@article {pmid41946900,
year = {2026},
author = {Wunderlin, M and Wicki, K and Teunissen, CE and Züst, MA},
title = {Deep sleep slow wave-spindle coupling is selectively linked to plasma amyloid-β levels in older adults in clinical trials.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41946900},
issn = {2045-2322},
support = {215333/WT_/Wellcome Trust/United Kingdom ; 2018-PI02 & 2021-CDA03//Stiftung Synapsis - Alzheimer Forschung Schweiz AFS/ ; 215333/WT_/Wellcome Trust/United Kingdom ; 215333/WT_/Wellcome Trust/United Kingdom ; 215333/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; *Amyloid beta-Peptides/blood ; Aged ; Male ; Female ; *Sleep, Slow-Wave/physiology ; Biomarkers/blood ; Cognition/physiology ; Aged, 80 and over ; Peptide Fragments/blood ; Alzheimer Disease/blood/physiopathology ; },
abstract = {Slow wave activity, the signature of deep/slow wave sleep, has consistently been linked to amyloid-beta (Aβ), a biomarker of neurodegeneration. Less is known about how Aβ relates to specific microstructural processes within slow wave sleep, such as the coupling of slow waves and spindles, where better functioning reflects younger age, increased memory, and less brain atrophy. Here, we pooled and re-analyzed data from three clinical trials where participants underwent an adaptation night, a baseline night and a three-night acoustic stimulation intervention to boost slow wave activity. The baseline analysis included 47 older adults (agemean = 70.5 (0.68)) with varying cognitive functioning, whereas the intervention analysis was conducted on a subsample of 39 older adults (agemean = 70.5 (0.74)) with varying cognitive functioning. Blood samples post-baseline and post-intervention were analyzed for Aβ 1-42/1-40-ratio. Irrespective of cognitive functioning, slow wave-spindle coupling was the best predictor for baseline Aβ, better than slow wave activity, age or cognitive functioning. Specifically, better Aβ-levels were linked to a coupling physiology resembling a younger brain. While intervention-induced increases in slow wave activity were linked to a beneficial Aβ-response across all cognitive levels, increases in slow wave-spindle coupling benefited Aβ-response exclusively in cognitively impaired individuals. Our results suggest a link between SW-spindle coupling and Aβ going beyond slow wave activity. This hints towards a potential specific function of SW-spindle coupling related to the early pathophysiology of Alzheimer's disease.},
}

Humans
*Amyloid beta-Peptides/blood
Aged
Male
Female
*Sleep, Slow-Wave/physiology
Biomarkers/blood
Cognition/physiology
Aged, 80 and over
Peptide Fragments/blood
Alzheimer Disease/blood/physiopathology

@article {pmid41946975,
year = {2026},
author = {Evans, TE and Harper, J and Salehi, A and Webb, AG and Cole, JH and Correa, A and Adams, HHH and Cash, DM and Jones, DK},
title = {The potential of low-field MRI for global dementia care.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {41946975},
issn = {1759-4766},
abstract = {With elderly populations increasing in many countries, rates of Alzheimer disease and related dementias (ADRD) are expected to rise worldwide in the coming years. Low-income and middle-income countries, where barriers to health care are most pronounced and research representation is limited, are predicted to experience the greatest increases in ADRD prevalence. Access to advanced diagnostic and research tools, such as neuroimaging, is severely restricted in these regions, but low-field MRI is emerging as a promising, accessible alternative to conventional imaging. By reducing infrastructure, cost and siting requirements, low-field MRI offers a potential pathway to expand access to dementia-relevant imaging beyond specialized centres. In this article, we summarize key structural imaging biomarkers in ADRD and review the current literature supporting the use of low-field MRI in the ADRD field. We highlight the utility of low-field MRI for the assessment of regional atrophy and cerebrovascular lesion burden and discuss emerging diffusion-based markers. We also consider challenges and future directions, offering insights to advance equitable access to diagnostic imaging, guide research priorities and support global implementation of low-field MRI in ADRD care and investigation.},
}

@article {pmid41946988,
year = {2026},
author = {Zhang, J and Liu, Z},
title = {Don't rush use of lymphatic surgery in Alzheimer's disease.},
journal = {Nature},
volume = {652},
number = {8109},
pages = {534},
doi = {10.1038/d41586-026-01093-8},
pmid = {41946988},
issn = {1476-4687},
}

@article {pmid41947394,
year = {2026},
author = {Li, H and Zhao, Y and Luo, Y and Bao, B and Hao, J and Duan, S and Liu, Z},
title = {Goat Milk Fat Globule Membrane Supplementation Ameliorates Alzheimer Disease Cognitive Impairment by Modulating the Gut Microbiota.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c11966},
pmid = {41947394},
issn = {1520-5118},
abstract = {Research has found Alzheimer disease (AD) is accompanied by cognitive dysfunction and gut microbiota imbalance. Goat milk fat globule membrane (GMFGM) derived from goat milk, is a membrane primarily composed of proteins and polar lipids that regulates the gut microbiota. However, its role in AD remains unclear. Therefore, we examined the neuroprotective effects of GMFGM in 5xFAD mice. Supplementation with GMFGM (400 mg/kg bw, 8 weeks) improved cognitive performance, reduced brain Aβ deposition, alleviated neuroinflammation, and upregulated neurotrophic factors. Moreover, GMFGM preserved gut barrier integrity, lowered serum LPS levels, and reshaped gut microbiota composition, decreasing Alistipes, Dorea formicigenerans, and Duncaniella dubosii while increasing Stenotrophomonas. Further fecal microbiota transplantation validated the mechanism by which GMFGM ameliorates AD cognitive impairment by modulating the gut microbiota. These results indicate that GMFGM may rescue cognition by modulating the gut microbiota, alleviating gut damage, reducing LPS levels, and consequently inhibiting neuroinflammatory.},
}

@article {pmid41947612,
year = {2026},
author = {Kim, AR and Yoo, YJ and Bak, EJ},
title = {Alteration in oral and non-oral tissues in ligature-induced periodontitis mice with the Alzheimer's disease risk factor APOE4.},
journal = {European journal of oral sciences},
volume = {},
number = {},
pages = {e70091},
doi = {10.1111/eos.70091},
pmid = {41947612},
issn = {1600-0722},
support = {//National Research Foundation of Korea/ ; NRF-2021R1I1A1A01044714//Korea government (MSIT)/ ; },
abstract = {The APOE4 gene, particularly the ε4 allele, is linked to susceptibility to Alzheimer's disease, and periodontitis can cause pathological changes in multiple organs, but combined effects of these conditions and the impact of tumor necrosis factor (TNF)-α regulation on the combined effects remain unclear. We examined the alterations in oral and non-oral tissues in APOE4-knockin mice with periodontitis and evaluated the effects of infliximab, a TNF-α inhibitor. Mice were grouped as control, periodontitis, APOE4-knockin, APOE4-knockin with periodontitis, infliximab-treated periodontitis, and infliximab-treated APOE4-knockin with periodontitis. There were no differences in alveolar bone volume and periodontal inflammatory cells among all periodontitis-induced groups. The APOE4-knockin with periodontitis group showed a decrease in hippocampal Cornu Ammonis 1 neurons (p < 0.05) and increased renal and hepatic fibrosis (p < 0.05) compared to control group. The infliximab-treated APOE4-knockin with periodontitis group had even greater neuronal loss (p < 0.001) and renal fibrosis (p < 0.01). Glial fibrillary acidic protein mRNA expression, a marker of astrocyte activation, was higher in the infliximab-treated APOE4-knockin with periodontitis group than in the control group. These suggest that APOE4 with periodontitis worsens neuronal loss and renal and hepatic fibrosis, and TNF-α inhibition in this coexistence may have harmful effects on both the brain and kidney.},
}

@article {pmid41947717,
year = {2026},
author = {Guo, ZX and He, XY and Ge, YJ and Zhao, B and Huang, LY and Chen, SD and Fu, Y and Gao, PY and Sheng, ZH and Huang, YM and Li, QY and Tan, L},
title = {Gene-Environment Interactions for Alzheimer's Disease Pathology in Cognitively Normal Adults: The CABLE Study.},
journal = {European journal of neurology},
volume = {33},
number = {4},
pages = {e70558},
doi = {10.1111/ene.70558},
pmid = {41947717},
issn = {1468-1331},
support = {82271475//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/cerebrospinal fluid/epidemiology ; Male ; Female ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *Gene-Environment Interaction ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Middle Aged ; Risk Factors ; Peptide Fragments/cerebrospinal fluid ; Life Style ; Amyloidosis/genetics/cerebrospinal fluid/pathology ; Aged, 80 and over ; },
abstract = {BACKGROUND: Characterizing the gene-environment interactions with early pathological changes in Alzheimer's disease (AD) is critical to precision medicine.

METHODS: We recruited 1007 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Multiple linear regression models were applied to explore the associations between polygenic risk scores (PRSs) and cerebrospinal fluid (CSF) biomarkers of AD, the interactions between PRSs and potentially modifiable risk factors, and the relationships between lifestyle categories and CSF AD biomarkers.

RESULTS: A higher AD-PRS was associated with more severe amyloidosis, as indicated by pTau/Aβ42 (β = 0.091, p = 0.005) and tTau/Aβ42 (β = 0.092, p = 0.004). There were significant interactions between AD-PRS and three modifiable risk factors (anemia, gingivitis, and anxiety) in AD biomarker ratios. Stratified analyses by AD-PRS indicated that anemia was associated with higher pTau/Aβ42 and tTau/Aβ42 in the first and second quartiles, while gingivitis and anxiety correlated with amyloidosis in the fourth quartile (all p < 0.05). Additionally, a favorable lifestyle was associated with milder amyloidosis in the high genetic risk group.

CONCLUSIONS: AD-PRS was associated with amyloidosis severity. The associations between modified risk factors (anemia, gingivitis, and anxiety) and biomarker ratios differed by genetic risk strata. Moreover, a healthy lifestyle was associated with less amyloid burden in individuals with high genetic risk. These findings can be used to generate hypotheses for future longitudinal studies to investigate whether targeted management of these factors influences AD pathological progression.},
}

Humans
*Alzheimer Disease/genetics/pathology/cerebrospinal fluid/epidemiology
Male
Female
Aged
Amyloid beta-Peptides/cerebrospinal fluid
*Gene-Environment Interaction
tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Middle Aged
Risk Factors
Peptide Fragments/cerebrospinal fluid
Life Style
Amyloidosis/genetics/cerebrospinal fluid/pathology
Aged, 80 and over

@article {pmid41947851,
year = {2026},
author = {Li, Z and Fu, J and Pu, J and Qian, Y and Gai, X and Li, L},
title = {The cerebro-pelvic axis: a unified framework linking higher brain function, pelvic floor control, and lower urinary tract dysfunction.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1773086},
pmid = {41947851},
issn = {1662-4548},
abstract = {Clinical practice often treats higher brain disorders (e.g., Alzheimer's disease and prolonged disorders of consciousness) and pelvic floor dysfunction (e.g., stress urinary incontinence and overactive bladder) as unrelated problems, despite frequent co-occurrence and overlapping vulnerability contexts (e.g., aging, frailty, medications). Here, "axis" denotes a control-architecture mapping and phenotyping heuristic for LUT control and pelvic-floor outlet coordination, rather than a claim of new anatomy or shared etiology. Accordingly, we use a hypothesis-generating control-loop framing that links descending executive control with ascending interoceptive signaling to account for this clinicobiological mismatch. Within this framework, two provisional working failure-mode categories: top-down disintegration, in which impaired supraspinal control weakens volitional inhibition and shifts continence toward reflex-dominant regulation; and bottom-up disturbance, in which persistent peripheral salience-like signals may up-weight interoceptive processing and contribute to maladaptive central network adaptations. These categories are LUT-focused working categories and are not intended as a comprehensive taxonomy of all LUT phenotypes. We further introduce Coordinated Axis Neuromodulation (CAN) as a hypothesis-driven intervention concept that temporally couples cortical, spinal, and peripheral stimulation and may facilitate control-loop-level rebalancing compared with single-node modulation; this proposal requires direct empirical validation. This framework yields testable predictions, including directionally specific coupling between cortical biomarkers (e.g., executive/salience network metrics) and peripheral readouts (e.g., pelvic-floor EMG timing indices and/or diary-defined urgency/UUI burden; urodynamics as supportive phenotyping/secondary mechanistic data when included), and differential response profiles of CAN protocols across failure-mode-stratified cohorts. We outline a validation route spanning synchronized neurophysiology-pelvic physiology paradigms (e.g., EMG timing and diary endpoints; urodynamics as supportive phenotyping/secondary mechanistic data when included), proof-of-mechanism studies, and safety-monitored, mechanism-oriented RCTs designed to falsify or refine the CPA/CAN hypothesis.},
}

@article {pmid41947859,
year = {2026},
author = {Licatini, LM and Licatini, LM and Haddadin, FA and Conklin, GC and Badhwar, A and Sarsoza, FM and Sukreet, S and Winston, CN},
title = {Pre-analytical characterization of CNS-derived extracellular vesicles from human saliva: effect of room temperature and cellular origin.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1765229},
pmid = {41947859},
issn = {1662-4548},
abstract = {INTRODUCTION: Blood-derived extracellular vesicles (EVs) from neurons and astrocytes carrying Alzheimer's disease (AD) biomarkers can predict progression from mild cognitive impairment (MCI) to AD; however, their potential in saliva remains largely unexplored. Saliva-derived extracellular vesicles (sEVs) represent a promising non-invasive biomarker source for AD and other age-related dementias (ADRD), but progress has been limited by a lack of standardized protocols for saliva collection, storage, and central nervous system (CNS)-derived EV isolation.

METHODS: This study had two primary objectives: (1) to optimize enrichment of CNS cell-specific sEVs from the same individuals, and (2) to evaluate the impact of cellular origin and storage temperature (room temperature, 4°C, -20°C) on the stability and quantification of AD-related biomarkers and inflammatory cytokines. Saliva was collected via passive drool from participants in the Nathan Shock Healthy Aging Study (mean age 71.3 years; n = 15). EVs of neuronal, astrocytic, microglial, and oligodendrocyte origin were isolated using ExoQuick-TC precipitation followed by magnetic bead immunocapture. Executive function and attention were assessed using the NIH Toolbox Cognition Battery. Biomarkers were quantified using high-sensitivity immunoassays (MSD, SIMOA Qunaterix).

RESULTS: Astrocyte-derived EVs demonstrated significant enrichment of key AD biomarkers, including Aβ40, Aβ42, and total tau. Phosphorylated tau (p-tau217) was largely undetectable across all fractions. TDP-43 was most abundant in EV-depleted saliva, while inflammatory cytokines were broadly distributed across all fractions. Storage temperature did not consistently alter biomarker levels; however, -20°C storage yielded optimal biomarker quantification. Importantly, lower levels of inflammatory cytokines (IFN-γ, IL-10, and IL-6) in EV-depleted saliva were associated with better working memory performance.

DISCUSSION: This study provides proof-of-concept validation for the characterization and comparison of multiple CNS-derived salivary EV fractions within the same individuals. The findings support saliva as a feasible, non-invasive matrix for assessing neurodegenerative and neuroinflammatory biomarkers. Establishing a standardized methodology for salivary EV isolation and storage lays the groundwork for future longitudinal studies aimed at diagnosing and predicting AD progression using saliva-based biomarkers.},
}

@article {pmid41947888,
year = {2026},
author = {McKinstry, D and Shi, Z and Ramos-Rolón, AP and Phillips, J and Das, S and Li, X and Hager, NM and Pond, T and Volkow, ND and Kranzler, HR and Dubroff, JG and Nasrallah, IM and Wiers, CE},
title = {Hippocampal Volume and Brain Tau Pathology in Opioid Use Disorder: Associations with Non-Fatal Opioid Overdose.},
journal = {Addiction neuroscience},
volume = {19},
number = {},
pages = {},
pmid = {41947888},
issn = {2772-3925},
abstract = {Opioid use disorder (OUD) is associated with high rates of overdose (OD)-related morbidity and mortality. OD can cause hypoxic-ischemic injury to oxygen-sensitive brain regions such as the hippocampus. Post-mortem studies show Alzheimer's disease-like hyperphosphorylated tau pathology in the brains of individuals with OUD. Neurocognitive impairments in individuals with OUD may reflect incipient dementia and contribute to poor clinical outcomes. Alternatively, OUD and OD could be independent risk factors for Alzheimer's disease. To date, no study has evaluated the effects of non-fatal ODs or chronic OUD on hippocampal volume and tau deposition in the human brain in vivo. To fill this gap, we examined hippocampal volumes in OUD individuals (n=60) and healthy controls (HC, n=30) using T1-weighted magnetic resonance imaging (MRI). We found lower bilateral hippocampal volumes in OUD patients than HCs (p<0.001), but no differences between OUD individuals with a history of OD and those without (NOD) (p=0.92). We measured brain tau deposition using Positron Emission Tomography (PET) with [[18]F]PI-2620 in n=4 HC, n=4 OUD-NOD, and n=4 OUD-OD individuals, and found no difference in brain tau between groups. Functional MRI assessment of episodic memory showed no differences in memory performance or hippocampal activity between groups, although OUD-OD individuals had poorer performance than HC with a medium effect size (d=0.56). In summary, we confirm prior findings of smaller hippocampal volumes in participants with OUD than in HC. However, with a limited sample size, our findings do not show evidence of brain tau deposition in OUD participants with or without OD histories.},
}

@article {pmid41947971,
year = {2026},
author = {Arreguín-Cano, JA and Santana-Delgado, SA and Villegas-Mercado, CE and Orozco-Molina, GG and González-Acosta, A and Bermúdez, M},
title = {Linking inflammation, metabolic dysfunction, and neurodegeneration: a comprehensive review of TLR2 pathways in type 2 diabetes.},
journal = {Frontiers in clinical diabetes and healthcare},
volume = {7},
number = {},
pages = {1791782},
pmid = {41947971},
issn = {2673-6616},
abstract = {Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder increasingly recognized as a systemic inflammatory condition with significant neurological effects. Growing evidence shows that chronic low-grade inflammation (CLGI), insulin resistance, and metabolic imbalance contribute to cognitive decline and the development of neurodegenerative diseases like Alzheimer's and Parkinson's. Toll-like receptor 2 (TLR2), a critical pattern-recognition receptor of the innate immune system, has emerged as an essential molecular link between metabolic dysfunction and neuroinflammation and neuronal damage. This review summarizes current experimental, clinical, and translational evidence on the role of TLR2 in T2DM-related inflammation, mitochondrial dysfunction, lipid imbalance, insulin resistance, and blood-brain barrier (BBB) issues. We explore how ongoing TLR2 activation by internal danger signals and metabolic stressors maintains systemic inflammation and fuels neuroimmune responses via microglial activation and cytokine release, thereby accelerating neurodegenerative processes. Additionally, we discuss new therapeutic strategies targeting TLR2 signaling, including drugs, dietary supplements, and the repurposing of antidiabetic medications with neuroprotective effects. By combining immunometabolic and neurodegenerative pathways, this review highlights TLR2 as a promising target for preventing or reducing diabetes-related cognitive decline neurodegeneration.},
}

@article {pmid41948063,
year = {2026},
author = {Yang, SO and Ahn, J and Jung, YH and Jang, H and Na, DL and Kim, H and Kim, JP and Seo, SW and Kwak, K},
title = {Deep learning-based detection of cerebral microbleeds on 2D T2*-weighted GRE MRI: toward ARIA-H risk assessment in Alzheimer's treatment.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1729422},
pmid = {41948063},
issn = {1663-4365},
abstract = {BACKGROUND: Amyloid-related imaging abnormalities with hemorrhage (ARIA-H) are a key safety concern in anti-amyloid therapies for Alzheimer's disease, as they are radiologically indistinguishable from cerebral microbleeds (CMBs). Accurate detection of CMBs is therefore essential for both treatment eligibility assessment and post-treatment safety monitoring. However, manual identification on 2D T2*-weighted gradient-recalled echo (GRE) MRI is labor-intensive and subject to variability.

OBJECTIVE: To develop and validate an artificial intelligence (AI)-based model for automated CMB detection using only 2D T2*-weighted GRE MRI, which is widely used in clinical settings.

METHODS: We implemented a YOLOv11-based deep learning model, preceded by a novel multi-channel preprocessing pipeline that enhances CMB visibility. The model was trained and tested using a dataset of 758 participants, with expert consensus used as the reference standard.

RESULTS: Using the optimized basic preprocessing with super-resolution (BP + SR) pipeline, the model achieved a lesion-level sensitivity of 0.694, precision of 0.705, and F1-score of 0.699. In patient-level analysis for detecting elevated CMB burden (≥4), the system demonstrated sensitivity of 0.933 and specificity of 0.935, supporting reliable stratification of CMB severity. Regional analysis showed sensitivity of 0.625 for lobar CMBs and 0.627 for deep structures.

CONCLUSION: This study demonstrates the feasibility of robust CMB detection using only 2D T2*-weighted GRE MRI. Based on current performance, we position this system as a decision-support tool for GRE-based CMB screening, in which lesion-level detections may be aggregated to inform patient-level CMB burden relevant to ARIA-H risk stratification, while final ARIA grading and clinical decisions require expert neuroradiological confirmation.},
}

@article {pmid41948064,
year = {2026},
author = {Xu, R and Song, W and Zhang, X},
title = {Interleukin-6, CD8[+] T cells, and Alzheimer's disease: unraveling neuroimmune crosstalk via genetic and mechanistic insights.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1767927},
pmid = {41948064},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with complex interplay between neuroinflammation and immune dysfunction. Interleukin-6 (IL-6), a pleiotropic cytokine, has emerged as a controversial player in AD pathogenesis, with conflicting roles reported in inflammation and neuroprotection. This review synthesizes genetic and mechanistic evidence linking IL-6 to AD, focusing on the mediating role of peripheral immune cells-particularly CD8[+] T cell subsets like CD28[+] CD45RA[-] CD8br absolute counts (AC). We discuss how Mendelian randomization (MR) studies, including our recent work, have clarified causal relationships between IL-6, immune cell phenotypes, and AD risk. Additionally, we explore underlying mechanisms, such as IL-6-driven T cell activation, blood-brain barrier (BBB) modulation, and neuroinflammation resolution. Current controversies, including ethnic heterogeneity in genetic effects and the dual nature of IL-6 in systemic vs. central immunity, are highlighted. Finally, we address translational implications, such as immune cell-based biomarkers and targeted anti-inflammatory therapies, offering perspectives for future research.},
}

@article {pmid41948065,
year = {2026},
author = {Oh, H and Kim, H and Kang, H and Kwon, D and French, L and Park, YH and Youn, YC and An, SS and Kim, S and Kang, S},
title = {Systemic proteomic and organ aging signatures associated with plasma Aβ oligomerization in a Korean cohort: a cross-sectional study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1620991},
pmid = {41948065},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) in the brain, which begins decades before the appearance of clinical symptoms. Blood from AD patients, when spiked with synthetic Aβ, exhibited a higher Aβ oligomerization tendency (OAβT) than the non-AD subjects. OAβT reflected early pathological changes of AD and is considered as a promising blood-based biomarker. However, the mechanism underlying OAβT remained elusive. This study aimed to identify proteomic signatures associated with OAβT and explore its role in AD diagnosis.

METHODS: Forty AD and non-AD subjects from a Korean cohort were divided into four groups based on the disease diagnosis, OAβT values (thresholded at 0.78 ng/mL), and amyloid PET status (A-PET): A-PET-positive AD patients with high or low OAβT values, A-PET-negative non-AD subjects with high or low OAβT values. Using aptamer-based proteomics, 7,288 proteins from plasma samples were quantified, and the group differences were assessed in protein levels and the enrichment of gene sets associated with annotations from the Gene Ontology database. Further, we assessed whether OAβT-PET mismatched cases (A-PET-positive but OAβT-low or A-PET-negative but OAβT-high) exhibited distinct blood proteome signatures in comparison to typical AD cases. Aging signatures for 11 organs were analyzed to explore systemic factors linked to OAβT-PET discrepancies. Additionally, the pharmacological influences on the OAβT-related proteome were investigated by comparing OAβT-correlated proteins with a database of drug-induced proteomic changes.

RESULTS: Elevated OAβT values, regardless of AD diagnosis, correlated with increased immune response and decreased cellular metabolism. Dementia-predicting proteins were enriched in non-AD individuals with high OAβT. Accelerated muscle aging was associated with high OAβT values and worse cognitive function. Furthermore, several potential pharmacological modulators of OAβT, including Minocycline and Anamorelin, were identified.

CONCLUSION: Our findings demonstrated OAβT as a reflection of systemic changes linked to early AD pathology. Moreover, the influence of medications and systemic aging on OAβT values pointed to the potential avenues for intervention and emphasized the importance of considering systemic factors in AD pathogenesis and treatment.},
}

@article {pmid41948329,
year = {2026},
author = {Hu, Q and Wang, J and Cao, R and Liu, W and Wang, L},
title = {Therapeutic potential of vagus nerve stimulation in neurodegenerative diseases: research progress and mechanisms.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1811107},
pmid = {41948329},
issn = {1664-3224},
mesh = {Humans ; *Vagus Nerve Stimulation/methods ; *Neurodegenerative Diseases/therapy/etiology ; Animals ; Vagus Nerve ; },
abstract = {Neurodegenerative diseases are a group of chronic, progressive neurological disorders caused by the degeneration and functional loss of neurons and glial cells, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD). Although numerous treatments are available for these diseases, therapeutic outcomes remain unsatisfactory because of their poorly understood pathogeneses of these diseases. Vagus nerve stimulation (VNS), a noninvasive or minimally invasive neuromodulation technique, has shown significant potential in mitigating neurodegenerative conditions. This review explores the mechanisms of action and clinical applications of VNS in neurodegenerative diseases, providing novel insights for the development of novel treatments.},
}

Humans
*Vagus Nerve Stimulation/methods
*Neurodegenerative Diseases/therapy/etiology
Animals
Vagus Nerve

@article {pmid41948388,
year = {2026},
author = {Park, CK and Kang, G and Choi, SJ and Lee, YS and Shin, EC and Kim, HI and Park, J and Oh, NS and Cho, HT and Kim, TG and Pan, JH and Shin, DH and Kim, YJ and Kim, JK},
title = {Sparassis crispa and a Bioactive Compound Therein, Ergosterol, Were Effective in Preventing Acetylcholinesterase Inhibition In Vitro and In Vivo.},
journal = {Food science & nutrition},
volume = {14},
number = {4},
pages = {e71653},
pmid = {41948388},
issn = {2048-7177},
abstract = {Alzheimer's disease (AD) is characterized by multifactorial pathological processes, including cholinergic dysfunction and oxidative stress, highlighting the need for safer, multi-target interventions beyond current synthetic acetylcholinesterase (AChE) inhibitors. In the present study, we screened ethanolic extracts from various edible and medicinal plants to identify natural sources with cholinesterase-modulating activity and found that Sparassis crispa (S. crispa) extract exhibited robust AChE inhibitory activity. The extract also demonstrated significant antioxidant capacity and protected rat pheochromocytoma cells against oxidative stress-induced cytotoxicity. Chemical characterization using gas chromatography-mass spectrometry identified ergosterol as a major bioactive constituent of S. crispa extract. Ergosterol directly inhibited AChE activity in vitro and was subsequently evaluated in vivo using a trimethyltin chloride (TMT)-induced mouse model of cognitive impairment. Dietary supplementation with S. crispa extract significantly improved spatial working memory and attenuated TMT-induced elevation of brain AChE activity. Notably, ergosterol supplementation produced dose-dependent improvements in both spatial working memory and aversive learning, accompanied by restoration of cholinergic function and reduction of lipid peroxidation in brain tissues. No signs of hepatic toxicity were observed following ergosterol administration. Collectively, these findings demonstrate that S. crispa extract exerts cognitive benefits through combined modulation of cholinergic dysfunction and oxidative stress, and identify ergosterol as a key bioactive contributor to these effects. This study provides mechanistic insight into the neuroprotective potential of S. crispa and supports its development, together with ergosterol, as functional food-derived candidates for the prevention or mitigation of cognitive decline.},
}

@article {pmid41948424,
year = {2026},
author = {Liu, Y and Wang, XP},
title = {Potential correlation between chronic pain and amyloid beta in Alzheimer's disease.},
journal = {Frontiers in pain research (Lausanne, Switzerland)},
volume = {7},
number = {},
pages = {1799860},
pmid = {41948424},
issn = {2673-561X},
abstract = {Pain refers to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Chronic pain is a common symptom among Alzheimer's disease (AD) patients. Due to the cognitive impairment characteristic of mid-to-late-stage AD, many AD patients fail to receive timely pain relief, leading to worsening of the disease. Understanding the relationship between chronic pain and the pathological progression of AD is crucial. Previous studies have confirmed a close correlation between pain occurrence and the metabolism of amyloid beta (Aβ) protein, one of the hallmark pathological features of AD. This article provides an overview of recent research progress on the interaction between pain and Aβ, analyzes its molecular mechanisms, and offers new research insights for effectively alleviating pain in AD patients and preventing or treating AD.},
}

@article {pmid41948483,
year = {2024},
author = {Suresh, PN and Kazemivash, B and Jensen, DM and Calhoun, V and Liu, J},
title = {Integrating Neuroimaging and Genetics via Contrastive Learning for Working Memory.},
journal = {... IEEE-EMBS International Conference on Biomedical and Health Informatics. IEEE-EMBS International Conference on Biomedical and Health Informatics},
volume = {2024},
number = {},
pages = {},
pmid = {41948483},
issn = {2641-3590},
abstract = {Understanding working memory's genetic and neural bases is crucial for advancing cognitive neuroscience and identifying biomarkers for cognitive impairments, particularly in the older population. This study integrates SNP and neuroimaging data from the UK biobank to improve the classification of high vs. low working memory capacity and reveal genetic factors associated with brain structure. 1060 SNPs belonging to Protein-Protein Interaction networks of amyloid precursor protein and A β of Alzheimer's disease were integrated with latent features of whole brain gray matter density, extracted by a pre-trained CNN, via supervised contrastive learning. Our model effectively extracts latent representations of both modalities through enhancing genetic-imaging relation within individuals and within working memory groups, in contrast to across individuals and groups. Features derived from contrastive learning outperformed other baseline models in terms of classification. Sparse canonical correlation analysis was applied to the latent representations and uncovered significantly related genetic variants and brain regions. Genetic components highlight SNPs in genes FYN, RPL28, MAPT, enriched in the pathways of dendrite and synapse, among others. The linked brain regions support the cerebellum and striatum's role in cognitive functions. These findings provide new insights into the genetic and neural mechanisms underlying working memory, potentially guiding future research and therapeutic strategies for cognitive impairment.},
}

@article {pmid41948539,
year = {2026},
author = {Luckett, PH and Petersen, M and O'Bryant, S and Mapstone, M and Christian, BT and Handen, B and Head, E and Ances, BM and , },
title = {Application of machine learning to blood-based biomarkers of Alzheimer's disease in Down syndrome.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70325},
pmid = {41948539},
issn = {2352-8729},
abstract = {INTRODUCTION: Blood-based biomarkers can improve Alzheimer's disease (AD) characterization in Down syndrome (DS). This study applied hierarchical clustering and machine learning-based feature selection to identify biomarkers associated with disease progression.

METHODS: Cross-sectional blood-based biomarkers were analyzed from 211 DS participants (n = 79 cognitively stable [CS]; n = 72 mild cognitive impairment [MCI]; n = 60 AD dementia [DS-AD]). These included markers of amyloid, tau, neurodegeneration, and inflammation. Clustering grouped biomarkers. Decision trees classified disease stage, and Shapley values identified the strongest predictors of disease stage.

RESULTS: The strongest predictors overall were neurofilament light chain (NfL), tau/amyloid beta (Aβ)40, Aβ42/Aβ40, alpha-2-macroglobulin (A2M), and interleukin (IL)-10. Within the CS group, NfL, tau/Aβ40, A2M, and IL-10 were strong predictors. In MCI, Aβ42/Aβ40, NfL, A2M, and IL-10 were strong predictors. In DS-AD, Aβ42/Aβ40, NfL, and tau/Aβ40 were the top predictors. Cluster membership varied based on disease stage.

DISCUSSION: These findings reveal evolving biomarker signatures and clustering patterns across cognitive stages, underscoring their potential for disease monitoring.},
}

@article {pmid41948540,
year = {2026},
author = {Khorsand, B and Ghanbarian, E and Rabin, LA and Sajjadi, SA and Ezzati, A},
title = {Incremental value of plasma biomarkers in predicting clinical decline among cognitively unimpaired older adults: Results from the A4 trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70321},
pmid = {41948540},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity complicates early detection and trial design. Scalable predictors may aid risk stratification. We assessed whether scalable baseline plasma biomarkers and neuropsychological measures predict 5‑year cognitive and functional decline in cognitively unimpaired older adults.

METHODS: We analyzed 866 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and 343 amyloid-negative individuals from the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. Decline was defined as a ≥0.5 increase in Clinical Dementia Rating-Global Score over 240 weeks. The separate and joint value of demographics, apolipoprotein E (APOE) ε4, amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR), plasma phosphorylated tau-217 (p-tau217), and Preclinical Alzheimer's Cognitive Composite (PACC) were assessed. A sub-study of 656 participants evaluated added value of plasma amyloid beta (Aβ)42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).

RESULTS: The p-tau217 and PACC significantly improved prediction. Full models achieved areas under the curve (AUCs) of 0.78-0.80 across cohorts. Additional plasma biomarkers offered modest AUC gains (1%-3%).

DISCUSSION: The p-tau217 and PACC enhanced prediction of preclinical decline, supporting their utility in early identification and trial enrichment in AD.},
}

@article {pmid41948549,
year = {2026},
author = {Rodríguez-Rosas, AM and Baldenebro-Félix, DL and Peréz-Villarreal, JM and García-Mena, J and Kawano-Soto, CA and Camberos-Barraza, J and Valdéz-Flores, MA and Calderón-Zamora, L and Angulo-Rojo, CE and Magaña-Gómez, JA and Guadrón-Llanos, AM},
title = {Gut Microbiota Diversity and Function in Adults With Type 2 Diabetes, Alzheimer's Disease, and Both Conditions.},
journal = {International journal of microbiology},
volume = {2026},
number = {},
pages = {5247744},
pmid = {41948549},
issn = {1687-918X},
abstract = {INTRODUCTION: Type 2 diabetes mellitus (T2DM) is known to increase the risk of Alzheimer's disease (AD), but the role of the gut microbiota in this relationship is not fully understood. This study investigated the gut microbiota profiles of adults with T2DM, adults with AD, both conditions (AD-T2DM), and healthy controls to identify patterns associated with metabolic and neurodegenerative conditions.

METHODS: A cross-sectional study was conducted with 148 participants divided into six groups: CTRL < 60 years, CTRL ≥ 60 years, T2DM < 60 years, T2DM ≥ 60 years, AD, and AD-T2DM. Clinical assessments and 16S rRNA gene sequencing of fecal samples were performed to analyze microbial diversity and composition.

RESULTS: Compared with controls, older adults with T2DM, AD, and AD-T2DM presented reduced microbial diversity and distinct microbial compositions. Notably, SCFA-producing genera (Veillonella and Dialister) decreased in T2DM patients ≥ 60 years, whereas Roseburia and Blautia were more abundant in AD patients and those with AD-T2DM. GDP-mannose biosynthesis was downregulated in AD-T2DM patients.

CONCLUSION: This study highlights changes in the microbiota in T2DM and AD-T2DM patients, suggesting that targeting these microbial alterations could offer new prevention strategies for metabolic-neurodegenerative comorbidities.

SIGNIFICANCE STATEMENT: T2DM and AD share metabolic and inflammatory pathways, yet their combined impact on the gut microbiota remains unexplored. By profiling 148 adults, healthy individuals, those with T2DM, AD, and co-occurring AD-T2DM, using 16S rRNA gene V4 region sequencing, we identified specific dysbiosis in AD-T2DM. Rather than examining T2DM and AD as independent conditions, the present study conceptualizes their coexistence as a metabolic-neurodegenerative interaction state and assesses whether this comorbidity is associated with a distinct gut microbiota composition and predicted functional profile. Therefore, we examine the gut microbiota of adults with AD-T2DM using an age-stratified design in an underrepresented Mexican population, integrating clinical, metabolic, cognitive, taxonomic, and functional data to explore potential mechanisms underlying metabolic-neurodegenerative crosstalk. These findings identify microbial genera that may mediate the "diabeto-neuro" crosstalk, offering novel targets for early intervention and precision microbiota-based therapies to mitigate metabolic-neurodegenerative comorbidity.},
}

@article {pmid41948553,
year = {2026},
author = {Sólyomvári, C and Makkai, G and Capelo-Carrasco, N and Strac, DS and Zelena, D and Farkas, S},
title = {Time-dependent histological characterization of amyloid-β induced cholinergic and glial alterations and their modulation by dehydroepiandrosterone sulfate (DHEAS).},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1764298},
pmid = {41948553},
issn = {1664-2392},
mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; Male ; *Neuroglia/drug effects/pathology/metabolism ; Mice ; *Cholinergic Neurons/drug effects/pathology/metabolism ; Mice, Inbred C57BL ; *Dehydroepiandrosterone Sulfate/pharmacology ; *Alzheimer Disease/pathology/metabolism/drug therapy ; *Peptide Fragments/toxicity ; Microglia/drug effects/pathology/metabolism ; Time Factors ; *Basal Nucleus of Meynert/drug effects/pathology/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by predominant - but not exclusive - pathological accumulation of amyloid-β (Aβ) in the brain. This process affects not only neurons (particularly cholinergic) but also glial cells, contributing to progressive neuronal loss and neuroinflammation. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are endogenous steroids that are hypothesized to exert neuroprotective and anti-inflammatory effects. This study aims to histologically characterize the in vivo temporal progression of Aβ-induced alterations in cholinergic neurons and glial morphology. Our secondary aim was to evaluate whether DHEAS protects cholinergic integrity and, if so, whether this effect is mediated through glial activation.

METHODS: Aβ1-42 was injected into the cholinergic nucleus basalis magnocellularis (NBM) region of C57BL6/J male mice and one hour later 10 mg/kg DHEAS or vehicle (0.9% saline) was applied intraperitoneally. After 3, 12 or 33 days, the mice were transcardially perfused and immunohistochemical staining was used to investigate cholinergic cell (ChAT) and fiber (AChE) loss, as well as microglia (IBA1) and astrocyte (GFAP) morphology.

RESULTS: Our findings confirmed that Aβ peptide exerted neurotoxic effects on the cholinergic system and triggered time-dependent activation in both glia cell types. Microglial cells initiated their response by day 3, adopting an amoeboid morphology, whereas delayed astrocytic reactivity was observed between days 3 and 12, demonstrated by increased ramification. DHEAS treatment preserved cholinergic fiber density, without effecting the number of cell bodies and modulated the inflammatory responses of glia cells, by decreasing the area occupied and number of microglia in a time dependent manner.

DISCUSSION: Aβ toxicity exerts time-dependent effects on both cholinergic neurons and glia cells, while DHEAS shows therapeutic promise, though its efficacy and exact mechanism require further investigation.},
}

Animals
*Amyloid beta-Peptides/toxicity
Male
*Neuroglia/drug effects/pathology/metabolism
Mice
*Cholinergic Neurons/drug effects/pathology/metabolism
Mice, Inbred C57BL
*Dehydroepiandrosterone Sulfate/pharmacology
*Alzheimer Disease/pathology/metabolism/drug therapy
*Peptide Fragments/toxicity
Microglia/drug effects/pathology/metabolism
Time Factors
*Basal Nucleus of Meynert/drug effects/pathology/metabolism

@article {pmid41948610,
year = {2026},
author = {Naim, A and Farooqui, AM and Badruddeen, and Khan, MI and Akhtar, J and Ahmad, A and Ashique, S and Islam, A},
title = {Nanoengineered phytochemicals overcome blood-brain barrier constraints in neurodegenerative disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1792829},
pmid = {41948610},
issn = {1664-2295},
abstract = {Neurodegenerative disorders represent a growing global health burden and remain largely incurable, with current therapies providing only symptomatic relief and limited disease modifications. A major obstacle to effective treatment is the inability of many neuroprotective agents to reach the brain at therapeutically relevant concentrations due to poor bioavailability and the restrictive nature of the blood-brain barrier. Plant-derived phytochemicals possess well-documented antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities; however, their clinical translation has been hindered by physicochemical instability, rapid metabolism, and insufficient brain exposure. This review critically examines nanoengineered delivery systems as a strategy to overcome these limitations and enable the effective brain targeting of neuroprotective phytochemicals. By integrating mechanistic insights with preclinical and emerging clinical evidence, we compared lipid-based, polymeric, vesicular, and dendritic nanocarriers, highlighting how particle size, surface chemistry, and ligand functionalization govern blood-brain barrier transport and intracerebral distribution. Particular emphasis is placed on rational design principles that consistently enhance brain bioavailability and therapeutic efficacy across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and related disorders. Beyond efficacy, we analyzed key translational challenges, including nanocarrier-associated neurotoxicity, standardization of herbal activities, and regulatory gaps unique to herbal nanomedicines. Collectively, this synthesis reframes nano-phytomedicine not as an incremental formulation upgrade but as a design-driven strategy capable of unlocking the therapeutic potential of phytochemicals for neurodegenerative disease management.},
}

@article {pmid41948713,
year = {2026},
author = {Swamy, A and Agrawal, DK},
title = {Enhancing Early Diagnosis: Multimodal AI Approaches for Neurodegenerative Diseases.},
journal = {Journal of biotechnology and biomedicine},
volume = {9},
number = {1},
pages = {67-76},
pmid = {41948713},
issn = {2642-9128},
abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's impose a staggering global burden, yet timely identification remains hindered by a fundamental mismatch between the slow unfolding of pathology and the static nature of traditional diagnostic frameworks. While conventional clinical markers often fail to identify decline until irreversible neuronal loss has occurred, artificial intelligence (AI)-driven biomarkers derived from neuroimaging, electrophysiology, and digital phenotyping offer a transformative proactive paradigm. This review evaluates how machine-learning models extract high- dimensional, subvisual patterns from MRI, PET, and EEG datasets to detect preclinical deviations that outpace traditional markers in predictive timelines. We argue that the primary value of these technologies lies in a categorical shift toward continuous, temporally informed disease modeling designed to fill the "detection gap" between early protein accumulation and overt clinical impairment. By synthesizing evidence across various modalities, we highlight the superior performance of multimodal fusion architectures in capturing the biological complexity of neurodegeneration. However, clinical translation faces significant hurdles, including data heterogeneity, the "black-box" nature of deep learning, and the necessity for global equity in dataset representation. Ultimately, by integrating explainable AI with longitudinal data streams, these biomarkers can redefine neurodegenerative care-transforming diagnosis from a reactive confirmation of damage into a precise tool for risk stratification, trial enrichment, and early therapeutic intervention.},
}

@article {pmid41948730,
year = {2026},
author = {Wang, Y and Duan, J and Zang, L and Sun, T and Lv, H and Liu, F and Ma, X},
title = {Hyaluronic acid: emerging roles and biomaterial innovations in Alzheimer's and Parkinson's disease therapy.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1772172},
pmid = {41948730},
issn = {1663-9812},
abstract = {Hyaluronic acid (HA) is a key component of the extracellular matrix (ECM). Owing to its anti-inflammatory properties, biocompatibility and ability to contribute to ECM remodeling, HA is considered a promising therapeutic candidate for neurodegenerative diseases. This review summarizes the application of HA to treat Alzheimer's disease (AD) and Parkinson's disease (PD) and outlines the current understanding of the mechanism of action and strategies for HA-based biomaterial modification. For AD, HA is involved in several mechanisms including stabilizing the perineuronal net, reducing the toxic effects of Aβ and hyperphosphorylated tau, and modulating neuroinflammation through CD44/RHAMM signaling pathways. HA-based nanoparticles and hydrogels enhance drug delivery across the blood-brain barrier, facilitate Aβ clearance, and enable sustained, controlled release of therapeutic agents. In PD, HA regulates autophagic flux, inhibits α-synuclein propagation, and remodels the ECM to protect dopaminergic neurons. Modifications such as HA hydrogels with neurotrophic factors improve cell transplantation outcomes, while conjugates enhance mitochondrial targeting and dopamine delivery. While numerous preclinical studies have shown promise, significant challenges remain, including the high variability of HA formulations, limited blood-brain barrier penetration efficiency, and a paucity of well-designed clinical trials to validate preliminary findings. Future directions include standardizing laboratory protocols, developing hybrid systems integrating vascular endothelial growth factor and gene therapy, and adopting a patient-specific approach that leverages HA's multi-targeted effects on the nervous system.},
}

@article {pmid41949026,
year = {2026},
author = {Boyd, RJ and Dong, D and Sagar, R and Iliuk, A and Ahmed, W and Androni, X and Porsteinsson, AP and Rosenberg, PB and Lyketsos, CG and Witwer, KW and Mahairaki, V},
title = {Proteomic profiling of brain organoids and extracellular vesicles identifies early Alzheimer's disease biomarkers and drug response heterogeneity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71273},
doi = {10.1002/alz.71273},
pmid = {41949026},
issn = {1552-5279},
support = {1RF1AG083801/GF/NIH HHS/United States ; AGR01054771/AG/NIA NIH HHS/United States ; AGR01050515/AG/NIA NIH HHS/United States ; AGR01046543/AG/NIA NIH HHS/United States ; AGR01071522/AG/NIA NIH HHS/United States ; //The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Extracellular Vesicles/metabolism ; *Organoids/metabolism ; *Proteomics ; *Brain/metabolism/pathology ; Biomarkers/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Male ; Female ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) exhibits high genetic and clinical heterogeneity that limits therapeutic success. Patient-derived brain organoids and their extracellular vesicles (EVs) provide physiologically relevant models to study disease mechanisms and individualized drug responses.

METHODS: We generated the largest brain organoid cohort to date, derived from 30 independent induced pluripotent stem cell (iPSC) lines from AD and control individuals. Comparative proteomic profiling was performed on both organoids and their secreted EVs to capture molecular diversity and treatment effects.

RESULTS: Organoids and EVs consistently recapitulated neuronal proteomic signatures and revealed early alterations in AD-related pathways, including synaptic and neurotransmitter dysfunction. Distinct proteomic responses mirrored individual variability in selective serotonin reuptake inhibitor sensitivity.

DISCUSSION: Integrating organoid and EV data provides a systems-level view of AD pathophysiology and treatment response, positioning this dual-platform model as a cost-effective tool for precision medicine and drug discovery.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology
*Extracellular Vesicles/metabolism
*Organoids/metabolism
*Proteomics
*Brain/metabolism/pathology
Biomarkers/metabolism
Induced Pluripotent Stem Cells/metabolism
Male
Female

@article {pmid41949058,
year = {2026},
author = {Lombardo, FL and Caraglia, N and Lorenzini, P and Vanacore, N and Cappa, SF and Cotelli, M and Iodice, F and Marra, C and Miraglia, F and Pappalettera, C and Perani, D and Quaranta, D and Redolfi, A and Spadin, P and Tagliavini, F and Vecchio, F and Rossini, PM and , },
title = {Mild cognitive impairment-to-Alzheimer's dementia progression risk: the contribution of the Interceptor project.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71204},
doi = {10.1002/alz.71204},
pmid = {41949058},
issn = {1552-5279},
support = {//Italian Ministry of Health/ ; //Italian Medicines Agency/ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/diagnosis/genetics/pathology ; *Disease Progression ; Male ; Female ; *Alzheimer Disease/diagnosis/diagnostic imaging ; Aged ; Neuropsychological Tests ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; Brain/diagnostic imaging/pathology ; Apolipoproteins E/genetics ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Risk Factors ; Electroencephalography ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is an intermediate stage between normal and pathological brain aging, with 30% to 50% progressing to dementia within 3 to 5 years. Early identification of individuals at high risk of progression is crucial for public health strategies.

METHODS: The INTERCEPTOR project included 398 MCI individuals. Baseline assessment included harmonized procedures for sociodemographic, clinical, neuropsychological, genetic (apolipoprotein E), cerebrospinal fluid (amyloid beta tau), electroencephalogram (brain connectivity), magnetic resonance imaging (hippocampal volumetry), and fluorodeoxyglucose positron emission tomography. The baseline and follow-up were completed by 351 individuals with MCI with neuropsychological tests every 6 months for 3 years.

RESULTS: Dementia developed in 104 individuals (29.6%), including 85 (22.4%) who met core clinical criteria for probable and possible Alzheimer's disease dementia. A Cox model combining clinical and sociodemographic data achieved a concordance index of 72%, which increased to 82% when neuropsychology and biomarkers were added.

DISCUSSION: The INTERCEPTOR nomogram represents a tool for predicting dementia progression risk, supporting public health strategies, including screening for risk assessment and risk/benefit ratio in innovative treatments.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/diagnosis/genetics/pathology
*Disease Progression
Male
Female
*Alzheimer Disease/diagnosis/diagnostic imaging
Aged
Neuropsychological Tests
Positron-Emission Tomography
Magnetic Resonance Imaging
Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
Brain/diagnostic imaging/pathology
Apolipoproteins E/genetics
tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Risk Factors
Electroencephalography

@article {pmid41949144,
year = {2026},
author = {Pradhan, R and Kumari, S and Singh, AK and Rao, AR and Yadav, Y and Upadhyay, AD and Mehta, PK and Dey, AB and Dey, S},
title = {Blood level of β-amyloid, Tau, and p-Tau in mild cognitive impairment and Alzheimer disease: A follow up study.},
journal = {The Indian journal of medical research},
volume = {163},
number = {2},
pages = {166-173},
doi = {10.25259/IJMR_2164_2025},
pmid = {41949144},
issn = {0971-5916},
mesh = {Humans ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/blood/pathology/genetics ; *Cognitive Dysfunction/blood/pathology ; Male ; Female ; Aged ; Biomarkers/blood ; Follow-Up Studies ; Disease Progression ; Phosphorylation ; *Peptide Fragments/blood ; Middle Aged ; Aged, 80 and over ; },
abstract = {Background and objectives Deposition of β-amyloid and phosphorylated-tau proteins are major neuropathological abnormality in brain of patients with Alzheimer disease. This study aimed to study the role of various serum protein biomarkers to aid in the diagnosis and progression of Alzheimer disease. Methods Blood samples were collected from 96 patients with Alzheimer disease, 75 patients with mild cognitive impairment, and 70 geriatric controls at baseline. The number of patients (Alzheimer disease and mild cognitive impairment) who progressed after 1 year was 12, while the number of non-progressors was 24. Serum levels of β-amyloid1-42 (Aβ1-42), Tau, and phosphorylated-Tau181 (pTau) were quantified using surface plasmon resonance and further validated by Western blot. Results Comparison of proteins between the three groups revealed significantly lower Aβ1-42, higher Tau and pTau protein expression in serum of patients with Alzheimer disease as compared to patients with mild cognitive impairment and controls. In patients who progressed after one year, the baseline concentration of Aβ1-42 protein was significantly higher than their follow-up levels. Tau and pTau levels also increased significantly over the years. In non-progressors, no significant difference was observed in Aβ1-42, Tau, and pTau concentration between the baseline and follow up. Interpretation and conclusions Aβ1-42, Tau, and pTau proteins can serve as potential blood-based biomarkers for the diagnosis and monitoring the progression of Alzheimer disease.},
}

Humans
*tau Proteins/blood
*Amyloid beta-Peptides/blood
*Alzheimer Disease/blood/pathology/genetics
*Cognitive Dysfunction/blood/pathology
Male
Female
Aged
Biomarkers/blood
Follow-Up Studies
Disease Progression
Phosphorylation
*Peptide Fragments/blood
Middle Aged
Aged, 80 and over

@article {pmid41949488,
year = {2026},
author = {Chen, Y and Zhao, S and Yang, F and Wang, Y and Han, Z and Han, F and Wang, Z and Chen, Z and Sun, K and Liang, P and Li, K},
title = {The interventional effect of acupuncture on overall cognitive function in Alzheimer's disease spectrum disorders: A meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261438495},
doi = {10.1177/13872877261438495},
pmid = {41949488},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) and mild cognitive impairment (MCI) cause progressive cognitive decline, with Western medicine only alleviating symptoms at present. Acupuncture shows potential for these disorders, but existing studies have inconsistent results.ObjectiveTo examine the effect of acupuncture on overall cognitive function in patients with AD and MCI via meta-analysis.MethodLiterature from six databases on acupuncture, AD, and MCI was searched. Meta-analyses and moderator analyses were performed using Comprehensive Meta Analysis V3.0.Results52 randomized controlled trials (RCTs) involving 3362 AD/MCI patients were included. Results showed that acupuncture alone outperformed blank or placebos (SMD=1.09, 95% CI = [0.60, 1.58], p < 0.001, I[2] = 91.39%). In addition, acupuncture alone (SMD = 0.45, 95% CI = [0.22, 0.67], p < 0.001, I[2] = 69.38%) and combined with Western medicine (SMD = 1.18, 95% CI = [0.92, 1.44], p < 0.001, I[2] = 90.73%) were superior to Western medicine alone. Moderator analysis revealed significant effect of type of patients, showing larger effect in AD than MCI in acupuncture combined with Western medicine (Q = 10.20, p = 0.001). Regarding types of acupuncture, manual acupuncture (MA) and electroacupuncture (EA) showed no significant difference between them (alone: Q = 0.38, p = 0.536; combined with Western medicine: Q = 0.57, p = 0.449) and both outperformed Western medicine alone.ConclusionsAcupuncture could improve overall cognitive function in AD and MCI, with similar effects between MA and EA. Due to the heterogeneity and variable methodological quality of the studies included, our results must be interpreted with caution. Still, these results suggest acupuncture may be an adjuvant to Western medicine for eligible patients and a potential alternative for short-term cognitive improvement when Western medicine is contraindicated.},
}

@article {pmid41949889,
year = {2026},
author = {McEvoy, LK and Zhang, B and Nguyen, S and Maihofer, AX and Nievergelt, CM and Casanova, R and Horvath, S and Lu, AT and Davatzikos, C and Erus, G and Resnick, SM and Espeland, MA and Rapp, S and Beckman, K and Ferrucci, L and LaCroix, AZ and Shadyab, AH},
title = {Association of epigenetic age acceleration with MRI biomarkers of aging and Alzheimer's disease neurodegeneration.},
journal = {Aging},
volume = {18},
number = {1},
pages = {303-326},
doi = {10.18632/aging.206369},
pmid = {41949889},
issn = {1945-4589},
abstract = {Epigenetic clocks of biological aging have been associated with cognitive impairment and dementia. Less is known about whether they are associated with an older-appearing brain or with an atrophy pattern associated with dementia. We examined associations of five epigenetic clocks measured at baseline with the Spatial Pattern of Atrophy for Recognition of Brain Aging (SPARE-BA) and the Alzheimer's Disease Pattern Similarity Score (AD-PS) derived from structural MRIs obtained an average of 8 years later among 1,196 older women. Using linear regression models adjusting for relevant covariates, we observed no associations between any epigenetic clock and accelerated brain aging based on SPARE-BA. We observed a significant association between AgeAccelGrim2 and AD-PS (β = 0.015; 95% CI 0.004 to 0.027; p = 0.01). This association appeared to be primarily driven by the association of a DNA methylation marker of smoking pack years with frontal and temporal lobe volumes. AgeAccelGrim2 was not associated with volumes in regions implicated in early AD (hippocampus and entorhinal cortex). Taken together with prior findings, these results suggest that measures of epigenetic and brain age acceleration capture different aspects of biological aging, and that AgeAccelGrim2 is predictive of neurodegenerative changes associated with smoking that increase risk of dementia.},
}

@article {pmid41949989,
year = {2026},
author = {Buchal, A and Dzialas, V and Doering, E and Giehl, K and Bischof, GN and Elmenhorst, D and van Eimeren, T and Drzezga, A and Hoenig, MC and , },
title = {Home-based sleep monitoring reveals associations between amyloid accumulation and sleep alterations in individuals with subjective and mild cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71326},
doi = {10.1002/alz.71326},
pmid = {41949989},
issn = {1552-5279},
support = {DR 445/9-1//Deutsche Forschungsgemeinschaft/ ; p21059//Alzheimer Forschung Initiative/ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/metabolism/physiopathology ; Male ; Female ; Aged ; Positron-Emission Tomography ; *Sleep Wake Disorders ; *Sleep/physiology ; Brain/metabolism/diagnostic imaging ; *Amyloid/metabolism ; Aged, 80 and over ; Middle Aged ; },
abstract = {INTRODUCTION: Sleep disturbances have been associated with Alzheimer's disease (AD), but their relevance in preclinical stages, such as subjective cognitive decline (SCD), and their relationship with brain pathology remain unclear.

METHODS: We used a portable sleep-monitoring headband over four consecutive nights to assess sleep in 19 cognitively unimpaired (CU), 15 SCD, and 20 mild cognitive impairment (MCI) participants with available amyloid positron emission tomography (PET). Linear-mixed-effects models compared sleep parameters across groups, accounting for amyloid burden, age, sex, education, and recording. Regional and voxel-wise analyses examined regional associations between sleep parameters and amyloid burden.

RESULTS: MCI patients presented reduced N3 (i.e., deep sleep), while SCD individuals showed longer N1 (i.e., light sleep) duration compared to CU. Regional amyloid burden was associated with longer light and deep sleep in amyloid-positive individuals. Higher education was linked to better sleep efficiency.

DISCUSSION: Sleep changes may serve as early indicators of cognitive dysfunction and regional amyloid accumulation.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/metabolism/physiopathology
Male
Female
Aged
Positron-Emission Tomography
*Sleep Wake Disorders
*Sleep/physiology
Brain/metabolism/diagnostic imaging
*Amyloid/metabolism
Aged, 80 and over
Middle Aged

@article {pmid41949995,
year = {2026},
author = {Borelli, PV and Machado, L and Carello-Collar, G and Ferreira, PCL and Lourenço de Lima, AMD and Bellaver, B and Pascoal, TA and Benedet, AL and Ashton, NJ and Zimmer, ER and Borelli, WV},
title = {Diagnostic performance of salivary markers of Alzheimer's disease: A systematic review.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71248},
doi = {10.1002/alz.71248},
pmid = {41949995},
issn = {1552-5279},
support = {AACSFD-22-928689/ALZ/Alzheimer's Association/United States ; AARGD-21-850670/ALZ/Alzheimer's Association/United States ; AARFD-22-974627/ALZ/Alzheimer's Association/United States ; 312410/2018-2//CNPq/ ; 435642/2018-9//CNPq/ ; 312306/2021-0//CNPq/ ; 409066/2022-2//CNPq/ ; 21/2551-0000673-0//ARD/FAPERGS/ ; 16/2551-0000475-7//ARD/FAPERGS/ ; 465671/2014-4//Brazilian National Institute of Science and Technology in Excitotoxicity and Neuroprotection/ ; Serra-1912-31365//Instituto Serrapilheira/ ; ALZ-NAN-22-928381//Alzheimer's Association and National Academy of Neuropsychology/ ; 88887.687008/2022-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 5R01AG075336/AG/NIA NIH HHS/United States ; 5R01AG073267/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; *Biomarkers/analysis/metabolism ; *Saliva/chemistry/metabolism ; *Amyloid beta-Peptides/analysis/metabolism ; Sensitivity and Specificity ; Lactoferrin/metabolism ; },
abstract = {High heterogeneity of diagnostic accuracy have been reported for salivary markers of Alzheimer's disease (AD), but the reasons remain unclear. This systematic review aims to evaluate the potential sources of heterogeneity in the diagnostic performance of salivary biomarkers for the identification of AD. We systematically reviewed four databases for studies from inception to 2025. We evaluated biomarker sensitivity, specificity, and area under the curve (AUC). This study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Of 3118 studies, 18 met the inclusion criteria. AUC data were available only for amyloid beta (Aβ)42 and lactoferrin. Pre-analytical properties were a major source of heterogeneity, comprehending prior orientation, time of collection, recipient material, and centrifugation methods. The main source of variability likely stems from substantial differences in pre-analytical procedures across studies. Further studies on salivary biomarkers in AD implementing standardized protocols are warranted.},
}

Humans
*Alzheimer Disease/diagnosis/metabolism
*Biomarkers/analysis/metabolism
*Saliva/chemistry/metabolism
*Amyloid beta-Peptides/analysis/metabolism
Sensitivity and Specificity
Lactoferrin/metabolism

@article {pmid41950003,
year = {2026},
author = {Scheidemantel, LP and de Paiva Lopes, K and Gaiteri, C and Menon, V and De Jager, PL and Schneider, JA and Buchman, AS and Wang, Y and Tasaki, S and Raittz, RT and Bennett, DA and Vialle, RA},
title = {Integration of aged brain multi-omics reveals cross-system mechanisms underlying Alzheimer's disease heterogeneity.},
journal = {Cell reports},
volume = {45},
number = {4},
pages = {117235},
doi = {10.1016/j.celrep.2026.117235},
pmid = {41950003},
issn = {2211-1247},
abstract = {The molecular correlates of Alzheimer's disease (AD) are increasingly being defined by multi-omics. However, findings from different data types are often difficult to reconcile. Here, we apply a data-driven multi-omics framework integrating seven omics layers from up to 1,358 aged human brain samples from the Religious Orders Study and Rush Memory and Aging Project. We demonstrate sprawling cross-omics biological factors relating to AD phenotypes. The strongest AD-associated factor (factor 8) is characterized by elevated immune activity at the epigenetic level, decreased heat shock gene expression in the transcriptome, and disrupted energy metabolism and cytoskeletal dynamics in the proteome. Unsupervised clustering reveals 11 molecular subtypes, including three AD-associated clusters displaying distinct molecular signatures and phenotypic characteristics. Our findings provide a comprehensive map of molecular mechanisms underlying AD heterogeneity, highlighting neuroinflammatory processes and yielding potential biomarkers and therapeutic targets for precision medicine approaches.},
}

@article {pmid41950014,
year = {2026},
author = {},
title = {Correction to "Effectiveness, safety, and biomarker dynamics of lecanemab in Chinese Alzheimer's disease population: A multicenter real-world study".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71347},
doi = {10.1002/alz.71347},
pmid = {41950014},
issn = {1552-5279},
}

@article {pmid41950049,
year = {2026},
author = {Robb, WH and Kaur, G and Huang, S and Martinez, F and Nguyen, B and Shin, CH and Yang, M and Conyers, CT and Grilli, CB and Upjohn, DP and Ortega, VE and Hohman, TJ and Keegan, RM and Parent, EE and Cogswell, PM and Graff-Radford, J and Johnson, DR and Ramanan, VK and Koran, ME},
title = {Health system patterns of imaging and fluid biomarker testing in the era of anti-amyloid therapies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71343},
doi = {10.1002/alz.71343},
pmid = {41950049},
issn = {1552-5279},
support = {//Alzheimer's Association Clinician Scientist Fellowship (MEK)/ ; K76AG088554/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; Female ; *Alzheimer Disease/drug therapy/diagnostic imaging/cerebrospinal fluid/diagnosis ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid/antagonists & inhibitors ; Retrospective Studies ; Aged ; Positron-Emission Tomography ; Apolipoproteins E/genetics ; Brain/diagnostic imaging ; Middle Aged ; tau Proteins/cerebrospinal fluid/blood ; Aged, 80 and over ; Electronic Health Records ; },
abstract = {INTRODUCTION: Anti-amyloid-β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real-world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care.

METHODS: Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019-Mar 2025) assessed trends in AD-relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid-beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated.

RESULTS: Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (-25/quarter), and plasma p-tau217 orders rapidly increased (+238/quarter). Females were more likely to be Aβ positive (p < 0.006). APOE-ε4 homozygotes were less likely to initiate lecanemab (HR = 0.11, p < 0.001).

DISCUSSION: The adoption of anti-Aβ therapies coincided with a rapid shift in diagnostic workflows.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
Female
*Alzheimer Disease/drug therapy/diagnostic imaging/cerebrospinal fluid/diagnosis
Male
*Amyloid beta-Peptides/cerebrospinal fluid/antagonists & inhibitors
Retrospective Studies
Aged
Positron-Emission Tomography
Apolipoproteins E/genetics
Brain/diagnostic imaging
Middle Aged
tau Proteins/cerebrospinal fluid/blood
Aged, 80 and over
Electronic Health Records

@article {pmid41950067,
year = {2026},
author = {Kanwal, A and Kerman, BE and Wang, S and Camey, K and Li, B and Flores-Aguilar, L and Ali, N and McIntire, LB and Shu, CA and Louie, SG and Head, E and Arvanitakis, Z and Yassine, HN},
title = {A perspective: PLA2G4A as drug target for vascular inflammation in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71320},
doi = {10.1002/alz.71320},
pmid = {41950067},
issn = {1552-5279},
support = {RF1AG076124/AG/NIA NIH HHS/United States ; R01AG055770/AG/NIA NIH HHS/United States ; R01AG067063/AG/NIA NIH HHS/United States ; R01AG054434/AG/NIA NIH HHS/United States ; R21AG056518/AG/NIA NIH HHS/United States ; P30AG066530/AG/NIA NIH HHS/United States ; R01AG082362/AG/NIA NIH HHS/United States ; P30AG10161/AG/NIA NIH HHS/United States ; P30AG72975/AG/NIA NIH HHS/United States ; R01AG15819/AG/NIA NIH HHS/United States ; R01AG078800/AG/NIA NIH HHS/United States ; R01AG072794/AG/NIA NIH HHS/United States ; GC-201711-2014197//Alzheimer's Drug Discovery Foundation (ADDF;/ ; //Vranos and Tiny Foundations/ ; P50AG05142/NH/NIH HHS/United States ; R01AG074549/NH/NIH HHS/United States ; RF1 AG059621/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Group IV Phospholipases A2/metabolism/antagonists & inhibitors ; *Cerebral Amyloid Angiopathy/drug therapy/metabolism ; *Inflammation/drug therapy/metabolism ; Animals ; },
abstract = {Anti-amyloid therapies for Alzheimer's disease (AD) modestly slow cognitive decline but carry significant risk of amyloid-related imaging abnormalities (ARIAs), brain swelling, and hemorrhage, particularly in apolipoprotein E ε4 carriers. Cerebral amyloid angiopathy (CAA) and vascular inflammation drive this vulnerability, highlighting the need for complementary strategies targeting upstream mechanisms of vascular injury. Cytosolic phospholipase A2 (cPLA2) regulates arachidonic acid and lysophosphatidylcholine-derived lipid signaling at the intersection of amyloid burden, oxylipin dysregulation, blood-brain barrier disruption, and neurovascular inflammation. By depleting protective membrane plasmalogens while amplifying inflammatory lipid mediators, cPLA2 creates a state of vascular vulnerability predisposing to ARIAs. This Perspective article synthesizes evidence from human, preclinical, and translational studies positioning cPLA2 as an upstream driver of CAA-related inflammation and vascular vulnerability in AD. We discuss biomarker and imaging approaches to assess cPLA2 activity in vivo and outline how targeting this pathway may enhance anti-amyloid therapy safety by mitigating ARIA risk.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Group IV Phospholipases A2/metabolism/antagonists & inhibitors
*Cerebral Amyloid Angiopathy/drug therapy/metabolism
*Inflammation/drug therapy/metabolism
Animals

@article {pmid41950270,
year = {2026},
author = {Gonzales, M and Kang, X and Cort, C and Adamson, MM and Chao, SZ and Yoon, BC and , },
title = {White matter microstructure disruption associated with PET and cognitive impairment in Alzheimer's disease.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346661},
doi = {10.1371/journal.pone.0346661},
pmid = {41950270},
issn = {1932-6203},
mesh = {Humans ; *White Matter/pathology/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging/pathology ; Male ; Female ; *Positron-Emission Tomography ; Aged ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Diffusion Tensor Imaging ; Aged, 80 and over ; Retrospective Studies ; Aniline Compounds ; Ethylene Glycols ; Middle Aged ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is associated with regional brain atrophy as well as elevated positron emission tomography (PET) markers of amyloid-beta (e.g., [[18]F]florbetapir (FBP)) and tau protein (e.g., [[18]F]flortaucipir (FTP). White matter microstructures have also been shown to be disrupted in AD, but there is limited understanding of their specific associations with FBP, FTP, and cognitive impairment. Herein, we used both voxel-based and fixel-based analyses of diffusion tensor imaging (DTI) to characterize microstructural white matter changes associated with PET and cognitive changes in AD. A retrospective study was performed using the data from 381 ADNI-3 participants (F:M = 200:181). FBP and FTP results were correlated with DTI metrics, including the apparent fiber density (AFD), complexity (CX), functional anisotropy (FA), fixel number (FN), and mean diffusivity (MD). Linear regression analysis was performed, adjusted for age, sex, education, and cognitive impairment. Greatest negative correlations were observed between FN and FBP standardized uptake value ratio (SUVR) in 15 out of 18 white matter tracts examined (beta coefficients of -0.3991 to -0.2877). No significant correlation was observed between DTI measures and FTP SUVR, independently. However, combined PET positivity (FBP + /FTP+) generally showed the greatest reductions in CX, FN, and FA of various tracts, compared to single PET-positive or PET-negative groups. Widespread changes in FA were positively associated with cognitive impairment, with stronger associations seen with the Montreal Cognitive Assessment (MoCA) than the Mini-Mental State Examination (MMSE). Only females showed significant correlations between MD and FBP/FTP levels and showed more widespread correlations between FA and MD changes and cognitive impairment. Taken together, these findings suggest specific patterns of white matter microstructure disruption in AD with underlying sex differences and support their potential role as early biomarkers.},
}

Humans
*White Matter/pathology/diagnostic imaging
*Alzheimer Disease/diagnostic imaging/pathology
Male
Female
*Positron-Emission Tomography
Aged
*Cognitive Dysfunction/diagnostic imaging/pathology
Diffusion Tensor Imaging
Aged, 80 and over
Retrospective Studies
Aniline Compounds
Ethylene Glycols
Middle Aged
Amyloid beta-Peptides/metabolism

@article {pmid41950299,
year = {2026},
author = {VanderGiessen, M and Harris, E and Yin, L and Heath, B and Carney, SK and Woodson, CM and Wu, X and Johnson, E and Xie, H and Theus, M and Kehn-Hall, K},
title = {Venezuelan equine encephalitis virus infection causes chronic neurobehavioral outcomes, cellular remodeling, and hippocampal single-cell transcriptomic changes.},
journal = {PLoS pathogens},
volume = {22},
number = {4},
pages = {e1014115},
doi = {10.1371/journal.ppat.1014115},
pmid = {41950299},
issn = {1553-7374},
abstract = {Venezuelan equine encephalitis virus (VEEV), a neuroinvasive alphavirus, can cause significant neurological deficits in humans. Viral infections, including VEEV, have been linked to neurological diseases such as Parkinson's and Alzheimer's, though mechanisms remain unclear. Currently, not only are there no therapeutic options for VEEV available, but there is also limited information on the host responses following infection that contribute to neurological sequelae. To fill this gap in knowledge, longitudinal neuropathological, behavioral, and single-cell transcriptomic changes were examined in C57BL/6 mice intranasally infected with VEEV TC-83. Acute infection significantly altered inflammatory and innate immune single-cell signaling, induced astrocyte and microglia activation, and resulted in the loss of neurons in the hippocampus. Persistent motor dysfunction, memory impairment, and reduced anxiety-like behavior were observed up to 106 days post-infection (DPI) and more significantly in animals that displayed neurological symptoms during acute infection. These changes correlated with alterations in synaptogenic signaling single-cell gene expression, neuron loss, and persistent glia cell activation at 106 DPI. Collectively, this study demonstrates that infection with VEEV induces chronic alterations in the hippocampus that correlate with neurological sequalae observed in human patients.},
}

@article {pmid41950304,
year = {2026},
author = {Dannert, A and Schulz, N and Klimmt, J and Knez, L and Groschup, B and Gonçalves, CC and Carraro, C and Schifferer, M and Brendel, M and Paquet, D},
title = {A human iPSC model of tauopathies engineered for 4R tau isoform expression endogenously develops late-stage neuronal tau pathology.},
journal = {Science translational medicine},
volume = {18},
number = {844},
pages = {eadu9845},
doi = {10.1126/scitranslmed.adu9845},
pmid = {41950304},
issn = {1946-6242},
mesh = {Humans ; *tau Proteins/metabolism/genetics ; *Tauopathies/pathology/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism/pathology ; *Neurons/metabolism/pathology ; Protein Isoforms/metabolism ; Phosphorylation ; *Models, Biological ; Mutation/genetics ; },
abstract = {Tauopathies, such as Alzheimer's disease and frontotemporal dementia, are common neurodegenerative diseases characterized by misfolding, hyperphosphorylation, and aggregation of tau. Molecular mechanisms underlying tauopathies are still poorly understood, which is in part due to a lack of human models autonomously developing major disease hallmarks. The formation of late-stage disease phenotypes may require adult tau isoform expression, which contributes to tau pathogenesis but is challenging to replicate in human stem cell-derived systems, thus impeding research on underlying mechanisms and drug development. Here, we show that induction of adult human brain-like 4R tau isoform expression enables cell-intrinsic formation of late-stage tauopathy hallmarks in induced pluripotent stem cell-derived neurons engineered to contain synergistic tau mutations without exogenous sources of tau pathology. Neurons accumulated seeding-competent and hyperphosphorylated tau in tangle-like structures. Furthermore, exclusive expression of mutant 4R in the absence of the 3R tau isoform disproportionately intensified pathology, resulting in abundant tau misfolding and aggregation. Last, we provide proof of principle that our model can be translationally applied both to test chemical disease modulators and evaluate human tau PET tracers. Collectively, our model corroborates the central role of 4R tau isoform expression for pathogenesis in human neurons and enables investigations to elucidate mechanisms underlying human tauopathy formation. Moreover, it may serve as a platform supporting urgently needed development of disease-modifying drugs.},
}

Humans
*tau Proteins/metabolism/genetics
*Tauopathies/pathology/metabolism/genetics
*Induced Pluripotent Stem Cells/metabolism/pathology
*Neurons/metabolism/pathology
Protein Isoforms/metabolism
Phosphorylation
*Models, Biological
Mutation/genetics

@article {pmid41950393,
year = {2026},
author = {Sun, H and Perry, B},
title = {Factors related to cognitive reserve: A comparative analysis of education, occupation, lifestyle, and social network factors based on brain measures.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag059},
pmid = {41950393},
issn = {1758-5368},
abstract = {OBJECTIVES: Cognitive reserve (CR) refers to the ability to sustain cognitive performance despite age- and disease-related brain changes, which supports prolonged independent living. Prior research suggests that education, occupational complexity, participation in cognitively engaging and social activities, lifestyle factors, and social connectedness may enhance CR. However, few studies directly compare the relative significance of these factors within the same sample, using magnetic resonance imaging (MRI) based brain markers to measure CR. We also examine whether, and to what extent, relatively proximal factors serve as downstream effects of education within a cumulative (dis)advantage framework.

METHODS: We analyzed data from 279 MRI visits from 201 older adults enrolled in the Social Networks and Alzheimer's Disease (SNAD) study, diagnosed as cognitively normal or with mild cognitive impairment. CR was assessed as residual global cognition based on MRI-derived brain measures and demographic covariates. Multivariate models estimated standardized effect sizes for each factor, followed by mediation analyses to assess whether they are downstream of education.

RESULTS: As expected, higher educational attainment was significantly associated with greater CR. Among occupational measures, only complexity with people showed a significant relationship, but this association diminished in fully adjusted models. Cognitive-oriented activities and social network bridging capital were independently associated with CR, while only bridging capital remained significant in fully adjusted models and mediated approximately 11% of the association between education and CR.

DISCUSSION: While early-life education appears fundamental to CR, broader and more diverse social networks are beneficial, partly reflecting downstream effects of education, and may represent a modifiable pathway to promote CR.},
}

@article {pmid41950435,
year = {2026},
author = {Park, SY and Setiawan, VW and Crimmins, EM and White, LR and Haiman, CA and Wilkens, LR and Le Marchand, L and Lim, U},
title = {Plant-Based Dietary Patterns and Risk of Alzheimer Disease and Related Dementias in the Multiethnic Cohort Study.},
journal = {Neurology},
volume = {106},
number = {9},
pages = {e214916},
doi = {10.1212/WNL.0000000000214916},
pmid = {41950435},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/epidemiology/ethnology ; Middle Aged ; *Dementia/epidemiology/ethnology ; Prospective Studies ; Longitudinal Studies ; Cohort Studies ; *Diet, Vegetarian ; Hawaii/epidemiology ; Ethnicity ; Risk Factors ; California/epidemiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Plant-based diets have been linked to slower cognitive decline, but data on long-term dietary changes and from diverse populations are limited. The primary aim of this study was to examine plant-based dietary patterns and their change over time in relation to Alzheimer disease and related dementias (ADRDs).

METHODS: This prospective longitudinal analysis of the Multiethnic Cohort Study, based in Hawaii and California (primarily Los Angeles County), included data on African American, Japanese American, Latino, Native Hawaiian, and White participants who completed food frequency questionnaires at baseline (1993-1996; age 45-75 years) and at 10-year follow-up (2003-2008) and whose Medicare claims were linked to identify incident ADRDs. A priori indices for the overall plant-based diet index (PDI), the healthful plant-based diet index (hPDI), and the unhealthful plant-based diet index (uPDI) were analyzed in Cox regression models for ADRD.

RESULTS: The analysis included 92,849 participants (mean age 59.2 years, 55.1% female, 21,478 with ADRDs) for the baseline diet and 45,065 participants (8,360 with ADRDs) for the 10-year dietary change. For the baseline diet, comparing the highest vs lowest quintile, PDI and hPDI were associated with 12% (hazard ratio [HR] 0.88; 95% CI 0.85-0.92) and 7% (HR 0.93; 95% CI 0.89-0.97) lower risks of ADRD, respectively, whereas uPDI was related to a 6% higher risk (HR 1.06; 95% CI 1.01-1.10). For the dietary change over time, the strongest association with ADRD was observed for uPDI rather than for PDI or hPDI. Compared with those with a stable score (<0.5 SD change), participants with a large increase in uPDI (≥1 SD) showed a 25% higher risk (HR 1.25; 95% CI 1.15-1.36) and those with a large decrease in uPDI showed an 11% lower risk (HR 0.89; 95% CI 0.84-0.94). The associations between the plant-based diet indices and ADRD were generally similar by age group (<60 vs ≥60 years at baseline), race and ethnicity, or APOE ℇ4 carrier status.

DISCUSSION: These findings suggest that adopting plant-based diets, specifically refraining from low-quality plant-based diets, even at an older age, is associated with a lower risk of ADRDs.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/epidemiology/ethnology
Middle Aged
*Dementia/epidemiology/ethnology
Prospective Studies
Longitudinal Studies
Cohort Studies
*Diet, Vegetarian
Hawaii/epidemiology
Ethnicity
Risk Factors
California/epidemiology

@article {pmid41950468,
year = {2026},
author = {Llibre-Guerra, JJ and Lu, R and Clarens, MF and Liu, I and Renton, A and Ryan, NS and Goate, AM and Aguillón, D and Allegri, RF and Benzinger, TLS and Berman, S and Chhatwal, JP and Chrem Mendez, P and Vigo, G and Cruchaga, C and Day, GS and Farlow, MR and Fox, NC and Gordon, BA and Hassenstab, J and Huey, ED and Ibanez, L and Ikeuchi, T and Jucker, M and Lee, JH and Levey, AI and Levin, J and Niimi, Y and Perrin, RJ and Rosa-Neto, P and Sánchez-Valle, R and Schofield, PR and Wang, G and Li, Y and Xiong, C and Morris, JC and Karch, C and Daniels, AJ and McDade, E and Bateman, RJ},
title = {Effect of Cognitive Reserve on Age at Symptom Onset and Cognitive Decline in Individuals With Dominantly Inherited Alzheimer Disease.},
journal = {Neurology},
volume = {106},
number = {8},
pages = {e214804},
doi = {10.1212/WNL.0000000000214804},
pmid = {41950468},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/genetics/psychology ; Male ; *Cognitive Reserve/physiology ; Female ; *Cognitive Dysfunction/genetics/psychology ; Age of Onset ; Middle Aged ; Aged ; Disease Progression ; Longitudinal Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: Cognitive reserve has been shown to modulate the onset and progression of Alzheimer disease (AD) symptoms. Although its role in sporadic AD is well-studied, how cognitive reserve influences the timing and progression of symptoms in dominantly inherited AD (DIAD) remains unclear. This study aimed to quantify cognitive reserve in DIAD carriers and test whether higher cognitive reserve is associated with later symptom onset and slower functional decline.

METHODS: We analyzed data from the Dominantly Inherited Alzheimer's Network study. Cognitive reserve was modeled using a residual-based latent variable approach, decomposing cognitive performance into demographic (CogD), biomarker (CogB), and reserve or residual (CogR) components. Primary outcomes were age at clinical symptom onset (CDR >0) and longitudinal change in the Clinical Dementia Rating-Sum of Boxes (CDR-SBs). Data were analyzed using Cox proportional hazards models and linear mixed-effects models, adjusting for estimated years from onset (EYO).

RESULT: A total of 710 Dominantly Inherited Alzheimer Network (DIAN) participants were included in the analysis, comprising 271 non-DIAD carriers (nMC), 284 asymptomatic DIAD carriers (aMC), and 155 symptomatic DIAD carriers. In asymptomatic carriers, using a zero-inflation model adjusted for EYO showed that a 1 SD increase in the reserve component (CogR) was associated with a 4.06-fold increase in the odds of being clinically unimpaired (CDR-SB = 0; 95% CI 1.84-8.95). Similarly, a 1 SD increase in the demographic (CogD) and biomarker (CogB) components increased the odds of being CDR-SB = 0 by 2.60 (95% CI 1.10-6.16) and 5.16 (95% CI 2.00-13.33), respectively. Among symptomatic carriers, only the reserve and the biomarker components were significant. A 1 SD increase in CogR was associated with a 0.81-fold reduction in baseline CDR-SB score (95% CI 0.72-0.92), and a 1 SD increase in CogB was associated with a 0.60-fold reduction in CDR-SB (95% CI 0.50-0.71).

DISCUSSION: Our findings indicate that higher cognitive reserve values are associated with delayed conversion to mild cognitive impairment and slower progression on clinical dementia rating scales. These findings suggest that cognitive reserve plays a protective role in modifying the clinical trajectory of genetically determined AD.},
}

Humans
*Alzheimer Disease/genetics/psychology
Male
*Cognitive Reserve/physiology
Female
*Cognitive Dysfunction/genetics/psychology
Age of Onset
Middle Aged
Aged
Disease Progression
Longitudinal Studies

@article {pmid41950469,
year = {2026},
author = {Jung, J},
title = {Cognitive Reserve in Genetic Alzheimer Disease: Why the Brain's "Buffer" Matters More Than We Thought.},
journal = {Neurology},
volume = {106},
number = {8},
pages = {e214887},
doi = {10.1212/WNL.0000000000214887},
pmid = {41950469},
issn = {1526-632X},
}

@article {pmid41950544,
year = {2026},
author = {Yau, WW and Raman, R and Chhatwal, J and Pruzin, JJ and Shirzadi, Z and Aggarwal, N and Brickman, AM and Cogswell, PM and Graff-Radford, J and Pillai, JJ and Vemuri, P and Rafii, MS and Yaari, R and Aisen, P and Sperling, R and , },
title = {Late-life body mass index and amyloid interaction on cognitive decline in unimpaired older adults.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100543},
doi = {10.1016/j.tjpad.2026.100543},
pmid = {41950544},
issn = {2426-0266},
abstract = {BACKGROUND: The late-life "obesity paradox" of reduced Alzheimer's disease (AD) risk is postulated to be driven by underlying preclinical/prodromal pathology. However, few studies have directly examined the joint associations of BMI and amyloid pathology with cognitive decline, especially in individuals with preclinical AD targeted in prevention trials.

OBJECTIVE: To determine whether late-life BMI and amyloid pathology have independent or interactive associations with cognition in clinically unimpaired older adults.

DESIGN: Secondary analyses of A4 randomized clinical trial and the companion observational LEARN Study (median follow-up 4.7 years).

SETTING: Multicenter across 67 sites in US, Canada, Australia, and Japan.

PARTICIPANTS: We included 1663 participants (Placebo n = 582, Solanezumab n = 563, LEARN n = 518) who were baseline cognitively unimpaired and medically stable, mean age 71.5 ± 4.7 years, 60% women.

MEASUREMENTS: BMI and global amyloid burden [Florbetapir PET] were measured at baseline. Cognition was measured longitudinally using Preclinical Alzheimer Cognitive Composite.

RESULTS: Higher BMI and amyloid burden were independently associated with worse baseline cognition. Longitudinally, a BMI*Amyloid*Time interaction emerged: lower/normal BMI was associated with more favorable cognitive trajectory at low amyloid levels, but with faster cognitive decline when amyloid was substantially elevated.

CONCLUSIONS: Our cross-sectional findings support a negative association between obesity and cognitive aging up to late-life. Longitudinally, we observed an "obesity paradox", where higher/obese BMI was associated with more favorable cognitive trajectories in the presence of advanced amyloid pathology. Together, our findings suggest that future trials targeting obesity to slow late-life cognitive decline may benefit from preferentially enrolling younger individuals or those without substantial amyloid accumulation.},
}

@article {pmid41950681,
year = {2026},
author = {Bai, X and Wei, Y and Zhao, D and Zhang, Y and Lian, X and Zhang, C and Li, M},
title = {A covalent organic framework nano-chelator orchestrates multitarget clearance of Alzheimer's pathologies.},
journal = {Journal of colloid and interface science},
volume = {717},
number = {},
pages = {140451},
doi = {10.1016/j.jcis.2026.140451},
pmid = {41950681},
issn = {1095-7103},
abstract = {Metal ion dysregulation is a critical pathological driver and a promising therapeutic target in Alzheimer's disease (AD). This study presents a novel multifunctional nanoplatform based on a covalent organic framework functionalized with 8-hydroxyquinoline (COF-HQ), engineered to simultaneously address the multifaceted pathology of AD. The material not only effectively chelates Cu[2+] to inhibit and reverse Cu[2+]-induced amyloid-β (Aβ) aggregation but also, upon coordination, forms a complex with potent superoxide dismutase (SOD)-mimetic activity. This catalytic function enables the continuous scavenging of reactive oxygen species (ROS), thereby alleviating oxidative stress in the neuronal microenvironment. Furthermore, COF-HQ drives microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 state and restores lysosomal acidification and function impaired by Aβ-Cu[2+], thereby enhancing microglial phagocytosis and clearance of Aβ to break the vicious cycle of impaired degradation. The multivalent porous architecture of the COF scaffold provides enhanced binding capacity and stability, resulting in superior anti-aggregation, antioxidant, and cytoprotective efficacy compared to its molecular building block. In vivo studies demonstrate that systemic administration of COF-HQ significantly improves cognitive performance in behavioral tests, reduces cerebral Aβ plaque burden, and attenuates synaptic and neuronal loss in an AD mouse model. This work establishes a new COF-based therapeutic paradigm that concurrently targets metal dyshomeostasis, protein misfolding, oxidative stress, and defective cellular clearance, offering a comprehensive and integrated nanotherapeutic strategy for AD.},
}

@article {pmid41951483,
year = {2026},
author = {Tang, L and Mo, Y and Bao, D and Chen, C},
title = {Application of digital tools in Alzheimer's disease.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.03.132},
pmid = {41951483},
issn = {0929-6646},
}

@article {pmid41943055,
year = {2026},
author = {Di Caro, V and Cho, E and Thiel, J and Lizama, BN and Koel-Simmelink, MJA and Pandey, K and Duong, D and Seyfried, NT and Grundman, M and Teunissen, CE and Zetterberg, H and Blennow, K and Caggiano, AO and Hamby, ME},
title = {Impact of zervimesine on the neuroinflammatory biomarker GFAP and related proteomic molecular correlates in plasma of participants from a phase 2 clinical trial in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02025-4},
pmid = {41943055},
issn = {1758-9193},
support = {1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; },
}

@article {pmid41943113,
year = {2026},
author = {Spruyt, L and Mlinarič, T and Dusart, N and Reinartz, M and Van Hulle, MM and Sunaert, S and Van Laere, K and Dupont, P and Vandenberghe, R},
title = {The electrophysiological basis of resting-state fMRI hyperconnectivity in early Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02003-w},
pmid = {41943113},
issn = {1758-9193},
support = {G094418N//Fonds Wetenschappelijk Onderzoek/ ; C14/21/109//KU Leuven Bijzonder Onderzoeksfonds/ ; HBC.2019.2523//Vlaams Agentschap voor Innovatie en Onderzoek/ ; 2022/0009//Stichting Alzheimer Onderzoek/ ; },
}

@article {pmid41943176,
year = {2026},
author = {Park, CH and Shin, D and Chung, KC},
title = {DAPK1-Mediated Parkin Inactivation Enhances Neurotoxicity via MITOL-Dependent Degradation.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {7},
pages = {e71132},
doi = {10.1111/jcmm.71132},
pmid = {41943176},
issn = {1582-4934},
support = {RS-2024-00450988//National Research Foundation of Korea/ ; },
mesh = {*Ubiquitin-Protein Ligases/metabolism/genetics ; *Death-Associated Protein Kinases/metabolism/genetics ; Humans ; *Mitochondria/metabolism ; Phosphorylation ; Proteolysis ; Animals ; Parkinson Disease/metabolism/pathology/genetics ; alpha-Synuclein/metabolism ; *Mitochondrial Proteins/metabolism ; Neurons/metabolism ; Oxidopamine/toxicity ; },
abstract = {Parkinson's disease (PD) is characterised by progressive neurodegeneration and is marked by the formation of Lewy bodies, which are intracellular aggregates primarily composed of α-synuclein. Mitochondrial dysfunction and impaired protein degradation pathways are thought to play critical roles in PD progression, contributing to the loss of dopaminergic neurons in the substantia nigra. Phosphorylation of α-synuclein has been shown to promote its aggregation, underscoring its potential role in disease progression. Parkin, an E3 ubiquitin ligase, is widely regarded as a pleiotropic neuroprotective protein that modulates the mitochondrial quality control, as well as metabolic turnover and the accumulation of α-synuclein. Death-associated protein kinase 1 (DAPK1), which is involved in the regulation of apoptosis and autophagy, has recently emerged as an important factor in neurodegeneration. While DAPK1 has been implicated in Alzheimer's disease through its role in tau aggregation and amyloid-β production, our findings suggest that DAPK1 may also influence PD-related pathways by phosphorylating parkin at Ser136 and Ser198. This phosphorylation promotes the mitochondrial transport of parkin, enhancing interaction with mitochondria-localised E3 ubiquitin ligase MITOL and consequently leading to the degradation of parkin. Given the neuroprotective role of parkin, its reduction increases the vulnerability of neurons to 6-hydroxydopamine-induced toxicity, potentially contributing to decreased neuronal survival. Together, these findings suggest that DAPK1 functions as a previously unrecognised modulator of parkin and could potentially influence PD-related neurodegenerative processes. This pathway may provide a mechanistic link between mitochondrial dysfunction, α-synuclein pathology and neuronal cell death.},
}

*Ubiquitin-Protein Ligases/metabolism/genetics
*Death-Associated Protein Kinases/metabolism/genetics
Humans
*Mitochondria/metabolism
Phosphorylation
Proteolysis
Animals
Parkinson Disease/metabolism/pathology/genetics
alpha-Synuclein/metabolism
*Mitochondrial Proteins/metabolism
Neurons/metabolism
Oxidopamine/toxicity

@article {pmid41943474,
year = {2026},
author = {Stahr, N and Moriarty, AK and Ma, SD and Keeter, WC and Kim, WK and Sanford, LD and Galkina, EV},
title = {STAT4-dependent regulation of neuroinflammation in atherosclerosis.},
journal = {Physiological reports},
volume = {14},
number = {7},
pages = {e70856},
doi = {10.14814/phy2.70856},
pmid = {41943474},
issn = {2051-817X},
support = {R01HL142129//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL139000//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HL142129-04S1//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 20PRE35180156//American Heart Association (AHA)/ ; },
mesh = {Animals ; *STAT4 Transcription Factor/metabolism/genetics ; *Atherosclerosis/metabolism/pathology ; Mice ; *Neuroinflammatory Diseases/metabolism/pathology ; Mice, Knockout ; Microglia/metabolism ; Male ; Mice, Inbred C57BL ; Receptors, LDL/genetics ; Brain/metabolism/pathology ; Diet, High-Fat/adverse effects ; Macrophages/metabolism ; },
abstract = {Atherosclerosis is linked to an increased risk of cognitive decline, with chronic inflammation being a common feature of both pathologies. IL-12 activates STAT4 to regulate myeloid cell functions, and blockade of this pathway alleviates cognitive impairment in Alzheimer's models. However, the mechanisms connecting vascular pathology to neuroinflammation remain unclear. Here, we examine whether STAT4 functions as a common mediator of neuroinflammation in atherosclerosis. We demonstrate that LysM[Cre]-specific STAT4 deficiency ameliorates deficits in long-term memory in low-density lipoprotein-deficient (Ldlr[-/-]) mice fed a high-fat diet (HFD-C). STAT4 deficiency moderately reduces Ser199-phosphorylated Tau burden. Atherosclerosis alters brain immune composition, characterized by increased numbers of CD45[+] leukocytes, activated microglia, and activated T and B cells, whereas STAT4 deficiency attenuates these effects. Nanostring gene-expression pathway analysis further highlights the importance of STAT4 in regulating multiple neuroinflammatory pathways and the Rhodopsin-like receptor signaling, which is associated with synaptic plasticity. LysM[Cre]-specific STAT4 deficiency supports microglial efferocytosis in atherosclerotic Ldlr[-/-] mice and increases the number of efferocytotic macrophages. Accordingly, STAT4 deficiency also reduces neuronal death. Overall, our data reveal an important role for myeloid-driven STAT4 expression in the pathogenesis of cognitive decline associated with atherosclerosis, mediated through impaired efferocytosis and enhanced leukocyte activation, leading to increased brain neuroinflammation.},
}

Animals
*STAT4 Transcription Factor/metabolism/genetics
*Atherosclerosis/metabolism/pathology
Mice
*Neuroinflammatory Diseases/metabolism/pathology
Mice, Knockout
Microglia/metabolism
Male
Mice, Inbred C57BL
Receptors, LDL/genetics
Brain/metabolism/pathology
Diet, High-Fat/adverse effects
Macrophages/metabolism

@article {pmid41943483,
year = {2026},
author = {Karabova, MK and Del Ser-Badia, A and Hedegaard, A and Washer, SJ and Baykam, Z and O'Brien, DP and Vendrell, I and Hester, SS and Fischer, R and Johnson, E and Melia, CE and Matthews-Palmer, TRS and Matadeen, R and Santambrogio, A and Metrick, MA and Vendruscolo, M and Keeling, S and Cheam, KAX and McEwan, WA and Kosik, KS and Day, TA and James, WS and Cowley, SA},
title = {Tracking tau and cellular responses in human iPSC-microglia: from uptake to seedable secretion, including in extracellular vesicles.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71337},
doi = {10.1002/alz.71337},
pmid = {41943483},
issn = {1552-5279},
support = {//The James Martin 21st Century Research Foundation/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism ; *tau Proteins/metabolism ; *Microglia/metabolism ; *Extracellular Vesicles/metabolism ; Alzheimer Disease/metabolism/pathology ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; Brain/metabolism ; },
abstract = {INTRODUCTION: Microglia have been implicated in the templated spread of tau aggregates in tauopathies through mouse studies. However, it is unclear whether these findings translate to human disease.

METHODS: We challenged human induced pluripotent stem cell (iPSC)-derived microglia-like-cells (iMGL) with monomeric and fibrillar recombinant tau and tau purified from Alzheimer's patient brains, examining in detail the uptake, processing, release, and seeding of tau by microglia.

RESULTS: iMGL take up tau via lipoprotein receptor-related protein 1 (LRP)1 and heparan sulfate proteoglycans, with leucine-rich repeat kinase 2 affecting LRP1 trafficking. Monomeric tau is digested effectively with minimal effects on iMGL, but recombinant or brain-derived tau fibrils induce chemokine/interferon response subtypes, alongside downregulation of homeostatic genes. Fibrillar tau is degradation-resistant, can escape into the cytoplasm, and becomes phosphorylated on two specific residues. iMGL release partially digested fibrillar tau, including in extracellular vesicles, visualized by cryo-electron microscopy, that seed aggregation in neurons.

DISCUSSION: Our study reveals new insights into human microglial responses to tau, highlighting opportunities to limit pathogenic tau spread.},
}

Humans
*Induced Pluripotent Stem Cells/metabolism
*tau Proteins/metabolism
*Microglia/metabolism
*Extracellular Vesicles/metabolism
Alzheimer Disease/metabolism/pathology
Low Density Lipoprotein Receptor-Related Protein-1/metabolism
Brain/metabolism

@article {pmid41943492,
year = {2026},
author = {Jung, DH and Park, E and Ju, HC and Moon, C and Jahanshahi, A},
title = {Glial pathology networks reveal early olfactory vulnerability in post mortem human Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71322},
doi = {10.1002/alz.71322},
pmid = {41943492},
issn = {1552-5279},
support = {RS-2020-NR049577//Ministry of Education/ ; RS-2023-00278057//Ministry of Science and ICT/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; Male ; *Olfactory Bulb/pathology/metabolism ; Female ; *Neuroglia/pathology/metabolism ; Aged ; *Olfactory Cortex/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; tau Proteins/metabolism ; Cognitive Dysfunction/pathology/metabolism ; Autopsy ; Apolipoproteins E/metabolism ; Microglia/pathology/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Astrocytes/pathology/metabolism ; },
abstract = {INTRODUCTION: The olfactory system is an early target in Alzheimer's disease (AD), yet regional glial pathology interactions remain poorly defined. We examined how glial activation and pathological burden differ between the olfactory cortex (OC) and olfactory bulb (OB) across disease stages.

METHODS: Post mortem OC and OB samples from cognitively normal (CN), mild cognitive impairment, and AD cases were analyzed using immunohistochemistry and immunofluorescence for amyloid beta (Aβ), phosphorylated tau (pTau), Iba1 (microglia), GFAP (astrocyte), and apolipoprotein E (apoE).

RESULTS: Both regions showed stage-dependent increases in Aβ and pTau, with regionally distinct glial responses. ApoE signal varied with clinical stage rather than genotype. Co-expression analyses revealed astrocyte-linked networks in the OC and microglia-linked relationships in the OB.

DISCUSSION: Findings demonstrate spatially heterogenous glial pathology architectures in the human olfactory system, supporting its role as an early and regionally diverse site of AD vulnerability.},
}

Humans
*Alzheimer Disease/pathology/metabolism
Male
*Olfactory Bulb/pathology/metabolism
Female
*Neuroglia/pathology/metabolism
Aged
*Olfactory Cortex/pathology/metabolism
Amyloid beta-Peptides/metabolism
Aged, 80 and over
tau Proteins/metabolism
Cognitive Dysfunction/pathology/metabolism
Autopsy
Apolipoproteins E/metabolism
Microglia/pathology/metabolism
Glial Fibrillary Acidic Protein/metabolism
Astrocytes/pathology/metabolism

@article {pmid41943532,
year = {2026},
author = {Acewicz, A and Tarka, S and Grzegorczyk, M and Rzepliński, R and Wierzba-Bobrowicz, T and Stępień, T},
title = {Associations between TMEM106B C-terminal fragment aggregation, age, and TDP-43 or tau pathology.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70090},
doi = {10.1111/bpa.70090},
pmid = {41943532},
issn = {1750-3639},
support = {//Institute of Psychiatry and Neurology, Warsaw, Poland/ ; },
abstract = {Transmembrane protein 106B (TMEM106B) is a lysosomal glycoprotein whose genetic polymorphisms contribute to the severity of neurodegenerative disorders associated with TDP-43 pathology. Recent studies have revealed that TMEM106B can form amyloid filaments composed of C-terminal fragments (CTFs) in the human brain. In the present study, we explored the relationships between TMEM106B, age, TDP-43, and tau aggregates, and their roles in neurodegeneration. We used immunohistochemistry with an antibody against CTFs of TMEM106B on postmortem human brain fragments (amygdala, hippocampus, temporal cortex, frontal cortex, and basal ganglia) from patients with and without TDP-43/tau pathology at different ages (6-94 years) and with different neurological conditions (subacute sclerosing panencephalitis, Alzheimer's disease, frontotemporal lobar degeneration, and neurologically healthy subjects). Our results revealed that TMEM106B CTF fibrillization is a common, nonspecific, diffuse, and age-dependent phenomenon (appearing after >52 years of age) that affects neurons and neuroglia (most numerous in astrocytes and oligodendrocytes) and broad neuroanatomical regions (most severe in the temporal cortex). We did not find TMEM106B CTF aggregates in young subjects with TDP-43/tau pathology (with subacute sclerosing panencephalitis), but we revealed differences in TMEM106B CTF fibrillization between Alzheimer's disease without TDP-43 pathology, frontotemporal lobar degeneration with TDP-43 pathology, and older healthy subjects without TDP-43/tau pathology. Our results suggest that TMEM106B CTF aggregation is an age-dependent phenomenon and may have a weak association with TDP-43 or tau pathology, shedding new light on the complex relationships among TMEM106B, TDP-43, and tau and the unclear role of TMEM106B fibril formation in the neurodegeneration process.},
}

@article {pmid41943538,
year = {2026},
author = {Marriott, AE and Schroeder, JP and Korukonda, A and Pate, BS and McCann, KE and Weinshenker, D and Kelberman, MA},
title = {Impact of early locus coeruleus lesions in the TgF344 Alzheimer's disease rat model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71334},
doi = {10.1002/alz.71334},
pmid = {41943538},
issn = {1552-5279},
support = {AG062581/AG/NIA NIH HHS/United States ; AG069502/AG/NIA NIH HHS/United States ; AG066511/AG/NIA NIH HHS/United States ; NS96050//and National Institute of Neurological Disorders and Stroke/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology ; *Locus Coeruleus/pathology/drug effects ; Disease Models, Animal ; Rats ; Rats, Transgenic ; Rats, Inbred F344 ; Male ; Plaque, Amyloid/pathology ; },
abstract = {INTRODUCTION: In murine models of Alzheimer's disease (AD), lesioning the locus coeruleus-norepinephrine (LC-NE) system with DSP-4 exacerbates AD-like neuropathology and cognitive impairment. However, the impact of LC lesions during prodromal stages is poorly characterized.

METHODS: TgF344-AD and wild-type rats received monthly injections of DSP-4 or saline from 1-5 months of age, a time point preceding forebrain plaque or tangle deposition in TgF344-AD rats, after which behavior and pathology were assessed.

RESULTS: DSP-4 compromised LC cell bodies, fibers, and NE content. LC lesion and the AD transgene each affected several affective behaviors and/or cognition individually, but few interactions were found, and DSP-4 failed to exacerbate behavioral phenotypes or neuropathology in TgF344-AD rats.

DISCUSSION: Combined with previous literature, our data suggest that LC lesions exacerbate pre-existing AD-like pathology and behavioral impairments, rather than accelerate their onset. Further characterization of LC lesions in TgF344-AD rats at different ages is warranted.},
}

Animals
*Alzheimer Disease/pathology
*Locus Coeruleus/pathology/drug effects
Disease Models, Animal
Rats
Rats, Transgenic
Rats, Inbred F344
Male
Plaque, Amyloid/pathology

@article {pmid41943580,
year = {2026},
author = {Ye, Y and Zhang, Z and Xiao, Y and Zhu, C and Wright, N and Asbury, J and Huang, Y and Wang, W and Gomez-Isaza, L and Troncoso, JC and He, C and Sun, S},
title = {DCPS modulates TDP-43-linked neurodegeneration through P-body-mediated RNA decay.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.01.018},
pmid = {41943580},
issn = {1097-4199},
abstract = {The proteinopathy of the RNA-binding protein TDP-43, characterized by nuclear clearance and cytoplasmic inclusion, is a hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). Through CRISPR interference (CRISPRi) screening in human neurons, we identified the decapping scavenger enzyme (DCPS) as a novel genetic modifier of TDP-43 loss-of-function (LOF)-mediated neurotoxicity. Our findings reveal that TDP-43 LOF leads to aberrant mRNA degradation via dysregulating the properties and activity of processing bodies (P-bodies). TDP-43 interacts with P-body component proteins, potentially influencing their dynamic equilibrium and assembly into ribonucleoprotein (RNP) granules. Loss of TDP-43 hyperactivates P-bodies, increasing mRNA association and RNA decay. Reducing DCPS restores P-body integrity and RNA turnover, ultimately improving neuronal survival. Overall, this study highlights a novel role of TDP-43 in RNA processing through P-body regulation and identifies DCPS as a potential therapeutic target for TDP-43 proteinopathy-related neurodegenerative diseases.},
}

@article {pmid41943747,
year = {2026},
author = {Bhatia, P and Rosales, JP and Patel, P and Brini, G and Singh, J and Patel, R and Petroski, J and Brisman, B and Sandhu, M and Santacroce, N and Singh, A and Kaur, G},
title = {The Crossroads of Neurodegeneration: Exploring the Overlap Between Alzheimer's Disease and Depression.},
journal = {Cureus},
volume = {18},
number = {3},
pages = {e104771},
pmid = {41943747},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) and depression are two prevalent and debilitating neuropsychiatric disorders that frequently occur together and share overlapping clinical and molecular features. Understanding shared features of AD and depression is critical for delaying disease progression and improving quality of life. The objective of this narrative review is to identify recent advances in the understanding of AD and its link to depression, with a focus on identifiable biomarkers. This review explores the converging pathophysiological pathways implicated in both AD and depression, with an emphasis on oxidative stress, mitochondrial dysfunction, microglial activation, vascular impairment, and metal ion dysregulation. Specific attention is given to biomarkers of lipid peroxidation, nucleic acid damage, and protein nitration, as well as to the role of telomerase activity and ferroptosis in neuronal cell death. Additionally, we evaluate the therapeutic potential of antidepressants in modifying disease trajectory and reducing depressive symptoms in AD patients. By investigating the molecular intersections of AD and depression, this review aims to provide a comprehensive understanding of their shared pathology and highlight new avenues for targeted interventions. Our review underscores the overlapping mechanisms between AD and depression, paving the way for earlier detection, targeted therapies, closer monitoring, and improved patient outcomes.},
}

@article {pmid41943971,
year = {2026},
author = {Aracki-Trenkic, A and Živanović, M and Milošević, V and Bašić, J and Radovanović, D and Malobabić, M},
title = {Structural MRI phenotyping in Alzheimer's disease: Comparison of visual rating scales, volumetry, and cortical thickness in a Serbian single-centre cohort.},
journal = {Biomolecules & biomedicine},
volume = {},
number = {},
pages = {},
doi = {10.17305/bb.2026.13974},
pmid = {41943971},
issn = {2831-090X},
abstract = {Alzheimer's disease (AD) is characterized by a heterogeneous clinical course, and magnetic resonance imaging (MRI)-based phenotyping has increasingly been utilized to elucidate this variability. The literature recognizes four predominant MRI phenotypes: typical, hippocampal-sparing, limbic-predominant, and minimal-atrophy. However, the compatibility of various MRI phenotyping methods remains insufficiently defined. This study aimed to assess the concordance between MRI phenotyping methods within a Serbian cohort consisting of 40 subjects. Four MRI phenotyping approaches were employed: scale-based, adjusted scale-based, volume-based, and thickness-based. The scale-based method exhibited moderate agreement with the adjusted scale-based approach and high concordance with volumetric methods. In contrast, the relationship between scale- and thickness-based phenotyping was less clear. The lack of significant agreement with demographic variables, along with the observed differences across clinical dementia rating (CDR) domains, further underscored the clinical heterogeneity among phenotypes. Overall, these findings suggest that visual scale-based MRI phenotyping may serve as a practical approach in resource-limited clinical settings where advanced methods are unavailable. However, the results must be interpreted with caution and require validation in larger independent cohorts. Further research is necessary to clarify the relationship between scale- and thickness-based phenotyping across different disease stages and to investigate discrepancies in demographic, apolipoprotein E (APOE)-related, and clinical phenotype patterns in this Serbian sample compared to other populations.},
}

@article {pmid41944116,
year = {2026},
author = {Özcan, F},
title = {Voice Biomarkers: Cognitive Impairment, including Alzheimer's Disease, Dementia, or Mild Cognitive Impairment: Introduction to Peripheral Neuropathy.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050454281260307134058},
pmid = {41944116},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's disease (AD) can cause certain nervous disorders, which in turn can lead to voice disorders and abnormal values for certain acoustic parameters. Mild cognitive impairment (MCI) is probably the early stage of the disease. Dementia is one of the causes of Alzheimer's disease. Whether or not there is a link between these three cognitive impairments, lesions affecting the vocal cords or articulators can be caused by neurological structures that influence phonation. The potential of biomarkers in the detection of cognitive impairment is remarkable. In our study, we will examine vocal biomarkers obtained from the extraction of acoustic features. The aim of this study is to combine vocal biomarkers with cognitive diseases.

METHODS: The standardised dataset used has recently been made publicly available. Cognitive impairment, including Alzheimer's disease, dementia, or MCI, is diagnosed from /a/ and diadochokinesis-pataka vocalisations using Mel-Frequency Cepstral Coefficients (MFCCs) transformed into 2D scalogram images. For processing, we will use the pre-trained OpenL3 network, and our less resource-intensive network called Op1Net to classify diseased and healthy groups.

RESULTS: A significant difference was observed compared to the control group. For the /a/ vocalisation, classification accuracy across all ages and genders was 82.1%, and the AUC value was 88.3%, while for diadochokinesis-pataka, accuracy was 69.8% and the AUC value was 75.4%. In the group of women over 55 years of age, the accuracy was 80.93%, and the AUC value was 87.12%.

DISCUSSION: Performance results clearly show that there is a correlation between the voice and the neurodegenerative disease AD, dementia, or MCI. We can see that the results of the data classification, including all ages and genders, for the sound /a/ are higher than those for the 'pataka' vocalisations. The prolonged vowel provides more information about the disease.

CONCLUSION: This preliminary multidisciplinary study clearly demonstrates the existence of a link between neurological disease and the voice, and raises several questions concerning the nervous system, particularly the vagus nerve and associated neuropathy.},
}

@article {pmid41944134,
year = {2026},
author = {Vijayalakshmi, A and Prabhakar, V},
title = {Pathogenic Protein Post-Translational Modifications in Alzheimer's Disease: Mechanisms and Therapeutic Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273448693251223103034},
pmid = {41944134},
issn = {1996-3181},
abstract = {BACKGROUND: Alzheimer's Disease (AD) pathology involves much more than just Amyloid- Beta (Aβ) and tau (Tau) deposition. A broad network of Post-Translational Modifications (PTMs) drives pathogenic protein conformations that accelerate neuroinflammation, synaptic dysfunction, aggregation, and trans-neuronal spread. Characterising PTM-dependent biochemical signatures allows earlier diagnosis and supports the development of molecularly targeted therapies.

METHODS: A comprehensive review was performed with clinical-trial registries, high-confidence proteomic repositories, and major bibliographic databases from 2000 to 2024, in line with PRISMA guidelines. Bioinformatic tools, curated PTM databases, protein-interaction networks, and computational structure-prediction platforms were utilized to analyse PTM interactions, pathway convergence, and structural impacts.

RESULTS: These include multiple PTMs such as phosphorylation, acetylation, truncation, glycation, oxidation, nitration, ubiquitination, SUMO conjugation, and O-GlcNAc modification that reshape Tau and Aβ solubility, trafficking, aggregation propensity, and clearance efficiency. Human brain proteomics has revealed stage-specific PTM signatures, providing evidence for a combinatorial "PTM code" that dictates disease progression. These PTM-defined proteoforms have directly informed biomarker development, e.g., plasma/Cerebrospinal Fluid (CSF) phosphorylated tau (p-tau) 217/231, and have improved therapeutic precision, including antibodies targeting pyroglutamatemodified Aβ. Therapeutic innovation is targeting kinases, phosphatases, acetylation machinery, OGlcNAc cycling enzymes, oxidative stress pathways, and proteostasis networks alongside RNAbased tau-lowering agents, PTM-guided immunotherapies, and rational combination strategies.

CONCLUSION: PTMs are a central, actionable dimension linking molecular pathology, biomarker specificity, and therapeutic response in AD. The integration of PTM signatures into discovery pipelines and clinical-trial frameworks may help to advance precision diagnostics and yield more effective, disease-modifying interventions.},
}

@article {pmid41944207,
year = {2026},
author = {Dinter, E and Margraff, JL and Schniewind, I and Reinhard, N and , and Reichmann, H and Bräuer, S and Falkenburger, BH},
title = {CSF alpha-Synuclein Seed Amplification Assay results in routine clinically collected samples.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261431201},
doi = {10.1177/1877718X261431201},
pmid = {41944207},
issn = {1877-718X},
abstract = {BackgroundLewy Body pathology can be detected by alpha-synuclein-Seed Amplification Assay (αSyn-SAA) in cerebrospinal fluid (CSF) with high sensitivity and specificity in cohort studies. Yet, little is known about the results that can be expected from αSyn-SAA in CSF in samples outside cohort studies as obtained in clinical routine.ObjectiveThis study analyzed the concordance of αSyn-SAA findings in CSF with clinical diagnosis in patients from clinical routine with diverse neurologic and psychiatric conditions.MethodsIn this cross-sectional study, CSF from patients who underwent lumbar puncture for therapeutic or diagnostic purposes were tested in αSyn-SAA. Analysis included binary αSyn-SAA findings, data collected during neurological examination, and structured medical history.ResultsAll 356 participants (Mean Age 67.1 years, SD = 16.2; 55.9% male) were included in the primary analysis, including 90 patients with Parkinsonian syndromes, 139 with predominant cognitive disorders, 25 with other movement disorders, 35 with inflammatory or (para)neoplastic syndromes, and 67 with further diseases. αSyn-SAA was positive in all samples from patients with Parkinson's disease (41), dementia with Lewy bodies (30), pure autonomic failure (4), and in a subset of patients with Alzheimer's disease (13/46), normal pressure hydrocephalus (7/14) and others.ConclusionsαSyn-SAA findings show high concordance with a clinical diagnosis of PD and DLB. Findings are comparable to results from well-characterized cohort studies, supporting potential diagnostic value in future clinical routine. Challenges may result from the fact that αSyn-SAA detect LB co-pathology that is known from neuropathological studies for several neurodegenerative diseases.},
}

@article {pmid41944257,
year = {2026},
author = {Alshaikhsalama, A and Thompson, K and Hashim, H and Patel, KG},
title = {Analyzing the association between age-related macular degeneration, retinal vascular occlusions, and dementia.},
journal = {European journal of ophthalmology},
volume = {},
number = {},
pages = {11206721261438587},
doi = {10.1177/11206721261438587},
pmid = {41944257},
issn = {1724-6016},
abstract = {PurposeTo investigate the association between age-related macular degeneration (AMD), retinal artery occlusion (RAO), and retinal vein occlusion (RVO) and the future development of Alzheimer's disease (AD), vascular dementia (VaD), and all-cause dementia (ACD).MethodsRetrospective propensity score-matched cohort study using TriNetX, a confederated healthcare network. The study population included 91,296 AMD, 15,372 RAO, 35,862 RVO, and 3,076,291 population control (PC) patients aged 65 and older. Propensity score matching was applied to control for baseline demographics and health characteristics. The primary outcome was the measured risk of developing AD, VaD, and ACD following incident diagnosis of AMD, RAO, or RVO.Major FindingsAMD was associated with a significantly elevated risk of AD (HR, 1.25; 95% CI, 1.17-1.34; P < 0.001), VaD (HR, 1.20; 95% CI, 1.11-1.31; P < 0.001), and ACD (HR, 1.12; 95% CI, 1.08-1.16; P < 0.001) following diagnosis with an average follow up of 45.0 ± 36.7 months. RVO patients also displayed higher risks across all dementia types (AD: HR, 1.46; 95% CI, 1.22-1.74; P < 0.001; VaD: HR, 1.51; 95% CI, 1.23-1.87; P < 0.001; ACD: HR, 1.34; 95% CI, 1.22-1.47; P < 0.001) with an average follow up of 46.6 ± 37.9 months.ConclusionsRetinal disease diagnoses may correlate with increased dementia risk. While AMD and RVO are associated with all dementias (AD, VaD, and ACD), RAO did not increase dementia risk.},
}

@article {pmid41944296,
year = {2026},
author = {Gong, W and Hui, W and Qiao, S and Ji, Q and Liu, M and Zhang, B and Liu, D and Wu, Y and Zhou, S},
title = {Brain and Liver Dual-Targeting Oridonin Nanoparticles to Enhance Aβ Clearance for Alzheimer's Disease Therapy.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e23458},
doi = {10.1002/advs.202523458},
pmid = {41944296},
issn = {2198-3844},
support = {2023-ZDYJSY-001//Shaanxi Administration of Traditional Chinese Medicine/ ; 2023JSYX16//Research Project from Air Force Medical University/ ; //Key Laboratory of New Drug Delivery System and New Technology for Formulation/ ; 82073775//National Natural Science Foundation of China/ ; 82071515//National Natural Science Foundation of China/ ; SZY-KJCYC-2025-ZY-013//Scientific Research Project of Shaanxi Administration of Traditional Chinese Medicine/ ; },
abstract = {The brain and liver are both critical organs involved in the pathogenesis of Alzheimer's disease (AD), particularly in the modulation of amyloid-beta (Aβ) metabolism and neuroinflammation. Based on this, a multifunctional nanodrug delivery system, termed OAF, was developed by encapsulating oridonin (ORI) into apoferritin (ApoFn), enabling simultaneous targeting of both brain and the liver through transferrin receptor 1 (TfR1). OAF upregulated the expression of low-density lipoprotein receptor-related protein 1 (LRP1) in cerebral capillary endothelial cells and hepatic parenchymal cells to promote Aβ clearance from the brain and subsequent hepatic degradation. In AD mice, OAF treatment markedly reduced Aβ deposition, neuroinflammation, and cognitive impairment, while ameliorating inflammation, oxidative stress, and mitochondrial dysfunction in both brain and liver. Overall, OAF synergistically combined Aβ clearance, anti-inflammatory, and antioxidant mechanisms, offering a novel therapeutic strategy for AD.},
}

@article {pmid41944313,
year = {2026},
author = {Chen, J and Li, B and Wang, Y and Zhu, F and Yang, W and Fu, X and Man, T and Wu, Q and Ren, K and Deng, S},
title = {Biolipid Film-Fused Electrochemiluminescence for Multipurpose In Situ Bioassays.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e24242},
doi = {10.1002/advs.202524242},
pmid = {41944313},
issn = {2198-3844},
support = {22374076//National Natural Science Foundation of China/ ; 22204077//National Natural Science Foundation of China/ ; 22504061//National Natural Science Foundation of China/ ; BK20231455//Natural Science Foundation of Jiangsu Province/ ; 2025201001//Fundamental Research Funds for the Central Universities/ ; 30924010201//Fundamental Research Funds for the Central Universities/ ; 30924010809//Fundamental Research Funds for the Central Universities/ ; TMSK-2024-115//Open Research Program of National Major Scientific and Technological Infrastructure for Translational Medicine/ ; KYCX24_0688//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; SKLACLS2412//State Key Laboratory of Analytical Chemistry for Life Science/ ; SKLACLS2402//State Key Laboratory of Analytical Chemistry for Life Science/ ; },
abstract = {Electrochemiluminescence (ECL) is intrinsically a surface-state-sensitive strategy, yet its seamless synergy with soft biomembranes remains sparsely explored. Herein, a biolipid-bound, membrane-interactive scaffold is built upon an ECL-emissive artificial nanochannel and smoothly blended into supported phospholipid bilayers containing cholesterol and diversified natural or synthetic lipids. Such bilayer-bridged assemblies preserve efficient emission while permitting dynamic membrane remodeling. The resulting biointerface enables label-free profiling of cytomembrane-active species, including divalent cations, amphiphilic pharmaceuticals, and pore-forming peptides, through real-time isotherm and kinetic analysis. By further integrating phospholipid-pendant recognition motifs, femtomolar detection of Alzheimer's disease biomarkers (β-amyloid polypeptide and tau protein) is achieved. Moreover, vesicle-mediated membrane merging embeds ECL emitters into living-cell plasmalemma, affording surface-confined single-cell visualization using endogenous oxygen as the coreactant. Collectively, this biointerface-compatible ECL paradigm enables multiplexed monitoring of molecular, membranous, and cellular processes via membrane-structural modulation.},
}

@article {pmid41944317,
year = {2026},
author = {Shao, L and Wang, F and Wang, Y and Du, J and Cao, W and Zhang, Q and Zhao, F and Wang, J and Fan, W and Zhou, Y and Wang, B and Pang, X and Yan, L},
title = {Rational design of environment-sensitive fluorescent probes for butyrylcholinesterase and their application in biological imaging.},
journal = {Analytical methods : advancing methods and applications},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ay00158k},
pmid = {41944317},
issn = {1759-9679},
abstract = {Butyrylcholinesterase (BChE) is closely associated with Alzheimer's disease (AD), with its expression significantly elevated in the brains of AD patients. This enzyme has emerged as a potential biomarker for monitoring AD progression. Therefore, developing a reliable chemical tool to detect BChE both in vitro and in vivo is of considerable interest. In this study, we rationally designed a series of environmentally sensitive fluorescent probes targeting BChE, based on a highly potent, selective, and reversible BChE inhibitor. Among these, the most promising probe ESP4 demonstrated an ultrafast response to BChE with exceptional sensitivity (LOD = 1.81 nM), enabling high-precision detection of BChE. Additionally, ESP4 maintained robust inhibitory activity against BChE in the low nanomolar range (IC50 = 71.78 ± 1.90 nM). Notably, ESP4 exhibited excellent selectivity for BChE, showing no interference from other biological species, including acetylcholinesterase (AChE). The probe also accurately measured the IC50 of tacrine (7.83 nM), a standard BChE inhibitor, demonstrating its reliability in evaluating BChE inhibition. Due to its high sensitivity, rapid response, and superior selectivity, ESP4 enabled real-time imaging of BChE in biological systems such as cells, zebrafish, and AD mouse models. Collectively, these findings highlighted ESP4 as a valuable tool for BChE detection, contributing to a deeper understanding of the physiological role of BChE in health and disease.},
}

@article {pmid41944335,
year = {2026},
author = {Hu, M and Knopman, DS and Therneau, T and Fought, AJ and Hofrenning, E and Lowe, VJ and Petersen, RC and Algeciras-Schimnich, A and Jack, CR and Stricker, NH and Mielke, MM and Vemuri, P and Graff-Radford, J},
title = {Breakpoints in Alzheimer's disease biomarkers and cognition across the aging spectrum: The Mayo Clinic Study of Aging.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71227},
doi = {10.1002/alz.71227},
pmid = {41944335},
issn = {1552-5279},
support = {P30 AG0062677/AG/NIA NIH HHS/United States ; RF1 AG069052/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01AG041851/AG/NIA NIH HHS/United States ; R01AG058738/AG/NIA NIH HHS/United States ; //GHR Foundation/ ; },
mesh = {Humans ; Male ; Biomarkers/blood ; Female ; *Alzheimer Disease/diagnostic imaging/blood ; Aged ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Positron-Emission Tomography ; *Aging ; Aged, 80 and over ; *Cognition/physiology ; Middle Aged ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; Peptide Fragments/blood ; Hippocampus/pathology/diagnostic imaging ; Cohort Studies ; },
abstract = {INTRODUCTION: We examined when Alzheimer's disease biomarkers become informative by identifying age-related breakpoints with slope-changing trajectories.

METHODS: In 2082 Mayo Clinic Study of Aging participants, we modeled plasma amyloid beta (Aβ)42/40, phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid/tau positron emission tomography (PET), hippocampal volume (HVa), and global cognition. Generalized additive models described age trends; Davies' test and piecewise linear regression estimated breakpoints. A C2N subsample (n = 462) provided mass-spectrometry plasma markers (p-tau181, p-tau217, their ratios, Aβ42/40).

RESULTS: In the full cohort, Aβ42/40, HVa, and cognition declined with age; p-tau181, NfL, GFAP, and amyloid/tau PET increased. We observed single breakpoints (years, 95% CI): GFAP 68.1 (63.5-71.8), NfL 70.7 (65.9-75.6), p-tau181 67.2 (60.3-70.3), amyloid PET 62.3 (56.2-69.3), HVa 68.1 (63.1-71.9), cognition 59.8 (55.4-66.0); tau PET showed none. In the mass-spectrometry subset, p-tau217 and p-tau181 broke at 72.6; their ratios and Aβ42/40 showed no breakpoints.

DISCUSSION: Breakpoints cluster near late midlife, suggesting windows for screening and monitoring.},
}

Humans
Male
Biomarkers/blood
Female
*Alzheimer Disease/diagnostic imaging/blood
Aged
Amyloid beta-Peptides/blood
tau Proteins/blood
Positron-Emission Tomography
*Aging
Aged, 80 and over
*Cognition/physiology
Middle Aged
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood
Peptide Fragments/blood
Hippocampus/pathology/diagnostic imaging
Cohort Studies

@article {pmid41944346,
year = {2026},
author = {Singh, A and Sahu, SK and Sah, AK},
title = {Natural Chiral Scaffolds in Alzheimer's Disease: Therapeutic Potential, Mechanism, and Clinical Aspects.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e5968529},
pmid = {41944346},
issn = {2314-6141},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Biological Products/therapeutic use/chemistry/pharmacology ; Stereoisomerism ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Drug Discovery ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive impairment, amyloid-β deposition, tau pathology, oxidative stress, neuroinflammation, and dysfunction of synapses. Current therapeutic options are largely symptomatic and lack disease-modifying efficacy. Target binding, pharmacokinetics, and therapeutic efficacy in AD are all significantly impacted by the stereochemistry of many bioactive natural scaffolds, which are enantiomerically defined molecules. Due to the complexity of their stereochemical structures and their multiple-target pharmacological attributes, natural chiral scaffolds have received significant attention as lead compounds to treat AD. The chirality has a critical impact on target selectivity, receptor binding, blood-brain barrier permeability, and pharmacokinetic behavior. By combining stereochemistry with pharmacological and clinical data, it is possible to expedite the discovery of safer and more effective disease-modifying therapies, thus making chiral natural products attractive for AD drug discovery in the future.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Biological Products/therapeutic use/chemistry/pharmacology
Stereoisomerism
Blood-Brain Barrier/metabolism/drug effects
Animals
Amyloid beta-Peptides/metabolism
Drug Discovery

@article {pmid41944421,
year = {2026},
author = {Rodrigues, JFR and Rodrigues, LP and Teshima, T and Yang, S and Wu, Y and Hu, X and Abarca, GIF and da Cruz, KCT and Rodriguez, MFS and Rubatino, FVM and Yamakawa, M and de Godoy, MF and Filho, GMA},
title = {Loneliness as an Interface Between Alzheimer's Disease and Suicidal Behaviour: A Systematic Review, Meta-Analysis and Meta-Analytic Factor Analysis.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {3},
pages = {e70165},
doi = {10.1111/psyg.70165},
pmid = {41944421},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/psychology/epidemiology ; *Loneliness/psychology ; *Suicidal Ideation ; Depression/psychology ; Factor Analysis, Statistical ; *Suicide/psychology ; *Suicide, Attempted/psychology ; Aged ; Risk Factors ; },
abstract = {Loneliness is an epidemic affecting mental health across all demographics. It is linked to mental disorders, such as anxiety and depression, and despair, highlighting a significant public health issue as persons feel more disconnected in a connected world. This study aims to investigate the relationship between loneliness, Alzheimer's disease and suicidal behaviour. This review was systematised in a dichotomous manner. Therefore, two systematic reviews were initially carried out following the PRISMA statement. The loneliness was understood as feeling lonely. One group searched for associations between loneliness and Alzheimer's disease and the other between loneliness and suicidal behaviour, with a consecutive meta-analysis. After that, it was searched for between the two groups to seek loneliness, such as an interface in meta-analytic factor analysis. Depression is the most studied and cited factor associated with loneliness as a link between Alzheimer's disease and suicide. Loneliness demonstrated association with Alzheimer's disease (OR = 1.89, 95% CI 1.57-2.28; p < 0.001); suicidal ideation (OR = 2.17, 95% CI 1.88-2.51; p < 0.001); suicidal planning (OR = 2.36, 95% CI 1.91-2.92; p < 0.001); suicide attempt (OR = 2.54, 95% CI 2.13-3.04; p < 0.001); and suicide (OR = 4.9, 95% CI 4.4-5.5; p < 0.001). Entrapment, hopelessness, insomnia and stress demonstrated significative correlation (r > 0.40; p < 0.001) with loneliness in the interface between AD and suicidal behaviour. Loneliness has been identified as a comorbid factor between AD and suicide. To prevent both AD and suicide, it is essential to monitor levels of stress, insomnia, feelings of entrapment and hopelessness. The triad of loneliness, hopelessness and insomnia seems to represent the greatest risk profile.},
}

Humans
*Alzheimer Disease/psychology/epidemiology
*Loneliness/psychology
*Suicidal Ideation
Depression/psychology
Factor Analysis, Statistical
*Suicide/psychology
*Suicide, Attempted/psychology
Aged
Risk Factors

@article {pmid41944428,
year = {2026},
author = {Hemmy, L and Cevasco-Trotter, A and Silverman, M and Wang, S and Yuan, SH},
title = {Music therapy interest in patients with Alzheimer's disease and Alzheimer's disease related dementia: A survey study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261437271},
doi = {10.1177/13872877261437271},
pmid = {41944428},
issn = {1875-8908},
abstract = {BackgroundMusic therapy can be an effective psychosocial intervention for people with Alzheimer's disease (AD) and Alzheimer's disease related dementia (ADRD). However, there is a lack of literature regarding people with AD and ADRD's interest in music therapy.ObjectiveThe purpose of this study was to examine interest in music therapy among patients receiving care at an outpatient memory clinic.MethodsA total of 70 patients receiving outpatient services at a university memory clinic completed a researcher-designed one-page survey assessing demographic information and interest in music therapy. Clinic staff recruited participants at check-in for their regularly scheduled appointments.ResultsParticipants were a mean 74.4 years old (SD = 9.5 years). Most participants identified as White (90%), had access to reliable internet (89.7%), and had not previously heard of music therapy (56.7%). Participants indicated they would prefer individual music therapy (58.2%) over group music therapy (10.9%). Participants tended to have low interest levels when asked to rate their interest in receiving music therapy in both in-person or teletherapy formats.ConclusionsAlthough music therapy can help maintain cognitive abilities in older adults, participants receiving care in our outpatient memory clinic expressed low interest in receiving music therapy in person or via telehealth. However, many participants were unfamiliar with music therapy, underscoring the need for education and advocacy to increase awareness and access to care. Implications, limitations, and suggestions for future research are provided.},
}

@article {pmid41944433,
year = {2026},
author = {Luo, X and Li, H and Yu, Y and Sheng, D and He, Z and Li, L and Su, Y and Zhu, Z and Wei, M and Ping, J and Huang, C and Jiang, T and Wang, Y and Liu, X and Wang, Y},
title = {Changes in frailty and its association with dementia risk in four prospective cohorts.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430305},
doi = {10.1177/13872877261430305},
pmid = {41944433},
issn = {1875-8908},
abstract = {BackgroundPrevious studies found baseline frailty is a key risk factor for dementia, but changes in frailty during follow-up were less considered. Clarifying the impact of frailty change may help prevent or delay dementia.ObjectiveThis study investigates frailty changes and their link to dementia risk.MethodsIn this cohort study, we used four prospective cohorts: Health and Retirement Study (HRS), English Longitudinal Study of Ageing (ELSA), China Health and Retirement Longitudinal Study (CHARLS), and Ageing and Retirement in Europe (SHARE). The Fried frailty phenotype classified participants as: robust, pre-frail, and frail. Dementia was defined as those with a combination of cognitive and functional impairment, or those who had self-reported doctor-diagnosed dementia. Cox proportional-hazards model was used to examine the association of changes in frailty with dementia risk.ResultsAfter exclusions, 28,679 participants from an initial sample of 134,834 were included in the analysis. Compared with stable robust participants, those progressing to pre-frail/frail had higher dementia risk (HRS, HR 2.05, 95% CI 1.54-2.72; ELSA, HR 2.24, 95% CI 1.20-4.17; CHARLS, HR 2.85, 95% CI 1.42-5.73; SHARE, HR 1.78, 95% CI 1.34-2.37). Conversely, frail participants who recovered to robust/pre-frail had lower risk than stable frail.ConclusionsAs the frailty status advances, the risks of incident dementia escalate. In contrast, when the frailty status recovers, the risks of incident dementia reduce.},
}

@article {pmid41944642,
year = {2026},
author = {Kemsawasd, V and Thangsiri, S and Sahasakul, Y and Aursalung, A and Inthachat, W and Temviriyanukul, P and Kittibunchakul, S and Suttisansanee, U},
title = {Evaluation of the underutilized Malpighia glabra L. fruits as a future functional food: nutritional composition, phenolic profile, biological activities, and synergistic effects with pharmaceutical drugs.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5fo03782d},
pmid = {41944642},
issn = {2042-650X},
abstract = {Malpighia glabra L., commonly known as acerola or Barbados cherry, is a non-commercial tropical fruit species in Thailand that is primarily consumed fresh by local communities. Limited scientific data have restricted its potential for future food applications. In this study, we investigated the nutritional composition, phenolic profiles, and in vitro biological activity of M. glabra fruits. Results demonstrated that the ripened fruits (100 g fresh weight) provided low energy (36.9 kcal) with negligible fat content but exceptionally high vitamin C content (838 mg). The ethanolic extract exhibited strong antioxidant activities as examined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay (250.98 µmol Trolox equivalent (TE) per g dry weight (DW)), ferric ion reducing antioxidant power (FRAP) assay (642.35 µmol TE per g DW), and oxygen radical absorbance capacity (ORAC) assay (443.90 µmol TE per g DW). These activities were attributed to the phenolic composition, of which rutin was the predominant compound, as detected by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The extract also demonstrated in vitro inhibition of α-glucosidase, with a half-maximal inhibitory concentration (IC50) of 4.81 mg mL[-1], and β-secretase, with an IC50 value of 5.45 mg mL[-1]. Synergistic interactions were observed in vitro between the extract and acarbose (an anti-diabetic drug) and the extract and donepezil (an anti-Alzheimer's drug). These findings characterize the nutritional composition and in vitro bioactivities of ripened M. glabra fruits, supporting further investigation into their potential development as functional food ingredients.},
}

@article {pmid41944714,
year = {2026},
author = {Ashok, AH and Field, S and Ramakrishnan, NK and Thompson, S and O'Brien, JT and Aigbirhio, FI},
title = {P2X7 receptor and neuroinflammation in neurodegenerative disorders: an autoradiography study with [18F]JNJ-64413739.},
journal = {Nuclear medicine communications},
volume = {},
number = {},
pages = {},
pmid = {41944714},
issn = {1473-5628},
abstract = {BACKGROUND: Neuroinflammation plays a crucial role in neurodegenerative disorders such as Alzheimer's disease. The P2X7 receptor (P2X7R), expressed on microglia, is involved in neuroinflammatory responses. Despite evidence of P2X7R upregulation in Alzheimer's disease models, its role in human Alzheimer's disease remains unclear. The PET radioligand [18F]JNJ-64413739 enables the assessment of P2X7R distribution in post-mortem Alzheimer's disease brain tissue.

METHODS: Post-mortem brain tissue from Alzheimer's disease and control subjects was obtained. [18F]JNJ-64413739 was synthesised and applied to tissue sections from the temporal and parietal cortex. Autoradiography was conducted with and without the P2X7R antagonist JNJ54173717.

RESULTS: [18F]JNJ-64413739 binding was observed across all brain regions, with effective blocking confirming specificity. No significant differences were found between Alzheimer's disease and controls in the temporal (P = 0.84) or parietal cortex (P = 0.90) in the first experiment. The second experiment, using a modified protocol also did not reveal a significant difference between controls and Alzheimer's disease in either temporal (P = 0.66) or parietal cortex (P = 0.38). White matter exhibited significantly higher binding than grey matter (P < 0.01), but no disease-specific differences were noted.

CONCLUSION: This study demonstrates P2X7 receptor-specific binding of [18F]JNJ-64413739 but finds no significant differences between post-mortem tissue of Alzheimer's disease cases and controls. These findings suggest that while the tracer shows promising in vitro characteristics, the role of P2X7R in Alzheimer's disease pathology and its utility as a biomarker require further validation through in vivo imaging studies across disease stages.},
}

@article {pmid41944723,
year = {2026},
author = {Tang, C and Sun, X and Tang, A and Ruan, W and Liu, F and Fang, H and Gai, Y and Liang, Z and Su, Y and Wang, X and Lan, X and , and , },
title = {Decoupling Alzheimer Disease Pathologic Abnormalities at PET with Improved Clinical Relevance by Interpretable Adversarial Decomposition Learning.},
journal = {Radiology},
volume = {319},
number = {1},
pages = {e252321},
doi = {10.1148/radiol.252321},
pmid = {41944723},
issn = {1527-1315},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Positron-Emission Tomography/methods ; Female ; Male ; Aged ; Retrospective Studies ; Brain/diagnostic imaging/pathology ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Aged, 80 and over ; *Deep Learning ; Neuroimaging/methods ; Clinical Relevance ; },
abstract = {Background Template-based PET metrics quantify Alzheimer disease (AD) amyloid-β (Aβ) and tau burden but compress whole-brain data into a single scalar, overlooking disease heterogeneity and sometimes causing imaging-clinical discordance. Artificial intelligence (AI) approaches capture richer patterns but often lack biologic interpretability. Purpose To develop and validate an interpretable deep-learning framework that separates AD-specific abnormalities from physiologic uptake using pathophysiologic constraints, generating a clinically meaningful AI biomarker. Materials and Methods In this retrospective study, Aβ and tau PET scans from the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging Biomarkers and Lifestyle study, Global Alzheimer's Association Interactive Network, and the authors' center were analyzed. An adversarial decomposition learning (ADL) network generated voxel-level pathologic maps and an AD adversarial decomposition (ADAD) score. Discriminatory performance for clinical AD versus cognitively normal individuals was evaluated using the area under the curve (AUC). Clinical relevance was assessed with cognitive, hippocampal volume, cerebrospinal fluid (CSF), and neuropathologic measures using longitudinal mixed-effects models and Spearman correlations. Results The study included 7457 Aβ PET scans from 3595 patients (median age, 71.4 years; IQR, 65.7-77.0 years; 1637 female patients) and 1894 tau PET scans from 1127 patients (median age, 72.0 years; IQR, 66.9-78.5 years; 545 female patients). External testing AUCs were 0.94 (95% CI: 0.89, 0.98) for Aβ and 0.98 (95% CI: 0.95, 1.00) for tau. ADL generated interpretable pathologic attribution maps that correlated with expert rankings (Aβ and tau, Spearman ρ = 0.79 and 0.63, respectively). Although Centiloid and CenTauRz showed numerically higher correlations with postmortem neuropathologic structure and stronger associations with CSF biomarkers, the ADAD score demonstrated independent baseline and longitudinal associations with cognitive outcomes and hippocampal atrophy after adjustment. Conclusion Pathophysiologic-constrained ADL provided interpretable, personalized pathologic maps and an AI-derived ADAD score that more closely linked PET pathologic abnormalities with multimodal clinical measures. © RSNA, 2026 Supplemental material is available for this article.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*Positron-Emission Tomography/methods
Female
Male
Aged
Retrospective Studies
Brain/diagnostic imaging/pathology
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Aged, 80 and over
*Deep Learning
Neuroimaging/methods
Clinical Relevance

@article {pmid41944915,
year = {2026},
author = {Kimura, K and Driscoll, I and Cook, N and Shahzad, S and Betthauser, TJ and Johnson, SC and Asthana, S and Gallagher, CL and Hermann, BP and Sager, MA and Blennow, K and Zetterberg, H and Carlsson, CM and Kollmorgen, G and Okonkwo, OC},
title = {Associations between air pollution and markers of neuroinflammation, synaptic dysfunction and core Alzheimer's disease pathology vary by APOE genotype.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41944915},
issn = {1476-3524},
support = {R01AG077507/AG/NIA NIH HHS/United States ; R01AG027161/AG/NIA NIH HHS/United States ; P30AG062715/AG/NIA NIH HHS/United States ; R01AG062167/AG/NIA NIH HHS/United States ; },
}

@article {pmid41944966,
year = {2026},
author = {Riaz, M and Qadir, H and Noman, M and Ahmed, S and Shah, FA and Malik, MU and Bashir, K and Farooq, U and Irshad, N},
title = {Mechanistic Insights into Bergapten by Modulation of Filamin A and GSK3β in STZ Induced Alzheimer's Disease: An Integrated In Silico, In Vitro and In Vivo Study.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41944966},
issn = {1573-6903},
}

@article {pmid41945082,
year = {2026},
author = {Falangola, MF and Voltin, J and Cole, M and Nietert, PJ and Liu, F and Iqbal, K and Jensen, JH},
title = {Corrigendum to Diffusion MRI measures detect brain microstructure changes due to early treatment with neurotrophic peptide mimetic P021 in the 3xTg-AD mouse model of Alzheimer's disease. Magn Reson Imaging. 2026 Jun;129:110641 Page: 9.},
journal = {Magnetic resonance imaging},
volume = {},
number = {},
pages = {110677},
doi = {10.1016/j.mri.2026.110677},
pmid = {41945082},
issn = {1873-5894},
}

@article {pmid41945181,
year = {2026},
author = {Sayehmiri, F and Parvenous, M and Vakili, K and Ebrahimi, R and Batool, Z and Bazgir, N and Kazemi, K and Moafi, M and Ebrahimi, MJ and Hajiesmaeili, M},
title = {The role of 2-Oxoglutarate dehydrogenase complex mitochondrial enzyme in alzheimer's disease: a literature review and bioinformatics workflow.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41945181},
issn = {1573-7365},
}

@article {pmid41945238,
year = {2026},
author = {Nabi, SU and Rasool, I and Khan, A and Haq, AU and Hussain, I and Khan, MS and Majid, S and Rashid, S and Rashid, SM and Sehar, N and Rather, MA and Rehman, MU},
title = {Peptide-based therapeutics in the management of Alzheimer's disease (AD) and their potential to develop novel strategies.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41945238},
issn = {1573-7365},
}

@article {pmid41945446,
year = {2026},
author = {Li, TT and Wang, G and D'Amico, AM and Christensen, LA and Vasquez, KM},
title = {Aging alters DNA structure-induced genetic instability in mice.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {15},
pages = {e2600482123},
doi = {10.1073/pnas.2600482123},
pmid = {41945446},
issn = {1091-6490},
support = {CA093729//NIH/NCI/ ; },
mesh = {Animals ; *Aging/genetics ; Mice ; *Genomic Instability ; *DNA, Z-Form/genetics/chemistry ; Mice, Transgenic ; Apoptosis/genetics ; DNA End-Joining Repair ; Mice, Inbred C57BL ; Nucleic Acid Conformation ; },
abstract = {Repetitive DNA sequences can adopt alternative (i.e., non-B) DNA structures, which represent an endogenous source of genetic instability. Z-DNA, a non-B-DNA structure, has been implicated in the development of age-related genetic disorders such as cancer and Alzheimer's disease. Previously, we found that Z-DNA is mutagenic in mammals; however, the impact of age on Z-DNA-induced genetic instability has not yet been explored. Here, we investigated the effects of aging on Z-DNA-induced genetic instability using a transgenic mutation reporter mouse model. We found that Z-DNA was more mutagenic than control B-DNA in all tissues tested. Contrary to initial expectations, Z-DNA-induced deletions decreased with age, whereas the point mutation frequencies remained unchanged. Our results suggest that while the cleavage activities on Z-DNA were similar in both age groups, the reduction of Z-DNA-induced deletion mutants in aged mice was due to attenuated DNA end-joining efficiency, which is required for the mutagenic processing of Z-DNA, and increased apoptosis. These results provide mechanistic insight into age-associated genetic instability and the aging-cancer link.},
}

Animals
*Aging/genetics
Mice
*Genomic Instability
*DNA, Z-Form/genetics/chemistry
Mice, Transgenic
Apoptosis/genetics
DNA End-Joining Repair
Mice, Inbred C57BL
Nucleic Acid Conformation

@article {pmid41945476,
year = {2026},
author = {Zhang, Y and Deng, Q},
title = {Revisiting the inverse relationship between breast cancer and Alzheimer's disease: insights and implications.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-9},
doi = {10.1159/000551898},
pmid = {41945476},
issn = {1423-0208},
}

@article {pmid41945799,
year = {2026},
author = {Barnwal, N and Dubey, S and Tiwari, P},
title = {Benzimidazole as a Versatile Scaffold for Developing Neurotherapeutics Against Neurodegenerative Diseases.},
journal = {ChemMedChem},
volume = {21},
number = {7},
pages = {e202500869},
doi = {10.1002/cmdc.202500869},
pmid = {41945799},
issn = {1860-7187},
mesh = {Humans ; *Benzimidazoles/chemistry/pharmacology/therapeutic use/chemical synthesis ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis ; Animals ; Molecular Structure ; Structure-Activity Relationship ; },
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss, leading to severe cognitive and motor dysfunction. Benzimidazole, a privileged heterocyclic scaffold, has emerged as a promising pharmacophore in modulating key pathological targets across these disorders. In AD, benzimidazole derivatives inhibit cholinesterases, glycogen synthase kinase-3β (GSK-3β), and glutaminyl cyclase (QC), thereby addressing cholinergic dysfunction, tau phosphorylation, and amyloid aggregation. In PD and HD, they act as monoamine oxidase-B (MAO-B) inhibitors, dopamine D1/D2 receptor modulators, and N-methyl D-aspartate receptor antagonists, improving dopaminergic signalling and reducing excitotoxicity. In ALS, benzimidazoles regulate acetylcholine dysfunction and inhibit receptor-interacting protein kinase 1 (RIPK1), limiting neuroinflammation and cell death. Preclinical studies demonstrate potent enzyme inhibition, often with IC50 values in the nanomolar to micromolar range, alongside favourable ADMET properties enabling blood-brain barrier penetration. Clinically, the glutaminyl cyclase inhibitor Varoglutamstat has advanced to Phase II trials for AD, while Riluzole remains the only food and drug administration (FDA)-approved benzimidazole drug for ALS. The structural versatility of benzimidazoles supports their development as multi-target-directed ligands, addressing overlapping mechanisms such as protein aggregation, oxidative stress, and neuroinflammation. Emerging strategies including hybrid molecules, nanocarrier delivery, and AI-driven design may accelerate their clinical translation.},
}

Humans
*Benzimidazoles/chemistry/pharmacology/therapeutic use/chemical synthesis
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis
Animals
Molecular Structure
Structure-Activity Relationship

@article {pmid41945862,
year = {2026},
author = {Gao, H and Hu, Y and Li, L and Moita, ASOH and Wang, X and Meng, Z and Han, Z and Liu, Y},
title = {Self-Assisted Charge Storage-Release Mechanism Enabling Flexible Design of Biomimetic Triboelectric Nanogenerators.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e22836},
doi = {10.1002/advs.202522836},
pmid = {41945862},
issn = {2198-3844},
support = {52575347//National Natural Science Foundation of China/ ; 52205318//National Natural Science Foundation of China/ ; U22A20183//National Natural Science Foundation of China/ ; 2024YFE0105500//International Research Programs and Strategic Innovative Programs of National Key R&D Program of China/ ; 226Z3601G//S&T Program of Hebei/ ; E2025203083//Natural Science Foundation of Hebei Province/ ; BJ2025064//Science Research Project of Hebei Education Department/ ; K202408//Opening Project of the Key Laboratory of Bionic Engineering (Ministry of Education), Jilin University/ ; },
abstract = {Triboelectric nanogenerators (TENGs) have attained a prominent position in the field of renewable energy conversion, and they exhibit immense promise for applications in self-powered sensors and wearable devices. However, their practical power output is highly dependent on triboelectric effectiveness. While micro-nano-structured surfaces have been widely adopted in previous studies to enhance electrostatic effects, such architectures often lead to electric breakdown at the protruding sites, which adversely counteract the original intention. This work introduces a unique Lithium-ion battery-mimetic into a mimosa-inspired TENG with a micro-array surface. By spontaneously regulating charge distribution, it confines the interfacial electric field below the breakdown threshold, thus integrating high flexibility with outstanding electrical performance. Benefiting from a spontaneous charge self-regulation mechanism, the TENG effectively suppresses air breakdown and achieves a high charge density of 396.50 µC m[-2]. Furthermore, this study demonstrates the practicality of the MLBA-TENG in a long-endurance intelligent insole for position monitoring, providing effective long-term protection for special populations such as patients with Alzheimer's disease. The results validate the promising application prospects of the MLBA-TENG in wearable intelligent devices, highlighting its potential to address critical needs in healthcare and mobile electronics.},
}

@article {pmid41945879,
year = {2026},
author = {Gokcal, E and Becker, JA and Horn, MJ and Das, AS and Viswanathan, A and Rosand, J and Polimeni, JR and Sperling, RA and Johnson, KA and Greenberg, SM and Gurol, ME},
title = {Extent of Tau and Its Cognitive Implications in Patients With Cerebral Amyloid Angiopathy Without Cognitive Impairment.},
journal = {Neurology},
volume = {106},
number = {8},
pages = {e214859},
doi = {10.1212/WNL.0000000000214859},
pmid = {41945879},
issn = {1526-632X},
mesh = {Humans ; Male ; Female ; Aged ; *tau Proteins/metabolism ; *Cerebral Amyloid Angiopathy/diagnostic imaging/metabolism/psychology/complications ; Cross-Sectional Studies ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Middle Aged ; Aniline Compounds ; Cognitive Dysfunction/diagnostic imaging/metabolism ; Aged, 80 and over ; *Brain/diagnostic imaging/metabolism ; Carbolines ; Thiazoles ; Neuropsychological Tests ; },
abstract = {BACKGROUND AND OBJECTIVES: Despite a well-established amyloid-tau neurodegeneration cascade in Alzheimer disease (AD), the extent and mechanistic relevance of tau pathology in cerebral amyloid angiopathy (CAA), a disease of vascular amyloid deposition, remain unclear. Focusing on patients with CAA without cognitive impairment to minimize concurrent AD pathology, we hypothesized that tau extent would be greater in patients with CAA than in healthy controls (HCs), largely attributable to amyloid burden, but it would not be associated with CAA-related imaging markers or cognitive scores in CAA.

METHODS: This cross-sectional study included patients with CAA and age-matched and sex-matched HCs, none of whom had cognitive impairment or dementia. All participants underwent brain MRI, Pittsburgh compound B (PiB)-PET for amyloid, and [18]F-flortaucipir (FTP)-PET for tau. Tau extent was estimated based on PET-Braak staging from cortical FTP uptake and categorized into earlier (Braak 0, I-II) vs later (Braak III-VI) PET-Braak stages. Cognitive scores obtained in CAA were standardized z-scores for memory, processing speed, and executive function. Multivariable regression models tested the association of tau extent with (1) CAA diagnosis and amyloid load in the whole cohort [CAA and HC] and (2) amyloid load, CAA-related imaging markers, and cognitive scores within the CAA cohort.

RESULTS: The mean age of patients with CAA (n = 50) was 70.3 ± 7.6 years and of HCs was 69.7 ± 7.5 years (p = 0.715) (n = 50); both groups were 56% male. Later PET-Braak stage was more frequent in patients with CAA than in HCs (46% vs 18%, p = 0.003). However, in multivariable models, later PET-Braak stage was independently associated with age (odds ratio [OR] 1.19, 95% CI 1.07-1.35, p < 0.001) and PiB uptake (OR 1.72, 95% CI 1.32-2.26, p < 0.001), but not with CAA diagnosis (p = 0.264). Within the CAA cohort, later PET-Braak stage was again independently associated with higher amyloid burden (OR 1.78, 95% CI 1.16-2.73, p = 0.008) but showed no relationship with CAA-related imaging markers or cognitive scores (all p > 0.2).

DISCUSSION: Our results suggest that tau extent is mainly driven by age and vascular amyloid among patients with CAA and that tau extent is not related to CAA-related imaging markers or cognitive scores. These findings further support the view that tau does not affect CAA-specific disease mechanisms among patients with CAA without cognitive impairment.},
}

Humans
Male
Female
Aged
*tau Proteins/metabolism
*Cerebral Amyloid Angiopathy/diagnostic imaging/metabolism/psychology/complications
Cross-Sectional Studies
Positron-Emission Tomography
Magnetic Resonance Imaging
Middle Aged
Aniline Compounds
Cognitive Dysfunction/diagnostic imaging/metabolism
Aged, 80 and over
*Brain/diagnostic imaging/metabolism
Carbolines
Thiazoles
Neuropsychological Tests

@article {pmid41945905,
year = {2026},
author = {Justo-Henriques, SI and Padeiro, M and Silva, RCG and Macedo, J and Borges-Machado, F and São João, RMV and Ribeiro, O},
title = {Digital and Analogical Cognitive Stimulation in Older Adults with Alzheimer's Disease: A Multicenter Randomized Controlled Trial Study Protocol.},
journal = {Acta medica portuguesa},
volume = {39},
number = {4},
pages = {281-286},
doi = {10.20344/amp.24360},
pmid = {41945905},
issn = {1646-0758},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Quality of Life ; Aged ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; *Cognitive Behavioral Therapy/methods ; Cognition ; Male ; Female ; },
abstract = {The growing incidence of neurodegenerative diseases in older adults, with the prevalence of Alzheimer's disease, progressively affects their quality of life. Cognitive stimulation is a psychosocial intervention that has shown consistent benefits in the lives of people with dementia from mild to moderate stages. The present study aims to evaluate the effectiveness of digital and analogical cognitive stimulation, when compared with usual care, on overall cognitive function, emotional state, and quality of life. It also aims to investigate whether institutional and territorial characteristics of social care services moderate these effects. This is a three-arm multicenter randomized controlled trial with repeated measures (pre-intervention, post-intervention, and follow-up). The intervention consists of 24 individually applied (digital and analogical) cognitive stimulation sessions, twice a week, for 12 weeks, in two intervention groups. The control group receives usual care. The study follows the recommendations of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT 2025), including the extension for non-pharmacological interventions. The sample size is estimated at 222 older adults with a probable diagnosis of mild to moderate Alzheimer's disease. Sociodemographic, social, health and clinical data, as well as information on care provider institutions, will be collected and analyzed. Outcomes include cognition (global cognition, memory, and executive function), emotional state (anxiety and depression), and quality of life. All outcomes will be assessed at baseline, endpoint, and follow-up, with comparisons between the intervention groups and the control group.},
}

Humans
*Alzheimer Disease/therapy/psychology
Quality of Life
Aged
Multicenter Studies as Topic
Randomized Controlled Trials as Topic
*Cognitive Behavioral Therapy/methods
Cognition
Male
Female

@article {pmid41946054,
year = {2026},
author = {Tang, S and Peng, Y and Li, Y and Li, Y and Sun, H and Piao, S and Liu, Z and Wu, Y and Hou, Z and Liu, Z and Liu, S and Wang, R},
title = {Congming decoction alleviates Alzheimer's Disease induced by Aβ25-35 in rats via the microbiota-metabolism-inflammation axis, demonstrating its formulation advantages.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {155},
number = {},
pages = {158139},
doi = {10.1016/j.phymed.2026.158139},
pmid = {41946054},
issn = {1618-095X},
abstract = {BACKGROUND: Congming decoction (CMD) is a traditional Chinese herbal formulation traditionally employed for enhancing memory. Despite its historical use, the specific mechanisms and advantages of CMD in the context of Alzheimer's disease (AD) remain inadequately understood.

PURPOSE: This study seeks to elucidate the therapeutic effects of CMD on AD in rats induced by Aβ25-35 and to clarify its underlying process through a multi-perspective approach.

STUDY DESIGN AND METHODS: Cognitive function and pathological alterations were assessed using behavioral tests, hematoxylin and eosin (HE) staining, and immunohistochemistry. Fecal metabolomics analysis, conducted via ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS), was utilized to investigate CMD's impact on metabolic disorders. The structure of the gut microbiota was analyzed through 16S rRNA sequencing. Short-chain fatty acids (SCFAs) and bile acids (BAs) in feces, serum, and brain tissue were quantified using gas chromatography-mass spectrometry (GC-MS) and ultra-high-performance liquid chromatography-tandem quadrupole mass spectrometry (UHPLC-TQ-MS). To establish causal relationships, experiments involving antibiotic-induced microbiota depletion (ABX) and fecal microbiota transplantation (FMT) were performed. Network pharmacology and molecular docking techniques were also employed to identify potential active components and targets. Inflammatory markers were evaluated using enzyme-linked immunosorbent assay (ELISA) kits, immunohistochemistry, and immunofluorescence in brain tissue.

RESULTS: CMD markedly enhanced learning and memory, mitigated pathological changes in the brain and colon, and reestablished gut microbiota equilibrium. It regulated 45 endogenous metabolites involved in BAs, α-linolenic acid, and linoleic acid metabolism. CMD also modulated the levels of SCFAs and BAs in fecal matter, serum, and brain tissue. Strong correlations were identified among gut microbiota, metabolites, and AD-related indicators. Antibiotic treatment inhibited the neuroprotective benefits of CMD, whereas FMT from CMD-treated donors successfully replicated its therapeutic benefits. Network pharmacology analysis indicated that the active components of CMD might target inflammatory pathways. Additionally, CMD exhibited a significant restorative impact on markers associated with the AKT/NF-κB signaling pathway.

CONCLUSION: CMD exerts anti-AD effects by modulating the microbiota-gut-brain axis through remodeling gut microbiota, regulating metabolic homeostasis, and reducing brain inflammation. Notably, CMD demonstrated superior efficacy compared to single herbs or herb pairs.},
}

@article {pmid41946261,
year = {2026},
author = {Zhu, Y and Lan, G and Li, A and Zhang, L and Jiang, M and Yang, J and Zhu, J and He, Z and Zhou, X and Li, M and Wang, Y and Sun, P and Cai, Y and Liu, Z and Wang, YJ and Han, Y and Bu, G and Guo, T},
title = {Association of plasma glial fibrillary acidic protein and APOE-ε4 with Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {164},
number = {},
pages = {19-27},
doi = {10.1016/j.neurobiolaging.2026.03.009},
pmid = {41946261},
issn = {1558-1497},
abstract = {Both Apolipoprotein E-ε4 (APOE-ε4) and astrocytic activation, as measured by glial fibrillary acidic protein (GFAP), play critical roles in Alzheimer's disease (AD). However, the influence of astrocytic activation on the relationship between APOE-ε4 and AD pathologies remains unclear. This study investigates the interrelationships among astrocytic activation, APOE-ε4, and AD pathophysiology in 529 participants who underwent plasma biomarker measurements, APOE genotyping, and cognitive testing. Additionally, 277, 284, and 104 underwent structural magnetic resonance imaging (MRI), amyloid-β (Aβ) positron emission tomography (PET), and tau PET, respectively. The associations of plasma GFAP, APOE-ε4, and AD-related biomarkers, as well as whether plasma GFAP mediates APOE-ε4-related effects on AD, were investigated. Higher plasma GFAP and APOE-ε4 were independently associated with more severe Aβ and tau aggregation, as well as cognitive decline. Mediation analyses showed a significant indirect effect of APOE-ε4 on plasma p-tau biomarkers (21.1%-24.9%), Aβ PET (16.4%), and cognition (19.6%), while the indirect effect on tau PET was trend-level (29.1%, pFDR = 0.051). These findings highlight the central role of astrocytic activation in AD pathogenesis and underscore plasma GFAP as a promising biomarker for risk stratification and therapeutic targeting.},
}

@article {pmid41946658,
year = {2026},
author = {Merlino, L and Rainone, F and Tollitt, J and Kalra, MJ and Williford, S and Rusconi, F and Battini, GG and Dunne, RA and Hackett, G and Kalra, PA},
title = {Safety of Testosterone Therapy in Chronic Kidney Disease: A Propensity Score-Matched Cohort Study.},
journal = {The world journal of men's health},
volume = {},
number = {},
pages = {},
doi = {10.5534/wjmh.250333},
pmid = {41946658},
issn = {2287-4208},
abstract = {PURPOSE: Testosterone deficiency is highly prevalent in men with chronic kidney disease (CKD) and contributes to frailty, fatigue, and cognitive decline. While testosterone replacement therapy (TRT) may alleviate these complications, concerns persist regarding its cardiovascular and oncologic safety in CKD. Evidence specific to this population is lacking.

MATERIALS AND METHODS: We performed a retrospective, propensity score-matched cohort study using the TriNetX Global Collaborative Network. Male patients aged 18-80 years with CKD stages 3-5 and hypogonadism were included. Patients were stratified by TRT exposure within six months of diagnosis. Exclusions were prior transplantation, eGFR <10 mL/min/1.73 m², dialysis or dementia occurring within one month of CKD. Outcomes over five years included all-cause mortality (primary outcome), vascular dementia, Alzheimer's disease, stroke, myocardial infarction, heart failure, and prostate cancer. Propensity score matching (1:1) balanced demographics, comorbidities, and laboratory measures. Cox proportional hazards models estimated hazard ratios (HRs).

RESULTS: After matching, 1,545 patients were included in each of the two cohorts (TRT treated or non-treated) with well-balanced characteristics (mean eGFR 47.7±15.1 mL/min/1.73 m²). Median follow-up was 3.7 years. All-cause mortality was lower in the TRT group (HR 0.78, 95% confidence interval 0.63-0.98). No significant differences were observed for cardiovascular outcomes, prostate cancer or dementia.

CONCLUSIONS: In men with CKD and hypogonadism, TRT was associated with improved survival and no excess risk of cardiovascular events, prostate malignancy or dementia. These findings suggest TRT is a safe therapeutic option in this high-risk population, warranting further prospective evaluation.},
}

@article {pmid41946675,
year = {2026},
author = {González, KA and Tarraf, W and Banks, SJ and Bangen, KJ and Pa, J and Gallo, LC and Stickel, AM and Filigrana, P and Isasi, CR and Daviglus, M and Testai, FD and Lamar, M and DeCarli, C and González, HM},
title = {Diabetes, hyperglycemia, and brain MRI biomarkers: results from SOL-INCA MRI study.},
journal = {Nutrition & diabetes},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41387-026-00415-z},
pmid = {41946675},
issn = {2044-4052},
support = {R01AG075758-02//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {OBJECTIVE: Hispanic/Latino individuals have higher rates of type 2 diabetes and Alzheimer's Disease and Related Dementia (ADRD) burden compared to non-Hispanic whites. Diabetes is a risk factor for ADRD, but the extent of its associations with brain markers in community-dwelling Hispanic/Latino individuals is unknown. We examined how glycemic dysregulation and diabetes associate with small vessel disease damage and neurodegeneration in Hispanic/Latino adults from a large and community-representative cohort study.

RESEARCH DESIGN AND METHODS: We used data from 2627 individuals, aged 35-85 years, from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL; 2008-2011) who underwent brain imaging through the SOL/Investigations of Neurocognitive Aging MRI (SOL-INCA MRI; 2018-2022) study. Exposures included diabetes status and HbA1c (%) levels. Outcomes included white matter hyperintensities, free water, fractional anisotropy, and volumetric regions including hippocampus, lateral ventricles, total brain, and cortical gray matter.

RESULTS: Diabetes status, compared to no diabetes, was associated with larger white matter hyperintensity volume, lower fractional anisotropy, and higher free water. Diabetes status was also associated with larger lateral ventricles as well as smaller total brain, frontal gray matter, and occipital gray matter volumes. The association between diabetes and brain MRI outcomes was stronger in middle-aged and older individuals (50 years and older) compared to younger individuals (35-49 years).

CONCLUSION: Diabetes was associated with markers of small vessel disease (white matter micro and macrostructural damage) and neurodegeneration (smaller brain volumes). White matter hyperintensities have been associated with increased risk of stroke and cognitive decline. Other work has found that free water and fractional anisotropy may predict worse cognitive performance, even in normal-appearing white matter. Smaller brain volumes have also been associated with cognitive deficits. These findings highlight the additional ADRD burden this population faces due to their higher diabetes prevalence.},
}

@article {pmid41946684,
year = {2026},
author = {Pedrolli, F and Morello, G and Gesmundo, I and Banfi, D and Ferro, A and Wangpaichitr, M and Sha, W and Tamagno, E and Schally, AV and Guglielmotto, M and Granata, R},
title = {Growth hormone-releasing hormone attenuates amyloid deposition and neuroinflammation in Alzheimer's disease models.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08699-w},
pmid = {41946684},
issn = {2041-4889},
support = {20223WSTY4//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 202229X8hW//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 106459/2023.1741//Fondazione CRT (CRT Foundation)/ ; 10683/2023.1759//Fondazione CRT (CRT Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau hyperphosphorylation, neuroinflammation, and synaptic loss. Existing therapies provide only modest symptomatic relief and fail to slow disease progression. Beyond its role in promoting pituitary growth hormone (GH) secretion, growth hormone-releasing hormone (GHRH) has shown neuroprotective effects in experimental ischemic stroke and spinal muscular atrophy. Here, we explored the therapeutic potential of GHRH and its agonist MR-409 in AD models. In vitro, GHRH(1-44)NH2 promoted survival, proliferation, and neuronal differentiation of rat hippocampal neural stem cells (NSCs) and human SH-SY5Y neuroblastoma cells under growth factor deprivation and amyloid beta (Aβ)1-42 exposure. These effects involved the cAMP/PKA/CREB, ERK1/2, and PI3K/Akt signaling pathways. GHRH also attenuated Aβ-induced neurotoxicity by reducing apoptosis, suppressing GSK-3β activity and tau phosphorylation, restoring nuclear β-catenin, and inhibiting NF-κB-mediated inflammation. In vivo, subcutaneous administration of MR-409 in 5xFAD mice reduced Aβ deposition, tau phosphorylation, gliosis, and proinflammatory cytokine expression. In addition, MR-409 mitigated neuronal and synaptic loss, activated survival and neurogenic pathways, and improved cognitive performance, without altering systemic GH and IGF1 levels. MR-409 also elevated NRF2 mRNA expression while reducing its negative regulator KEAP1. Overall, these findings indicate that GHRH and its analog MR-409 exert neuroprotective effects by modulating key pathological features of AD, including neurodegeneration, impaired neurogenesis, neuroinflammation, and oxidative stress. Given their ability to modulate multiple pathological pathways, GHRH agonists may represent promising therapeutic candidates for AD and other neurodegenerative disorders.},
}

@article {pmid41946775,
year = {2026},
author = {Phemphunananchai, K and Waiwut, P and Phetcharaburanin, J and Poonsawas, P and Boonyarat, C},
title = {Repurposing FDA-approved drugs as multi-target neuroprotective agents for Alzheimer's disease via computational screening and experimental validation.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-46708-2},
pmid = {41946775},
issn = {2045-2322},
support = {67-2(7)/2567//Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand/ ; RA2567-M109//The Research Assistant Program, Khon Kaen University, Thailand/ ; },
}

@article {pmid41936903,
year = {2026},
author = {Senkowska, Z and Weglarz-Tomczak, E},
title = {Decoding the Secretase Puzzle in Amyloid-β Generation: A State-of-the-Art Overview of the Protease-Mediated APP Processing Cascade in Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103116},
doi = {10.1016/j.arr.2026.103116},
pmid = {41936903},
issn = {1872-9649},
abstract = {The accumulation of amyloid β (Aβ) protein in the brain is a central pathological hallmark of Alzheimer's disease (AD). This process has become a major focus of interdisciplinary research and a critical target in drug development. Aβ is produced through the proteolytic processing of amyloid precursor protein (APP) by a group of enzymes known as secretases. They belong to different protease classes and operate through proteolytic cleavage of the peptide bond through several catalytic hydrolysis. Dysregulation of the expression or/and activity of proteases involved in APP processing disrupts the balance between the amyloidogenic and non-amyloidogenic pathways-often shifting it toward the amyloidogenic route. This shift leads to excessive production and further aggregation of Aβ peptides, ultimately resulting in neuronal toxicity. In this review, we integrate current state-of-the-art knowledge on all proteases reported to cleave APP, encompassing both canonical and non-canonical pathways, and offer detailed examination of cleavage-site topology, and catalytic mechanisms. By integrating the spatial and sequential hierarchy of APP proteolysis across cellular compartments, we establish a unifying mechanistic framework that captures the complexity of the process. We further delineate how distinct proteases-through defined active-site architectures, conserved catalytic motifs, and nucleophile-driven peptide bond hydrolysis-precisely regulate APP processing. This mechanistic perspective advances our molecular understanding of A pathogenesis and delineates critical catalytic control nodes amenable to therapeutic intervention. By defining these targets at a mechanistic level, it establishes a rational framework for precision drug design and the development of next-generation therapeutics.},
}

@article {pmid41936993,
year = {2026},
author = {Lizard, G and Sassi, K and Mackrill, JJ and Ghzaiel, I and Meziane, S and Hassen, E and Abdelkarim, M and Masmoudi-Kouki, O and Ghrairi, T and Brahmi, F and Gargouri, A and Rezig, L and Benkalifa, R and Khallouki, F and El Midaoui, A and Pincemail, J and Atanasov, AG and Vejux, A and Millot, N},
title = {7-ketocholesterol as a theranostic target: potential applications and future perspectives.},
journal = {Chemistry and physics of lipids},
volume = {},
number = {},
pages = {105588},
doi = {10.1016/j.chemphyslip.2026.105588},
pmid = {41936993},
issn = {1873-2941},
abstract = {7-Ketocholesterol (7KC) is mainly formed by cholesterol autoxidation and is a pro-oxidant and pro-inflammatory bioactive lipid that also induces different types of cell death, including oxiapoptophagy. It is frequently associated with major age-related diseases, such as cardiovascular diseases, age-related macular degeneration, and Alzheimer's disease. 7KC can therefore be considered a biomarker for these diseases, offering the possibility of developing theranostic strategies combining diagnosis and treatment. Currently, all the elements are in place to develop tools for the design of theranostic therapies targeting 7KC in diseased organs: antibodies, nanoparticles used as nanoplatforms, molecules that neutralize 7KC such as enzymes which degrade it, as well as natural or synthetic compounds that inhibit the cytotoxic signaling pathways associated with oxidative stress, inflammation and cell death activated by 7KC. Identifying and neutralizing 7KC biological activities using a theranostic approach could also be of interest for growing medical fields such as space medicine widely concerned by oxidative stress, aging and age-related diseases, driven by microgravity. This review supports that most of key tools are now available to develop theranostic treatments targeting 7KC in age-related pathologies, especially in cardiovascular diseases associated with atheroma, but also in age-related macular degeneration and Alzheimer's disease. Discovery of effective treatments for these diseases is a major challenge and will answer an important need for both patients and caregivers.},
}

@article {pmid41937092,
year = {2026},
author = {Baldasso, GM and Paes, RS and Moreira, AG and Salvadori, SG and Limberger, C and Roviezzo, F and Capasso, R and Dutra, RC},
title = {The role of cannabinoid ligands in neurodegenerative diseases: emerging anti-inflammatory, immunomodulation and disease-modifying perspectives.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108185},
doi = {10.1016/j.phrs.2026.108185},
pmid = {41937092},
issn = {1096-1186},
abstract = {Neurodegenerative diseases (NDs) constitute a growing global health burden driven by population aging and remain without disease-modifying therapies. Although chronic neuroinflammation and aberrant protein aggregation are widely recognized as shared pathological hallmarks of major NDs - including Alzheimer's, Parkinson's, Huntington's diseases and multiple sclerosis - the causal relationships linking immunoinflammatory signaling to neurodegenerative progression remain contentious. Therapeutic strategies targeting neuroinflammation have thus far yielded limited clinical success, underscoring the need for mechanistically grounded and context-specific interventions. The endocannabinoid system (ECS) is a key regulator of synaptic function, glial activity, and immune homeostasis in the central nervous system (CNS), and its dysregulation has been consistently reported in neurodegenerative settings. However, ECS alterations across NDs are heterogeneous and often disease- and stage-dependent, with conflicting findings regarding cannabinoid receptor expression, endocannabinoid tone, and functional outcomes. Moreover, while preclinical studies demonstrate robust anti-inflammatory and neuroprotective effects of cannabinoid ligands, clinical translation has been constrained by issues of receptor specificity, psychoactive side effects, limited brain penetration, and an incomplete understanding of long-term ECS modulation. In this Review, we critically evaluate current evidence linking ECS signaling to neuroinflammatory mechanisms in neurodegeneration, highlighting both convergent pathways and unresolved controversies. We discuss the translational implications of ECS-targeted strategies, including the development of selective receptor modulators, allosteric and/or bitopic/dualsteric ligands, and enzyme inhibitors, as well as emerging approaches to mitigate adverse effects and improve therapeutic precision. By integrating mechanistic insights with clinical challenges, this Review delineates key obstacles and opportunities for advancing ECS-based interventions toward disease-modifying therapies for neurodegenerative disorders.},
}

@article {pmid41937403,
year = {2026},
author = {Borda, MG and O'Hara-Veintimilla, K and Aarsland, D},
title = {Older Adults, Anti-Amyloid Therapy, and Frailty: What Oncology Can Teach Us.},
journal = {European journal of neurology},
volume = {33},
number = {4},
pages = {e70567},
doi = {10.1111/ene.70567},
pmid = {41937403},
issn = {1468-1331},
support = {//Helse Vest/ ; //Nasjonalforeningen for Folkehelsen/ ; },
mesh = {Humans ; *Frailty/diagnosis ; Aged ; *Geriatric Assessment/methods ; *Alzheimer Disease/drug therapy ; *Medical Oncology/methods ; Clinical Decision-Making ; Frail Elderly ; },
abstract = {BACKGROUND: Anti-amyloid therapies, such as lecanemab or donanemab, represent the first disease-modifying treatments approved for early Alzheimer's disease (AD) in individuals with confirmed amyloid pathology. Their implementation in routine care raises important challenges, particularly in older adults with heterogeneous functional reserve and multimorbidity. We address the role of frailty in refining clinical decision-making for anti-amyloid therapies.

METHODS: This short communication presents a conceptual discussion informed by geriatric oncology, where frailty assessment and comprehensive geriatric assessment (CGA) are routinely used to individualize treatment in heterogeneous older populations. We describe how similar principles may be applied to anti-amyloid monoclonal antibodies once regulatory eligibility has been established, and outline a frailty-informed conceptual framework to support clinical decision-making in routine care.

RESULTS: This conceptual analysis proposes a stepwise, frailty-informed clinical framework that integrates regulatory eligibility assessment with brief frailty screening and targeted comprehensive geriatric assessment. The framework defines differentiated clinical pathways for robust, pre-frail, and frail individuals, linking frailty status to specific decisions regarding treatment initiation, need for prehabilitation, intensity of monitoring, and consideration of treatment deferral. By embedding frailty assessment within routine clinical workflows, the framework operationalizes evaluation of physiological reserve, anticipates treatment burden and monitoring feasibility, and provides a structured approach to individualized risk-benefit appraisal for anti-amyloid therapies.

CONCLUSIONS: Frailty-informed frameworks may offer a pragmatic and ethically grounded approach to support real-world implementation of anti-amyloid therapies, guiding treatment selection as well as longitudinal decisions on monitoring, continuation, and reassessment over time.},
}

Humans
*Frailty/diagnosis
Aged
*Geriatric Assessment/methods
*Alzheimer Disease/drug therapy
*Medical Oncology/methods
Clinical Decision-Making
Frail Elderly

@article {pmid41937689,
year = {2026},
author = {Helphrey, JH and Hart, J and McClintock, SM and Peters, ME and Thakkar, VJ and LoBue, C},
title = {A scoping review of frontal cortex tDCS on neuropsychological functioning in older adults with mild cognitive impairment and Alzheimer's Clinical Syndrome.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/09540261.2026.2647921},
pmid = {41937689},
issn = {1369-1627},
abstract = {Mild cognitive impairment (MCI) and Alzheimer's Clinical Syndrome (ACS) are prevalent, incurable, and are expected to increase in incidence over the next 30 years. Finding new treatments to address the cognitive and behavioral problems in MCI and ACS represent an urgent need. Brain circuitry disruption can cause cognitive dysfunction and neuropsychiatric symptoms (NPS) in both MCI and ACS. Therefore, one promising avenue of treatment is non-invasive brain stimulation through transcranial direct current stimulation (tDCS). This scoping review examined the current knowledge base for the potential neuropsychological and neuropsychiatric effects of frontal cortex tDCS in older adults with MCI and ACS. Of the 17 randomized controlled trials reviewed, treatment parameters such as session length, current intensity, number of treatments, and time between treatments varied widely across studies, which restricted identification of optimal tDCS treatment protocols. Mixed findings on neuropsychological outcomes were observed, though significant improvements were most commonly seen in studies measuring global cognition (10) followed by executive function (6). Only three studies yielded clinically significant cognitive improvement, and few studies assessed NPS outcomes. Additional rigorous research is indicated to enhance our understanding of tDCS as a treatment for cognitive and neuropsychiatric symptoms in older adults with MCI and ACS.},
}

@article {pmid41937703,
year = {2026},
author = {Salim, MW and Zhang, W and Collins-Praino, L and Wang, Y and Care, A},
title = {Small Extracellular Vesicles from Neural Cells: Physiological and Pathological Roles, and Potential in Neurodegenerative Therapy.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e04608},
doi = {10.1002/adhm.202504608},
pmid = {41937703},
issn = {2192-2659},
support = {//Higher Education Commission/ ; //International Macquarie University Research Excellence Scholarship/ ; FT210100737//ARC Future Fellowship/ ; //Dementia Australia Research Foundation/ ; //Mason Foundation/ ; //National Foundation for Medical Research & Innovation/ ; },
abstract = {Small extracellular vesicles (sEVs) have emerged as central mediators of intercellular communication in the central nervous system (CNS) and are increasingly recognized for their dual roles in the pathogenesis and treatment of neurodegenerative diseases (NDDs). In disease contexts, sEVs facilitate the intercellular dissemination of pathogenic proteins and nucleic acids, thereby contributing to the propagation of Alzheimer's disease (AD) and Parkinson's disease (PD) pathology. Conversely, their intrinsic biocompatibility, capacity to traverse brain barriers, and inherent organotropic properties position sEVs as highly promising nanocarriers for CNS drug delivery. While mesenchymal stem cell-derived sEVs have been widely investigated in preclinical NDD models, accumulating evidence suggests that sEVs derived from neural cells, including neural stem cells, neurons, astrocytes, microglia, oligodendrocytes, and brain endothelial cells may offer superior brain targeting, disease relevance, and functional efficacy. This review provides a comprehensive and critical analysis of current knowledge on neural cell-derived sEVs, encompassing their physiological roles in brain homeostasis, their involvement in AD and PD pathogenesis, and their emerging therapeutic applications. We discuss cell-type-specific sEV cargo profiles, mechanisms underlying blood-brain and blood-cerebrospinal fluid barrier traversal, and recent advances in endogenous and exogenous engineering strategies that enhance cargo loading, targeting precision, and therapeutic performance. Importantly, we address key translational challenges that currently limit clinical implementation. By integrating mechanistic insights with therapeutic and engineering perspectives, this review highlights neural cell-derived sEVs as a biologically informed and versatile platform, underscoring their potential to advance next-generation neuro-nanomedicine for NDDs.},
}

@article {pmid41937809,
year = {2026},
author = {Mehmood, A and Farman, M and Afzal, F and Nisar, KS and Ahmed, MA and Hafez, M},
title = {Correction: A Physics Informed Neural Network (PINN) framework for fractional order modeling of Alzheimer's disease.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1821637},
doi = {10.3389/fninf.2026.1821637},
pmid = {41937809},
issn = {1662-5196},
abstract = {[This corrects the article DOI: 10.3389/fninf.2026.1748481.].},
}

@article {pmid41938067,
year = {2026},
author = {Cao, H and Liang, J and Dong, X and Xia, Z and Luo, X and Liu, B},
title = {Protein lactylation in Alzheimer's disease: bridging metabolism, pathology, and therapeutic opportunity.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1790090},
pmid = {41938067},
issn = {1663-4365},
abstract = {Lactate, long regarded as a mere by-product of glycolysis, is increasingly recognized as a signaling metabolite and epigenetic regulator through protein lactylation. This lysine-specific post-translational modification functionally couples cellular metabolic states to gene regulatory programs and orchestrates cell type-specific functions across neurons, astrocytes, and microglia, thereby shaping synaptic plasticity, neuroinflammatory responses, and protein aggregation. Accumulating evidence implicates dysregulated lactylation in the pathogenesis of Alzheimer's disease (AD), where it modulates amyloid-β deposition, tau aggregation, and glial reactivity. In this Review, we summarize the enzymatic regulation of protein lactylation, delineate its context-dependent roles in distinct central nervous system cell types, and highlight its function as a metabolic-epigenetic-immune nexus in AD progression. We further discuss emerging therapeutic strategies targeting lactate metabolism and lactylation pathways, and outline critical knowledge gaps that must be addressed to translate these insights into innovative diagnostic and therapeutic approaches. By integrating metabolic reprogramming, epigenetic control, and cell-specific mechanisms, this Review positions lactylation as a compelling and emerging frontier in AD research.},
}

@article {pmid41938070,
year = {2026},
author = {Samokhina, E and Buskila, Y},
title = {Astrocytic K[+] regulation during neurodegenerative diseases.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1782460},
pmid = {41938070},
issn = {1663-4365},
abstract = {Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in specific areas of the central nervous system. Historically, a "neurocentric" paradigm viewed glial cells, such as astrocytes, as cells that provided adequate support for neuronal energy metabolism and controlled local cerebral blood flow. However, studies from the past two decades found that astrocytes are involved in synaptic function through different mechanisms, including the uptake of extracellular glutamate molecules and potassium ions following synaptic neuronal transmission. Also, astrocytes respond to neurotransmitters and neuromodulators through alterations of intracellular ion concentrations (e.g., Na[+], Ca[2+], K[+]) and the release of gliotransmitters. Astrocytes play a pivotal role in preserving potassium homeostasis within the central nervous system through their potassium channels, a process known as "potassium clearance." Impaired astrocytic potassium clearance mechanisms can result in neuronal hyperexcitability, leading to increased glutamate release, overactivation of glutamate receptors, and cytotoxicity. Recent studies suggest that these factors can cause cell death and neurodegeneration, and further indicate a region-specific glial dysfunction in neurodegeneration, which reflects the heterogeneity of glial cell function and sensitivity across different brain regions. Overall, this manuscript offers novel insights into a relatively new concept that glial cells can actively shape neuronal activity and survival.},
}

@article {pmid41938171,
year = {2026},
author = {He, Y and Qu, M and Yu, L and He, L and Lu, Y and Hong, J and Sun, M and Yang, H and Mi, W and Guo, H and Ma, Y},
title = {Blood-Brain Barrier: Structure, Function, Diseases, and Drug Delivery Systems.},
journal = {MedComm},
volume = {7},
number = {4},
pages = {e70712},
pmid = {41938171},
issn = {2688-2663},
abstract = {The blood-brain barrier (BBB) is a highly selective and dynamic neurovascular interface essential for maintaining central nervous system homeostasis. This specialized barrier comprises brain microvascular endothelial cells interconnected by tight junctions, supported by pericytes and astrocytic end-feet within the neurovascular unit. While protecting the brain from circulating pathogens and toxins, the BBB presents formidable obstacles to drug delivery, restricting approximately 98% of small-molecule therapeutics and nearly all large biomolecules from reaching the brain parenchyma. BBB dysfunction is critically implicated in the pathogenesis and progression of numerous neurological disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and brain tumors. This comprehensive review systematically examines the structural organization and functional characteristics of the BBB, elucidates its pathophysiological roles across major neurological diseases, and critically evaluates innovative drug delivery strategies designed to overcome this biological barrier. We analyze passive targeting approaches, active targeting mechanisms via receptor-mediated transcytosis, and stimuli-responsive systems including focused ultrasound and magnetic guidance. Additionally, we discuss multifunctional nanoplatforms, biomimetic cell membrane-coated delivery systems, current preclinical evidence, and clinical translation challenges. Finally, we propose future research directions and identify specific experimental pathways to accelerate the development of next-generation BBB-targeted therapeutics from preclinical promise to clinical application.},
}

@article {pmid41938337,
year = {2026},
author = {Saranya, K and Joseph, ER and Kalaiarasi, T and Karthiga, M},
title = {Generative AI in drug repurposing and biomarker discovery: a multimodal approach.},
journal = {Frontiers in bioinformatics},
volume = {6},
number = {},
pages = {1755412},
pmid = {41938337},
issn = {2673-7647},
abstract = {INTRODUCTION: Computational drug repurposing has been widely explored using similarity-based methods, network diffusion, matrix factorization, deep learning, and graph neural networks (GNNs). However, recent heterogeneous GNN models, such as TxGNN and GAT-based models, demonstrate serious limitations for real-world biomedical applications, including poor generalization to sparsely annotated diseases, limited disease-level adaptation, and inability to effectively combine heterogeneous evidence from curated databases, multi-omics profiles, and unstructured biomedical literature.

METHODS: This article proposes a heterogeneous attention-based meta-learning graph neural network named HAMGNN, which employs three major innovations: (i) relation-sensitive multi-head attention to prioritize biologically significant interactions among heterogeneous edge types, (ii) a disease-focused meta-learning framework enabling rapid adaptation to newly observed or under-informed diseases, and (iii) a literature-enhanced knowledge graph construction pipeline encoding high-confidence, LLM-extracted therapeutic information. The model was tested on a large multimodal biomedical knowledge graph assembled from DrugBank, DisGeNET, and Hetionet, comprising more than 2.2 million edges, using a stringent disjoint disease-based (cold-start) evaluation protocol.

RESULTS: HAMGNN achieved a receiver operating characteristic-area under the curve (ROC-AUC) of 0.98 and precision of 0.95, representing a 10%-15% improvement over TxGNN and GAT-GNN on unseen disease generalization. Translational applicability was demonstrated through Alzheimer's disease and Long COVID case studies, identifying clinically plausible repurposing candidates and disease-associated biomarker signatures via mechanistic pathways.

DISCUSSION: HAMGNN offers a generalized, biologically grounded, and unified framework for evidence-based drug repurposing and biomarker discovery in complex and emerging diseases.},
}

@article {pmid41938524,
year = {2026},
author = {Raj, N and R, SP and Ammar, RB and Rajendran, P and Chellappan, BV},
title = {Non-Coding DNA-Derived Mimotopes of Aβ42 as Novel Candidates for Alzheimer's Peptide Vaccine Design.},
journal = {International journal of medical sciences},
volume = {23},
number = {4},
pages = {1320-1332},
pmid = {41938524},
issn = {1449-1907},
mesh = {*Amyloid beta-Peptides/immunology/chemistry/genetics ; *Alzheimer Disease/immunology/therapy/prevention & control/genetics ; Humans ; *Peptide Fragments/immunology/chemistry/genetics ; *Vaccines, Subunit/immunology ; Epitopes, B-Lymphocyte/immunology/genetics/chemistry ; *Alzheimer Vaccines/immunology ; Molecular Docking Simulation ; Peptide Library ; Protein Subunit Vaccines ; },
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is a progressive neurodegenerative disorder marked by memory loss, cognitive decline, and characteristic neuropathology involving amyloid-β (Aβ) plaques and tau tangles. Among emerging therapeutic strategies, Aβ-targeted immunotherapy using monoclonal antibodies or peptide vaccines offers the most promising disease-modifying potential. Mimotopes, short peptides that mimic antigenic epitopes of Aβ, have recently gained attention as safe and effective candidates for vaccine development. In this study, we employed a computational immunoinformatics approach to identify novel Aβ42-mimicking peptides derived from non-coding DNA sequences, representing an unconventional yet rich source of bioactive peptides. A virtual peptide library was generated from intergenic regions of the Escherichia coli genome and screened using B-cell epitope prediction, MHC-binding analysis, and structural similarity modeling to identify potential immunogenic mimotopes. Selected candidates were further evaluated through peptide-antibody docking with Aβ42-specific antibody fragments to assess binding affinity and epitope mimicry. Our findings demonstrate a novel computational framework for mining non-coding DNA to identify therapeutic peptide mimotopes. The identified Aβ42-like peptides exhibit strong potential as synthetic vaccine candidates for Alzheimer's disease, supporting a new direction in rational vaccine design against neurodegenerative disorders.},
}

*Amyloid beta-Peptides/immunology/chemistry/genetics
*Alzheimer Disease/immunology/therapy/prevention & control/genetics
Humans
*Peptide Fragments/immunology/chemistry/genetics
*Vaccines, Subunit/immunology
Epitopes, B-Lymphocyte/immunology/genetics/chemistry
*Alzheimer Vaccines/immunology
Molecular Docking Simulation
Peptide Library
Protein Subunit Vaccines