@article {pmid41692954,
year = {2026},
author = {Zhu, S and Resnick, B and Boltz, M and Galik, E and Mcpherson, R and Kuzmik, A and Wells, C and Lee, E and Shim, S},
title = {Bidirectional Associations Between Physical Function and Physical Activity Among Older Adults Living with Dementia.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag027},
pmid = {41692954},
issn = {1758-535X},
abstract = {BACKGROUND: Previous research has suggested a likely reciprocal relationship between physical function and physical activity among older adults, but few assessed those living with dementia. This study examined the bidirectional relationship between physical function and physical activity among older adults living with dementia during hospitalization and post discharge periods, and whether the relationship differs by severity of dementia.

METHODS: This secondary analysis included 455 older adult patients aged 55 years and older living with dementia from a randomized clinical trial, assessed during admission, discharge, 1-, 6-, and 12-month post-discharge periods. Random intercept cross-lagged panel models were used to assess the bidirectional relations, controlling for age, comorbidities, admission location, length of stay, discharge location, and intervention status.

RESULTS: Average age was 82.47 (SD = 8.49) and majority were female (62.6%) and White (65.3%). The average SLUMS score was 7.51 (SD = 5.90) with 77% (n = 351) having a severe level of cognitive impairment. Antecedent physical function at admission, discharge, and 1-month predicted physical activity at corresponding cross-lagged timepoint separately (range of unstandardized coefficients b's: .037-.043, p's<.05); physical activity at discharge predicted physical function at 1-month (b=.708, p=.016). This bi-directional relationship varied by severity of dementia, appearing at the first two cross-lagged time points in patients with severe dementia (b's: .039-.049 and .464-.848, all p's <.05), but not in those with moderate dementia.

CONCLUSIONS: Physical activity and physical function commonly co-occur among older adults with dementia. Intervention studies promoting both physical function and physical activity among older adults with dementia may achieve greater effectiveness when tailored to differences in dementia severity.},
}

@article {pmid41692891,
year = {2026},
author = {More, SA and Mundke, R and Sikkalgar, A and Tarwani, RS and Siddique, MUM and Goyal, SN and Agrawal, YO and Nakhate, KT and Rathod, SS},
title = {Neuroprotective efficacy of hentriacontane against rotenone-induced apoptosis in SH-SY5Y cells: In silico and in vitro evidence of GSK3β association.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41692891},
issn = {1432-1912},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), are marked by gradual neuronal loss, frequently associated with mitochondrial dysfunction. Hentriacontane is a naturally occurring long-chain saturated hydrocarbon found in beeswax and certain herbal plants, and has antioxidant, anti-inflammatory and cytoprotective properties, suggesting its therapeutic potential in oxidative stress-associated neurodegeneration. Rotenone, a mitochondrial complex I inhibitor, induces oxidative stress and apoptosis, making it a widely used neurotoxic agent for investigating neurodegenerative disorders like AD. We initially performed in silico molecular docking, molecular dynamics, MM/GBSA, and ADMET pharmacokinetic analyses of hentriacontane against GSK3β to evaluate binding affinities and energies and assess the stability and dynamics of protein-ligand complexes. An in vitro drug safety assay was conducted using the MTT assay in SH-SY5Y cells. The cells were pretreated with 100 μM rotenone two hours before the assay. A 96-well tissue culture-grade microplate was prepared with 100 μL of cell suspension (1 × 10[4] cells/mL), and test compounds were added at concentrations of 20, 40, 60, 80, and 100 μg/mL. Biochemical assays were conducted on cell supernatant to evaluate oxidative stress, proinflammatory, and apoptotic markers. Hentriacontane exhibited a significant binding affinity, with lower RMSD, RMSF, and a more negative ΔG_bind. ADMET analyses indicated favorable pharmacokinetic features. In vitro studies demonstrated that hentriacontane significantly enhanced cell viability, reduced oxidative stress markers, suppressed apoptotic and pro-inflammatory markers, and GSK3β protein levels. The collaborative significance of in silico and in vitro investigations suggests that hentriacontane may serve as a promising therapeutic candidate for mitigating oxidative stress-induced neurotoxicity via modulation of the GSK3β pathway.},
}

@article {pmid41692872,
year = {2026},
author = {Zhang, L and Li, X and Luo, H and Huo, Y and Zhou, G and Wang, P and Wu, S and Lin, X and Dai, K and Shi, J and Wang, Z and Xu, J and Li, R and Chen, S and Sun, Z and Zhao, C and Zhou, Z and Wang, Z and Liang, C and Zhu, J and Chen, X and Luo, J and Yu, Y and Zhang, Z and Wang, G},
title = {Mitochondrial double-stranded RNA drives aging-associated cognitive decline.},
journal = {Cell research},
volume = {},
number = {},
pages = {},
pmid = {41692872},
issn = {1748-7838},
support = {32450418, 91949103, 32071159//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2017YFA0504600//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; },
abstract = {Aging is the primary cause of cognitive decline. Despite extensive study, the molecular mechanisms driving aging-associated cognitive decline remain unclear. Here, we describe a proteostasis-independent function of SEC61A1 and its involvement in aging-associated cognitive decline. SEC61A1 regulates ER-mitochondria contact sites, affecting mitochondrial DNA and RNA synthesis and subsequently leading to changes in innate immune signaling mediated by mitochondrial double-stranded RNA (mt-dsRNA). This pathway is activated in aged wild-type mice, Alzheimer's disease patients, and 5×FAD mice. Tissue-specific overexpression of Sec61a1 in the mouse cortex (Sec61a1[Tg]) is sufficient to induce cognitive decline without affecting motor activity. Knockdown of Sec61a1 or Mavs ablates mt-dsRNA-mediated innate immune signaling and alleviates cognitive decline in naturally aging wild-type mice. These results reveal a molecular mechanism of aging- and disease-associated cognitive decline and provide a potential therapeutic tool for intervention.},
}

@article {pmid41692846,
year = {2026},
author = {Nguyen, VTD and Pham, P and Hy, TS},
title = {Enabling multi-target drug discovery through latent evolutionary optimization and synthesis-aware prioritization (EVOSYNTH).},
journal = {Communications chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42004-026-01945-4},
pmid = {41692846},
issn = {2399-3669},
abstract = {Complex diseases, such as cancer and neurodegeneration, feature interconnected pathways, making single-target therapies ineffective due to pathway redundancy and compensatory mechanisms. Polypharmacy, which combines multiple drugs to target distinct proteins, addresses this but often leads to drug-drug interactions, cumulative toxicity, and complex pharmacokinetics. To overcome these challenges, we introduce EVOSYNTH, a modular framework for multi-target drug discovery that combines latent evolution and synthesis-aware prioritization to generate and prioritize candidates with high translational potential. Latent evolution navigates a chemically and functionally informed latent space to identify candidates with strong predicted affinity across multiple targets. Synthesis-aware prioritization evaluates both retrosynthetic feasibility and the trade-off between synthetic cost and therapeutic reward, enabling practical and efficient candidate selection. Applied to dual inhibition of JNK3 and GSK3β in Alzheimer's disease and PI3K and PARP1 in ovarian cancer, EVOSYNTH consistently outperforms baseline generative models, achieving higher predicted affinities, improved scaffold diversity, and lower synthesis costs. These findings highlight EVOSYNTH's ability to integrate target-driven generation with practical synthesizability, establishing a scalable framework for multi-target and polypharmacological drug discovery. Our source code and data to reproduce all experiments are publicly available on GitHub at: https://github.com/HySonLab/EvoSynth.},
}

@article {pmid41692408,
year = {2026},
author = {Saeed, S and Khan, S and Noor, A and Zerr, I and Zafar, S},
title = {Therapeutic Potential of Amyloid-β Interactors in Rapidly Progressive Alzheimer's Disease-An In Silico Study.},
journal = {Molecular informatics},
volume = {45},
number = {2},
pages = {e70024},
doi = {10.1002/minf.70024},
pmid = {41692408},
issn = {1868-1751},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism/chemistry ; Humans ; Molecular Docking Simulation ; Computer Simulation ; Protein Interaction Maps ; },
abstract = {Rapidly progressive Alzheimer's disease (rpAD) is a rare but severe form of Alzheimer's disease characterized by accelerated cognitive decline and limited therapeutic options. Conventional anti-amyloid-β interventions have shown little success due to poor target specificity, neurotoxicity, and lack of efficacy, underscoring the need for novel therapeutic strategies. This study aimed to identify and prioritize molecular targets associated with rpAD by investigating the protein interactome of amyloid-β (Aβ42) using integrative computational approaches. Functional enrichment, protein-protein interaction network analysis, and community clustering revealed that rpAD-specific Aβ42 interactors were predominantly involved in mitochondrial bioenergetics, redox regulation, and cytoskeletal stability, pathways central to neuronal survival and synaptic function. Molecular docking identified fumarate hydratase, carbonyl reductase 1, and the F-actin capping protein as high-affinity interactors of Aβ42, linking these proteins to energy failure, oxidative stress, and synaptic dysfunction. Virtual screening of a therapeutic drug library against fumarate hydratase identified several compounds with strong binding affinities, among which quinestrol, estradiol benzoate, norethindrone, tamibarotene, drospirenone, and ketanserin emerged as lead candidates. Pharmacokinetic profiling, including ADMET modeling, confirmed their blood-brain barrier permeability and drug-likeness, supporting their potential as central nervous system active agents. Together, this work highlights key molecular targets in rpAD and proposes repurposed, pharmacologically diverse compounds with multitarget neuroprotective potential. By utilizing in silico analysis, the study provides a rational framework for target discovery and drug prioritization in rpAD, offering a foundation for future experimental validation and the development of translational research.},
}

*Alzheimer Disease/drug therapy/metabolism
*Amyloid beta-Peptides/metabolism/chemistry
Humans
Molecular Docking Simulation
Computer Simulation
Protein Interaction Maps

@article {pmid41692246,
year = {2026},
author = {Strickland, MR and Wang, Z and Golden, LR and Wang, H and Lu, P and Ren, Y and Tabor, GT and Zhao, N and Ulrich, JD and Han, X and Peng, J and Holtzman, DM},
title = {Lipidome and Proteome of Astrocyte and Microglia ApoE Lipoprotein Reveal Differences Based on Cell Type and ApoE Isoform.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {101000},
doi = {10.1016/j.jlr.2026.101000},
pmid = {41692246},
issn = {1539-7262},
abstract = {Apolipoprotein E (ApoE) is the primary, most abundant apolipoprotein of the central nervous system (CNS) and plays an important role in brain metabolism and lipid homeostasis. In the CNS, ApoE is primarily secreted by astrocytes under homeostatic conditions and by microglia in certain disease-related conditions. APOE has three major alleles: APOE2, APOE3, and APOE4. APOE4 is the strongest genetic risk factor for late onset Alzheimer's disease (AD) and APOE2 results in decreased risk relative to APOE3. ApoE derived from astrocytes and microglia have been hypothesized to play different roles in the disease pathogenesis of Alzheimer's disease. In this study, we profiled the lipidome and proteome of ApoE lipoproteins secreted by astrocytes or microglia and found that they differed according to the cellular source of ApoE and ApoE isoform. Lipidomics revealed microglia-derived ApoE lipoproteins were enriched in cholesterol esters whereas astrocyte ApoE lipoproteins were enriched in sphingomyelin. Proteomics revealed astrocyte ApoE lipoproteins were enriched in proteins involved in glucose metabolism and acute phase response. Microglia-secreted lipoproteins were enriched in proteins involved in complement activation, synapse pruning, proteolysis, and the innate immune response. Further comparison of ApoE lipoproteins from APOE4 microglia revealed that ApoE4 lipoproteins were enriched in C1q and Lpl compared to ApoE2 and ApoE3 microglial lipoproteins which were enriched in Ankk1 and ApoC1. These results provide the molecular foundation for better understanding of how ApoE functions as an apolipoprotein with the lipoprotein cargo being dependent on the cellular source and ApoE isoform, ultimately contributing to CNS homeostasis and disease pathogenesis.},
}

@article {pmid41692216,
year = {2026},
author = {Roland, NJ and Zigmond, JW and Manganaro, JE and Daniel Estrella, L and Stauch, KL},
title = {APOE4 induces sex-dependent synaptic mitochondrial cholesterol, proteome, and respiratory function alterations in mice.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106125},
doi = {10.1016/j.neuint.2026.106125},
pmid = {41692216},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by synapse damage and loss, correlating strongly with cognitive decline. APOE4, the strongest genetic risk factor for AD, impairs synapses with the mechanisms remaining unclear. APOE, the central nervous system's primary lipid and cholesterol carrier, is critical for axonal growth, synapse formation, and spine remodeling. To investigate how APOE4 affects cholesterol and synaptic dysfunction, we studied male and female human APOE3 and APOE4 knock-in mice. Cholesterol levels were measured in brain homogenates, synaptosomes, and mitochondria using bioluminescent assays, and APOE protein expression was analyzed via immunoblotting. Proteomics of synaptosomes and mitochondrial respiratory function assessments were performed using mass spectrometry and the Seahorse XF Analyzer, respectively. We found that cholesterol levels did not differ between APOE3 and APOE4 mice in brain homogenates or synaptosomes. However, male APOE4 mice exhibited lower cholesterol levels in synaptic mitochondria than APOE3 mice, with no changes in non-synaptic mitochondria or female mice. APOE protein was present in synaptosomes and mitochondrial fractions without changes due to APOE4 expression. Synaptosomal proteomics uncovered synaptic mitochondrial membrane proteins were differentially expressed in APOE4 versus APOE3 mice. Proteomic analysis also revealed altered neurotransmitter signaling and metabolic pathways in the APOE4 mice, predominantly in males. Notably, proteins involved in synaptic vesicle endocytosis and aerobic respiration were differentially expressed. Mitochondrial respiratory function was disrupted in female APOE4 mice, which displayed increased maximal respiration and spare respiratory capacity at the synapse. These findings identify a role for APOE in regulating synaptic mitochondrial cholesterol, protein expression, and respiratory function in a sex-dependent manner, contributing to synaptic dysfunction in AD.},
}

@article {pmid41692211,
year = {2026},
author = {Yue, S and Xing, H and Du, X and Wang, Y and Qin, R and He, J and Yu, J and Zhangsun, D and Craik, DJ and McIntosh, JM and Wu, Y and Zhu, X and Luo, S},
title = {α-Conotoxin LvID, an antagonist of α7 nicotinic acetylcholine receptor, mitigates Alzheimer-associated phenotypes by inhibiting Aβ deposition and reactive astrogliosis.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {150933},
doi = {10.1016/j.ijbiomac.2026.150933},
pmid = {41692211},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is the most common form of dementia in older adults. Neuritic plaques and reactive astrogliosis are neuropathological hallmarks of AD. Amyloid beta (Aβ), the major component of neuritic plaques, is derived from amyloid precursor protein (APP) by sequential cleavages by β-secretase and γ-secretase. The dysregulation of α7 nicotinic acetylcholine receptors (α7 nAChRs) is associated with both reactive astrogliosis and Aβ deposition. However, the role of nAChR antagonists in AD pathogenesis and underlying mechanisms remains elusive. In this study, we explored the effect of α-conotoxin LvID, a marine-derived peptide from Conus lividus, acts as a selective antagonist of α7 nAChRs, on AD pathogenesis. We found that LvID rescues learning and memory deficits in AD model mice in Morrios water maze, This led to a doubling of the memory of the AD model mice. Moreover, LvID treatment can reduce it by 50% in Aβ levels and also inhibited the proliferation of reactive astrocytes in AD model mice compared to non-treated AD model mice. Furthermore, the effect of LvID on learning and memory deficits and Aβ generation is mediated by an α7 nAChR‑calcium-CaMKII signaling pathway. These findings suggest that LvID may offer therapeutic potential for AD treatment by modulating α7 nAChR-mediated pathways involved in Aβ production. The work demonstrates that LvID is a potential drug template for AD treatment.},
}

@article {pmid41692182,
year = {2026},
author = {Dos Santos, JR and Pedrazzi, JF and Alberici, LC and Catalão, CHR},
title = {Enhanced avoidance learning associated with elevated anxiety in the 3xTg-AD mouse model of Alzheimer's disease.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115269},
doi = {10.1016/j.physbeh.2026.115269},
pmid = {41692182},
issn = {1873-507X},
abstract = {Alzheimer's disease (AD) is the world's most prevalent degenerative neurological disease, characterized by extracellular accumulation of misfolded Aβ peptide and intracellular formation of neurofibrillary tangles. In addition to cognitive deficits, psychological and behavioral manifestations such as fear, anxiety, and depression are present in patients with AD. The relationship between these noncognitive symptoms and memory and learning deficits remains unknown. Using a genetic mouse model of the disease, we assessed fear-based learning and anxiety through the active avoidance test (AAT) and elevated plus maze (EPM) in middle-aged 3xTg-AD mice. Animals were tested in four consecutive daily sessions, and measures of avoidance rate, avoidance latency, escape rate, and escape latency were performed. After seven days, the mice were placed in the EPM, and the number of entries and time spent on the open arms were quantified. The AAT revealed that 3xTg-AD animals exhibited a higher avoidance rate in sessions 3 (p < 0.001) and 4 (p < 0.01), a shorter escape rate in sessions 3 (p < 0.01) and 4 (p < 0.05), and a shorter escape latency in session 3 (p < 0.05). Furthermore, 3xTg-AD mice had a lower percentage of entries (p < 0.001) and a shorter time spent (p < 0.001) in the open arms of the EPM compared to the control group. These results suggest that the high performance of transgenic animals in learning to avoid shocks may be related to an intrinsic state of alertness, making the 3xTg-AD mouse a reliable model for investigating the neurobiological and pathological mechanisms of anxiety and fear in AD.},
}

@article {pmid41692179,
year = {2026},
author = {Khangura, MS and Spratt, MA and Gao, A and Manhapra, A and Siegel, NH and Chen, X and Poulaki, V and Ness, S and Stein, T and Subramanian, ML},
title = {The Association Between Diabetic Retinopathy Severity and Dementia Risk: A TriNetX Longitudinal Cohort Study.},
journal = {American journal of ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajo.2026.02.014},
pmid = {41692179},
issn = {1879-1891},
abstract = {PURPOSE: Diabetes mellitus (DM) and diabetic retinopathy (DR) have been associated with higher incidence of dementia and may serve as clinical indicators for underlying cognitive disease. This study investigated whether severity of DR is linked to increased risk of dementia.

DESIGN: Retrospective cohort study.

PARTICIPANTS: Participants were categorized into four groups: proliferative diabetic retinopathy (PDR), nonproliferative DR (NPDR), type 2 DM (DM2) without DR, and no DM. Individuals under age 65 and those with macular edema were excluded.

METHODS: Groups were propensity score matched 1:1 for demographic and clinical covariates. Outcomes included incidence of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD), assessed using Cox proportional hazard ratios (HR) with 95% confidence intervals (CIs). Kaplan-Meier analysis evaluated time to dementia onset.

MAIN OUTCOME MEASURES: Incidence and hazard ratios of all-cause dementia, AD, and VD.

RESULTS: The TriNetX database identified 14,034 individuals with PDR, 29,188 individuals with NPDR, 208,640 with DM2 without DR, and 447,054 without DM. Compared to non-diabetics, all three diabetic groups (PDR, NPDR, and DM2 without DR) had a higher risk of all-cause dementia (HR 1.583, p<0.0001 PDR; 1.405, p<0.0001 NPDR; 1.262, p<0.0001 DM2 without DR), AD (HR 1.175, p=0.0419 PDR; 1.233, p<0.0001 NPDR; 1.117, p<0.0001 DM2 without DR), and VD (HR 2.077, p<0.0001 PDR; 1.917, p<0.0001 NPDR; 1.384, p<0.0001 DM2 without DR). Compared to participants with DM2 without DR, those with PDR and NPDR had higher risk for all-cause dementia (HR 1.202, p<0.0001 PDR; 1.113, p<0.0001 NPDR) and VD (HR 1.504, p<0.0001 PDR; 1.322, p<0.0001 NPDR), but not AD. When stratified by DR severity, PDR was associated with a higher risk of all-cause dementia (HR 1.121, p=0.0003 PDR) and VD (HR 1.177, p=0.0126 PDR), but not AD, compared to NPDR.

CONCLUSION: Greater severity of DR is associated with an increased risk of all-cause dementia and VD in individuals with DM2 without DR, whereas AD risk appears elevated only when compared to nondiabetic participants. These findings suggest that progressive DR reflect systemic microvascular injury that parallels cerebral small vessel disease. Routine ophthalmologic screening in patients with DM may provide an opportunity for early identification of individuals at higher risk of cognitive decline.},
}

@article {pmid41692154,
year = {2026},
author = {Chen, YC and Chiu, TJ and Wu, YY and Wang, YT and Wu, KH and Yeh, TH and Hsieh, YJ and Chen, WS and Chiu, CC},
title = {ALDH2 activation protects against mutant TOMM40-mediated mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124274},
doi = {10.1016/j.lfs.2026.124274},
pmid = {41692154},
issn = {1879-0631},
abstract = {AIMS: TOMM40 (translocase of outer mitochondrial membrane 40) is crucial for mitochondrial protein import. Mutations in TOMM40 increase the risk of Alzheimer's disease (AD) and trigger neuroinflammation. ALDH2 (aldehyde dehydrogenase 2) has neuroprotective effects, but the therapeutic role of ALDH2 activation in targeting neuroinflammation-induced AD remains unclear.

MATERIALS AND METHODS: In this study, it was hypothesized that TOMM40 mutations cause BV2 microglial activation and neuronal loss by impairing mitochondrial functions and that ALDH2 activation by small-molecule activator Alda-1 exerts anti-neuroinflammatory effect on HT22 hippocampal neurons.

KEY FINDINGS: Expression of mutant TOMM40 (F113L or F131L) induced BV2 microglial activation, reduced ALDH2 activity, and impaired mitochondrial function in BV2 microglia. ALDH2 activation by Alad-1 attenuated mutant TOMM40-induced microglial activation, mitochondrial dysfunction, ROS production, and lipid droplet accumulation. Alda-1 also suppressed mutant TOMM40-induced ROS/NF-κB/NLRP3 inflammasome axis and reduced the secretion of IL-1β, IL-6, and TNF-α. Conditioned medium from mutant TOMM40-expressing microglia induced apoptosis, neurite degeneration, and neuronal death in HT22 hippocampal neurons, which were alleviated by Alda-1 treatment.

SIGNIFICANCE: These findings suggest that ALDH2 activation prevents neuroinflammation-induced hippocampal neuronal death by downregulating NLRP3 inflammasome pathway, reducing lipid droplet accumulation, and enhancing mitochondrial function and neurite outgrowth.},
}

@article {pmid41692031,
year = {2026},
author = {Hobday, JV and Rosopa, PJ and Rosopa, EB and Hobday, A and Gaugler, JE},
title = {An Online Training Program to Reduce Antipsychotic Medication Use in Nursing Homes: The CARES Method.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106122},
doi = {10.1016/j.jamda.2026.106122},
pmid = {41692031},
issn = {1538-9375},
abstract = {The objective of this Pragmatic Innovation article is to present a case study examining whether an online, asynchronous staff dementia care training program (CARES) was associated with reductions in the use of antipsychotic medications and improved staff perceptions in a New Mexico residential long-term care setting. Staff at Lakeview Christian nursing home began using the CARES Dementia 5-Step Method-Complete Catalog online training and certification program in 2019. The asynchronous, scalable CARES online dementia care modules were implemented successfully and sustained at Lakeview Christian as a core strategy to reduce antipsychotic medication use. The reductions in antipsychotic medication use at Lakeview Christian were more pronounced than those in peer nursing homes in New Mexico during the CARES implementation period (2019-2024). Various elements of CARES appeared to drive its implementation success, including its flexibility and self-paced module delivery, its comprehensive focus on behaviors, and its alignment with Lakeview Christian's culture and its focus on reducing antipsychotic medication use. The implementation process of CARES also highlighted the need for person-centered dementia care education, training, and principles for prescribing physicians.},
}

@article {pmid41691984,
year = {2026},
author = {Zhang, X and Cao, K and Wan, J and Liu, Z and Ren, Z and Wang, W and Wang, H},
title = {Neuroprotective effects and mechanism of ginseng aqueous extract against Alzheimer's disease.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {153},
number = {},
pages = {157943},
doi = {10.1016/j.phymed.2026.157943},
pmid = {41691984},
issn = {1618-095X},
abstract = {Limitations of current Alzheimer's disease (AD) therapies necessitate novel neuroprotective strategies. This study elucidated the multi-target mechanisms of ginseng aqueous extract (GAE) using complementary in vitro and in vivo AD models. Structural characterization indicated that the active ingredients of GAE included total saponins (19.64 ± 0.89%), total flavonoids (0.04±0.03%) and total polyphenols (6.41±0.15%). The primary active components in GAE are total saponins, which account for its highest compositional proportion. In vitro, GAE (0.8 mg/ml) exhibited potent antioxidant activity, evidenced by DPPH scavenging (27.14%), ABTS[+] reduction (59.49%), and ·OH quenching (28.08%). It restored neuronal homeostasis by normalizing intracellular Ca[2+] levels, reinstating mitochondrial membrane potential, and reducing ROS production. In transgenic Drosophila, GAE conferred multi-mechanistic neuroprotection via upregulation of antioxidant genes, autophagy activation, and enhanced insulin signaling. These actions translated to functional improvements, including reduced Aβ deposition, decreased neuronal apoptosis, preserved gut barrier integrity, extended lifespan, and improved locomotion-stress tolerance. Collectively, GAE represents a promising multi-target therapeutic candidate for AD by synergistically modulating oxidative stress, protein homeostasis and metabolic pathways.},
}

@article {pmid41691953,
year = {2026},
author = {Sandoval-Diez, N and Loizeau, N and Huss, A and Röösli, M and Vienneau, D},
title = {Long-term residential magnetic field exposure and neurodegenerative disease mortality: An 18-year nationwide cohort study in Switzerland.},
journal = {Environment international},
volume = {208},
number = {},
pages = {110145},
doi = {10.1016/j.envint.2026.110145},
pmid = {41691953},
issn = {1873-6750},
abstract = {BACKGROUND: Epidemiological evidence on the association between extremely low-frequency magnetic fields (ELF-MF) exposure and neurodegenerative diseases (NDD) remains inconsistent. Few population-based studies using exposure from high-voltage power lines (HVPL) have found mixed findings, and none have yet considered exposure from railway lines.

METHODS: We followed 3,555,064 adults from the Swiss National Cohort (2001-2018), contributing 55.4 million person-years. Long-term ELF-MF exposure from HVPL (50 Hz) and railway lines (16.7 Hz) was modelled using validated proximity models and updated over four intervals (2001-2005, 2006-2010, 2011-2015, 2016-2018). Long-term ELF-MF exposure was calculated as a time-weighted average exposure over 10-year windows preceding each interval. Cox proportional hazards models estimated hazard ratios (HRs) for mortality from Alzheimer's disease (AD), other types of dementia (OTD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS), adjusting for sociodemographic and environmental co-exposures.

RESULTS: During follow-up, 146,655 NDD deaths occurred. Less than 1% of the population was exposed to long-term ELF-MF ≥ 0.3 µT from HVPL and 2.4% from railway lines. HVPL exposure was positively associated with mortality from AD (HR per 1 µT increase in exposure = 1.54; 95% CI: 1.23-1.92) and OTD (HR = 1.31; 95% CI: 1.13-1.52). Associations for railway exposure were weaker and attenuated after adjusting for environmental co-exposures. No associations were observed for ALS, PD, or MS.

CONCLUSIONS: Long-term ELF-MF exposure was associated with higher dementia mortality risk in the general population, but not with ALS, PD, or MS. Causal inference remains limited by the absence of established biological mechanisms.},
}

@article {pmid41691754,
year = {2026},
author = {Emam, NE and Refaey, RH and El-Ashrey, MK and Mahmoud, WR and Nissan, YM and Seif, EM},
title = {Development of coumarin-based acetylcholinesterase inhibitors: Synthesis, biological assessment and computational simulations.},
journal = {Bioorganic chemistry},
volume = {173},
number = {},
pages = {109630},
doi = {10.1016/j.bioorg.2026.109630},
pmid = {41691754},
issn = {1090-2120},
abstract = {Novel coumarin-based derivatives (5, 6a-c and 10a-j) have been designed, synthesized and biologically assessed as multimodal anti-Alzheimer agents targeting acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and glycogen synthase kinase-3β (GSK-3β). The synthesized derivatives have been afforded in a good yield and the structures confirmed by the spectral analysis. Among these derivatives, four derivatives (10c, 10d, 10 f and 10i) exhibited remarkable inhibitory activity against the acetylcholinesterase enzyme in nanomolar concentration (IC50 = 5.93 ± 0.06, 3.97 ± 0.15, 3 ± 0.1, and 4.97 ± 0.06 nM, respectively), surpassing the reference donepezil drug (IC50 = 7.03 ± 0.15 nM). Moreover, derivative 10 f demonstrated a significant BuChE inhibitory activity (IC50 = 303 ± 0.03 nM), about 2-fold the donepezil activity. Consequently, derivative 10 f was selected for the GSK-3β inhibition assay and displayed a greater inhibitory activity in nanomolar range (7.58 ± 0.83 nM) than the reference broad-spectrum kinase inhibitor staurosporine (8.63 ± 0.94 nM). Additionally, derivative 10 f was assayed for the iron chelating capacity and showed significant activity compared to the iron chelator EDTA. The molecular docking of derivatives 10c, 10d, 10 f, and 10i utilizing the AChE enzyme as a target protein (PDB: 4EY7) was evaluated and highlighted 10 f as a promising lead candidate with favorable interactions and high affinity. The key hydrogen bonds, hydrophobic contacts, and π-π stacking interactions support the observed bioactivity. Furthermore, molecular dynamics simulations indicated the stability of the compound-enzyme complexes, with low RMSD fluctuations and favorable binding free energies. Collectively, these findings emerge as derivative 10 f, a promising lead scaffold for Alzheimer's disease with multimodal activity.},
}

@article {pmid41691696,
year = {2026},
author = {Baniasadipour, B and Bagheri, F and Hendudari, F and Koopaee, S and Amini, SM and Kamalabadi, MA and Fatemidokht, A},
title = {Molecular and Microstructural MRI of Neuroinflammation in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050420458251115070244},
pmid = {41691696},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a leading cause of cognitive decline in older adults, often diagnosed late when pathology and symptoms are established, reducing treatment effectiveness. Both AD and mild cognitive impairment (MCI) trigger neuroinflammation, leading to molecular and microstructural changes, including oxidative stress, mitochondrial dysfunction, glial activation, synaptic and neurotransmitter disturbances, myelin degradation, and white matter dysfunction. The blood-brain barrier (BBB) is also compromised.

METHODS: Advanced magnetic resonance imaging (MRI) techniques, such as magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), magnetization- transfer imaging (MTI), chemical exchange saturation transfer (CEST), contrast-enhanced MRI (CE-MRI), and arterial spin labeling (ASL), offer promise for the early detection of Alzheimer's disease (AD)-related molecular and microstructural changes.

RESULTS: Based on recent studies, advanced MRI modalities-including magnetic resonance spectroscopy, diffusion imaging, contrast-enhanced imaging, and chemical shift imaging-can highlight metabolic dysfunction, white matter degradation, microstructural disruption, blood-brain barrier dysfunction, cerebral hypoperfusion, vascular dysfunction, and pH alterations caused by neuroinflammation in Alzheimer's patients.

DISCUSSION: The integration of advanced MRI modalities into clinical practice could improve the diagnosis and management of Alzheimer's disease (AD). Magnetic resonance spectroscopy and diffusion imaging can identify metabolic and microstructural changes years before brain atrophy occurs, aiding professionals in the early detection of AD. Additionally, perfusion imaging and magnetization transfer imaging can help distinguish between Alzheimer's disease, frontotemporal dementia (FTD), and vascular dementia. Finally, contrast-enhanced MRI can monitor the integrity of the blood-brain barrier to evaluate responses to drug treatments.

CONCLUSION: Despite challenges, such as longer scan times and limited specificity, advanced MRIbased approaches are at the forefront of identifying reliable biomarkers for early detection of Alzheimer's disease and determining optimal management and treatment strategies.},
}

@article {pmid41691694,
year = {2026},
author = {Yang, Z and Tangli, M and Tan, Y and Chen, H and Shu, N and Ke, Z and Hu, Z and Ye, Q and Meng, H and Chen, H and Xu, Y},
title = {Repetitive Transcranial Magnetic Stimulation Alters Brain Communication Networks to Improve the Cognitive Function in Patients with Amnestic Mild Cognitive Impairment - A Clinical Trial.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X389814251019160424},
pmid = {41691694},
issn = {1875-6190},
abstract = {INTRODUCTION: Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive intervention that could effectively enhance the cognitive function in patients with amnestic mild cognitive impairment (aMCI). However, the mechanism and predictive biomarkers for therapeutic response remain poorly understood.

METHODS: Fifty-three aMCI patients underwent either neuro-navigated rTMS (n=28) or sham stimulation (n=25) targeting the left angular gyrus over four weeks (registered in 2021: ChiCTR2100050496). Multimodal MRI and comprehensive neuropsychological assessments were conducted pre- and post-intervention. Changes in brain communication networks and their correlation with cognitive improvements were analysed, with random forest models applied to predict treatment efficacy.

RESULTS: Episodic memory (p<0.001) and general cognitive function (p<0.05) of aMCI patients were significantly improved after intervention. Novel alterations in brain communications networks were identified in 5 sensorimotor areas, executive control regions, and emotion-cognition processing hubs. Communication alterations between the right precentral gyrus and right angular gyrus were positively correlated with the improvements in episodic memory (r=0.38, p=0.046), while the alterations between right precentral gyrus and right angular gyrus were negatively correlated with improvements in general cognitive function (MMSE, r=-0.44, p=0.019; MoCA, r=-0.43, p=0.024). Notably, the random forest model integrating communication network patterns with baseline demographic and neuropsychological data showed strong power in predicting rTMS effects.

DISCUSSION: These findings advance understanding of rTMS mechanisms by linking network plasticity to cognitive gains, addressing critical knowledge gaps.

CONCLUSION: Neuro-navigated rTMS targeting the left angular gyrus may enhance cognitive function in aMCI patients by improving inter-brain regions communication. Baseline communication patterns hold promise as predictive biomarkers, facilitating personalized treatment strategies.},
}

@article {pmid41691677,
year = {2026},
author = {Xinyang, L and Yuling, L and Shuai, M and Jing, H and Jianjun, C and Yang, G and Caixia, L and Ke, H and Yazhen, S},
title = {Network Pharmacology and Experimental Approaches Reveal the Effects of Scutellaria barbata Flavonoids Against Alzheimer's Diseasevia CREB Phosphorylation in Rats.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673417632251125054314},
pmid = {41691677},
issn = {1875-533X},
abstract = {INTRODUCTION: In this study, we investigated the effects and molecular mechanisms by which Scutellaria barbata flavonoids (SBFs) enhance neurogenesis and ameliorate memory impairment mediated by CREB phosphorylation in rats, using a network pharmacology approach.

METHODS: The active ingredients of SBFs and their targets were identified using the Traditional Chinese Medicine Systems Pharmacology platform. An Alzheimer's disease (AD) model was established by intracerebroventricular injection of Aβ25-35 combined with AlCl₃ and RHTGF-β1 (composited Aβ) in rats. The Morris water maze was used to confirm the successful establishment of the AD rat model. Successfully modeled rats were randomly divided into three groups: a model group and two treatment groups receiving either 140 mg/kg SBFs or 0.5 mg/kg Rolipram (positive control). After 38 days, the Morris water maze test was performed to assess learning and memory abilities. Hematoxylin-eosin (HE) staining, immunohistochemistry, quantitative PCR (qPCR), and Western blotting (WB) were conducted to evaluate neuronal morphology, NeuN protein expression, the mRNA levels of TrkB, RSK, CREB, and BDNF, and the protein expression of NeuN, TrkB, RSK, P-CREB-Ser133, and BDNF in the hippocampus and cerebral cortex of the rats.

DISCUSSION: These results indicate that SBFs and Rolipram ameliorate learning and memory impairment, reduce neuropathological changes, promote neurogenesis, and upregulate the BDNF- RSK-CREB signaling pathway through the activation of CREB phosphorylation. The findings suggest that the effects of SBFs are similar to those of Rolipram and that SBFs may also act as activators of CREB phosphorylation. Overall, SBFs promote neurogenesis and improve learning and memory deficits, possibly by enhancing CREB phosphorylation. This study identified the key targets and signaling pathways of SBFs in AD, indicating that SBFs represent a promising multitarget therapeutic candidate for the treatment of AD. However, our research has some limitations. Further studies are needed to determine the absorption route, major active components, and metabolic forms of the bioactive substances in SBFs. In future work, we aim to clarify the potential mechanisms of SBFs in AD by integrating multiple omics approaches and to evaluate the safety and efficacy of SBFs in AD treatment.

RESULTS: Thirty-seven targets were identified based on the intersection between AD-related targets and the components of SBFs. SBFs were involved in anti-AD activity through the MAPK signaling pathway, including the BDNF-RSK-CREB pathway. SBFs attenuated memory impairment, ameliorated neuropathological changes, increased NeuN protein expression, and regulated the mRNA expression of TrkB, RSK, CREB, and BDNF, as well as the protein expression of NeuN, TrkB, RSK, P-CREB-Ser133, and BDNF. Rolipram produced similar effects to SBFs.

CONCLUSION: Network pharmacology analysis and animal experiments confirmed that SBFs promote neurogenesis and ameliorate learning and memory impairment in AD model rats, primarily by facilitating CREB phosphorylation, similar to Rolipram. This study indicates that SBFs may be a promising therapeutic candidate for the treatment of AD.},
}

@article {pmid41691604,
year = {2026},
author = {Zhong, P and Shaker, T and Li, P and Yan, Z},
title = {Compromised synaptic signal from prefrontal cortex to mediodorsal thalamus in Alzheimer's disease models and its rescue by kinase inhibitors.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP289018},
pmid = {41691604},
issn = {1469-7793},
support = {AG064656/NH/NIH HHS/United States ; AG067597/NH/NIH HHS/United States ; },
abstract = {One of the most important neural circuits controlling cognitive processes is the projection from prefrontal cortex (PFC) to thalamus. To determine the strength of PFC projections to different thalamic nuclei, we performed optogenetic experiments by injecting channelrhodopsin-2 (ChR2) to medial PFC and recording synaptic responses evoked by light stimulation of ChR2-expressing terminals in thalamic neurons. The mediodorsal thalamus (MD) had markedly larger synaptic currents than neighbouring areas, suggesting that PFC sends prominent signals to MD. To determine whether the PFC to MD pathway is altered at early stages of Alzheimer's disease (AD), we used two mouse models (∼4 months old), transgenic mice carrying the human P301S mutation of microtubule-associated protein tau (Tau), and familial AD mice carrying five mutations on APP and PS1 (5xFAD). Both AD mouse models exhibited a more significant decline in short-term depression (STD) of synaptic responses in response to repeated light stimulation of MD ChR2 signals. Optogenetic imaging showed that Tau mice had significantly reduced ChR2 expression in MD axon terminals innervated by PFC. Next, we inhibited two kinases, serum and glucocorticoid-regulated kinase 1 (SGK1) and glycogen synthase kinase-3 beta (GSK3β), both of which can induce tau hyperphosphorylation and the ensuing disruption of microtubule-based transport in AD. Treatment with SGK1 or GSK3β inhibitor normalized STD of PFC to MD synaptic responses in Tau mice, but not in 5xFAD mice. These results suggest that the synaptic connectivity in the PFC-to-MD pathway is compromised in AD, which may be due to tau kinase-induced disruption of axonal transport. KEY POINTS: Optogenetic recordings reveal the strong connection from prefrontal cortex (PFC) to mediodorsal thalamus (MD). Short-term depression (STD) of PFC to MD synaptic responses is altered in P301S Tau and 5xFAD mouse models of Alzheimer's disease (AD). Optogenetic imaging uncovers the significantly reduced PFC to MD projection in Tau mice. Inhibition of tau kinase SGK1 or GSK3β normalizes STD of PFC to MD synaptic responses in Tau mice, but not 5xFAD mice. These results suggest that the synaptic information transfer from PFC to MD pathway is compromised in AD, probably via tau kinase-induced disruption of axonal transport.},
}

@article {pmid41691336,
year = {2026},
author = {Wang, X and Pan, T and Chen, S and Webb, GI and Jiang, Y and Rozowsky, J and Gerstein, M and Song, J},
title = {Predicting disease-specific histone modifications and functional effects of non-coding variants by leveraging DNA language models.},
journal = {Genome biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13059-026-04003-3},
pmid = {41691336},
issn = {1474-760X},
support = {APP1127948, APP1144652, APP2036864//National Health and Medical Research Council of Australia/ ; },
abstract = {BACKGROUND: Epigenetic modifications play a vital role in the pathogenesis of human diseases, particularly neurodegenerative disorders such as Alzheimer's disease, where dysregulated histone modifications are strongly implicated in disease mechanisms. While recent advances underscore the importance of accurately identifying these modifications to elucidate their contribution to Alzheimer's disease pathology, existing computational methods remain limited by their generic approaches that overlook disease-specific epigenetic signatures.

RESULTS: To bridge this gap, we develop a novel large language model-based deep learning framework tailored for disease-contextual prediction of histone modifications and variant effects. Focusing on Alzheimer's disease as a case study, we integrate epigenomic data from multiple patient samples to construct a comprehensive, disease-specific histone modification dataset, enabling our model to learn Alzheimer's disease -associated molecular signatures. A key innovation of our approach is the incorporation of a Mixture of Experts architecture, which effectively distinguishes between disease and healthy epigenetic states, allowing for precise identification of Alzheimer's disease -relevant epigenetic modification patterns. Our model demonstrates robust performance in disease-specific histone modification prediction, significantly outperforming existing state-of-the-art methods that lack disease context. Beyond accurate modification site prediction, our framework provides important biological insights by successfully prioritizing Alzheimer's disease-associated genetic variants, which show significant enrichment in disease-relevant pathways.

CONCLUSIONS: Our framework establishes a powerful new paradigm for epigenetic research that can be extended to other complex diseases, offering both a valuable tool for variant effect interpretation and a promising strategy for uncovering novel disease mechanisms through epigenetic profiling.},
}

@article {pmid41566378,
year = {2026},
author = {Wu, Q and Ding, J and He, R and Hui, L and Liu, J and Li, Y},
title = {Exploring phenotype-related single-cells through attention-enhanced representation learning.},
journal = {Genome medicine},
volume = {18},
number = {1},
pages = {21},
pmid = {41566378},
issn = {1756-994X},
support = {2025ZD01901900//Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project/ ; 2023YFF1204701//National Key Research and Development Program of China/ ; SRPG22007//the Self-supporting Program of Guangzhou Laboratory/ ; 2023B1515130008//Guangdong Basic and Applied Basic Research Foundation/ ; GZNL2025C01013//the Major Project of Guangzhou National Laboratory/ ; No.12371485 and No.82400622//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Atlas-level single-cell investigations elucidate disease pathogenesis and progression. Accurate interpretation of phenotype-related single-cell data necessitates pre-defining cell subtypes and identifying their abundance variations. However, batch correction and clustering resolution biases can impact this interpretation. To overcome these challenges, an end-to-end integrative approach that combines both cell- and gene-level information is needed to more accurately connect single-cell characteristics to clinical phenotypes.

METHODS: We developed scPhase, a deep learning framework using attention-based multiple instance learning (AMIL). It treats each patient sample as a bag of single cells, learning a comprehensive representation from their gene expression profiles. By incorporating a Mixture-of-Experts (MoE) aggregation layer, it predicts clinical phenotypes that generalize across patient cohorts. Furthermore, it includes an interpretability framework that uses cellular attention and gene attribution scores to pinpoint the key cell profiles that drive its predictions.

RESULTS: We evaluated scPhase across diverse single-cell disease atlases, covering COVID-19 infection, aging, neurodegeneration, and oncology, using single-cell data from peripheral blood mononuclear cells (PBMCs), brain, and tumor tissues. The model consistently outperforms baselines in classifying diverse clinical phenotypes, achieving area under the curve (AUC) scores of 0.895 for COVID-19, 0.840 for Alzheimer’s disease, and 0.951 and 0.962 for lung and colorectal cancers. It shows robust performance in age regression with a Pearson correlation coefficient (PCC) of 0.87. The model’s interpretability framework effectively pinpointed clinically relevant cell populations, enhancing its utility in identifying disease-specific cellular signatures.

CONCLUSIONS: scPhase offers an interpretable supervised learning framework for single-cell data, accurately predicting sample-level clinical phenotypes while uncovering key biological mechanisms. Furthermore, it can be readily adapted for broader atlas-level clinical phenotype analyses.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-026-01598-x.},
}

@article {pmid41691306,
year = {2026},
author = {Orellana, P and Henríquez, F and Cabral-Miranda, F and Hernandez, H and Ferreira, PCL and Bellaver, B and Caviedes, A and Pizarro, M and Gonzalez-Silva, C and Marin-Diaz, N and Riquelme, P and Pozo, N and Damm, F and Court, FA and Gonzalez-Billault, C and Lillo, P and Thumala-Dockendorff, D and Cerda, M and Villagra, R and de la Cruz, R and K Karikari, T and Ibañez, A and Zetterberg, H and A Pascoal, T and Duran-Aniotz, C and Slachevsky, A},
title = {Plasma ATN biomarkers across the alzheimer's disease continuum in a Chilean community- and clinic-based cohort.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01974-0},
pmid = {41691306},
issn = {1758-9193},
abstract = {BACKGROUND: Plasma biomarkers have emerged as robust indicators of Alzheimer's disease (AD) pathology, offering accessible tools for staging and stratification. However, their expression across globally diverse populations remains poorly characterized. The aim of this study was to evaluate whether the combination of plasma biomarkers could distinguish different stages along the AD continuum and assess their clinical associations in a Latin American cohort.

METHODS: We evaluated plasma amyloid, tau, and neurodegeneration (ATN) biomarkers in 318 older adults from a Chilean community- and clinic-based cohort, including individuals with subjective cognitive complaints (SCC), mild cognitive impairment (MCI), and Alzheimer's disease dementia (ADD), alongside cognitively unimpaired (CU) participants. Plasma ATN biomarkers (Aβ42/Aβ40, p-tau217, NfL, and GFAP) were quantified using Simoa technology. Global cognition was assessed with the Addenbrooke's Cognitive Examination (ACE), memory with the Free and Cued Selective Reminding Test (FCSRT), and functional ability with the Technology-Activities of Daily Living Questionnaire (T-ADLQ). Group differences in plasma biomarkers were examined using ANCOVA models adjusted for age, sex, and education, and associations with cognitive performance were evaluated through linear regression analyses. In addition, supervised machine-learning models were implemented to classify participants across diagnostic categories based on plasma biomarker profiles, using cross-validation to evaluate predictive performance.

RESULTS: We observed a progressive decline in the Aβ42/Aβ40 ratio and elevations in p-tau217 and GFAP across the clinical continuum. Additionally, p-tau217 and NfL levels were inversely associated with cognitive, memory, and functional performance. Notably, p-tau217 distinguished ADD from CU with high accuracy (AUC = 0.88), although its performance in earlier stages was limited.

CONCLUSION: These findings support the biological consistency of plasma biomarkers in AD-related neurodegeneration and provide novel evidence from a Latin American population. Further studies are needed to improve early-stage detection and to better understand how genetic, environmental, and health factors shape biomarker expressions in underrepresented regions.},
}

@article {pmid41691301,
year = {2026},
author = {Penny, LK and Arastoo, M and Lofthouse, R and Abdallah, A and Imoesi, PI and Schwab, K and Shiells, H and Melis, V and Riedel, G and Harrington, CR and Wischik, CM and Porter, A and Palliyil, S},
title = {Timing matters: early administration of a high-affinity antibody targeting the tau repeat domain prevents aggregation in a mouse tauopathy model.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01985-x},
pmid = {41691301},
issn = {1758-9193},
}

@article {pmid41691109,
year = {2026},
author = {Zhao, P and El Fadel, O and Le, A and Mangleburg, CG and Dhindsa, J and Wu, T and Zhao, J and Huang, M and Amoh, B and Marella, AS and Li, Y and Seyfried, NT and Levey, AI and Liu, Z and Al-Ramahi, I and Botas, J and Shulman, JM},
title = {Systems genetic dissection of brain gene expression reveals excitotoxic mechanisms of Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41691109},
issn = {1476-5578},
support = {U01AG061357, R01AG057339, and RF1AG078660//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, and U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30CA125123, P30CA125123, 1S10OD023469//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; RP200504//Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)/ ; },
abstract = {Gene expression changes likely mediate the impact of Alzheimer's disease (AD) neuropathology on cognition, but there are challenges to resolve the proximal causal pathways from postmortem brain transcriptome profiles which lack temporal resolution and are further confounded by mixed pathologies. Here, we functionally dissect 30 AD-associated human brain gene co-expression modules using fruit fly (Drosophila melanogaster) models. Integrating longitudinal RNA-sequencing and behavioral phenotyping, we interrogated the consequences of amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and aging, highlighting hundreds of conserved, differentially expressed genes. To pinpoint causal modules and drivers, we manipulated 344 prioritized targets in vivo, identifying 141 modifiers of Aβ- or tau-induced neurodegeneration. We discovered an upregulated immune module enriched for AD risk variants that promotes neurodegeneration based on genetic manipulations in neurons. By contrast, a downregulated human brain synaptic regulatory network includes many loss-of-function suppressors of Aβ/tau and modulates glutamatergic hyperexcitation injury. Additional analyses support a biphasic model in which early AD pathology activates expression of a synaptic transcriptional signature that promotes neuronal injury, followed by a decrease that is compensatory. In sum, our cross-species strategy establishes a causal chain linking AD pathology, transcriptome perturbation, N-Methyl-D-Aspartate receptor excitotoxicity, and neurodegeneration.},
}

@article {pmid41690978,
year = {2026},
author = {Pan, Y and Cho, H and Lou, Q and Zhang, W and Asken, B and Song, Q},
title = {Genetic risk in Alzheimer's disease.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00665-8},
pmid = {41690978},
issn = {2056-7189},
abstract = {Alzheimer's disease (AD) has a strong genetic predisposition. Genome-wide association studies have identified multiple risk loci, yet many non-coding variants remain uncharacterized. Machine learning-based polygenic risk scores (PRS) enhance prediction by modeling genetic epistasis and sex-specific risks. This review summarizes AD genetic risk factors, PRS methodologies, and ML-based AD risk prediction. It also highlights challenges such as population bias, functional validation, and integrating multi-omics for precision medicine.},
}

@article {pmid41690969,
year = {2026},
author = {Lorincz-Comi, N and Song, W and Chen, X and Paz, IR and Hou, Y and Zhou, Y and Xu, J and Martin, W and Barnard, J and Pieper, AA and Haines, JL and Chung, MK and Cheng, F},
title = {Combining xQTL and genome-wide association studies from diverse populations improves druggable gene discovery.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-69236-z},
pmid = {41690969},
issn = {2041-1723},
support = {R01AG066707//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG084250//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG076448//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG082118//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG092462//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG092591//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG082211//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R33AG083003//U.S. Department of Health Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P01HL158501//U.S. Department of Health Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; },
abstract = {Repurposing existing medicines to target disease-associated genes represents a promising strategy for developing effective treatments for complex diseases. However, progress has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies. Gene-based association tests provide a more powerful alternative to traditional SNP-based methods, yet current approaches often fail to leverage shared heritability across populations and to effectively integrate functional genomic data. To address these challenges, we develop GenT and its various extensions, comprising a framework of gene-based tests utilizing summary-level data from genome-wide association studies. Using GenT, we identify 16, 15, 35, and 83 candidate genes linked to Alzheimer's disease, amyotrophic lateral sclerosis, major depression, and schizophrenia, respectively, not detected by Genome-Wide Association Studies (GWAS). Additionally, we use our multi-ancestry gene-based test (MuGenT) to identify 28 candidate genes associated with type 2 diabetes. By integrating brain expression and protein quantitative trait loci into our analysis, we identify 43 candidate genes associated with Alzheimer's disease that have supporting xQTL evidence. We also perform experimental assays to demonstrate that the NTRK1 inhibitor GW441756 significantly reduces tau hyper-phosphorylation (including p-tau181 and p-tau217) in Alzheimer's disease patient-derived iPSC neurons, providing mechanistic support for our predictions.},
}

@article {pmid41690817,
year = {2026},
author = {Yang, Y and Bhullar, R and Conde, S and , },
title = {Spatial abilities in aging adults with Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71159},
doi = {10.1002/alz.71159},
pmid = {41690817},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; UO1 AG051406//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; UO1 AG051412//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {Humans ; *Down Syndrome/psychology/complications/physiopathology ; Male ; Female ; Middle Aged ; *Aging/physiology ; *Cognitive Dysfunction/diagnosis/physiopathology ; Neuropsychological Tests/statistics & numerical data ; Aged ; Adult ; *Space Perception/physiology ; *Alzheimer Disease/diagnosis ; },
abstract = {INTRODUCTION: People with Down syndrome (DS) have a higher likelihood of developing Alzheimer's disease (AD). Deficits in spatial abilities could serve as early indicators of AD. We examined age effects on visuospatial construction and visuomotor integration in DS and whether spatial tasks could distinguish various extents of cognitive decline in DS.

METHODS: We used the Alzheimer's Biomarkers Consortium-Down Syndrome project dataset, where 376 DS participants completed a series of cognitive measures.

RESULTS: Age effects were found in visuomotor integration but not in visuospatial construction. Both abilities declined with AD progression. While both abilities showed relatively poor discrimination between cognitively stable (CS) and mild cognitive impairment (MCI) and between MCI and AD, they showed excellent or acceptable discrimination between CS and AD. Visuospatial construction showed better discrimination than visuomotor integration.

DISCUSSION: Visuomotor integration declines more with aging than visuospatial construction in DS. When used alone, neither may effectively diagnose cognitive decline in DS.

HIGHLIGHTS: We examined two spatial abilities in aging adults with Down syndrome using the ABC-DS project. Age effects were found in visuomotor integration. Age effects were not found in visuospatial construction abilities. Both visuomotor integration and visuospatial construction abilities distinguished between CS and AD in people with DS. Block Design had the highest predictive power in distinguishing cognitive stability from AD.},
}

Humans
*Down Syndrome/psychology/complications/physiopathology
Male
Female
Middle Aged
*Aging/physiology
*Cognitive Dysfunction/diagnosis/physiopathology
Neuropsychological Tests/statistics & numerical data
Aged
Adult
*Space Perception/physiology
*Alzheimer Disease/diagnosis

@article {pmid41690816,
year = {2026},
author = {Shishegar, R and Doecke, JD and Lim, YY and Bourgeat, P and Dore, V and Tallapragada, B and Laws, SM and Porter, T and Burnham, S and Feizpour, A and Gillman, A and Weiner, M and Hassenstab, J and Rowe, CC and Villemagne, VL and Masters, CL and Fripp, J and Sohrabi, H and Maruff, P and , },
title = {Harmonizing neuropsychological test data across prospective studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71186},
doi = {10.1002/alz.71186},
pmid = {41690816},
issn = {1552-5279},
support = {P50 AG00561/GF/NIH HHS/United States ; P30 NS09857781/GF/NIH HHS/United States ; P01 AG026276/GF/NIH HHS/United States ; P01 AG003991/GF/NIH HHS/United States ; R01 AG043434/GF/NIH HHS/United States ; UL1 TR000448/GF/NIH HHS/United States ; R01 EB009352/GF/NIH HHS/United States ; 5R01AG058676/GF/NIH HHS/United States ; 1156891//NHMRC/ ; 1132604//NHMRC/ ; 1156891//National Health and Medical Research Council/ ; 1132604//National Health and Medical Research Council/ ; 1140853//National Health and Medical Research Council/ ; 1152623//National Health and Medical Research Council/ ; /NH/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; //Department of Defense/ ; //California Department of Public Health/ ; //University of Michigan/ ; //Hillblom Foundation/ ; /ALZ/Alzheimer's Association/United States ; //Johnson & Johnson/ ; //Kevin and Connie Shanahan/ ; //GE/ ; //VUmc/ ; //Australian Catholic University/ ; //Stroke Foundation/ ; //Veterans Administration/ ; },
mesh = {Humans ; *Neuropsychological Tests/statistics & numerical data/standards ; *Alzheimer Disease/diagnosis/psychology ; Male ; Female ; Aged ; Prospective Studies ; Neuroimaging ; Australia ; Machine Learning ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) research relies on large datasets and advanced statistical models. However, individual population studies often lack sufficient sample size for conclusive results. Harmonizing cognitive test data across studies can address this gap, despite differences in testing protocols. This study harmonizes cognitive data from three major AD cohorts to support robust clinical-pathological modelling.

METHODS: Information from the Alzheimer's Disease Neuroimaging Initiative (N = 1446); Australian Imaging, Biomarkers and Lifestyle (N = 1764); and Open Access Series of Imaging Studies-3 (N = 440) were integrated, including cognitive scores, demographics, genetics, and clinical and neuroimaging data. Neuropsychological tests relevant to AD were harmonized using MissForest, a machine learning-based imputation method. Validation involved assessing imputation accuracy and analyzing composite cognitive scores across clinical-pathological groups.

RESULTS: Imputation showed high accuracy (mean absolute error ≤ test-retest variability in cognitively unimpaired participants). Composite scores reflected known disease patterns with significant stratification across clinical-pathological groups.

DISCUSSION: The validated harmonization approach demonstrated reliable imputation, enabling more powerful AD models and supporting future diagnostic and therapeutic advances.},
}

Humans
*Neuropsychological Tests/statistics & numerical data/standards
*Alzheimer Disease/diagnosis/psychology
Male
Female
Aged
Prospective Studies
Neuroimaging
Australia
Machine Learning
Aged, 80 and over

@article {pmid41690814,
year = {2026},
author = {Fung, M and Chai, YL and Cheng, YL and Tabassum, N and Lim, VJT and Kalaria, RN and Jo, DG and Chen, CP and Lai, MKP and Arumugam, TV},
title = {Characterizing TDP-43 involvement in vascular dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71196},
doi = {10.1002/alz.71196},
pmid = {41690814},
issn = {1552-5279},
support = {2019100//National Health and Medical Research Council of Australia/ ; MOH-001086-00//National Medical Research Council of Singapore/ ; },
mesh = {*Dementia, Vascular/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; Humans ; Animals ; *Brain/metabolism/pathology ; Aged ; Female ; Male ; Phosphorylation ; Neurons/metabolism/pathology ; Disease Models, Animal ; Aged, 80 and over ; Carotid Stenosis/complications ; },
abstract = {INTRODUCTION: Vascular dementia (VaD) is a major therapeutic challenge. Tar DNA-binding protein 43 (TDP-43), known for its role in neurodegeneration, may contribute to VaD pathogenesis under chronic cerebral hypoperfusion (CCH). This study investigates TDP-43 dysregulation in VaD.

METHODS: TDP-43 and phosphorylated TDP-43 (pTDP-43) expression and localization were assessed in a VaD animal model, neuronal cells exposed to oxygen-glucose deprivation (OGD), and post mortem human brain tissues.

RESULTS: Bilateral Common Carotid Artery Stenosis (BCAS)-induced CCH led to increased pTDP-43 and aberrant redistribution of both TDP-43 and pTDP-43. In vitro OGD triggered similar mislocalization. Post mortem VaD brains showed no TDP-43 abnormalities, while Alzheimer's and mixed dementia cases exhibited marked pathology.

DISCUSSION: TDP-43 dysregulation appears early in VaD under hypoperfusive stress, distinguishing it from other dementia subtypes. These findings indicate that TDP‑43 may warrant further investigation as a potential early molecular feature of VaD.

HIGHLIGHTS: Tar DNA-binding protein 43 (TDP-43) is dysregulated early in vascular dementia models. Hypoperfusion triggers TDP-43 mislocalization and phosphorylation. TDP-43 pathology is absent in late-stage human vascular dementia. TDP-43 is a transient, novel target for vascular cognitive impairment.},
}

*Dementia, Vascular/metabolism/pathology
*DNA-Binding Proteins/metabolism
Humans
Animals
*Brain/metabolism/pathology
Aged
Female
Male
Phosphorylation
Neurons/metabolism/pathology
Disease Models, Animal
Aged, 80 and over
Carotid Stenosis/complications

@article {pmid41690676,
year = {2026},
author = {Trainum, K and Stuifbergen, A and Becker, H and Morgan, S},
title = {Statewide Examination of Rural-Urban Differences in Assisted Living Facilities.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106121},
doi = {10.1016/j.jamda.2026.106121},
pmid = {41690676},
issn = {1538-9375},
abstract = {OBJECTIVES: To compare facility characteristics between rural and urban assisted living facilities (ALFs).

DESIGN: A descriptive, cross-sectional study.

SETTING AND PARTICIPANTS: A convenience sample of 517 ALFs (143 rural) that included facilities from all public health regions in Texas.

METHODS: Survey data were collected from administrative staff at each facility. Data were analyzed using descriptive statistics, χ[2] analysis, and Mann-Whitney U tests.

RESULTS: Overall, rural areas had relatively more Type A and fewer Type B facilities (the latter require 24-hour attendants) than did urban areas. Rural facilities (vs urban) also had significantly fewer Alzheimer's disease certifications and licensed beds. Provided services differed significantly between rural and urban facilities: urban facilities more often offered concierge, medical, and nursing services, whereas rural facilities more often provided transportation, wound care, and physical/occupational therapy. Antipsychotic use was high across all facilities (26.6%), but only 38.5% reported initiating gradual dose reductions.

CONCLUSIONS AND IMPLICATIONS: Findings highlight rural-urban differences in service availability and dementia care. Combined with high rates of antipsychotic use, these findings suggest a need for policy reforms, especially as resident acuity in ALFs increases. Additional research is needed to improve ALF quality measurement and to better understand factors influencing care quality in rural and urban settings.},
}

@article {pmid41690630,
year = {2026},
author = {Hwang, G and Blair, NO and Claesges, SA and Reynolds, CF and Davatzikos, C and Goveas, JS},
title = {Accelerated brain aging in prolonged grief disorder of later life: Influence of comorbid depression.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {121387},
doi = {10.1016/j.jad.2026.121387},
pmid = {41690630},
issn = {1573-2517},
abstract = {BACKGROUND: Prolonged Grief Disorder (PGD) in later life may involve volumetric patterns indicative of accelerated brain aging. This study examined whether structural brain age differs between individuals with PGD and those with integrated grief (IG), and whether it is associated with clinical severity.

METHODS: Chronically grieving older adults with PGD (n = 36) and IG (n = 56), equated on demographics and time since loss, underwent structural MRI. Machine learning-derived indices were computed for each participant: Brain Age Gap (SPARE-BAG), Alzheimer's disease-like atrophy (SPARE-AD), and five dominant brain aging patterns. Group differences and associations with symptom severity were assessed, along with moderation by age, cognitive status, medical burden, and current and past depression.

RESULTS: Compared to IG, the PGD group showed significantly higher SPARE-BAG (t = 2.61, pcorrected = 0.021), SPARE-AD (t = 2.04, pcorrected = 0.045), and medial temporal lobe atrophy pattern (t = 3.44, pcorrected = 0.005). However, these findings were attenuated and no longer significant after accounting for comorbid depressive symptoms. In the PGD group, both SPARE scores positively correlated with grief and depressive symptom severity (pcorrected < 0.03). The SPARE-BAG-grief symptom association was moderated by younger age (z = -2.92, pFDR = 0.018) and higher depressive symptoms (z = 1.88, p = 0.061); SPARE-AD-depressive symptom correlation was moderated by past depression history (z = 2.64, pcorrected = 0.041).

CONCLUSION: Adults with PGD exhibit structural brain patterns consistent with accelerated and AD-like aging. However, these findings were largely driven by comorbid depressive symptoms. The brain aging indices were associated with both grief and depressive symptom severity, highlighting the cumulative neurobiological burden associated with PGD and co-occurring depression and underscoring the need for integrative clinical approaches addressing both conditions.},
}

@article {pmid41690530,
year = {2026},
author = {Swart, DH and Stevens, J and de Haan, M and Ulu, N and Henning, RH and van der Graaf, AC and Touw, DJ and Mian, P and Krenning, G},
title = {Absorption, distribution, metabolism and excretion of SUL-138 in rats and minipigs.},
journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences},
volume = {},
number = {},
pages = {107469},
doi = {10.1016/j.ejps.2026.107469},
pmid = {41690530},
issn = {1879-0720},
abstract = {SUL-138 is an orally bioavailable 6-chromanol which is in development as therapeutic against Noncommunicable Chronic Diseases (NCDs) including Chronic Heart Failure, Chronic Kidney Disease, Alzheimer's and Parkinson's Disease. The compound improves mitochondrial function by preserving respiration through activation of complex I and IV during disease. Thorough comprehension of preclinical Absorption, Distribution, Metabolism and Excretion (ADME) is pivotal for the safety assessment prior to starting Phase I clinical trials. To this end, a single oral or intravenous dose of [[14]C]-SUL-138 at a therapeutic and near Maximum Tolerated Dose (MTD) dose level were administered to rats and minipigs for characterization of ADME properties. Non-radiolabelled SUL-138 and radiolabelled [[14]C]-SUL-138 were administered as single oral or intravenous dose to intact and bile duct-canulated rats and to minipigs to investigate pharmacokinetics of total radioactivity and SUL-138, tissue distribution by Quantitative Whole-Body Autoradiography (QWBA), excretion and metabolite profiling. The pharmacokinetic profiles of [[14]C]-SUL-138 and SUL-138 indicated rapid absorption, tissue distribution and extensive metabolism in both species. In rats, the QWBA showed that drug-related radioactivity was widely distributed throughout nearly all tissues shortly after dosing. Total radioactivity was completely eliminated; in rats excretion was mainly via the faecal route, whereas in minipigs elimination was equal between the faecal and renal excretory routes. Primary metabolic pathways for clearance of SUL-138 were oxidation, N-dealkylation and glucuronidation. Plasma exposure to the parent was low compared to the main circulating oxidation metabolite M2 and glucuronide conjugate M7 in rats and glucuronide conjugates M7 and M8 in minipigs. In conclusion, ADME properties of SUL-138 are characterized by rapid absorption, wide tissue distribution, extensive metabolism and excretion via the renal and faecal route. Oxidation and glucuronidation are the main metabolic pathways in both nonclinical safety species.},
}

@article {pmid41690259,
year = {2026},
author = {Eckenweber, S and Völter, F and Franzmeier, N and Palleis, C and Wagemann, O and Weidinger, E and Katzdobler, S and Wlasich, E and Sandkühler, K and Böning, G and Gnörich, J and Scheifele, M and Eckenweber, F and Janowitz, D and Kurz, C and Perneczky, R and Bürger, K and Danek, A and Höglinger, G and Levin, J and Brendel, M and Schönecker, S},
title = {Additive value of early-phase β-Amyloid-PET for the differential diagnosis of non-Alzheimer's disease dementia.},
journal = {NeuroImage. Clinical},
volume = {49},
number = {},
pages = {103963},
doi = {10.1016/j.nicl.2026.103963},
pmid = {41690259},
issn = {2213-1582},
abstract = {PURPOSE: Recent studies demonstrated strong agreement between early-phase β-amyloid-PET perfusion imaging and glucose hypometabolism assessed by [[18]F]FDG-PET, indicating the potential of early-phase β-amyloid-PET as a surrogate biomarker of neuronal injury. We therefore aimed to investigate the additive value of early-phase β-amyloid-PET for the differential diagnosis of non-Alzheimer's disease dementia syndromes in clinical routine.

MATERIALS AND METHODS: [[18]F]florbetaben- and [[18]F]flutemetamol-PET scans (n = 379) performed between July 2013 and July 2021 were analyzed for their amyloid status and the presence of a neurodegenerative hypoperfusion pattern using visual assessment and z-score maps. In patients visually rated as amyloid-negative/neurodegeneration-positive (A-N+), the most likely diagnosis based on perfusion patterns was compared to the final clinical diagnosis, i.e. frontotemporal dementia or psychiatric disorders, suspected 4R-tauopathy, and suspected non-Alzheimer pathophysiology. Logistic regression models based on a data-driven selection of cerebral regions of hypoperfusion by principal component analysis were used to predict neurodegenerative disease and clinical diagnoses. Diagnostic accuracy was compared between visual assessment and the regression models.

RESULTS: Neurodegeneration status was correctly identified in 78.8% (119/151) of amyloid-negative patients through visual rating, compared to 67.5% (102/151) using logistic regression. Visual assessment assigned 75.3% (67/89) of A-N+ patients to the correct diagnostic category. In contrast, the regression model classified 69.7% (62/89) of patients.

CONCLUSIONS: The current study demonstrates an additive value of early-phase β-amyloid-PET for the differential diagnosis of dementia syndromes. While visual assessment of early-phase β-amyloid-PET already provides substantial diagnostic accuracy, a data-driven analysis approach could aid in cases of uncertainty.},
}

@article {pmid41690071,
year = {2026},
author = {El-Moaty, HIA and Sameh, A and Saber, S and Hamad, RS and Elmorsy, EA and Alsoqih, NS and Farrag, AA and Eissa, H and El-Kott, AF and Negm, S and AlShehri, MA and Ali, MAM and Hasan, WA and Gaafar, A and Khalifa, HS and Ibrahim, EH and Morsy, K and Elnaghy, F},
title = {Adenosine A2A receptor as a dual-acting molecular switch: Glial morphological changes and neurovascular tissue remodeling in neuroinflammation and neurodegeneration.},
journal = {Tissue & cell},
volume = {100},
number = {},
pages = {103389},
doi = {10.1016/j.tice.2026.103389},
pmid = {41690071},
issn = {1532-3072},
abstract = {Neuroinflammation appears in a variety of neurological disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The adenosine A2A receptor (A2AR), a Gs protein-coupled receptor that affects cAMP signaling and downstream kinases like PKA, CREB, and NF-κB, is one of the primary regulators of this process. Context-dependent effects of A2AR activation include lowering acute inflammation and promoting neuronal survival when stimulated moderately, but increasing glial activation and cytokine production when overexpressed over an extended period of time. In microglia and astrocytes, A2AR signaling regulates inflammatory pathways mediated by NF-κB and MAPK, affecting oxidative stress, blood-brain barrier (BBB) stability, and excitotoxicity. Acute or transient (short-term) A2AR activation, on the other hand, increases the production of anti-inflammatory cytokines like IL-10 and enhances neurotrophic support through BDNF. A2AR antagonists, including istradefylline and SCH58261, may reduce microglial triggering and have neuroprotective benefits, according to clinical and experimental data. The context-dependent activity of the receptor is shown by the fact that total receptor blockage interferes with adaptive immune control. Therefore, the therapeutic challenge is to carefully modify A2AR signaling in particular cell populations, specifically targeting astrocytic or microglial receptors while maintaining the peripheral immunoregulatory activities. The dual regulatory role of A2AR in neuroinflammation is summarized in this review along with its molecular mechanisms, disease-specific actions, and therapeutic significance. Developing next-generation neuroprotective strategies that reduce A2AR signaling's pro-inflammatory and neurotoxic effects while preserving its beneficial homeostatic effects will require an understanding of the temporal and cell-specific dynamics of this signaling.},
}

@article {pmid41689888,
year = {2026},
author = {Perry, R and Kipps, C and Soto Martín, ME and Bozzali, M and Logroscino, G and Trafford, S and Dhadda, S and Kanekiyo, M and Goodwin, A and Hodgkinson, M and Hersch, S and Irizarry, M and Kramer, L and Froelich, L},
title = {Lecanemab for treatment of individuals with early Alzheimer's Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100507},
doi = {10.1016/j.tjpad.2026.100507},
pmid = {41689888},
issn = {2426-0266},
abstract = {BACKGROUND: Lecanemab, an antibody directed at Aβ-protofibrils and plaque, showed meaningful delay in disease progression and biological effects consistent with disease modification in the phase 3 Clarity AD trial.

OBJECTIVE: The objective of this paper is to present efficacy and safety results in ApoE ε4 non-carriers or heterozygotes population of Clarity AD.

DESIGN: Clarity AD is an 18-month, randomized study (core) in participants with early AD, with an open-label extension phase (OLE) phase.

SETTING: Academic and clinical centers.

PARTICIPANTS: All eligible ApoE ε4 participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly); the results presented herein are for the ApoE4 heterozygote or non-carrier participants.

MEASUREMENTS: Endpoints included change from baseline at 18 months in the global cognitive and functional scale, CDR-SB, amyloid positron emission tomography (PET), Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and health-related quality-of-life (HRQoL) assessments. Amyloid imaging related abnormalities (ARIA) occurrence was monitored throughout the study by central reading of magnetic resonance imaging. Following 18 months treatment in the Core, eligible participants transitioned to the OLE where they received open-label lecanemab. Clinical outcomes (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL) were evaluated by examining 'delayed start' (core:placebo followed by OLE:lecanemab) and 'early start' (core:lecanemab followed by OLE:lecanemab) cohorts as well as natural history cohorts. Time to progression to next stage of AD was also evaluated through 36 months.

RESULTS: 1795 participants with early AD were enrolled in Clarity AD, of which 1521 were ApoE ε4 heterozygotes or non-carriers (85 %). Lecanemab significantly reduced clinical decline on CDR-SB at 18 months compared to placebo in the ApoEε4 heterozygotes or non-carriers subgroup. Amyloid PET, ADAS-Cog14, ADCS-MCI-ADL, and HRQoL results were consistent with the CDR-SB findings. In the analysis subgroup, the most common adverse reactions for lecanemab were infusion-related reactions (26 %), ARIA-H (13 %), fall (11 %), headache (11 %), and ARIA-E (9 %). In the OLE, lecanemab-treated participants continued to accrue benefit in CDR-SB through 36 months, with continued separation through 36 months relative to the ADNI natural history cohort. Delayed start results follow a parallel trajectory relative to early start results, but do not catch up, confirming a disease modifying effect and reflecting importance of early treatment initiation. Results were similar for ADAS-Cog14 and ADCS-MCI-ADL. Lecanemab reduced the risk of progression to next stage of AD by 28 % on lecanemab as compared to the ADNI natural history cohort.

CONCLUSION: In the ApoE ε4 heterozygotes or non-carrier subgroup of Clarity AD, lecanemab slowed decline in disease progression and reduced markers of amyloid, with expanding benefit over time.

GOV IDENTIFIER: Clarity AD NCT03887455.},
}

@article {pmid41689887,
year = {2026},
author = {Lephart, ED and Hedges, DW and Naftolin, F and Draelos, ZD},
title = {The future of HRT/MHT and Alzheimer's disease risk, onset and progression.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100508},
doi = {10.1016/j.tjpad.2026.100508},
pmid = {41689887},
issn = {2426-0266},
}

@article {pmid41689882,
year = {2026},
author = {Hanazawa, R and Sato, H and Suzuki, K and Hirakawa, A},
title = {Applying a statistical model-based AI method to identify prognostic factors for long-term cognitive decline in Alzheimer's disease: Evidence from pooled placebo data of four phase III trials.},
journal = {International journal of medical informatics},
volume = {211},
number = {},
pages = {106337},
doi = {10.1016/j.ijmedinf.2026.106337},
pmid = {41689882},
issn = {1872-8243},
abstract = {BACKGROUND: Heterogeneity in the long-term progression of Alzheimer's disease (AD) challenges the efficiency of clinical trials. Identifying long-term prognostic factors is critical for enhancing trial efficiency, although it has been limited by the lack of appropriate statistical approaches. We applied a recently developed statistical model-based AI method to identify the baseline prognostic factors for long-term cognitive decline in a clinical trial population.

METHODS: We analyzed pooled placebo arm data (N = 1,597) from four Phase III trials in patients with mild-to-moderate AD. Long-term trajectories for the Mini-Mental State Examination (MMSE), 11- and 14-item versions of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog11, ADAS-Cog14), and Clinical Dementia Rating-Sum of Boxes (CDR-SB) were predicted from their short-term data (≤80 weeks). Trajectories were compared between subgroups defined by six baseline factors (age, sex, apolipoprotein E ε4 [APOE ε4] status, years of education, years from diagnosis, and years from disease onset) using the area under the curve (AUC).

RESULTS: Longer years of education (≥13 years) was the most robust predictor associated with faster progression across all four outcomes (e.g., for 20-year ADAS-Cog11, AUC ratio, 1.11, p < 0.001). Younger age (<74 years) was associated with a faster decline in MMSE and ADAS-Cog scores, but not in CDR-SB. APOE ε4 status, sex, years from diagnosis, and years from disease onset were not significantly associated with long-term progression.

CONCLUSIONS: Baseline educational level and age were significant prognostic factors of long-term cognitive decline. These findings will help optimize patient stratification in future clinical trials on AD.},
}

@article {pmid41689708,
year = {2026},
author = {Huang, H and Cheng, S and Lu, W and Gao, X and Liu, Z and , },
title = {Elevated branched-chain amino acids linked to hippocampal volumes and cognitive improvement in mild cognitive impairment.},
journal = {Brain imaging and behavior},
volume = {20},
number = {1},
pages = {15},
pmid = {41689708},
issn = {1931-7565},
support = {2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; },
}

@article {pmid41689668,
year = {2026},
author = {Sui, Y and Zhang, N and Chen, X and Tortorella, MD and He, J},
title = {Entorhinal Cholecystokinin in Alzheimer's Disease: Its Earliest Vulnerability and Rescue Effects Across Different Disease Stages in a Mouse Model.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01689-8},
pmid = {41689668},
issn = {1573-6830},
support = {CityUHK 11103922, CityUHK 11104923, CityUHK 11104524//Hong Kong Research Grants Council, General Research Fund/ ; C1043-21G, C1002-24W//Hong Kong Research Grants Council, Collaborative Research Fund/ ; SRFS2324-1S02//Hong Kong Research Grants Council, Senior Research Fellow Scheme/ ; 09203656//Hong Kong Health Bureau, Health and Medical Research Fund/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. The entorhinal cortex (Ent) is among the earliest affected regions, and its neuropeptide cholecystokinin (CCK) supports neocortical-associated memory. Although our previous work demonstrated that CCK treatment rescues cognition and neuroplasticity in aged AD mice, the correlations among CCK expression, synaptic function, and cognitive decline with aging remain poorly understood. Using 3xTg-AD mice (2-18 months), we performed stereological, histological, and molecular analyses to evaluate brain atrophy, neuronal loss, glial responses, and gene expression. Cognitive function was assessed using the novel object recognition test (NOR), motor learning was evaluated using the rotarod test, and synaptic integrity was measured via electrophysiological recordings. We also investigated the therapeutic potential of CCK-B receptor (CCK-BR) agonists on learning and memory and neuroplasticity across disease stages of AD. In 3xTg-AD mice, the Ent exhibits significant atrophy and excitatory neuronal loss as early as 7 months of age, confirming its role as one of the earliest and most severely affected regions in AD. CCK was downregulated earlier than other synaptic genes in the Ent and other brain regions. Cholecystokinin tetrapeptide (CCK-4) treatment rescued deficits in synaptic plasticity, cognition, and motor learning in 3xTg-AD mice across multiple disease stages. Long-term administration of HT-267, a CCK-BR agonist with a prolonged half-life, in young 3xTg-AD mice delayed cognitive decline, enhanced synaptic scaffolding, and restored long-term potentiation in both the cortex and hippocampus (HPC). Our findings identify CCK downregulation as an early biomarker in AD and demonstrate the therapeutic effects of CCK-BR agonists in mitigating cognitive and synaptic deficits from mild to severe disease stages. The ability of long-term CCK-4 analogue treatment to decelerate AD progression indicates its promise as an early intervention strategy.},
}

@article {pmid41689616,
year = {2026},
author = {Li, S and Xiong, B and Xu, N and Nie, L and He, K and Zhang, G and Chen, C and Zhang, Z and Hoi, MPM and Yang, X},
title = {ARC-18 Alleviates Alzheimer-like Pathology and Cognitive Deficits via AdipoR1-Mediated Activation of Autophagy and Modulation of APP Processing.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {438},
pmid = {41689616},
issn = {1559-1182},
support = {FDCT/0023/2020/AFJ//the Science and Technology Development Fund of the Macao SAR/ ; MYRG2022-00248-ICMS//the University of Macau Research Funding/ ; SZSM202211010//Sanming Project of Medicine in Shenzhen/ ; },
mesh = {Animals ; *Autophagy/drug effects ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; *Receptors, Adiponectin/metabolism ; Mice ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Male ; Hippocampus/metabolism/drug effects/pathology ; Disease Models, Animal ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildup of amyloid-beta peptide (Aβ) and phosphorylated tau in the brain. It is reported that arctigenin (ATG) reduces the level of the enzyme 1 that cleaves β-site amyloid precursor protein and increases Aβ clearance by enhancing autophagy. Compound ARC-18 is a derivative of ATG. The main objective of this study is to investigate whether ARC-18 could improve cognitive function and disease progression by promoting autophagy in Alzheimer-like animal models. Three-month-old 5 × FAD mice were orally treated with the drug for three consecutive months. Water maze and novel object recognition were used to assess cognitive abilities of 5 × FAD mice. In the hippocampus of the mice' brain, APP processing-related proteins (sAPPβ, BACE1) and autophagy-related proteins (LC3B, P62, LAMP1) were detected. N2a/APPswe cells were used to do experiments to further identify the effect and mechanisms of the drug. Our study demonstrated that ARC-18 enhances the behavioral performance of 5 × FAD mice and mitigates Aβ aggregation in the hippocampus and cortex. This effect is achieved through the activation of adiponectin receptor 1 (AdipoR1)-mediated autophagy and the reduction of Aβ production by modulating amyloid precursor protein (APP) processing. Therefore, ARC-18 holds promise as a potential therapeutic agent for Alzheimer's disease.},
}

Animals
*Autophagy/drug effects
*Alzheimer Disease/drug therapy/pathology/metabolism
*Amyloid beta-Protein Precursor/metabolism
*Cognitive Dysfunction/drug therapy/metabolism/pathology
*Receptors, Adiponectin/metabolism
Mice
Mice, Transgenic
Amyloid beta-Peptides/metabolism
Male
Hippocampus/metabolism/drug effects/pathology
Disease Models, Animal
Maze Learning/drug effects

@article {pmid41689409,
year = {2026},
author = {Stroud, J and Cummings, JL and Chumki, SR and Such, P and Wang, D and Palma, AM and Zhang, Z and Grossberg, GT},
title = {Brexpiprazole for treating agitation in different groups of people with Alzheimer's dementia: a plain language summary.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17582024.2026.2623968},
pmid = {41689409},
issn = {1758-2032},
}

@article {pmid41689240,
year = {2026},
author = {Lingler, JH},
title = {Leading by example: How the Webster team's systematic review quietly rebuked the field's preoccupation with biomarker "disclosure," and why it matters.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251412917},
doi = {10.1177/13872877251412917},
pmid = {41689240},
issn = {1875-8908},
abstract = {In this issue, Webster and colleagues report findings and provide direction following a systematic review and evidence synthesis designed to understand the decisional needs of research participants considering whether to receive biomarker or genetic risk information. The report serves as a foundation for a future of participant-centered approaches to the return of individual results in Alzheimer's disease research. This Ethics Response comments on the authors' terminology choices highlighting the notable absence of references to disclosure. The Response concludes that alternative terms like return or sharing of results offer less stigmatizing and more patient-centered approaches to communicating biomarker and genetic test results.},
}

@article {pmid41689141,
year = {2026},
author = {Jauhari, A and Singh, T and Carlisle, DL and Friedlander, RM},
title = {Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {5},
pmid = {41689141},
issn = {2047-9158},
mesh = {Humans ; *DNA, Mitochondrial/genetics/metabolism/immunology ; Animals ; *Neurodegenerative Diseases/metabolism/genetics/immunology ; *Neuroinflammatory Diseases/metabolism/genetics/immunology ; *Mitochondria/metabolism ; Signal Transduction ; },
abstract = {Mitochondrial DNA (mtDNA) plays a pivotal role in the regulation of neuroinflammation, acting as a potent trigger of innate immune responses when released into the cytoplasm or extracellular space. mtDNA is structurally similar to bacterial DNA, containing unmethylated CpG motifs that are readily recognized by immune sensors. Under conditions of cellular stress, injury, or mitochondrial dysfunction, mtDNA can escape into the cytoplasm, where it activates the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway, or it can be detected extracellularly by Toll-like receptors on immune cells. These signaling events lead to the production of pro-inflammatory cytokines and type I interferons, amplifying neuroinflammatory responses. In the central nervous system, this process contributes to the pathogenesis of various neurodegenerative and inflammatory conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), etc.. The dual role of mtDNA as both a damage-associated molecular pattern and a signaling molecule underscores its importance as a therapeutic target for modulating neuroinflammation and protecting against progressive neuronal damage. In this review, we will discuss the implications of mtDNA-mediated neuroinflammation in neurodegenerative diseases, including AD, PD, and HD, highlighting its potential as a diagnostic biomarker and therapeutic target.},
}

Humans
*DNA, Mitochondrial/genetics/metabolism/immunology
Animals
*Neurodegenerative Diseases/metabolism/genetics/immunology
*Neuroinflammatory Diseases/metabolism/genetics/immunology
*Mitochondria/metabolism
Signal Transduction

@article {pmid41689059,
year = {2026},
author = {Kettenmann, H and Lassmann, H and Ugursu, B and Xiang, X},
title = {The functional role of glial cells in the pathologic brain as reviewed by Alois Alzheimer in 1910.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00933-5},
pmid = {41689059},
issn = {1750-1326},
}

@article {pmid41689046,
year = {2026},
author = {Cui, D and Liu, S and Liu, Y and Luo, S and Sheng, Y and Zhang, S and Lin, P},
title = {MST1 promotes microglial pyroptosis and neuroinflammation in alzheimer's disease by regulating the novel DPP8/NLRP1/Caspase-1/GSDMD-N axis.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03732-3},
pmid = {41689046},
issn = {1742-2094},
support = {Grant No. 2025CXPT133//the Key R&D Program of Shandong Province, China/ ; No. qnts202306347//the Taishan Young Scholar Program/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) induced disruption of brain homeostasis, leading to neuronal damage and cognitive impairment. Increasing evidence confirms that microglia-driven neuroinflammation serves as a core mechanism driving the progression of AD. Mammalian Ste20-like kinase 1 (MST1) plays a crucial regulatory role in apoptosis, immune inflammation, and oxidative stress. Our team's previous research revealed that MST1 regulates mitochondrial oxidative stress in neurons, contributing to the pathogenesis of AD. Here, we show that MST1 is activated as p-MST1 in the peripheral blood of AD patients, the serum of 5xFAD mice, and the hippocampal and cortical brain tissues of 5xFAD mice, an effect which was associated with microglial pyroptosis under chronic inflammatory stimulation. Knocking down MST1 in hippocampal and cortical tissues of 5xFAD mice improved cognitive deficits, reduced p-tau protein levels, and alleviated neurodegeneration and neuroinflammatory responses. Concurrently, MST1 knockdown suppressed abnormal microglial activation, decreased inflammatory cytokine release, and ultimately mitigated microglial pyroptosis. Mechanistically, we found that MST1 knockdown modulated DPP8 protein expression, thereby regulating the NLRP1/Caspase-1/GSDMD-N signaling axis to inhibit microglial pyroptosis and attenuate neuroimmune inflammation. In summary, MST1 knockdown improved AD disease progression by preventing disruption to the immune-inflammatory homeostasis of microglia. Therefore, we propose targeting MST1 as a promising therapeutic strategy to halt neuroinflammation and progression in Alzheimer's disease.},
}

@article {pmid41688855,
year = {2026},
author = {Bach, DH and Nguyen, TL},
title = {Immunometabolism Reframes Alzheimer's Disease: From Systemic Dysmetabolism to Glial Rewiring.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01691-0},
pmid = {41688855},
issn = {1573-6830},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder of dysregulated immunometabolism at the neurovascular-glia-neuron interface. Systemic metabolic stressors such as insulin resistance, dyslipidaemia, and obesity converge on brain innate immune cells to reprogram energy pathways and sustain maladaptive inflammation. In microglia, metabolic rewiring across glycolysis-oxidative phosphorylation balance, glutaminolysis, and lipid handling governs trained-immunity programs that dictate amyloid and tau clearance, synaptic maintenance, and neurotoxicity. These processes converge on druggable nodes including AMPK-mTOR signaling, HIF-1α, and tricarboxylic-acid intermediates. Neurovascular fuel delivery is likewise impaired: endothelial GLUT1 loss and mitochondrial stress at the blood-brain barrier accelerate amyloid accumulation and neuronal injury. Lipid metabolism bridges metabolism and inflammation, as APOE4-driven microglial lipid droplets link genetic risk to inflammatory phenotypes. NLRP3 integrates metabolic danger signals into chronic neuroinflammation. Translational momentum now builds around metabolic interventions particularly GLP-1 receptor agonists and SGLT2 inhibitors that modulate glial metabolism, systemic inflammation, and barrier integrity. Converging metabolomic, lipidomic, and extracellular-vesicle biomarkers enable tracking of these pathways in humans, defining an immunometabolic axis of AD and supporting precision-medicine strategies to reprogram metabolism for disease modification.},
}

@article {pmid41688826,
year = {2026},
author = {Caviedes, A and Cabral-Miranda, F and Orellana, P and Hernández, H and Henríquez, F and Gonzalez-Gomez, R and Pizarro, M and Migeot, J and Ochoa-Rosales, C and Gonzalez-Silva, C and Marin-Diaz, N and Coronel-Oliveros, C and Santamaría-García, H and Carmona, D and García, AM and Slachevsky, A and Singleton, A and Qi, AY and Lawlor, B and Miller, B and Dhooge, C and Pantazis, C and Udeh-Momoh, CT and Aguillón, D and Matallana, DL and Zimmer, ER and Resende, EPF and Farina, FR and Cabello, F and Lopera, F and Zetterberg, H and Avila-Funes, JA and Acosta-Uribe, J and Possin, KL and Kosik, KS and Hu, K and Takada, LT and de Oliveira, MO and Maito, MA and Suárez-Calvet, M and Godoy, ME and Behrens, MI and Parra, MA and Del Campo, M and Bruno, M and Gelvez, N and Pozo-Castro, N and Cochran, JN and Custodio, N and Ortega, R and Santibanez, R and de la Cruz, R and Montesinos, R and McDonagh, S and Bandres-Ciga, S and Javandel, S and Brucki, SMD and Pina-Escudero, SD and Valcour, V and Li, Z and Yokoyama, JS and Ibañez, A and Duran-Aniotz, C and , },
title = {Blood-based AT(N) biomarkers for Alzheimer's disease and frontotemporal lobar degeneration in Latin America.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41688826},
issn = {2662-8465},
abstract = {Dementia diagnosis increasingly relies on blood-based biomarkers, yet their performance in diverse populations remains insufficiently characterized. Latin America, with substantial genetic and environmental heterogeneity, is particularly underrepresented in biomarker research. Here we show that plasma AT(N) biomarkers can distinguish Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) in a multinational Latin American cohort (N = 605). Aβ42/Aβ40 amyloid-β ratios were reduced and levels of phosphorylated tau (p-tau217, p-tau181) and neurofilament light chain (NfL) were elevated in both disorders, with NfL showing greater increases in FTLD. Classification models achieved receiver operating characteristic areas under the curve (ROC AUCs) of 83% for AD and 88% for FTLD. Meta-analyses confirmed consistency across countries, and these markers correlated with executive, memory and global cognitive impairment. Biomarker alterations combined with disease-specific neuroimaging patterns and cognitive measures further improved accuracy (ROC AUCs of 89% for AD and 95% for FTLD). These findings indicate that plasma AT(N) biomarkers, combined with neuroimaging and clinical assessments, can enhance dementia diagnosis across diverse Latin American populations.},
}

@article {pmid41688789,
year = {2026},
author = {Novotný, JS and Čarná, M and Dammer, EB and Mao, Z and Stokin, GB},
title = {Rethinking Alzheimer's: novel miRNAs illuminate a disease beyond the brain.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41688789},
issn = {1476-5578},
abstract = {Alzheimer's disease (AD) poses major health, social and economic challenges to the modern world. Despite the advances in understanding AD, our knowledge about its pathogenesis remains incomplete. Recent data suggest that circulating microRNAs (miRNAs) undergo complex changes in AD. Since these changes are yet to be comprehensively characterized, we investigated miRNAs in the context of AD using two meta-analytical approaches. We reproducibly identified 2895 miRNAs in a cohort of 4186 individuals from 22 studies. Here we show that 194 miRNAs exhibited widespread changes in AD, including some novel miRNAs not yet linked to AD. These novel AD miRNAs broaden the landscape of research on the role of miRNAs in AD. Targets of these miRNAs further uncovered many biological pathways that, to date, remain poorly understood in AD with several "AD miRNAs" never described in the brain. "AD miRNAs" described outside the brain significantly influenced interleukin signaling, Toll receptor signaling, p38 MAPK pathway and insulin/IGF pathway. Our results reveal a greater complexity of biological pathways involved in AD than previously thought and raise the question of whether AD is indeed a brain-specific and not a systemic disorder. These findings advance current understanding of AD pathogenesis and lay the ground for the development of next-generation AD biomarkers and design of miRNA-engaged therapies.},
}

@article {pmid41688738,
year = {2026},
author = {Wang, S and Ponnusamy, M and Patel, O and Hansen, M and Collier, L and Collier, S and Thinakaran, G},
title = {Spatiotemporal transcriptomic profiling reveals upregulation of glycolysis pathway genes before overt tauopathy in the PS19 mouse model.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41688738},
issn = {2092-6413},
support = {AG054223//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; G077610//U.S. Department of Health & Human Services | Administration for Community Living (U.S. Department of Health and Human Services, Administration for Community Living)/ ; S10OD030346//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; AARF-61441339/ALZ/Alzheimer's Association/United States ; },
abstract = {The abnormal accumulation of hyperphosphorylated tau in neurofibrillary tangles is a hallmark of neurodegenerative diseases, such as Alzheimer's disease (AD) and frontotemporal dementia. In AD, tangle pathology characteristically develops in brain regions with heightened vulnerability, such as the entorhinal cortex and hippocampus. Emerging evidence implicates mitochondrial dysfunction and metabolic disturbances in AD progression, yet the relationship between regional vulnerability and pretangle tau-driven transcriptomic changes remains unclear. Here, to address this critical gap, we utilized the tau P301S transgenic mouse model (PS19 line), which develops tau inclusions. Using spatial transcriptomic profiling across the hippocampal and cortical regions at selected disease stages, we captured spatiotemporal transcriptional responses to tauopathy. Our findings reveal that disease-associated microglia and astrocyte phenotypes emerge concurrently with phosphorylated tau accumulation across multiple brain regions. Intriguingly, the expression of Pgk1, a hub gene of the glycolytic pathway, was upregulated along with other metabolic pathway genes in the CA3 region at 2 months of age, preceding the onset of detectable tau tangle pathology, and correlated with tangle severity, suggesting early metabolic dysregulation in vulnerable regions. Further analysis of differentially expressed genes uncovered region-specific and temporally dynamic transcriptional patterns in the cortex and hippocampus. Early saturable alterations in ATP metabolic processes, glycolysis and oxidative phosphorylation appeared in the hippocampus at 2 months of age, with delayed engagement in the cortical regions. These results underscore the contributions of metabolic stress and glial activation to tauopathy and regional vulnerability, highlighting spatial transcriptomics as a powerful tool for uncovering region-specific molecular insights into disease mechanisms.},
}

@article {pmid41688439,
year = {2026},
author = {Wu, K and Lee, S and Martinez-Serra, R and Zhang, L and Lynham, S and Giese, KP},
title = {Low concentrations of amyloid-beta oligomers induce synaptogenesis characteristic for mild cognitive impairment and alter the de novo proteome.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03905-x},
pmid = {41688439},
issn = {2158-3188},
support = {AS-PG-21-008/ALZS_/Alzheimer's Society/United Kingdom ; 576/ALZS_/Alzheimer's Society/United Kingdom ; MR/N013700/1//RCUK | Medical Research Council (MRC)/ ; },
abstract = {Alzheimer's disease (AD) is characterized by synaptic dysfunction and proteostatic imbalance, partly driven by amyloid-beta oligomers (Aβo). This study focuses on the effects of low-concentration Aβo exposure on synaptic architecture and de novo protein synthesis in primary cortical neurons, and assesses the neuroprotective potential of the MAP kinase interacting kinase (MNK) inhibitor, eFT508. Using expansion microscopy, we observed that 5-day exposure of low concentrations of Aβo significantly increased synapse density, particularly single synaptic boutons (SSBs) and multi-innervated spines (MIS). This finding indicates that we modelled increases in synapses characteristic of mild cognitive impairment (MCI), a transition to AD. The clinically approved MNK inhibitor eFT508 partially suppressed these synaptic alterations, restoring synapse density to control levels. While total de novo protein synthesis remained unchanged under Aβo exposure using bioorthogonal non-canonical amino acid tagging (BONCAT), subsequent proteomic profiling identified selective changes in de novo protein synthesis that are involved in synaptic function, cytoskeletal regulation, mitochondrial activity, autophagy, and the ubiquitin-proteasome system, and part of these dysregulations could be inhibited by eFT508. These findings indicate that Aβo exposure in an in vitro model of AD leads to synaptogenesis and dysregulation in de novo protein synthesis and they identify eFT508 as a compound that can counteract some of these Aβo-induced dysfunctions.},
}

@article {pmid41688417,
year = {2026},
author = {Nagata, T and Shinagawa, S and Noto, S and Yamato, K and Mori, N and Onuki, K},
title = {Family Caregiver Burden and Neuropsychiatric Symptoms in Japanese Community-Dwelling People With Alzheimer's Disease: A Cross-Sectional Study Using a Web-Based Questionnaire.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {2},
pages = {e70143},
doi = {10.1111/psyg.70143},
pmid = {41688417},
issn = {1479-8301},
support = {//Otsuka Pharmaceutical/ ; },
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/psychology/nursing/therapy ; *Caregivers/psychology/statistics & numerical data ; Middle Aged ; Aged ; Japan/epidemiology ; Cross-Sectional Studies ; Surveys and Questionnaires ; *Independent Living/psychology ; Adult ; *Caregiver Burden/psychology/epidemiology ; Aged, 80 and over ; *Cost of Illness ; Internet ; East Asian People ; },
abstract = {BACKGROUND: Previous studies of community-dwelling people with Alzheimer's disease (AD) have reported an association between the severe neuropsychiatric symptoms (NPS) of dementia and caregiver burden. We explored the current status of family caregiver burden, NPS of dementia, and care service usage in Japanese community-dwelling people with AD.

METHODS: A web-based questionnaire was administered to cohabitant family caregivers of community-dwelling people with AD from 13 to 27 November 2023. Amongst 8108 participants registered in the panel data, 705 family caregivers (age: 19-79 years) were selected. Participants completed the Japanese version of the Neuropsychiatric Inventory-Brief Questionnaire.

RESULTS: Family caregivers (n = 705) had a mean ± standard deviation (SD) age of 54.6 ± 11.5 years, 56.9% were male, and 84.0% cared for a parent or in-law with AD. Patients with AD had a mean ± SD age of 84.2 ± 8.8 years; 26.2% were male, and 90.6% had NPS, including 73.4% with hyperactivity (agitation, disinhibition, irritability and aberrant motor behaviour). Mean ± SD caregiving time per week was higher for caregivers of patients with NPS versus without NPS (24.1 ± 22.1 vs. 17.6 ± 14.0 h). The dissatisfaction with nursing care support services was higher amongst caregivers of patients with NPS vs. without NPS. To manage hyperactivity, 11.3% of caregivers administered medication and 11.5% relocated patients to a calm environment; 16.6% of the caregivers had no way to cope. Amongst caregivers who responded 'administer medication' in response to hyperactivity, 32.1% had care staff or a medical provider come in and administer oral medication and 18.9% took the patient to a medical facility to receive an injection or intravenous treatment.

CONCLUSIONS: Caregiving for AD patients with NPS (vs. without NPS) was associated with longer duration of caregiving, greater usage of nursing care services and dissatisfaction with nursing care support services.},
}

Humans
Male
Female
*Alzheimer Disease/psychology/nursing/therapy
*Caregivers/psychology/statistics & numerical data
Middle Aged
Aged
Japan/epidemiology
Cross-Sectional Studies
Surveys and Questionnaires
*Independent Living/psychology
Adult
*Caregiver Burden/psychology/epidemiology
Aged, 80 and over
*Cost of Illness
Internet
East Asian People

@article {pmid41688290,
year = {2026},
author = {Wang, C and Liu, X and Fan, Y and Liu, GY and Wu, P and Li, SC and Du, YJ},
title = {Silk fibroin@polydopamine for acupoint catgut-embedding therapy in Alzheimer's disease.},
journal = {Journal of integrative medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.joim.2026.01.010},
pmid = {41688290},
issn = {2095-4964},
abstract = {OBJECTIVE: We developed a novel silk fibroin@polydopamine (SF@PDA) material and investigated the mechanism of SF@PDA acupoint implantation for the treatment of Alzheimer's disease (AD) in a mouse model.

METHODS: In the materials research phase, we characterized the surface morphology and properties of the novel SF@PDA composites and evaluated their safety using the cell counting kit-8 assay. Following the intervention, C57BL/6 mice underwent open-field experiments and the Morris water maze test. We analyzed the collected tissues with hematoxylin-eosin staining, immunofluorescent staining, Western blotting, reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay.

RESULTS: After acupoint implantation, SF@PDA reduced amyloid-β (Aβ) deposition and preserve neurons, thereby improving cognitive performance. In particular, SF@PDA can reduce the expression of inflammatory factors, including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α, and inhibit the inflammatory response, thereby further reducing Aβ accumulation and neuronal damage. The SF@PDA treatment resulted in an increase in exploratory behavior and a decrease in the number of errors in mice. Meanwhile, the number of Aβ plaques in the brain was significantly reduced (P < 0.05), and inflammatory cell infiltration was lessened.

CONCLUSION: SF@PDA acupoint implantation has significant therapeutic effects on AD model mice. The mechanism can be related to the inhibition of inflammatory response, reduction of Aβ deposition, and promotion of nerve regeneration. Please cite this article as: Wang C, Liu X, Fan Y, Liu GY, Wu P, Li SC, Du YJ. Silk fibroin@polydopamine for acupoint catgut-embedding therapy in Alzheimer's disease. J Integr Med. 2026; Epub ahead of print.},
}

@article {pmid41688277,
year = {2026},
author = {Ryskamp, D and Wu, L and Wu, J and Kim, D and Rammes, G and Geva, M and Hayden, M and Bezprozvanny, I},
title = {Corrigendum to 'Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor' [Neurobiology of Disease Volume 124 April 2019 Pages 489-504].},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107311},
doi = {10.1016/j.nbd.2026.107311},
pmid = {41688277},
issn = {1095-953X},
}

@article {pmid41688274,
year = {2026},
author = {Bykova, M and Karavani, E and Danziger, M and Tonegawa-Kuji, R and Martin, W and Sha, Z and Pieper, AA and Rosen-Zvi, M and Cheng, F},
title = {Network-based prediction and real-world patient data observation identify doxycycline as a repurposable drug in Alzheimer's disease.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00836},
doi = {10.1016/j.neurot.2026.e00836},
pmid = {41688274},
issn = {1878-7479},
abstract = {Alzheimer's disease (AD), a leading global cause of dementia, disability, and mortality, represents a critical unmet need for effective therapeutic interventions. Drug repurposing offers an expedited pathway to address this challenge compared to traditional drug development. Here, we leveraged network-based prediction and real-world patient data validation, a comprehensive strategy to identify unanticipated therapeutic applications for existing medications. Traumatic brain injury (TBI), a major risk factor for earlier and more severe AD, exhibits heterogenous clinical outcomes influenced by genetic susceptibility, suggesting that TBI-diagnosed populations represent a cohort enriched for neurodegeneration vulnerability. Building on this premise, we integrated network-based multi-omics and endophenotypic disease modules from individuals with TBI and AD histories with large real-world patient data analysis from insurance claims to prioritize repurposable drugs. A network proximity algorithm applied to TBI- and AD-associated gene sets identified statistically ranked candidates, including doxycycline and irbesartan. We then assessed all candidates' AD risk reduction potential using a nationwide Medicare database encompassing nearly 9 million individuals. In a retrospective observational study of AD-free elderly individuals monitored for up to 3 years, propensity-score adjusted survival analyses demonstrated a significantly reduced cumulative incidence of AD in doxycycline and irbesartan-prescribed individuals, with risk ratios of 0.92 and 0.83, respectively, at a 95 % confidence interval. These findings nominate doxycycline and irbesartan as potential repurposable drugs for AD and demonstrate the translational potential of synergizing network-based prediction with real-world patient evidence in drug repurposing for neurodegenerative disease if broadly applied.},
}

@article {pmid41688173,
year = {2026},
author = {Li, D and Zhang, YJ and Liu, T and Fang, JS and Tan, YQ and Meng, XL},
title = {[Impact and mechanisms of enriched environment on cognitive function in Alzheimer's disease model mice].},
journal = {Zhonghua yi xue za zhi},
volume = {106},
number = {7},
pages = {658-663},
doi = {10.3760/cma.j.cn112137-20250829-02233},
pmid = {41688173},
issn = {0376-2491},
support = {2023TSYCLJ0029//"Tianshan Talents" Cultivation Program-Leading Talents in Science and Technology Innovation/ ; 2022A03019-1-5//Major Special Project of Xinjiang Uygur Autonomous Region/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism ; Mice ; Disease Models, Animal ; Male ; *Cognition ; Mice, Inbred C57BL ; Sirtuin 1/metabolism ; Maze Learning ; tau Proteins/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; *Environment ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; },
abstract = {Objective: To investigate the effects and mechanisms of enriched environment(EE) on cognitive function in Alzheimer's disease (AD) model mice. Methods: Sixteen male 6-month-old APP/PS1 mice of SPF grade were randomly divided into standard environment group (AD group), and enriched environment group (ADEE group), with 8 mice in each group. Additionally, 16 C57BL/6J mice with matched body weight were selected as the control group and randomly divided into an enriched environment group (NCEE group) and a control group (NC group), with 8 mice in each group. The mice were adapted to the environment for 2 weeks, followed by 12 weeks of intervention. The Morris water maze test was used to assess learning, memory, and exploration abilities; Immunofluorescence staining and Western blot (WB) were performed to detect the levels of Aβ, Tau protein, silent information regulator 1 (SIRT1), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Results: The Morris water maze test showed that the AD group had fewer platform crossings, fewer effective area crossings, shorter effective area dwell time, fewer target quadrant entries, and shorter target quadrant dwell time compared to the NC group (all P<0.05). In contrast, the ADEE group exhibited more effective area crossings, longer effective area dwell time, more target quadrant entries, and longer target quadrant dwell time compared to the AD group (all P<0.05). Immunofluorescence staining results revealed more Aβplaques and Tau protein positive cells in the AD group and ADEE group compared to the NC group and NCEE group (all P<0.01). After EE intervention, the ADEE group exhibited lower Aβ plaques and Tau protein positive cells than the AD group (all P<0.05). Immunofluorescence staining and WB both demonstrated that SIRT1 and PGC-1α expression in AD mice was lower than in NCEE and NC mice (all P<0.05). Following EE intervention, both the ADEE and NCEE groups showed higher SIRT1 and PGC-1α levels compared to the AD group and NC group (all P<0.05). Conclusion: EE may improve the pathological progression and cognitive impairment of AD by activating the SIRT1/PGC-1α signaling pathway.},
}

Animals
*Alzheimer Disease/metabolism
Mice
Disease Models, Animal
Male
*Cognition
Mice, Inbred C57BL
Sirtuin 1/metabolism
Maze Learning
tau Proteins/metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
*Environment
Amyloid beta-Peptides/metabolism
Mice, Transgenic

@article {pmid41688105,
year = {2026},
author = {Fatih, N and Bhaskaran, K and Kwok, ACH and Ebmeier, KP and Nichols, T and Gelernter, J and Christodoulou, MD and Topiwala, A},
title = {Relationships between alcohol use and dementia: protocol for an observational study in the UK Clinical Practice Research Datalink.},
journal = {BMJ open},
volume = {16},
number = {2},
pages = {e112153},
doi = {10.1136/bmjopen-2025-112153},
pmid = {41688105},
issn = {2044-6055},
mesh = {Humans ; *Dementia/epidemiology/etiology ; United Kingdom/epidemiology ; *Alcohol Drinking/adverse effects/epidemiology ; Risk Factors ; Observational Studies as Topic ; Incidence ; Research Design ; Female ; Male ; Electronic Health Records ; },
abstract = {INTRODUCTION: Alcohol consumption is an increasingly recognised modifiable risk factor for dementia, yet whether it has differential impacts on dementia subtypes and its role in disease progression remains unclear. This study aims to: (1) quantify the association between alcohol intake and incidence of dementia subtypes and (2) examine whether individuals who drink heavily and develop dementia referred to hereafter as 'alcohol-related'-have poorer post-diagnosis outcomes compared with other dementia cases. Clarifying these relationships will determine whether alcohol selectively increases risk for specific dementia phenotypes or broadly heightens neurodegenerative vulnerability, with implications for prevention, clinical counselling and therapeutic targeting.

METHODS AND ANALYSIS: This population-based cohort study of alcohol and dementia will use linked UK electronic health records from Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics (ONS). Participants will be eligible if they have available linked data from January 1998, when ONS death registrations became available, until the end of follow-up. Alcohol exposure will be defined through self-reported recorded weekly alcohol units and diagnostic codes for harmful or dependent alcohol use. Primary outcomes including incident all-cause and subtype-specific dementia (eg, Alzheimer's, vascular, Lewy body, Parkinson's, frontotemporal) as well as secondary outcomes (ie, mortality, care-home entry and neuropsychiatric symptoms). Key covariates encompassing socio-demographic factors, smoking and relevant comorbidities will be adjusted for. Multivariable Cox proportional hazards and Fine-Gray competing risk models will estimate associations with dementia incidence. Post-diagnosis prognosis will be compared for dementia in individuals with a history of heavy alcohol use ('alcohol-related') and dementia in individuals with minimal alcohol exposure ('non-alcohol-related') cases using survival and logistic regression models. Multiple testing correction will be applied across dementia subtype comparisons. Alcohol exposure will be modelled continuously and non-linearly using restricted cubic splines and categorically using binary indicators of harmful/dependent use. Missing covariate data will be assessed and addressed using appropriate methods, including multiple imputation and complete-case analysis. Data extraction and analysis are scheduled from October 2025 to October 2026.

ETHICS AND DISSEMINATION: Use of de-identified routine data will proceed under existing Research Ethics Committee and data governance approvals. Findings will be disseminated via open-access peer-reviewed journals, academic conferences and summaries targeted at patient, public and policy audiences. The results of this study will be reported according to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) and The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) guidelines.},
}

Humans
*Dementia/epidemiology/etiology
United Kingdom/epidemiology
*Alcohol Drinking/adverse effects/epidemiology
Risk Factors
Observational Studies as Topic
Incidence
Research Design
Female
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@article {pmid41687996,
year = {2026},
author = {Gautam, AS and Anju, K and Singh, RK},
title = {Treatment with Interleukin-17 A antibody restored behavioral and neuronal biomarkers in Amyloid-beta1-42-exposed model of Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {150856},
doi = {10.1016/j.ijbiomac.2026.150856},
pmid = {41687996},
issn = {1879-0003},
abstract = {The neuroinflammation in Alzheimer's disease (AD) is due to amyloid-beta1-42 (Aβ1-42) triggered cytokines release from the brain resident immune cells. Interleukin-17 A (IL-17 A) is one of the crucial cytokines involved in orchestrating neuroinflammation and exacerbating AD pathology. Thus, IL-17 A may be considered as one of the key therapeutic options to control AD progression. This study was conducted using BALB/c mice divided into four groups, such as control group, Aβ1-42 (5 μg) group, Aβ1-42 (5 μg) + IL-17 A neutralizing antibody (1 μg) group, and Aβ1-42 (5 μg) + antibody control (IgG1 isotype, 1 μg) group. The intranasal exposure of either Aß1-42 or vehicle was administered once daily for the first seven consecutive days. The intranasal exposure to anti-mouse IL-17 A neutralizing antibody or isotype control was performed once daily from day 5 to day 7, one hour after Aß1-42 exposure. The memory evaluations were conducted through the Morris water maze, novel object recognition test, and passive avoidance test. The brain IL-17 A cytokine levels were increased >2-fold in Aβ1-42-exposed mice as compared to control. IL-17 A antibody exposure led to significant partial improvement in cognitive memory and significantly reduced the expression of AD biomarkers (amyloid precursor protein, beta secretase, phosphorylated tau) along with a significant suppression of IL-17 A signaling axis, astrogliosis, neuronal damage and cytokines in the brain regions of Aβ1-42-exposed animals. In conclusion, neutralizing IL-17 A prevented Aβ1-42-mediated effects and revealed IL-17 A as a potential therapeutic target involved in the regulation of AD progression and pathology.},
}

@article {pmid41687947,
year = {2026},
author = {Yuvika, and Sharma, D and Sharma, A},
title = {Molecular insights into physiological impact of micro- and nano-plastics on the digestive system and gut-brain axis.},
journal = {Comparative biochemistry and physiology. Toxicology & pharmacology : CBP},
volume = {},
number = {},
pages = {110473},
doi = {10.1016/j.cbpc.2026.110473},
pmid = {41687947},
issn = {1532-0456},
abstract = {Microplastics (MPs) and Nanoplastics (NPs) represent an alarming and persistent threat to global human health, owing to their resilience and ubiquity in the environment. Ingestion via contaminated food and water is the primary exposure route, resulting in the accumulation of MNPs in key organs such as the gastrointestinal tract (GI), liver, and pancreas, highlighting the urgent need to understand their potential cumulative and systemic effects. This review critically evaluates recent molecular-level insights into the physiological impacts of MNPs, with particular emphasis on the GI system and the intricate gut-brain axis. MNPs induce cellular toxicity through oxidative stress (OS) and mitochondrial dysfunction, which activate inflammatory and apoptotic pathways. Accumulation in the GI tract causes gut microbiota dysbiosis and a compromised intestinal barrier, and translocates systemically to the liver and pancreas, leading to hepatotoxicity, insulin resistance, and chronic inflammation. Crucially, the disruption of the gut barrier facilitates MNPs access to the central nervous system (CNS) via the gut-brain axis, leading to a breach of the Blood-Brain Barrier. CNS-accumulated MNPs induce neuroinflammation and neurotoxicity, accelerating neurodegenerative disorders such as Parkinson's, Alzheimer's, and multiple sclerosis. This review elucidates the complex mechanisms and highlights significant gaps in understanding MNPs risks, which are currently limited by the use of short-term animal and in vitro models, as well as a lack of precise human data. Future research should prioritize the development of standardized quantification techniques and advanced tracking methods to accurately assess the biodistribution, metabolism, and long-term health effects of MNPs. This approach will facilitate the development of targeted therapeutic interventions and preventive measures.},
}

@article {pmid41687944,
year = {2026},
author = {Fu, X and Zang, Z and Ji, R and Yu, Y and Wu, S and Wang, Z},
title = {Investigating the "homotherapy for heteropathy" mechanism of Danggui Shaoyao San in Alzheimer's disease and polycystic ovary syndrome via MAPK signaling pathway and metabolomics.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121360},
doi = {10.1016/j.jep.2026.121360},
pmid = {41687944},
issn = {1872-7573},
abstract = {Danggui Shaoyao San (DSS), a classic TCM formula traditionally for gynecological diseases, shows promising efficacy in Alzheimer's disease (AD) per recent studies. It regulates metabolic disorders, which is a key feature of AD and polycystic ovary syndrome (PCOS), yet the mechanism of its "homotherapy for heteropathy" across these diseases remains unclear.

AIM OF THE STUDY: This study aimed to verify the therapeutic effects of DSS on both AD and PCOS, and explore its underlying mechanisms involving metabolic regulation, gut microbiota modulation, and the MAPK signaling pathway.

MATERIALS AND METHODS: Materials and methods: AD models were established by Aβ25-35 hippocampal injection, and PCOS models by testosterone propionate combined with high-fat diet. These models were validated via behavior tests and histopathology. Network pharmacology was used to predict DSS targets. Western blot and qPCR were employed to detect the activation status of the MAPK pathway. Metabolic assays and 16S rRNA sequencing were applied to analyze metabolic indexes and gut microbiota structure.

RESULTS: DSS inhibited overactivation of the MAPK pathway in both models, which is consistent with network pharmacology predictions. It restored lipid/steroid hormone homeostasis and increased the abundance of beneficial Lactobacillus in gut microbiota, while alleviating AD and PCOS pathological phenotypes.

CONCLUSION: DSS exerts "homotherapy for heteropathy" effects on AD and PCOS by synergistically regulating the MAPK pathway, metabolic balance, and gut microbiota, providing experimental evidence for its clinical application in these metabolically linked diseases.},
}

@article {pmid41687942,
year = {2026},
author = {Wang, S and Guo, Y and Wang, S and Wang, Y and Huo, S and Li, M and Chen, Q and Zhang, L and Kuang, H and Pan, J and Liu, Y},
title = {Polygonatum Sibiricum polysaccharide ameliorates Alzheimer's disease by alleviating cuproptosis and activating the PI3K/AKT signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {362},
number = {},
pages = {121359},
doi = {10.1016/j.jep.2026.121359},
pmid = {41687942},
issn = {1872-7573},
abstract = {Defined by the selective loss of central nervous system neurons, a progressive neurodegenerative disorder is what Alzheimer's disease (AD) constitutes. It is recognized as the leading cause of dementia globally. Polygonatum sibiricum, also known as "tiger ginger" and "chicken-head ginseng", was hailed as a "treasure herb" by the ancient Chinese pharmacologist Li Shizhen. As a traditional Chinese medicine, its primary active component, Polygonatum sibiricum polysaccharide (PSP), has demonstrated well-defined neuroprotective effects.

AIM OF THE STUDY: The core objective of the present research was to dissect the molecular mechanisms that underlie the therapeutic actions of PSP in AD.

MATERIALS AND METHODS: PSP was purified through water extraction, alcohol precipitation, decolorization, Sevag method deproteinization, and dialysis. The purified polysaccharide was characterized by ultraviolet and infrared spectroscopy. Spatial learning was evaluated as examined by performance in the Morris water maze. To investigate the pathological processes involved in PSP's effects, a range of techniques were employed, including Nissl staining, biochemical assays, immunohistochemistry, transmission electron microscopy, immunofluorescence, and western blotting. The interaction between PSP and the DLAT protein was examined using the CETSA.

RESULTS: Experimental findings indicated that administration of PSP mitigated cognitive impairments in mice with AD and attenuated the loss of neuronal cells. Furthermore, PSP ameliorated mitochondrial damage, modulated cuproptosis-related proteins, and activated the phosphorylation of PI3K and AKT.

CONCLUSION: The present study demonstrates that PSP improves cognitive impairments in 3 × Tg-AD mice by targeting DLAT and subsequently activating the PI3K/AKT pathway. The findings from in vitro cellular models align with those observed in vivo studies. Consequently, PSP emerges as a promising agent endowed with therapeutic potential for AD treatment.},
}

@article {pmid41687939,
year = {2026},
author = {He, S and Fu, XJ and Sun, YH and Zhou, P and Zhang, S and Wang, ZG},
title = {Haikun Shenxi Capsule Alleviates Alzheimer's Disease by Targeting Mitophagy to Clear Turbidity Toxin.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121367},
doi = {10.1016/j.jep.2026.121367},
pmid = {41687939},
issn = {1872-7573},
abstract = {"Turbidity toxin damages brain" has been identified as a critical etiopathogenetic mechanism in Alzheimer's disease (AD). Haikun Shenxi Capsule (HKSX), a traditional Chinese medicine (TCM) formula with efficacy in dissolving turbidity and eliminating toxicant, is clinically used for chronic renal failure (CRF).

AIM OF THE STUDY: Based on the TCM theory of "treating different diseases with the same therapy", this study aimed to investigated the neuroprotective effects and molecular mechanisms of HKSX on AD.

MATERIALS AND METHODS: SAMP8 mice and N2aApp695 cells were used as AD models, behavioral, pathological assessments, as well as metabolomics, transmission electron microscopy (TEM), immunofluorescence (IF), immunohistochemistry (IHC) and western blot analyses, were conducted to validate HKSX's therapeutic effects and underlying mechanisms on AD.

RESULTS: Behavioral testing results showed that HKSX significantly improved learning and memory impairments of SAMP8 mice in novel object recognition (NOR) test and Morris Water Maze (MWM) test, along with reduced levels of Aβ and p-Tau at Thr231 in hippocampus. In metabolomics profiling, HKSX was demonstrated to modulate 73 metabolites and key metabolic pathways, including unsaturated fatty acid biosynthesis, tricarboxylic acid (TCA) cycle, and D-glutamine/D-glutamate metabolism, which are closely related with mitochondria. TEM showed that HKSX improved mitochondrial swelling and cristae rupture in SAMP8 mice, accompanied by increased autolysosomes. HKSX also enhanced mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels, reduced reactive oxygen species (ROS) content, suggesting that it significantly improved mitochondrial structure and function. IHC showed that HKSX administration significantly increased PINK1-positive staining. IF double-labeling results indicated that HKSX promoted the co-localization of Parkin-Tom20, LC-3-LAMP, and mitochondria-lysosomes, providing direct evidence of mitophagy activation. However, inhibition of mitophagy with Mdivi-1 abrogated HKSX-induced activation of PINK1-Parkin signaling, blocked clearance of turbidity toxins, such as Aβ, p-Tau and ROS, and suppressed autophagosome formation in N2a/APP695 cells, confirming that HKSX-mediated neuroprotection is mitophagy-dependent.

CONCLUSIONS: This study established that HKSX alleviated AD-like pathological features and cognitive deficits by activating PINK1-mediated mitophagy pathway. These results suggest that mitophagy may be involved in the cellular process of "eliminating turbidity toxins and detoxification," which provide a novel therapeutic angle for exploring TCM remedies that resolve turbidity in the treatment of AD.},
}

@article {pmid41687930,
year = {2026},
author = {Leong, KF and Chen, Z and Coghi, P},
title = {From nature to novelty: Enhancing rosmarinic acid's therapeutic potential through smart molecular design.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107137},
doi = {10.1016/j.fitote.2026.107137},
pmid = {41687930},
issn = {1873-6971},
abstract = {Rosmarinic acid (RA), a naturally occurring ester of caffeic acid and 3,4-dihydroxyphenyllactic acid, is widely distributed in medicinal plants of the Lamiaceae families. It has attracted considerable attention due to its broad spectrum of pharmacological properties, including strong antioxidant, anti-inflammatory, antiviral, neuroprotective, and anticancer activities. Nevertheless, the therapeutic application of RA has been hampered by poor cell membrane penetration ability, and limited oral bioavailability. To address these challenges, extensive efforts have been devoted to the chemical modification of RA, leading to a wide range of semi-synthetic and fully synthetic derivatives. This review systematically summarizes and evaluates the bioactivity of current RA derivatives. We highlight how different structural modifications, such as esterification, amidation, dimerization, ring expansion, alkyl chain elongation, and metal coordination, can enhance pharmacological potency or improve pharmacokinetic behavior. A comparative "Relative Activity" assessment is also introduced to unify cross-study evaluations by directly comparing the activity of derivatives with the parent compound. Moreover, we discuss structure-activity relationships and underlying mechanisms, with emphasis on the therapeutic relevance of RA derivatives in oxidative stress, inflammation, cancer progression, viral infection, and metabolic disorders. Finally, we outline future perspectives on the rational development of RA-based drug candidates and their potential application in multifunctional theranostic systems.},
}

@article {pmid41687833,
year = {2026},
author = {Liu, J and Zhang, C and Zhao, L and Liu, R and Cao, T and Zhang, D and Liu, Z and Sun, D and Zhang, Y and Yu, X and Kong, W and Wu, H},
title = {Self-assembling ferritin nanoplatform enables amyloid-β-targeted immunotherapy and cognitive rescue in APP/PS1 mice.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106486},
doi = {10.1016/j.bbi.2026.106486},
pmid = {41687833},
issn = {1090-2139},
abstract = {Alzheimer's disease (AD) is a progressively neurodegenerative disorder. The accumulation and pathological aggregation of amyloid-β (Aβ) peptides are key events in the occurrence and progression of AD, positioning Aβ-targeted immunotherapy as a precision therapeutic approach. We present a click chemistry-assisted modular nanoparticle vaccine, Fe-Spy-3CAβ, constructed via SpyCatcher-SpyTag-mediated site-specific conjugation of Aβ1-6 epitopes onto engineered ferritin nanocages. This self-assembling nanoparticle vaccine elicited enhanced immunogenicity in APPswe/PSEN1dE9 transgenic mice, generating high-titer antibodies that specifically recognize neurotoxic Aβ42 oligomers. The vaccine promotes robust clearance of Aβ plaques in the cortical and hippocampal regions while rescuing spatial memory deficits. Notably, sex-specific differences are observed in pathological clearance and behavioral improvements, with male mice exhibiting better cognitive performance and reduced neuroinflammation compared to female counterparts, highlighting sex-specific differences in AD progression. Further immunization of rhesus monkeys confirmed the potent immunogenicity and favorable safety of Ferritin-based Aβ vaccine. Critically, serum antibodies from vaccinated monkeys specifically bound Aβ plaques in AD model mouse brain tissues.Our modular nanoassembly platform overcomes key limitations of conventional AD vaccines regarding immune activation efficiency and safety profiles, while offering a versatile approach for developing immunotherapies for neurodegenerative diseases.},
}

@article {pmid41687804,
year = {2026},
author = {Wu, L and Hou, F and Wang, Z and Wu, M and Wang, X and Cao, J and Wang, Y and Cai, H},
title = {Mitochondrial calcium uniporter knockdown in hippocampal neurons effectively attenuates synaptic plasticity impairment and pathology in APP/PS1/tau model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115686},
doi = {10.1016/j.expneurol.2026.115686},
pmid = {41687804},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, in which mitochondrial dysfunction plays a critical role. The mitochondrial calcium uniporter (MCU) is a key regulator of mitochondrial calcium (mCa[2+]) uptake, and its dysregulation contributes to calcium imbalance and mitochondrial impairment. In this study, we investigated the effects of MCU knockdown in hippocampal neurons on synaptic plasticity and neuropathology in APP/PS1/tau mice. It was found that MCU knockdown reduced mCa[2+] overload, restored mitochondrial membrane potential (MMP), and attenuated excessive reactive oxygen species (ROS) production in the hippocampus. These mitochondrial improvements were associated with a rescue of impaired synaptic plasticity, including enhanced long-term potentiation (LTP) and reduced long-term depression (LTD) through activating the CaMKII/CREB/BDNF/TrkB signaling pathway. Furthermore, MCU knockdown alleviated hippocampal amyloid β (Aβ) pathology by decreasing APP/BACE1/RAGE levels while increasing NEP/LRP1 levels, and mitigated tau pathology through downregulation of GSK3β/CDK5 expression. In addition, hippocampal neuronal number and activity were improved, as reflected by increased N-acetylaspartic acid (NAA)/creatine (Cr) and glutamic acid (Glu)/Cr. Collectively, these findings indicated that MCU knockdown in hippocampal neurons ameliorated mitochondrial dysfunction, synaptic deficits, and AD-related pathology, highlighting MCU as a potential therapeutic target for AD.},
}

@article {pmid41687786,
year = {2026},
author = {Morovati, A and Moussa, Y and Kalupahana, NS and Zu, Y and Jun, H and Fokar, M and Moustaid-Moussa, N},
title = {Neuroinflammation in Alzheimer's Disease: The Role of Obesity, Gut Microbiota, and Therapeutic Potential of Omega-3 Fatty Acids and Neural Stem Cells.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {101407},
doi = {10.1016/j.tjnut.2026.101407},
pmid = {41687786},
issn = {1541-6100},
abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive cognitive decline. According to the amyloid cascade hypothesis, amyloid-β (Aβ) accumulation plays a central role in initiating and driving AD progression. However, therapeutic strategies targeting Aβ have yielded limited and inconsistent clinical benefits, highlighting the need for broader, multi-targeted approaches. Growing evidence identifies neuroinflammation as a central, disease-modifying mechanism in AD pathogenesis, supported by elevated inflammatory markers and immune-related genetic risk variants in patients. Multiple factors converge to sustain maladaptive neuroinflammation, including aging, genetic susceptibility, obesity, and the gut microbiota. Obesity, marked by white adipose tissue expansion and chronic low-grade systemic inflammation, promotes blood-brain barrier dysfunction and primes microglia toward pro-inflammatory phenotypes. In parallel, gut microbiota dysbiosis alters microbial metabolite production, increasing gut permeability, systemic endotoxemia, and neuroinflammatory signaling. Obesity is also associated with alterations in gut microbiota composition and metabolite profiles. Together, these metabolic and microbial cues mechanistically link peripheral dysfunction to central immune activation, accelerate amyloid and tau pathology, and are further amplified by genetic susceptibility and aging. This review synthesizes evidence connecting neuroinflammation with amyloid and tau pathology, emphasizing how obesity and gut microbiota dysbiosis amplify neuroinflammation and AD progression. We further evaluate two anti-inflammatory therapeutic strategies: omega-3 polyunsaturated fatty acids, which modulate immune signaling and gut microbiota composition, and neural stem cell-based interventions, which suppress neuroinflammation through paracrine immunomodulation and microglial reprogramming. By defining key drivers of pathological neuroinflammation and strategies to modulate them, this work provides a framework for developing innovative, multi-targeted interventions that can be applied alone or in combination with classical anti-amyloid therapies.},
}

@article {pmid41687556,
year = {2026},
author = {Zhou, X and Zhang, L and Zhi, J and Zhao, L and Shen, R and Yang, A and Kou, X},
title = {Zinc-porphyrin complex as multifunctional anti-AD agent: Synthesis, X-ray single crystal analysis and activity study.},
journal = {Journal of inorganic biochemistry},
volume = {278},
number = {},
pages = {113245},
doi = {10.1016/j.jinorgbio.2026.113245},
pmid = {41687556},
issn = {1873-3344},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathogenesis. Currently, there are still no drugs on the market that have a significant therapeutic effect. Zinc, an essential trace element, played a double-edged role in neuronal function-zinc deficiency accelerated cognitive decline and neurodegeneration, however overloaded zinc may cause β-amyloid (Aβ) aggregation. In contrast, the brains of AD patients exhibited significantly elevated copper concentrations around Aβ plaques, where this localized high copper concentration microenvironment catalyzed oxidative reactions and Aβ aggregation, thereby exacerbating neuronal damage. To address the interconnected pathological targets, a novel carbamate porphyrin derivative (1) and its zinc complex (1-Zn) were designed and synthesized. Single crystals of both compounds were successfully obtained and analyzed. And with further Hirshfeld surface analysis, molecular dynamics predictions and frontier molecular orbital studies, their structure characteristics and intermolecular interactions were systematically analyzed. Subsequently, metal chelation assays, antioxidant activity evaluations, Aβ aggregation inhibition assays, and anticholinesterase assays were performed to assess the multi-target therapeutic potential. Notably, 1-Zn exhibited a dual-function metal dyshomeostasis regulation ability, namely, chelating excess Cu[2+] and at the same time releasing a specific amount of Zn[2+] to the system. In addition, 1 and 1-Zn showed comparable ROS scavenging ability (in vitro and in vivo) and Aβ aggregation inhibition ability to the positive control drugs. 1-Zn also showed similar cholinesterase inhibition activity as rivastigmine. Consequently, this study demonstrated that 1 and 1-Zn held potential as multifunctional anti-AD agents, meriting further investigation for clinical translation.},
}

@article {pmid41687551,
year = {2026},
author = {Antequera, D and Carrero, L and Romualdi, D and Buetas, E and Garcia-Consuegra, I and Cantero, JL and Mira, A and Municio, C and Carro, E},
title = {Porphyromonas gingivalis in Alzheimer's disease: Association with salivary lactoferrin and inflammatory response.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {196},
number = {},
pages = {119112},
doi = {10.1016/j.biopha.2026.119112},
pmid = {41687551},
issn = {1950-6007},
abstract = {Recent evidence has highlighted the role of the oral microbiome in the inflammatory response and pathogenesis of Alzheimer's disease (AD). The oral pathogen Porphyromonas gingivalis (P. gingivalis) and its gingipain virulence factors may be involved in the development of AD. Concurrently, a decline in the antimicrobial protein lactoferrin has been observed in AD saliva. In this study, we analyzed whether the presence of P. gingivalis and gingipain were associated with salivary lactoferrin and inflammatory markers in patients with AD, mild cognitive impairment (MCI) and age-matched controls. Salivary presence of P. gingivalis was higher in MCI and AD patients and exhibited a negative correlation with global cognitive function. We further showed a marked reduction in salivary lactoferrin with AD progression. Salivary/plasma levels of pro-inflammatory and anti-inflammatory cytokines were significantly higher and lower, respectively, in MCI and AD patients compared to controls. Specifically, salivary levels of Interleukin-6 (IL-6) and IL-23 were higher in MCI and AD patients compared to controls, while the IL-1 receptor antagonist (IL-1ra) and IP-10 were reduced in both saliva and plasma in AD patients. Moreover, stromal cell derived factor 1α (SDF1α)/CXCL12, macrophage inflammatory protein-1β (MIP-1β), and vascular endothelial growth factor (VEGF) salivary and plasma levels were reduced in AD patients. Correlation analyses revealed an inverse relationship between salivary lactoferrin and bacterial load and cytokine concentrations. Our findings suggest that AD is associated with alterations to the oral environment, as revealed by higher P. gingivalis presence, lower lactoferrin levels and elevated pro-inflammatory cytokines.},
}

@article {pmid41687433,
year = {2026},
author = {Libriani, S and Facchinetti, G and Marti, F and Tolentino Diaz, MY and Sandri, E},
title = {The association between gut microbiota and cognitive decline: A systematic review of the literature.},
journal = {Nutrition research (New York, N.Y.)},
volume = {147},
number = {},
pages = {16-31},
doi = {10.1016/j.nutres.2026.01.003},
pmid = {41687433},
issn = {1879-0739},
abstract = {The gut-brain axis has emerged as a key pathway in the pathogenesis of neurodegenerative disorders, with age-related shifts in gut microbiota potentially contributing to cognitive decline and dementia progression. This systematic review evaluated the effects of microbiota-targeted interventions on cognitive outcomes in adults aged >45 years with cognitive impairment or at risk of dementia. Randomized controlled trials and quasi-experimental studies published up to June 2025 were identified through PubMed, COCHRANE, CINAHL, Web of Science, and EMBASE. Methodological quality, assessed using the Joanna Briggs Institute Critical Appraisal Checklist, ranged from moderate to high.Fifteen studies involving 4,275 participants across Europe, Asia, North America, and the Middle East met inclusion criteria. Interventions included probiotic supplementation, fecal microbiota transplantation, and dietary strategies such as Mediterranean and ketogenic diets. Cognitive outcomes were measured using validated tools, including the Mini-Mental State Examination, Montreal Cognitive Assessment, and Repeatable Battery for the Assessment of Neuropsychological Status. Narrative synthesis indicated that microbiota modulation was associated with improvements in memory, executive function, and global cognition, particularly in individuals with prodromal or mild cognitive impairment. Reported benefits correlated with increased microbial diversity, enhanced short-chain fatty acid production, and reduced neuroinflammatory markers. In contrast, effects were limited in advanced Alzheimer's disease.Overall, gut microbiota modulation represents a promising nonpharmacological strategy to support cognitive health, with early intervention appearing crucial for optimal benefit. Nevertheless, heterogeneity in study design and intervention protocols highlights the need for large-scale, longitudinal randomized controlled trials to confirm efficacy and clarify underlying biological mechanisms.},
}

@article {pmid41687346,
year = {2026},
author = {Mazzoleni, E and Malavolti, M and Rossetti, A and Mazzoli, R and Vinceti, M and Filippini, T},
title = {Coffee and tea consumption and risk of dementia: a dose-response meta-analysis of cohort and cohort-nested case-control studies.},
journal = {Journal of epidemiology and population health},
volume = {74},
number = {1},
pages = {203168},
doi = {10.1016/j.jeph.2026.203168},
pmid = {41687346},
issn = {2950-4333},
abstract = {INTRODUCTION: Dementia is a neurodegenerative disease in which environmental and lifestyle factors, including dietary habits, appear to play an important etiologic role. In particular, the effects of tea and coffee consumption are still under debate, having shown both protective and risk effects. This review aimed to assess the dose-response relation between coffee and tea consumption and risk of dementia.

METHODS: We performed a systematic literature search to identify relevant studies using the electronic databases PubMed and EMBASE until December 9, 2025. Inclusion criteria were: population free of chronic diseases and without previous diagnosis of dementia, assessment of tea or coffee intake and of the risk of developing dementia, and cohort or cohort-nested case-control design. We assessed the quality of the studies with the ROBINS-E tool. We performed nonlinear dose-response modeling of dementia for increasing tea and coffee consumption.

RESULTS: Ten studies were included in the analysis, with more than 450,000 participants at baseline and mean follow-up duration of 11.5 years. We found a progressive and linear decrease in all-cause dementia risk with increasing tea consumption, with comparable results for all tea types and for green tea only. Coffee demonstrated a U-shaped relation with the lowest risk between 2-3 cups/day (about 300/450 mL/day). The relation with Alzheimer's dementia showed no difference in risk until 3 cups of coffee per day when risk started to increase.

CONCLUSIONS: This study shows that moderate coffee consumption does not seem to affect dementia risk, while high coffee consumption (≥3 cups/day) could increase risk of all-cause dementia and Alzheimer's dementia. Conversely, tea consumption appears to linearly decrease all-cause dementia risk, while for Alzheimer's dementia there seems to be no further decrease in risk with consumption above one cup/day.},
}

@article {pmid41687295,
year = {2026},
author = {Cai, S and Fan, BW and Qin, J and Pu, CY and Qin, YJ and Wu, CT and Xu, W and Li, J},
title = {From biosensing to herbal discovery: A nanozyme cascade platform for acetylcholinesterase monitoring and inhibitor screening in synthetic and natural sources.},
journal = {Talanta},
volume = {304},
number = {},
pages = {129523},
doi = {10.1016/j.talanta.2026.129523},
pmid = {41687295},
issn = {1873-3573},
abstract = {Early diagnosis and therapeutic intervention for Alzheimer's disease (AD) necessitate advanced tools for detecting acetylcholinesterase (AChE) activity and screening AChE inhibitors (AChEIs). This study developed a novel bimetallic MOF nanozyme, Cu-NH2-88B(Fe), exhibiting significant peroxidase-like activity. This nanozyme was integrated with AChE to construct a dual-enzyme cascade biosensing platform, which achieved highly sensitive AChE detection, with a detection limit of 0.01 mU/mL, and demonstrated excellent accuracy in fetal bovine serum (spiked recoveries: 92.07-111.09%). Additionally, the platform also enabled quantitative assessment of synthetic AChEIs, determining IC50 values for donepezil (9.85 nM), neostigmine (1.41 μM), huperzine A (6.21 μM), and galantamine (611.31 μM), all of which exhibited broad linear ranges and high sensitivity. All four compounds exhibited a broad linear range and excellent sensitivity. Innovatively, the platform was applied to screen AChE inhibitory activity in seven traditional Chinese medicines (TCMs). Crucially, when comparing four extraction methods, ultrasound-assisted extraction (UAE) proved most effective in liberating active compounds. The UAE-obtained extract of Poria cocos (Yunnan) showed the strongest inhibition, achieving an AChE inhibition rate of 39.03% at 0.01 mg/mL. Notably, the screening results across different species, origins, and extraction methods (including the superior UAE) showed high consistency with the classical Ellman method, validating the platform's reliability. This study not only provides a low-cost, easy-to-operate, sensitive, and reliable analytical strategy for AChE activity detection and AChE inhibitor development, but more importantly, it successfully applies nanozyme technology to the complex system of TCMs, offering strong technical support for the screening and preliminary identification of potential anti-AD active components from TCM resources.},
}

@article {pmid41687258,
year = {2026},
author = {Kabeto, MU and Sharma, M and Ford, D and Faul, JD},
title = {Association between allostatic load and incident dementia, and race/ethnic disparities in the association in the U.S. health and retirement study.},
journal = {Psychoneuroendocrinology},
volume = {187},
number = {},
pages = {107779},
doi = {10.1016/j.psyneuen.2026.107779},
pmid = {41687258},
issn = {1873-3360},
abstract = {OBJECTIVE: Allostatic load (AL), the cumulative physiological burden of chronic stress, is a significant health issue and has been linked with adverse health outcomes, including cognitive decline. We examined the association between AL and incident dementia in the United States.

METHOD: We used data from the United States Health and Retirement Study (HRS) cohort (2016-2020) and the 2016 Venous Blood Study (VBS) to examine the association between AL quartile and incident dementia among participants who were aged 56 and older at baseline. Dementia status was determined by cognitive performance of immediate and delayed word recall, serial 7's, backward count, as well as self-report of dementia and Alzheimer's disease. A composite score of biomarkers from neuroendocrine, immune, metabolic, and cardiovascular systems was used to create AL quartiles. The Cox regression model was used to examine the association between AL quartile and incident dementia.

RESULTS: Of the 6806 non-Hispanic White, non-Hispanic Black, and Hispanic participants, 331 (4.9 %) developed dementia by the end of 5 years, with an incident rate of 12.8 per 1000 person-years. In the age and sex adjusted model, incident dementia was higher in the highest AL quartile than the lowest AL quartile (HR = 1.96, 95 % CI [1.37, 2.80], p < .001). The association was attenuated (HR = 1.59, 95 % CI [1.08, 1.10], p < .05) after adjusting for sociodemographic and health behaviors. Race/ethnicity did not modify the association between AL and incident dementia despite higher incident dementia among minorities.

DISCUSSION: The findings highlight the relationship between AL and incident dementia. Further studies of the context of social determinants of health with longer follow-up are needed. Findings may inform the need for interventions to reduce stress stimuli and regular monitoring of biomarkers, thereby delaying the onset of dementia.},
}

@article {pmid41687240,
year = {2026},
author = {Zhu, W and Yin, Z and Fu, Y and , },
title = {CGLK-GNN : A connectome generation network with large kernels for GNN based Alzheimer's disease analysis.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {199},
number = {},
pages = {108689},
doi = {10.1016/j.neunet.2026.108689},
pmid = {41687240},
issn = {1879-2782},
abstract = {Alzheimer's disease (AD) is a currently incurable neurodegenerative disease, with early detection representing a high research priority. AD is characterized by progressive cognitive decline accompanied by alterations in brain functional connectivity. Based on its data structure similar to the graph, graph neural networks (GNNs) have emerged as important methods for brain function analysis and disease prediction in recent years. However, most GNN methods are limited by information loss caused by traditional functional connectivity calculation as well as common noise issues in functional magnetic resonance imaging (fMRI) data. This paper proposes a graph generation based AD classification model using resting state fMRI to address this issue. The connectome generation network with large kernels for GNN (CGLK-GNN) based AD Analysis contains a graph generation block and a GNN prediction block. The graph generation block employs decoupled convolutional networks with large kernels to extract comprehensive temporal features while preserving sequential dependencies, contrasting with previous generative GNN approaches. This module constructs the connectome graph by encoding both edge-wise correlations and node-embedded temporal features, thereby utilizing the generated graph more effectively. The subsequent GNN prediction block adopts an efficient architecture to learn these enhanced representations and perform final AD stage classification. Through independent cohort validations, CGLK-GNN outperforms state-of-the-art GNN and rsfMRI-based AD classifiers in differentiating AD status. Furthermore, CGLK-GNN demonstrates high clinical value by learning clinically relevant connectome node and connectivity features from two independent datasets.},
}

@article {pmid41687112,
year = {2026},
author = {Padeiro, M and Borges-Machado, F and Ribeiro, O and Sousa, L and Almendra, R and Santana, P},
title = {[Prevalence of Dementia and Cognitive Decline in Portuguese Residential Care Homes: A Cross-Sectional Study].},
journal = {Acta medica portuguesa},
volume = {39},
number = {2},
pages = {104-113},
doi = {10.20344/amp.23847},
pmid = {41687112},
issn = {1646-0758},
mesh = {Humans ; Cross-Sectional Studies ; Portugal/epidemiology ; *Dementia/epidemiology/diagnosis ; *Cognitive Dysfunction/epidemiology ; Prevalence ; Female ; Male ; Aged ; *Homes for the Aged/statistics & numerical data ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Dementia is one of the leading causes of dependency among older people and poses a critical challenge for long-term care systems. Despite the importance of the issue, national data on the prevalence of dementia in residential care homes remain limited.

METHODS: A cross-sectional, observational, and institution-based study was conducted within the framework of the SINDIA project. The study was based on an online survey addressed to the technical directors of residential care homes for older people in Portugal, carried out between January and July 2024. The questionnaire collected information on institutional characteristics (sector, territorial location, base monthly fee, dementia specialization, and total number of residents) and on the prevalence of formally diagnosed dementia cases and of cognitive decline without a recorded diagnosis. Data were analyzed using the R software (version 4.1.2). Mean percentages and 95% confidence intervals (Student's t-method), weighted by NUTS-2 region, were calculated. A hierarchical cluster analysis (Ward's method) was also performed to identify distinct institutional profiles.

RESULTS: On average, 31.7% of residents had a formal dementia diagnosis and 22.3% showed signs of undiagnosed cognitive decline, resulting in 50.2% of the resident population presenting some degree of cognitive impairment, after data cleaning. The proportion varied across territories, institutional sectors, monthly fees and self-reported specialization. A cluster analysis identified three distinct institutional profiles, with a majority group of facilities characterized by lower diagnostic formalization, especially in the non-profit sector and among lower-cost institutions.

CONCLUSION: The findings are suggestive of a very high prevalence of cognitive impairment in Portuguese residential care homes. These results highlight the need for public policies aimed at improving early diagnosis, enhancing staff training, and reducing territorial and institutional inequalities in the response to dementia.},
}

Humans
Cross-Sectional Studies
Portugal/epidemiology
*Dementia/epidemiology/diagnosis
*Cognitive Dysfunction/epidemiology
Prevalence
Female
Male
Aged
*Homes for the Aged/statistics & numerical data
Aged, 80 and over

@article {pmid41686995,
year = {2026},
author = {Bacsu, JD and Mero, K and O'Connell, ME and Funk, M and Ménard, A and Norman, M and Blackstock, S and Mann, J and Hulko, W and D'Souza, MS and Fraser, S},
title = {Mapping the Landscape, Knowledge Gaps, and Areas for Innovation in Brain Health and Dementia Research in Canada: Protocol for a Scoping Review of Reviews.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e79020},
doi = {10.2196/79020},
pmid = {41686995},
issn = {1929-0748},
mesh = {Humans ; Scoping Reviews as Topic ; *Dementia ; Canada ; *Brain ; *Biomedical Research ; Research Design ; },
abstract = {BACKGROUND: Dementia is one of Canada's most pressing public health challenges, with rates expected to surge in response to the country's aging population. Given the rapidly growing issue of dementia, understanding national research efforts is critical to prioritizing and advancing strategic directions in brain health and dementia research. Recently, the Canadian Institutes of Health Research awarded a 1-year funding grant from the Brain Health and Cognitive Impairment in Aging Research Initiative to map the scope of brain health and dementia research in Canada.

OBJECTIVE: This scoping review of reviews protocol aims to address this call by outlining the methodology that will be used for mapping the research landscape, documenting the knowledge gaps, and identifying areas of innovation to advance brain health and dementia research in Canada.

METHODS: Given the large volume of literature, a scoping review of Canadian-led reviews was selected as the most appropriate method because it would allow for a robust synthesis of nationally relevant research while mapping knowledge gaps and innovation. Our scoping review of reviews will follow the framework by Arksey and O'Malley along with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The search will focus on peer-reviewed literature reviews published between January 1, 2020, and January 1, 2025, to capture the current state of knowledge since the national dementia strategy's publication in 2019. This search will be conducted using 5 electronic databases: CINAHL, PubMed, PsycInfo, Scopus, and Web of Science. Our data extraction table will include the following categories: author, province, and year; aim; review timeline; method; theme; knowledge gaps; innovations; and findings. The data will be analyzed using a combination of deductive and inductive thematic analysis.

RESULTS: This protocol was registered on June 5, 2025, with the Open Science Framework. This study was funded by the Canadian Institutes of Health Research from November 2024 to November 2025. The anticipated timeline for the publication of the full scoping review of reviews is May 2026. The findings from this review will be shared through targeted knowledge mobilization activities such as presentations at national funding agency meetings, academic conferences, and community workshops.

CONCLUSIONS: Our scoping review of reviews will provide a robust synthesis of the brain health and dementia research landscape, helping document critical knowledge gaps and identify areas for innovation. The results of this research will provide critical data to help inform strategic funding initiatives and future research directions. The findings from our scoping review will have implications for research funders, policymakers, community organizations, and researchers that are working to accelerate brain health and dementia research across Canada.},
}

Humans
Scoping Reviews as Topic
*Dementia
Canada
*Brain
*Biomedical Research
Research Design

@article {pmid41686674,
year = {2026},
author = {Luo, Y and Wen, H and Li, W and Wang, X and Zheng, X and Ge, H and Yin, Y and Chen, L and Wu, X and Hou, W},
title = {Acute deep brain stimulation induces sustained changes in theta and gamma oscillations in Alzheimer's disease model mice.},
journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNSRE.2026.3664396},
pmid = {41686674},
issn = {1558-0210},
abstract = {Hippocampal theta and gamma oscillations degenerate early in Alzheimer's disease (AD), and may be a critical pathogenic factor and therapeutic target for AD. Deep brain stimulation (DBS) improves abnormal theta and gamma oscillations in AD; however, how these oscillations dynamically change after stimulation remains unclear. Exploring the prolonged neuroregulatory effects of DBS is essential for optimizing parameters and treatment strategies. Therefore, we investigated the sustained changes in the theta and gamma oscillations of the hippocampal cornu ammonis 1 region induced by acute DBS of the entorhinal cortex in APP/PS1 model mice and explored the underlying mechanisms. The results showed that the theta (4-8 Hz), low gamma (30-50 Hz) and high gamma (50-100 Hz) power of DBS-treated APP/PS1 mice exhibited a dynamic increase-decrease-increase trend, and the modulation index of theta and high gamma increased significantly and persisted for three weeks after DBS. Compared with the pre-DBS state, the firing rates of interneurons in APP/PS1 mice decreased significantly, while those of pyramidal neurons increased significantly, and the mean vector lengths of pyramidal neurons and interneurons with theta and gamma oscillations decreased significantly. Furthermore, the expression of CaMKII-α and GAD67 increased significantly. These findings suggest that acute DBS targeting the entorhinal cortex induces compensatory changes in the power of theta and gamma oscillations in APP/PS1 mice potentially by regulating the neuronal excitatory/inhibitory balance, thereby improving neuronal information transmission.},
}

@article {pmid41686334,
year = {2026},
author = {Bautista, JLC and Abellanosa, EAM and Jardiolin, JG and Calpo, RAA and Noriega, CNC and Devanadera, MKP and Lopez, SMM and Guevarra, LA},
title = {Web of Potentials: Neuroactive Components of Spider Venom and Their Emerging Pharmacologic Applications in Neurologic Diseases.},
journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy},
volume = {},
number = {},
pages = {},
pmid = {41686334},
issn = {1179-190X},
abstract = {Spider venom has emerged as a promising source of neuroactive compounds with potential applications in the treatment of complex neurological disorders. With over 53,000 described species and more yet to be studied, spiders possess one of the most chemically diverse venoms in the animal kingdom. This diversity has evolved through ecological adaptation, enabling spiders to paralyze and manipulate the nervous systems of a wide range of prey. These same mechanisms, which target ion channels, neurotransmitter receptors, and signaling enzymes, coincide with pathways implicated in human neurologic diseases. By examining the structure-function relationships of spider venom components, this review highlights how venom compounds can modulate neuronal excitability, synaptic transmission, inflammation, and neurodegeneration. Evidence of therapeutic relevance is found in diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, erectile dysfunction, and anxiety, where specific spider-derived components have demonstrated potential disease-modifying effects. Furthermore, by integrating molecular action with disease relevance and ecological context, this review proposes a shift in how spider venom is viewed-not simply as a source of isolated toxins, but as a platform for next-generation therapeutics. This integration of ecological, molecular, and therapeutic dimensions not only synthesizes current knowledge but also charts a path for future interdisciplinary research by revealing critical translational gaps and offering strategies to bridge them toward effective neurotherapeutics.},
}

@article {pmid41686328,
year = {2026},
author = {Sahu, MR and Ahmad, MH and Mondal, AC},
title = {Xmu-mp-1 attenuates streptozotocin-induced neurotoxicity in SH-SY5Y cells: potential role of Hippo pathway modulation.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {384},
pmid = {41686328},
issn = {1573-4978},
support = {BT/PR47726/CMD/150/26/2023//Department of Biotechnology, Ministry of Science and Technology, India/ ; },
}

@article {pmid41686291,
year = {2026},
author = {Gaeta, AM and Viñarás, LG and Barbé, F and Martínez Olmos, P and Pamplona, R and Dakterzada, F and Muñoz-Barrutia, A and Piñol-Ripoll, G},
title = {Capturing silent oxidative stress in early Alzheimer's disease: prediction of CSF biomarkers from sleep qEEG data.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41686291},
issn = {2509-2723},
support = {2021SGR00761//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 464/C/2014//Fundació la Marató de TV3/ ; PERIS 2019 SLT008/18/00050//Ministerio de Sanidad, Consumo y Bienestar Social/ ; PI22/01687//Instituto de Salud Carlos III/ ; PID2023-152631OB-I00//Spanish National Plan for Scientific and Technical Research and Innovation/ ; PID2021-123182OB- I00//Ministerio de Ciencia e Innovación/ ; PID2023-152233OB-I00//Ministerio de Ciencia e Innovación/ ; 2021SGR0099//Ministerio de Ciencia e Innovación/ ; PERIS ref. SLT002/16/00250//Departament de Salut, Generalitat de Catalunya/ ; ND2022/TIC- 23550//Fundación BBVA/ ; ELLIS Unit Madri//Comunidad de Madrid/ ; ICREA program//Comunidad de Madrid/ ; },
abstract = {Oxidative stress is a central pathogenic process in the earliest stages of Alzheimer's disease (AD), promoting non-enzymatic protein modifications that accumulate in cerebrospinal fluid (CSF) before measurable neurodegeneration. These alterations impair proteostasis and disrupt sleep-regulating neural circuits, producing characteristic changes in sleep electroencephalographic patterns. Because CSF sampling is invasive, quantitative electroencephalography (qEEG) has emerged as a promising non-invasive proxy for early oxidative processes. Here, we investigated whether nonlinear and time-domain sleep qEEG features can estimate CSF oxidative stress biomarkers in early AD using machine learning (ML) models. Forty-two mild-to-moderate AD patients underwent overnight polysomnography, from which sleep qEEG features were extracted. CSF protein oxidation biomarkers-glutamic semialdehyde, aminoadipic semialdehyde, N-carboxyethyl-lysine, N-carboxymethyl-lysine, and N-malondialdehyde-lysine-were quantified by gas chromatography/mass spectrometry, and ML models were trained to predict CSF biomarker levels from qEEG features. The best-performing model was a random forest trained on the first principal component, achieving an R 2 of 0.625 and a mean absolute error (MAE) of 467.1 pg/mL. Features derived from frontal and central electrodes during slow-wave sleep and rapid eye movement sleep contributed most strongly to predictive performance. Predictions for healthy controls displayed distributions distinct from those of AD patients, supporting the biological specificity of the qEEG-based estimates. These exploratory analyses suggest that sleep qEEG combined with ML can noninvasively capture silent oxidative processes involved early in AD pathological cascades, with potential for risk stratification, disease monitoring, and non-invasive upstream biomarkers development.},
}

@article {pmid41686158,
year = {2026},
author = {Dallari, C and Ladurner, G and Kendrisic, M and Caria, FF and Manzl, C and Ponticelli, L and Perego, L and Goretti, F and Credi, C and Prokesch, M and Wöhrer, A and Baumann, B and Leitgeb, R and Pavone, FS},
title = {Ultrasensitive Saliva-Based Detection of Early Alzheimer's Disease Biomarkers via Nanoparticle-Enhanced Evanescent Scattering Microscopy.},
journal = {ACS sensors},
volume = {},
number = {},
pages = {XXX},
doi = {10.1021/acssensors.5c04842},
pmid = {41686158},
issn = {2379-3694},
abstract = {Non-invasive biomarkers for early Alzheimer's disease (AD) screening remain a critical unmet need. Current cerebrospinal fluid (CSF) assays, while highly informative, are invasive and unsuitable for large-scale or repeat testing, whereas blood-based biomarkers, despite recent diagnostic advances, still face challenges related to assay standardization, analytical complexity, and sophisticated instrumentation requirements. Saliva represents an attractive alternative matrix due to its accessibility and minimal burden on patients; however, the extremely low abundance and instability of amyloid-β (Aβ) peptides have thus far limited the development of reliable salivary diagnostics. We developed and validated a nanoparticle-enhanced total internal reflection scattering (TIRS) microscopy platform for ultrasensitive, real-time quantification of salivary Aβ proteins. Metallic nanoparticles functionalized with anti-Aβ antibodies were used to amplify scattering signals and enable robust detection at sub-picogram concentrations. The assay was evaluated in two established AD mouse models, APPsl and 5xFAD, in comparison with wild-type controls (n = 33 and n = 34, respectively). Since the validation of Aβ levels in saliva is not feasible with current state-of-the-art technologies, we validated the findings by measuring Aβ levels in the cortex and hippocampus via immunohistochemistry and ELISA. The TIRS assay demonstrated high analytical sensitivity and specificity for Aβ detection in saliva. In both APPsl and 5xFAD models, salivary Aβ42 concentrations were significantly elevated in transgenic mice and showed strong correlations with brain amyloid deposition. Logistic regression and support vector machine (SVM) classifiers were applied to quantify diagnostic performance and threshold-based discrimination based on salivary Aβ42, identified as the most discriminative Aβ form in descriptive analyses. In APPsl mice, logistic regression and SVM models achieved 92% classification accuracy with balanced sensitivity and specificity. These findings establish nanoparticle-enhanced TIRS as a rapid, accurate, and non-invasive tool for salivary Aβ quantification. By overcoming historical limitations of saliva-based biomarker detection, this technology provides a foundation for future translational development, including validation in human cohorts and optimization toward scalable and point-of-care diagnostic implementations.},
}

@article {pmid41685967,
year = {2026},
author = {Ramesh, M and Padmaja, P and Ugale, V and Shirkhedkar, A and Pawara, R and Lokwani, D and Manda, S and Reddy, PN},
title = {Structural Exploration of Pyrazine-1,2,3-Triazole Hybrids as Selective Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {Drug development research},
volume = {87},
number = {2},
pages = {e70249},
doi = {10.1002/ddr.70249},
pmid = {41685967},
issn = {1098-2299},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Alzheimer Disease/drug therapy ; *Triazoles/chemistry/pharmacology ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism/chemistry ; Animals ; Structure-Activity Relationship ; *Pyrazines/chemistry/pharmacology ; Humans ; Butyrylcholinesterase/metabolism ; Mice ; Cell Line ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to gradual deterioration of cognitive functions. Cholinesterase enzymes play a critical role in regulating acetylcholine levels in the brain, and their dysfunction leads to impaired cholinergic neurotransmission, which is a primary hallmark of AD and contributes significantly to the cognitive decline and dementia. Here, a series of pyrazine-1,2,3-triazole molecular hybrids incorporating a trifluoromethyl (-CF3) group were synthesized (8a-o). Synthesized compounds were then evaluated in vitro for cytotoxicity and cholinesterase inhibitory activities. All synthesized compounds were found to be nontoxic toward BV-2 cells in the cytotoxicity screening. The in vitro inhibition assays revealed that these derivatives exhibited greater inhibitory potency against acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). Among them, compound 8h demonstrated the most potent AChE inhibition compared to BuChE (AChE, IC50 = 5.43 µM; BuChE, IC50 = 127.12 µM). The most active compound 8h was further subjected to molecular docking and dynamic simulation (100 ns) to investigate its binding affinity, thermodynamic behavior, and stability within the active site of cholinesterase enzymes. Overall, the findings suggested that the synthesized compounds represent promising drug candidates as selective acetylcholinesterase inhibitors for the treatment of AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
*Alzheimer Disease/drug therapy
*Triazoles/chemistry/pharmacology
Molecular Docking Simulation
Acetylcholinesterase/metabolism/chemistry
Animals
Structure-Activity Relationship
*Pyrazines/chemistry/pharmacology
Humans
Butyrylcholinesterase/metabolism
Mice
Cell Line

@article {pmid41685837,
year = {2026},
author = {Jia, X and Guan, Y and Cao, W and Zhang, X and Duan, H and Guo, H and Chen, H and Wang, B and Li, T and Liao, J},
title = {NIR-responsive upconversion nanoplatforms: an anionic drug carrier for ROS amplification induced by β-amyloid fibrils.},
journal = {Dalton transactions (Cambridge, England : 2003)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5dt03121d},
pmid = {41685837},
issn = {1477-9234},
abstract = {Alzheimer's disease (AD), marked by the misfolding/aggregation of β-amyloid (Aβ), is a major global health challenge. Polyoxometalates (POMs), as anionic therapeutic agents, exhibit potential in depolymerizing Aβ fibrils, inhibiting Aβ fibrillation, and acting as a photocatalyst. To achieve targeted reactive oxygen species (ROS) amplification, we developed a chitosan-modified near-infrared (NIR)-responsive upconversion nanoplatform, UCNPs(Tm/Er)@SiO2@GPS@CH, as a targeted carrier for POMs. The nanoplatform was constructed by sequentially modifying upconversion nanoparticles (UCNPs) with a silica layer, 3-glycidoxypropyltrimethoxysilane (GPS, as a linker), and chitosan (CH, a cationic biomacromolecule). The cationic CH layer enabled efficient loading of anionic POMs through electrostatic interactions with an optimal POM loading capacity of 415.41 μg mg[-1] that positively correlated with CH modification levels. Under NIR irradiation, the nanoplatform triggered a photodynamic effect with abundant ROS. Notably, compared with the control group and Aβ monomer group, the ROS generation in the Aβ fibril group was approximately doubled, which further enhanced the targeted therapeutic efficacy of the system. By integrating NIR responsiveness, cationic chitosan, targeted ROS generation, and low systemic toxicity, the nanoplatform provides a novel strategy for the photooxidative treatment of AD and offers insights into the design of chitosan-modified upconversion nanoparticle-based drug carrier systems.},
}

@article {pmid41685767,
year = {2026},
author = {K, SY and Goswami, AK and Prasad, MR and Chauhan, VS and Yadav, N},
title = {Alzheimer's Disease: Evolving Therapeutics, Scientific Progress, and Key Challenges.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c02468},
pmid = {41685767},
issn = {1520-4804},
abstract = {Alzheimer's disease is a progressive neurological disorder marked by amyloid-beta aggregation, tau abnormalities, impaired neuronal signaling, and related toxicities. Aβ aggregation, while a key factor, is one of several contributors, and its role as a therapeutic target continues to be explored. Efforts to target Aβ aggregation-prone regions with structure-based inhibitors face challenges like poor bioavailability, off-target effects, and limited clinical efficacy. Strategies such as small molecules, peptide therapeutics, and immunotherapies have been explored to inhibit fibrillization, while metal chelators, β-sheet breakers, and molecular chaperones help modulate aggregation and maintain protein homeostasis. Given Alzheimer's multifaceted nature, tau-directed therapies, anti-inflammatory agents, and synaptic modulators are also under investigation. Drug delivery to the brain is constrained by the blood-brain barrier, yet advances in medicinal chemistry, molecular modeling, and rational design of drugs and delivery systems are improving therapeutic strategies. This review emphasizes Aβ aggregation mechanisms and the importance of multifunctional, targeted treatments.},
}

@article {pmid41685608,
year = {2026},
author = {Clark, HP and Horsley, D and Serpell-Stevens, A and Horton, T and Larsson, AI and Oluwabusola, ET and Ebel, R and De Clippele, LH and Jaspars, M},
title = {New Compounds From the Deep-sea Sponge Mycale lingua.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {2},
pages = {e03519},
doi = {10.1002/cbdv.202503519},
pmid = {41685608},
issn = {1612-1880},
support = {BB/M010996/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 730984//ASSEMBLE Plus AmpLOPHELIA project/ ; GCBC//Department for Environment, Food and Rural Affairs, UK Government/ ; DEEPEND//Department for Environment, Food and Rural Affairs, UK Government/ ; },
mesh = {*Porifera/chemistry ; Animals ; Molecular Structure ; tau Proteins/metabolism/antagonists & inhibitors ; Humans ; Magnetic Resonance Spectroscopy ; },
abstract = {Three compatible solutes and one compound of unknown ecological function were isolated and characterized from the deep-sea sponge Mycale lingua (Bowerbank, 1866), collected from Tisler reef in Norway. These included the first isolation of asterubine and sulcatin from M. lingua as well as two new sulcatin analogues, sulcatin B and sulcatin C, which have not previously been reported from natural sources. Compound structures were elucidated through high-resolution liquid chromatography-mass spectrometry, and one- and two-dimensional nuclear magnetic resonance spectroscopic methods. All four compounds were tested in tau-tau aggregation assays to determine if they had potential for the treatment of Alzheimer's disease. No activity was displayed in either the cell-free or cell-based tau aggregation assays for any of the compounds.},
}

*Porifera/chemistry
Animals
Molecular Structure
tau Proteins/metabolism/antagonists & inhibitors
Humans
Magnetic Resonance Spectroscopy

@article {pmid41685556,
year = {2026},
author = {de Waal, MWJ and van der Lee, SJ and Lunding, M and Boonkamp, L and Barrett, N and Monti, G and Jensen, AMG and Vaegter, CB and Raska, J and Cesnarikova, S and Sedmik, J and Trieu, C and Weiss, MM and van Spaendonk, R and Vermunt, L and Ozhegov, G and Tesi, N and Hulsman, M and Januliene, D and Moller, A and Bohaciakova, D and van der Flier, WM and Andersen, OM and Teunissen, CE and Holstege, H},
title = {Soluble SORL1 in cerebrospinal fluid as a marker for functional impact of rare SORL1 variants.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71042},
doi = {10.1002/alz.71042},
pmid = {41685556},
issn = {1552-5279},
support = {JPND2019-466-197//EU Joint Programme - Neurodegenerative Disease Research/ ; #73305095007/ZONMW_/ZonMw/Netherlands ; #733051110/ZONMW_/ZonMw/Netherlands ; #10510032120002/ZONMW_/ZonMw/Netherlands ; #10510032120003/ZONMW_/ZonMw/Netherlands ; //Danish Innovation Foundation and the Velux Foundation Denmark/ ; 8F20009//Ministry of Education, Youth and Sports of the Czech Republic/ ; LX22NPO5107//Ministry of Education, Youth and Sports of the Czech Republic/ ; NU22J-08-00075//Czech Health Research Council/ ; #101112145//IHI- PROMINENT/ ; #101132933//IHI-AD-RIDDLE/ ; 101156175//European Union's Horizon Europe research and innovation programme/ ; 831434//European Union's Horizon Europe research and innovation programme/ ; 101034344//European Union's Horizon Europe research and innovation programme/ ; 22HLT07NEuroBioStand//European Union's Horizon Europe research and innovation programme/ ; 831434//Innovative Medicines Initiative 2 Joint Undertaking (JU)/ ; 101034344//IMI 2 Joint Undertaking (JU)/ ; 22HLT07NEuroBioStand//European Partnership on Metrology/ ; 860197//Marie Curie International Training Network/ ; 101119596//Marie Curie International Training Network/ ; #733050512//NWO/ ; #LSHM20106//Health∼Holland - Topsector Life Sciences & Health/ ; },
mesh = {Humans ; *LDL-Receptor Related Proteins/genetics/cerebrospinal fluid ; *Membrane Transport Proteins/genetics/cerebrospinal fluid ; Female ; Male ; *Alzheimer Disease/cerebrospinal fluid/genetics ; Biomarkers/cerebrospinal fluid ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; Enzyme-Linked Immunosorbent Assay ; Middle Aged ; tau Proteins/cerebrospinal fluid ; },
abstract = {INTRODUCTION: The sortilin-related receptor (SORL1) directs APP and Aβ trafficking within the retromer pathway. Cleavage at the cell surface releases soluble SORL1 (sSORL1) into cerebrospinal fluid (CSF). We examined whether CSF-sSORL1 can serve as an in vivo marker of genetically impaired SORL1.

METHODS: CSF-sSORL1 was quantified by enzyme-linked immunosorbent assay (ELISA) in 218 participants: 90 carriers of SORL1 variants, 78 SORL1-wildtype (WT) AD patients, and 50 SORL1-WT controls.

RESULTS: sSORL1 concentrations were significantly lower in carriers of protein-truncating and damaging missense variants. In SORL1-WT patients, CSF-sSORL1 correlated with pTau181 but not with Aβ42 among AD patients, and did not differ between patients and controls.

DISCUSSION: These findings suggest that impaired SORL1 trafficking reduces receptor delivery to the cell surface and thereby decreases sSORL1 shedding, supporting its potential use as a pathway-specific biomarker.

HIGHLIGHTS: Enzyme-linked immunosorbent assay (ELISA) enables quantitative measurement of soluble sortilin-related receptor (sSORL1) in cerebrospinal fluid (CSF). sSORL1 levels are reduced in CSF from carriers of a pathogenic SORL1 variant. CSF-sSORL1 levels correlate with tau pathology in Alzheimer's disease. sSORL1 levels represent an in vivo biomarker of SORL1 function.},
}

Humans
*LDL-Receptor Related Proteins/genetics/cerebrospinal fluid
*Membrane Transport Proteins/genetics/cerebrospinal fluid
Female
Male
*Alzheimer Disease/cerebrospinal fluid/genetics
Biomarkers/cerebrospinal fluid
Aged
Amyloid beta-Peptides/cerebrospinal fluid
Enzyme-Linked Immunosorbent Assay
Middle Aged
tau Proteins/cerebrospinal fluid

@article {pmid41685554,
year = {2026},
author = {Brugulat-Serrat, A and Tsoy, E and Sánchez-Benavides, G and Milà-Alomà, M and Gaynor, LS and Grau-Rivera, O and Gispert, JD and Kramer, JH and Possin, KL and , },
title = {Detecting early memory changes in preclinical Alzheimer's disease using TabCAT favorites test: Data from the European Prevention of Alzheimer's Disease (EPAD) cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71035},
doi = {10.1002/alz.71035},
pmid = {41685554},
issn = {1552-5279},
support = {SG-21-818099-EPAD//an Alzheimer's Association/ ; AACSF-23-1145154//Alzheimer's Association Clinician Scientist Fellowship Program/ ; R21AG080410//Alzheimer's Association Clinician Scientist Fellowship Program/ ; R35AG072362//Alzheimer's Association Clinician Scientist Fellowship Program/ ; U01NS128913//Alzheimer's Association Clinician Scientist Fellowship Program/ ; P30AG062422//Alzheimer's Association Clinician Scientist Fellowship Program/ ; R01AG059183//Alzheimer's Association Clinician Scientist Fellowship Program/ ; UG3AG090679//Alzheimer's Association Clinician Scientist Fellowship Program/ ; //Global Brain Health Institute/ ; PID2020-119556RA-I00//Spanish Research Agency/ ; AARF-23-1141384//Alzheimer's Association Research Fellowship Program/ ; IJC2020-043417-I//Alzheimer's Association Research Fellowship Program/ ; RYC‑2013‑13054//the Spanish Ministry of Science and Innovation/ ; 115952//AMYPAD/ ; RTI2018‑102261//Ministerio de Ciencia y Universidades/ ; U01NS128913 UH3NS105557//the NIH/ ; R35AG072362//the NIH/ ; U01NS128913//Foundation for the National Institutes of Health/ ; //EU/EFPIA/ ; UH3 NS105557/NS/NINDS NIH HHS/United States ; None//EIT Digital/ ; 115952//Innovative Medicines Initiative/ ; RTI2018‑102261//Ministerio de Ciencia, Innovación y Universidades/ ; PI19/00117//Instituto de Salud Carlos III/ ; RYC‑2013‑13054//Ministerio de Ciencia e Innovación/ ; R35 AG072362/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/cerebrospinal fluid/psychology ; Male ; Female ; *Neuropsychological Tests ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; Cross-Sectional Studies ; tau Proteins/cerebrospinal fluid ; Longitudinal Studies ; Cohort Studies ; Europe ; *Memory Disorders/diagnosis ; Middle Aged ; },
abstract = {INTRODUCTION: Sensitive memory paradigms may allow the detection of subtle memory changes associated with early Alzheimer's pathology in individuals without established clinical symptomatology.

METHODS: We explored the cross-sectional association between performance on Tablet-based Cognitive Assessment Tool (TabCAT) Favorites, a brief computerized memory test, with cerebrospinal fluid AT status (A for amyloid-β and T for phosphorylated tau) and its discriminative validity in 727 clinically asymptomatic participants from the European Prevention of Alzheimer's Disease (EPAD) Longitudinal Cohort Study. Episodic memory was also evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS-MI).

RESULTS: Compared to A-T- individuals, poorer TabCAT Favorites Total Correct (Favorites-TC) cross-sectional performance was associated with an increased likelihood of A+T+ status, but not A+T- status. There were no significant associations between AT status and RBANS-MI. Among individuals with low Favorites-TC performance, AT status predicted progression on the Clinical Dementia Rating > 0.

DISCUSSION: Favorites-TC is a sensitive measure for the early detection of cognitive changes in the early stages of the AD continuum.

HIGHLIGHTS: We explored Tablet-based Cognitive Assessment Tool (TabCAT) Favorites scores and cerebrospinal fluid (CSF) AT status (A for amyloid-β and T for phosphorylated tau) in asymptomatic individuals. Poorer Favorites performance linked to higher A+T+ likelihood. TabCAT Favorites is a sensitive tool for detecting early cognitive changes in Alzheimer's disease (AD).},
}

Humans
*Alzheimer Disease/diagnosis/cerebrospinal fluid/psychology
Male
Female
*Neuropsychological Tests
Aged
Amyloid beta-Peptides/cerebrospinal fluid
Cross-Sectional Studies
tau Proteins/cerebrospinal fluid
Longitudinal Studies
Cohort Studies
Europe
*Memory Disorders/diagnosis
Middle Aged

@article {pmid41685552,
year = {2026},
author = {Dunlop, SR and Matchett, BJ and Mannsbart, AF and Al-Shaikh, FSH and Peng, Z and Rothberg, DM and Tranovich, JF and Duara, R and Uribe, IV and Gondrez, J and Carter, RE and Ferman, TJ and Day, GS and Graff-Radford, NR and Dickson, DW and Grinberg, LT and Murray, ME},
title = {Greater locus coeruleus vulnerability in atypical clinicopathologic forms of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71140},
doi = {10.1002/alz.71140},
pmid = {41685552},
issn = {1552-5279},
support = {R01 AG054449/AG/NIA NIH HHS/United States ; R01 AG075802/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; //Florida Department of Health/ ; 6AZ01//Ed and Ethel Moore Alzheimer's Disease Research Program/ ; 8AZ06//Ed and Ethel Moore Alzheimer's Disease Research Program/ ; 20A22//Ed and Ethel Moore Alzheimer's Disease Research Program/ ; //Alzheimer's Association Florida Gulf Coast Chapter/ ; },
mesh = {Humans ; *Locus Coeruleus/pathology ; *Alzheimer Disease/pathology ; Male ; Female ; Aged ; Aged, 80 and over ; *Neurons/pathology ; Hippocampus/pathology ; Age of Onset ; Middle Aged ; },
abstract = {INTRODUCTION: The locus coeruleus (LC) degenerates early in Alzheimer's disease (AD). However, the extent of rostrocaudal degeneration across clinicopathologic heterogeneity remains underexplored in AD.

METHODS: Using digital pathology, we quantified LC neuronal density and area at three neuroanatomic levels in a large AD series.

RESULTS: Analysis of neuropathologic AD subtypes revealed greater middle LC vulnerability in hippocampal sparing AD compared to typical and limbic predominant AD. Regression analyses identified distinct predictor variables associated with the degeneration of rostral and middle LC. Age at onset predicted 24% of the variability in rostral LC neuronal density, whereas Braak stage, brain weight, Lewy body disease, and age at onset accounted for 15% of the variability in middle LC. Analyses of clinical presentations revealed lower rostral LC neuronal density in non-amnestic compared to amnestic AD cases.

DISCUSSION: These insights demonstrate greater LC degeneration in atypical clinicopathologic forms of AD, including hippocampal sparing, young-onset, and non-amnestic presentations.},
}

Humans
*Locus Coeruleus/pathology
*Alzheimer Disease/pathology
Male
Female
Aged
Aged, 80 and over
*Neurons/pathology
Hippocampus/pathology
Age of Onset
Middle Aged

@article {pmid41685551,
year = {2026},
author = {Santambrogio, A and Metrick, MA and Xu, P and Gallagher, NCT and Koga, S and Ghetti, B and Dickson, DW and Caughey, B and Vendruscolo, M},
title = {Classification of tauopathies from human brain homogenates through salt-modulated tau amplification.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71112},
doi = {10.1002/alz.71112},
pmid = {41685551},
issn = {1552-5279},
support = {10059436//UKRI/ ; 10061100//UKRI/ ; 10138075//UKRI/ ; R01AG080001//Department of Pathology and Laboratory Medicine, Indiana University School of Medicine/ ; P30AG072976//Department of Pathology and Laboratory Medicine, Indiana University School of Medicine/ ; 10059436//UK Research and Innovation/ ; 10061100//UK Research and Innovation/ ; 10138075//UK Research and Innovation/ ; },
mesh = {Humans ; *Tauopathies/classification/diagnosis/metabolism/pathology ; *tau Proteins/metabolism ; *Brain/metabolism/pathology ; Spectroscopy, Fourier Transform Infrared ; Benzothiazoles ; },
abstract = {INTRODUCTION: Tauopathies are a heterogeneous group of neurodegenerative disorders defined by abnormal aggregation of tau protein. Although cryogenic electron microscopy (cryo-EM) has uncovered disease-specific tau structures, translating these insights into diagnostic tools remains difficult.

METHODS: We developed a heparin-free, salt-modulated real-time quaking-induced conversion (RT-QuIC) assay using K12 and K11 tau substrates, targeting aggregation-prone regions. This current method improves on previous methodology by minimising the number of required substrates by modulating reaction salt content in order to differentiate yet-undistinguished tauopathy strains. Thioflavin T fluorescence kinetics and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) spectroscopy were used to classify tau aggregates from human brain homogenates.

RESULTS: This method differentiated eight tauopathies, including Alzheimer's disease, Pick disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), frontotemporal dementia with parkinsonism associated with chromosome 17 with N279K mutation (FTDP-17 N279K), and globular glial tauopathies types II and III. Subclassification of 4R tauopathies was achieved by modulating salt conditions and analyzing aggregation profiles. FTIR confirmed preservation of conformational differences.

DISCUSSION: This salt-modulated, heparin-free RT-QuIC platform enables sensitive tauopathy classification based on strain-specific kinetics and structure. It offers a practical tool for diagnostic development, mechanistic studies, and therapeutic screening.},
}

Humans
*Tauopathies/classification/diagnosis/metabolism/pathology
*tau Proteins/metabolism
*Brain/metabolism/pathology
Spectroscopy, Fourier Transform Infrared
Benzothiazoles

@article {pmid41685542,
year = {2026},
author = {Kumar, GA and Pravallika, P and Thirumalai, V and Bukke, SPN and Rao, PBB and Thalluri, C and Chettupalli, AK and Onohuean, H},
title = {Persicaria hydropiper attenuates oxidative stress and reactive oxygen species, and inhibits amyloid-β/tau in SH-SY5Y cell lines via multiple pathways of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418555},
doi = {10.1177/13872877261418555},
pmid = {41685542},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder with progression leading to a decline in cognition. Despite the extensive research, conventional therapies have limited activity and often cause side effects. This demands the need for novel, safer, and effective treatment of AD.ObjectiveThe objective of this study was to determine the phytochemical constituents and determine the anti-Alzheimer's activity of Persicaria hydropiper.MethodsThe total phenol and flavonoid content of the Persicaria (MP) methanol extract was determined, and active principles were identified using GC-MS. The neuroprotective activity was investigated using biochemical assays against Aβ1-42-induced neurodegeneration in SH-SY5Y neuroblastoma cell lines.ResultsPhytochemical analysis revealed the presence of phenols (258.33 mg GAE) and flavonoids (48.31 mg QE). GC-MS identified the anti-inflammatory and antioxidant bioactive compounds. MP exhibited strong ABTS and DPPH radical-scavenging activities and inhibited AChE and BACE1 enzymes. In SHSY5Y cells, MP prevented Aβ1-42 aggregation, restored cell morphology, reduced reactive oxygen species levels, and preserved mitochondrial membrane potential. It suppressed Aβ and tau fibrillation, downregulated Bax and Caspase, upregulated Bcl2, Beclin-1, LC3B-II, and LAMP1, and reduced IL-6, TNF-α, and GSK3β expression, indicating potent neuroprotective, antioxidant, and anti-inflammatory effects.ConclusionsOverall, the results imply that Persicaria hydropiper exhibits protective activity on neuroblastoma cell lines by mitigating oxidative stress, Aβ/tau fibrils, cell death, and inflammation while also inducing autophagy induced by Aβ1-42. Further in vivo studies are needed to validate the findings to establish the plant as a potential source of anti-Alzheimer's drug.},
}

@article {pmid41685522,
year = {2026},
author = {Egervari, G and Alexander, DC and Huang, H and Donahue, G and Hogan, C and Mendoza, M and Xu, H and Lee, V and Garcia, B and Bonini, N and Berger, S},
title = {Multiomic single nuclei profiling the mouse hippocampus reveals that ACSS2 confers neuronal resilience to tauopathy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e70998},
doi = {10.1002/alz.70998},
pmid = {41685522},
issn = {1552-5279},
support = {RO1AA027202//by NIH/ ; K99AA028577//by NIH/ ; R00AA028577//by NIH/ ; T32 GM-07229//by NIH/ ; T32 AG000255-28//by NIH/ ; F31 CA247348-02//by NIH/ ; YIG31527//the NARSAD Young Investigator/ ; //the Brain and Behavior Research Foundation/ ; AARF-19-618159//Egervari), Alzheimer's Association Research Fellowship/ ; T32 AG000255-28/AG/NIA NIH HHS/United States ; AARF-19-618159/ALZ/Alzheimer's Association/United States ; //Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation/ ; F31 CA247348-02/CA/NCI NIH HHS/United States ; T32 GM-07229/GM/NIGMS NIH HHS/United States ; K99AA028577/AA/NIAAA NIH HHS/United States ; },
mesh = {Animals ; *Hippocampus/metabolism/pathology ; *Tauopathies/genetics/metabolism/pathology ; Mice ; Disease Models, Animal ; Reelin Protein ; *Acetate-CoA Ligase/genetics/metabolism ; *Neurons/metabolism ; Mice, Knockout ; tau Proteins/metabolism ; Humans ; },
abstract = {INTRODUCTION: Epigenomic dysregulation contributes to Alzheimer's disease (AD) and related tauopathies. Acetyl-CoA synthetase 2 (ACSS2), a nuclear-localized metabolic enzyme in neurons, supports histone acetylation and learning-related gene expression. We examined how ACSS2 loss affects molecular and behavioral phenotypes in a mouse model of tauopathy.

METHODS: We induced tauopathy in ACSS2 knockout and control mice via injection of pathological human tau. We assessed transcriptomic, epigenomic, and behavioral changes, and tested long-term acetate supplementation as a rescue strategy.

RESULTS: ACSS2 loss worsened tau-seeding-related phenotypes, particularly in hippocampal pyramidal neurons and Cajal-Retzius cells. Acetate supplementation rescued learning in an ACSS2-dependent manner and restored gene expression linked to cognition.

DISCUSSION: ACSS2 acts as a neuroprotective metabolic enzyme in vulnerable hippocampal neurons, and targeting this pathway through dietary supplementation may offer therapeutic potential for AD and related tauopathies.

HIGHLIGHTS: We combine tau seeding with deletion of acetyl-CoA synthetase 2 (ACSS2) to test this enzyme in an Alzheimer's disease model. Loss of ACSS2 exacerbates transcriptional and behavioral responses to tau injection. We observe robust transcriptional dysregulation in pyramidal neurons in the hippocampus. We observe reduced numbers of reelin-producing Cajal-Retzius cells in the hippocampus. Acetate supplementation rescues transcriptional and behavioral responses to tau.},
}

Animals
*Hippocampus/metabolism/pathology
*Tauopathies/genetics/metabolism/pathology
Mice
Disease Models, Animal
Reelin Protein
*Acetate-CoA Ligase/genetics/metabolism
*Neurons/metabolism
Mice, Knockout
tau Proteins/metabolism
Humans

@article {pmid41685496,
year = {2026},
author = {Datta, SC and Banerjee, S and Roy, UB and Datta, S},
title = {Empowering Alzheimer's and Related Dementia Prevention Through Primary Care Using Responsible AI: A Pilot Walk-in Memory Sync Booth.},
journal = {Studies in health technology and informatics},
volume = {334},
number = {},
pages = {143-144},
doi = {10.3233/SHTI260040},
pmid = {41685496},
issn = {1879-8365},
mesh = {Humans ; *Alzheimer Disease/diagnosis/prevention & control ; Pilot Projects ; Aged ; Primary Health Care ; *Artificial Intelligence ; *Dementia/prevention & control/diagnosis ; Female ; Middle Aged ; Male ; Cognitive Dysfunction/diagnosis ; },
abstract = {Alzheimer's disease and related dementias (ADRD) remain underdiagnosed early due to reliance on costly, invasive, and time-intensive assessments, prompting development of the Memory Sync Booth, an AI-assisted walk-in screening tool for older adults. The booth delivers accessible, automated, and secure tablet-based evaluations which include orientation, attention, naming, picture description, voice analysis, and clock drawing, then processed using NLP, speech recognition, and computer vision for consistent scoring. Grounded in Responsible AI and Digital Health Innovation, it enables equitable deployment across senior community spaces and long-term care settings, with optional direct result-sharing to family doctors and automated alerts for cognitive decline. Tested with 20 volunteers aged 60+, the pilot demonstrated feasibility and potential for earlier MCI detection, reduced clinical wait times, and more proactive dementia management.},
}

Humans
*Alzheimer Disease/diagnosis/prevention & control
Pilot Projects
Aged
Primary Health Care
*Artificial Intelligence
*Dementia/prevention & control/diagnosis
Female
Middle Aged
Male
Cognitive Dysfunction/diagnosis

@article {pmid41685448,
year = {2026},
author = {Cary, GA and Wiley, JC and Carter, GW and Levey, AI},
title = {Beyond the streetlight: a TREAT-AD perspective on where to find new Alzheimer's targets.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71142},
doi = {10.1002/alz.71142},
pmid = {41685448},
issn = {1552-5279},
support = {U54AG065187//Emory-Sage-SGC-JAX TREAT-AD Center/ ; },
mesh = {*Alzheimer Disease/drug therapy/genetics ; Humans ; Clinical Trials as Topic ; Brain/metabolism ; },
abstract = {Despite extensive investments in Alzheimer's disease (AD) therapeutic development, progress toward effective interventions remains modest. The landscape of potential novel therapeutic strategies is rapidly growing, but prioritization, validation, and tools to advance targets to trial are lagging. The Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) consortium has integrated systems-level data from large-scale studies profiling thousands of human brains, yielding target-specific risk scores that partition disease risk into discrete biological domains and enable data-driven target interrogation. Here, we compared clinical trial targets with top-ranked TREAT-AD targets and found a limited overlap as well as differences in the biology emphasized by each set. The current AD therapeutic development landscape remains largely under the "streetlight" of familiar biology, while unbiased measures of disease risk point toward other disease-associated processes that remain comparatively underexplored. These findings underscore opportunities to more deliberately diversify therapeutic portfolios and complement existing development efforts with evidence derived from unbiased human data. HIGHLIGHTS: Clinical AD trials remain focused on well-characterized biology. TREAT-AD integrates genetic and multi-omic data to prioritize novel targets. Limited overlap exists between clinical and high-risk data-driven targets. Risk-associated targets uniquely implicate mitochondrial, lipid, and other pathways. Advancing "dark" targets is critical to diversify AD therapeutic strategies.},
}

*Alzheimer Disease/drug therapy/genetics
Humans
Clinical Trials as Topic
Brain/metabolism

@article {pmid41685442,
year = {2026},
author = {Tsiknia, AA and Terner, JA and Tsokolas, ZE and Shin, DC and Joe, EB and Conti, PS and Lepping, RJ and Kelley, BJ and Zhang, R and Billinger, SA and Chui, HC and Marmarelis, VZ and Braskie, MN},
title = {Cerebrovascular regulation dynamics and Alzheimer's neuroimaging phenotypes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71146},
doi = {10.1002/alz.71146},
pmid = {41685442},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; R01AG058162/AG/NIA NIH HHS/United States ; S10OD032285//NIH Office of the Director/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology/pathology ; Male ; Aged ; Female ; *Cerebrovascular Circulation/physiology ; *Neuroimaging ; Phenotype ; *Brain/diagnostic imaging/pathology ; Positron-Emission Tomography ; Spectroscopy, Near-Infrared ; Hemodynamics/physiology ; Aged, 80 and over ; Magnetic Resonance Imaging ; Ultrasonography, Doppler, Transcranial ; },
abstract = {INTRODUCTION: Cerebrovascular dysfunction may contribute to Alzheimer's disease (AD) pathogenesis. We examined how novel cerebral hemodynamic markers relate to neuroimaging phenotypes associated with AD dementia in cognitively impaired and unimpaired older adults.

METHODS: Statistical hemodynamic indices were computed for each participant from stochastic dynamic models relating resting-state spontaneous arterial blood pressure and end-tidal CO2 fluctuations to transcranial doppler-derived blood velocity and near infrared spectroscopy-derived cortical tissue oxygenation. Linear regressions related these hemodynamic indices to hippocampal volume, WMH volume, cortical thickness in an AD-signature region, and brain amyloid burden measured by PET.

RESULTS: Higher hemodynamic indices, indicating proximity to normal cerebrovascular function correlated with neuroimaging phenotypes typically associated with better cognitive status: greater hippocampal volume and lower amyloid burden.

DISCUSSION: Our findings provide further support for the role of cerebrovascular dysfunction in AD pathogenesis and for the potential clinical utility of model-based indices of cerebral hemodynamics.},
}

Humans
*Alzheimer Disease/diagnostic imaging/physiopathology/pathology
Male
Aged
Female
*Cerebrovascular Circulation/physiology
*Neuroimaging
Phenotype
*Brain/diagnostic imaging/pathology
Positron-Emission Tomography
Spectroscopy, Near-Infrared
Hemodynamics/physiology
Aged, 80 and over
Magnetic Resonance Imaging
Ultrasonography, Doppler, Transcranial

@article {pmid41685429,
year = {2026},
author = {Doring, TH},
title = {TropMol: a cloud-based web tool for virtual screening and early-stage prediction of acetylcholinesterase inhibitors using machine learning.},
journal = {Organic & biomolecular chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ob00094k},
pmid = {41685429},
issn = {1477-0539},
abstract = {Alzheimer's disease (AD) is the most common type of dementia, accounting for at least two-thirds of dementia cases in people aged 65 and older. Numerous approaches have been studied for the treatment of this disease, including the cholinergic hypothesis. Acetylcholinesterase (AChE) is the most promising target studied within the cholinergic hypothesis for the treatment of AD. Therefore, it is necessary to develop predictive models for the identification of AChE inhibitors. Thus, general drug design models can assist chemical synthesis groups and biochemical testing laboratories by enabling virtual screening and drug design. In this work, the objective is to build a generic molecular screening prediction model for public, online and free use based on pIC50, using a random forest model (RF). For this, a dataset with approximately 16 000 compounds and 134 classes of descriptors was used, resulting in more than 2 000 000 calculated descriptors. Other algorithms were studied, such as gradient boosting, XGBoost, LightGBM, and RF with descriptors from principal component analysis (PCA), but none demonstrated significantly superior results compared to the RF model. The final model studied obtained an R[2] = 0.76 with a 15% test set and obtained an R[2] = 0.73 with a 30% test set, with rigorous Y-scrambling confirming the absence of chance correlation. External validation performed on an independent test set comprising 10% of the data yielded an R[2] of 0.77 and an RMSE of 0.67, statistically confirming that the model retains high predictive accuracy for novel chemical scaffolds and is free from overfitting. It is suggested that compounds containing oxime groups (RR'C = NOH) and those with high structural branching (higher Balaban index) tend to be less potent AChE inhibitors (negative correlation). In addition, some descriptors indicate that electronic charge distribution, molecular surface area, and hydrophobicity play important roles in correlating with the inhibitory activity (pIC50) of the compounds. The presence of linear alkane chains also seems relevant to activity (positive correlation and greater importance). The data and models are available at the following link: (https://colab.research.google.com/drive/1gMcuXAsrqTIBMNnsCEWG9xfkK7aaZAbn?usp=sharing).},
}

@article {pmid41685419,
year = {2026},
author = {Lam, A and Almgren, H and Palmer, J and D'Rozario, AL and D'Souza, A and Yee, BJ and Mowszowski, L and Calamante, F and Naismith, SL},
title = {Microscopic white matter changes in the cingulum contribute to memory impairment among older adults with obstructive sleep apnea in the memory clinic.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71197},
doi = {10.1002/alz.71197},
pmid = {41685419},
issn = {1552-5279},
support = {GNT1152945//National Health and Medical Research Council (NHMRC) Centre of Research Excellence to Optimise Sleep in Brain Ageing and Neurodegeneration/ ; SIESTA APP2018668//Synergise, Integrate, and Enhance Sleep Research to Transform Brain Ageing/ ; GNT1135639//NHMRC Boosting Dementia Leadership Fellowship/ ; GNT2008001//NHMRC Emerging Leadership 2 Fellowship/ ; GNT2008001//National Health and Medical Research Council/ ; },
mesh = {Humans ; *Sleep Apnea, Obstructive/complications/pathology ; Male ; Female ; Aged ; *White Matter/pathology/diagnostic imaging ; *Memory Disorders/pathology/etiology/diagnostic imaging ; Neuropsychological Tests ; Polysomnography ; Middle Aged ; Magnetic Resonance Imaging ; *Gyrus Cinguli/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: Obstructive sleep apnea (OSA) is prevalent in memory clinic patients and is associated with learning and memory deficits. In a memory clinic sample, we investigated the relationship between memory-related white matter pathways and OSA.

METHODS: Eighty-two participants (mean age 67.0) underwent neuropsychological testing and neuroimaging. Fixel-based white matter analyses were conducted in the anterior thalamic radiation (ATR), cingulum, uncinate fasciculus (UF), and fornix. Oxygen desaturation index (ODI) from overnight polysomnography classified participants as controls (ODI < 5, n = 26), mild OSA (ODI 5-14, n = 32), or moderate and severe OSA (ODI ≥ 15, n = 24).

RESULTS: In mild OSA, white matter changes were seen in the ATR, UF, and fornix. In moderate and severe OSA, alterations were observed in the cingulum and fornix. Cingulum changes were linked to poorer verbal learning and memory.

DISCUSSION: OSA is associated with disrupted memory-related pathways. Cingulum changes are associated with memory performance in moderate and severe cases.},
}

Humans
*Sleep Apnea, Obstructive/complications/pathology
Male
Female
Aged
*White Matter/pathology/diagnostic imaging
*Memory Disorders/pathology/etiology/diagnostic imaging
Neuropsychological Tests
Polysomnography
Middle Aged
Magnetic Resonance Imaging
*Gyrus Cinguli/pathology/diagnostic imaging

@article {pmid41685378,
year = {2026},
author = {Ghaddaripouri, K and Molavi, R and Montazeryan, S and Kharaghani, MS and Soudejani, FT and Vafamand, M and Erfannia, L},
title = {The Effect of Telehealth on Alzheimer's Disease, Dementia and Mild Cognitive Impairment: A Systematic Review of Clinical Trials.},
journal = {Healthcare technology letters},
volume = {13},
number = {1},
pages = {e70065},
pmid = {41685378},
issn = {2053-3713},
abstract = {Alzheimer's disease is a prevalent chronic condition characterised by the gradual deterioration of memory and personal abilities due to nervous system damage, requiring prolonged care and management. In contemporary healthcare, telehealth has gained recognition as an effective approach for managing chronic illnesses by improving equitable access to quality medical services and minimising expenses. The purpose of this systematic review is to evaluate the role of telehealth in enhancing the well-being of patients with Alzheimer's disease and supporting their caregivers, as evidenced by findings from randomised controlled trials (RCTs). This systematic review concentrated on RCTs published in English, with no constraints on publication date. The search process was accomplished on 11 August, 2025, using appropriate keywords across well-established scientific databases, including PubMed, Embase, Scopus, ScienceDirect, Web of Science and ProQuest. The quality of the studies was assessed using the Joanna Briggs Institute checklist and only those scoring above seven were included in the analysis. From an initial collection of 1242 articles, 14 trials were ultimately included in this review. Telehealth interventions demonstrated significant improvements in cognitive function, mobility and quality of life among individuals with mild cognitive impairment and Alzheimer's Disease, while also reducing caregiver burden and psychological distress. These interventions, implemented through synchronous and asynchronous delivery methods, were deemed feasible, well-received and associated with strong adherence rates. Nonetheless, limitations such as small sample sizes and restricted access to technological resources emphasise the need for additional research to address these gaps. The findings from 13 out of 14 articles in this systematic review indicate that telehealth interventions, including virtual reality, video conferencing, computerised cognitive training and group movement programs, have the potential to significantly enhance health outcomes and quality of life for individuals with Alzheimer's disease and their caregivers compared to traditional in-person treatments. These interventions, delivered through diverse and flexible modalities, also demonstrate cost-effectiveness and improved caregiver well-being, reinforcing telehealth as a scalable and effective approach for comprehensive Alzheimer's care.},
}

@article {pmid41685371,
year = {2026},
author = {Zhang, T and Song, W},
title = {Fight Alzheimer's disease with cancer.},
journal = {Cell insight},
volume = {5},
number = {2},
pages = {100300},
pmid = {41685371},
issn = {2772-8927},
}

@article {pmid41685094,
year = {2026},
author = {Luo, YJ and Su, WK and Yao, W and Jiang, H and McHugh, TJ and Li, YD},
title = {Wakefulness regulation of memory encoding and retrieval: structure and activity.},
journal = {National science review},
volume = {13},
number = {3},
pages = {nwaf520},
pmid = {41685094},
issn = {2053-714X},
abstract = {Sleep-wake states are fundamental regulators of memory processing. While memory consolidation relies on sleep, memory encoding and retrieval depend primarily on wakefulness. Although the role of sleep in memory consolidation has been extensively characterized, the contribution of wakefulness to memory encoding and retrieval remains less systematically summarized. In this review, we synthesize current evidence on how wakefulness regulates memory through two key dimensions: (i) structural organization, defined by the anatomical innervation of memory-related brain regions by the wakefulness system; and (ii) activity-dependent regulation, in which arousal states modulate the efficiency of memory encoding and retrieval. We highlight three major mechanisms-memory engrams, synaptic plasticity and neural oscillations-and propose adult hippocampal neurogenesis (AHN) as an additional timescale-specific mechanism linking wakefulness to memory. Finally, we discuss how wakefulness abnormalities disrupt memory encoding and retrieval in aging, Alzheimer's disease and post-general anesthesia, and suggest that moderate enhancement of arousal level provides a novel strategy for improving memory function.},
}

@article {pmid41684944,
year = {2026},
author = {Rahman, MT and Al Olaimat, M and Bozdag, S and , },
title = {DyGraphTrans: A temporal graph representation learning framework for modeling disease progression from Electronic Health Records.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.28.702347},
pmid = {41684944},
issn = {2692-8205},
abstract = {MOTIVATION: Electronic Health Records (EHRs) contain vast amounts of longitudinal patient medical history data, making them highly informative for early disease prediction. Numerous computational methods have been developed to leverage EHR data; however, many process multiple patient records simultaneously, resulting in high memory consumption and computational cost. Moreover, these models also often lack interpretability, limiting insight into the factors driving their predictions. Efficiently handling large-scale EHR data while maintaining predictive accuracy and interpretability therefore remains a critical challenge. To address this gap, we propose DyGraphTrans, a dynamic graph representation learning framework that represents patient EHR data as a sequence of temporal graphs. In this representation, nodes correspond to patients, node features encode temporal clinical attributes, and edges capture patient similarity. DyGraphTrans models both local temporal dependencies and long-range global trends, while a sliding-window mechanism reduces memory consumption without sacrificing essential temporal context. Unlike existing dynamic graph models, DyGraphTrans jointly captures patient similarity and temporal evolution in a memory-efficient and interpretable manner.

RESULTS: We evaluated DyGraphTrans on Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Alzheimer's Coordinating Center (NACC) for disease progression prediction, as well as on the Medical Information Mart for Intensive Care (MIMIC-IV) dataset for early mortality prediction. We further assessed the model on multiple benchmark dynamic graph datasets to evaluate its generalizability. DyGraphTrans achieved strong predictive performance across diverse datasets. We also demonstrated interpretability of DyGraphTrans aligned with known clinical risk factors. The source code and datasets are available at https://github.com/bozdaglab/DyGraphTrans .

CONTACT: Serdar.Bozdag@unt.edu.

SUPPLEMENTARY: Uploaded as an attachment.},
}

@article {pmid41684835,
year = {2026},
author = {Moallemian, S and Saghafi, A and Deshpande, R and Perez, JM and Budak, M and Fausto, BA and Elahi, FM and Gluck, MA},
title = {Machine learning for missing data imputation in Alzheimer's research: predicting medial temporal lobe dynamic flexibility.},
journal = {Cognitive neurodynamics},
volume = {20},
number = {1},
pages = {51},
pmid = {41684835},
issn = {1871-4080},
abstract = {Alzheimer's disease (AD) pathology begins years before symptoms appear, and dynamic flexibility of the medial temporal lobe (MTL) may serve as an early functional biomarker. Using data from 656 older adults in the Rutgers Aging and Brain Health Alliance study, we evaluated whether cognitive, genetic, biochemical, and demographic predictors could estimate MTL dynamic flexibility, despite substantial missingness (1,866 missing values; 25.86%). Only 42 participants (6.40%) had complete data; therefore, we compared case deletion with five imputation strategies (MICE, GAIN, MissForest, MIWAE, ReMasker) and eight regression models, assessing prediction accuracy using repeated 5-fold cross-validation. Complete-case analysis yielded limited performance (average [Formula: see text], [Formula: see text]). After imputation, all methods improved accuracy, with MissForest paired with Bagging Trees or Random Forest achieving the lowest prediction error ([Formula: see text]). The greatest improvement in concordance occurred when GAIN was combined with Bagging Trees/Random Forest ([Formula: see text]), representing a 57% gain over the best complete-case model. A Scheirer-Ray-Hare ANOVA confirmed significant differences across imputation strategies ([Formula: see text]). Runtime analyses showed GAIN and MissForest to be both accurate and computationally efficient, while deep generative imputers were slower. These findings demonstrate that robust imputation is essential for maximizing data utility and predictive reliability in high-missingness neuroimaging studies and highlight the potential of ensemble tree models combined with advanced imputation techniques for estimating MTL dynamic flexibility in aging populations.},
}

@article {pmid41684773,
year = {2026},
author = {, },
title = {Retraction: PKCε activation restores loss of PKCε, manganese superoxide dismutase, vascular endothelial growth factor, and microvessels in aged and Alzheimer's disease hippocampus.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1792359},
doi = {10.3389/fnagi.2026.1792359},
pmid = {41684773},
issn = {1663-4365},
abstract = {[This retracts the article DOI: 10.3389/fnagi.2022.836634.].},
}