standard cross-sectional and longitudinal FreeSurfer modes, focusing on AD-relevant entorhinal cortex, hippocampus, lateral ventricles, choroid plexus, and the AD cortical thickness signature. Reliability was quantified using absolute and root-mean-square test-retest differences, standard deviation of differences, and intraclass correlation coefficients. Longitudinal processing improved precision by 15-50% across most measures compared with cross-sectional processing, with the largest gain observed for entorhinal thickness. Larger, anatomically well-defined regions (e.g., hippocampus, AD signature) demonstrated higher reliability than small structures or those with complex geometry (e.g., entorhinal cortex, choroid plexus). Image quality, indexed by the Euler characteristic, was the only factor significantly associated with measurement variability; reliability was unrelated to age, sex, cognitive status, inter-scan interval, or amyloid/tau PET burden. Power analyses indicated that detecting a 1% within-individual change requires sample sizes ranging from 36 (AD signature) to >300 (entorhinal cortex). We observed low reliability of choroid plexus volumetry by FreeSurfer 7. These results provide practical benchmarks for expected FreeSurfer measurement variability in older adults. They highlight the advantages of longitudinal processing and rigorous quality control for research on brain aging and AD.},
}

@article {pmid41966346,
year = {2026},
author = {Matuszewska, M and Cieślik, M and Sulejczak, D and Wilkaniec, A and Czapski, GA},
title = {BET protein inhibitor JQ1 reduces inflammationand hippocampal amyloid-β level without altering Tau phosphorylation in LPS-challenged adult wild-type mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {150318},
doi = {10.1016/j.brainres.2026.150318},
pmid = {41966346},
issn = {1872-6240},
abstract = {A growing body of evidence highlights the role of infection and inflammation in the progression of Alzheimer's disease (AD). In this study, we aimed to analyze the impact of JQ1, an inhibitor of bromodomain and extraterminal domain (BET) proteins, which are key readers of the epigenetic acetylation code, on AD-related gene expression changes and biochemical alterations in the hippocampus during a lipopolysaccharide (LPS)-induced systemic inflammatory response in mice. JQ1 and LPS were administered intraperitoneally to adult male wild-type C57BL/6J mice. Changes in selected general and brain-specific parameters were measured for up to 12 h. Our results demonstrated that inhibition of BET proteins reduced LPS-induced sickness behavior and time-dependent elevation of proinflammatory signaling. LPS did not significantly alter amyloid-β (Aβ) levels; however, a significant reduction in Aβ load was observed in JQ1-treated animals overall, suggesting that BET proteins play a crucial role in regulating Aβ levels in the brain. At the same time, JQ1 treatment did not affect LPS-induced increases in phospho-Tau levels. Our results suggest that inhibiting BET proteins, in addition to their anti-inflammatory action, may be an effective strategy for reducing Aβ levels in the brain. However, a mechanistic explanation of this phenomenon requires further investigation.},
}

@article {pmid41966430,
year = {2026},
author = {Bertolli, A and Halhouli, O and Weber, MA and Liu-Martínez, Y and Wendt, LH and Blaine, B and Thangavel, R and Smadi, S and Pellatz, PJ and Liu, D and Bornhoft, KN and Gupta, K and Dean, R and Tish, MM and Kerr, G and Heiney, SA and Emmons, EB and Zhang, Q and Gumusoglu, SB and Narayanan, NS and Geerling, JC and Aldridge, GM},
title = {Renovating the Barnes maze for mouse models of dementia with STARR FIELD: A 4-day protocol for learning rate, retention, and cognitive flexibility.},
journal = {Methods (San Diego, Calif.)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymeth.2026.04.004},
pmid = {41966430},
issn = {1095-9130},
abstract = {Land-based spatial mazes are a low-stress method to evaluate learning in rodent models of dementia. By using innate exploratory and hiding behavior, the Barnes maze requires fewer trials, allowing examination of early learning rate and retention, as well as executive and motivational features that can be characteristic of non-amnestic dementias. However, unwanted odor cues may disrupt interpretation of acquisition rate during typical learning trials. We designed and tested our Barnes FIELD protocol (Find the Invisible Exit to Locate the Domicile) to improve reproducibility, allow evaluation of learning trials, and limit experimenter influence. The protocol uses 3D-printed escape shuttles and docking tunnels, allowing mice to exit the maze to the home cage. We show evidence that our shuttles mitigate the possibility of undesired cues. We demonstrate the feasibility of our protocol across several models of cognitive impairment and aging, and develop an additional stage, the STARR (Spatial Training And Rapid Reversal) maze, to better challenge behavioral flexibility. By examining commonly used outcome measures we identify important considerations for interpretation. These insights are used to evaluate several models of cognitive change, including deficits in an Alzheimer's disease mouse model and behavioral flexibility in a model of brainstem dysfunction. This work provides comprehensive instructions to build, perform, and analyze a robust spatial maze that expands the range of behavioral and motivational outcomes that can be identified and screened. Our findings will aid interpretation of traditional protocols, enhance rigor and reproducibility, and provide an updated method to screen for cognitive changes in mice.},
}

@article {pmid41966598,
year = {2026},
author = {Gerards, M and Sannemann, L and Jessen, F},
title = {Structural social factors modify the association between Alzheimer's pathology and cognitive function.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100563},
doi = {10.1016/j.tjpad.2026.100563},
pmid = {41966598},
issn = {2426-0266},
abstract = {BACKGROUND: Social factors have been linked to cognitive decline and risk of dementia. However, our understanding of their impact on cognition in the context of Alzheimer's disease (AD) pathology is still limited.

OBJECTIVES: This study examined whether two structural social factors, relationship status (RS) and living situation (LS), modify the association between AD pathology and cognition.

DESIGN: Observational, analysis of existing cohort data.

SETTING: Data were obtained from the National Alzheimer's Coordinating Center (NACC) and the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study.

PARTICIPANTS: Participants with available data on cognitive performance, AD pathology, and structural social factors.

MEASUREMENTS: We used the Mini-Mental State Examination (MMSE), a widely used brief screening measure of global cognitive status. For the description of AD, postmortem neuropathology (NACC) reports, or amyloid PET (IDEAS) were used. RS and LS were coded according to the respective datasets. Group comparisons and regression models were used to evaluate interactions between RS or LS with AD pathology on cognition.

RESULTS: Across cohorts, up to 31% of individuals were not in a relationship, and up to 22% lived alone. Individuals in a relationship (RS+) or those who lived with someone (LS+) showed poorer cognitive performance than those not in a relationship (RS-) or living alone (LS-) at comparable levels of AD pathology. Interaction analyses indicated that the association between AD pathology and MMSE differed by LS, with LS+ being associated with slightly lower MMSE scores across pathology levels, an effect primarily driven by participants living with someone who is not a partner. In contrast, within the NACC cohort, RS+ individuals showed overall lower MMSE scores, while the association between AD pathology and MMSE was weaker compared to RS- individuals.

DISCUSSION: LS and RS showed differences in how AD pathology related to global cognitive status. Being in a relationship was linked to a weaker association between AD pathology and global cognitive status, whereas living with someone was associated with a lower global cognitive status at comparable levels of pathology. While the direction of these associations remains unclear, our findings suggest that the relationship between AD pathology and cognitive status may vary across different structural social contexts.},
}

@article {pmid41966601,
year = {2026},
author = {Zhao, Y and Luo, G and Huang, C and Chen, Z and Wei, Y and Chen, Q and Wang, F and Gan, Y and Yin, X},
title = {Comparative effects of some pharmacological and non-pharmacological interventions on cognitive function in Alzheimer's disease: A Bayesian network meta-analysis.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100564},
doi = {10.1016/j.tjpad.2026.100564},
pmid = {41966601},
issn = {2426-0266},
abstract = {BACKGROUND: Given the growing global public health burden of Alzheimer's disease, this study used the Bayesian network meta-analysis to assess the effects of pharmacological and non-pharmacological interventions on cognitive function in the population with Alzheimer's disease.

METHODS: Two investigators screened the literature from English databases (PubMed, MEDLINE, Embase, Cochrane CENTRAL, and Web of Science) and three major Chinese bibliographical databases (China National Knowledge Infrastructure Database, Wanfang Database, and VIP Database). We assessed the risk of bias and publication bias of the selected literature. Subsequently, a Bayesian network meta-analysis and meta-regression were conducted to further investigate the comparative efficacy of different interventions on cognitive outcomes.

RESULTS: A total of 4788 cases were initially identified. Photobiomodulation [SMD=0.66, 95%CrI (0.29, 1.02)], enriching environment [SMD=0.69, 95%CrI (0.08, 1.31)], pharmacological therapy [SMD=0.36, 95%CrI (0.17, 0.55)], cognitive stimulation therapy [SMD=0.32, 95%CrI (0.11, 0.55)] and exercise therapy [SMD=0.28, 95%CrI (0.06, 0.51)] showed considerable enhancements in cognitive function among individuals with Alzheimer's disease. Photobiomodulation and enriching environment stood out, with their effects more potent than those of other therapies, as indicated by the surface under the cumulative ranking curve - photobiomodulation clocked in at 87.3%, while enriching environment scored 83.8%, versus pharmacological therapy's 54.7%.

CONCLUSIONS: Among the interventions evaluated, photobiomodulation and enriching environment were associated with better improvements in cognitive function than pharmacological therapy. Exercise therapy and cognitive stimulation therapy also demonstrated beneficial effects. Music therapy showed no statistical difference from the control group. In addition, the research developed an innovative approach to contrast pharmacological and non-pharmacological treatments for Alzheimer's disease.

REGISTRATION: PROSPERO 2025 CRD420251075628. Available from https://www.crd.york.ac.uk/PROSPERO/view/CRD420251075628.},
}

@article {pmid41966622,
year = {2026},
author = {Cooper, G},
title = {It's time to address the recruitment bottleneck.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100571},
doi = {10.1016/j.tjpad.2026.100571},
pmid = {41966622},
issn = {2426-0266},
}

@article {pmid41966670,
year = {2026},
author = {Kaur, N and Gupta, S and Bansal, G and Bansal, Y},
title = {BACE-1 inhibitors as potential drug candidates for treatment of Alzheimer's disease: a systematic review.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {41966670},
issn = {1573-501X},
}

@article {pmid41966687,
year = {2026},
author = {Hua, J and Sheng, Q and Xiao, S and Zhou, Y and Qi, J and Jin, S},
title = {PACells identifies phenotype-associated cell states from single-cell chromatin accessibility profiles.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2026.03.012},
pmid = {41966687},
issn = {1537-6605},
abstract = {Identifying cell states that drive clinical phenotypes is crucial for dissecting regulatory landscapes, pathogenesis, and targeted therapies of disease in single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq). Here, we present PACells, a framework that links clinical phenotypes from bulk ATAC-seq data with individual cells from scATAC-seq data to identify critical cell states at single-cell resolution. PACells outperforms other methods in predicting cells and molecular signatures associated with disease and gene mutation. PACells discerns clinical cell states and regulatory elements relevant to Alzheimer disease (AD) and poor survival in glioblastoma. Further, PACells is extended to transcriptomics for melanoma datasets with immunotherapy outcomes.},
}

@article {pmid41966729,
year = {2026},
author = {Stinson, SE and Shadrin, AA and Rahman, Z and Rødevand, L and Broce, IJ and Selbæk, G and Stefansson, H and Haavik, J and Parker, N and Koch, E and Frei, O and O'Connell, KS and Smeland, OB and Djurovic, S and Dale, AM and van der Meer, D and Andreassen, OA},
title = {Distinct metabolic signatures of Alzheimer's and Parkinson's disease revealed through genetic overlap.},
journal = {EBioMedicine},
volume = {127},
number = {},
pages = {106254},
doi = {10.1016/j.ebiom.2026.106254},
pmid = {41966729},
issn = {2352-3964},
abstract = {BACKGROUND: Metabolic dysfunction is a major risk factor for neurodegeneration, yet the genetic architecture linking systemic metabolism to Alzheimer's disease (AD) and Parkinson's disease (PD) remains unclear.

METHODS: We integrated genome-wide association data for 249 circulating metabolites and proglucagon with summary statistics for AD, PD, and cardiometabolic traits. Genetic correlations, polygenic overlap, causal relationships, and shared genetic loci were quantified using linkage disequilibrium score regression, high-definition likelihood, bivariate mixture modelling, Mendelian randomisation, and conjunctional false discovery rate analyses, followed by functional and tissue-specific enrichment analyses.

FINDINGS: AD displayed a metabolic-genetic profile aligned with body mass index, type 2 diabetes, coronary artery disease, and stroke, whereas PD exhibited largely opposing patterns (Spearman's rs = -0.26). Mendelian randomization analyses supported causal effects of lipoprotein subclasses, glutamine, and proglucagon on AD risk, with opposite or null effects in PD. Shared loci between metabolites and AD were enriched for lipid metabolism and cholesterol transport, whereas PD-associated loci were enriched for mitochondrial function, vesicle trafficking, and stress-response signalling.

INTERPRETATION: AD and PD are shaped by fundamentally distinct metabolic-genetic architectures. Metabolically targeted interventions, particularly those modulating lipid, amino acid, and proglucagon pathways, may require disease-specific and genetically informed strategies for prevention and treatment of neurodegenerative diseases.

FUNDING: Novo Nordisk Foundation (NNF23OC0099658), Marie Skłodowska-Curie Actions (801133), the Research Council of Norway (334920, 351751, 296030, 324252, 324499, 326813), the National Institutes of Health (U24DA041123, R01AG076838, U24DA055330, OT2HL161847, 5R01MH124839-02), NordForsk (164218), South-Eastern Norway Regional Health Authority (2020060), and the European Union's Horizon 2020 (847776, 964874, 101057454).},
}

@article {pmid41966730,
year = {2026},
author = {Henjum, K and Neerland, BE and Blennow, K and Zetterberg, H and Pollmann, CT and Olsen, RB and Solberg, L and Myrstad, M and Ødegaard, OT and Karabeg, A and Gulestøl, A and Idland, AV and Watne, LO},
title = {Biomarkers of Alzheimer's disease pathophysiology and delirium.},
journal = {EBioMedicine},
volume = {127},
number = {},
pages = {106252},
doi = {10.1016/j.ebiom.2026.106252},
pmid = {41966730},
issn = {2352-3964},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterised by amyloid-beta (A) and tau (T) pathology, and neurodegeneration (N). AT(N) neuropathology precedes the symptomatic presentation of the disease. This asymptomatic phase may present vulnerability towards delirium, but studies are inconclusive. In this cross-sectional study of hip fracture patients, we aimed to explore the association between AD biomarkers for AT(N) neuropathology and delirium, with focus on patients without clinical dementia.

METHODS: The AT(N) biomarkers were analysed in cerebrospinal fluid (CSF) in hip fracture patients (n = 401). Pre-fracture dementia was defined by IQCODE ≥3.44 (n = 164). Delirium was diagnosed according to the DSM-5 criteria. The CSF concentrations of amyloid-beta1-42 (Aβ42), amyloid-beta1-40 (Aβ40), phosphorylated tau181 (p-tau) and total-tau (t-tau) were quantified by Lumipulse G assays (Fujirebo, Ghent, Belgium). The Aβ42/Aβ40 ratio (cutoff A+ <0.72), p-tau181 (T+ >50 pg/ml) and t-tau (N+ >409 pg/ml) were used to determine A, T and N status, respectively.

FINDINGS: Hip fracture patients with delirium had lower CSF Aβ42 concentrations and higher concentrations of CSF p-tau and CSF t-tau than those without delirium (student's t-test, all p-values <0.001). Brain Aβ-deposition, A+ was more common in patients with delirium (χ[2] p < 0.001). In patients without pre-fracture dementia, delirium was associated with lower CSF Aβ42 concentrations (student's t-test, p = 0.005), and higher CSF concentrations of p-tau (student's t-test p = 0.004) and t-tau (student's t-test p = 0.002). A higher proportion developed delirium among those A+T+ (33%) compared to A-T- (17%, χ[2] p = 0.02).

INTERPRETATION: These findings support that the AD AT neuropathology is a risk factor for delirium in patients without clinical dementia.

FUNDING: South-Eastern Norway Regional Health Authorities (# 2017095), the Norwegian Health Association (#16149, #19536, #1513) and by Wellcome Leap's Dynamic Resilience Program (jointly funded by Temasek Trust) (#104617).},
}

@article {pmid41966804,
year = {2026},
author = {Tejero, A and Benito-Patón, V and Griñán-Ferré, C and Pallás, M and León-Navarro, D and Martín, M},
title = {Resveratrol induces molecular changes in cholesterol homeostasis in SAMP8 mice cerebellum.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {198},
number = {},
pages = {119319},
doi = {10.1016/j.biopha.2026.119319},
pmid = {41966804},
issn = {1950-6007},
abstract = {Resveratrol (Rsv) is a natural polyphenol with neuroprotective properties that modulates several pathways implicated in Alzheimer's disease (AD). Cholesterol homeostasis is disrupted in AD patients, and this imbalance plays a key role in amyloid precursor protein (APP) processing, β-amyloid aggregation and membrane stability. The effect of Rsv on the cerebellum, an emerging structure in cognitive networks and AD pathology due to its high connectivity with other brain regions, remains largely unexplored. This study aims to characterize the effects of Rsv on the cerebellum of SAMP8 mice, an animal model of AD, at different ages (5- and 7-month-old mice) and to investigate how it act as a neuroprotective polyphenol in this structure via modulation of cholesterol metabolism. Aging caused a significant increase in cerebellar membrane free cholesterol levels, which were reversed by Rsv treatment. HMG-CoA reductase levels were significantly reduced by Rsv treatment in 5-month-old mice, suggesting that this polyphenol modulates cholesterol synthesis. Parameters related to cholesterol trafficking were also modulated, with increased LDL receptor levels, but without affecting ApoE. Mitochondrial electron transport chain complexes were also upregulated by Rsv treatment in 5-month-old animals, without affecting mitochondrial dynamics. Collectively, these data demonstrate-for the first time-that Rsv modulates key aspects of cholesterol metabolism and mitochondrial function in the cerebella of SAMP8 mice.},
}

@article {pmid41966869,
year = {2026},
author = {Iordan, AD and Pruitt, PJ and Ploutz-Snyder, R and Ghosh, B and Devignes, Q and Hampstead, BM},
title = {2 mA is NOT 2 mA: Electric field variability in high-definition tDCS and its implications for precision neuromodulation in aging.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {},
number = {},
pages = {2111877},
doi = {10.1016/j.clinph.2026.2111877},
pmid = {41966869},
issn = {1872-8952},
abstract = {OBJECTIVE: To evaluate intra- and inter-subject variability in electric field (EF) delivered by high-definition transcranial direct current stimulation (HD-tDCS) in neurologically mixed older adults, and test whether using multiple MRI sequences reduces variability.

METHODS: We used ROAST to simulate EF distributions for two HD-tDCS 4 × 1 montages in 442 adults (age 50-94) across the "normal" to dementia continuum. Individualized head models were built from structural MRI, using T1-weighted alone or T1T2 dual-contrast segmentation. Montages targeted left inferior frontal gyrus (IFG) or right superior parietal lobule (SPL). EF magnitude was extracted from anatomically defined grey matter regions (left IFG, right SPL).

RESULTS: EF magnitude varied by up to 400% across, and up to 35% within, individuals even after excluding segmentation and EF outliers. Left IFG consistently showed higher and more variable EF than the right SPL. Dual-contrast (T1T2) segmentation improved non-brain tissue delineation but EF variability persisted (up to 300%).

CONCLUSIONS: Consonant with prior findings, 2 mA is NOT 2 mA within or across individuals, as delivered EF depends strongly on targeted region(s) and individual brain morphology.

SIGNIFICANCE: These findings reinforce the need for individualized modeling, especially for older and clinical populations, and for moving beyond scalp-based to delivered dose at brain level.},
}

@article {pmid41967035,
year = {2026},
author = {Bracone, F and Di Castelnuovo, A and Costanzo, S and Gialluisi, A and Bonaccio, M and Persichillo, M and De Curtis, A and Magnacca, S and Panzera, T and Orlandi, S and Cherubini, A and Cerletti, C and Donati, MB and de Gaetano, G and Iacoviello, L},
title = {Frailty index predicts the risk of 17 health outcomes in distinct ways: prospective findings from the Moli-sani Study.},
journal = {Age and ageing},
volume = {55},
number = {4},
pages = {},
doi = {10.1093/ageing/afag091},
pmid = {41967035},
issn = {1468-2834},
support = {DM 1557 11.10.2022//Investment PE8 - Project Age-It: 'Ageing Well in an Ageing Society'/ ; //National Recovery and Resilience Plan/ ; //Next Generation EU/ ; //Italian Ministry of University and Research (MIUR, Rome, Italy)/ ; },
mesh = {Humans ; Male ; Female ; Aged ; *Frailty/diagnosis/mortality/epidemiology ; Middle Aged ; Italy/epidemiology ; Prospective Studies ; Risk Factors ; Risk Assessment ; Hospitalization ; *Frail Elderly ; *Geriatric Assessment/methods ; Aged, 80 and over ; Chronic Disease/epidemiology/mortality ; Adult ; Age Factors ; Time Factors ; Proportional Hazards Models ; },
abstract = {BACKGROUND: Frailty reflects systemic vulnerability and is a major public health concern in ageing. This study examined how frailty relates to risk of death, hospitalisation and major chronic diseases.

METHODS: We analysed data from 20 975 adults (≥35 years, 52% women) recruited in 2005-10 from the population-based Moli-sani Study (Italy) and followed for a median of 15 years. Frailty was assessed using a multidimensional 29-item frailty index (FI). Cox models accounting for competing risks estimated hazard ratios (HR) for 17 incident outcomes, adjusted for age, sex and common covariates, including social status indicators.

RESULTS: Frailty was associated with increased risk of several adverse outcomes. Per 1-SD increase in FI, the risk of type-2 diabetes and coronary heart disease rose by 82% (HR = 1.82; 95% confidence interval 1.73-1.92; 1541 events) and 33% (HR = 1.33; 1.23-1.44; 756). FI was also associated with an increased risk of Parkinson's disease (HR = 1.25; 1.05-1.47; 158) and non-Alzheimer dementia (HR = 1.31; 1.11-1.54; 150). Cancer associations varied by site. FI also predicted hospitalisations for any cause (HR = 1.31; 1.28-1.34; 11 193), and all-cause mortality (HR = 1.35; 1.30-1.40; 2631). Analyses comparing frail and prefrail with fit categories, excluding early events, and stratified by sex showed consistent results, with indications of somewhat stronger associations among individuals younger than 65 years in certain outcomes.

CONCLUSION: FI predicts a wide range of chronic diseases, especially cardiometabolic and neurodegenerative outcomes, and their negative consequences, including hospitalisation and mortality. These findings reinforce the importance of frailty assessment in preventive strategies, risk stratification and integrated surveillance in the general population.},
}

Humans
Male
Female
Aged
*Frailty/diagnosis/mortality/epidemiology
Middle Aged
Italy/epidemiology
Prospective Studies
Risk Factors
Risk Assessment
Hospitalization
*Frail Elderly
*Geriatric Assessment/methods
Aged, 80 and over
Chronic Disease/epidemiology/mortality
Adult
Age Factors
Time Factors
Proportional Hazards Models

@article {pmid41967036,
year = {2026},
author = {Sanchez-Martinez, J and Solis-Urra, P and Fernandez-Gamez, B and Fernández-Ortega, J and Sánchez-Aranda, L and Erickson, KI and Ortega, FB and Esteban-Cornejo, I},
title = {Effects of a 24-week resistance exercise program on Alzheimer's disease brain signatures in cognitively unimpaired older adults: a secondary analysis of the AGUEDA randomized controlled trial.},
journal = {Age and ageing},
volume = {55},
number = {4},
pages = {},
doi = {10.1093/ageing/afag086},
pmid = {41967036},
issn = {1468-2834},
support = {PID2022-137399OB-I00//MCIN/AEI/10.13039/501100011033 and FSE+/ ; FPU22/03052 and FPU21/06192//Spanish Ministry of Science, Innovation and Universities/ ; N°72,220,164//National Agency for Research and Development (ANID)/Scholarship Program/DOCTORADO BECAS CHILE/2022/ ; RYC2019-027287-I//MCIN/AEI/10.13039/501100011033/and 'ESF Investing in your future'/ ; RTI2018-095284-J-I00//MCIN/AEI/10.13039/501100011033/and 'ERDF A way of making Europe'/ ; PID2022-137399OB-I00//MCIN/AEI/10.13039/501100011033/and 'ERDF A way of making Europe'/ ; CNS2024-154835//MCIN/AEI/10.13039/501100011033/and 'ERDF A way of making Europe'/ ; },
mesh = {Humans ; Aged ; Female ; Male ; *Alzheimer Disease/diagnostic imaging/psychology/therapy/physiopathology ; *Resistance Training/methods ; *Cognition ; Single-Blind Method ; *Brain/diagnostic imaging/physiopathology ; Aged, 80 and over ; Treatment Outcome ; Time Factors ; Diffusion Magnetic Resonance Imaging ; Age Factors ; },
abstract = {BACKGROUND: Brain imaging markers may help detect early cognitive decline and Alzheimer's disease (AD). Although exercise-related effects on AD-specific brain signatures remain unclear.

OBJECTIVE: To examine the effects of a 24-week resistance exercise (RE) program on AD brain signatures in cognitively unimpaired older adults, to explore potential moderators and to assess associations with cognition, including mediation effects.

METHODS: This secondary analysis of a single-site, two-arm, single-blinded randomized controlled trial included 90 participants (72 ± 4 years; 58% female) randomly assigned by a blind external researcher to an RE group (3 sessions/week, 60 min/session, n = 46) or a wait-list control group (CG, n = 44). T1- and diffusion-weighted MRI were acquired at baseline and post-intervention. Primary outcomes were thickness/volume and grey matter mean diffusivity (GMMD) signatures, derived from cortical and hippocampal regions. Moderators included age, sex, education, multimorbidity, apolipoprotein E ϵ4 status, amyloid beta (Aβ) status and baseline AD brain signatures. Secondary outcomes included cognitive function. Outcome measures and analyses were conducted by staff blinded to intervention assignment.

RESULTS: Compared with the CG, the RE group showed a reduction in the thickness/volume signature (-0.23 standardized mean difference [SMD]; 95% CI, -0.43 to -0.02), but no effect on the GMMD signature (0.08 SMD; 95% CI, -0.13 to 0.29). Aβ-status moderated the effect, as Aβ-positive participants in the RE group showed a larger reduction in the thickness/volume signature than those in the CG (-0.64 SMD; 95% CI, -1.09 to -0.18), whereas no effect was observed in Aβ-negative participants. Thickness/volume and GMMD reductions were associated with improvements in executive function and attentional/inhibitory control, respectively. Changes in AD signatures did not mediate cognitive outcomes.

CONCLUSION: Our findings suggest that reductions in the macrostructural AD signature following a 24-week RE program may reflect adaptive, rather than detrimental, brain changes, particularly in Aβ-positive older adults, as these changes were associated with improved executive function.

TRIAL REGISTRATION: Registered on Clinicaltrials.gov (Identifier: NCT05186090).},
}

Humans
Aged
Female
Male
*Alzheimer Disease/diagnostic imaging/psychology/therapy/physiopathology
*Resistance Training/methods
*Cognition
Single-Blind Method
*Brain/diagnostic imaging/physiopathology
Aged, 80 and over
Treatment Outcome
Time Factors
Diffusion Magnetic Resonance Imaging
Age Factors

@article {pmid41967112,
year = {2026},
author = {Alam, MS and Kaddurah-Daouk, R and Luo, S},
title = {Joint modeling of high-dimensional longitudinal data and survival using supervised low-rank tensor decomposition.},
journal = {Biostatistics (Oxford, England)},
volume = {27},
number = {1},
pages = {},
doi = {10.1093/biostatistics/kxag007},
pmid = {41967112},
issn = {1468-4357},
support = {R01AG064803/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Longitudinal Studies ; Alzheimer Disease/diagnostic imaging ; *Models, Statistical ; Monte Carlo Method ; Survival Analysis ; Computer Simulation ; Proportional Hazards Models ; Neuroimaging ; Biostatistics/methods ; Algorithms ; },
abstract = {High-dimensional longitudinal data are increasingly available in biomedical research, especially from omics platforms, but pose substantial challenges for joint modeling with survival outcomes. These challenges include modeling complex temporal dynamics, accommodating cross-feature dependencies, and maintaining computational feasibility. We propose a novel joint modeling framework that addresses these issues using supervised low-rank functional tensor decomposition to capture latent structure in multivariate longitudinal data and proportional hazards modeling for time-to-event outcomes. The longitudinal process is represented as a multivariate functional tensor, with a low-rank approximation that incorporates supervision from baseline covariates. Estimation is performed using a likelihood-based Monte Carlo Expectation-Maximization algorithm, enabling coherent inference and individualized prediction. Our method produces dynamic predictions of both longitudinal feature trajectories and survival probabilities. Simulation studies demonstrate substantial improvements in estimation accuracy and predictive performance over a standard two-stage approach, particularly under high censoring and limited sample sizes. In application to the Alzheimer's Disease Neuroimaging Initiative lipidomics data, the proposed model explains over 99% of variation with four components, and identifies significant subject-level latent predictors of dementia onset. This framework provides a scalable and interpretable strategy for integrating high-dimensional longitudinal biomarkers into joint models for disease progression and risk stratification.},
}

Humans
Longitudinal Studies
Alzheimer Disease/diagnostic imaging
*Models, Statistical
Monte Carlo Method
Survival Analysis
Computer Simulation
Proportional Hazards Models
Neuroimaging
Biostatistics/methods
Algorithms

@article {pmid41967208,
year = {2026},
author = {Guo, Y and Wang, N and Tao, Z and Huang, X and Yu, W and Zeng, J and Liu, X and Chen, S and Hua, F and Wang, X},
title = {The Ubiquitin-proteasome system in neuroinflammation and neurodegeneration: Molecular insights and therapeutic avenues.},
journal = {International immunopharmacology},
volume = {179},
number = {},
pages = {116599},
doi = {10.1016/j.intimp.2026.116599},
pmid = {41967208},
issn = {1878-1705},
abstract = {BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), represent a major and growing public health burden. Neuroinflammation is a critical driver of pathology in these disorders, and the ubiquitin-proteasome system (UPS) has emerged as a central regulator of inflammatory signaling within the nervous system. This review systematically examines the molecular interplay between the UPS and neuroinflammation in the progression of AD and PD.

MAIN BODY: We synthesize the core advances of the past decade in targeting the UPS to modulate neuroinflammation for therapeutic intervention. The UPS, primarily through the specific actions of E3 ubiquitin ligases and deubiquitinating enzymes, exerts precise control over key neuroinflammatory pathways, including NF-κB and the NLRP3 inflammasome, thereby critically shaping the functional states of microglia and astrocytes. In AD, UPS-targeted strategies have evolved beyond the clearance of Aβ and tau to include the reprogramming of microglial phenotype via nodes such as A20 and C/EBPβ. In PD, therapeutic focus has centered on augmenting PINK1/Parkin-dependent mitophagy and on suppressing specific pro-inflammatory factors like Peli1 and USP9X to disrupt pathogenic neuroinflammatory circuits.

CONCLUSIONS: This review provides a focused update on the mechanisms linking UPS dysfunction to neuroinflammation in AD and PD. It highlights the translational potential of targeting specific UPS components to modulate glial cell activation, with particular emphasis on the NF-κB and NLRP3 inflammasome axes as key regulatory hubs for future therapeutic development.},
}

@article {pmid41967284,
year = {2026},
author = {Kurihara, M and Ihara, R and Yoshii, G and Shimasaki, R and Hatano, K and Bannai, T and Suzuki, F and Ishibashi, K and Furuta, K and Satoh, K and Tokumaru, AM and Ishii, K and Iwata, A},
title = {ATNIVS biomarker heterogeneity in real-world patients receiving lecanemab.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100567},
doi = {10.1016/j.tjpad.2026.100567},
pmid = {41967284},
issn = {2426-0266},
abstract = {BACKGROUND: While amyloid-β (Aβ) biomarker positivity is sufficient before initiating anti-Aβ antibody therapy, recent revised criteria also highlight the importance of other biomarkers (ATNIVS) to understand heterogeneity in AD.

We reviewed patients who attended our specialty clinic between December 2023 and October 2024. Some participated in tau PET study ([18]F-MK6240). MRI was assessed using Fazekas score. Remaining samples were analyzed for plasma neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and CSF α-synuclein seed amplification assay (SAA).

RESULTS: During the period, 200 attended and 147 proceeded to screening. Lecanemab was started in 93 of 108 A+ patients; mean age 74.2 years, 73.1% female. While all tested started on lecanemab were positive on amyloid PET, 21% had only regional positivity with lower Aβ burden (centiloid 31.3 ± 17.5 vs 67.6 ± 20.2) and higher age (79.2 ± 5.1 vs 73.3 ± 8.9). While all tested had CSF Aβ42/40 values below the single cut-off 0.067 in Japan, three (8.6%) had values close to the cutoff (0.059-0.067), all of whom were male. Other biomarkers also widely varied from normal to fully abnormal; CSF pTau181 (40.5-168 pg/mL, cut-off 56.5), tau PET-based Braak stage (0-VI), NfL (10.0-103.3 pg/mL), GFAP (121.9-652.5 pg/mL), Fazekas score (0-3), and positive α-synuclein SAA (25-33%). Some associations were indicated including higher Fazekas scores in amyloid PET regional-positive group and higher plasma NfL in CSF Aβ42/40 0.059-0.067 group.

CONCLUSIONS: We identified substantial heterogeneity in ATNIVS biomarker profiles among patients receiving lecanemab in a real-world setting.},
}

@article {pmid41967651,
year = {2026},
author = {Balasubramanian, N and Gaudencio, G and Khan, KM and Biggerstaff, N and Marcinkiewcz, CA},
title = {Adolescent social isolation facilitates tau spread in raphe nuclei, linking depression and hyperalgesia in Alzheimer's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107393},
doi = {10.1016/j.nbd.2026.107393},
pmid = {41967651},
issn = {1095-953X},
abstract = {Tau pathology in brainstem serotonergic circuits drives early neuropsychiatric dysfunction in Alzheimer's disease (AD), yet mechanisms linking social stress exposures to depression and altered pain perception remain unclear. Here, we show that adolescent social isolation, a critical psychosocial exposome factor, facilitates tau propagation in the dorsal raphe nucleus (DRN) and downstream raphe nuclei, producing both neuropsychiatric and pain-related sequelae. Tau[P301L] was transduced into the DRN of 30-day-old socially isolated or group-housed C57BL/6 J mice using AAV, with controls receiving AAV-GFP. Four weeks post-transduction, anxiety, social behavior, and pain sensitivity were assessed. Behavior data revealed that adolescent isolation alone increased anxiety-like behavior, while social deficits were observed only in tau[P301L] mice and were further exacerbated by isolation. Moreover, hyperalgesia was observed only in isolated tau[P301L] mice. Histological analysis at 8 weeks revealed focal phosphorylated tau (p-tau) in the DRN and trans-synaptic spread to median raphe (MRN) and raphe magnus (RMg) serotonergic neurons, accompanied by reduced TPH2 and increased p-tau in downstream nuclei. Fluorescence in situ hybridization confirmed altered expression of Slc6a4 and Tgm2, a stress-responsive gene implicated in AD. These results indicate that DRN p-tau under adolescent isolation stress drives neuropsychiatric phenotypes, while p-tau spread to MRN and RMg disrupts serotonergic modulation of pain. This study provides the first evidence that adolescent stress promotes p-tau propagation within the raphe nuclei, linking early neuropsychiatric and pain-processing deficits to prodromal Alzheimer's disease and identifying a critical pathway through which psychosocial exposome risk converges with p-tau pathology to enable early intervention.},
}

@article {pmid41967873,
year = {2026},
author = {Emery, CEG and Love, S and Miners, JS},
title = {New perspectives on VEGF signalling in Alzheimer's disease.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70100},
doi = {10.1111/bpa.70100},
pmid = {41967873},
issn = {1750-3639},
abstract = {Vascular endothelial growth factor (VEGF) signalling mediates pleiotropic effects within the brain, encompassing angiogenesis, neuronal survival, and immune signalling. There is growing interest in the role of VEGF signalling in the pathophysiology of Alzheimer's disease (AD). The generation of single-cell brain atlases and recent large multi-omic studies, including analysis of CSF and bloods alongside post-mortem brain tissue, have provided novel insights into the role of VEGF signalling in AD. Disruption of the VEGF-A/VEGFR2 signalling pathway, due in part to elevated soluble VEGFR1 expression may contribute to pathogenic angiogenesis, BBB leakiness, and neuronal loss in AD. Induction of VEGF-B/VEGFR1 signalling in microglia suggests that dysregulated VEGF-mediated immune cell signalling is a further influence on AD pathogenesis. A reduction in expression of the 'protective' VEGFR3 and co-receptors neuropilin 1 and 2 has also been recently linked to cognitive decline in AD. In large clinical studies, lower VEGF-A levels in CSF and serum, raised soluble VEGFR1in CSF and elevated PlGF in CSF and serum, are predictive of more rapid cognitive decline and accelerated Alzheimer's disease neuropathological change (ADNC). This review discusses findings from recent multi-omic studies of large clinical and neuropathological studies that prompt reconsideration of the nature of VEGF signalling in AD and shed light on some of the complexities and previous conflicts within the field.},
}

@article {pmid41967915,
year = {2026},
author = {Woo, KA and Jang, Y and Kim, HJ and Park, PJ},
title = {GLP1R expression and parkinson's disease and related disorders in GLP-1RA-treated type 2 diabetes.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag130},
pmid = {41967915},
issn = {1460-2156},
abstract = {Preclinical and epidemiologic data suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce the risk of Parkinson's disease and related disorders (PDRD), yet clinical trial findings have been mixed, raising the possibility of biologically meaningful heterogeneity. We tested whether interindividual differences in systemic GLP1R expression are associated with PDRD risk among adults with type 2 diabetes initiating GLP-1RAs. We conducted an electronic health record (EHR)-based new-user cohort study in the National Institutes of Health All of Us Research Program, focusing on adults with type 2 diabetes aged 50 years or older who initiated a GLP-1RA between 2005 and 2023 and had no prior PDRD or Alzheimer's disease and related dementias (ADRD). Systemic GLP1R expression was genetically proxied by a 15-variant cis-expression quantitative trait locus (cis-eQTL) genetic risk score dichotomized at the cohort median. Follow-up ended at the earliest of incident PDRD, death, or October 1, 2023. Hazard ratios were estimated using multivariable Cox proportional hazards models adjusting for baseline covariates, and incidence rates and rate differences per 1,000 person-years were estimated using Poisson models. Prespecified sensitivity analyses excluded early outcome events and short drug exposure; an exploratory analysis evaluated incident ADRD. The cohort included 7,039 initiators (3,520 high vs 3,519 low genetic score; mean age 61.7 ± 8.4 years; 59.8% female; mean follow-up 3.8 ± 3.1 years). Compared with the low-score group, the high-score group had a lower hazard of incident PDRD (hazard ratio 0.78; 95% confidence interval 0.62 to 0.98) and a lower incidence rate (rate difference -1.36 per 1,000 person-years; 95% confidence interval -2.51 to -0.20). Associations were consistent across sensitivity analyses. No association was observed for incident ADRD (hazard ratio 1.02; 95% confidence interval 0.81 to 1.28). These findings link a mechanism-anchored genetic proxy for higher systemic GLP1R expression to a lower risk of incident PDRD among GLP-1RA-treated adults with type 2 diabetes. Systemic GLP1R-mediated pathways may be relevant to interindividual differences in observed PDRD risk, and genetic instruments for GLP1R expression may inform hypotheses for future PDRD trial design.},
}

@article {pmid41967920,
year = {2026},
author = {Funakawa, K and Kurihara, M and Takahashi, K and Ihara, R and Kakumoto, T and Ishibashi, K and Ishii, K and Fujii, Y and Kobayashi, S and Iwata, A},
title = {[Early-onset Alzheimer's disease with PSEN1 G206D mutation presenting with amnesia at an onset age of 29 years old].},
journal = {Rinsho shinkeigaku = Clinical neurology},
volume = {},
number = {},
pages = {},
doi = {10.5692/clinicalneurol.cn-002216},
pmid = {41967920},
issn = {1882-0654},
abstract = {The patient was a 36-year-old woman with normal birth and development. The patient experienced gradual memory loss from the age of 29 years old. The patient showed irritability at 35, convulsion at 36, and was diagnosed to have early-onset dementia. Family history of early-onset dementia was suspected in her mother and her brother. Brain MRI showed atrophy mainly in parietal lobe and posterior cingulate cortes. Amyloid PET was positive and cerebrospinal fluid showed decreased amyloid-beta 42/40 ratio and increased phospho-tau 181, leading to a diagnosis of Alzheimer's disease (AD). Genomic analysis revealed known pathogenic variant c.617G>A (p.G206D) in PSEN1. The clinical presentation of very-early-onset memory loss followed by psychiatric symptoms and convulsion matched previous reports of the same variant. This patient represents the first reported case in Japan carrying the p.G206D variant and has the youngest age at onset among previously reported cases. This case highlights the importance of considering AD even in very-early-onset cases and detailed family history taking is important in earlier diagnosis.},
}

@article {pmid41968010,
year = {2026},
author = {Bonthron, CK and Durrant, CS},
title = {A timeline of tau-mediated synaptotoxicity.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.03.011},
pmid = {41968010},
issn = {1878-108X},
abstract = {Oligomeric tau has been increasingly implicated in synaptic impairments observed in Alzheimer's disease. In a recent study, Pareja-Navarro and colleagues provide insights into the precise timeline of synaptic deficits induced by oligomeric forms of tau. Such knowledge could aid in the design of therapeutic interventions to prevent synaptic loss.},
}

@article {pmid41775902,
year = {2026},
author = {Sabir, U and Csubak, BA and Ilchenko, S and Ansari, MY and Kanaan, NM and Tsai, TH and Srinivasan, D and Dengler-Crish, CM and Kasumov, T},
title = {Sex-specific effects of acetylation on tauopathy in aging htau mice.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41775902},
issn = {2045-2322},
support = {R21 AA029784/AG/NIA NIH HHS/United States ; 1R21AG085590-01/GF/NIH HHS/United States ; R21 AA029784/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: Alzheimer’s disease involves extracellular β-amyloid accumulation and intracellular phosphorylated tau aggregates, with higher disease prevalence and neuropathological burden in aging females. While tau phosphorylation contributes to tau pathology, other modifications, such as acetylation, also promote aggregation. Aging disrupts proteostasis, in part through acetylation, a post-translational modification affecting protein function and stability; however, its role in sex-specific tauopathy remains unclear. This study investigated acetylation in an age-, sex-specific manner across presymptomatic (3–5 months), progressive (11–14 months), and advanced (> 16 months) stages of tauopathy in htau mice using immunoassays. In females, cortical tau K174 acetylation increased with age and disease progression, correlating with tau accumulation. In males, tau phosphorylation increased without acetylation changes, indicating sex-specific regulation. Free ubiquitin, a marker of impaired proteasomal degradation, rose with age in both females and males. Autophagy markers also showed marked age-related decline in both sexes, contributing to tau accumulation. Increased mTOR expression in aged mice further suggested mTOR-driven autophagy inhibition. These findings suggest that aging-related disruptions in brain acetylation are associated with accelerated tau pathology, with females potentially being more vulnerable due to elevated tau acetylation coinciding with impaired protein degradation pathways.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-41691-0.},
}

@article {pmid41963831,
year = {2026},
author = {Ngan, E and Bhandari, P and Parekh, PA and Badachhape, AA and Annapragada, AV and Ghaghada, KB and Starosolski, ZA},
title = {Nano-radiomics of molecular MRI for early amyloid associated patterns in an Alzheimer's disease mouse model via an automatic pipeline.},
journal = {BMC medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12880-026-02337-9},
pmid = {41963831},
issn = {1471-2342},
}

@article {pmid41963989,
year = {2026},
author = {Digma, LA and Young, CB and Winer, JR and Cody, KA and Younes, K and Sheng, J and Insel, PS and Rissman, RA and Sperling, R and Mormino, EC},
title = {Continuum of Core 1 biomarkers in preclinical Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02044-1},
pmid = {41963989},
issn = {1758-9193},
support = {K99AG071837/NH/NIH HHS/United States ; AARFD-21-849349/ALZ/Alzheimer's Association/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; },
}

@article {pmid41957344,
year = {2026},
author = {Zhang, Z and Huang, P and Yang, Y and Wu, H and Yao, X and Wang, Y and Yi, H and Ning, K and Chen, Y and Wu, Y and Chen, Z and Shen, P and Hong, D and Huang, X and Zou, WQ},
title = {Astrocyte-related proteins mediate the association of YWHAG with Alzheimer's pathology and enhance its diagnostic value.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04020-7},
pmid = {41957344},
issn = {2158-3188},
abstract = {Recent advances have identified YWHAG as a promising synaptic biomarker, with evidence showing that the YWHAG:NPTX2 ratio strongly predicts cognitive decline and Alzheimer's disease (AD) progression independent of amyloid and tau pathology. However, the links between YWHAG and astrocytic processes-key regulators of amyloid clearance, tau phosphorylation, and neuroinflammation-remain poorly understood. A total of 530 participants were included. Levels of YWHAG and a panel of biologically relevant astrocyte-derived proteins were measured using a proximity extension assay and validated immunoassay platforms. Associations with AD biomarkers and cognition were examined using multivariable regression, longitudinal mixed-effects models, and mediation analyses. Path analysis was performed to explore the potential pathways from YWHAG through astrocytic proteins to AD pathology and cognition. We evaluated whether combining YWHAG with astrocyte-related proteins improves its predictive performance, by comparing the area under the curve (AUC) of the combined model with that of YWHAG alone. YWHAG was positively associated with glial fibrillary acidic protein (GFAP, β = 0.558, p < 0.001), vimentin (β = 0.329, p < 0.001), aquaporin-4 (AQP4, β = 0.097, p = 0.044), thrombospondin (THBS) -1 (β = 0.470, p < 0.001), and THBS2 (β = 0.285, p < 0.001), while showing negative associations with gap junction alpha-1 protein (GJα1, β = -0.161, p < 0.001) and serpin family A member 3 (SERPINA3, β = -0.350, p < 0.001). Mediation analysis indicated that certain astrocyte-related proteins may be involved in the association between YWHAG and AD pathology. Additionally, path analysis suggested a potential pathway involving YWHAG, GJα1, Aβ42, and cognitive function. The combination of YWHAG with SERPINA3 and THBS1 achieved an AUC of 0.981, outperforming YWHAG alone (AUC = 0.885). YWHAG is associated with astrocyte-related proteins, and combining them enhances its predictive accuracy for AD, highlighting its potential utility in early clinical screening.},
}

@article {pmid41957377,
year = {2026},
author = {Collij, LE and Salvadó, G and Horie, K and Barthélemy, NR and Betthauser, TJ and Strandberg, O and Smith, R and Palmqvist, S and Schindler, SE and Ossenkoppele, R and Janelidze, S and Mattsson-Carlgren, N and Bateman, RJ and Hansson, O},
title = {Trajectories of plasma and CSF MTBR-tau243 and phosphorylated-tau species across the Alzheimer's disease continuum.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {41957377},
issn = {2041-1723},
mesh = {Humans ; *Alzheimer Disease/blood/cerebrospinal fluid/diagnostic imaging/pathology ; *tau Proteins/blood/cerebrospinal fluid/metabolism ; Phosphorylation ; Biomarkers/blood/cerebrospinal fluid ; Male ; Female ; Aged ; Disease Progression ; Middle Aged ; Positron-Emission Tomography ; Sweden ; Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Aged, 80 and over ; },
abstract = {To efficiently implement plasma and cerebrospinal fluid (CSF) biomarkers for staging and prognosis of Alzheimer disease (AD), we must understand their dynamics across disease progression. We analyzed participants from the Swedish BioFINDER-2 study with mass spectrometry measurements of plasma and CSF tau species, including eMTBR-tau243/MTBR-tau243 and phosphorylation occupancies (%p-tau). Disease duration was estimated using Aβ-PET and tau-PET with the SILA algorithm. Bootstrapped LOESS models showed that %p-tau217 changes earliest, increasing just before Aβ-PET positivity. Other p-tau species changed later, with smaller dynamic ranges and earlier ceiling effects. %p-tau205 and MTBR-tau243 changes aligned with tau-PET positivity onset, while MTBR-tau243-especially plasma eMTBR-tau243-tracked cortical tau burden in later stages. Non-phosphorylated mid-region tau may serve as a late-stage biomarker. Taken together, concurrent assessments of plasma or CSF %p-tau217, %p-tau205, and (e)MTBR-tau243 provides information about different biological events in the disease cascade, which can benefit clinical trials and patient management in clinical practice.},
}

Humans
*Alzheimer Disease/blood/cerebrospinal fluid/diagnostic imaging/pathology
*tau Proteins/blood/cerebrospinal fluid/metabolism
Phosphorylation
Biomarkers/blood/cerebrospinal fluid
Male
Female
Aged
Disease Progression
Middle Aged
Positron-Emission Tomography
Sweden
Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Aged, 80 and over

@article {pmid41957486,
year = {2026},
author = {Milicevic, KD and Abreu, AC and Chandran, G and Zhu, YMD and Hu, X and Ivanova, VO and Jami, M and Simon, B and Fernández, I and Yan, R and Antic, SD},
title = {Prodromal changes in cortical neuron physiology before amyloid pathology in a mild model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-47370-4},
pmid = {41957486},
issn = {2045-2322},
support = {778405//UConn IBACS Seed Grant/ ; 65539//Cure Alzheimer's Fund/ ; NS138991/NS/NINDS NIH HHS/United States ; 4242 "NIMOCHIP"//Science Fund RS/ ; },
}

@article {pmid41957539,
year = {2026},
author = {Ferguson, SJ and Choi, YD and Walker, AE},
title = {Contributions of vascular ageing to late-onset Alzheimer's disease.},
journal = {Experimental physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/EP092909},
pmid = {41957539},
issn = {1469-445X},
support = {ALZDISCOVERY-1049110/ALZ/Alzheimer's Association/United States ; AG064016/AG/NIA NIH HHS/United States ; },
abstract = {Late-onset Alzheimer's disease (LOAD) is an age-related disease that is strongly associated with vascular risk factors and cerebrovascular impairments. As such, changes in the vasculature with advancing age likely contribute to LOAD, but the mechanisms underlying these contributions remain incompletely understood. With advancing age, there is dysregulation of cerebral blood flow, impairment of neurovascular coupling, and increased blood-brain barrier permeability, which may initiate or contribute to the neuropathology associated with LOAD. Changes to the vasculature outside of the brain, including increases in blood pressure and arterial stiffness, may initiate age-related cerebrovascular impairments. Age-related increases in oxidative stress and inflammatory signalling, as well as contributions to LOAD-related neuropathology, such as amyloid-β and hyperphosphorylated tau, impair cerebrovascular cells. In this review, we summarize the evidence for the role of vascular ageing in LOAD, describing age-related cerebrovascular impairments and their causes.},
}

@article {pmid41957813,
year = {2026},
author = {Avilés-Granados, C and Gea-González, A and Sáez-Leyva, J and Perez, SE and Mufson, EJ and Granholm, AC and Carmona-Iragui, M and Zetterberg, H and Blennow, K and Fortea, J and García-Ayllón, MS and Sáez-Valero, J},
title = {Cerebrospinal fluid and frontal cortex TMPRSS2 and ACE2 protein levels differ in Down syndrome and Alzheimer's disease.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02289-9},
pmid = {41957813},
issn = {2051-5960},
support = {PRE2022-104182//Agencia Estatal de Investigación/ ; CIACIF/2021/426//Generalitat Valenciana/ ; PO1AG014449, RF1AG081286, R01AG061566/AG/NIA NIH HHS/United States ; PO1AG014449, RF1AG081286, R01AG061566/AG/NIA NIH HHS/United States ; CA2018010//BrightFocus Foundation/ ; CA2018010//BrightFocus Foundation/ ; 5 R01 AG071228-02, R01AG070153, 1U24AG092191-01, and 5 R01 AG061566//NIH grants/ ; GRT-2023b/2277//Foundation Lejeune grant to the DSBC brain bank consortium/ ; (#2023-00356, #2022-01018 and #2019-02397//Swedish Research Council/ ; #2017-00915 and #2022-00732//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//Alzheimer's Drug Discovery Foundation/ ; #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; NEuroBioStand, #22HLT07//European Partnership on Metrology/ ; FO2022-0270//the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden/ ; No 860197 (MIRIADE)//H2020 Marie Skłodowska-Curie Actions/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the UK Dementia Research Institute at UCL/ ; #AF-930351, #AF-939721, #AF-968270, and #AF-994551//Swedish Alzheimer Foundation/ ; #ALZ2022-0006, #FO2024-0048-TK-130 and FO2024-0048-HK-24//Hjärnfonden, Sweden/ ; #ALFGBG-965240 and #ALFGBG-1006418//ALF-agreement. Swedish state/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//Alzheimer's Association 2021 Zenith Award/ ; SG-23-1038904 QC//Alzheimer's Association 2022-2025 Grant/ ; PI22/01329//Instituto de Salud Carlos III/ ; AICO/2021/308//Conselleria de Cultura, Educación y Ciencia, Generalitat Valenciana/ ; },
}

@article {pmid41958080,
year = {2026},
author = {Caniceiro, AB and Agostinho, SP and Piochi, LF and Rosário-Ferreira, N and Moreira, IS},
title = {The GPCR Connection: Linking Alzheimer's Disease and Glioblastoma.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {7},
pages = {e71131},
doi = {10.1111/jcmm.71131},
pmid = {41958080},
issn = {1582-4934},
support = {MPr-2023-09//COMPETE2030-FEDER-01475900 SI I&DT Individual/ ; 10.54499/UID/PRR/04539/2025//Fundação para a Ciência e a Tecnologia/ ; LA/P/0058/2020//Fundação para a Ciência e a Tecnologia/ ; 2024.07255.IACDC//Fundação para a Ciência e a Tecnologia/ ; 2022.12479.BD//Fundação para a Ciência e a Tecnologia/ ; 2024.03713.BDANA//Fundação para a Ciência e a Tecnologia/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Glioblastoma/metabolism/pathology ; *Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; Animals ; *Brain Neoplasms/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) and glioblastoma multiforme (GBM) are biologically distinct age-related brain disorders with opposing clinical phenotypes. AD is characterised by progressive neurodegeneration and cognitive decline, whereas GBM is characterised by aggressive cellular proliferation and a poor prognosis. Despite these differences, converging evidence indicates that both conditions share molecular pathways and network-level dysfunction that emerge during brain ageing. Central to this convergence are G protein-coupled receptors (GPCRs), which act as integrative signalling hubs that regulate inflammation, metabolism, calcium (CA[2+]) homeostasis, and cell survival. In AD, GPCR signalling modulates amyloid-β production and clearance, Tau phosphorylation, intracellular CA[2+] dynamics, and glial-driven neuroinflammation. In contrast, the same receptor families promote tumour growth, angiogenesis, immune evasion, and therapeutic resistance in patients with GBM. Core intracellular cascades, such as PI3K-AKT-mTOR and MAPK-ERK, are dysregulated in both diseases and function as shared signalling backbones, with outcomes dictated by cellular context rather than receptor identity. CXCR4, LPA1, and FPR1 exemplify this duality, driving either oncogenic proliferation or neuronal dysfunction, depending on the biological environment. Recent advances in integrative multiomics, computational modelling, artificial intelligence, and organoid systems have revealed GPCR-centred regulatory nodes and accelerated the identification of druggable targets. Collectively, these findings suggest that AD and GBM, although pathologically antithetical, share a molecular fingerprint shaped by ageing-associated inflammation, metabolic disruption, cellular senescence and dysregulated GPCR networks. Deciphering this context-dependent duality may enable precision therapeutic strategies to either restore neuronal integrity in AD or suppress malignant programmes in GBM while fostering cross-fertilisation between neurodegeneration and neuro-oncology research.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Glioblastoma/metabolism/pathology
*Receptors, G-Protein-Coupled/metabolism
Signal Transduction
Animals
*Brain Neoplasms/metabolism/pathology

@article {pmid41958117,
year = {2026},
author = {Lv, Y and Han, K and Xie, D and Zhao, P and Xie, S and Jiang, Q and Zou, L and Zhu, G and Zhang, Y and Li, J and Yang, X},
title = {Study on Cholinesterase Inhibitory Activities and AChE Inhibition Mechanism of Gastrodin Compounds Based on Molecular Docking and Kinetic Simulation.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {4},
pages = {e03705},
doi = {10.1002/cbdv.202503705},
pmid = {41958117},
issn = {1612-1880},
support = {202205AC160049//Young and Middle-Aged Academic and Technological Leaders of Yunnan Province/ ; 22267018//the National Natural Science Foundation of China/ ; 32060107//the National Natural Science Foundation of China/ ; 32060327//the National Natural Science Foundation of China/ ; 202501BD070001-027//Yunnan Fundamental Research Projects/ ; 202401AT070295//Yunnan Fundamental Research Projects/ ; 202401BD070001-103//Yunnan Fundamental Research Projects/ ; 202503AC100002//Yunnan Fundamental Research Projects/ ; 202205AF150068//Zhang Xia Expert Workstation of the Yunnan Province/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; *Molecular Docking Simulation ; *Benzyl Alcohols/chemistry/pharmacology/chemical synthesis ; *Acetylcholinesterase/metabolism ; *Glucosides/chemistry/pharmacology/chemical synthesis ; Kinetics ; Butyrylcholinesterase/metabolism ; Structure-Activity Relationship ; Humans ; Molecular Structure ; Dose-Response Relationship, Drug ; },
abstract = {Alzheimer's disease (AD) is characterized by cholinergic neurotransmission dysfunction, and inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) represents a key therapeutic strategy. Gastrodin exhibits broad biological activity. In vitro enzyme inhibition assays, enzyme kinetic analysis, fluorescence spectroscopy, and molecular docking simulations validated the inhibitory effects of gastrodin and its analogues on acetylcholinesterase. All compounds exhibited concentration-dependent inhibition curve inhibition against AChE, with compound 3 demonstrating significant inhibitory activity, yielding an AChE IC50 value of 25.64 ± 4.59 µM. The inhibitory activity against AChE was ranked as follows: 2-hydroxymethylphenyl-β-D-glucopyranoside (compound 3) > 4-hydroxymethylphenyl-β-D-glucopyranoside (compound 2) > 4-methoxyphenyl-β-D-glucopyranoside (compound 4) > phenyl-β-D-glucopyranoside (compound 1). Enzyme kinetics revealed that compounds 1-4 exhibit reversible mixed-site inhibition mechanisms, simultaneously binding to both the catalytic active site (CAS) and peripheral anion site (PAS) of acetylcholinesterase. Fluorescence spectroscopy indicated that compounds 1-3, except compound 4, form stable complexes with acetylcholinesterase via static quenching. Molecular docking studies revealed multiple bond interactions between the compounds and AChE, with compound 3 exhibiting the lowest binding free energy. Subsequent investigation of the compounds' inhibitory activity against BChE demonstrated that they also possess significant inhibitory effects on BChE. This study elucidates the inhibitory mechanism of gastrodin-derived compounds against AChE and their structure-activity relationship, providing a theoretical basis for developing anti-Alzheimer's disease drug candidates based on these compounds.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
*Molecular Docking Simulation
*Benzyl Alcohols/chemistry/pharmacology/chemical synthesis
*Acetylcholinesterase/metabolism
*Glucosides/chemistry/pharmacology/chemical synthesis
Kinetics
Butyrylcholinesterase/metabolism
Structure-Activity Relationship
Humans
Molecular Structure
Dose-Response Relationship, Drug

@article {pmid41958244,
year = {2026},
author = {Zhou, CH and Han, F and Gao, F and Zhou, LX and Yao, M and Ni, J and Cui, LY and Li, ML and Jin, ZY and Zhang, SY and Shen, Y and Zhang, DD and Zhu, YC},
title = {Cerebral small vessel disease burden relates to cognitive decline via impaired amyloid clearance in the general population.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261437577},
doi = {10.1177/0271678X261437577},
pmid = {41958244},
issn = {1559-7016},
abstract = {Our aim is to examine the interplay between cerebral small vessel disease (CSVD) pathology, Alzheimer's disease (AD) related amyloid-β (Aβ) clearance, and cognition in general population. Cross-sectional structural equation modeling (SEM) was conducted to evaluate CSVD burden, cognition, and plasma Aβ42/40 ratios in 1026 participants without dementia from a prospective community-based cohort. CSVD burden was quantified using five established MRI markers, while cognition was assessed with the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), verbal fluency test, and reverse digit span. Models were adjusted for age, sex, education, body mass index, vascular risk factors (hypertension, diabetes mellitus, hyperlipidemia, and smoking), antihypertensive medication use, and APOE4 carrier status. Greater CSVD burden was significantly associated with poorer cognition (B = -2.607 ± 1.016, β = -0.167, p = 0.010), with white matter hyperintensity volume (∆R[2] = 0.3%, p = 0.016) and brain parenchymal fraction (∆R[2] = 0.4%, p = 0.019) contributing most strongly. CSVD burden was also negatively correlated with plasma Aβ42/40 ratios (B = -0.280 ± 0.074, β = -0.140, p < 0.001), which partially mediated the CSVD-cognition association (B = -0.241 ± 0.087, β = -0.015, p = 0.006). These findings underscore potential CSVD involvement in AD-related pathology across aging.},
}

@article {pmid41958409,
year = {2026},
author = {Lu, WC and Tsai, MS and Huang, SH and Lee, HH and Hsu, JL and Chang, YL},
title = {A normative study of the free and cued selective reminding test in Mandarin-speaking adults in Taiwan.},
journal = {Journal of the International Neuropsychological Society : JINS},
volume = {},
number = {},
pages = {1-12},
doi = {10.1017/S1355617726101957},
pmid = {41958409},
issn = {1469-7661},
abstract = {OBJECTIVE: Episodic memory decline is among the earliest and most prominent cognitive changes observed in both normal aging and Alzheimer's disease. The Free and Cued Selective Reminding Test (FCSRT) enhances differentiation of memory deficits through controlled semantic encoding and cue-based retrieval. However, culturally appropriate normative data for Mandarin-speaking adult populations have been lacking. This study aimed to establish normative data for the Taiwan version of the FCSRT (T-FCSRT), examine demographic effects on test performance, and evaluate its psychometric properties and clinical applicability.

METHOD: A total of 372 cognitively healthy adults aged 45-86 years were recruited using stratified sampling to reflect the Taiwanese population across sex, age, and education levels. Participants completed the T-FCSRT, and regression-based analyses were used to adjust for demographic effects. Reliability and validity were assessed using test-retest data and correlations with established neuropsychological measures.

RESULTS: All T-FCSRT core indices were significantly influenced by age and education level, whereas sex effects were confined to immediate and delayed free-recall measures. The T-FCSRT demonstrated good test-retest reliability, criterion-related and construct validity, and regression-based percentile norms that provide population-representative benchmarks.

CONCLUSION: The T-FCSRT demonstrates strong psychometric properties and provides culturally appropriate normative data for Mandarin-speaking adults in Taiwan. These findings support its utility for clinical assessment and research on episodic memory, enabling more accurate differentiation between normal and pathological aging.},
}

@article {pmid41958469,
year = {2026},
author = {Voigt, RM and Chaudhary, A and Naqib, A and Engen, PA and Adnan, D and Dhana, K and Green, SJ and Villanueva, M and Agarwal, P and Barnes, LL and Sacks, F and Keshavarzian, A},
title = {Weight loss and metabolic improvements dominate the microbiome response in the MIND diet intervention: a randomized controlled trial.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70239},
pmid = {41958469},
issn = {2352-8737},
abstract = {INTRODUCTION: Observational studies link the MIND diet to reduced risk of Alzheimer's disease (AD) and slower cognitive decline. However, a recent randomized controlled trial found no differential cognitive benefit of the MIND diet over a control diet in the context of shared caloric restriction. Given that both groups achieved significant weight loss and metabolic improvements, this study aimed to disentangle the impact of the MIND diet and host metabolic improvements on the intestinal microbiome.

METHODS: A subset of participants (n = 213) from the MIND trial were analyzed in this study. Clinical data and stool samples were collected at baseline, Year 1, Year 2, and Year 3, and longitudinal changes in microbiome composition were assessed via shotgun metagenomics.

RESULTS: Both groups exhibited significant, transient microbiome remodeling at Year 1 (the period of most active weight loss). The control group demonstrated a broad range of altered metabolic pathways, whereas the MIND diet group showed only one, suggesting a functional buffering effect of the MIND diet. Prospective modeling independent of diet group revealed that a poorer cognitive trajectory was significantly associated with increased inositol degradation (PWY-7237) and purine nucleotide salvage (PWY66-409); conversely, a better cognitive trajectory was associated with increased degradation of deoxy sugars (FUC-RHAMCAT-PWY).

DISCUSSION: Caloric restriction, weight loss, and host metabolic improvement are the dominant factors shaping the intestinal microbiome, overshadowing diet-specific taxonomic shifts. The MIND diet appeared to provide a modest stabilizing effect on the microbial functional profile against perturbations during active weight loss; however, these dietary associations did not persist in covariate-adjusted models, suggesting that host metabolic improvements remained the primary driver of functional shifts.},
}

@article {pmid41958476,
year = {2026},
author = {Nguyen, TD and Tran, TK and Truong, CK and Can, DC and Nguyen, BT and Chén, OY},
title = {High-dimensional Many-to-many-to-many Mediation Analysis.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41958476},
issn = {2331-8422},
abstract = {We study high-dimensional mediation analysis in which exposures, mediators, and outcomes are all multivariate, and both exposures and mediators may be high-dimensional. We formalize this as a many (exposures)-to-many (mediators)-to-many (outcomes) (MMM) mediation analysis problem. Methodologically, MMM mediation analysis simultaneously performs variable selection for high-dimensional exposures and mediators, estimates the indirect effect matrix (i.e., the coefficient matrices linking exposure-to-mediator and mediator-to-outcome pathways), and enables prediction of multivariate outcomes. Theoretically, we show that the estimated indirect effect matrices are consistent and element-wise asymptotically normal, and we derive error bounds for the estimators. To evaluate the efficacy of the MMM mediation framework, we first investigate its finite-sample performance, including convergence properties, the behavior of the asymptotic approximations, and robustness to noise, via simulation studies. We then apply MMM mediation analysis to data from the Alzheimer's Disease Neuroimaging Initiative to study how cortical thickness of 202 brain regions may mediate the effects of 688 genome-wide significant single nucleotide polymorphisms (SNPs) (selected from approximately 1.5 million SNPs) on eleven cognitive-behavioral and diagnostic outcomes. The MMM mediation framework identifies biologically interpretable, many-to-many-to-many genetic-neural-cognitive pathways and improves downstream out-of-sample classification and prediction performance. Taken together, our results demonstrate the potential of MMM mediation analysis and highlight the value of statistical methodology for investigating complex, high-dimensional multi-layer pathways in science. The MMM package is available at https://github.com/THELabTop/MMM-Mediation.},
}

@article {pmid41958504,
year = {2026},
author = {Laslo, A and Laslo, L and Brinzaniuc, K},
title = {Intrahippocampal injection in mice used for experimental studies in Alzheimer's disease: a challenging procedure for neuroscience purposes.},
journal = {Journal of medicine and life},
volume = {19},
number = {2},
pages = {136-141},
pmid = {41958504},
issn = {1844-3117},
mesh = {Animals ; *Alzheimer Disease/pathology ; Mice ; *Hippocampus/pathology/surgery ; Disease Models, Animal ; Microinjections/methods ; *Neurosciences/methods ; Stereotaxic Techniques ; Male ; },
abstract = {Neuroscience has advanced over the years largely due to animal experiments, particularly in mice. These experiments are generally challenging and require thorough preparation to be successfully carried out. The training required to perform procedures on mice must be rigorous to minimize the risk of errors that could lead to experimental failure and, equally important, to prevent unnecessary suffering of the animals involved. In this study, we present a detailed description of the surgical procedure for intrahippocampal injection in mice using a motorized stereotaxic system equipped with synchronized drilling and microinjection modules. The protocol emphasizes precise anatomical targeting, controlled infusion parameters, and standardized procedural steps designed to enhance reproducibility and minimize tissue trauma. Key aspects of the technique include stereotaxic atlas alignment, skull reference acquisition, controlled drilling to the dura mater, and microinjection of small tracer volumes under physiologically relevant conditions. This methodological framework provides a reliable platform for investigating brain parenchymal transport mechanisms, including intramural periarterial drainage pathways implicated in neurodegenerative disorders such as Alzheimer's disease.},
}

Animals
*Alzheimer Disease/pathology
Mice
*Hippocampus/pathology/surgery
Disease Models, Animal
Microinjections/methods
*Neurosciences/methods
Stereotaxic Techniques
Male

@article {pmid41958631,
year = {2026},
author = {Kransberg, J and Sjøli Bråthen, AC and Falch, ES and Øverbye, KEØ and Garrido, PF and Fjell, AM and Stangl, M and Wolbers, T and Sneve, MH and Walhovd, KB},
title = {Failure to detect entorhinal grid-like signals in a passive navigation human fMRI study.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {41958631},
issn = {2837-6056},
abstract = {Grid cells in the human entorhinal cortex (EC) play a critical role in spatial navigation and memory. The EC is also one of the first regions affected by ageing and Alzheimer's disease. This pre-registered functional magnetic resonance imaging (fMRI) study aimed to detect grid-cell-like signals (GLS) in a passive virtual navigation task. Contrary to our hypotheses and previous findings, we did not observe significant GLS at a population level, even in younger participants. Further exploratory analyses investigated the impact of task-engagement, as inferred from object-location memory performance, and showed no relationship with GLS magnitude. We also examined potential influences of a confounding one-fold directional signal and various data-processing choices but observed no consistent patterns. Our findings, consistent with recent null results from similar studies, suggest that passive navigation paradigms may be insufficient for reliably eliciting grid-like signals in human fMRI.},
}

@article {pmid41958634,
year = {2026},
author = {Ayyıldız, N and Mueller, K and Hardikar, S and Beyer, F and Enzenbach, C and Baber, R and Wirkner, K and Zachariae, S and Girbardt, J and Hassett, JD and Anwander, A and Elze, T and Wang, M and Witte, AV and Rauscher, FG and Villringer, A},
title = {Retinal nerve fibre layer thickness reflects characteristics of brain grey and white matter.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {41958634},
issn = {2837-6056},
abstract = {The retina is an optically accessible part of the central nervous system. Using high-resolution optical coherence tomography, we explored the relationship between retinal thickness and structural features of the brain obtained with magnetic resonance imaging. We hypothesized that there are associations between circumpapillary (i.e., around optic disc) retinal nerve fibre layer thickness and structural features of (i) brain areas and pathways related to visual information processing and (ii) more widespread brain areas affected by the consequences of cardiovascular risk factors and/or age-related neurodegeneration. In a population-based sample of over 500 subjects, in support of the first hypothesis, we showed associations of circumpapillary retinal nerve fibre layer thickness with visual cortex grey matter density and with optic radiation fractional anisotropy. These correlations were stronger for the right eye, possibly reflecting right ocular dominancy. Regarding the second hypothesis, while we confirmed the broad impact of cardiovascular risk factors such as body mass index, diabetes, and hypertension on brain structure, we did not find (adequate) significant partial correlations between circumpapillary retinal nerve fibre layer thickness and cardiovascular risk factors. Consequently, we were unable to confirm an association between circumpapillary retinal nerve fibre layer thickness and the impact of cardiovascular risk factors on brain structure especially on grey matter rather than white matter. However, even when the effects of cardiovascular risk factors were accounted for statistically, circumpapillary retinal nerve fibre layer thickness (particularly on the right side) was associated with fractional anisotropy of limbic system tracts, that is, the fornix and stria terminalis including hippocampus and amygdala, areas which are commonly affected by Alzheimer's disease. To further explore the structural associations between eye and brain, in terms of a possible common underlying pathology related to cardiovascular risk factors and progressive neurodegenerative diseases on the central nervous system, longitudinal and interventional studies are necessary.},
}

@article {pmid41958871,
year = {2026},
author = {Leung, SK and Walker, EM and Policicchio, S and Dahir, A and Vellame, DS and Smith, AR and Swarbrick, R and Lunnon, K and Dempster, EL and Ahmed, Z and Hannon, E and Castanho, I and Mill, J},
title = {Methylomic signatures of tau and amyloid-beta in transgenic mouse models of Alzheimer's disease neuropathology.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {23},
pmid = {41958871},
issn = {3005-1940},
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration driven by tau and amyloid-β (Aβ) pathology, although the underlying molecular mechanisms remain incompletely understood. Emerging evidence implicates altered DNA methylation (DNAm) in AD but comprehensive analyses in experimental models are limited. Here, we profile DNAm dynamics in two widely used transgenic mouse models of tau (rTg4510) and Aβ (J20) neuropathology, focusing on the entorhinal cortex and hippocampus. Using reduced representation bisulfite sequencing (RRBS) and methylation arrays across multiple disease stages, we identified widespread pathology-associated DNAm alterations in both models. Tau pathology in rTg4510 mice was associated with extensive DNAm remodeling at genes involved in neuronal plasticity, apoptosis, and lipid metabolism, including Dcaf5, Creb3l4, and As3mt. In contrast, J20 mice exhibited more modest changes, primarily at immune-related loci such as Grk2, Ncam2, and Prmt8. Tau-associated DNAm changes were more consistent across brain areas than those associated with Aβ pathology. Comparison with human AD DNAm datasets revealed overlapping DNAm differences, including hypermethylation at Ank1 and Prdm16 in rTg4510 mice. These findings provide robust evidence for early, pathology-associated epigenetic alterations in AD and highlight the utility of epigenomic profiling in transgenic models for identifying novel targets for early intervention in AD.},
}

@article {pmid41958924,
year = {2026},
author = {Xiao, J and Li, B and Li, B and Wang, J and Tang, R and Gao, C and Che, X and Xu, X and Chen, S and Ren, R and Wang, G},
title = {A prospective real-world study of the efficacy and safety of aducanumab in China: Focus on early-onset and autosomal dominant Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70328},
pmid = {41958924},
issn = {2352-8729},
abstract = {INTRODUCTION: Aducanumab is the first anti-amyloid therapy used for Alzheimer's disease (AD) in China.

METHODS: This 12-month, single-center, real-world study enrolled 12 participants with early AD receiving aducanumab 10 mg/kg every 4 weeks (ChiCTR2200066153). The primary outcomes were changes in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores at 12 months. Secondary outcomes included amyloid clearance, brain structure measures, and biomarker assessments.

RESULTS: No amyloid-related imaging abnormalities occurred. The mean CDR-SB score increased by 0.88 at 12 months, with cortical and hippocampal atrophy, enlarged choroid plexus, and ventricular volumes. Two autosomal dominant AD patients exhibited transient amyloid burden elevation at 6 months and subsequent reduction at 12 months, alongside increased serum glial fibrillary acidic protein (GFAP) levels. In the remaining 10 patients, the mean amyloid clearance reached -34.93 Centiloids, alongside decreased serum GFAP levels.

DISCUSSION: Aducanumab showed good tolerability and favorable biological outcomes, with different responses in autosomal dominant mutation carriers.},
}

@article {pmid41958981,
year = {2026},
author = {Daniel, SF and Lee, C and Mollenkopf, T and Lee, M and Arbuckle, J and Fiabane, E and Gabitto, MI and Johansen, N and Kapen, I and Kraft, AW and Lai, J and Li, SY and McGinty, R and Miller, JA and Welch-Moosman, S and Otto, S and Sawyer, L and Shepard, N and Thompson, CL and Tjärnberg, A and Waters, J and Zhen, X and Macosko, E and Lein, ES and Ng, L and Zeng, H and Mufti, S and Yao, Z and Hawrylycz, MJ},
title = {MapMyCells: High-performance mapping of unlabeled cell-by-gene data to reference brain taxonomies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.710160},
pmid = {41958981},
issn = {2692-8205},
abstract = {Single-cell mapping methods convert raw, heterogeneous single-cell datasets into interpretable and comparable representations of biological identity. As reference cell-type taxonomies mature, mapping new datasets to shared references has become a central strategy for enabling cross-study integration, reproducible annotation, and cumulative biological knowledge. Here we present MapMyCells , an open-source framework designed to align diverse single-cell omics datasets to hierarchical reference taxonomies with minimal preprocessing. MapMyCells provides out-of-the-box support for an expanding set of high-quality brain cell-type references generated by the Allen Institute for Brain Science, the BRAIN Initiative, and the Seattle Alzheimer's Disease Brain Cell Atlas, including whole-brain mouse and human atlases, aging and Alzheimer's disease cohorts, and a cross-species consensus taxonomy initially focused on the basal ganglia. MapMyCells enables efficient mapping of hundreds of thousands of cells on standard workstations without specialized hardware, providing a deterministic, scalable, and modality-agnostic approach that is robust across species and molecular assays. The framework produces interpretable confidence metrics and quantitative summaries of mapping performance, allowing users to evaluate assignment precision and accuracy. We demonstrate the mapping of unlabeled transcriptomic, epigenomic, and spatial datasets to reference taxonomies and describe a general workflow for preparing arbitrary hierarchical taxonomies for reference-based mapping. As the ecosystem of single-cell reference atlases expands, MapMyCells offers a practical and reproducible solution for community-scale cell-type annotation and cross-dataset integration, supporting the development of unified and extensible brain cell atlases.},
}

@article {pmid41959011,
year = {2026},
author = {Mallick, A and Du, Y and Haynes, C},
title = {Impaired Endosomal Recycling of Signaling Receptors Activates an Extracellular UPR.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.12.711310},
pmid = {41959011},
issn = {2692-8205},
abstract = {Mitochondrial dysfunction and extracellular protein aggregation occur in neurodegenerative diseases such as Alzheimer's disease (AD). However, it remains unclear if these processes are functionally linked. Here, we identify a signaling pathway that is activated upon accumulation of aggregation-prone proteins in the extracellular space. We find that the transcription factor ATFS-1, which regulates the mitochondrial unfolded protein response, also regulates transcripts required for endosomal recycling, multiple plasma membrane-localized signaling receptors, and secreted proteins that bind aggregation-prone proteins in the extracellular space, including transthyretin and Aβ, and promote their degradation. Interestingly, Aβ(1-42) aggregation induces atfs-1 -dependent transcription by promoting degradation of the bZIP protein ZIP-3, which antagonizes ATFS-1. ZIP-3 accumulates in the cytosol when it is phosphorylated by kinases that function downstream of plasma membrane-localized signaling receptors, including the WNT and glutamate receptors. Upon ligand binding, the signaling receptors stimulate the cognate kinase, many of which we found phosphorylate ZIP-3, impeding ZIP-3 degradation, allowing it to antagonize atfs-1 -dependent transcription. However, accumulation of aggregation-prone proteins such as Aβ(1-42) causes endosomal swelling, which impairs endosomal recycling, instead diverting signaling receptors to lysosomes for degradation. In turn, the depletion of signaling receptors reduces the level of ZIP-3 phosphorylation, resulting in ZIP-3 degradation and activation of atfs-1 -dependent transcription, which promotes extracellular proteostasis. Our findings uncover an unexpected coupling between endocytic quality control and mitochondrial signaling, revealing a circuit that preserves extracellular proteostasis and promotes organismal resilience.},
}

@article {pmid41959017,
year = {2026},
author = {Levine, CM and Caggiano, C and Anderson, T and Kelberman, MA and Weinshenker, D and Lail, HL and Wanders, D and Bangasser, DA and Kanoski, SE and Parent, MB},
title = {Hypothalamus amyloid levels are associated with early sex-dependent alterations in energy homeostasis in TgF344-AD rats.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.08.710398},
pmid = {41959017},
issn = {2692-8205},
abstract = {We reported previously that diet-induced obesity exacerbates early-stage Alzheimer's disease (AD)-like pathology in TgF344-AD rats. Our findings also suggested that TgF344-AD rats may be prone to weight gain during early AD development, which we assessed here. Energy intake, body composition, and the impact of glucose administration on blood glucose were also assessed. Body temperature, intrascapular brown adipose tissue (iBAT) mass, and iBAT uncoupling protein-1 (UCP1) expression were used as indicators of thermogenic function. Soluble amyloid β 40 (Aβ 40) and Aβ 42 were quantified in hypothalamus. Male TgF344-AD rats began to outweigh wildtype (WT) littermates by 5 weeks of age; this increase emerged later in female TgF344-AD rats (~5 months). Female TgF344-AD rats ingested more energy from chow and a high fat, high sugar (HFHS) diet, gained more weight on the HFHS diet, and had lower UCP1 than WT rats, effects not observed in male TgF344-AD rats. Surprisingly, male and female TgF344-AD rats had increased body temperatures. This was restricted to the dark phase in females, which is when they ingest excess calories. Finally, the HFHS diet disrupted glucose regulation in male but not female TgF344-AD rats. These findings suggest that increases in energy intake and decreases in UCP1 may contribute to the additional weight gain in female TgF344-AD rats. The causes for these increases in males remain unclear. Hypothalamic Aβ 42 correlated with glucose dysregulation in male TgF344-AD rats and BAT mass in female TgF344-AD rats, raising the possibility that increases in Aβ 42 in hypothalamus produce sex-specific disruptions in energy homeostasis.},
}

@article {pmid41959086,
year = {2026},
author = {Pereira, FL and Lew, C and Li, SH and Rizzi, L and Soloviev, AV and Paes, V and Brooks, SD and Spina, S and Rexach, JE and Newell, KL and Leite, REP and Seeley, WW and Suemoto, CK and Ghetti, B and Murray, ME and Grinberg, LT},
title = {Single-nucleus transcriptomics identifies a shared vulnerable excitatory neuronal population across typical and atypical Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.30.715299},
pmid = {41959086},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) presents with substantial clinical and anatomical heterogeneity, including both typical amnestic and atypical variants such as posterior cortical atrophy and logopenic primary progressive aphasia. Although neurofibrillary tangle (NFT) burden is a defining pathological feature of AD, its regional distribution varies across clinical phenotypes, suggesting that selective neuronal vulnerability may shape disease presentation. However, the cellular and molecular determinants underlying this vulnerability remain incompletely understood. Here, we profiled single-nucleus transcriptomes across multiple brain regions, including hippocampal (CA1) and neocortical (superior temporal gyrus and occipital cortex) regions, from individuals with typical and atypical AD and healthy controls. Integrative analysis identified major cell classes and resolved diverse excitatory and inhibitory neuronal subpopulations that were reproducibly observed across regions and individuals. Using quasi-binomial regression models to assess compositional changes, we quantified subtype-specific vulnerability associated with AD pathology. We identified a distinct excitatory neuronal subpopulation characterized by NRGN and BEX1 expression, which showed reproducible depletion across multiple regions, with the strongest evidence in amnestic AD and in neocortical regions in lvPPA. This vulnerable population showed concordance with previously reported AD-associated excitatory neuron signatures, supporting a conserved transcriptional program of susceptibility. Genes enriched in this population were associated with chemical synaptic transmission and regulation of synaptic plasticity and formed interconnected networks in protein-protein interaction analyses. These findings suggest that intrinsic properties related to synaptic function may predispose specific neuronal populations to degeneration in AD. Together, our results define a conserved, transcriptionally distinct excitatory neuron subpopulation that is selectively vulnerable across AD phenotypes and brain regions. This work provides a framework for linking regional pathology to cell-type-specific susceptibility and highlights synaptic regulatory pathways as potential contributors to neuronal degeneration in Alzheimer's disease.},
}

@article {pmid41959105,
year = {2026},
author = {Burberry, A and Benchek, P and Lowe, M and Shin, W and McCourt, B and Beamon, Q and Chakrabarti, S and Ramaiah, S and Woidke, E and Khrestian, M and Maecker, H and Bekris, LM and Rao, S and Ontaneda, D and Leverenz, JB and Bush, W and Pillai, JA},
title = {Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716122},
pmid = {41959105},
issn = {2692-8205},
abstract = {Neuroinflammation, along with amyloid beta (Aβ) deposition, phospho-tau (ptau) accumulation, blood-brain barrier (BBB) disruption, and cognitive decline are recognized components of Alzheimer's disease (AD). However, the timing and nature of peripheral immune changes across AD biological and clinical stages remain poorly understood. Here we performed mass cytometry profiling of whole blood and cerebrospinal fluid (CSF) immune cells from 351 human samples across two independent clinical cohorts spanning the AD continuum. We identify coordinated peripheral immune signaling signatures that emerge during preclinical stage of AD and precede significant elevation of plasma ptau217, CSF ptau181 and BBB disruption measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). AD-enriched immune features, including increased phospho-Akt signaling in naï ve T killer cells and phospho-PLCγ2 signaling in granulocytes, were not observed in patients with Frontotemporal lobar degeneration or treatment-naï ve multiple sclerosis. Furthermore, these immune signaling states could be induced in healthy donor immune cells following exposure to plasma or CSF from individuals with AD, indicating that circulating factors can drive these peripheral immune alterations. Together, our findings demonstrate that dynamic peripheral immune state changes arise early in AD and precede canonical biomarker and vascular changes, highlighting immune signaling pathways as potential targets for early therapeutic intervention.},
}

@article {pmid41959110,
year = {2026},
author = {Murtha, K and Chongtham, A and Song, WM and Ilkov, M and Wang, M and Chen, CQ and Sanctis, C and Datta, R and Purohit, D and Lee, EB and Zhang, B and Pereira, AC},
title = {Single-Nuclei Transcriptomic Characterization of APOE4 -Associated Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.03.715591},
pmid = {41959110},
issn = {2692-8205},
abstract = {Apolipoprotein E (APOE) genotype contributes significantly to Alzheimer's disease (AD) risk and pathogenesis. Cell-type specific effects of APOE alleles have been studied. However, due to the variable prevalence of APOE genotypes within human populations, characterization of cell-type specific transcriptomes across APOE genotypes has been challenging. Here, we integrated previous and newly generated single-nuclei sequencing (snRNA-seq) data in the prefrontal cortex (PFC) from individuals across APOE genotypes (2/2 , 2/3 , 3/3 , 3/4 , 4/4). Clustering analysis revealed distinct excitatory and microglial subpopulations that were uniquely enriched or depleted for APOE4/4 AD. Notably, an excitatory neuronal cluster exhibited neurofibrillary tangle (NFT) signatures and was selectively depleted in APOE4/4 AD cases. In addition, several microglial subpopulations were influenced by both APOE4 dosage and disease status. Among these, the putative AD risk gene FRMD4A emerged as APOE4 dose and AD-dependent. These findings were validated by RNAscope in an extended cohort. Together, our findings provide insights into how APOE4 reshapes cellular states and contributes to cell-type-specific vulnerability in AD.},
}

@article {pmid41959118,
year = {2026},
author = {Waghmare, SG and Krishna, MM and Maccoux, EC and Franitza, AL and Link, BA and E, L},
title = {Functional Analysis of Late-Onset Alzheimer's Disease Risk Genes in Caenorhabditis elegans Identifies Regulators of Neuronal Aging.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.26.714531},
pmid = {41959118},
issn = {2692-8205},
abstract = {BACKGROUND: Genome-wide studies in late-onset Alzheimer's disease (LOAD) have uncovered many risk loci, yet identifying the causal genes and clarifying how these genetic signals connect to molecular and cellular mechanisms relevant to AD pathogenesis in vivo remains challenging.

METHODS: Using Caenorhabditis elegans as a model to identify LOAD-associated genes that drive neurodegenerative processes, we focused on 14 understudied genes and their homologs: ABI3/abi-1 , B4GALT3/bre-4 , CCDC6/T09B9.4 , CLPTM1 (two homologs C36B7.6 and R166.2), CNN2/cpn-2 , DMWD/wdr-20 , ECHDC3/ech-2 , MADD/aex-3 , NCK2/nck-1 , RABEP1/rabn-5 , RIN3/rin-1 , SLC39A13/zipt-13 , TRAM1/tram-1 , and USP6NL/tbc-17 . We knocked down these genes by RNAi and quantified lifespan, aging-associated degeneration of two neuron classes, PVD and PLM, and associative learning and short-term memory.

RESULTS: Lifespan was unaffected by most knockdowns, and only nck-1 and tbc-17 shortened lifespan. Across neuronal assays, multiple homologs modulated aging with clear neuron-class selectivity. Knockdown of aex-3 , C36B7.6 , cpn-2 , ech-2 , rabn-5 , rin-1 , T09B9.4 , and zipt-13 attenuated late-life PVD degeneration, whereas R166.2 and tram-1 accelerated early PVD aging. Only two genes affected PLM aging: R166.2 knockdown exacerbated degeneration, while tbc-17 knockdown attenuated it despite its lifespan-shortening effect. In PLM neurons, tbc-17 knockdown, targeting a Rab GTPase-activating protein, also preserved mitochondrial architecture during early aging and shifted heat stress-induced mitochondrial remodeling toward a pattern consistent with improved quality control. In behavioral assays, ech-2 knockdown, targeting an enoyl-CoA-hydratase, enhanced short-term memory during early stages of aging. To further assess how LOAD-linked genes interact with Aβ-driven neurodegeneration, we developed a model that combines the PVD aging assay with a background expressing human Aβ 1-42 panneuronally. In this model, Aβ expression accelerated age-dependent PVD degeneration, whereas ech-2 knockdown abolished this Aβ-induced effect.

CONCLUSIONS: Our findings show that conserved homologs of several understudied LOAD risk genes causally modulate neuronal aging in vivo in a neuron-class-selective manner, often dissociable from organismal longevity. This C. elegans framework translates human genetic associations into quantitative, aging-linked neuronal phenotypes, and our results further emphasize early endosomal and lipid-related processes as key pathways that warrant functional testing in neuronal aging. This study also provides a tractable platform to prioritize targets for cross-species validation and to test synergy with established LOAD risk genes.},
}

@article {pmid41959128,
year = {2026},
author = {Hughes, JB and Sandholm, A and Croll, D and Senchyna, F and Schneider, K and Butterfield, R and McHugh, TLM and Brown, I and Deguchi, H and Hilsabeck, TAU and Mak, S and Wilson, KA and Davtyan, H and Blurton-Jones, M and Herdy, J and Higuchi-Sanabria, R and Gage, FH and Furman, D and Ellerby, LM and Desprez, PY and Campisi, J},
title = {DNA damage drives a unique, Alzheimer's disease-relevant senescent state in neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716205},
pmid = {41959128},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) shares molecular hallmarks with the canonical drivers of cellular senescence. Senescent cells have also been shown to accumulate in the brain with age, yet the mechanisms linking AD pathology to the accumulation of senescent cells in the brain remain unclear. Here, we demonstrate that DNA damage in patient-derived directly induced neurons (iNs) drives a senescent-like cell state with relevance to AD. DNA damage-induced senescent iNs show significant transcriptional concordance with human AD neurons and a weighted gene co-expression network analysis (WGCNA) uncovers candidate regulators associated with the senescent-like state in neurons. Direct comparison of iNs to the original patient fibroblasts reveals striking cell-type specific senescence signatures following DNA damage. iNs adopt a p21-associated senescent-like state characterized by a senescence-associated secretory phenotype (SASP) and predicted activation of NF-κꞴ1. In contrast, fibroblasts develop a p16-associated senescent state lacking a SASP phenotype and show a predicted repression of NF-κꞴ1. Early responses to DNA damage further reveal divergent DNA damage response (DDR), with neurons exhibiting higher accumulation of damage lesions relative to fibroblasts. Together, these findings demonstrate that DNA damage drives a unique senescent-like neuronal state that models molecular features of AD, while also revealing fundamental cell-type specific differences in senescent-like phenotypes and DDR.},
}

@article {pmid41959177,
year = {2026},
author = {Travi, F and Mehta, A and Castro, E and Li, H and Reinen, J and Dhurandhar, A and Meyer, P and Slezak, DF and Cecchi, GA and Polosecki, P},
title = {Alzheimer's Disease Brain Phenotypes are Age-dependent.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.31.715296},
pmid = {41959177},
issn = {2692-8205},
abstract = {A widespread view of neurodegenerative disorders, including Alzheimer's Disease (AD), frames their effects as accelerated aging, with the brain-age gap (BAG, the deviation of predicted 'brain age' from chronological age) as a staple biomarker. However, BAG relies on a fundamental, untested assumption: that AD can be identified via age-invariant brain phenotypes. Using invariant representation learning on brain MRI from 44,178 individuals, we created neural representations that optimally convey age information (age-aware) or conversely remove it (age-invariant) while minimizing reconstruction distortion. We provide the first causal evidence that age information is necessary in brain biomarkers for AD detection: age-aware representations achieve competitive state-of-the-art performance and significantly outperform age-invariant ones (0.84 vs. 0.77 AUC, p < 0.001, with external validation). This necessity reveals a conceptual flaw in BAG: by subtracting chronological age, it discards the very information essential for accurate detection. Using conditional decoders to simulate aging trajectories, we found that healthy aging and AD operate along multiple independent anatomical dimensions (deep gray matter, frontoparietal, temporal). AD patients diverge from rather than accelerate healthy aging, showing pathological temporal shifts alongside, remarkably, relative frontoparietal preservation. Furthermore, representational similarity analysis suggests that even models pretrained on non-age tasks (e.g., sex or BMI) implicitly converge toward age-related features when optimized for AD. Given that the AD phenotype cannot be decoupled from age, our results establish a hard limit for age-independent biomarkers and favor multidimensional models that preserve aging structure over unidimensional summaries like BAG.},
}

@article {pmid41959199,
year = {2026},
author = {Lin, L and Chuang, KH and Dai, C},
title = {c-MYC is an aggregation-prone, amyloidogenic protein.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.12.711438},
pmid = {41959199},
issn = {2692-8205},
abstract = {As a master transcription factor, c-MYC governs a plethora of biological processes. Despite being a prominent oncoprotein, counterintuitively, c-MYC also possesses an intrinsic tumor suppressor activity through induction of apoptosis, a phenomenon known as "the paradox of c-MYC". Serendipitously, we discover that c-MYC is aggregation-prone, becoming detergent-insoluble upon heat shock. Even in the absence of heat shock, c-MYC assembles into soluble oligomers exhibiting characteristics of amyloids in both human cancer tissues and, surprisingly, human Alzheimer's disease brains. In vitro , recombinant c-MYC proteins form amyloid oligomers as well as protofibrils spontaneously. By contrast, its obligate dimerization partner MAX is non-amyloidogenic and, moreover, antagonizes the amyloidogenesis of c-MYC. Screening of the c-MYC synthetic peptide library identifies two intrinsically disordered short linear fragments, which are amyloidogenic in vitro . This amyloidogenesis of c-MYC, importantly, induces apoptosis largely independently of transcription. Thus, our findings unveil a previously unrecognized amyloidogenicity of c-MYC, which may contribute to its tumor-suppressing activity. Upon loss of the stringent control of its expression, conceptually, this amyloidogenesis of c-MYC may serve as a built-in failsafe mechanism to self-destruct its troublesome oncogenic potential.},
}

@article {pmid41959262,
year = {2026},
author = {Uhl, GR and Kannan, B and Hess, E and Henderson, and Schultz, K},
title = {Quercetin and 6-Br-quercetin: antioxidant properties and off target screening results advance glycosylated 6BrQ as developmental candidates for Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.10.710855},
pmid = {41959262},
issn = {2692-8205},
abstract = {Quercetin is an abundant dietary flavonol with interesting in vitro properties that include substrate-selective positive allosteric modulation (PAM) of the activity of the receptor type protein tyrosine phosphatase D (PTPRD) and substantial antioxidant actions. Its in vivo activities include reducing incidence of Alzheimer's disease (AD) and reducing AD neurofibrillary pathology in mouse models. Structure-activity studies have identified quercetin analogs with improved in vitro and in vivo properties, including the improved PTPRD PAM 6-bromoquercetin (6BrQ). However, there is no comparison of the antioxidant properties of 6BrQ to those of quercetin. There is no systematic screening for activities of quercetin or of 6BrQ using a panel of targets for most currently-used drugs. We now report that both quercetin and 6BrQ provide equivalent results in cyclic voltammetric and biochemical antioxidant assays. We also report that neither 10 [-7] M quercetin nor 6BrQ provides any significant (>50%) effects on any of the 104 assays in a Eurofins off-target screening panel. At 10 [-5] M, both quercetin and 6BrQ exert significant effects in assays for glycogen synthase kinase 3 (GSK3β) as well as those for serotonin 5HT2B receptor, adenosine transport, adenosine A2A receptors, cyclooxygenases COX1 and COX2, phosphodiesterases PDE3A and 4D2 and PPAR gamma. These data extend prior characterization of quercetin's biochemical effects, provide novel results for 6BrQ and support the likelihood that both quercetin and 6BrQ can a) directly inhibit GSK3, b) reduce GSK3 activities via enhancement of its dephosphorylation by PTPRD and c) display modest numbers of off target activities at high concentrations, several of which could conceivably contribute to anti-AD activities. These results advance bioavailable glycosylated prodrugs that can be metabolized to 6BrQ as developmental candidates for AD.},
}

@article {pmid41959283,
year = {2026},
author = {Jones, A and Loeffler, T and Wu, E and Varma, VR and Im, HK and Thambisetty, M},
title = {Network pharmacology-based discovery and experimental validation of novel drug repurposing candidates in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.05.709917},
pmid = {41959283},
issn = {2692-8205},
abstract = {Despite a growing body of evidence implicating genetic variants and proteins encoded by them with risk and pathogenesis of Alzheimer's disease (AD), this knowledge has not been successfully translated into effective AD treatments. We integrated current genomic, transcriptomic and proteomic profiles of AD into a network pharmacology framework that leverages comprehensive gene-gene and drug-target interactions. This approach allowed us to screen 2,413 drugs for repurposing opportunities in AD. Computational validation and drug prioritization was followed by experimental validation in 33 cell culture-based phenotypic assays combined with Bayesian hypothesis testing. Our network-based screen rediscovered drugs in clinical trials for AD, providing computational validation. Besides many cancer drugs, the screen identified three drugs previously implicated in AD-related endophenotypes: the primary bile acid chenodiol, arundine (3,3'-diindolylmethane), and cysteamine. In analysis of results from culture-based phenotypic assays, large Bayes factors supported the hypothesized benefits of arundine and the chenodiol derivative, tauroursodeoxycholic acid (TUDCA), in amyloid- β clearance and release and neuroinflammation. Follow-up network analyses mechanistically implicated Regulator of G protein signaling 4 (RGS4) in the plausible therapeutic actions of arundine and TUDCA. A network pharmacology approach identified TUDCA and arundine as promising repurposing candidates in AD that rescue disease-relevant molecular phenotypes by acting on AD-associated genes through regulation of G protein signaling.},
}

@article {pmid41959306,
year = {2026},
author = {Wang, T and Shang, Y and McLean, JW and Yin, F and Brinton, RD},
title = {APOE4 Accelerates Menopause-Associated Brain Metabolic Shift and Disrupts Bioenergetic Adaptation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.11.710133},
pmid = {41959306},
issn = {2692-8205},
abstract = {INTRODUCTION: Disruption of brain glucose and lipid metabolism contributes to Alzheimer's disease (AD) and often emerges before clinical symptoms. Women are at elevated AD risk due to menopause-associated estrogen decline, which impairs mitochondrial function and glucose metabolism. Women's risk of AD is further elevated by the APOE4 allele, the strongest genetic risk factor for late-onset AD.

METHODS: To investigate the impact of APOE genotype on the menopausal metabolic transition, brain metabolomic and lipidomic profiling was conducted in humanized female APOE3/3, APOE3/4, and APOE4/4 mice across chronological and endocrinological stages of peri-to postmenopausal transition.

RESULTS: APOE3/3 mice exhibited dynamic regulation of brain metabolic systems that supported postmenopausal bioenergetic demand. In contrast, APOE3/4 and APOE4/4 mice displayed accelerated and altered metabolic shifts, resulting in postmenopausal amino acid depletion, reduced tricarboxylic acid (TCA) cycle intermediates, lipid accumulation, and alterations in brain lipid composition. A single APOE4 allele was sufficient to impair metabolic adaptation, while APOE4 homozygosity resulted in greater severity of deficits.

DISCUSSION: Outcomes of these analyses revealed that APOE4 accelerated menopause-related metabolic decline and compromised bioenergetic adaptation, providing a mechanistic basis for increased AD susceptibility and earlier onset in APOE4-positive women.},
}

@article {pmid41959309,
year = {2026},
author = {Komlo, R and Sengupta, K and Strus, E and Naidoo, N},
title = {Chronic short sleep in early life accelerates cognitive decline via disrupted proteostasis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.26.714554},
pmid = {41959309},
issn = {2692-8205},
abstract = {Chronic short sleep (CSS) is an emerging public health issue that frequently begins in adolescence and is common among healthcare professionals and others engaged in shift work. Epidemiological studies associate CSS and sleep disruption with metabolic disorders, cardiovascular disease, cognitive decline, and heightened Alzheimer's disease risk. Building on our prior findings that sleep deprivation perturbs proteostasis and activates endoplasmic reticulum (ER) stress pathways, we investigated the long-term consequences of CSS in young adult wild-type mice over the course of one year. Mice exposed to CSS displayed impaired cognition in hippocampal dependent tasks by 28 weeks of age, indicating emerging memory deficits. At the molecular level, CSS disrupted hippocampal proteostasis-particularly protein folding processes-and triggered ER stress and activation of the unfolded protein response (UPR). Importantly, disrupted proteostasis preceded the behavioral decline, with diminution of the key chaperone and UPR regulator BiP occurring at 20-22 weeks of age. CSS also increased markers of cellular stress and neuroinflammation while reducing the expression of proteins associated with memory function. Age also seemed to be a cellular stressor, causing a longitudinal increase in UPR, ISR, and neuroinflammation markers. Together, these results indicate that both chronic short sleep and age compromise proteostasis and promote neuroinflammation, contributing to progressive cognitive dysfunction.},
}

@article {pmid41959421,
year = {2026},
author = {Zanderigo, E and Fatima, M and Becker, S and O'Neil, A},
title = {Alzheimer's Disease Brain Organoids as a Source of Disease-Relevant Amyloid-Beta Oligomers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.09.710594},
pmid = {41959421},
issn = {2692-8205},
abstract = {Amyloid plaques are a hallmark of Alzheimer's disease (AD) progression; however, the early stages of plaque formation and the specific amyloid-beta (Aβ) species involved remain difficult to study. While post-mortem tissue provides insight into end-stage mature plaques, therapeutic development requires targeting the earliest Aβ oligomers to arrest plaque formation. Furthermore, inherently toxic soluble Aβ oligomers off-pathway from plaque formation are implicated as a driving force of AD pathology. It also remains unclear if the specific nature of key disease-relevant species can be accurately replicated in preparations of synthetic peptides.. To bridge this gap, we utilize brain organoids carrying AD mutations as a biologically authentic source for Aβ peptides and oligomers. We demonstrate that these mutations do not disrupt organoid development and that the resulting conditioned media contains Aβ oligomers with disease-relevant structures. Finally, we show that these oligomers can be concentrated and segregated via differential ultracentrifugation for further experimental applications.},
}

@article {pmid41959428,
year = {2026},
author = {Anderton, E and Burton, JB and King, CD and Foulger, AC and Bhaumik, D and Timonina, D and Mayeri, Z and Chamoli, M and Andersen, JK and Schilling, B and Lithgow, GJ},
title = {Shifts in protein aggregate stability define proteostasis decline in the aging human brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.27.714902},
pmid = {41959428},
issn = {2692-8205},
abstract = {Loss of proteostasis and the accumulation of insoluble protein aggregates are features of aging across model organisms and occur in all major age-related neurodegenerative diseases; yet how aggregation proceeds during normal human brain aging remains unknown. Here, using detergent-fractionation proteomics, we show that brain aging does not involve uniform aggregate accumulation; rather, the insoluble proteome undergoes asymmetric remodeling beginning in midlife, with maximum-stability aggregates declining sharply by old age and intermediate-stability aggregates accumulating progressively before accelerating after age 80. Intermediate-stability aggregates are prone to liquid-liquid phase separation and are enriched among Alzheimer's disease plaque and tangle constituents. Proteasome and cytosolic chaperone capacity predict individual differences in aggregate burden as strongly as chronological age, offering human-level evidence in support of therapies targeting these pathways. These findings establish aggregate remodeling as a feature of normal brain aging and position intermediate-stability aggregate accumulation as a molecular event on the path to neurodegenerative disease.},
}

@article {pmid41959502,
year = {2026},
author = {Hauser, RM and Limbo, HL and Brazell, JN and Moyers, BA and Lauzon, SN and Barinaga, EA and Johnston, SQ and Rogers, BB and Taylor, JW and Cochran, JN},
title = {Promoter mutagenesis and a massively parallel reporter screen of the MAPT locus identifies cis-regulatory elements and genetic variation effects.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.710116},
pmid = {41959502},
issn = {2692-8205},
abstract = {Tau neurofibrillary tangles are a hallmark of several neurodegenerative diseases called tauopathies, including frontotemporal dementia and Alzheimer's Disease. Ongoing clinical trials for tauopathies seek to reduce Tau in the brain through immunotherapy, antisense oligonucleotides, and siRNA. MAPT codes for Tau, therefore understanding how the MAPT gene is regulated and the effect of genetic variation at its regulatory elements is likely to have high relevance for tauopathies. We screened a ∼3 Mb region including the MAPT locus using 2 different massively parallel reporter assay (MPRA) strategies in KOLF2.1J h-NGN2 neurons and HEK293FT cells, identifying previously unannotated cis-regulatory elements (CREs). Using CRISPR interference (CRISPRi) in mixed neuron cultures, we identified a new CRE for MAPT , as well as 2 CREs for another nearby gene of interest, KANSL1 . Known genetic variation from the Alzheimer's Disease sequencing project was tested in a separate MPRA at the top CREs near the MAPT gene, identifying variants with altered regulatory effects including those at previously identified CREs for MAPT . Using a saturation mutagenesis screen of a 2,000 bp region encompassing the MAPT promoter, we assessed regulatory effects of each possible single nucleotide variant in this region. We identified several neuron-specific regulatory variant effects at this region, including a high confidence binding site for the transcription factors EGR2, ZBTB14, and TCLF5 at a region of high MPRA activity and genetic conservation.},
}

@article {pmid41959530,
year = {2026},
author = {Pandey, S and Talo, M and Siderovski, DP and Sumien, N and Bozdag, S},
title = {From General-Purpose to Disease-Specific Features: Aligning LLM Embeddings on a Disease-Specific Biomedical Knowledge Graph for Drug Repurposing.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.07.707871},
pmid = {41959530},
issn = {2692-8205},
abstract = {Identifying new therapeutic uses for existing drugs is a major challenge in biomedicine, especially for complex neurodegenerative conditions such as Alzheimer disease and related dementias (ADRD), where treatment options remain limited and relevant data are often sparse, heterogeneous, and difficult to integrate. Although general-purpose Large Language Model (LLM) embeddings encode rich semantic information, they often lack the task-specific biomedical context needed for inference tasks such as computational drug repurposing. We introduce Contextualizing LLM Embeddings via Attention-based gRaph learning (CLEAR), a multimodal representation-fusion framework that aligns LLM embeddings with the topological structure of a context-specific Knowledge Graph (KG). Across five benchmark datasets, CLEAR achieved state-of-the-art results, improving predictive performance (e.g., F1 score) by up to 30% over prior methods. We further applied CLEAR to identify FDA-approved drugs with potential for repurposing for ADRD, including Parkinson disease-related dementia and Lewy Body dementia. CLEAR learned a biologically coherent embedding space, prioritized leading ADRD drug candidates, and accurately summarized known therapeutic relationships for FDA-approved Alzheimer disease drugs. Overall, CLEAR shows that grounding biomedical LLM embeddings with context-specific KG signals can improve drug repurposing in data-sparse, real-world settings. GitHub: https://github.com/bozdaglab/CLEAR.},
}

@article {pmid41959564,
year = {2026},
author = {Simula, ER and Ercoli, T and Ruiu, E and Fais, M and Noli, M and Solla, P and Sechi, LA},
title = {Asparaginase-like protein 1 and human endogenous retroviruses link immune and gene dysregulation in dementia.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1777560},
pmid = {41959564},
issn = {2235-2988},
mesh = {Humans ; *Endogenous Retroviruses/immunology ; *Dementia/immunology/virology/genetics ; Male ; Female ; Leukocytes, Mononuclear/immunology ; Aged ; Aged, 80 and over ; Middle Aged ; *Gene Expression Regulation ; Immunity, Humoral ; Enzyme-Linked Immunosorbent Assay ; Antibodies, Viral/blood ; },
abstract = {Dementia is increasingly recognized as a condition characterized not only by neurodegeneration but also by significant immune alterations, with potential consequences for both humoral immunity and peripheral gene regulation. However, the relationship between these processes when targeting neuronal and retroviral antigens remains poorly understood. This study investigated immune responses to asparaginase-like protein 1 and human endogenous retroviruses in different types of dementia. Plasma and peripheral blood mononuclear cells were collected from patients with dementia. Antibody reactivity against asparaginase-like protein 1 and human endogenous retroviruses was assayed by enzyme-linked immunosorbent assay, while peripheral gene expression was quantified by qPCR. Group comparisons and correlation analyses were performed. Patients exhibited increased antibody responses against asparaginase-like protein 1 and human endogenous retroviruses despite reduced peripheral expression of the corresponding genes. Within patients, antibodies against asparaginase-like protein 1 were inversely correlated with its transcript levels, whereas antibody responses to human endogenous retroviruses correlated positively with residual gene expression. Immune and transcriptional measures targeting these molecules were interrelated, indicating shared immune pathways. For the first time, this study identifies a coordinated relationship between humoral immune responses and peripheral gene expression in the dementia such as AD, MCI and mixed Dementia offering a novel context for interpreting immune dysregulation and suggesting potential immune-based biomarkers linked to neurodegenerative processes.},
}

Humans
*Endogenous Retroviruses/immunology
*Dementia/immunology/virology/genetics
Male
Female
Leukocytes, Mononuclear/immunology
Aged
Aged, 80 and over
Middle Aged
*Gene Expression Regulation
Immunity, Humoral
Enzyme-Linked Immunosorbent Assay
Antibodies, Viral/blood

@article {pmid41959610,
year = {2026},
author = {Pereira, LEC and Castro, FN and de Almondes, KM},
title = {The clock drawing test as a screening tool for detecting cognitive decline: an analysis in adults and elderly people from Natal (RN).},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1768390},
pmid = {41959610},
issn = {1662-5161},
abstract = {INTRODUCTION: The Clock Drawing Test (CDT) is widely used as a screening instrument for cognitive decline due to its simplicity and rapid administration. Despite its widespread clinical use, evidence regarding its diagnostic performance in the Brazilian Northeast region remains scarce.

METHODS: This study examined CDT performance in a clinical sample of 113 adults and older adults assessed at a neuropsychology service in Northeastern Brazil, focusing on CDT ability to identify cognitive decline and the effects of age, educational level, and clinical diagnoses. The study tested the following hypotheses: (1) there is a significant association between age and CDT scores; (2) there are significant differences in CDT scores across different educational levels; (3) there are significant differences in CDT scores across different clinical conditions, indicating potential for differential diagnosis; and (4) the test would demonstrate high sensitivity, specificity, and accuracy in the overall sample, as well as high sensitivity in detecting each diagnostic condition. Using Shulman's scoring method, descriptive analyses, Spearman's correlation, Kruskal-Wallis tests and metrics of sensitivity, specificity, and accuracy were conducted.

RESULTS: The sample had a mean age of 65.19 years and was predominantly characterized by low educational attainment. A negative, albeit weak, correlation was observed between age and CDT scores, as well as significant differences across educational levels. Diagnostic group comparisons also revealed significant differences, most notably between cognitively unimpaired individuals and patients diagnosed with Major Neurocognitive Disorder due to Alzheimer's disease. Although the CDT demonstrated adequate specificity, its overall sensitivity and accuracy were low. Sensitivity was high for Major Neurocognitive Disorder Due to Alzheimer's Disease, moderate for Major Neurocognitive Disorder due to Non-Alzheimer's Disease (Major Vascular Neurocognitive Disorder, Parkinson's Disease, Mixed Dementia, Wernicke-Korsakoff syndrome and Major Frontotemporal Neurocognitive Disorder) and low for Mild Neurocognitive Disorder.

DISCUSSION: These findings demonstrate that Shulman's method of CDT is not suitable for assessing cognitive decline in the illiterate and low-education population and raise important concerns regarding its standalone clinical utility, especially in specific neurological conditions. The present study underscores the need for future research employing alternative scoring methods and more representative samples to refine the applicability and diagnostic value of the CDT in clinical practice.},
}

@article {pmid41959735,
year = {2026},
author = {Zhang, X and Zhang, Z},
title = {Receptor-mediated endocytosis by Megalin: Exploring its role in ligand interaction and disease mechanisms.},
journal = {Genes & diseases},
volume = {13},
number = {4},
pages = {101891},
pmid = {41959735},
issn = {2352-3042},
abstract = {This review comprehensively summarizes the interaction mechanisms between Megalin and several key ligands, including calcium ions, gentamicin, ApoE, ANKRA2, FVIII, TTR, STC1, RAP, and MMP-9, focusing on the specific amino acid binding sites involved. The analysis highlights the structural basis of these interactions and their clinical relevance, particularly concerning diseases such as nephrotoxicity, Alzheimer's disease, metabolic disorders, and renal pathologies. This review comprehensively summarizes the specific binding sites of Megalin with its ligands and explores the mechanisms, including protein reabsorption, blood coagulation, and neuroprotection, by integrating the results of animal studies and human clinical studies. This review proposes a theoretical framework for designing therapeutic strategies that target the binding sites of Megalin with its ligands. Gene editing technology and monoclonal antibody therapy aim to regulate Megalin receptor-ligand interactions to achieve therapeutic effects on related diseases.},
}

@article {pmid41959743,
year = {2026},
author = {Guo, Y and Jiang, Q and Gu, Z and Cao, H and Zuo, C and Huang, Y and Song, Y and Chen, X and Wang, F},
title = {ACSL4 in Alzheimer's disease: Pathogenetic mechanisms and potential therapeutic targets.},
journal = {Genes & diseases},
volume = {13},
number = {4},
pages = {101858},
pmid = {41959743},
issn = {2352-3042},
abstract = {Iron metabolism plays a vital role in maintaining physiological homeostasis, and its dysregulation is implicated in a range of pathological consequences and illnesses, including Alzheimer's disease (AD). Prior studies have demonstrated that Tau protein and amyloid precursor protein are involved in iron homeostasis disorder. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key contributor to AD pathogenesis and a promising therapeutic target. Acyl-CoA synthetase long-chain family 4 (ACSL4) is a lipid metabolizing enzyme that enhances ferroptosis sensitivity by promoting the incorporation of oxidizable polyunsaturated fatty acids into membrane phospholipids. Beyond ferroptosis, ACSL4 also plays crucial roles in neuroinflammation and oxidative stress, which are implicated in AD progression. Therefore, targeting ACSL4 is fantastic and has a lot of promise for treating AD. Nevertheless, the precise mechanisms through which ACSL4 contributes to AD pathology have yet to be fully elucidated. This review reveals a potentially vital role of ACSL4 in AD, focusing on its involvement in ferroptosis, oxidative stress, and neuroinflammation. Additionally, we describe some natural and synthetic compounds targeting ACSL4 with therapeutic potential in AD. Building on the theoretical findings of earlier studies about focused interventions of the ACSL4 path, our evaluation provided a broad basis for the clinical transformation in the treatment of AD strategies.},
}

@article {pmid41959752,
year = {2026},
author = {Earnest, TW and Yang, BY and Chowdhury, A and Ha, SM and Bani, A and Kim, SJ and Nazeri, A and Morris, JC and Benzinger, TLS and Gordon, BA and , and , and Sotiras, A},
title = {A unified model for staging amyloid and tau pathology in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.30.26349752},
pmid = {41959752},
abstract = {UNLABELLED: Biological staging models are a key tool for assessing the severity of Alzheimer's disease (AD), supporting personalized medicine and playing a critical role in clinical trial design. Recently, researchers have leveraged positron emission tomography (PET) to inform data-driven staging models of brain pathology related to AD. However, most approaches have focused on staging either amyloid or tau progressions separately, while both pathologies constitute defining factors of AD. Here, we aimed to derive a data-driven staging model which encompasses the spatial spread of both amyloid and tau. We assembled a large sample (n=3,293) of individuals with both amyloid and tau PET imaging stemming from 8 neuroimaging studies of AD and aging. We applied unsupervised machine learning to estimate brain areas which showed coordinated pathological accumulation across our sample, and we used these regions to inform a data-driven model for staging amyloid and tau. The resulting six stage model showed two stages of amyloid progression followed by four stages of tau spread, which were associated with cross-sectional and longitudinal assessments of cognitive decline. Comparison of our biological staging model with clinical disease stages recommended by the Alzheimer's Association showed evidence of heterogenous symptom profiles. Replication of results in holdout data demonstrated the generalizability and prognostic value of our staging model. Together, these findings establish a comprehensive and rigorously validated biological staging model that jointly characterizes amyloid and tau progression, advances beyond global or anatomically predefined summaries, and provides a scalable framework for studying disease heterogeneity and progression in AD.

ONE SENTENCE SUMMARY: Using PET imaging from a large sample of individuals (n=3,293), we derive a data-driven model for staging amyloid and tau pathology.},
}

@article {pmid41959753,
year = {2026},
author = {Hanseeuw, BJ and Quenon, L and Bayart, JL and Boyer, E and Colmant, L and Salman, Y and Gérard, T and Huyghe, L and Malotaux, V and Kienlen-Campard, P and Pirson, FB and Lhommel, R and Dricot, L and Ivanoiu, A and Shamsundar, K and Pak, W and Soldo, J and Iqbal, K},
title = {Tau pathological activity in plasma before the onset of symptomatic Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.03.26350110},
pmid = {41959753},
abstract = {Alzheimer's disease (AD) and other tauopathies are characterized by the hyperphosphorylation of tau (pTau), leading to its aggregation in the brain, a process strongly predictive of neurodegeneration and future cognitive decline. Currently, tau positron emission tomography (PET) is the only validated method for detecting tau aggregates in vivo. However, its high cost, invasiveness, and limited accessibility restrict its use in clinical settings and preclude large-scale screening. Moreover, existing plasma biomarkers that quantify the level of pTau at specific sites (e.g., pTau217) have limited specificity for confirming AD-related tau aggregation, partly due to the heterogeneous and irregular phosphorylation patterns of pTau. Besides, the concentration of pTau is frequently elevated in the context of isolated amyloid-β pathology, which is less strongly associated with cognitive decline in the absence of aggregated tau. There is therefore an urgent need for a reliable and scalable blood-based biomarker of tau pathology. A key mechanism underlying AD tau pathology is the ability of pathologically active pTau (PA pTau) to bind to and seed normal tau, facilitating prion-like propagation of insoluble tau aggregates. Here, we assessed the diagnostic performance of the VeraBIND Tau assay, the first functional assay to detect PA pTau seeding activity in plasma. Seventy-nine cognitively unimpaired (CU) and 66 cognitively impaired older adults underwent blood sampling, cognitive assessment, amyloid-PET or cerebrospinal fluid (CSF) analysis, and [ [18] F]-MK6240 tau-PET imaging. Plasma pTau217 concentrations were quantified using the Lumipulse platform (Fujirebio). The VeraBIND Tau assay isolated PA pTau from plasma and evaluated its ability to bind recombinant normal tau using a tagged-tau chemiluminescent readout. VeraBIND Tau demonstrated 94.2% sensitivity and 96.1% specificity for predicting tau-PET positivity (AUC=0.97). It outperformed plasma pTau217 in CU individuals (PPV=85.9%), regardless of the pTau217 threshold used (maximal PPV of 57.5% using the 0.256pg/mL pTau217 threshold). This higher VeraBIND Tau diagnostic accuracy was driven by early tau-PET stages (Braak-like tau-PET stages 1-3; AUC=0.96 vs. 0.74 for pTau217, p=0.003). Moreover, both cross-sectional values and annual changes in VeraBIND Tau were significantly correlated with cognitive performance and entorhinal tau-PET signal (all absolute Spearman r≥0.23, p<0.05). These findings highlight the strong potential of VeraBIND Tau as a scalable and accurate screening tool to detect AD tau pathology in the general population. The assay may also help enrich clinical trials with tau-PET positive CU individuals, enhance clinical diagnostic workflows and support monitoring of tau-targeted therapies. Future work should evaluate its utility in optimizing triage and early-intervention strategies.},
}

@article {pmid41959759,
year = {2026},
author = {Mora Pinzon, M and Pasqualini, R and Navarro, V and Del Carmen Rosales, M and Franzese, O and Perales-Puchalt, J},
title = {When Care Depends on the Caregiver: Lived Experiences of Latino Families Navigating Dementia Care Pathways.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.29.26349413},
pmid = {41959759},
abstract = {INTRODUCTION: Latino families shoulder a disproportionate share of dementia care in the United States, yet encounter multilayered barriers that shape access, timeliness, and quality. This study explores the experiences of Latino care partners, focusing on how system-level, cultural, and linguistic factors shape dementia care.

METHODS: We conducted a qualitative study using semi-structured interviews with care partners of Latino individuals living with Alzheimer's disease and related dementias (ADRD). Interviews were conducted by phone or videoconference by a bilingual interviewer, and the interviews were recorded and transcribed verbatim. Data was analyzed using reflexive thematic analysis.

RESULTS: Twenty-three participants were recruited. Two meta-themes captured participants' experiences. (1) Mismatch Between the Healthcare System and the Lived Realities of Latino Families Affected by Dementia, which included three subthemes: a) Linguistic barriers that referred to the quality and dialect fit (over-literal jargon, unfamiliar regional vocabulary, poor adaptation to literacy); b) Cultural misfit, were dementia-care programs were not culturally or linguistically appropriate, or programs where cultural norms were disregarded; and c) Structural and systemic barriers, such as communication failures (e.g. voicemail loops, no responsiveness) and long waits/fragmented pathways that broke clinical momentum (e.g. months to a year for specialty appointment). The second theme was: The Central Role of the Latino Caregiver in Navigating Dementia Care, where, in the absence of pathway ownership, care partners served as navigators, interpreters, coordinators, and safety monitors, while also bearing the emotional and financial strain.

DISCUSSION: The narratives from care partners reveal specific mechanisms (e.g., caregiver hyper-advocacy and "maze-like" coordination failures) that, if addressed, can guide intervention design and policy aimed at redistributing coordination back to the system and improving outcomes for Latino families.},
}

@article {pmid41959760,
year = {2026},
author = {Belder, CRS and Heslegrave, AJ and Swann, O and Abel, E and Beament, M and Nasir, M and Rice, H and Weston, PSJ and Ryan, NS and Palmer, LJ and Brodtmann, A and Kleinig, T and Zetterberg, H and Fox, NC},
title = {Presymptomatic plasma biomarkers in autosomal dominant Alzheimer's disease: sequence and timing.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.30.26349682},
pmid = {41959760},
abstract = {BACKGROUND: Autosomal dominant Alzheimer's disease (ADAD) serves as a model for presymptomatic biomarker discovery. Characterising the temporal profile of plasma biomarker levels in presymptomatic individuals may enhance understanding of disease pathogenesis, inform future clinical trials, and guide clinical interpretation.

METHODS: We evaluated 124 proteins using a NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) panel in 270 plasma samples from a longitudinal cohort study of ADAD, comprising 113 individuals (73 mutation carriers and 40 non-carriers). We determined the plasma proteomic changes that distinguished mutation carriers from non-carriers. We then used predicted age at symptom onset to determine the approximate timing of presymptomatic divergence in biomarker levels in carriers relative to non-carriers.

RESULTS: Nine proteins (Aβ42, BACE1, GFAP, pTau181, pTau231, pTau217, MAPT, NfL, and AChE) robustly differed between carriers and non-carriers, cross-sectionally. Longitudinal analyses showed Aβ42 levels were elevated in carriers at least 26 years before expected symptom onset. Carriers diverged from non-carriers in phosphorylated tau markers at 21-24 years before expected symptoms, total-tau at 19 years, GFAP and BACE1 at 14 years, and NfL at 6 years. Differences in AChE were seen in symptomatic individuals, likely reflecting cholinesterase inhibitor use.

CONCLUSION: Multiple plasma proteins are elevated in presymptomatic and symptomatic autosomal dominant AD mutation carriers relative to non-carriers. Changes in eight biomarkers occur sequentially from 26 to 6 years prior to symptom onset. Combining biomarkers may help in staging presymptomatic AD and optimise clinical trial inclusion. Further work is needed to assess how these findings generalise to non-monogenic AD.

The molecular pathology of Alzheimer's disease develops many years before the onset of symptoms, and multiple plasma biomarkers of Alzheimer's pathology have been identified. Understanding the timing of biomarker abnormality is important to guide trial design for the timing of interventions to prevent the onset of dementia.

WHAT THIS STUDY ADDS: Using an autosomal dominant Alzheimer's disease cohort, we identify multiple plasma biomarkers that distinguish mutation carriers from non-carrier familial controls and characterise the timing of these changes relative to symptom onset. We demonstrate that biomarkers show change many years before symptom onset: markers of abnormal tau phosphorylation more than 20 years prior, followed by markers of reactive astrocytosis and synaptic dysfunction approximately 15 years prior, and neurodegenerative markers within 10 years of symptoms.

Plasma biomarkers could be used in pre-clinical autosomal dominant Alzheimer's disease to chart disease trajectories and predict symptom onset, allowing targeted disease-modifying therapy implementation and optimised clinical trial design.},
}

@article {pmid41959766,
year = {2026},
author = {Betthauser, TJ and Teague, JP and Bruzzone, H and Heston, MB and Coath, W and Morse, JD and Ruiz de Chavez, EL and Carey, FJ and Navaratna, R and Cody, KA and Langhough, RE},
title = {Estimating tau onset age from tau PET imaging in two longitudinal cohorts using sampled iterative local approximation.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.01.26349872},
pmid = {41959766},
abstract = {UNLABELLED: Understanding the time course of Alzheimer's disease biomarkers of amyloid and tau pathology and their temporal relation to clinical symptoms is key to identifying optimal windows for disease intervention and planning future drug trials. The goal of this work was to determine the extent to which Sampled Iterative Local Approximation (SILA), an algorithm extensively validated for amyloid PET, is capable of modeling longitudinal tau (T) PET trajectories and estimating person-level tau positivity onset ages in two commonly analyzed brain regions and two tracers from two different cohorts.

METHODS: 385 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; mean (SD) age = 73.4 (7.3) years) with longitudinal flortaucipir tau PET and 288 participants from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center (collectively referred to as WISC; mean (SD) age = 67.4 (6.7) years) with longitudinal MK-6240 tau PET were included in the study. Standard uptake value ratios (SUVRs) in the entorhinal cortex and a meta-temporal ROI were modeled with SILA separately, for each cohort and region. Forward and backward SUVR and T+/- prediction were characterized with ten-fold cross-validation and in-sample validation techniques. Accuracy of estimated T+ onset ages (ETOA) was characterized in T- to T+ converters. Differences in ETOA were tested between APOE-e4 carriers and non-carriers, as well as differences in time T+ between levels of cognitive impairment.

RESULTS: SILA was able to accurately estimate retrospective change in tau SUVR in the meta-temporal region regardless of age, sex, APOE-e4 carriage, tau SUVR, and dementia (p >0.05) whereas dementia was associated with model residuals in entorhinal cortex (p ≤0.05; ADNI). In subsets of observed T- to T+ converters, the difference between "observed" and estimated meta-temporal T+ onset age [95% CI] was 0.12 [-0.27, 0.52] years for ADNI and -0.09 [0.93, 0.74] years for WISC. ETOA was significantly earlier, and odds of SILA-estimated T+ status were higher amongst APOE-e4 carriers (p <0.05) and those with dementia (p <0.05).

CONCLUSIONS: Our results suggest SILA can be used to accurately model longitudinal tau PET trajectories and retrospectively estimate individual T+ onset ages in the meta-temporal region. The accuracy of SILA time estimates in entorhinal cortex worsened amongst those with dementia in ADNI suggesting entorhinal cortex may only be suitable for studying the temporal progression of tau during the preclinical time frame.},
}

@article {pmid41959774,
year = {2026},
author = {Lin, W and Beric, A and Wisch, JK and Baker, B and Jerome, G and Minton, M and Preminger, S and Stauber, J and Schindler, SE and Dage, JL and Allegri, R and Aguillon, D and Benzinger, T and Chhatwal, J and Daniels, A and Day, GS and Devenney, E and Fox, NC and Goate, A and Gordon, BA and Barthélemy, NR and Hassenstab, J and Huey, E and Ikeuchi, T and Jayadev, S and Jucker, M and Ishiguro, T and Lee, JH and Levey, AI and Levin, J and Morris, JC and Perrin, RJ and Renton, A and Roh, JH and Xiong, C and Bateman, RJ and Ances, BM and Cruchaga, C and Karch, CM and Supnet-Bell, C and Llibre-Guerra, J and McDade, E and , and Ibanez, L},
title = {Abnormalities in core AD biomarkers precede inflammatory and glial markers in CSF in Autosomal Dominant Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.31.26349851},
pmid = {41959774},
abstract = {BACKGROUND: Increasing evidence suggests that accurate prediction of Alzheimer's disease (AD) symptom onset requires more than amyloid- and tau-centric biomarkers such as cerebrospinal fluid (CSF) Aβ42/40, total tau and p-tau181 and plasma p-tau217. Autosomal dominant AD (ADAD), caused by pathogenic PSEN1, PSEN2 and APP mutations with predictable age at symptom onset, presents a unique opportunity to characterize the chronological changes in proteins beyond amyloid and tau and clarify them as early biomarkers of disease onset or as biomarkers related to disease staging and progression monitoring.

METHODS: We measured 972 CSF samples corresponding to 484 participants of the Dominantly Inherited Alzheimer Disease Network (DIAN) using the NULISASeq 120 CNS Disease Panel. We first benchmarked the technology against gold-standard measurements followed by the identification of proteins that were differentially abundant in relation to mutation status and symptomatology. Next, we determined the chronological emergence of protein changes in relation to the estimated years to onset (EYO). Finally, we assessed whether specific protein measures improved the prediction of EYO in the ADAD.

FINDINGS: NULISA measurements were comparable to those previously published. We demonstrated that known early alterations in CSF amyloid and tau were followed by inflammatory and neurodegenerative responses suggesting that clinical manifestation of AD happens before the inflammatory processes is fully developed. Finally, we found a multi-protein composite approach for predicting EYO that outperformed single biomarker values.

INTERPRETATION: Our results suggest that the main CSF proteomic landscape changes in ADAD are due to the presence of a pathogenic mutation and occur prior to symptom onset. Improved performance of multi-protein composite to predict EYO compared to single biomarker values highlights the added value of multiplex proteomic signatures for biomarker panel development.

FUNDING: National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea, Spanish Institute of Health Carlos III.},
}

@article {pmid41959792,
year = {2026},
author = {Biondo, N and Suntay, JM and Sandhu, M and Estaban, JS and Pillai, J and Mandelli, ML and Mamuyac, E and Reyes, RJ and Guevarra, A and Henry, ML and Dronkers, NF and Gorno Tempini, ML and Grasso, SM and de Leon, J},
title = {Cognitive and brain reserve in bilingual speakers with clinical AD variants.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.27.26349575},
pmid = {41959792},
abstract = {INTRODUCTION: Bilingualism may confer resilience via enhanced neural integrity. However, evidence for bilingualism's neuroprotective effect is mixed, and studies across Alzheimer's disease (AD) variants are scarce. This study examined gray matter volume (GMV) differences between bilinguals and monolinguals with amnestic AD and logopenic variant primary progressive aphasia (lvPPA).

METHODS: In 136 amnestic AD and 88 lvPPA participants with neuropsychological assessments and structural MRI, we analyzed differences between monolinguals and bilinguals within each variant, controlling for demographic covariates.

RESULTS: Amnestic AD bilinguals exhibited less GMV in hippocampal, fusiform, and occipital regions compared to monolinguals. LvPPA bilinguals had less temporal and occipital volumes, but they had greater volumes in inferior parietal regions, which are considered a disease epicenter in lvPPA. Cognitive performance in monolinguals and bilinguals was comparable within variants.

DISCUSSION: Bilingualism may support cognitive reserve (preserved cognition despite reduced GMV) in both AD variants, with additional brain reserve in lvPPA.},
}

@article {pmid41959815,
year = {2026},
author = {Li, H and Yu, Y and Bhandarkar, A and Kumar, R and Clark, IH and Hu, Y and Cao, W and Zhao, N and Li, F and Tao, C},
title = {BSO-AD: An Ontology for Representing and Harmonizing Behavioral Social Knowledge in ADRD.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.30.26349756},
pmid = {41959815},
abstract = {OBJECTIVE: Behavioral and social factors (BSFs) substantially influence the risk, onset, and progression of Alzheimer's disease and related dementias (ADRD). A systematic representation of their interplay is essential for advancing prevention and targeted interventions. However, BSF-related knowledge is scattered across heterogeneous sources, limiting scalable evidence synthesis and computational analysis. To address this, we created a B ehavioral S ocial Data and Knowledge O ntology for AD RD (BSO-AD) to represent and integrate BSFs with respect to ADRD.

MATERIAL AND METHODS: BSO-AD was developed following established ontology design principles, prioritizing reuse of existing ontology elements to ensure semantic interoperability. It was built upon the Social Determinants of Health Ontology (SDoHO) and the Drug-Repurposing Oriented Alzheimer's Disease Ontology (DROADO). BSF-related classes were enriched with ICD-10-CMZ55-Z65 codes and ADRD-related classes with AD-Onto. Relationships between BSFs and ADRD were derived through literature mining. Ontology quality was evaluated through Hootation-based expert review and an LLM-assisted framework assessing structural coverage and semantic coherence.

RESULTS: BSO-AD contains 2,275 classes, 153 object properties, and 49 data properties. Expert review demonstrated strong rational agreement (0.95), with disagreements resolved through discussion. LLM-based evaluation showed high category coverage rates (≥ 0.97) and robust semantic alignment with the relevant literature (average completeness = 0.79; conciseness = 0.94).

DISCUSSION AND CONCLUSION: BSO-AD is, to our knowledge, the first ontology to systematically represent BSFs and hierarchically model their interrelationships in ADRD. It establishes a semantic backbone for computational analysis and knowledge integration. The LLM-assisted evaluation framework demonstrates the feasibility of scalable, automated ontology assessment.},
}

@article {pmid41959833,
year = {2026},
author = {Grasso, SM and Bao, W and Marqués-Kiderle, SK and Casart Muñoz, N and Calabria, M and Sala, I and Sánchez-Saudinós, MB and Vera-Campuzano, E and Selma-González, J and Videla, L and Vaqué-Alcázar, L and Bejanin, A and García-Castro, J and Rodríguez-Baz, Í and Zhu, N and Arranz, J and Maure-Blesa, L and Rubio-Guerra, S and Barroeta, I and Illan-Gala, I and Carmona-Iragui, M and Belbin, O and Alcolea, D and Fortea, J and Lleó, A and Santos Santos, MÁ},
title = {Evidence for bilingualism as a cognitive reserve factor in biomarker-confirmed Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.31.26349879},
pmid = {41959833},
abstract = {INTRODUCTION: Bilingualism is a proposed cognitive reserve factor that delays symptom onset in Alzheimer's disease (AD), though current evidence lacks biomarker confirmation. This retrospective study examined bilingualism's association with symptom onset across AD clinical stages, including biomarker-confirmed cases.

METHODS: Participants from the Sant Pau Memory Unit spanning amnestic mild cognitive impairment (MCI), amnestic dementia, and biomarker-confirmed AD were analyzed, with balanced representation of active and passive Spanish-Catalan bilinguals. Linear regression models evaluated associations between bilingualism and reported age at symptom onset, controlling for education, sex, and disease severity.

RESULTS: Active bilingualism was associated with delayed symptom onset in amnestic MCI (2.21 years), amnestic dementia (1.42 years), and biomarker-confirmed AD (1.45 years; p s < .05). Higher education was associated with earlier onset, likely representing healthcare seeking behavior.

DISCUSSION: Bilingualism protects against earlier symptom manifestation in MCI and AD, supporting bilingualism as a contributor to cognitive reserve.},
}

@article {pmid41959929,
year = {2026},
author = {Wang, X and Yi, B},
title = {Molecular Mechanisms and Clinical Applications of Neural Regeneration Through Dental Pulp Stem Cells.},
journal = {Stem cells international},
volume = {2026},
number = {},
pages = {8069882},
pmid = {41959929},
issn = {1687-966X},
abstract = {Neural injuries affecting both the central nervous system (CNS) and peripheral nervous system (PNS) pose a great clinical challenge due to the neural tissue's limited self-regenerative capacity. Human dental pulp stem cells (hDPSCs), derived from the neural crest and easily obtained from extracted teeth, exhibit considerable potential for neural regeneration. This potential is attributed to their ability to directly differentiate into various neuronal cell types, paracrine effects, and interactions with biomaterial scaffolds. In this review, we reviewed the molecular mechanisms by which hDPSCs support neural repair, highlighting their direct neuronal differentiation function, neuroprotection function via paracrine signaling, and recent innovations in biomaterial scaffolds that enhance the viability of hDPSCs for neuroregenerative applications. Preclinical studies have shown promising therapeutic effects of hDPSCs in spinal cord injuries (SCI), strokes, Parkinson's disease (PD), Alzheimer's disease (AD), and peripheral nerve injuries. However, challenges remain, including optimizing neuronal differentiation specificity, ensuring immunological safety, and achieving scalable clinical applications. Future research should focus on standardizing manufacturing protocols, implementing strict quality control, and developing functional assays linked to neural recovery to maximize the potential of hDPSCs for nervous system regeneration.},
}

@article {pmid41960309,
year = {2026},
author = {Lee, WP and Wang, H and Leung, YY and Cheng, PL and Zheng, W and Valladares, O and Chung, WH and Kuzma, A and Naj, A and Vardarajan, B and Grsiwold, A and Haines, J and Wang, LS and Schellenberg, G},
title = {Rare coding variants from ADSP R5 whole-genome sequencing implicate novel genes in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9013646/v1},
pmid = {41960309},
issn = {2693-5015},
abstract = {The Alzheimer's Disease Sequencing Project (ADSP) Release 5 provides whole-genome sequencing data from 58,507 individuals across diverse ancestries to discover rare coding variants and genes associated with Alzheimer's disease (AD) and AD-related traits. Gene-based aggregation tests identified 40 genes surpassing a Bonferroni-corrected gene-wide significance threshold, including established loci (TREM2, PSEN1) and putative novel candidates. In replication analyses, 21 genes showed nominal support in UK Biobank and Alzheimer's Disease Genetics Consortium (ADGC) cohorts, with eight genes (TREM2, ACADS, MFSD12, NUP210L, PIEZO2, PSEN1, SMURF2, AKAP13) supported under identical masks. Carrier-based analyses of AD-related traits linked rare variants to age at onset, neuropathology, cognition, and cerebrospinal fluid biomarkers (Aβ42, total tau, pTau181). Furthermore, we observed that AD-enriched variants were more likely to be ancestry-concentrated, and coalescent analyses indicated that AD risk alleles are younger than background variants. Together, these findings provide a multi-ancestry rare-variant resource for AD gene discovery.},
}