@article {pmid41870711,
year = {2026},
author = {Garland, IJZ and Engel, S and Scalf, M and Payne, NR and Lee, AM and Graves, SM},
title = {Decreased Length of Locus Coeruleus Norepinephrine Axons and Increased Amyloid Beta Pathology in Male APP/PS1 Mice During Protracted Abstinence From Alcohol.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41870711},
issn = {1476-3524},
abstract = {Alzheimer’s disease (AD) is the leading cause of dementia and evidence suggests that alcohol, the most commonly used addictive substance, may increase AD risk. Locus coeruleus (LC) neurons are the primary source of norepinephrine in the brain and these neurons degenerate early in AD. In rodent models, lesioning the LC increases amyloid beta (Aβ) pathology suggesting that LC integrity and norepinephrine signaling obstruct Aβ pathogenesis. We recently reported a decrease in the number of LC norepinephrine neurons and increased Aβ pathology when measured after protracted abstinence from chronic intermittent alcohol consumption in female APP/PS1 mice. Clinically, female subjects are at a higher risk for AD; additionally, female mice consume more alcohol than male mice making it unclear as to whether alcohol consumption would produce similar adverse outcomes in male subjects. To address this gap, male APP/PS1 and non-transgenic mice underwent chronic intermittent access (IA) to alcohol followed by protracted abstinence with water drinking controls run in parallel, consistent with our prior study. In contrast to our previous results with female mice, the number of LC norepinephrine neurons was unchanged in male APP/PS1 mice that had IA to alcohol; however, the length of LC axons was decreased and Aβ pathology was increased in male APP/PS1 mice that consumed alcohol. These data demonstrate that alcohol consumption during early adulthood results in negative consequences in male APP/PS1 mice, although the effect may not be as severe as previously observed in female mice.},
}

@article {pmid41876055,
year = {2026},
author = {Wang, Y and Sun, ZP and Zhou, P and Tu, T and Zhang, XJ and Tu, E and Chen, HP and Cheng, HY and Pan, A and Zhang, QL and Wang, J and Yan, XX},
title = {Early-onset axonal pathology and β-amyloidosis in human brains with hematological malignances and cardiovascular diseases.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.03.032},
pmid = {41876055},
issn = {1873-7544},
abstract = {β-Amyloid (Aβ) and tau pathologies are hallmark lesions of Alzheimer's disease (AD) and they develop in human brain following differential spatiotemporal trajectories. Accordingly, young/adult-onset tau-independent β-amyloidosis is rare. We encountered four such cases among 397 banked brains, with the donors died of hematological malignances (blood cancers) or cardiovascular diseases. To explore the pathological implication, we examined 17 brains (10-87 year-old, y) from blood cancer patients and three (52-82 y) with cardiovascular diseases, focusing on vascular injury, axonal pathology and Aβ formation. Aβ plaques occurred in two adult brains (31 y, 63 y) with blood cancers and two (52 y, 65 y) with cardiovascular diseases in the absence of tau pathology. In the blood cancer brains, 17/17 had vascular injuries seen in hematoxylin-eosin stained sections, 13/17 had iron leakage, and 13/17 had axonal pathology. Malignant cell infiltration was found in 5/14 brains with myeloid, lymphocytic and lymphoma malignances, with light chain infiltration in 3/3 brains with multiple myeloma. In the cardiovascular disease brains, Aβ deposition primarily as diffuse plaques occurred in the cerebral cortex, with vascular and axonal pathologies in the white matter, striatum and internal capsule. Using a multi-labeling approach, the injury/stress induced axonal pathology was associated with β-amyloid processor protein and β-secretase 1 upregulation, but not with intra-axonal amyloid tracer staining. The current findings suggest that hematological malignances and cardiovascular diseases are risk conditions for early-onset cerebral axonal pathology and β-amyloidosis, potentially attributable to vascular injury.},
}

@article {pmid41876395,
year = {2026},
author = {Rosa-Grilo, M and Mallon, D and Thomas, DL and Beament, M and Chughtai, HR and Liu, W and Magill, N and Malone, IB and Meyer, H and Parker, GJM and Triantafyllou, C and Barkhof, F and Fox, NC and Mummery, CJ},
title = {Accelerated 3D MRI for ARIA monitoring in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71297},
doi = {10.1002/alz.71297},
pmid = {41876395},
issn = {1552-5279},
support = {577 [AS-PG-21-045]//Alzheimer's Society Heather Corrie Impact Fund/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; CF-2022-2/128//Rosetrees Trust/ ; //Biogen Idec UK/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Male ; Female ; Aged ; *Imaging, Three-Dimensional/methods ; Sensitivity and Specificity ; *Brain/diagnostic imaging/pathology ; Middle Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Amyloid-targeting therapies for Alzheimer's disease require regular MRI monitoring for amyloid-related imaging abnormalities (ARIA). 3D scans are more sensitive but time intensive; ultra-fast implementations could improve access and reduce burden.

METHODS: Eighty scans from 20 participants were acquired with standard 2D fluid-attenuated inversion recovery (FLAIR) and T2*-gradient recalled echo (T2*-GRE), or accelerated Wave-controlled aliasing in parallel imaging (Wave-CAIPI) 3D FLAIR and susceptibility-weighted imaging (SWI) at 3 T. Two neuroradiologists graded ARIA-E (edema/effusion) and ARIA-H (hemosiderin deposits). Bayesian models estimated sensitivity, specificity, severity agreement, and interchangeability between acquisitions.

RESULTS: Accelerated sequences reduced acquisition time by up to 56%. Four participants had ARIA-E and microbleeds; five had microbleeds alone. Sensitivity and specificity for ARIA-E were identical (1.00; 0.94-0.95); severity was comparable. Replacing standard with accelerated FLAIR did not decrease severity agreement (interchangeability 1.4; 95% highest-density interval [HDI] -3.6% to 5.4%). Fast SWI showed higher microbleed severity gradings.

DISCUSSION: Wave-CAIPI offers fast high-resolution FLAIR acquisitions with comparable performance for ARIA-E monitoring. Wave-CAIPI SWI provides high-quality scans that may aid ARIA-H interpretation.},
}

Humans
*Alzheimer Disease/diagnostic imaging
*Magnetic Resonance Imaging/methods
Male
Female
Aged
*Imaging, Three-Dimensional/methods
Sensitivity and Specificity
*Brain/diagnostic imaging/pathology
Middle Aged
Aged, 80 and over

@article {pmid41876548,
year = {2026},
author = {Kuragano, M and Nishishita, N and Araya, K and Kobayashi, A and Noguchi, TQP and Watanabe, K and Watanabe, S and Baar, S and Uwai, K and Tokuraku, K},
title = {A high-throughput conditioned-media-based screening system identifies inhibitors of aggregation induced by iPSC-secreted amyloid β.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-71078-8},
pmid = {41876548},
issn = {2041-1723},
support = {JPMJPF2213//MEXT | JST | Center of Innovation Program (COI)/ ; },
abstract = {In early drug discovery, in vitro screening is frequently used, but selected candidates often fail in vivo. Induced pluripotent stem cell (iPSC)-based disease models offer improved physiological relevance; however, the high costs of media and differentiation procedures limit large-scale testing. Here, we develop a high-throughput conditioned-media-based screening system-the High-throughput screening technology for Aggregation Inhibitors of Diseased cell-derived Aggregative Proteins (HaiDap) system-to identify inhibitors of aggregation induced by iPSC-secreted amyloid β (Aβ). Using conditioned media derived from differentiated iPSCs of a male Alzheimer's disease patient, we screen extracts from 22 edible plants. Whereas PBS-based assays showed 40.9% (9/22) apparent selectivity, the HaiDap system demonstrates higher specificity (13.6%; 3/22). All three identified extracts (O. aristatus, S. aromaticum, and G. yesoense) significantly delay Aβ aggregation on neuronal surfaces in an iPSC-based assay. These findings suggest that the HaiDap system enables efficient, accurate, and low-cost screening of amyloid aggregation inhibitors.},
}

@article {pmid41876672,
year = {2026},
author = {Prókay, AP and Konkoly, J and Kormos, V and Biró-Sütő, T and Kriszta, G and Szentmártoni, HP and Berta, G and Gaszner, B and Zelena, D and Pintér, E},
title = {Age-dependent alterations of TRPA1 and urocortin 1 signaling in the Edinger-Westphal nucleus in a mouse model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-44022-5},
pmid = {41876672},
issn = {2045-2322},
abstract = {Cholinergic neurons of the preganglionic Edinger-Westphal nucleus (EW) are involved in Alzheimer's disease (AD), however, the role of urocortin 1 (UCN1) positive peptidergic neurons of the centrally projecting EW (EWcp) remains unclear. EWcp cells exclusively express transient receptor potential ankyrin 1 (TRPA1) ion channels, implicated in neurodegenerative disorders. We hypothesized that the EWcp/UCN1/Trpa1 neurons may be involved in AD-related pathologies. Age-dependent (2, 6, 9, 12 and 18 months) Trpa1 mRNA expression (RNAscope in situ hybridization) and UCN1 peptide (immunostaining) content of the EWcp were examined in male triple transgenic mouse (3xTg-AD) model of AD. [1]H-MRI spectroscopy was performed in the hippocampus at 6, 12 and 18 months to evaluate the taurine and N-acetylaspartate levels, metabolites reflecting neuroprotection and neuronal integrity as AD prognostic markers. Trpa1 expression was lower in 2 and 6-months-old 3xTg-AD than controls. Later the genotype differences disappeared due to the progressive, age-related reduction of Trpa1 mRNA transcripts in the controls. In contrast, the Trpa1 expression of transgenic mice remained persistently low. Similarly, the UCN1 peptide content was also lower in the 2 and 6-months-old 3xTg-AD compared to controls. However, UCN1 level increased with age, which was more pronounced in 3xTg-AD than controls abolishing the genotype differences. Age-dependent decrease in taurine level was detected in transgenic animals leading to significantly lower taurine/creatine ratio in 12 and 18-months-old 3xTg-AD animals compared to the controls. This age-related dynamics of Trpa1 and UCN1 expression of 3xTg-AD mice suggests that altered UCN1 signaling may contribute to AD-associated mood disorders and memory decline.},
}

@article {pmid41876811,
year = {2026},
author = {Chaung, W and Ma, G and Lapin, D and Sharma, A and Wang, P and Brenner, M},
title = {Radiation-induced eCIRP Causes Alzheimer's Disease-like Neuronal Tau Phosphorylation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41876811},
issn = {1559-1182},
support = {R35GM11833/GM/NIGMS NIH HHS/United States ; R01AA028947/AA/NIAAA NIH HHS/United States ; U01AI186997//National Institute of Allergy and Infectious Diseases/ ; U01AI170018//National Institute of Allergy and Infectious Diseases/ ; },
mesh = {*tau Proteins/metabolism ; Animals ; Phosphorylation/radiation effects/drug effects ; *Alzheimer Disease/metabolism/pathology ; *Neurons/metabolism/pathology/radiation effects/drug effects ; Mice, Inbred C57BL ; Cyclin-Dependent Kinase 5/metabolism ; *RNA-Binding Proteins/metabolism/antagonists & inhibitors ; Hippocampus/metabolism/pathology ; Male ; Mice ; },
abstract = {Cranial radiotherapy is associated with neuroinflammation, cognitive dysfunction, and dementia. Tau pathology plays a key role in Alzheimer's disease (AD) but has not been studied in the context of radiation injury. Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel neuroinflammatory mediator that activates neuronal IL6Rα/p25/Cdk5, leading to tau hyperphosphorylation. We hypothesized that radiation promotes pathological tau phosphorylation via the eCIRP/IL6Rα/p25/Cdk5 pathway, which can be mitigated by the eCIRP inhibitor C23. Adult C57BL/6 and CIRP[-/-] mice were exposed to a single dose of 10-Gy X-rays at a dose-rate of 1 Gy/min. Hippocampal tissue lysates were analyzed for p25, phosphorylated tau, and CIRP using Western blotting. Cdk5 activity was assessed utilizing a modified Cdk5/p35 kinase enzyme system. Serum and cerebrospinal fluid (CSF) eCIRP was quantified using ELISA. eCIRP (1 µg) was injected intracerebroventricularly (icv) and C23 (8 mg/kg BW) retro-orbitally. N2a and primary neurons were pre-treated with 3 μg/ml IL-6Rα neutralizing Abs or IgG control, or 25 µg/mL C23 and stimulated with up to 2.5 μg/mL eCIRP for 48 h. Irradiation significantly increased hippocampal p25 expression, Cdk5 activity, and tau phosphorylation [AT-8 (Ser202/Thr205/Ser208), and combined Ser199/Ser202 and Ser396 p-tau antibodies] at 48 h post-irradiation. eCIRP increased by 1.2-fold in the serum and 2.6-fold in the CSF, and CIRP increased by 65% in hippocampal lysates after irradiation. Irradiated CIRP[-/-] mice had a 44% reduction in hippocampal p25 and a 59% reduction in hippocampal phosphorylated tau. Mice icv-injected with eCIRP presented p25 and p-tau protein levels as high as irradiated mice. eCIRP increased p-tau in N2a and primary neurons and was inhibited by IL-6Rα Abs and by C23. C23 markedly attenuated the radiation-induced increase in hippocampal p25 and tau phosphorylation. Radiation causes AD-like tau phosphorylation via the eCIRP/IL-6Rα/p25/Cdk5 pathway, which is effectively mitigated by targeting eCIRP with C23. eCIRP is a novel neuroinflammatory mediator with consequential effects for tau pathology and cognitive dysfunction. These novel findings are directly relevant to the pathogenesis and mitigation of radiation-induced cognitive dysfunction, as well as to the etiopathogenesis of AD.},
}

*tau Proteins/metabolism
Animals
Phosphorylation/radiation effects/drug effects
*Alzheimer Disease/metabolism/pathology
*Neurons/metabolism/pathology/radiation effects/drug effects
Mice, Inbred C57BL
Cyclin-Dependent Kinase 5/metabolism
*RNA-Binding Proteins/metabolism/antagonists & inhibitors
Hippocampus/metabolism/pathology
Male
Mice

@article {pmid41876895,
year = {2026},
author = {Luzzi, S and Cherubini, V and Rosettani, P and Baldinelli, S and Fiori, C and Silvestrini, M and Scandola, M},
title = {An updated italian normative data for a short version of the stroop colour word test.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {4},
pages = {},
pmid = {41876895},
issn = {1590-3478},
}

@article {pmid41876945,
year = {2026},
author = {Malin, SK and Battillo, DJ and Beeri, MS and Mustapic, M and Kapogiannis, D},
title = {A Single Bout of Aerobic Exercise Increases Neuronal Extracellular Vesicle-Derived Insulin Signaling Biomarkers in Adults With Cardiometabolic Risk.},
journal = {Comprehensive Physiology},
volume = {16},
number = {2},
pages = {e70131},
doi = {10.1002/cph4.70131},
pmid = {41876945},
issn = {2040-4603},
support = {//Brain Health Institute, Rutgers University/ ; R01DK133598-01A1/DK/NIDDK NIH HHS/United States ; },
mesh = {Humans ; *Insulin/metabolism/blood ; *Exercise/physiology ; Male ; *Extracellular Vesicles/metabolism ; Female ; Adult ; Middle Aged ; Biomarkers/blood/metabolism ; Signal Transduction ; *Neurons/metabolism ; Obesity/metabolism/blood ; Blood Glucose/metabolism ; Cardiometabolic Risk Factors ; },
abstract = {UNLABELLED: Exercise may lower Alzheimer's Disease and Related Dementia (ADRD) risk. While insulin has been proposed to benefit cognition, the effect of exercise on neuronal insulin signaling in humans is unclear.

PURPOSE: We tested the hypothesis that a single bout of aerobic exercise would raise insulin signaling mediators from plasma-derived neuronal extracellular vesicles (nEVs).

METHODS: Fifteen sedentary adults with obesity (12F; ~56y; ~31 kg/m[2]) completed an evening rest and acute exercise condition (70% maximal oxygen consumption (VO2max)) in a randomized, counterbalanced order. Following an overnight fast, plasma was collected for analysis of nEV insulin signaling biomarkers before and after intranasal insulin spray (INI, 40 IU) as well as 60 min following a 75 g oral glucose tolerance test (OGTT). Plasma glucose and insulin were also measured at 30 and 60 min during the OGTT, and total area under the curve (tAUC) was calculated.

RESULTS: Exercise tended to lower glucose tAUC0-150min (p = 0.08, d = 0.50), independent of insulin tAUC0-150min (p = 0.99, d = 0.00). Exercise increased pIR-Tyr1162/Tyr1163 (p = 0.05, η[2] = 0.05), pIRS-1-Ser636 (p = 0.02, η[2] = 0.07), pAkt-Ser473 (p = 0.03, η[2] = 0.06), and pTSC2-Ser939 (p = 0.01, η[2] = 0.08) with medium effect sizes across blood draws, compared with the resting condition. Exercise also raised fasting and decreased pp70S6K-Thr412 before and after the OGTT, compared with increased levels after rest during the OGTT (p = 0.02, η[2] = 0.10). Exercise had no effect on other insulin signaling proteins (e.g., pmTOR-Ser2448, pGSK3β-Ser9, etc.).

CONCLUSIONS: A single bout of aerobic exercise increases some nEV-associated insulin signaling phosphoproteins in people with cardiometabolic risk. Additional work is warranted to determine if changes in brain insulin signaling translate to lower ADRD risk.

CLINICAL TRIALS REGISTRATION: NCT05853913.},
}

Humans
*Insulin/metabolism/blood
*Exercise/physiology
Male
*Extracellular Vesicles/metabolism
Female
Adult
Middle Aged
Biomarkers/blood/metabolism
Signal Transduction
*Neurons/metabolism
Obesity/metabolism/blood
Blood Glucose/metabolism
Cardiometabolic Risk Factors

@article {pmid41876971,
year = {2026},
author = {Chondur, R and Zhao, Y and Unnikrishnan, R and Wright, A and Burgess, P and Lamba, G},
title = {Tobacco Smoking-Attributable Burden of Disease in the Adult Northern Territory Population, 2014-18.},
journal = {The Australian journal of rural health},
volume = {34},
number = {2},
pages = {e70155},
doi = {10.1111/ajr.70155},
pmid = {41876971},
issn = {1440-1584},
mesh = {Humans ; Northern Territory/epidemiology ; Adult ; Middle Aged ; Male ; Female ; Aged ; *Cost of Illness ; Prevalence ; *Tobacco Smoking/adverse effects/mortality/epidemiology ; *Smoking ; },
abstract = {INTRODUCTION: Tobacco smoking is an important preventable cause of death and disease in Australia. Smoking rates are higher in the Northern Territory (NT) among Aboriginal peoples living in remote areas. Understanding smoking-attributable mortality and burden of disease in the NT population is important for building awareness and implementing targeted public health strategies.

OBJECTIVE: To estimate the impact of tobacco smoking on mortality and morbidity in the NT Aboriginal and non-Aboriginal populations aged 30 years and above between 2014 and 2018.

SETTING: NT, Australia.

PARTICIPANTS: Adults (> 30 years) who were NT residents.

METHODS: We used the NT Burden of Disease study (2014-2018) results and Global Burden of Disease methods to estimate smoking-attributable deaths and smoking-attributable burden of disease for the NT Aboriginal and non-Aboriginal populations. The smoking prevalence data were based on 2018-19 National Aboriginal and Torres Strait Islander Heath Survey and 2016 National Drugs Strategy Household Survey.

RESULTS: Smoking was attributable to 18.3% of the total deaths for NT adults aged 30 years and above with 23.8% in Aboriginal and 13.9% in the non-Aboriginal population. Smoking explained 19.5% and 10.7% of total disability adjusted life years among the NT Aboriginal and non-Aboriginal populations respectively. The top three smoking-attributable burden of diseases for the Aboriginal population were ischaemic heart disease, diabetes and chronic obstructive pulmonary disease. In the non-Aboriginal population, lung cancer, chronic obstructive pulmonary disease and back pain were the leading causes of smoking-attributable burden. Leading causes of smoking-related mortality in the Aboriginal population were ischaemic heart disease, chronic obstructive pulmonary disease, lung cancer and diabetes, while in non-Aboriginal population the most common causes were lung cancer, chronic obstructive pulmonary disease, ischaemic heart disease, and Alzheimer's disease.

CONCLUSIONS: Tobacco smoking was associated with a higher burden of disease among the Aboriginal population than the non-Aboriginal population. Our study quantifies the disproportionate impact of tobacco smoking within the Aboriginal population and the NT as a whole compared to the rest of Australia.},
}

Humans
Northern Territory/epidemiology
Adult
Middle Aged
Male
Female
Aged
*Cost of Illness
Prevalence
*Tobacco Smoking/adverse effects/mortality/epidemiology
*Smoking

@article {pmid41877131,
year = {2026},
author = {Wang, N and Yu, G and Wang, Z and Alnobani, A and Jeevaratnam, S and Zhang, X and McReynolds, M and Chang, Y and Qi, F and Tauer, W and Rosenberg, C and Wren, M and Ikezu, TC and Martens, YA and Wang, M and Zhang, B and Carter, GW and Sasner, M and Holtzman, DM and Peng, J and Wu, LJ and Kanekiyo, T and Liu, CC and Bu, G},
title = {Molecular characterization of humanized APOE mouse models reveals source and genotype dependent differences.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00940-6},
pmid = {41877131},
issn = {1750-1326},
support = {U54AG054345//NIH/NIA/ ; 1RF1AG055104//NIH/NIA/ ; U19AG069701//NIH/NIA/ ; },
}

@article {pmid41877170,
year = {2026},
author = {Younas, N and Younas, A and Hermann, P and Flores, LCF and Dittmar, K and Zafar, S and Budde, H and Legler, TJ and Saleem, T and Schmitz, M and Zerr, I},
title = {Reduced plasma TIA-1: bridging established pathology and novel biomarker potential.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02020-9},
pmid = {41877170},
issn = {1758-9193},
}

@article {pmid41877246,
year = {2026},
author = {Shen, R and Sung, K and Ding, J and Wu, C},
title = {Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {41877246},
issn = {2047-9158},
mesh = {Humans ; *Neurodegenerative Diseases/pathology/therapy ; *Axons/pathology ; Animals ; },
abstract = {Axons are unique structural and functional features of nerve cells, which play a critical role in regulating neuronal homeostasis. Dysfunction and degeneration of axons (axonopathy) has been established as an early and prominent contributing mechanism to the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In this review, we briefly summarize the structure and function of axons, and highlight recent advances in the understanding of the role of axons in health and disease. We argue that axons are a potential target for developing novel therapies for neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/pathology/therapy
*Axons/pathology
Animals

@article {pmid41877272,
year = {2026},
author = {Scenna, MS and Maceroni, E and Cimini, A and Castelli, V and d'Angelo, M},
title = {Hypertension and brain damage: evidence from rodent models.},
journal = {Laboratory animal research},
volume = {42},
number = {1},
pages = {},
pmid = {41877272},
issn = {1738-6055},
abstract = {Hypertension is a prevalent condition that significantly raises the incidence of cerebrovascular and cognitive disorders. This review focuses on the factors most closely linked to stroke, cognitive impairment, and Alzheimer's disease. Research into pathophysiology and treatment of hypertensive brain damage has greatly benefited from rodent models, which have been crucial in uncovering the underlying mechanisms and developing effective therapeutic strategies. Rodent models, particularly spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHR-SP), have been essential in elucidating the pathophysiological mechanisms connecting hypertension to brain damage. These models exhibit structural and functional cerebrovascular alterations, including blood-brain barrier disruption, microvascular rarefaction, and neuroinflammation. Interventions targeting the renin-angiotensin system have shown promise in mitigating these adverse effects. This review synthesizes current findings from rodent studies, underscoring the pivotal impact of hypertension in brain pathology and the potential therapeutic benefits of antihypertensive treatments.},
}

@article {pmid41877277,
year = {2026},
author = {Lao, ZK and Xu, NJ},
title = {Deciphering the microenvironment of adult neurogenesis: a perspective from neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {41877277},
issn = {2047-9158},
support = {2021ZD0202801//National Major Science and Technology Projects of China/ ; 32030042//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Neurogenesis/physiology ; *Neurodegenerative Diseases/pathology/physiopathology ; Animals ; *Neural Stem Cells/physiology ; *Stem Cell Niche/physiology ; *Brain/pathology ; },
abstract = {Neurodegenerative diseases are characterized by progressive neuron loss and brain atrophy. While conventional studies focused on neuronal death as the primary cause of these diseases, accumulating evidence suggests that impaired neurogenesis, particularly the dysfunction of adult neural stem cells (NSCs), may also contribute significantly to disease pathogenesis. Adult neurogenesis occurs primarily in two adult NSC niches. These specialized niches are enriched with complex cytokine networks, neuronal activity, and non-cellular components such as the extracellular matrix. Understanding the regulation of NSCs in the adult brain and how their dysregulation exacerbates neurodegeneration provides novel insights into therapeutic strategies. This review proposes that dysfunction of the NSC microenvironment, rather than neuronal death alone, may drive neurodegeneration, and that restoring this microenvironment offers a novel research direction of stem cell-based therapies.},
}

Humans
*Neurogenesis/physiology
*Neurodegenerative Diseases/pathology/physiopathology
Animals
*Neural Stem Cells/physiology
*Stem Cell Niche/physiology
*Brain/pathology

@article {pmid41877305,
year = {2026},
author = {Wu, X and Lu, C and Kong, H and Chen, R and Wang, Z and Deng, Z and Xiao, W and Huang, Z and Li, Q and Yao, D and Ding, X and Zhao, C},
title = {Recalibrating the epigenetic clock reveals divergent DNA methylation age signatures across schizophrenia, bipolar disorder and major depressive disorder.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-9},
doi = {10.1192/bjp.2025.10508},
pmid = {41877305},
issn = {1472-1465},
abstract = {BACKGROUND: Few studies have quantitatively characterised the shared and distinct features of the epigenetic age signature of schizophrenia, bipolar disorder and major depressive disorder.

AIMS: To construct a multi-platform epigenetic clock tailored to human blood and brain tissues, and to characterise variations in epigenetic age acceleration across these three common psychiatric disorders.

METHOD: We integrated 31 publicly available DNA methylation data-sets generated on the platforms Illumina 27K, 450K and EPIC (850K) from patients with schizophrenia, bipolar disorder or major depressive disorder, and from matched controls. Using elastic net regression combined with sure independence screening, we developed the blood–brain clock and applied it to assess disorder-specific epigenetic age acceleration in blood and brain.

RESULTS: The blood–brain clock achieved high accuracy across tissues and outperformed established predictors, particularly in brain samples. Epigenetic age acceleration was reduced in schizophrenia, increased in bipolar disorder and major depressive disorder and strongly elevated in Alzheimer’s disease (positive control). Alterations appeared earlier in blood than in brain. Meta-analysis confirmed that both reduced acceleration (schizophrenia) and increased acceleration (bipolar disorder, major depressive disorder, Alzheimer’s disease) were significantly associated with disease prevalence. Differential methylation analyses further revealed that the blood–brain clock probes captured disease-associated signals, with schizophrenia showing the greatest overlap with causal risk loci, and opposite methylation patterns distinguishing schizophrenia from bipolar disorder or major depressive disorder. A subset of blood DNA methylation probes enabled high-precision classification between schizophrenia and bipolar disorder or major depressive disorder.

CONCLUSIONS: This blood–brain clock reveals distinct patterns of epigenetic age acceleration across psychiatric disorders, reflecting disorder-specific and shared biological ageing signatures. The manifestation of these alterations in peripheral blood highlights its potential as a non-invasive biomarker for early detection, risk stratification and differential classification of schizophrenia, bipolar disorder and major depressive disorder.},
}

@article {pmid41877517,
year = {2026},
author = {Oliveira, FF and Miraldo, MC and Castro-Neto, EF and Almeida, SS and Matas, SLA and Bertolucci, PHF and Naffah-Mazzacoratti, MDG},
title = {Fluid Biomarkers of Motor and Non-Motor Experiences of Daily Living in Dementia with Lewy Bodies and Alzheimer's Disease.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-10},
doi = {10.1017/cjn.2026.10559},
pmid = {41877517},
issn = {0317-1671},
abstract = {BACKGROUND: Associations of cerebrospinal fluid biomarkers with sleep, functionality and the MDS-UPDRS in dementia with Lewy bodies (DLB) and late-onset Alzheimer's disease (AD) help elucidate their pathophysiological underpinnings.

METHODS: Consecutive outpatients with DLB and AD were matched by sex, cognitive scores and dementia stage, along with cognitively healthy controls matched by age and sex to investigate associations of cerebrospinal fluid amyloid-β (Aβ42,Aβ40,Aβ38), tau, phospho-tauThr181, ubiquitin, α-synuclein and neurofilament light (NfL) with sleep duration, Schwab & England scale and MDS-UPDRS, adjusted for sex, age and APOE-ϵ4 alleles.

RESULTS: Patients with DLB (APOE-ϵ4+:n=11, 76.64±9.0years; APOE-ϵ4-:n=16, 79.75±9.0years) were paired with patients with AD (APOE-ϵ4+:n=12, 80.17±5.7years; APOE-ϵ4-:n=15, 81.67±5.9years) and controls (APOE-ϵ4+:n=4, 82.00±6.4years; APOE-ϵ4-:n=23, 77.87±9.0years); two-thirds were women. APOE-ϵ4 carriers with dementia had more amyloidosis, higher phospho-tauThr181/Aβ42 and α-synuclein/Aβ42. In DLB, APOE-ϵ4 non-carriers had lower Schwab & England scores and higher MDS-UPDRS-I&II scores, lower tau/phospho-tauThr181 and higher ubiquitin and NfL than APOE-ϵ4 carriers. In controls, APOE-ϵ4 non-carriers had lower Aβ42 and Aβ42/Aβ38, higher phospho-tauThr181/Aβ42 and α-synuclein/Aβ42 than APOE-ϵ4 carriers. In DLB, sleep duration was associated with Aβ38 and α-synuclein and inversely associated with tau/phospho-tauThr181 and tau/ubiquitin; Schwab & England scores were associated with tau/ubiquitin and inversely associated with tau/phospho-tauThr181; MDS-UPDRS-I&II was associated with Aβ42/Aβ38; MDS-UPDRS-III was associated with tau/phospho-tauThr181; MDS-UPDRS-V ON was associated with Aβ42 and Aβ42/Aβ40, and MDS-UPDRS-V OFF was associated with Aβ42, Aβ42/Aβ40 and Aβ42/Aβ38. In AD, MDS-UPDRS-III was associated with ubiquitin.

CONCLUSION: Biomarker ratios were superior to isolated biomarkers in associations with motor and non-motor experiences in DLB, though not so prominently in AD due to less motor impairment.},
}

@article {pmid41877619,
year = {2026},
author = {Fisher, DW and Mehta, R and Morrow, CB and Kerr, KF and Jayadev, S and Domoto-Reilly, K and Schrift, MJ and Darvas, M},
title = {Affective neuropsychiatric symptom metrics in the National Alzheimer's Coordinating Center dataset.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427462},
doi = {10.1177/13872877261427462},
pmid = {41877619},
issn = {1875-8908},
abstract = {BackgroundIn dementia research, affective neuropsychiatric symptoms (NPS)-depression, anxiety, and apathy-remain understudied. Improving strategies to ensure robust and comparable identification of clinically relevant NPS is essential for better research.ObjectiveWe sought to determine how often objective metrics and clinical gestalt metrics agree on NPS presence or absence. We further sought to determine optimal cut-offs for affective NPS presence/absence using the Neuropsychiatric Inventory Questionnaire (NPIQ) severity ratings.MethodsWe assessed agreement for NPS presence/absence among 5 different depression metrics, 4 anxiety metrics, and 2 apathy metrics via Jaccard indices using the National Alzheimer's Coordinating Center (NACC) dataset. Analysis included exploring four different NPIQ severity rating thresholds of ">0", ">1", ">2", and "=0 and >1".ResultsNPIQ cut-off >1 for presence and =0 for absence of an NPS led to the best agreement with other metrics. However, there was poor agreement for NPS presence across depression metrics (6%) and across anxiety metrics (7%). Choice of metric could greatly skew the frequency of an NPS being present. All 3 affective NPS were more common in Lewy body disorder compared to Alzheimer's disease or vascular cognitive impairment, regardless of metric.ConclusionsThough NPIQ severity rating cut-off choice should depend on study design, using a severity score of >1 for presence and =0 for absence may best fit clinical gestalt for affective NPS. Lewy body disorders present with more affective NPS than other common dementia etiologies. Future consensus on criteria for depression and anxiety syndromes in dementia may improve their identification.},
}

@article {pmid41877626,
year = {2026},
author = {Zhou, X and Wang, R and Yan, J and Wu, X and Yuan, D and Wang, Q and Li, H and Zhao, W},
title = {Atractylenolide I mitigates Alzheimer's disease pathology in ApoE [-/-] mice via ARG1/nNOS axis and lipid homeostasis regulation.},
journal = {Acta biochimica et biophysica Sinica},
volume = {},
number = {},
pages = {},
doi = {10.3724/abbs.2026055},
pmid = {41877626},
issn = {1745-7270},
abstract = {Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer's disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Atractylodes macrocephalaKoidz., exhibits multimodal bioactivities with demonstrated anti-inflammatory and neuroprotective properties. To explore its therapeutic potential against AD pathology, we use high-fat diet (HFD)-fed ApoE knockout (ApoE [-/-]) mice treated with or without AI for 12 weeks. Integrated bioinformatics analyses and experimental validation reveal that AI treatment markedly attenuates systemic lipid dyshomeostasis, particularly cerebral lipid deposition, suppresses neuroinflammation via downregulation of M1 macrophage polarization markers, and restores cognitive function through neuronal preservation in hippocampal regions. Mechanistically, AI orchestrates cholesterol efflux by upregulating ATP-binding cassette transporter A1 (ABCA1) and liver X receptor (LXR) expression, while concurrently modulating the abundance of arginine biosynthesis metabolites (urea, malic acid, and creatinine) to rebalance neurovascular homeostasis. Notably, western blot and RT-qPCR analyses reveal that AI differentially regulates key enzymes including arginase 1 (ARG1) and simultaneously upregulates the expression of neuronal nitric oxide synthase (nNOS). Further molecular docking and surface plasmon resonance (SPR) analyses confirm the direct binding of AI to ARG1, indicating a novel neuroprotective mechanism involving the modulation of arginine metabolism. These findings delineate the pleiotropic effects of AI against AD pathology and establish a preclinical foundation for the development of AI-based therapeutics targeting neurodegenerative-cardiovascular comorbidities.},
}

@article {pmid41877657,
year = {2026},
author = {Arwini, A and Kirk, A and O'Connell, M and Morgan, D},
title = {Predictors of long-term care admission in a rural and remote memory clinic.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261434989},
doi = {10.1177/13872877261434989},
pmid = {41877657},
issn = {1875-8908},
abstract = {BackgroundCaregivers face unique challenges when the care recipient transitions from at-home care to long-term care (LTC).ObjectiveWe aimed to elucidate predictors of LTC admission within two years of initial presentation to a Rural and Remote Memory Clinic in Saskatchewan.MethodsAnalysis included 635 patients seen between March 2004 and June 2019 (admitted to LTC within two years = 222, not admitted = 413). Patients were assessed neuropsychologically and administered questionnaires.ResultsThe majority of those who moved to LTC were diagnosed with Alzheimer's disease. The multivariate logistic regression model revealed no statistically significant results. However, univariate logistic regressions showed that advanced age (OR = 1.05, CI = 1.04-1.07), female sex (OR = 1.79, CI = 1.28-2.52), higher Functional Activities Questionnaire (OR = 1.09, CI = 1.06-1.11), lower Mini-Mental State Examination (OR = 0.861, CI = 0.827-0.897), and higher Clinical Dementia Rating score (OR = 1.13, CI = 1.06-1.21) were significant predictors (p < 0.001).ConclusionsBeing older, female, more dependent in activities of daily living, and having more severe dementia predicted LTC admission, potentially helping in planning care.},
}

@article {pmid41877664,
year = {2026},
author = {Pennington, C and Apurva, P and Chen, A and Duncan, A and Mackay, G and Masters, H and Paramore, K and Russ, T and Skinner, H and Zeidler, M},
title = {Disease modifying treatments for Alzheimer's disease: Clinician perspectives.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261429859},
doi = {10.1177/13872877261429859},
pmid = {41877664},
issn = {1875-8908},
abstract = {In recent years there have been exciting developments in the diagnosis and treatment of mild cognitive impairment and dementia due to Alzheimer's disease. Robust biomarkers and potentially disease modifying therapies are now available, with multiple other agents in clinical trials alongside on-going validation studies of blood-based biomarkers. Recent and probable future developments in the diagnosis and care of people with Alzheimer's disease pathology warrants serious re-evaluation of the structure and function of cognitive clinical services. Here we report recommendations from the November 2024 Brain Health Scotland roundtable discussion of opportunities and challenges for modern memory services.},
}

@article {pmid41877687,
year = {2025},
author = {Hayat, B and Alone, DP},
title = {Unfolded proteins and aggregates: The role of proteostasis in pseudoexfoliation pathology.},
journal = {Molecular vision},
volume = {31},
number = {},
pages = {463-484},
pmid = {41877687},
issn = {1090-0535},
mesh = {Humans ; *Exfoliation Syndrome/metabolism/pathology ; *Proteostasis ; *Unfolded Protein Response ; *Protein Aggregates ; Animals ; Autophagy ; *Protein Aggregation, Pathological/metabolism/pathology ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; Endoplasmic Reticulum Stress ; Protein Folding ; Aging/metabolism ; },
abstract = {BACKGROUND: Proteostasis impairment is central to cellular dysfunction in protein aggregation disorders such as Alzheimer disease, Parkinson disease, and age-related macular degeneration. Pseudoexfoliation (PEX), a systemic age-related disorder and a leading cause of secondary glaucoma, is increasingly recognized as a protein aggregation disease. It is characterized by the deposition of pseudoexfoliative material (PEXM) in ocular tissues, leading to elevated intraocular pressure and optic neuropathy.

OBJECTIVE: This review synthesizes current evidence on the role of proteostasis failure in PEX pathogenesis, with a focus on molecular mechanisms, stress response pathways, and potential therapeutic interventions.

METHODS: We conducted a comprehensive literature review of studies examining proteostasis mechanisms in PEX. Emphasis was placed on cellular pathways regulating protein synthesis, folding, and degradation, including the unfolded protein response (UPR), ubiquitin-proteasome system (UPS), and autophagy, as well as environmental and aging-related triggers of proteotoxic stress.

RESULTS: Evidence indicates that chronic proteotoxic stress, arising from aging, oxidative damage, and environmental influences, disrupts the proteostasis network (PN). Dysregulation of ER stress signaling, cytosolic stress responses, and protein degradation pathways contributes to the accumulation of misfolded proteins and extracellular matrix deposits in ocular tissues. These molecular alterations underlie disease onset and progression in PEX syndrome (PEXS) and PEX glaucoma (PEXG).

CONCLUSIONS: Proteostasis dysfunction plays a pivotal role in PEX pathogenesis by promoting protein misfolding, aggregation, and extracellular deposition. Targeting the proteostasis network, through modulation of stress responses and enhancement of degradation pathways, represents a promising therapeutic strategy for PEXS and PEXG.},
}

Humans
*Exfoliation Syndrome/metabolism/pathology
*Proteostasis
*Unfolded Protein Response
*Protein Aggregates
Animals
Autophagy
*Protein Aggregation, Pathological/metabolism/pathology
Proteasome Endopeptidase Complex/metabolism
Ubiquitin/metabolism
Endoplasmic Reticulum Stress
Protein Folding
Aging/metabolism

@article {pmid41878054,
year = {2026},
author = {Mi, F and Ren, L and Pan, D and Yu, C},
title = {Advancements in Therapy for Alzheimer's Disease Based on the Cerebral Lymphatic System.},
journal = {Degenerative neurological and neuromuscular disease},
volume = {16},
number = {},
pages = {574901},
pmid = {41878054},
issn = {1179-9900},
abstract = {BACKGROUND: Conventional therapeutic interventions for Alzheimer's disease (AD) are limited by multiple drawbacks, including anticholinesterase inhibitors, glutamate receptor antagonists, intestinal flora regulators and Aβ-targeting monoclonal antibodies, which only achieve modest symptomatic relief, are accompanied by notable adverse events (e.g., intracerebral hemorrhage, cerebral edema) and have suboptimal clinical efficacy. In recent years, the cerebral lymphatic system, consisting of the glial lymphatic system (GLS) and meningeal lymphatic vessels (MLVs), has been identified as a key mediator of amyloid β-protein (Aβ) clearance and a critical driver of AD pathogenesis. Lymphatic dysfunction in this system precedes and exacerbates Aβ deposition and cognitive decline in AD patients, revealing the close association between cerebral lymphatic system impairment and AD progression.

PURPOSE: This study aims to focus on the emerging therapeutic advancements for AD targeting the cerebral lymphatic system, moving beyond the conventional symptomatic treatments and Aβ-centric interventions. It also intends to systematically summarize the relevant mechanisms of the cerebral lymphatic system in AD and the diverse therapeutic strategies targeting this system, thus providing a framework for developing innovative clinical interventions for AD.

METHODS: This study adopted a review approach, systematically collating and analyzing existing research on the cerebral lymphatic system and AD, including the cerebral lymphatic pathway of Aβ clearance, the pathological consequences of lymphatic impairment in AD, and various therapeutic strategies targeting the cerebral lymphatic system that have been reported in current studies.

RESULTS: The review identified and summarized multiple categories of effective therapeutic strategies targeting the cerebral lymphatic system for AD, covering pharmacological agents (VEGF-C, traditional Chinese medicines, oxytocin), photobiotherapies (808 nm near-infrared light, 40 Hz multisensory stimulation), physiotherapies (aerobic exercise, rTMS), gene therapy (DSCR1 upregulation), and surgical interventions (lymphatic-venous anastomosis). All these strategies are designed to optimize cerebral lymphatic function and thereby enhance Aβ drainage in the brain.

CONCLUSION: Optimizing cerebral lymphatic function to enhance Aβ drainage is a viable, disease-modifying therapeutic direction for AD. This therapeutic approach targeting the cerebral lymphatic system can serve as a complementary or alternative method to current symptomatic or Aβ-targeted treatments for AD, and also provides a theoretical and practical framework for the development of innovative clinical interventions for the disease.},
}

@article {pmid41878314,
year = {2026},
author = {Tang, S and Liao, Y and Yang, M and Yue, R},
title = {Brain insulin resistance: a key pathological hub linking metabolic and neuropsychiatric comorbidities.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1716291},
pmid = {41878314},
issn = {1663-4365},
abstract = {The high rate of comorbidity between metabolic diseases and neuropsychiatric disorders suggests a shared underlying pathogenic mechanism. However, the biological basis of this relationship remains unclear. This study aims to clarify the role of brain insulin resistance (BIR) in linking metabolic dysfunction to neuropsychiatric symptoms based on existing evidence. The analysis shows that BIR disrupts limbic system function through two primary molecular pathways: (1) impairment of the PI3K/Akt/mTOR pathway, which decreases the expression of synaptic plasticity-related proteins and causes deficits in long-term potentiation (LTP); (2) activation of the TLR4/MyD88 inflammatory axis, promoting pro-inflammatory cytokine release from glial cells. These changes result in characteristic neuropsychiatric phenotypes, including amygdala hyperactivity (emotional disorders), hippocampal atrophy (memory impairment), and decreased prefrontal cortex (PFC) function (executive dysfunction). This review highlights that interventions targeting BIR might simultaneously improve metabolic outcomes and neuropsychiatric symptoms, providing a theoretical foundation for trans-diagnostic treatment models. The findings support the view of BIR as a modifiable interface for metabolic- neuropsychiatric comorbidities and advocate for the development of a multidisciplinary collaborative framework to facilitate mechanism-based precision therapy.},
}

@article {pmid41878379,
year = {2026},
author = {Hersch, GG and Leka, G and Acosta, GE and Xicota, L and Lee, JH and Pulsifer, MB and Hom, CL and Lai, F and Rosas, HD},
title = {A Tale of Monozygotic Twins With Down Syndrome: Divergent Clinical Paths to Dementia.},
journal = {Neurology open access},
volume = {2},
number = {1},
pages = {},
pmid = {41878379},
issn = {2998-7601},
abstract = {OBJECTIVES: Individuals with Down syndrome (DS) have a very high risk for developing Alzheimer's disease (AD) due to the triplication of the amyloid precursor protein gene on chromosome 21. We describe a unique set of female monozygotic twins with Trisomy 21 and mild intellectual disability with significantly discordant rates of cognitive decline.

METHODS: The twins were followed longitudinally, starting at age 42, using cognitive assessments (Down Syndrome Mental Status Examination and Modified Cued Recall). Caregiver assessments included the Dementia Questionnaire for People with Learning Disabilities, National Task Group - Early Detection Screen for Dementia and the Neuropsychiatric Inventory. Blood was collected for AD biomarkers.

RESULTS: Performance on baseline cognitive assessments was similar; however, by Timepoint 1, Twin 2 met criteria for mild cognitive impairment (MCI) and by Timepoint 2 met criteria for dementia due to AD. In contrast, Twin 1 remained cognitively stable. Caregiver assessment at baseline showed concerns about Twin 2's social skills, which remained stable across timepoints. AD protein biomarker levels were similar.

DISCUSSION: Discordant cognitive decline could not be explained by clinical co-morbidities, medications, or environment, suggesting that other factors, such as epigenetics, could underlie phenotypic variability and variable risk for AD in DS and deserves further study.},
}

@article {pmid41878504,
year = {2026},
author = {Kempuraj, D and Ramesh Babu, PR and Jayakumar, N and Belur, MG and Cohan, CH and Sharma, A and Sanchez-Guerrero, E and Anderson, T and Kong, D and Chinnappan, B and Pena, C and Klimas, NG and Theoharides, TC},
title = {Neurosenescence, inflammaging and neuroinflammation in neurodegenerative disorders.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1756670},
pmid = {41878504},
issn = {2673-6217},
abstract = {Senescence is the biological aging associated with the gradual deterioration of cells and functions of various organs over time. This irreversible process is caused by genetic, metabolic, and environmental factors, such as telomere shortening, exposure to cytotoxic substances, and accumulated cellular damage over time, although the rate of degradation can be modified by lifestyle factors. Immunosenescence specifically refers to senescent changes in the innate and adaptive immunity and is associated with low inflammation known as inflammaging. As immunosenescence implies, reduced immune function leads to impaired tissue function and an increased risk of infection and heightened susceptibility to chronic, autoimmune, and neurodegenerative disorders, such as Alzheimer's disease (AD) in the elderly. An increase in senescent cells is common in aging, which leads to age-associated diseases. Cellular senescence may also contribute to the onset and severity of Parkinson's disease (PD) neuropathology. Inflammaging with high levels of proinflammatory marker expression may result from changes in immune responses, chronic antigenic stimulation, and senescence-associated secretory phenotype (SASP) factors, such as increased expression of interleukin-6 (IL-6), insulin-like growth factor binding proteins (IGFBPs), transforming growth factor-beta (TGF-β) and matrix metalloproteinase-10 (MMP-10) has been reported in AD patients. The levels of the senescence marker p16INK4a and several SASP factors, such as MMP-3, IL-6, IL-1α and IL-8 are elevated along with low levels of astrocytic lamin B1 in the substantia nigra of PD. This review discusses recent developments in neurosenescence and immunosenescence in AD and PD, as well as potential senolytic therapies.},
}

@article {pmid41878543,
year = {2026},
author = {Jaeger, A and Carreira, EX and Gomide, G and da Gama, NAS and de Queiroz, MC and Caramelli, P and Schilling, LP and de Souza, LC},
title = {Spatial memory retrieval under cueing in behavioral frontotemporal dementia and Alzheimer's disease.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250413},
pmid = {41878543},
issn = {1980-5764},
abstract = {UNLABELLED: Recent studies indicate that episodic memory is impaired in behavioral variant frontotemporal dementia (bvFTD), with deficits as severe as those seen in Alzheimer's disease (AD). Also, both bvFTD and AD patients exhibit executive dysfunction, but the extent to which such dysfunction contributes to memory impairments remains unclear.

OBJECTIVE: The aim of this study was to investigate interactions between executive functions and episodic memory in AD and bvFTD by manipulating executive control in a spatial source memory task.

METHODS: Twenty bvFTD patients, 18 AD patients, and 20 healthy controls completed a source memory test in which they should remember whether objects were previously seen on the left or right side of a computer screen. Critically, arrow cues (66.7% valid, 33.3% invalid) indicated the likely prior location of each object during retrieval.

RESULTS: bvFTD and AD patients showed overall similar memory performances but were impaired compared to controls. While cueing affected memory performances of controls and bvFTD patients, AD patients showed undistinguishable performances after valid and invalid cueing.

CONCLUSION: These findings support the notion that episodic memory deficits in bvFTD can be as severe as in AD and demonstrate that, unlike bvFTD patients, patients with AD show difficulties in using information conveyed by cues during memory judgments, probably because of underlying attentional deficits.},
}

@article {pmid41878908,
year = {2026},
author = {Álvarez Velásquez, C and Álvarez Mercado, M and Negrón López, R and Neira-Maldonado, C and Salazar-Méndez, J and Coronado, JC and Cuyul-Vásquez, I and Ponce-Fuentes, F},
title = {Effects and reporting quality of the vitamin supplementation on cognitive function in older adults with Alzheimer's disease ‒ A systematic review.},
journal = {Nutricion hospitalaria},
volume = {},
number = {},
pages = {},
doi = {10.20960/nh.06434},
pmid = {41878908},
issn = {1699-5198},
abstract = {BACKGROUND: evidence supporting the effectiveness of vitamin supplementation on cognitive function in older adults with Alzheimer's disease (AD) is limited, and the reporting quality of existing research is often overlooked.

OBJECTIVES: to a) evaluate the effectiveness of vitamin supplementation on cognitive function in older adults with AD; b) describe the characteristics of supplementation protocols; and c) assess the reporting quality of these interventions.

METHODS: a systematic search of seven databases was conducted for randomized controlled trials (RCTs) up to February 2026. Included studies involved vitamin supplementation for patients with AD and assessed cognitive outcomes. The risk of bias and reporting quality were evaluated.

RESULTS: seventeen RCTs (n = 2,478 participants) were included. While eight studies reported some cognitive improvements or stabilization with vitamin B3, D, E, folic acid or specialized multi-nutrient formulations, nine found no significant benefit. A high risk of bias was identified in seven studies, while only five were rated as low risk. The median TIDieR score of 10/12 indicates a good description of the vitamin supplementation protocols.

CONCLUSIONS: the current evidence for vitamin supplementation in older adults with AD is inconclusive. While some protocols show potential for stabilizing or improving cognitive domains, results are compromised by methodological heterogeneity and a high risk of bias. Future research must focus on enhancing methodological quality and achieving greater homogeneity in vitamin supplementation prescription and dosing to ensure robust clinical evidence for patients with AD.},
}

@article {pmid41878910,
year = {2026},
author = {Liu, Y and Liu, H and Chen, Y and Cheng, D and Zhao, Y and Lv, Z and Li, P},
title = {Interpretable machine learning models predict cognitive impairment in adults aged 50 and over with diabetes: influence of dietary nutrients.},
journal = {Nutricion hospitalaria},
volume = {},
number = {},
pages = {},
doi = {10.20960/nh.06195},
pmid = {41878910},
issn = {1699-5198},
abstract = {INTRODUCTION: diabetes mellitus increases the risk of cognitive impairment, but the role of dietary nutrients remains unclear.

OBJECTIVES: to develop interpretable machine learning (ML) models to identify associations with cognitive impairment in adults aged 50 years and older with diabetes, and to identify key dietary nutrients associated with cognitive outcomes.

METHODS: data from the 2011-2014 National Health and Nutrition Examination Survey were analyzed. Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning Test, the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). A total of 46 dietary nutrients and other covariates were included. Feature selection was performed using the Boruta algorithm. Six ML models were trained with ten-fold cross-validation. SHapley Additive Explanations and Local Interpretable Model-Agnostic Explanations were applied for model interpretation.

RESULTS: XGBoost achieved the highest performance in the CERAD model (AUC = 0.982), whereas Random Forest outperformed other models in the AFT and DSST models (AUC = 0.958 and 0.856, respectively). Caffeine emerged as a key protective factor. Copper, zinc, and moisture intake were also associated with reduced risk of cognitive impairment.

CONCLUSIONS: interpretable ML models can effectively predict cognitive impairment in older adults with diabetes. Nutritional profiling may support early screening and targeted intervention strategies based on observed associations.},
}

@article {pmid41879199,
year = {2026},
author = {Urso, D and Valguarnera, A and Volpe, G and Rollo, E and Barone, R and Vilella, D and Gnoni, V and Giugno, A and Giannoni, S and Andersson, N and Hachinski, V and Logroscino, G},
title = {A simple translational metric of integral brain health: Preliminary results.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431799},
doi = {10.1177/13872877261431799},
pmid = {41879199},
issn = {1875-8908},
abstract = {BackgroundComprehensive real-world tools for evaluating brain health are increasingly needed to complement established cognitive assessments and to capture multidimensional aspects of functioning relevant to dementia risk. The Integral Brain Health Questionnaire is a brief three-question, self-referenced multidomain self-assessment, not yet validated in clinical populations.ObjectiveAssess feasibility and construct validity of the Integral Brain Health Questionnaire in patients with cognitive impairment and assess its association with severity of cognitive loss and dementia risk factors.MethodsA consecutive series of 169 individuals with subjective memory complaints, mild cognitive impairment, or mild dementia at a tertiary care center in Southern Italy. Participants completed the Integral Brain Health Questionnaire, Mini-Mental State Examination (MMSE), the Clinical Dementia Rating (CDR) scale, and evaluations of dementia risk factors, including depression, social engagement, and sleep health.ResultsThe questionnaire showed good internal consistency (Cronbach's α = 0.843). Total scores correlated with MMSE (r = 0.322, p < 0.001), and CDR Sum of Boxes (r = -0.165, p = 0.041). Lower scores were associated with depression, poor sleep, and social isolation, while higher scores correlated with social engagement and sleep health. Women reported lower mental and social health scores. The tool showed moderate discriminative ability between mild cognitive impairment and mild dementia.ConclusionsThe Integral Brain Health Questionnaire is a simple, reliable proxy for assessing multidimensional brain health and cognitive loss severity. Apparent independence from age and education and associations with modifiable risk factors support its potential utility in clinical and population settings.},
}

@article {pmid41879255,
year = {2026},
author = {Rivero, M and Pacheco-Garcia, JL and Vankova, P and Loginov, D and Quereda-Moraleda, I and Martin-Garcia, JM and Man, P and Pey, AL and Medina, M},
title = {Tyrosine residues at the substrate binding site in human NQO1 homodimer: Protein conformational dynamics and optimization of substrate binding geometry.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70511},
pmid = {41879255},
issn = {1742-4658},
support = {PID2022-136369NB-I00//Spanish State Research Agency, AEI/ ; PID2023-151100NB-I00//Spanish State Research Agency, AEI/ ; RTI2018-096246-B-I00//Spanish State Research Agency, AEI/ ; E35_23R//Departamento de Educación, Cultura y Deporte, Gobierno de Aragón/ ; P18-RT-2413//Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía/ ; CNS2022-135713//European Union Next Generation/ ; B-BIO-84-UGR20//ERDF/Counseling of Economic transformation, Industry, Knowledge and Universities/ ; },
abstract = {Human NQO1 is a homodimeric flavoenzyme essential for the redox metabolism of many substances and implicated in major global health challenges such as cancer and Alzheimer's disease. X-ray crystallographic studies have identified several residues within its substrate binding site (including Tyr126 and Tyr128) that may regulate catalytic competent binding of substrates, cofactor redox properties, half-site reactivity, and/or functional inter-active site negative cooperativity. To elucidate the functional role of Tyr126 and Tyr128, we generated point mutants at these positions and assessed their dynamics and kinetic properties. Hydrogen-deuterium exchange coupled to mass spectrometry revealed that non-conservative mutations, particularly at Tyr126, notably disrupted dynamics not only within the substrate binding site but also in structural elements connecting the two active sites of the NQO1 homodimer. Rapid-mixing pre-steady-state kinetics experiments of the reduction of NQO1 by NAD(P)H showed that mutations to Phe caused a mild decrease in hydride transfer (HT) efficiency from the coenzyme to the FAD cofactor. In contrast, mutations to Ala resulted in a significantly greater impact and mutations to Glu nearly abolished HT. Despite these effects, some mutations moderately affected the non-synchronous catalysis between the two alternating active sites, but hardly produced an impact on the selectivity for NADPH versus NADH as hydride donor coenzymes. However, all variants exhibited markedly impaired enzyme turnover, highlighting alterations in the enzyme's substrate specificity toward quinones. The data presented here demonstrate that Tyr126 and Tyr128 optimize both substrate binding geometry as well as overall enzyme conformational dynamics during the asymmetric catalytic cycle of the NQO1 homodimer.},
}

@article {pmid41879263,
year = {2026},
author = {Li, X and Zeng, X and Li, J and Zheng, Y and Tian, S and Wang, Z and Ma, C and Lin, Y and Lin, G and Zeng, Y and Xiao, Z and Tan, H and Yang, M and Liang, S and Liu, Z and Gao, P and Wang, Q and Lu, H and Zhong, X and Chen, B and Ning, Y},
title = {Altered temporal dynamics of intrinsic brain activity in mild cognitive impairment with olfactory dysfunction.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431797},
doi = {10.1177/13872877261431797},
pmid = {41879263},
issn = {1875-8908},
abstract = {BackgroundOdor identification (OI) impairment in mild cognitive impairment (MCI) elevates the risk for Alzheimer's disease (AD). The present study was designed to clarify the underlying neural mechanisms by investigating brain network aberrations in MCI patients with OI impairment using dynamic resting-state functional magnetic resonance imaging (rs-fMRI).ObjectiveThis study aimed to delineate the profile of dynamic intrinsic brain activity in MCI patients with and without OI impairment. It further aimed to establish the clinical relevance of these dynamic neural signatures by linking them to cognitive and olfactory function.MethodsIn 194 participants (97 MCI and 97 healthy controls [HC]), we analyzed dynamic metrics including dynamic fractional Amplitude of Low-Frequency Fluctuations (dfALFF), dynamic Amplitude of Low-Frequency Fluctuations (dALFF), dynamic Degree Centrality (dDC), and dynamic Regional Homogeneity (dReHo), and their correlation with cognitive performance and OI.ResultsThe MCI with OI impairment (MCI-OII) group (n = 22) performed worse across all cognitive domains than both HC and the MCI without OI impairment (MCI-NOII) group (n = 75, p < 0.001). These patients exhibited elevated dALFF, dfALFF, dDC, and dReHo variability in regions including the fusiform gyrus, insula, precuneus, and cingulate cortex (p < 0.001). These dynamic metrics correlated with olfactory and cognitive scores (p < 0.05). Additionally, dReHo in the right precuneus partially mediated the relationship between olfactory function and delayed recall memory.ConclusionsThis study demonstrates that MCI patients with OI impairment exhibit widespread disruptions in dynamic brain activity. These alterations correlate with clinical deficits, and precuneus dReHo may partially link olfactory and cognitive decline in MCI.},
}

@article {pmid41879271,
year = {2026},
author = {Luca, A and Piccoli, T and Tomaselli, A and Di Marco, S and Nicoletti, A and Lo Coco, D and Rolandi, E and Sensi, SL and Sucapane, P and Bruni, AC and Perani, D and Guarnieri, B and , },
title = {Cognitive and behavioral determinants of burden in caregivers of patients with Alzheimer's disease: A focus on sex and gender. The SexDemCare Multicentric Italian Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435213},
doi = {10.1177/13872877261435213},
pmid = {41879271},
issn = {1875-8908},
abstract = {BackgroundPrevious studies assessed the relationship between caregivers' characteristics and caregiver burden. However, comprehensive evaluations of caregivers' behavioral and psychological traits remain comparatively limited.ObjectiveTo explore the possible association between the cognitive and behavioral characteristics of caregivers of patients with Alzheimer's disease (AD) and the burden they experience, with a focus on sex/gender differences.MethodsIn this multicenter cross-sectional study within the SINdem "Sex and Gender Differences in Dementia" group, informal caregivers of non-institutionalized AD patients attending the Italian Memory Clinics were enrolled. Caregivers completed the Montreal Cognitive Assessment, Revised Scale for Caregiver Self-Efficacy, 20-Item Toronto Alexithymia Scale, Barratt Impulsiveness Scale-11, Brief COPE, 14-Item Resilience Scale, Ten-Item Big Five Inventory, Five Facet Mindfulness Questionnaire, Empathy Quotient-Short, and the Caregiver Burden Inventory. Sex was considered as a binary variable (female/male); gender-related dimensions were explored indirectly through caregivers' behavioral and psychological characteristics.Results238 caregivers and 238 AD patients were enrolled. A higher burden was associated with more daily caregiving hours, lower self-efficacy, greater impulsivity, difficulties identifying feelings, acting without awareness, a stronger tendency to judge, and higher neuroticism. Female caregiver burden was associated with attentional/motor impulsiveness, lower mindfulness, lower resilience, and lower emotional empathy. Male caregivers showed associations with lower self-efficacy, greater reliance on emotion-focused coping, difficulties identifying feelings, lower non-judging, lower agreeableness, and reduced cognitive empathy.ConclusionsCaregiver burden was associated with caregivers' own behavioral and psychological profiles and sex, beyond patient-related factors. These findings support the importance of integrating sex/gender perspectives and targeted interventions into caregiver assessment and support.},
}

@article {pmid41879275,
year = {2026},
author = {Zhang, H and Zeng, QY and Liu, C and Wu, Y and Liu, JK and Wang, FH and Luo, X},
title = {Association between omeprazole and memory impairment: Insights from NHANES data analysis and network pharmacology studies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435988},
doi = {10.1177/13872877261435988},
pmid = {41879275},
issn = {1875-8908},
abstract = {BackgroundPost-marketing surveillance indicates a possible link between omeprazole consumption and changes in cognitive abilities; however, existing observational studies have yielded conflicting outcomes. This highlights the lack of consensus and underscores the imperative for further systematic investigation to elucidate this relationship.ObjectiveThis investigation thoroughly examined the connection between omeprazole administration and reported memory issues, with the goal of supplying empirical support for evaluating the medication's safety profile and determining its risk-benefit balance in clinical practice.MethodsWe employed a range of analytical approaches, including descriptive statistics, multivariable logistic regression, and receiver operating characteristic curve analysis, to systematically evaluate the association between omeprazole use and memory function. Network pharmacology further characterized omeprazole's molecular targets and pathways linked to memory deficits.ResultsIn the National Health and Nutrition Examination Survey (NHANES) analysis, it revealed a significant positive association between omeprazole consumption and memory impairment (OR [95% CI] = 3.51 [1.87, 6.59]). Through network pharmacology, 342 core targets related to Alzheimer's disease were identified. The top 10 potential binding targets of omeprazole-UBA52, RPL23, RPS18, RPL4, RPL15, RPL11, RPS6, EGFR, RPL13, and RPS20-exhibited strong binding affinities. The enrichment analysis implies a role for omeprazole in causing memory issues, possibly by affecting processes like carboxylic acid metabolism and membrane transportation.ConclusionsMounting research from both large-scale population studies and drug safety surveillance reports paints a clear picture: regular omeprazole consumption appears to hike the chances of experiencing cognitive hiccups related to memory function.},
}

@article {pmid41879277,
year = {2026},
author = {Tavan, Y and Roozegar, S and Mohammadi, ZF and Akbari, A and Nasiri, K and Memarmoghaddam, M and Talebi, V and Patel, DI},
title = {Aerobic exercise significantly alters Notch1 signaling in a neurotoxic hippocampal rat model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261434058},
doi = {10.1177/13872877261434058},
pmid = {41879277},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder and a major cause of dementia.ObjectiveThe aim of this study was to investigate the effect of aerobic training on the expression changes of Notch1, Rbpjk, Hes1, and Hey1genes in the hippocampus of Alzheimer rats.MethodsForty, 8-week-old male Wistar rats were divided into four groups: control (n = 10), exercise (n = 10), AD (n = 10), AD + exercise (n = 10). Endurance training was implemented with increasing intensity starting at 15 m/min in the first week and progressing to speeds of 16-20 m/min over the next five weeks with increased durations each week. After 6 weeks, animals were euthanized and hippocampus was collected, frozen and RNA was isolated to quantify Notch1, Rbpjk, Hes1, and Hey1 expression. All statistical analyses and graphs were conducted using SPSS and visualized using GraphPad Prism, with significance set at p < 0.05.ResultsOne-way analysis of variance with Tukey's post-hoc analysis found that the Alz group had significantly lower expression of Notch1 with increased expression of Rbpjk and Hes1. Conversely, the AD + Ex group was observed to have significantly higher Notch1 and significantly lower Rbpjk compared to the AD group.ConclusionsThese findings suggest that exercise may serve as a complementary neuroprotective intervention via manipulation of Notch1 signaling. Overall, the study highlights the need for further research on the relationship between physical activity and gene expression in the context of AD.},
}

@article {pmid41879312,
year = {2026},
author = {Wang, J and Liu, H and Lai, H and Bao, Y and Shen, M and Li, C and Ma, L and Wu, T and Yang, S and Du, X and O'Brien, TJ and Zhang, J and Zhang, L},
title = {Identifying candidate gut microbiota indicators for Alzheimer's disease through integrated data.},
journal = {mSystems},
volume = {},
number = {},
pages = {e0175425},
doi = {10.1128/msystems.01754-25},
pmid = {41879312},
issn = {2379-5077},
abstract = {UNLABELLED: Alzheimer's disease (AD) is associated with the gut microbiota, and identifying reliable gut microbiota biomarkers enhances AD diagnosis. We aim to characterize the gut microbiota in AD patients by integrating data from multiple populations and identifying key candidate gut microbiota indicators with diagnostic value for AD. Public data from studies on AD and gut microbiota were collected, including participants from AD dementia, mild cognitive impairment (MCI), and normal control (NC) groups. Microbiota composition, diversity, and network analyses were used to characterize the gut microbiota of the three groups. Differential bacterial genera identified simultaneously by seven common methods served as candidate indicators. The study included 799 AD dementia, 170 MCI, and 731 NC participants. The AD dementia group demonstrated a lower relative abundance of Bacteroides and Faecalibacterium and lower α-diversity than the MCI and NC groups (P < 0.05). The microbial network density in the AD dementia group was reduced by 1.5% and 1.6% compared with the NC and MCI groups, respectively. We identified 35 bacterial genera as candidate indicators for AD, including first-time reports of RF39 and Oligella. Faecalibacterium was the most important candidate indicator in the overall population, Akkermansia in the Chinese population, Collinsella in the "Turkish and Kazakh" population, and Actinomyces in the "American and Canadian" population. Our findings contribute to the development of non-invasive biomarkers for AD diagnosis and targeted microbiota therapies and provide a valuable reference for selecting specific biomarkers for different application scenarios.

IMPORTANCE: This study characterized the gut microbiota of Alzheimer's disease (AD) patients and identified candidate indicators for AD diagnosis using a large, multi-population data set. The AD dementia group consistently showed lower α-diversity and a sparser microbiota interaction network than the other groups. We identified 35 bacterial genera as candidate indicators for AD, including first-time reports of RF39 and Oligella. Faecalibacterium was the most important candidate indicator in the overall population, Akkermansia in the Chinese population, Collinsella in the "Turkish and Kazakh" population, and Actinomyces in the "American and Canadian" population. These findings provide a valuable reference for selecting biomarkers for different application scenarios.},
}

@article {pmid41879387,
year = {2026},
author = {Cheng, J and Zhang, C and Yang, L and Li, G and Jiang, X and Chen, P and Duan, X},
title = {An integrated strategy including chemical profiling, network pharmacology and experimental evaluation was used to investigate the effects of Rubia yunnanensis water decoction on vascular dementia.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {5},
pages = {1262-1283},
doi = {10.36721/PJPS.2026.39.5.REG.14029.1},
pmid = {41879387},
issn = {1011-601X},
mesh = {Animals ; *Network Pharmacology/methods ; *Dementia, Vascular/drug therapy/metabolism/pathology/psychology ; *Drugs, Chinese Herbal/pharmacology/chemistry ; Rats ; *Neuroprotective Agents/pharmacology ; Male ; Rats, Sprague-Dawley ; Disease Models, Animal ; Signal Transduction/drug effects ; Apoptosis/drug effects ; },
abstract = {BACKGROUND: Vascular dementia (VaD) is the second most prevalent cause of dementia following Alzheimer's disease. Rubia yunnanensis, a medicinal plant recorded in the Chinese Materia Medica, has historically been utilized for managing cerebral ischaemia-related disorders. While recent attention has focused on its neuroprotective potential, the specific mechanisms underlying the effects of Rubia yunnanensis water decoction (RY-W) on VaD remain unelucidated.

OBJECTIVES: This study aimed to identify the active chemical components and elucidate the molecular mechanisms of RY-W in the treatment of VaD by integrating network pharmacology with experimental validation.

METHODS: The chemical constituents of RY-W and their potential therapeutic targets were analyzed using UPLC-MS/MS and network pharmacology techniques. To validate these findings, the cerebral protective effects of RY-W were assessed in a rat model of VaD. Cognitive function was evaluated using the Morris Water Maze (MWM) test. Pathological changes and molecular markers were analyzed via Hematoxylin and Eosin (HE) staining, Nissl staining, TUNEL fluorescence staining, Immunohistochemistry (IHC), and Western blotting.

RESULTS: Network pharmacology analysis identified IL-6, IL-1β, ALB, TNF, and AKT1 as potential core targets for RY-W. Experimental results demonstrated that RY-W significantly alleviated cognitive deficits in VaD rats. Furthermore, RY-W exhibited anti-inflammatory properties and reduced neuronal apoptosis. These neuroprotective effects appear to be mediated through the regulation of ALB and the PI3K-Akt signaling pathway.

CONCLUSION: RY-W effectively ameliorates VaD pathology by exerting anti-inflammatory and anti-apoptotic effects. These findings highlight the involvement of ALB and the PI3K-Akt signaling pathway in the therapeutic action of RY-W, supporting its potential as a treatment for vascular dementia.},
}

Animals
*Network Pharmacology/methods
*Dementia, Vascular/drug therapy/metabolism/pathology/psychology
*Drugs, Chinese Herbal/pharmacology/chemistry
Rats
*Neuroprotective Agents/pharmacology
Male
Rats, Sprague-Dawley
Disease Models, Animal
Signal Transduction/drug effects
Apoptosis/drug effects

@article {pmid41879392,
year = {2026},
author = {Fu, C and Guo, K and Liu, T and Gong, J and Dong, H},
title = {Unveiling AKT1 as a key target of β-asarone in Alzheimer's disease through network pharmacology and molecular dynamics simulations.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {5},
pages = {1340-1349},
doi = {10.36721/PJPS.2026.39.5.REG.15243.1},
pmid = {41879392},
issn = {1011-601X},
mesh = {Allylbenzene Derivatives ; *Anisoles/pharmacology/therapeutic use/chemistry/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; Molecular Dynamics Simulation ; *Alzheimer Disease/drug therapy/metabolism/enzymology ; Network Pharmacology/methods ; Humans ; Molecular Docking Simulation ; Signal Transduction/drug effects ; *Neuroprotective Agents/pharmacology ; Protein Interaction Maps/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and complex, multi-factorial pathology. Current single-target drugs provide only limited benefits, and there is a need for more effective therapeutic strategies. β-asarone, a major volatile component of Acorus tatarinowii used in traditional Chinese medicine (TCM), has demonstrated neuroprotective effects, including anti-apoptotic, anti-inflammatory, and anti-amyloid β (Aβ) toxicity properties. However, the molecular targets and signaling mechanisms of β-asarone in AD remain underexplored.

OBJECTIVE: This study aims to explore the molecular targets and signaling mechanisms of β-asarone in AD by integrating network pharmacology, molecular docking, and molecular dynamics simulations.

METHODS: Network pharmacology was used to identify overlapping targets between β-asarone and AD. Protein-protein interaction networks were constructed using STRING, and key targets were analyzed for enrichment in the PI3K-AKT/MAPK pathways. Molecular docking was conducted to assess the binding affinity of β-asarone with multiple targets along the PI3K-AKT axis. Additionally, molecular dynamics (MD) simulations of the β-asarone-AKT1 complex were performed for 100 ns to assess the stability of the interaction.

RESULTS: Seventy-four overlapping targets of β-asarone and AD were identified, with key hub genes enriched in the PI3K-AKT/MAPK pathways. Molecular docking revealed that β-asarone binds to critical nodes along the PI3K-AKT axis with binding free energies (ΔG) of approximately -6.2 kcal/mol and to HRAS/IGF1 with ΔG ≈ -5.2/-4.1 kcal/mol. MD simulations showed stable trajectories for the β-asarone-AKT1 complex (RMSD ~3.5-4.0 Å) with persistent hydrogen bonds, indicating a durable interaction in the ATP-binding pocket.

CONCLUSION: β-asarone interacts with multiple interconnected signaling nodes, particularly the PI3K-AKT pathway, to modulate apoptosis, neuroinflammation, and cellular energetics. These findings support the potential of β-asarone as a TCM-derived candidate for the development of therapeutic strategies for AD.},
}

Allylbenzene Derivatives
*Anisoles/pharmacology/therapeutic use/chemistry/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
Molecular Dynamics Simulation
*Alzheimer Disease/drug therapy/metabolism/enzymology
Network Pharmacology/methods
Humans
Molecular Docking Simulation
Signal Transduction/drug effects
*Neuroprotective Agents/pharmacology
Protein Interaction Maps/drug effects
Phosphatidylinositol 3-Kinases/metabolism

@article {pmid41879434,
year = {2026},
author = {Hu, S and Chen, Z and Fu, Y},
title = {EEG Oscillations and the Modulation of tES and TMS in Patients with Mild Cognitive Impairment.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050430368260120052142},
pmid = {41879434},
issn = {1875-5828},
abstract = {Mild cognitive impairment (MCI) is characterized by objective cognitive decline that does not severely impact daily independence. This clinical stage may stem from various underlying causes, including Alzheimer's disease pathology. MCI provides a valuable opportunity to study interventions that could slow cognitive decline. Individuals with MCI show alterations in neural oscillations linked to cognitive impairment. Non-invasive brain stimulation (NIBS) techniques, including transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), along with their major forms, transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), can effectively modulate neural oscillations and improve cognition in MCI patients. Due to the potential of NIBS in the treatment of MCI, this review focuses on EEG abnormalities of neural oscillations in MCI patients and examines how repetitive TMS (rTMS), tDCS, and tACS improve cognitive function by targeting specific EEG frequency bands. A literature review was conducted for this study using the PubMed database, including studies published up to May 2025. Studies demonstrated that MCI patients have significant changes in EEG activity, with increases in the low-frequency band (δ-θ, 0.5-8 Hz) and decreases in the high-frequency band (β-γ, 12-100 Hz), and there are few reports on changes in mid-frequency α (8-12 Hz) EEG activity. Notably, tDCS improves cognition in MCI patients by decreasing low-frequency and increasing highfrequency EEG activity, whereas rTMS and tACS achieve similar effects mainly by increasing highfrequency EEG activity. Overall, this review provides an understanding of the role of NIBS in modulating neural oscillations and improving cognition in MCI, which may guide future therapeutic strategies. Future studies could explore the specific molecular pathways of neural oscillatory dysfunction in MCI and investigate the correlation between neural oscillations and other biomarkers, such as amyloid plaques and tau tangles, for a more comprehensive understanding of the disease.},
}

@article {pmid41879435,
year = {2026},
author = {Zhang, Y and Li, Z and Li, H and Zhang, K},
title = {Research on Alzheimer's Disease Risk Assessment Models and Biomarker Screening Based on Bioinformatics Analysis and Machine Learning Algorithms.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050425330260122093903},
pmid = {41879435},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is among the most prevalent neurodegenerative disorders globally, yet effective early diagnostic strategies remain lacking. Advances in multi-omics technologies and the integration of artificial intelligence into medicine have created new opportunities for developing predictive models for AD. Biomarker-based models hold significant promise for enhancing early detection. In this study, we integrated multi-omics data to identify core risk genes with potential causal links to AD and developed an early diagnostic model, thereby providing a theoretical framework for precision intervention.

METHODS: We integrated Mendelian Randomization (MR), differential expression analysis, and Weighted Gene Co-Expression Network Analysis (WGCNA) to identify candidate genes with potential causal relevance to AD. Functional enrichment analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), along with immune infiltration profiling, were performed to investigate the biological roles of these genes. We then applied eight machine learning algorithms to evaluate gene importance scores and selected the most diagnostically informative features to construct the Nomogram predictive model. The model's performance was validated in an independent external cohort. Finally, Gene Set Enrichment Analysis (GSEA) was conducted to further elucidate the mechanistic involvement of core risk genes in AD pathogenesis.

RESULTS: Integrated analyses using multiple machine learning models (all with AUC values exceeding 0.88) identified VASP, PIP4K2A, RRP36, METTL7A, and AP2M1 as key diagnostic feature genes. The nomogram constructed based on these five genes demonstrated robust diagnostic performance in the validation cohort (AUC = 0.964). Notably, RRP36 and PIP4K2A consistently emerged as core risk genes across diverse machine learning approaches. GSEA results further suggested that RRP36 may contribute to neurodegeneration by modulating cytoskeletal remodeling and neuroinflammatory responses, while PIP4K2A may be implicated in synaptic dysfunction.

DISCUSSION: This study is the first to integrate MR, differential gene expression, and WGCNA for systematic AD risk gene discovery, combined with a multi-algorithm machine learning strategy to enhance model robustness and translational potential. RRP36 and PIP4K2A, as core risk genes, may drive AD progression by orchestrating cytoskeletal reorganization, neuroinflammation, and synaptic impairment, offering promising targets for future mechanistic investigations and therapeutic development.

CONCLUSION: This study identified and validated RRP36 and METTL7A as core risk genes for AD. The resulting nomogram, based on a five-gene panel, exhibited high diagnostic accuracy and provides new biomarkers and methodological support for the early screening and precise intervention of AD.},
}

@article {pmid41879436,
year = {2026},
author = {Hu, G and Zhang, M},
title = {Efficacy and Safety of Donanemab in the Treatment of Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050425914260119063736},
pmid = {41879436},
issn = {1875-5828},
abstract = {INTRODUCTION: Donanemab is a monoclonal antibody targeting amyloid-β plaques. This study aims to quantify donanemab's consistent cognitive benefits, biomarker efficacy, and safety risks by pooling data from all available RCTs.

MATERIALS AND METHODS: Systematic searches were conducted in PubMed, the Cochrane Library, Web of Science, and Embase. Phase II/III randomized controlled trials comparing donanemab with placebo in amyloid-positive early Alzheimer's disease were included. After screening 133 records, two trials met the inclusion criteria.

RESULTS: Donanemab significantly reduced cognitive decline (iADRS +2.93; 95% CI: 1.52- 4.33; P < 0.0001) and functional progression (CDR-SB -0.66; 95% CI: -0.90 to -0.42; P < 0.00001), with amplified benefits in low/medium tau burden patients (iADRS +3.80; 95% CI: 2.10- 5.50). Amyloid clearance was dramatically higher with donanemab (risk ratio (RR) = 234.46; 95% CI: 68.17-806.38; P < 0.00001), with 76.4% achieving amyloid-negative status. There were significantly elevated risks of ARIA-E (RR = 12.90; 95% CI: 8.15-20.43; P < 0.00001), ARIA-H (RR = 2.86; 95% CI: 1.61-5.06; P = 0.0003), and treatment discontinuation (RR = 3.26; 95% CI: 2.38- 4.47; P < 0.00001), whereas all-cause mortality was not significantly different (RR = 1.44; 95% CI: 0.69-3.00).

DISCUSSION: Donanemab showed statistically significant cognitive benefits, but its clinical meaningfulness warrants careful interpretation. The iADRS improvement of 2.93 points and the CDRSB reduction in all patients of 0.66 points did not approach their minimal clinically important difference (MCID).

CONCLUSION: Donanemab provides statistically significant but modest benefits in early AD, particularly in low-tau subgroups. However, the magnitude of cognitive and functional improvement did not approach the threshold for a MCID in the overall population, which requires stringent safety monitoring for ARIA. Clinical implementation should prioritize PET stratification and APOEguided surveillance.},
}

@article {pmid41879449,
year = {2026},
author = {Li, Y and Xu, M and Tang, Y and Zhao, X and Chen, M},
title = {Mechanisms and Research Progress of SGLT-2 Inhibitors in Diabetes Mellitus-Related Cognitive Impairment.},
journal = {Current diabetes reviews},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115733998444053260211052025},
pmid = {41879449},
issn = {1875-6417},
abstract = {Diabetes Mellitus (DM) increases the risk of Mild Cognitive Impairment (MCI) and dementia, severely impacting patients' quality of life and long-term future prospects. Sodium-glucose cotransporter 2 inhibitors (SGLT-2i), a class of oral hypoglycemic drugs, have recently been shown to have neuroprotective effects. Studies show that SGLT-2i ameliorates cognitive dysfunction in diabetic animal models through various mechanisms such as insulin pathways in the brain, cerebrovascular function, neuroinflammation and oxidative stress, inhibition of Alzheimer's disease pathology, andneurotrophic factor expression. Clinical studies also show that SGLT-2i improves cognitive performance in diabetic patients, significantly reducing the risk of dementia and MCI. Further studies and more robust clinical evidence are needed for its clinical application. Despite the promising role of SGLT-2i in preventing and treating DM-related cognitive impairment, further studies and more robust clinical evidence are needed for its clinical application.},
}

@article {pmid41879491,
year = {2026},
author = {Chernov, Y},
title = {Associations between Handwriting Decline and Cognitive-Motor Impairment in Dementia.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050459901260112045555},
pmid = {41879491},
issn = {1875-5828},
abstract = {INTRODUCTION: Handwriting reflects the integration of cognitive and motor functions, making it a potential indicator of neurodegenerative changes. Handwriting deterioration often mirrors cognitive and motor decline in dementia, particularly Alzheimer's disease (AD). However, objective assessment methods remain limited. This study is based on the AD-HS instrument, which includes 42 handwriting features and three linguistic features. Their assessment is non-trivial. To ensure an objective and reliable evaluation, the features are given exact and unambiguous definitions. The formal, quantitative association of handwriting dimensions with cognitive and motor changes in dementia enriches previously published statistical results.

MATERIALS AND METHODS: Handwriting samples from 53 individuals with mild cognitive impairment (MCI) or Alzheimer's disease (AD) were analyzed against a reference group across six dimensions: spatial organization, letter formation, writing dynamics, stroke building, and overall appearance. Statistical analysis determined the significance of each dimension and its contribution to the overall AD-index (ADI).

RESULTS: The ADI effectively distinguished dementia samples from the reference group. The strongest diagnostic indicators were found in writing dynamics, followed by letter formation and spatial organization. The characteristics of early deterioration reflect cognitive impairment rather than purely motor impairment, which are less prevalent in the early stages.

DISCUSSION: Longitudinal data show that handwriting in early dementia deteriorates gradually, with diagnostic value arising from the combined presence of multiple affected features. The earliest changes appear in dynamic aspects, followed by spatial and organizational deficits, reflecting early cognitive disruption while motor programs remain largely intact. These findings support the validity of the AD-HS instrument for capturing handwriting changes associated with emerging dementia.

CONCLUSION: The ADI offers a concise, quantitative measure of handwriting deterioration related to cognitive decline. Future research should focus on collecting longitudinal data and more strictly differentiating between age-related changes and cognitive decline.},
}

@article {pmid41879495,
year = {2026},
author = {Singh, K and Sethi, P and Jain, D and Gupta, JK and Alsaidan, OA and Alzarea, SI and Kumar, A and Tabish, M and Sharma, MC},
title = {Emerging Roles of Small-molecule Derivatives in Modulating Neurodegenerative Pathways: From Molecular Targets to Therapeutic Applications.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575429412260112060311},
pmid = {41879495},
issn = {1875-5607},
abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease involve progressive neuronal dysfunction driven by mechanisms including protein aggregation, oxidative stress, mitochondrial impairment, and neuroinflammation. Current treatments are largely symptomatic, with limited disease-modifying options. Advances in medicinal chemistry have led to the development of small-molecule derivatives targeting specific pathological pathways, offering new therapeutic opportunities. This review summarizes recent progress in designing and optimizing such molecules to modulate amyloid-β metabolism, tau acetylation, α-synuclein aggregation, RNA-binding protein interactions, and NLRP3 inflammasome activation. Compounds acting on key signaling cascades, including PI3K/Akt, MAPK/ERK, Nrf2/ARE, and Wnt/β-catenin, are discussed, alongside drug repurposing strategies and preclinical-to-clinical translation. Special focus is given to microglial modulation, challenges in crossing the blood-brain barrier, and integration of precision medicine, metabolomics, and artificial intelligence into drug discovery. The review also highlights novel therapeutic concepts such as multi- target ligands, metal-chelation approaches, and modulation of neuroinflammatory pathways. Despite promising leads, significant challenges remain in optimizing pharmacokinetics, target selectivity, and delivery. Future directions include the identification of robust biomarkers, advanced imaging techniques, and computational tools to accelerate candidate validation. Collectively, smallmolecule therapeutics hold considerable promise in addressing unmet needs in neurodegenerative disease management, but their successful translation will require multidisciplinary approaches bridging molecular insights and clinical application.},
}

@article {pmid41879865,
year = {2026},
author = {Chen, Y and Zhang, D and Zhang, Q and Li, Q and Yan, D and Qin, H and Xiong, Y and Zhang, C and Wan, Y and Yan, M},
title = {Cofilin-1 Exacerbates Tau-Induced Mitochondrial Damage, Oxidative Stress, and Apoptosis in Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41879865},
issn = {1573-6903},
support = {No. 82301439//the National Natural Science Foundation of China/ ; No. WJ2025Q044//the Health Commission of Hubei Province Scientific Research Project/ ; },
}

@article {pmid41880022,
year = {2026},
author = {Angel Pinto, MJ and García Cordero, I and Dorman, G and Mizraji, G and Anastassiadis, C and Gershanik, O and Couto, B},
title = {Amyloid and Tau Co-pathology in Parkinson Disease and Atypical Parkinsonism.},
journal = {Current neurology and neuroscience reports},
volume = {26},
number = {1},
pages = {},
pmid = {41880022},
issn = {1534-6293},
support = {Pilot#2025-002//Association for Frontotemporal Degeneration/ ; 24AACSFD-1244095//Alzheimer's Association,United States/ ; 684-2023-06-Pathway//CurePSP/ ; },
mesh = {Humans ; *tau Proteins/metabolism ; *Parkinson Disease/pathology/metabolism ; *Parkinsonian Disorders/pathology/metabolism ; *Amyloid beta-Peptides/metabolism ; Biomarkers ; },
abstract = {PURPOSE OF REVIEW: We performed a narrative review of the literature of amyloid and tau co-pathology in Parkinson Disease and atypical parkinsonism in Pubmed database, including articles published between January 2020 to July 2025.

RECENT FINDINGS: In the last decade, different multicenter research efforts have worked to improve the accuracy of clinical-pathological diagnosis in neurogenerative disease. In this search, growing evidence from neuropathology, neuroimaging and fluid biomarkers have highlighted the role of Alzheimer's disease (AD) co-pathology in Parkinson's disease (PD) and atypical parkinsonism (AP) disorders potentially affecting progression, motor phenotype and cognitive status. Regarding studies of structural and functional imaging evidencing the presence of Amyloid-β (Aβ), tau, as co-pathologies contribute to α-synuclein-related profile of cortical atrophy, network disruption, as well as clinical heterogeneity in PD and AP disorders. In AP fluid biomarkers have shown limited diagnostic accuracy. Neuropathological evidence from systematic post-mortem surveys confirmed that diffuse and neuritic Aβ plaques are uncommon in non-demented PD (10%), intermediate in PD-dementia (30-40%), and frequent in Dementia with Lewy Bodies (60-80%). The evidence in PD and DLB showed that Aß fluid biomarkers may predict clinical trajectory and cognitive decline, while Aβ-imaging would help stratifying patients and directing therapeutic pipeline designs. In AP disorders, including progressive supranuclear palsy and corticobasal degeneration, a combined multimodal assessment of molecular imaging, structural and functional magnetic resonance with fluid biomarkers shall guarantee future differential diagnosis and prediction of clinical outcomes. Although there are no currently accepted biomarkers for PD or AP, the recent design of plasma tau biomarkers and seed-amplification assays are promising approaches which are also reviewed here.},
}

Humans
*tau Proteins/metabolism
*Parkinson Disease/pathology/metabolism
*Parkinsonian Disorders/pathology/metabolism
*Amyloid beta-Peptides/metabolism
Biomarkers

@article {pmid41880092,
year = {2026},
author = {Liu, S and Bush, WS and Kunkle, BW and Byrd, GS and Reitz, C and Tosto, G and Rajabli, F and Caban-Holt, AM and Cuccaro, M and Starks, T and Adams, LD and Feliciano, BE and Akinyemi, R and Vance, JM and Pericak-Vance, M and Haines, JL and Crawford, DC and Williams, SM},
title = {Dissecting Alzheimer's disease heritability across populations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71236},
doi = {10.1002/alz.71236},
pmid = {41880092},
issn = {1552-5279},
support = {R01AG072547/AG/NIA NIH HHS/United States ; U19AG074865/AG/NIA NIH HHS/United States ; U01AG058654/AG/NIA NIH HHS/United States ; //Diana Jacobs Kalman/AFAR for Research in the Biology of Aging/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology ; Male ; Female ; Aged ; *Genetic Predisposition to Disease ; Aged, 80 and over ; Pedigree ; Apolipoprotein E4/genetics ; White People/genetics ; Middle Aged ; Netherlands ; },
abstract = {INTRODUCTION: Late-onset Alzheimer's disease (LOAD) is highly heritable; however, its estimated incidence across populations remains unclear.

METHODS: We computed family-based heritability leveraging Alzheimer's Disease Sequencing Project pedigrees from non-Hispanic White (404 pedigrees), non-Hispanic Black (13 pedigrees), Dominican (100 pedigrees), and Dutch isolate (10 pedigrees), with four models incorporating age, sex, apolipoproten E epsilon4 (APOE ε4), and contributing study using two methods.

RESULTS: Heritability estimates varied by method, model, and study populations. Statistical Analysis for Genetic Epidemiology (S.A.G.E.) estimates were highest for Dutch isolate (78.3%), followed by non-Hispanic Blacks (39.1%), Dominicans (31.7%), and non-Hispanic Whites (29.1%), adjusted for age and sex. APOE adjustment reduced estimates (4.9% on average), while study adjustment primarily affected groups that included multiple studies. Sequential Oligogenic Linkage Analysis Routines (SOLAR-Eclipse) estimates were higher (45.2% to 80.2%) than S.A.G.E. (20.4% to 80.9%) but behaved in parallel, except for the Dutch isolate.

DISCUSSION: LOAD heritability estimates are dependent on study population and may reflect or indicate differences in LOAD risk by population.},
}

Humans
*Alzheimer Disease/genetics/epidemiology
Male
Female
Aged
*Genetic Predisposition to Disease
Aged, 80 and over
Pedigree
Apolipoprotein E4/genetics
White People/genetics
Middle Aged
Netherlands

@article {pmid41880326,
year = {2026},
author = {Wu, J and Lu, X and Zhang, J and Wang, S and Lu, Z and Han, Y and Yang, R and Su, Y and Tan, C and Huo, D and Liu, YU and Sima, J},
title = {Astrocytic AEBP1-NPAS3-LIPA pathway coordinates cholesterol homeostasis to regulate Alzheimer's pathology.},
journal = {Cell reports},
volume = {45},
number = {4},
pages = {117193},
doi = {10.1016/j.celrep.2026.117193},
pmid = {41880326},
issn = {2211-1247},
abstract = {Astrocytes regulate brain cholesterol homeostasis, but the astrocyte-specific mechanisms disrupted in Alzheimer's disease (AD) are poorly understood. By integrating human bulk transcriptomes with single-nucleus RNA sequencing (RNA-seq), we identified adipocyte enhancer-binding protein 1 (AEBP1) as an astrocyte-enriched factor upregulated in AD. In postmortem human tissue and 5×FAD mice, astrocytic AEBP1 levels rise with age and disease progression. Astrocyte-specific AEBP1 knockdown ameliorates, while overexpression worsens, amyloid-β (Aβ) pathology in 5×FAD mice, confirming causality in vivo. In cultured astrocytes, AEBP1 overexpression represses lysosomal acid lipase (LIPA), leading to lipid droplet accumulation, excess cholesteryl ester storage, and lysosomal Aβ retention. LIPA restoration reverses these effects. Hippocampal transcriptomics and metabolomics from AEBP1-knockdown or LIPA-overexpressing 5×FAD mice show converged cholesterol/lipid pathway remodeling, reduced Aβ burden, and cognitive improvement. Mechanistically, AEBP1 sequesters NPAS3 in the cytoplasm, reducing its binding to the Lipa promoter. Thus, the astrocytic AEBP1-NPAS3-LIPA axis links lysosomal cholesterol catabolism to AD pathology.},
}

@article {pmid41880327,
year = {2026},
author = {Gilles, V and Flaus, A and Teillac, A and Verny, M and Blanc, F and Paccalin, M and Desmidt, T and Louchart de la Chapelle, S and Dumay, C and Sauvée, M and Lehmann, S and Hirtz, C and Cotton, F and Bathsavanis, A and Gervais, F and Novais, T and Desestret, V and Boublay, N and Krolak-Salmon, P and Dautricourt, S and Garnier-Crussard, A},
title = {Associations between frailty, biomarkers of cerebral pathology, cognitive and neuropsychiatric symptoms: a memory clinic study.},
journal = {The Journal of frailty & aging},
volume = {15},
number = {3},
pages = {100148},
doi = {10.1016/j.tjfa.2026.100148},
pmid = {41880327},
issn = {2260-1341},
abstract = {BACKGROUND: Frailty is a prevalent condition among older adults with neurocognitive disorders.

OBJECTIVES: To ascertain whether frailty contributes to the severity of cognitive impairment and neuropsychiatric symptoms, and its association with cerebral pathology measured in vivo by fluid and imaging biomarkers.

DESIGN: We conducted cross-sectional and longitudinal analyses based on CLEM Study, a multicentre memory-clinic cohort that recruited participants between 2014 and 2018.

SETTING: CLEM Study occurred in eight memory centres in France (Lyon, Paris, Strasbourg, Poitiers, Tours, Grenoble) and Monaco.

PARTICIPANTS: A total of 168 participants (mean age 80.5 ± 4.8 years) with mild to moderate dementia due to at least one aetiological diagnosis between Alzheimer's disease, dementia with Lewy bodies or vascular dementia were included in the study.

MEASUREMENTS: The participants were evaluated at baseline and followed up for two years. The concept of frailty was operationalised using a 45-item Frailty Index. Cognition was assessed using the ADAS-cog scale, while neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory. The cerebral pathological score, a proxy for brain pathologies, was a composite score based on the presence of several in vivo biomarkers: presynaptic dopaminergic denervation on [123]I-FP-CIT SPECT (DaTscan®), vascular lesions on MRI, elevated blood-based pTau181, neurofilaments light-chain or glial fibrillary acid protein. Linear and mixed regression analyses were conducted to model the relationships between cognitive or neuropsychiatric symptoms, frailty and cerebral pathologic score, adjusted for age, sex and education.

RESULTS: The findings indicate an impact of both frailty (β = 0.28, 95 % CI [0.14-0.43], p < 0.001) and cerebral pathological score (β = 0.30, 95 % CI [0.13-0.47], p = 0.002) on cognitive impairment. However, only frailty was associated with neuropsychiatric symptoms (β = 0.28, 95 % CI [0.14-0.43], p < 0.001), particularly with apathy (β = 0.40, 95 % CI [0.26-0.53], p < 0.001). We found an association between cerebral pathological score and longitudinal cognitive decline (β = 0.36, 95 % CI [0.19-0.53], p < 0.001) in exploratory analyses with available longitudinal data at 24 months (n = 74).

CONCLUSIONS: Neurocognitive disorders are complex entities, where cognitive and neuropsychiatric symptoms are not fully influenced by the same factors. When cognitive symptoms seem more driven by cerebral pathology than frailty, neuropsychiatric symptoms appear to be more influenced by general state of frailty. Measuring and treating frailty might be a key factor in dealing with neuropsychiatric symptoms and their consequences.},
}

@article {pmid41880569,
year = {2026},
author = {Mosconi, M and Leonardi, C and Armour-Garb, Z and Rocutto, B and Beeg, M and Meisl, G and Ortigosa-Pascual, L and Broggini, L and Salmona, M and Ricagno, S and Knowles, TPJ and Diomede, L},
title = {Tau catalyzes amyloid-β aggregation and toxicity in a polymorph-dependent manner.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {13},
pages = {e2532775123},
doi = {10.1073/pnas.2532775123},
pmid = {41880569},
issn = {1091-6490},
support = {2023-2025//Fondazione Sacchetti/ ; 2025//Mario Negri Alumni Association/ ; 2024-NAZ-0018//Fondazione Cariplo (Cariplo Foundation)/ ; Telethon GJC23044//Fondazione Caripo/Telethon/ ; IG 2024 ID 30307//Fondazione AIRC per la ricerca sul cancro ETS (AIRC)/ ; 2024//Università di Milano Seed 4 Innovation/ ; },
mesh = {*tau Proteins/metabolism/chemistry/genetics ; *Amyloid beta-Peptides/metabolism/chemistry/genetics/toxicity ; Humans ; Animals ; Caenorhabditis elegans/metabolism/genetics ; Alzheimer Disease/metabolism/pathology ; Cell Line, Tumor ; *Protein Aggregation, Pathological/metabolism ; *Peptide Fragments/metabolism/chemistry ; Animals, Genetically Modified ; Protein Aggregates ; },
abstract = {Interactions between amyloidogenic proteins are emerging as critical drivers of neurodegenerative diseases. Among others, in Alzheimer's disease (AD) and severe forms of chronic traumatic encephalopathy (CTE), codeposition of tau and amyloid-β (Aβ) leads to worsening of clinical outcomes and disease progression. Despite the importance of such heterotypic interactions, the underlying molecular mechanisms have proven challenging to be established. Here, we investigated the direct interaction between Aβ and tau, combining in vitro reconstruction, and in vivo models. We find that characteristic AD paired helical filament (PHF) and CTE folds catalyze the primary nucleation of Aβ42 in a fold-specific manner with enzyme-like kinetics. In particular, CTE fibrils exhibit the highest catalytic activity and constrain Aβ42 polymorphism, suggesting templating effects. Moreover, PHF and CTE tau fibrils increase Aβ42 toxicity in SH-SY5Y neuroblastoma cells and transgenic Caenorhabditis elegans, preserving fold-dependent reactivities. Our findings shed light on the molecular mechanisms of heterotypic interaction between amyloidogenic proteins in disease-relevant conditions, highlighting the role of amyloid structure and recognition mechanisms as key determinants. These results offer insights into the pathological mechanisms of multiple proteinopathies. The mechanisms described here might be used as a blueprint for structure-based design of new therapeutic agents targeting specific amyloidogenic interactions.},
}

*tau Proteins/metabolism/chemistry/genetics
*Amyloid beta-Peptides/metabolism/chemistry/genetics/toxicity
Humans
Animals
Caenorhabditis elegans/metabolism/genetics
Alzheimer Disease/metabolism/pathology
Cell Line, Tumor
*Protein Aggregation, Pathological/metabolism
*Peptide Fragments/metabolism/chemistry
Animals, Genetically Modified
Protein Aggregates

@article {pmid41880688,
year = {2026},
author = {Shomali, T and Trempe, JF},
title = {Targeting of kinases to treat neurodegenerative diseases.},
journal = {Pharmacological reviews},
volume = {78},
number = {3},
pages = {100128},
doi = {10.1016/j.pharmr.2026.100128},
pmid = {41880688},
issn = {1521-0081},
abstract = {Neurodegenerative diseases, including Alzheimer, Parkinson, and multiple sclerosis, represent a growing global health crisis with limited therapeutic options that address disease progression. Protein kinases, which are crucial regulators of diverse cellular processes such as endolysosomal trafficking, neuroinflammation, and mitochondrial homeostasis, are frequently dysregulated in these conditions, making them attractive drug targets. This review explores the therapeutic potential of targeting key kinases implicated in neurodegeneration, specifically p38 MAPK, BTK, c-Abl/ABL1, CDK5, GSK3, JNK, LRRK2, and PINK1. We delve into their specific roles in disease pathophysiology, current therapeutic strategies, and the structural insights guiding our understanding of these kinases and the development of more selective inhibitors. Although significant challenges remain, particularly regarding selectivity and drug delivery to the brain, the advancements in our understanding of kinase biology and novel therapeutic modalities offer substantial promise for developing disease-modifying treatments. This review highlights the urgent need for continued research to identify new targets and translate these scientific breakthroughs into effective therapies for patients. SIGNIFICANCE STATEMENT: This review outlines the roles of protein kinases in neurodegenerative diseases and highlights emerging strategies for their therapeutic modulation. By integrating current knowledge of kinase signaling, drug development, and pharmacokinetics, this work provides a timely and practical framework to guide the development of disease-modifying treatments in an area of pressing clinical need.},
}

@article {pmid41880816,
year = {2026},
author = {Kumari, V and Shahrukh, M and Jabin, K and Ali, N and Hasan, N and Aqil, M and Ahmad, FJ},
title = {Emerging role of cell membrane-coated nanoparticles in targeted therapy for brain disorders.},
journal = {Biomaterials advances},
volume = {184},
number = {},
pages = {214822},
doi = {10.1016/j.bioadv.2026.214822},
pmid = {41880816},
issn = {2772-9508},
abstract = {Brain disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as conditions like multiple sclerosis and ischemic stroke, represent a significant global health burden. These disorders are often marked by progressive neuronal degeneration, cognitive impairment, and motor dysfunction. Effective therapeutic intervention remains a challenge due to the protective but restrictive nature of blood-CNS barriers, particularly the blood-brain barrier (BBB), which limits drug delivery to the brain. Nanotechnology-based drug delivery systems have emerged as promising solutions for addressing these barriers. However, issues such as limited biocompatibility, cytotoxicity, and suboptimal pharmacokinetics still hinder their widespread application. Cell membrane-coated nanoparticles (CMCNPs) offer a novel approach to overcome these challenges. These biomimetic nanocarriers integrate natural cell membranes sourced from red blood cells, platelets, or stem cells, with nanoparticles, enhancing biocompatibility, immune evasion, and BBB penetration. This review provides a comprehensive overview of recent advances in CMCNPs for brain disorders, highlighting their design, fabrication methods, and therapeutic potential. The unique properties of CMCNPs, such as prolonged systemic circulation, targeted drug delivery, and enhanced BBB permeability, make them promising candidates for neuroprotective and theranostic applications.},
}

@article {pmid41880913,
year = {2026},
author = {Yang, M and Zhao, Y and Chen, S and Liu, C and Yan, Y and Tian, H},
title = {Trinity synergy of guanidine-functionalized polymer brush-modified β-cyclodextrin polymer magnetic beads for recognition of phosphopeptides in serum of Alzheimer's disease.},
journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences},
volume = {1276},
number = {},
pages = {125033},
doi = {10.1016/j.jchromb.2026.125033},
pmid = {41880913},
issn = {1873-376X},
abstract = {Systematic profiling of protein phosphorylation is pivotal for elucidating the molecular pathogenesis of Alzheimer's disease (AD). Here, we report the rational design of ‌magCEP@PEI@G‌, a multifunctional magnetic adsorbent integrating β-cyclodextrin-epichlorohydrin polymers, polyethyleneimine (PEI), and guanidino functional groups to enable synergistic phosphopeptide enrichment. This hybrid material achieves unprecedented performance: ‌10-cycle reusability‌ with >95% retention of enrichment efficiency, an ultra-low limit of detection (‌0.2 fmol‌), exceptional selectivity (‌5000:1‌ phospho/non-phospho peptide ratio), rapid elution (‌10 min‌), and near-perfect recovery (‌105.0 ± 0.5%‌). Applied to serum samples from three AD patients, magCEP@PEI@G enabled the robust identification of ‌135 unique phosphopeptides. These results establish magCEP@PEI@G as a highly efficient, scalable platform for the sensitive enrichment of low-abundance phosphopeptides and hold substantial promise for the ‌early diagnosis of Alzheimer's disease‌.},
}

@article {pmid41881052,
year = {2026},
author = {Noguchi-Shinohara, M and Ono, K},
title = {Successful Amyloid Removal by Donanemab Treatment in a Female Patient With Alzheimer Disease: A Case Report.},
journal = {Neurology},
volume = {106},
number = {8},
pages = {e214817},
doi = {10.1212/WNL.0000000000214817},
pmid = {41881052},
issn = {1526-632X},
}

@article {pmid41881216,
year = {2026},
author = {Jones, K and Pennell, A and He, P and Gibson, J and Zhang, F and Pomin, VH and Wang, C},
title = {Marine sulfated glycan inhibits tau-heparan sulfate interaction and tau cellular uptake.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {151592},
doi = {10.1016/j.ijbiomac.2026.151592},
pmid = {41881216},
issn = {1879-0003},
abstract = {Heparan sulfate (HS) proteoglycans mediate the cellular uptake of tau, a critical step in the prion-like spread of tau pathology in Alzheimer's disease. In this study, we tested if several marine sulfated glycan of diverse structures can inhibit the tau-HS interaction. Through experiments of SPR we found that marine-derived sulfated fucans bind tau with similar affinity to heparin, whereas fucosylated chondroitin sulfates (FucCS) from several holothurian species bind tau with substantially higher affinity. Using solution NMR, we further characterized FucCS-tau interactions with residue-level resolution, revealing complex binding behavior distinct from heparin-tau binding. A high-affinity site is observed as peak intensity loss spanning the middle of PRR2 through R' of tau at low FucCS concentration, whereas another weaker binding site is characterized by both chemical shift perturbation and gradual peak intensity attenuation from the end of N2 through the middle of PRR2. Finally, we demonstrated that FucCSs inhibit tau uptake in SH-SY5Y cells with an IC50 of 130 μg/mL, shown by both confocal microscopy and flow cytometry. Together, these findings have identified marine-derived polysaccharides as promising candidates for therapeutic development targeting tau-HS interactions.},
}

@article {pmid41866633,
year = {2026},
author = {Kim, D and Kim, NY and Kwak, MJ and Heo, KH and Lee, HG and Kwon, S and Cho, SY and Park, SU and Jung, WS and Moon, SK and Ko, CN and Kim, HG and Jahng, GH and Park, JM},
title = {Effects of the herbal prescription Kami Guibi-tang on brain function in amnestic mild cognitive impairment: a task-based and resting-state fMRI study.},
journal = {Brain imaging and behavior},
volume = {20},
number = {2},
pages = {},
pmid = {41866633},
issn = {1931-7565},
support = {RS-2021-KH121820//the Ministry of Health and Welfare of the Republic of Korea/ ; },
abstract = {UNLABELLED: Amnestic mild cognitive impairment represents a prodromal stage of Alzheimer’s disease characterized by episodic memory deficits and subtle alterations in brain function. Although the traditional herbal formula Kami Guibi-tang (KGT) has been reported to exert cognitive benefits, its neural effects have not been evaluated using functional neuroimaging. In this randomized, double-blind, placebo-controlled trial, 84 individuals with amnestic mild cognitive impairment received either KGT or placebo for 24 weeks. A total of 73 participants (36 in the KGT group and 37 in the placebo group) completed the intervention and were included in the final analyses. All participants underwent functional magnetic resonance imaging during a face-name association task and a working memory task, as well as resting-state scans. Task-based imaging data were analyzed using voxel-wise and region-of-interest approaches, and associations between changes in task-related activation and cognitive performance were also examined. Resting-state functional connectivity was analyzed to examine regional connectivity changes. At baseline, the placebo group showed greater activation in memory- and attention-related regions, including the posterior cingulate cortex, frontal areas, and thalamus. These voxel-wise differences were no longer observed after the intervention. Region-of-interest analyses using linear mixed-effects models revealed significant group × time interactions in several frontal, cingulate, and thalamic regions, with activation declining in the placebo group but remaining relatively preserved or showing modest increases in the KGT group. Resting-state analyses further demonstrated increased connectivity between the left precuneus and right posterior cingulate cortex following KGT administration. These findings suggest that KGT may modulate brain activity and connectivity in regions involved in episodic and working memory. While preliminary, these results provide neuroimaging-based evidence for its potential effects on memory-related neural processes in the early stages of cognitive decline.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11682-026-01138-6.},
}

@article {pmid41872054,
year = {2026},
author = {Man, VH and He, X and Niu, T and Cai, L and Han, F and Nguyen, P and Wang, J},
title = {K16F/E22F Mutation Promotes Oligomerization and Alters β-Sheet Topology of Aβ16-22 Peptides: Insights from Molecular Dynamics Simulations.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00003},
pmid = {41872054},
issn = {1948-7193},
abstract = {Amyloid-β (Aβ) aggregation into toxic oligomers and fibrils is a hallmark of Alzheimer's disease. The Aβ16-22 fragment plays a critical role in the early stages of the aggregation of full-length Aβ peptides. Aggregation of Aβ16-22 is primarily driven by hydrophobic interactions within the LVFF core and electrostatic attraction between flanking residues K16 (+) and E22 (-). To dissect the relative contributions of these forces, we introduced a K16F/E22F double mutation, which eliminates charged residues while enhancing hydrophobicity and aromaticity. This substitution provides a controlled system to evaluate how specific interactions influence aggregation behavior. Using a novel computational protocol, featuring a strategically designed 4-mer system, multiple independent and long-time scale trajectories, and specialized analysis, we directly tracked and comprehensively characterized the oligomerization process. The mutation significantly enhanced both intra- and intermolecular interactions, promoting aggregation. It also altered the oligomerization pathways, as reflected in the distinct distribution across ten possible states formed by four Aβ16-22 peptides. Furthermore, while the wild-type peptide predominantly formed antiparallel β-sheets, the mutant favored parallel and mixed β-sheet arrangements. These results indicated that increased hydrophobicity and aromaticity facilitate more stable and polymorphic aggregation pathways. Our findings highlight the dominant role of hydrophobic interactions in early-stage Aβ aggregation and emphasize the therapeutic potential of targeting hydrophobic hotspots, such as the LVFF core, while accounting for structural polymorphism rather than focusing solely on disrupting electrostatic interactions.},
}

@article {pmid41872227,
year = {2026},
author = {Wang, JL and Zhao, Q and Zheng, R and Fang, Y and Cao, J and Zhang, BR},
title = {Cerebrospinal fluid and plasma metabolites in Parkinson's disease: a Mendelian randomization study.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41872227},
issn = {2045-2322},
mesh = {Humans ; *Parkinson Disease/blood/cerebrospinal fluid/genetics/metabolism ; *Mendelian Randomization Analysis ; Male ; Female ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Genome-Wide Association Study ; *Metabolome ; Middle Aged ; Polymorphism, Single Nucleotide ; Longitudinal Studies ; },
abstract = {Metabolites in cerebrospinal fluid (CSF) and plasma have been implicated in Parkinson's disease (PD), but their causal roles remain unclear. This study aims to investigate the causal relationships between specific CSF and plasma metabolites and PD risk, using Mendelian Randomization (MR) analysis. We utilized MR with inverse-variance weighting (IVW) as the primary analytical method, supplemented by four additional MR models to validate robustness. Data included 1,400 plasma metabolites from the Canadian Longitudinal Study on Aging, and 338 CSF metabolites from the Wisconsin Alzheimer's Disease Research Center and Wisconsin Registry for Alzheimer's Prevention, USA. metabolites from the Canadian Longitudinal Study on Aging. PD outcome data were obtained from a GWAS meta-analysis by the International Parkinson's Disease Genomics Consortium. MR analysis identified six CSF metabolites with suggestive causal relationships with PD. Dimethylglycine, gluconate, oxalate (ethanedioate), and an unknown metabolite (X-12015) were positively associated with PD risk, while (1-enyl-palmitoyl)-2-arachidonoyl-GPC (P-16:0/20:4) and an unknown compound (X-23587) were negatively associated. In plasma, 49 metabolites demonstrated suggestive causal relationships with PD risk. Key metabolites included hydroxy-3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (hydroxy-CMPF), carnitine C14, and 1-dihomo-linolenylglycerol (20:3) with positive associations, and tryptophan, succinate to acetoacetate ratio, and O-sulfo-L-tyrosine with negative associations. Notably, O-sulfo-L-tyrosine emerged as the most significant protective metabolite in plasma, showing robust associations across four MR models. This study highlights causal relationships between specific CSF and plasma metabolites and PD risk, underscoring O-sulfo-L-tyrosine as a potential biomarker and therapeutic target. These findings provide a foundation for further exploration of metabolic pathways in PD pathogenesis and intervention strategies.},
}

Humans
*Parkinson Disease/blood/cerebrospinal fluid/genetics/metabolism
*Mendelian Randomization Analysis
Male
Female
Aged
Biomarkers/blood/cerebrospinal fluid
Genome-Wide Association Study
*Metabolome
Middle Aged
Polymorphism, Single Nucleotide
Longitudinal Studies

@article {pmid41872339,
year = {2026},
author = {Vrillon, A and Götze, K and Dumurgier, J and Cognat, E and Hourrègue, C and Munoz-Musat, E and Decaix, T and Hugon, J and Estrada, J and Sebbagh, M and Bouaziz-Amar, É and Lilamand, M and Paquet, C},
title = {Eligibility for lecanemab treatment in a French memory clinic setting.},
journal = {Journal of neurology},
volume = {273},
number = {4},
pages = {},
pmid = {41872339},
issn = {1432-1459},
support = {1310194//Foundation Alzheimer Young Researcher Program/ ; },
mesh = {Humans ; Female ; Male ; Aged ; France ; Retrospective Studies ; *Alzheimer Disease/drug therapy/cerebrospinal fluid/diagnosis ; Aged, 80 and over ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Eligibility Determination ; Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; *Patient Selection ; },
abstract = {INTRODUCTION: Anti-amyloid monoclonal antibodies, including lecanemab and donanemab, are now available for the treatment of Alzheimer's disease (AD). Defining real-world patient eligibility and identifying barriers to access are critical for their effective implementation in routine clinical practice.

METHODS: Retrospective observational multicenter study of patients who underwent CSF AD biomarker testing at Lariboisière Hospital (Paris, France) from 2023 to 2024, assessing lecanemab eligibility using CLARITY AD trial criteria and the French Memory Clinic Federation appropriate use recommendations (AURs) following EMA authorization.

RESULTS: From a source population of 3075 patients, 676 underwent CSF testing, and 356 had biomarker-confirmed AD; 315 patients with MRI, APOE status, and MMSE data available (mean age 73.2 ± 8.1 years; 47.8% female; median MMSE 22 [IQR 19-26]) were screened. Using CLARITY AD trial criteria, 90 patients (28.6%) were eligible; low MMSE scores and MRI findings were the most frequent exclusion criteria. French AURs reduced eligibility to 75 patients (23.8%), excluding patients with a CSF A + T - profile and APOE ε4 homozygotes. Eligibility did not differ by age group. Eligibility rates from the entire source population equated to only 2.9% of patients using the CLARITY AD criteria and 2.4% using the French AURs. At follow-up, 34.5% of initially eligible patients no longer met the MMSE eligibility criteria.

DISCUSSION: In specialized settings, lecanemab eligibility remained limited, highlighting the need for early AD diagnosis and efficient screening pathways.},
}

Humans
Female
Male
Aged
France
Retrospective Studies
*Alzheimer Disease/drug therapy/cerebrospinal fluid/diagnosis
Aged, 80 and over
Middle Aged
*Antibodies, Monoclonal, Humanized/therapeutic use
*Eligibility Determination
Amyloid beta-Peptides/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Magnetic Resonance Imaging
*Patient Selection

@article {pmid41872468,
year = {2026},
author = {Ojo, OA and Gyebi, GA and Iyobhebhe, M and Dada, S and Daramola, T and Ojo, AB and Oyebamiji, AK and Oyinloye, BE and Ajiboye, BO},
title = {Deciphering the mechanisms underlying the dual-target inhibition of carbohydrate-digesting and neurodegenerative enzymes by Syzygium aromaticum (L.) Merr. & L.M. via molecular docking and dynamics simulations.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-45482-5},
pmid = {41872468},
issn = {2045-2322},
abstract = {Syzygium aromaticum (L.) Merr. & L.M. Perry is a known spice with a high phytochemical content that can be explored in drug discovery. We investigated the in vitro enzyme inhibitory activities of a flavonoid-rich extract of S. aromaticum (FRESA) against type II diabetes (T2D) and Alzheimer's disease (AD) and identified its anti-T2D and anti-AD phytochemicals via computational prediction. The in vitro enzyme inhibitory activities of a flavonoid-rich extract of Syzygium aromaticum were evaluated via standard protocols following flavonoid-enriched extraction procedures. High-performance liquid chromatography (HPLC) was employed to characterize the constituent bioactive flavonoids. Molecular docking of eight phytochemicals was performed via AutoDock Vina in PyRx 0.8, which identified apigenin, myricetin, and quercetin as hit compounds with high binding affinities and multitarget activities against α-amylase, α-glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase (MAO). Molecular dynamics simulations (100 ns) were conducted via GROMACS 2019.2, and binding free energy calculations were performed via the MM-GBSA approach to validate the stability and interaction integrity of the hit phytochemicals. FRESA (IC50 = 961.943 ± 21.031 μg/mL) exhibited moderate activity against α-amylase compared with that of acarbose (IC50 = 27.104 ± 0.270 μg/mL). Compared with acarbose (IC50 = 17.389 ± 0.436 μg/mL), FRESA had appreciable activity against α-glucosidase (IC50 = 562.045 ± 6.714 μg/mL). FRESA demonstrated significant (p < 0.0001) inhibition of acetylcholinesterase (IC50 = 26.911 ± 0.058 µg/mL), surpassed galantamine (IC50 = 27.950 ± 0.122 µg/mL), and moderately inhibited butyrylcholinesterase (IC50 = 28.168 ± 0.702 µg/mL) to galantamine (IC50 = 23.126 ± 0.683 µg/mL). FRESA also significantly suppressed monoamine oxidase activity in Fe[2][+]-induced brain damage in a concentration-dependent manner. HPLC-DAD analysis identified apigenin, caffeic acid, ferulic acid, gallic acid, kaempferol, myricetin, quercetin, and syringic acid as major constituents. Molecular docking revealed apigenin, myricetin, and quercetin as top-ranked multitarget inhibitors, exhibiting strong binding affinities (- 9.0 to - 10.2 kcal/mol) comparable to those of reference inhibitors across α-amylase, α-glucosidase, AChE, BChE, and MAO. Molecular dynamics simulations and MM-GBSA confirmed the binding strength of the hit phytoconstituents in the active pockets of α-amylase, α-glucosidase, AChE, BChE, and MAO, with multitargeting inhibitory activities supporting the in vitro and ex vivo enzyme activities. ADMET profiling indicated favorable drug likeness for apigenin, whereas myricetin and quercetin displayed acceptable pharmacokinetic properties with minimal violations. Our findings provide scientific validation of the anti-T2D and anti-AD properties of S. aromaticum and identify apigenin, myricetin, and quercetin, which could be used for the development of inhibitors of α-amylase, α-glucosidase, AChE, BChE, and MAO as dual therapies to combat T2D and AD. Additional in vivo validation is recommended to ensure a thorough assessment in the present research.},
}

@article {pmid41872484,
year = {2026},
author = {Li, YY and Wang, XY and Pu, YJ and Psakhye, I and Wang, Y and Chen, Z and Li, WL},
title = {Pathophysiological roles of neural stem cells in neuropsychiatric diseases: from plasticity to pharmacological targeting.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41872484},
issn = {1745-7254},
abstract = {Neural stem cells (NSCs) persist throughout adulthood and contribute to circuit maintenance through controlled neurogenesis and trophic, metabolic, and immunomodulatory signaling. However, across neurological and psychiatric disorders, NSCs are not passive bystanders but direct targets of disease pathology and active participants in its progression. Evidence from stroke, Alzheimer's disease, Parkinson's disease, epilepsy, depression, anxiety, bipolar disorder, autism spectrum disorder, and schizophrenia shows that pathogenic conditions, such as neuroinflammation, oxidative and metabolic stress, and hypothalamic-pituitary-adrenal axis dysregulation disrupt intrinsic NSC programs. These insults suppress NSC activation, impair lineage commitment, and alter the NSC secretome in ways that exacerbate synaptic dysfunction and network instability. Despite interest in NSC-based transplantation, structural replacement remains constrained by poor survival, migration, long-range integration, and safety considerations. In contrast, paracrine mechanisms and extracellular vesicles drive more consistent functional benefits by suppressing neuroinflammation, protecting vulnerable neurons, restoring neurovascular integrity, and modulating immune and metabolic homeostasis. NSCs with gene editing, bioengineered scaffolds, extracellular matrix-mimetic hydrogels, and exosome-based delivery offer renewed translational potential. By repositioning NSCs as both vulnerable targets and mechanistic drivers of disease rather than secondary responders, this review reframes shared pathological processes across brain disorders and highlights NSCs as a tractable entry point for therapeutic intervention and circuit repair.},
}

@article {pmid41872793,
year = {2026},
author = {Yang, A and Hu, B and Ye, M and Zhang, X and Yu, W and Yin, J},
title = {A mobile app (mWITH ME) for family caregivers of persons living with Alzheimer's disease: development and initial evaluation.},
journal = {BMC medical informatics and decision making},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12911-026-03456-7},
pmid = {41872793},
issn = {1472-6947},
support = {No.20AC003//the National Social Science Foundation of China/ ; },
}

@article {pmid41872889,
year = {2026},
author = {Merikle, E and Presnall, C and Feaster, T and Moxon, R and Siemers, E and Kerwin, D and Cline, S},
title = {Elucidating the phase 1 trial experience among study participants following completion of the INTERCEPT-AD study of sabirnetug (ACU193) for early Alzheimer's disease: a qualitative interview study.},
journal = {Trials},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13063-026-09656-w},
pmid = {41872889},
issn = {1745-6215},
abstract = {BACKGROUND: Recruitment and retention remain persistent challenges in Alzheimer's disease (AD) clinical trials, particularly as studies increasingly focus on earlier disease stages and require longer participation and more invasive procedures. Understanding how trial enrollment and participation are experienced is critical to improving acceptability and sustaining engagement. Qualitative interviews conducted alongside clinical trials offer an opportunity to capture participant and study partner perspectives on the trial experience. In INTERCEPT-AD, a phase 1 trial evaluating safety and tolerability of the Aβ oligomer-selective monoclonal antibody sabirnetug (ACU193) among participants with mild cognitive impairment or mild dementia due to Alzheimer's disease (AD), semi-structured qualitative interviews concerning trial experience were conducted with a subset of participants and their study partners.

METHODS: Participant/study partner dyads completed qualitative interviews following the final study visit. A semi-structured interview guide elicited descriptions regarding motivations for participating, enrollment decision-making, and positive and negative aspects of participation. Principles of applied qualitative thematic analysis guided the qualitative analyses. Exploratory analyses examined how factors differ by participant gender.

RESULTS: Twenty-eight participants (64.2% female) and their study partners were interviewed, representing 43% of the trial population (n = 65; 53.8% female). Participants and study partner dyads described varied pathways to trial awareness and enrollment decision-making, including both independent and family-involved decisions. Motivations for participation reflected anticipated personal benefit as well as altruistic goals. While interactions with study staff were viewed positively, dyads reported meaningful burdens related to travel, time commitment, and study procedures, with cognitive testing more frequently described as challenging than invasive procedures. A recurring theme was the desire for clearer communication and greater access to study-related information, including test results and treatment assignment. Exploratory analyses suggested that perceived burden and enrollment decision-making may differ by participant gender.

CONCLUSIONS: Study findings suggest opportunities to enhance the AD trial experience by addressing trial-related burdens and logistical aspects of participation. Exploratory gender analyses yielded additional insight into the patient trial experience but should be further examined along with race/ethnicity and study partner characteristics to enhance clinical study design and execution.},
}

@article {pmid41873111,
year = {2026},
author = {Jamali, A and Sisara, MA and Nasab, EK and Van Dam, D and Amiri, M},
title = {G-ALPS: An index for evaluating cognitive decline and aging using diffusion tensor imaging.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71118},
doi = {10.1002/alz.71118},
pmid = {41873111},
issn = {1552-5279},
support = {4030788//National Institute for Medical Research Development/ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/pathology ; *Diffusion Tensor Imaging/methods ; Male ; Female ; Aged ; *Aging/pathology ; *Alzheimer Disease/diagnostic imaging ; Aged, 80 and over ; *Glymphatic System/diagnostic imaging/pathology ; Neuropsychological Tests ; *Brain/diagnostic imaging/pathology ; Mental Status and Dementia Tests ; },
abstract = {INTRODUCTION: The glymphatic system dysfunction is associated with cognitive decline in neurodegenerative diseases such as Alzheimer's disease (AD).

METHODS: We introduce the G-Along Perivascular Space (G-ALPS) index, an optimized version of the ALPS index derived using Genetic Programming, and use it to analyze 217 diffusion tensor imaging (DTI) samples.

RESULTS: Compared to the ALPS, the proposed G-ALPS index shows a stronger correlation with cognitive measures, including Mini-Mental State Examination (MMSE, 2.78% improvement), Clinical Dementia Rating (CDR, 5.13% improvement), and Functional Activities Questionnaire (FAQ, 10% improvement), as demonstrated by the analysis of fiber diffusivities in DTI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Furthermore, the G-ALPS exhibits enhanced sensitivity in identifying the effects of aging (94.81% improvement in AD individuals, 105% improvement in patients with mild cognitive impairment [MCI], and 81.25% improvement in normal controls) and sleep-related disorders (21.27% improvement in correlation with MMSE, and 2.53% improvement in correlation with Pittsburgh Sleep Quality Index [PSQI]) using the Human Connectome Project (HCP) dataset.

DISCUSSION: Our results suggest that the G-ALPS index may be an indirect metric for assessing the glymphatic system's function or dysfunction.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/pathology
*Diffusion Tensor Imaging/methods
Male
Female
Aged
*Aging/pathology
*Alzheimer Disease/diagnostic imaging
Aged, 80 and over
*Glymphatic System/diagnostic imaging/pathology
Neuropsychological Tests
*Brain/diagnostic imaging/pathology
Mental Status and Dementia Tests

@article {pmid41873153,
year = {2026},
author = {Lao, K and Li, Y and Xiao, Y and Sun, Y and Dai, Y and Li, H and Yang, Y and Zhang, Y and Wang, J and Li, W and Gou, X and Guan, L},
title = {Discovery of ferulic acid carbamate derivatives as dual-targeting agents of BuChE and Nrf2 for Alzheimer's disease.},
journal = {Journal of enzyme inhibition and medicinal chemistry},
volume = {41},
number = {1},
pages = {2645483},
doi = {10.1080/14756366.2026.2645483},
pmid = {41873153},
issn = {1475-6374},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Coumaric Acids/pharmacology/chemistry/chemical synthesis ; *NF-E2-Related Factor 2/metabolism/antagonists & inhibitors ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; Animals ; *Butyrylcholinesterase/metabolism ; Caenorhabditis elegans/drug effects ; *Carbamates/pharmacology/chemistry/chemical synthesis ; Structure-Activity Relationship ; Molecular Structure ; *Drug Discovery ; Humans ; Dose-Response Relationship, Drug ; Mice ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Amyloid beta-Peptides/antagonists & inhibitors ; Oxidative Stress/drug effects ; Cell Line ; },
abstract = {Given the multifactorial aetiology of Alzheimer's disease, multi-target strategies have emerged as a promising therapeutic approach. In this study, we designed and synthesised a series of ferulic acid carbamate derivatives to selectively inhibit BuChE and stimulate Nrf2 pathway. The biological evaluation revealed that compound 5c and 5e were the most potent, exhibiting over 150-fold selectivity for BuChE. Also, 5c, 5g and 5h significantly reversed both H2O2[-] and Aβ-induced toxicity in HT22 cells. These compounds were further shown to eliminate ROS accumulation induced by Aβ and upregulated HO-1 and GCLM by promoting the nuclei translocation of Nrf2. In Aβ transgenic C. elegans, three lead compounds alleviated Aβ-induced paralysis and cognitive deficits. In silico study revealed that compound 5c fitted well into the active sites of BuChE and Keap1 while maintaining favourable CNS drugability. This dual strategy of cholinesterase inhibition and oxidative stress mitigation is a promising approach for novel AD therapeutics.},
}

*Alzheimer Disease/drug therapy/metabolism
*Coumaric Acids/pharmacology/chemistry/chemical synthesis
*NF-E2-Related Factor 2/metabolism/antagonists & inhibitors
*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
Animals
*Butyrylcholinesterase/metabolism
Caenorhabditis elegans/drug effects
*Carbamates/pharmacology/chemistry/chemical synthesis
Structure-Activity Relationship
Molecular Structure
*Drug Discovery
Humans
Dose-Response Relationship, Drug
Mice
*Neuroprotective Agents/pharmacology/chemical synthesis/chemistry
Amyloid beta-Peptides/antagonists & inhibitors
Oxidative Stress/drug effects
Cell Line

@article {pmid41873211,
year = {2026},
author = {Gupta, R and Kumar, R and Kumar, N and Singh, P},
title = {Reimagining Brain Drug Delivery: Mechanistic and Translational Advances in Carbon Nanotube Nanomedicine.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70154},
pmid = {41873211},
issn = {1099-1263},
abstract = {Neurological and neurodegenerative disorders (NDDs) present ongoing therapeutic challenges attributed to the structural complexity of the central nervous system (CNS) and the restrictive properties of the blood-brain barrier (BBB), which inhibit the effective penetration of most drugs into the brain. Thus, carbon nanotubes (CNTs) possess a high aspect ratio, tunable surface chemistry, and exceptional electrical and mechanical properties, establishing them as versatile nanoplatforms that can address significant challenges in CNS drug delivery. Despite the exploration of various nanocarriers, a significant gap persists in the comprehensive understanding of the convergence of CNT structure, functionalization, mechanistic transport pathways, and safety-by-design strategies for translational neurological applications. This review synthesizes recent advancements in CNT engineering, mechanisms of BBB traversal, cell-specific targeting, and intracellular trafficking, as well as insights into CNT-induced neurotoxicity and clearance pathways. Further, the review emphasizes therapeutic advancements in CNT-mediated interventions for Alzheimer's disease (AD), Parkinson's disease (PD), brain tumors, stroke, and epilepsy, focusing on multifunctional applications in drug delivery, neuroregeneration, immunomodulation, neuromodulation, theranostic, and biosensing. Additionally, it assesses preclinical results, safety factors, regulatory challenges, and the growing influence of artificial intelligence (AI)-driven design in enhancing nanoscale behavior, functionalization, and biocompatibility. Lastly, the current review integrates technological innovations with mechanistic toxicology and translational challenges, establishing CNTs as promising neuro-nanomedicine platforms that may effectively address unmet clinical needs in CNS disorders. Trial Registration: ClinicalTrials.gov: NCT04495634, NCT02873585, NCT01246336, NCT07034248, NCT07034248.},
}

@article {pmid41873327,
year = {2026},
author = {Priya, S and Kowalski, EL and Popov, M and Orlando, R},
title = {Prediction and Characterization of Glycated Peptides and Proteins using Hydrophilic Interaction Liquid Chromatography coupled with Mass Spectrometry (HILIC-MS).},
journal = {Journal of biomolecular techniques : JBT},
volume = {37},
number = {1},
pages = {27-37},
pmid = {41873327},
issn = {1943-4731},
mesh = {Hydrophobic and Hydrophilic Interactions ; Chromatography, Liquid/methods ; Glycosylation ; *Peptides/chemistry ; Glycation End Products, Advanced/chemistry ; *Mass Spectrometry/methods ; Humans ; Protein Processing, Post-Translational ; *Proteins/chemistry ; },
abstract = {Glycation is an important post-translational modification (PTM) that has been linked to diabetes, cataract, Alzheimer's, and Rheumatoid arthritis. This reaction occurs between a reducing sugar and a primary amine at the N-terminus of a protein or at a lysine side chain. Ultimately, this interaction can lead to advanced glycation end products (AGEs) that are associated with several disease complications. Glycation can occur during the manufacturing and storage of therapeutic proteins, including monoclonal antibodies (mAbs), necessitating the characterization of this modification to ensure the safety and efficacy of therapeutic drug products. Hydrophilic Interaction Liquid Chromatography (HILIC) has been previously employed to characterize hydrophilic modifications. It can also be used to characterize glycated species, as the hydrophilic nature of the glycation product can lead to a characteristic shift in HILIC retention. This work focuses on deriving a retention coefficient that describes the extent of hydrophilicity imparted by glycation modification in HILIC using in vitro glycated peptide and protein samples. The HILIC retention coefficient can be used to predict the retention times of tryptic peptides with glycation modifications in complex, unknown protein samples, including immunoglobulins (IgGs).},
}

Hydrophobic and Hydrophilic Interactions
Chromatography, Liquid/methods
Glycosylation
*Peptides/chemistry
Glycation End Products, Advanced/chemistry
*Mass Spectrometry/methods
Humans
Protein Processing, Post-Translational
*Proteins/chemistry

@article {pmid41873625,
year = {2026},
author = {Guan, DX},
title = {Reviewer Comment on Oliveira et al. "Fluid Biomarkers of Motor and Non-Motor Experiences of Daily Living in Dementia with Lewy Bodies and Alzheimer's Disease".},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1},
doi = {10.1017/cjn.2026.10560},
pmid = {41873625},
issn = {0317-1671},
}

@article {pmid41873784,
year = {2026},
author = {Shiner, T and Nathan, T and Levy, MH and David, AB and Omer, N and Awad, AA and Ash, E and Weisz, MG and Goldstein, O and Alcalay, Y and Regev, K and Lamoureux, J and Van Keuren-Jensen, K and Blauwendraat, C and Alcalay, RN and Bregman, N},
title = {Alpha-synuclein co-pathology in a real-world early Alzheimer's disease cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71240},
doi = {10.1002/alz.71240},
pmid = {41873784},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/pathology ; *alpha-Synuclein/cerebrospinal fluid ; Male ; Female ; Aged ; *Cognitive Dysfunction/cerebrospinal fluid/pathology ; Biomarkers/cerebrospinal fluid ; Prospective Studies ; Cohort Studies ; Aged, 80 and over ; REM Sleep Behavior Disorder/cerebrospinal fluid ; Olfaction Disorders ; },
abstract = {BACKGROUND: Most Alzheimer's disease (AD) cases show mixed pathology, with α-synuclein (αSyn) aggregates present in a substantial proportion. The cerebrospinal fluid (CSF) α-synuclein seed amplification assay (αS-SAA) enables in vivo detection of pathogenic αSyn aggregates, but its clinical significance remains unclear.

METHODS: We prospectively evaluated 108 individuals with mild cognitive impairment or mild dementia due to suspected AD undergoing lumbar puncture for anti-amyloid therapy (ATT) eligibility. CSF AD biomarkers and αS-SAA were analyzed alongside cognitive, olfactory, and rapid eye movement sleep behavior disorder (RBD) assessments.

RESULTS: Of 65 participants with biomarker-confirmed AD, 21 (32.3%) were αS-SAA positive. Positivity was linked to older age at testing and self-reported olfactory impairment (P = 0.004), but not other demographic or cognitive features. Within the αS-SAA-positive group, RBD presence correlated with faster seeding kinetics.

CONCLUSIONS: αS-SAA positivity is common in early AD and associated with olfactory dysfunction. Longitudinal follow-up is required to test if assay status predicts response to ATTs.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/pathology
*alpha-Synuclein/cerebrospinal fluid
Male
Female
Aged
*Cognitive Dysfunction/cerebrospinal fluid/pathology
Biomarkers/cerebrospinal fluid
Prospective Studies
Cohort Studies
Aged, 80 and over
REM Sleep Behavior Disorder/cerebrospinal fluid
Olfaction Disorders

@article {pmid41873958,
year = {2026},
author = {Alkam, T and Tarshizi, E and Benschoten, AHV},
title = {Risk Stratification for In-Hospital Mortality in Alzheimer's Disease Using Interpretable Regression and Explainable AI.},
journal = {Geriatrics (Basel, Switzerland)},
volume = {11},
number = {2},
pages = {},
doi = {10.3390/geriatrics11020023},
pmid = {41873958},
issn = {2308-3417},
abstract = {BACKGROUND: Older adults with Alzheimer's disease (AD) face a heightened risk of adverse hospital outcomes, including mortality. However, early identification of high-risk patients remains a challenge. While regression models provide interpretable associations, they may miss non-linear interactions that machine learning can uncover.

OBJECTIVE: To identify key predictors of in-hospital mortality among AD patients using both survey-weighted logistic regression and explainable machine learning.

METHODS: We analyzed hospitalizations among AD patients aged ≥60 in the 2017 Nationwide Inpatient Sample (NIS). The outcome was in-hospital death. Predictors included demographics, hospital variables, and 15 comorbidities. Logistic regression used survey weighting to generate nationally representative inference; XGBoost incorporated NIS discharge weights as sample weights during 5-fold hospital-grouped cross-validation and used the same weights in performance evaluation. Missing-value imputation and feature scaling were performed within the cross-validation pipelines to prevent data leakage. Model performance was assessed using AUROC, AUPRC, Brier score, and log loss. Feature importance was assessed using adjusted odds ratios and SHapley Additive exPlanations (SHAP). A sensitivity analysis excluded palliative care and DNR status and was re-evaluated under the same grouped cross-validation.

RESULTS: In the full model, logistic regression achieved AUROC 0.879 and AUPRC 0.310, while XGBoost achieved AUROC 0.887 and AUPRC 0.324. Palliative care (aOR 6.19), acute respiratory failure (aOR 5.15), DNR status (aOR 2.20), and sepsis (aOR 2.26) were the strongest logistic predictors. SHAP analysis corroborated these findings and additionally emphasized dysphagia, malnutrition, and pressure ulcers. In sensitivity analysis excluding palliative care and DNR status, logistic regression performance declined (AUROC 0.806; AUPRC 0.206), while XGBoost performed similarly (AUROC 0.811; AUPRC 0.206). SHAP corroborated the dominant signals from end-of-life documentation and acute organ failure in the full model; in the restricted model (excluding DNR and palliative care), SHAP highlighted physiologic and frailty-related features (e.g., dysphagia, malnutrition, aspiration risk) that may be more actionable when end-of-life documentation is absent.

CONCLUSIONS: Combining regression with explainable machine learning enables robust mortality risk stratification in hospitalized AD patients. Restricted models excluding end-of-life indicators provide actionable risk signals when such documentation is absent, while the full model may better support resource allocation and goals-of-care workflows.},
}

@article {pmid41873967,
year = {2026},
author = {Cao, Y and Lee, J and Seol, J and Tsunoda, K and Shibuya, K and Yoon, J and Arai, T and Okura, T},
title = {Dose-Response Relationship Between Sleep Regularity Index and Stage-Specific Alzheimer's Disease: Cross-Sectional Evidence from Japanese Adults.},
journal = {Geriatrics (Basel, Switzerland)},
volume = {11},
number = {2},
pages = {},
doi = {10.3390/geriatrics11020032},
pmid = {41873967},
issn = {2308-3417},
support = {(JPMJPF2017 to T.O.)//the COI STREAM initiative launched in 2013 by MEXT, and the COI-NEXT initiative launched in 2020 by MEXT/ ; (25K03004 to T.O.)//JSPS KAKENHI, Grant-in-Aid for Scientific Research (B)/ ; },
abstract = {Background/Objectives: Daily sleep patterns are associated with cognitive health and Alzheimer's disease (AD). However, it remains unclear how suboptimal irregular sleep manifests in AD from the preclinical stage to dementia. This study aimed to establish the dose-response association between sleep irregularity and psychometrically defined stage-specific AD as well as executive dysfunction, among adults with subjective cognitive and sleep issues. Methods: Cross-sectional data were obtained from 532 Japanese adults (mean age = 63.9 years) between March 2023 and April 2024. Sleep irregularity was quantified using the Sleep Regularity Index (SRI) with 24/7 accelerometer data. A modified Poisson regression with cubic splines was performed to establish the dose-response association. Results: This study identified novel non-linear associations. The prevalence ratios of cognitive impairment, defined as being in the preclinical and more advanced stages of AD, significantly declined beyond a median SRI of 60. Participants within this SRI range also showed significantly lower prevalence ratios of poorer Trail Making Test B performance. All results were independent of age, sleep duration, and risk of depression. Conclusions: Maintaining balanced-to-regular daily sleep patterns might be optimal for AD progress from its preclinical stages, with a potential benchmark at SRI of 60, especially for those individuals at risk for cognitive decline and sleep disorders. Further research is needed to replicate this benchmark in diverse populations and to evaluate the effect of rigid sleep regularity on cognitive health.},
}

@article {pmid41874041,
year = {2026},
author = {Papadogiani, M and Fasilis, T and Despoti, A and Kamtsadeli, V and Hantzopoulou, M and Tsinia, N and Lykou, E and Chatziantoniou, L and Chousos, D and Siarkos, K and Papatriantafyllou, JD},
title = {The Benson Complex Figure Test for the Differential Diagnosis of Dementias.},
journal = {NeuroSci},
volume = {7},
number = {2},
pages = {},
doi = {10.3390/neurosci7020038},
pmid = {41874041},
issn = {2673-4087},
abstract = {The Benson Complex Figure Test (BCFT) is a neuropsychological tool designed to assess visuospatial construction and visual memory with lower complexity than traditional tests. This study evaluated its ability to differentiate between major dementia subtypes. In a retrospective cross-sectional analysis of 1428 participants from a Greek third-age day center (healthy participants [Controls]; patients diagnosed with Alzheimer's disease dementia [ADD], Lewy body dementia [LBD], Frontotemporal dementia [FTD: behavioral variant (BV), non-fluent variant (NFV), semantic variant (SV)], Corticobasal dementia [CBD], Parkinson's disease dementia [PDD], and mixed Cardiovascular dementia with Alzheimer's disease [CVD/AD]), all participants completed the BCFT and the Mini-Mental State Examination (MMSE). Multinomial logistic regression, adjusted for age, sex, and education, revealed distinct BCFT profiles across dementia subtypes. Patients with CBD showed significantly lower copy scores than those with ADD (p = 0.006). The FTD-NFV group exhibited superior memory scores compared to all other dementia subtypes (p < 0.001). Poorer BCFT recognition performance was strongly associated with diagnoses of ADD (OR = 0.39, p = 0.012), FTD-BV (OR = 0.22, p = 0.025), and PDD (OR = 0.26, p < 0.001). Classification accuracy was highest for controls and ADD (sensitivity > 89%) but low for rarer subtypes (<25%), partly reflecting sample size limitations. In conclusion, the BCFT captures distinct visuospatial and memory profiles across dementia syndromes, supporting its potential utility in differential diagnosis, particularly for common subtypes such as ADD. Its simpler design may facilitate assessment in older adults, although validation in larger and more balanced cohorts is required for rarer dementias.},
}

@article {pmid41874070,
year = {2026},
author = {Kebsi, D and Barki, C and Dergaa, I and Gouider, R and Ceylan, Hİ and Maddouri, A and Jemai, A and Elloumi, M and Bragazzi, NL and Boussi Rahmouni, H},
title = {Personalized Hearing Loss Care Using SNOMED CT-Aligned Ontology and Random Forest Machine Learning: A Hybrid Decision-Support Framework.},
journal = {Audiology research},
volume = {16},
number = {2},
pages = {},
doi = {10.3390/audiolres16020037},
pmid = {41874070},
issn = {2039-4330},
abstract = {BACKGROUND: Hearing loss affects over 466 million individuals globally and is recognized as a major risk factor for Alzheimer's disease, yet treatment personalization remains limited due to the complexity and diversity of underlying causes. Current diagnostic and therapeutic approaches lack standardized methods to accurately predict the most appropriate intervention for individual patients. The integration of medical ontologies with machine learning offers a promising solution for enhancing diagnostic accuracy and treatment personalization.

AIM: Our study aimed to (i) develop a Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT)-aligned clinical ontology for hearing loss using Semantic Web Rule Language for automated reasoning; (ii) implement a Random Forest classifier trained on ontology-enriched patient data to classify hearing loss types (conductive, sensorineural, mixed, or normal); and (iii) predict optimal personalized treatments based on laterality, severity, audiometric thresholds, and medical history using real-world patient data.

METHODS: We developed a task ontology using Protégé 5.6.3 with Web Ontology Language (OWL), integrated SNOMED CT terminology alignment, and implemented Semantic Web Rule Language rules executed by the Pellet 2.2.0 reasoner. The framework was trained and evaluated on 3723 adult patients from the 2015-2016 National Health and Nutrition Examination Survey (NHANES) dataset with complete audiometric and clinical data. Random Forest models were developed using an 80-20 train-test split with stratified sampling and five-fold cross-validation. Performance was compared between K-Means clustering-based labeling and ontology-based semantic inference using accuracy, precision, recall, F1-score, and log loss metrics.

RESULTS: The ontology successfully generated semantic labels for all 3723 patients, enabling precise classification of hearing loss types, severity levels, and laterality. The Random Forest model with K-Means clustering achieved a test accuracy of 90.2% with a log loss of 0.2766 and a cross-validation mean accuracy of 91.22% (standard deviation 1.2%). Integration of ontology-based semantic enrichment significantly improved performance, achieving a test accuracy of 92.48% with a cross-validation mean accuracy of 92.80% (standard deviation 0.9%). F1-scores improved across all classes, with mixed hearing loss showing a notable increase from 0.86 to 0.92. Feature importance analysis identified audiometric thresholds, ontology-derived severity labels, and medical history as top predictors, enhancing clinical interpretability.

CONCLUSIONS: This study demonstrates that combining SNOMED CT-aligned ontology with Random Forest classification achieves superior diagnostic accuracy and enables personalized treatment recommendations for hearing loss. The hybrid framework provides clinically interpretable decision support while ensuring semantic interoperability with electronic health records. Multi-institutional validation studies are necessary to assess generalizability across diverse populations before clinical deployment.},
}

@article {pmid41874134,
year = {2026},
author = {Oh, S and Nairuz, T and Park, SJ and Lee, JH},
title = {Simultaneous Analysis of Microsaccades and Pupil Size Variations in Age-Related Cognitive Impairment Using Eye-Tracking Technology.},
journal = {Journal of eye movement research},
volume = {19},
number = {2},
pages = {},
doi = {10.3390/jemr19020029},
pmid = {41874134},
issn = {1995-8692},
support = {HI23C0942, RS-2024-00433896, 2020R1A6C101B189, 25DIH-17, 2025-RISE-03-002//Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea, Korea Basic Science Institute (National research Facilities and Equipment Center) grant fun/ ; },
abstract = {Age-related cognitive impairment represents a critical stage in the continuum of neurodegenerative disorders, including Alzheimer's disease (AD), highlighting the need for objective and non-invasive physiological indicators of early neurological change. This study investigates the simultaneous analysis of microsaccadic eye movements and pupil size variations as ocular biomarkers associated with age-related cognitive impairment using eye-tracking technology. A total of 70 participants were recruited and categorized into three age groups: individuals in their 20s, 60s, and 70s. Participants in their 70s were further categorized based on MMSE-K scores into cognitively normal (≥24) and impaired (≤23) subgroups. Quantitative analyses showed a significant age-related increase in microsaccade frequency along both axes, with significantly higher microsaccade frequencies (p < 0.01) among individuals with lower cognitive scores within the same age group. Pupil size variation, including constriction and dilation rates, declined with age, while response speed remained relatively unchanged across all age groups. These findings highlight a clear association between age related-cognitive decline and involuntary ocular responses. The proposed dual-biomarker method offers a non-invasive and quantitative framework that may complement traditional cognitive screening tools. Future studies involving larger cohorts and clinically diagnosed AD populations are required to determine the diagnostic utility of these ocular biomarkers.},
}

@article {pmid41874242,
year = {2026},
author = {Mei, Y and Chen, F and Chen, X},
title = {Exploring the Attention Distribution Around Perceptual Boundaries of English Continuous Speech.},
journal = {Journal of speech, language, and hearing research : JSLHR},
volume = {},
number = {},
pages = {1-11},
doi = {10.1044/2025_JSLHR-25-00461},
pmid = {41874242},
issn = {1558-9102},
abstract = {PURPOSE: In everyday life, people tend to segment real-life ongoing experience into discrete events. The same is true for perceptual segmentation of language. However, little research has examined how attention is distributed across perceptual event boundaries, specifically at the three distinct preboundary, on-boundary, and postboundary points. This study aimed to explore the distribution of attention around the perceptual boundaries of continuous speech.

METHOD: A total of 26 native English speakers (16 women, 10 men; ages ranged from 19 to 29 years) were instructed to listen to and remember a series of isolated English spoken sentences where an attention (syllable) probe "ba" was embedded at preboundary, on-boundary, and postboundary points. Meanwhile, they were asked to press the key as soon as possible whenever they heard an incidental syllable "ba." A linear mixed-effects model was applied to compare response times (RTs) of "ba" at different points.

RESULTS: Participants showed faster RTs at postboundary points than at both on-boundary and preboundary points. That is, they allocated more attention at postboundary points (as indicated by negative correlations between RTs and attention) than either on-boundary or preboundary points, showing a low-low-high attention pattern.

CONCLUSIONS: Enhanced attention at postboundary points implies that event model updating might occur at these points. Thus, the well-established event boundary advantage effect in prior studies may be more closely related to intensified attention at postboundary points. Additionally, the low-low-high attention pattern has the potential to serve as an indicator of normal perceptual segmentation. This finding provides implications for future research on diagnosing atypical populations, such as schizophrenia, obsessive-compulsive disorder, Parkinson's disease, lesions of the prefrontal cortex, and Alzheimer's disease, as these populations often exhibit impaired segmentation abilities.},
}

@article {pmid41874248,
year = {2026},
author = {},
title = {Drugs for dementia.},
journal = {The Medical letter on drugs and therapeutics},
volume = {68},
number = {1751},
pages = {49-56},
doi = {10.58347/tml.2026.1751a},
pmid = {41874248},
issn = {1523-2859},
}

@article {pmid41874250,
year = {2026},
author = {},
title = {Comparison table: Drugs for Alzheimer's disease dementia.},
journal = {The Medical letter on drugs and therapeutics},
volume = {68},
number = {1751},
pages = {e57-e58},
doi = {10.58347/tml.2026.1751c},
pmid = {41874250},
issn = {1523-2859},
}

@article {pmid41874251,
year = {2026},
author = {},
title = {Comparison table: Amyloid beta-directed antibodies for Alzheimer's disease.},
journal = {The Medical letter on drugs and therapeutics},
volume = {68},
number = {1751},
pages = {e59-e60},
doi = {10.58347/tml.2026.1751d},
pmid = {41874251},
issn = {1523-2859},
}

@article {pmid41874311,
year = {2026},
author = {Alvaro-Espinosa, L and Marquez-Galera, A and Priego, N and García-Calvo, V and Perea-García, M and Hernandez-Oliver, C and Retana, D and Sanchez, O and de Pablos-Aragoneses, A and García-Gómez, P and Graña-Castro, O and Lapuente-Santana, Ó and Serrano-Ron, L and Al-Shahrour, F and Cayuela López, A and Peset, I and Megías, D and Ola, M and Varešlija, D and Young, LS and Martí-Mateos, Y and Enríquez, JA and Hernández-Encinas, E and Blanco-Aparicio, C and Soengas, MS and Bernhagen, J and Antón-Fernández, A and Ávila, J and Marchena, MA and Torres, M and de Castro, F and Márquez-Ropero, M and Sierra, A and Lopez-Atalaya, JP and Group, R and Valiente, M and Baena Galán, P and Sobrino, C and Almenara, I and Alba-Olano, D and Ortega-Sabater, C and Artiga, MJ and Ortega-Paino, E and González Piñeiro, A and Fiaño Valverde, C and de la Lama Zaragoza, A and Londoño Quiroz, A and Delgado López, PD and Pascual-Llorente, M and Díaz-Piqueras, Á and Arriaga Aragón, ÁA and Nam-Cha, S and Barrena-López, C and Plans Ahicart, G and Escolano Otín, B and Gil Aldea, I and Delgado-Fernández, J and Sepúlveda-Sánchez, JM and Perez-Nuñez, A and Hernández-Laín, A and Toldos González, O and Gargini, R and Alcivar, D and Fernández Alén, JA and Blasco García de Andoain, G and Cepeda Chafla, S and Martínez Zamorano, E and Mollejo Villanueva, M and Opazo Rodríguez, MS and Rodriguez de Lope Llorca, Á and Arbaiza Martínez, M and Múzquiz Rueda, GM and Benavente, S and Martínez-Ricarte, F and Ramón Y Cajal, S and Sesé Faustino, M and Fernández Cabré, L and Hernández-Losa, J and Martínez-Saez, E and Calero Félix, L and Vargas-Osorio, K},
title = {MIF-Induced CD74+ Microglia and Macrophages Promote Progression of Brain Metastasis and are Clinically Relevant Across Central Nervous System Disorders.},
journal = {Cancer research},
volume = {},
number = {},
pages = {},
doi = {10.1158/0008-5472.CAN-25-4018},
pmid = {41874311},
issn = {1538-7445},
abstract = {The upregulation of CD74, a chaperone involved in MHC-II antigen processing, has been mostly interpreted as indicative of antigen presentation in multiple brain disorders. However, CD74 expression has also been described in cancer cells across multiple tumor types and in the tumor microenvironment, notably in glioma. Here, we found that the presence of CD74+ microglia/macrophages, which was induced by increased levels of interferon gamma in brains affected by metastases, did not relate to its canonical pathway. Instead, the alternative function of CD74 as a cytokine receptor was pivotal. Proliferating cancer cells produced high levels of the ligand MIF that bound the CD74 receptor and induced its translocation to the nucleus where it activated a NF-κB-dependent program that promoted metastatic progression. In patients, a CD74 signature was associated with more aggressive progression of brain metastatic disease, while it had no clinical correlation with the matched primary tumor. Interestingly, a pan-disease non-canonical and clinically relevant signature derived from the CD74+ myeloid population was identified that occurred in additional brain disorders including Alzheimer's disease and multiple sclerosis. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreased brain metastasis in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. These findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a vulnerability that could be exploited therapeutically against brain metastases, and possibly other brain disorders.},
}

@article {pmid41874386,
year = {2026},
author = {LaPlume, AA and Mellah, S and , and Rajah, MN and Belleville, S},
title = {Educational attainment mitigates hippocampal-related episodic memory decline in individuals at risk of Alzheimer's disease.},
journal = {Journal of neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnp.70039},
pmid = {41874386},
issn = {1748-6653},
support = {/CAPMC/CIHR/Canada ; //Courtois Foundation/ ; //Réseau québécois de recherche sur le vieillissement/ ; //Fonds de recherche du Québec (FRQ)/ ; //Fonds de recherche du Québec - Santé (FRQS)/ ; //Quebec Consortium for the early identification of Alzheimer's disease (CIMA-Q)/ ; //Canadian Consortium for Neurodegeneration in Aging (CCNA)/ ; //Fondation Famille Lemaire/ ; //Natural Sciences and Engineering Research Council of Canada/ ; },
abstract = {Ageing and Alzheimer's disease lead to declines in the brain region underlying memory for past events (hippocampus), and subsequently in memory for past events (episodic memory). However, some people show considerable adaptability in maintaining cognitive processes despite brain ageing or disease. The cognitive reserve model proposes that individual factors (e.g., higher education) may provide cognitive resilience. We measured whether the expected hippocampal-memory association differs according to educational attainment (a proxy of cognitive reserve). At baseline, 62 older adults (65-88 years old) at risk of Alzheimer's disease reported the amount of education completed and received anatomical 3D-T1-w structural MRIs to measure hippocampal volume. They completed a Face-Name Association episodic memory task at baseline, 2 years later, and 4 years later. Educational attainment significantly moderated the effect of hippocampal volume on episodic memory over time, β = -1.97 (SE = .93). Lower hippocampal volume caused greater memory decline at low (mean - 1 SD), but not at moderate (mean) or high (mean + 1 SD) education levels. A Johnson-Neyman analysis revealed that over 14 years of educational attainment is the threshold to eliminate a significant hippocampal-memory effect. The results did not differ by sex. Findings support the cognitive reserve model that individual factors, such as educational attainment, contribute to a cognitive reserve that enables better cognitive performance than would be expected given ageing or disease-related brain changes. Importantly, the findings specify the amount of educational attainment that is protective. Over 14 years of education mitigates hippocampal-related memory decline in people at the risk of Alzheimer's disease.},
}

@article {pmid41874395,
year = {2025},
author = {Park, G and Chakrabarty, P and Efron, PA and Nagpal, R},
title = {Dysbiosis and the gut-brain axis impairment in the pathophysiology of Alzheimer's disease and related dementias: is 'pathobiome' an etiological element?.},
journal = {Essays in biochemistry},
volume = {69},
number = {6},
pages = {},
doi = {10.1042/EBC20253055},
pmid = {41874395},
issn = {1744-1358},
mesh = {Humans ; *Dysbiosis/microbiology/complications/physiopathology ; *Alzheimer Disease/physiopathology/microbiology/etiology/metabolism/pathology ; *Gastrointestinal Microbiome ; *Brain/metabolism/physiopathology ; Animals ; *Dementia/physiopathology/microbiology/etiology ; },
abstract = {The gut microbiome plays a pivotal role in host metabolic, cardiovascular, and immune health. Increasing evidence also links it to aging-associated neurocognitive decline and neurodegenerative disorders, including Alzheimer's disease (AD) and related dementias. While the precise mechanisms of the gut-microbiome-brain axis remain incompletely understood, recent findings challenge the traditional view of AD as a disease confined to the central nervous system. Aging-associated gut dysbiosis, marked by loss of beneficial microbes, expansion of opportunistic pathogens, and reduced microbial diversity, can compromise intestinal barrier integrity, leading to 'leaky gut' and increased translocation of microbial components or pathogens into the circulation. These elements may cross a weakened blood-brain barrier, triggering neuroinflammation, amyloid-beta accumulation, tau hyperphosphorylation, and neuronal injury. Such pathobiome-driven inflammatory cascades may initiate or accelerate AD pathology, shifting the etiological perspective beyond the amyloid and tau hypotheses toward systemic and peripheral contributors. Our work and others' have identified distinct dysbiotic microbiome signatures in AD, supporting the possibility that AD pathogenesis may begin in the gut. Restoring microbial homeostasis through targeted interventions could attenuate neuroinflammatory and neurodegenerative processes, offering a novel preventive and therapeutic avenue. This emerging paradigm underscores the need for comprehensive, mechanistic, and longitudinal studies to define how aging-driven microbiome alterations influence the gut-brain axis and contribute to AD progression.},
}

Humans
*Dysbiosis/microbiology/complications/physiopathology
*Alzheimer Disease/physiopathology/microbiology/etiology/metabolism/pathology
*Gastrointestinal Microbiome
*Brain/metabolism/physiopathology
Animals
*Dementia/physiopathology/microbiology/etiology

@article {pmid41874810,
year = {2026},
author = {Jalalian, S and Weickenmeier, J},
title = {Alzheimer's Disease Accelerates Cerebral Atrophy by Over a Decade Compared to Healthy Aging.},
journal = {Annals of biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {41874810},
issn = {1573-9686},
support = {1953323//Directorate for Engineering/ ; U19NS120384/NS/NINDS NIH HHS/United States ; },
abstract = {Brain aging is accompanied by progressive morphological and neurobiological changes, which are significantly accelerated in neurodegenerative diseases, such as Alzheimer's disease. Detecting and differentiating these changes early is crucial for diagnosis, treatment planning, and therapeutic development. In this work, we present a computational multiphysics framework that couples protein biomarker propagation with tissue-level atrophy to distinguish between cognitively normal aging, mild cognitive impairment, and Alzheimer's disease. Our model integrates a network-based simulation of amyloid beta and tau protein spread with a finite element model of brain mechanics to simulate longitudinal brain shape changes over 40 years. Notably, we observe that amyloid beta accumulation precedes tau-driven degeneration by over a decade, aligning with empirical biomarker studies. We also introduce several mechanomarkers which are quantitative metrics of brain morphology such as displacement, cortical thickness, curvature, and sulcal depth. They serve as quantitative measures of disease-specific deformation patterns. Our simulations predict that Alzheimer's disease accelerates cerebral atrophy by about 12 years relative to normal aging, with early divergence in medial temporal and occipital regions. Our findings identify cortical thickness and area stretch as early and sensitive markers to distinguish between healthy and abnormal aging. Spatially, the supramarginal gyrus and entorhinal cortex should be considered as regions of early vulnerability. These results underscore the potential of physics-informed computational models to improve early detection of neurodegeneration and guide the development of region- and stage-specific diagnostic tools.},
}

@article {pmid41874868,
year = {2026},
author = {Ma, YN and Wang, Z and Liang, Y and Tan, G and Hu, X and Xia, Y},
title = {Olfactory Mucosa Mesenchymal Stem Cell-Derived Exosomes Enhance Microglia M2 Polarization via the FGFR1/PLCγ1 Axis to Alleviate Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41874868},
issn = {1559-1182},
mesh = {Animals ; *Receptor, Fibroblast Growth Factor, Type 1/metabolism ; *Mesenchymal Stem Cells/metabolism ; *Microglia/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; *Exosomes/metabolism ; *Phospholipase C gamma/metabolism ; *Olfactory Mucosa/metabolism ; Mice ; *Cell Polarity ; Amyloid beta-Peptides ; Mice, Inbred C57BL ; Signal Transduction ; Male ; },
abstract = {This study aims to investigate the effect of exosomes derived from olfactory mucosa mesenchymal stem cells (OM-MSCs-Exo) on microglial polarization and its potential therapeutic role in Alzheimer's disease (AD). OM-MSCs-Exo were isolated and purified from the mice olfactory mucosa, followed by phenotypic characterization. Proteins transferred by OM-MSCs-Exo were screened using proteomic analysis. The AD model was established in microglial cells and mice with Aβ1-42. Immunofluorescence and biochemical assays were employed to assess the impact of OM-MSCs-Exo and its secreted protein FGFR1 on microglial polarization. Protein-protein interactions and immunoprecipitation were used to identify the target proteins of FGFR1 in microglial cells. Additionally, the effects of OM-MSCs-Exo-induced microglial polarization on neuronal inflammation and cognitive function in mice were evaluated. OM-MSCs-Exo were successfully isolated and purified. FGFR1 was significantly upregulated in OM-MSCs-Exo compared to OM-MSCs. Aβ1-42 induced M1 polarization and suppressed M2 polarization of microglia, which was reversed by OM-MSCs-Exo. FGFR1 overexpression in OM-MSCs-Exo further enhanced M2 polarization in microglial cells. Phospholipase C gamma 1 (PLCγ1) was identified as the target of FGFR1, and knocking down PLCγ1 reversed the effects of FGFR1-overexpressing OM-MSCs-Exo. OM-MSCs-Exo alleviated cognitive decline and neuroinflammation in AD mice, with FGFR1 overexpression further enhancing these effects. OM-MSCs-Exo promote M2 polarization of microglia in AD mice through the FGFR1/PLCγ1 pathway, alleviating neuronal inflammation and cognitive dysfunction.},
}

Animals
*Receptor, Fibroblast Growth Factor, Type 1/metabolism
*Mesenchymal Stem Cells/metabolism
*Microglia/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
*Exosomes/metabolism
*Phospholipase C gamma/metabolism
*Olfactory Mucosa/metabolism
Mice
*Cell Polarity
Amyloid beta-Peptides
Mice, Inbred C57BL
Signal Transduction
Male

@article {pmid41875216,
year = {2026},
author = {Castillo-Moral, Á and Toda-Ferran, C and Bulló, M and Teichenné, J and Escoté, X},
title = {Nutraceuticals and the Microbiota-Gut-Brain Axis: A Pathway for Preventing Cognitive Decline.},
journal = {Nutrition reviews},
volume = {},
number = {},
pages = {},
doi = {10.1093/nutrit/nuag017},
pmid = {41875216},
issn = {1753-4887},
support = {//Vicente Lopez Program (Eurecat)/ ; //Autonomous Government of Catalonia/ ; 2021 SGR 00213//Departament de Recerca i Universitats de la Generalitat de Catalunya to the Nutrition and Metabolic Health Research Group/ ; 2021 SGR 01556//Precision Nutrition, Wellness and Prevention of Metabolic Diseases/ ; },
abstract = {With the global rise in aging populations, cognitive impairment and neurodegenerative diseases, such as Alzheimer's disease (AD), present a growing public health issue. Current pharmacological treatments primarily target symptoms rather than underlying causes, necessitating the exploration of alternative preventive strategies. Nutraceuticals have emerged as promising candidates for neuroprotection due to their ability to modulate oxidative stress, neuroinflammation, and mitochondrial function. This narrative review aimed to evaluate the neuroprotective potential of nutraceuticals and their interactions with the microbiota-gut-brain axis in preventing age-related cognitive decline. A comprehensive search of the scientific literature using the PubMed, Scopus, and Web of Science databases was undertaken, focusing on publications during the period 2010-2025. Nutraceuticals, including vitamins, omega-3 fatty acids, coenzyme Q10, polyphenols, and isothiocyanates, exhibit neuroprotective properties through antioxidant, anti-inflammatory, and mitochondrial-support mechanisms. The gut microbiota plays a crucial role in regulating the bioavailability and efficacy of these compounds. Microbiome-based interventions, such as prebiotics, probiotics, and fecal microbiota transplantation demonstrate potential in modulating neuroinflammatory responses and supporting cognitive function. Nutraceutical and microbiome-targeted interventions represent promising, low-risk strategies for preventing cognitive decline. Their ability to modulate neuroinflammation and oxidative stress underscores their potential for future clinical applications. Further large-scale studies are needed to validate their efficacy and explore personalized approaches adapted to individual microbiome profiles.},
}

@article {pmid41875305,
year = {2026},
author = {Betat, A and Santos, VD and Oliveira, CGA and Alflen, L and Ferreira, CF and Izídio, GS and Lataro, RM},
title = {Does hypercholesterolemia worsen cognitive decline in arterial hypertension? Insights from clinical and experimental studies.},
journal = {Journal of hypertension},
volume = {},
number = {},
pages = {},
doi = {10.1097/HJH.0000000000004277},
pmid = {41875305},
issn = {1473-5598},
abstract = {BACKGROUND: Arterial hypertension has been linked to cognitive decline, potentially through cerebrovascular alterations and associations with Alzheimer's disease. A positive correlation between elevated serum cholesterol levels and cognitive impairment has been observed. However, the impact of hypercholesterolemia on cognitive decline in both hypertensive rats and patients remains unclear. This study aimed to test the hypothesis that hypercholesterolemia exacerbates cognitive decline in hypertensive rats and human patients.

METHODS: Spontaneously hypertensive rats (SHR) with diet-induced hypercholesterolemia underwent behavioral testing to assess recognition, spatial, and working memory. In patients with stage 2 hypertension, cognitive function was assessed using the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) instruments.

RESULTS: In SHRs, hypercholesterolemia did not alter cognitive performance. Treatment of SHR with amlodipine or captopril decreased arterial pressure; however, this reduction did not improve cognition performance. The MMSE and MoCA, respectively, revealed cognitive impairment in 87.1 and 97.6% of the hypertensive patients. Nevertheless, no significant differences were found in the mean scores between hypertensive patients with and without hypercholesterolemia. No significant correlation was observed between cognitive scores and the use of antihypertensive or lipid-lowering agents.

CONCLUSION: These observations provide evidence that hypercholesterolemia does not exacerbate cognitive impairment in hypertension. Furthermore, our current findings support the hypothesis that antihypertensive treatment, in the absence of strict blood pressure control, may be insufficient to prevent hypertension-related cognitive decline.},
}

@article {pmid41875318,
year = {2026},
author = {Coca, A and Sánchez, R and Molina de Salazar, DI and Peñaherrera, E and Alcocer, L and Barbosa, E and Grassi, G and Lopez-Jaramillo, P and Lurbe, E and Parra-Carrillo, J and Ramirez, AJ and Redón, J and Sebba-Barroso, W and Acosta, A and Aristizábal, D and Bryce, A and Cerezo, G and Cohen, RV and Diaz-Velasco, ME and Hernández, R and Lanas, F and Machado, L and Musso, C and Piskorz, D and Ponte-Negreti, CI and Ramos, O and Sánchez, MJ and Valdez, O and Vicario, A and Villar, R and Parati, G and Whelton, PK and Wyss, F and Mancia, G},
title = {2026 Latin American consensus for the management of patients with hypertension and cardio-renal and metabolic disturbances: endorsed by the Latin American Society of Hypertension, the Iberoamerican Hypertension League, and the World Hypertension League.},
journal = {Journal of hypertension},
volume = {},
number = {},
pages = {},
doi = {10.1097/HJH.0000000000004290},
pmid = {41875318},
issn = {1473-5598},
abstract = {Hypertension is the main risk factor for cardiovascular disease (CVD), affecting 20-40% of Latin American (LATAM) adults, and responsible for more than two million deaths annually due to CVD. The different ethnic, economic, geographic, and cultural characteristics of the LATAM population influence the high prevalence of all cardiovascular risk factors (CVRF), particularly metabolic disturbances such as type 2 diabetes (DM2), obesity and the metabolic syndrome. Their main determinants in LATAM includes environment, food quality, social inequity, low education, political aspects, contextual behaviour, and genetics. The prevalence of overweight and obesity in LATAM increased during the last four decades reaching figures of 10-20% in childhood, 30-40% in adolescence, and 60-70% in adults. Many studies in the region have reported the extremely low rates of awareness, treatment, and control of CVRF in the general population of LATAM, particularly in patients with metabolic disorders, and the consequent high cardiovascular morbidity and mortality. This 2026 LATAM consensus is developed by a large group of experts from different LATAM countries, the USA and Europe, representing areas of internal medicine, cardiology, nephrology, endocrinology, geriatrics, paediatrics, pharmacology, and epidemiology. A careful search for novel studies in LATAM, together with new evidence that has emerged since the 2019 LATAM consensus, support the statements and recommendations in the current report. This update aims to provide clear and useful recommendations for health professionals to improve awareness, treatment, and control of hypertension and associated CVRF in the region.},
}

@article {pmid41875454,
year = {2026},
author = {Avendaño, EJ and Castillo, AP},
title = {[Relación entre la susceptibilidad a enfermedades neurodegenerativas y los factores genéticos en poblaciones expuestas al mercurio en Medellín, Colombia].},
journal = {Biomedica : revista del Instituto Nacional de Salud},
volume = {46},
number = {1},
pages = {30-47},
doi = {10.7705/biomedica.7634},
pmid = {41875454},
issn = {2590-7379},
mesh = {Humans ; Colombia/epidemiology ; *Mercury/toxicity ; *Genetic Predisposition to Disease ; *Neurodegenerative Diseases/genetics/epidemiology/chemically induced ; Polymorphism, Single Nucleotide ; Multidrug Resistance-Associated Protein 2 ; Adult ; Female ; Male ; Alzheimer Disease/genetics/epidemiology ; Parkinson Disease/genetics/epidemiology ; *Environmental Exposure/adverse effects ; Genotype ; Middle Aged ; },
abstract = {UNLABELLED: Introducción. Las enfermedades neurodegenerativas, por ejemplo la de Alzheimer y la de Parkinson, están asociadas con factores genéticos y ambientales como la exposición al mercurio, un metal pesado con efectos neurotóxicos.

OBJETIVOS: Identificar y analizar los alelos y genes vinculados a las enfermedades neurodegenerativas, en relación con la exposición al mercurio en Colombia. Materiales y métodos. Se recopiló información de la literatura científica y, también, genotipos poblacionales de bases de datos públicas, abarcando 94 adultos colombianos genotipificados bajo la referencia CLM (Colombians from Medellín). La trazabilidad de los datos se asegura mediante el registro ID en la base de datos del proyecto 1000 Genomas, garantizando el consentimiento informado y la aprobación bioética. Se analizaron 11 genes (GSTP1, ATP7B, BDNF, GCLC, GCLM, MT1A, MT4, ABCC2, ABCB1, GPX1 y GPX4) con 18 polimorfismos distribuidos en 10 cromosomas, utilizando el programa SNPstatsTM. Se aplicó la prueba de c² para evaluar el equilibrio de Hardy-Weinberg, considerando significativas las desviaciones con p < 0,05.

RESULTADOS: Los resultados demostraron una gran probabilidad de relación entre las enfermedades neurodegenerativas, como la de Alzheimer y la de Parkinson, y la exposición al mercurio en personas que tienen variantes génicas relacionadas con el metabolismo del glutatión o con las rutas metabólicas para el transporte y la excreción del mercurio.

CONCLUSIONES: La bioacumulación de mercurio, el paso de la barrera hematoencefálica, la inflamación del sistema nervioso central y el estrés oxidativo por especies reactivas de oxígeno y nitrógeno, repercuten en las alteraciones genéticas o su expresión y aumentan la posibilidad de desarrollar las enfermedades de Alzheimer y Parkinson.},
}

Humans
Colombia/epidemiology
*Mercury/toxicity
*Genetic Predisposition to Disease
*Neurodegenerative Diseases/genetics/epidemiology/chemically induced
Polymorphism, Single Nucleotide
Multidrug Resistance-Associated Protein 2
Adult
Female
Male
Alzheimer Disease/genetics/epidemiology
Parkinson Disease/genetics/epidemiology
*Environmental Exposure/adverse effects
Genotype
Middle Aged

@article {pmid41875506,
year = {2026},
author = {Kerslake, LD and Noonan, C and Davies, DS and Kim, D and Eshou, VA and Goldsbury, CS and Cullen, KM},
title = {Ferritin-positive microglial clusters associate with microvessels and markers of vascular injury in MCI and Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {163},
number = {},
pages = {46-62},
doi = {10.1016/j.neurobiolaging.2026.03.004},
pmid = {41875506},
issn = {1558-1497},
abstract = {Progressive cognitive decline in Alzheimer's disease is coupled with altered microglial function, and cerebrovascular pathologies. We investigated whether reactive microglia cell clusters and microvascular breakdown spatially overlap in human brain sections impacted by Alzheimer's neuropathology. Immunofluorescence analysis was performed on thick (100-150 μm) autopsy human brain sections of inferior temporal cortex, from controls, individuals with mild cognitive impairment, and Alzheimer's disease. Ferritin-positive microglia clusters and capillary integrity across neuropathological disease stages were assessed. Microglia displayed morphologies representative of reactivity, with ferritin-positive areal density and extent of microglial cell clustering highest in cases with mild cognitive impairment or mid-stage Braak pathology. Localisation of microglia clusters was primarily perivascular and overlapped neuritic plaques. These clusters were proximal to vascular abnormalities, including evidence of endothelial disruption (extravascular lectin-positive staining), capillary thinning, tortuosity, and string vessels. A significant decrease in capillary widths was observed in Alzheimer's disease cases. This data supports a model in which early microglia activation state changes, and their perivascular clustering in response to vascular injury is a precursor to local neuritic tau inclusion development. Progressive microvessel injury may promote neuroinflammation early in disease. These findings highlight the importance of microglial-vascular interactions in the early pathogenesis of AD and underscore the potential for immunovascular biomarkers and interventions targeting early-stage disease.},
}

@article {pmid41875607,
year = {2026},
author = {Negi, M and Amulya, E and Phatale, V and Kumar, R and Srivastava, S},
title = {Nose-to-brain delivery of berberine-loaded nanoemulsion: Amelioration of brain targeting, behavioral, pharmacokinetic, and biodistribution insights for Alzheimer's intervention.},
journal = {Biomaterials advances},
volume = {184},
number = {},
pages = {214835},
doi = {10.1016/j.bioadv.2026.214835},
pmid = {41875607},
issn = {2772-9508},
abstract = {Berberine (BER), a benzylisoquinoline alkaloid, has garnered attention for its multifaceted pharmacological properties, including pronounced antioxidant, anti-inflammatory, and neuroprotective effects. Despite its therapeutic potential in neurodegenerative disorders, including Parkinson's disease, cerebral ischemia, and epilepsy, its clinical translation in Alzheimer's disease (AD) is hindered by poor aqueous solubility, limited systemic bioavailability, and restricted blood-brain barrier (BBB) permeability. This study aimed to overcome these limitations by formulating a BER-loaded nanoemulsion (BER-NE) for intranasal (IN) delivery to achieve direct nose-to-brain (N2B) targeting. The optimized NE exhibited a droplet size of 138.5 ± 0.96 nm and a polydispersity index (PDI) of 0.203 ± 0.007, indicating a monodisperse system. The BER-NE demonstrated a drug content of 99.62 ± 1.02%, confirming efficient drug incorporation. In vitro studies on SH-SY5Y neuroblastoma cells demonstrated that BER-NE reduced reactive oxygen species (ROS) levels by 2.09-fold and restored mitochondrial membrane potential (MMP) with a 3.61-fold increase in red/green fluorescence intensity compared to SCOP-induced cells. Further, pharmacokinetic (PK) profiling revealed that IN BER-NE achieved a 3.2- and 3.6-fold increase in brain Cmax compared to BER-SUS IN and BER-NE IV, respectively. The IN BER-NE demonstrated a 1.7- and 1.9-fold increase in %DTE and %DTP compared to the IN SUS, which supports the efficient N2B delivery. Behavioral assessments demonstrated dose-dependent reversal of SCOP-induced cognitive, depressive, and motor impairments. Additionally, treatment with HD BER-NE and MD BER-NE via the IN route markedly reduced the nitrite accumulation by 4.3- and 3.5-fold compared to the SCOP group, indicating attenuation of nitrosative stress. Collectively, these findings underscore the potential of IN BER-NE as a targeted and non-invasive therapeutic strategy for the management of AD.},
}

@article {pmid41875759,
year = {2026},
author = {Algaidi, SA},
title = {Carbon monoxide and anti-amyloid-β combination therapy modulates miR-381 and molecular biomarkers in an aluminum chloride-induced rat model of Alzheimer's disease.},
journal = {Journal of neuroimmunology},
volume = {416},
number = {},
pages = {578912},
doi = {10.1016/j.jneuroim.2026.578912},
pmid = {41875759},
issn = {1872-8421},
abstract = {BACKGROUND: Alzheimer's disease (AD) involves intersecting amyloid, tau, oxidative stress, and apoptotic pathways.

OBJECTIVE: To determine whether combining controlled carbon monoxide (CO) exposure with anti-amyloid-β (Aβ) immunotherapy confers additive benefits on AD-relevant molecular and histological readouts in adult male Sprague-Dawley rats.

METHODS: Adult male Sprague-Dawley rats were assigned to one of five groups: Control, AD, CO, anti-Aβ, and a combination group (CO plus anti-Aβ), after induction of AD-like pathology with aluminum chloride (AlCl3). Outcomes included hippocampal Aβ, phosphorylated tau (p-tau), acetylcholinesterase (AChE), NRF2, and p53 (ELISA); hippocampal miR-381 expression (qRT-PCR); and hippocampal/cortical histology. Data were analyzed at the animal level using one-way ANOVA with post hoc tests.

RESULTS: CO and anti-Aβ monotherapies each reduced Aβ burden and tau phosphorylation versus the AD group. The combination produced the most significant shifts toward Control across Aβ, p-tau, AChE, NRF2, and p53, accompanied by significant upregulation of miR-381 and improved histopathology.

CONCLUSIONS: CO-mediated epigenetic/redox modulation and antibody-driven Aβ clearance act in complementary ways to mitigate AD-like pathology. These findings support epigenetic-immunologic combination strategies as a promising direction for preclinical AD therapy.},
}

@article {pmid41875826,
year = {2026},
author = {Chen, P and Wang, R and Zhou, T and Sun, Y and Kirchhoff, F and Miao, Z and Zhuang, C},
title = {Targeting STAT3 in Alzheimer's disease: Potential mechanisms and therapeutic implications.},
journal = {European journal of medicinal chemistry},
volume = {310},
number = {},
pages = {118785},
doi = {10.1016/j.ejmech.2026.118785},
pmid = {41875826},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide, with no disease-modifying treatments to halt or reverse progressive neurodegeneration. Chronic neuroinflammation is a core unresolved pathological driver of AD, and signal transducer and activator of transcription 3 (STAT3) has emerged as a critical yet controversial master mediator of the associated neuroinflammatory and neurodegenerative processes. This review systematically explores the multifaceted, cell-type-specific relationship between STAT3 signaling and AD pathology, focusing on its roles in neuroinflammation, amyloid precursor protein processing, tau phosphorylation, neuronal survival, and synaptic function. We further critically evaluate therapeutic strategies targeting STAT3 pathways in AD, underscoring the immediate relevance of STAT3 as both a promising biomarker and a tractable target for translational drug development.},
}

@article {pmid41875888,
year = {2026},
author = {Shrestha, HK and Sun, H and Yarbro, JM and Lee, D and Liu, D and Wang, E and McReynolds, M and Zhang, N and Xie, B and Yang, S and Yu, K and Poudel, S and Li, Y and Yuan, ZF and Kong, D and Wang, M and Wang, Z and Niu, M and Wang, H and Zaman, M and Wang, J and Vanderwall, DR and Sun, Y and Wu, Z and Chen, PC and Bai, B and High, AA and Faura, J and Liu, C and Bennett, DA and Johnson, ECB and Seyfried, NT and Levey, AI and Haroutunian, V and Serrano, GE and Beach, TG and DeTure, M and Kanekiyo, T and Petersen, RC and Bu, G and McLean, PJ and Dickson, DW and Rademakers, R and Yu, G and Wang, X and Zhang, B and Peng, J},
title = {Pan-neurodegeneration proteomics reveals disease subtypes and molecular signatures.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.02.026},
pmid = {41875888},
issn = {1097-4172},
abstract = {Neurodegenerative diseases (NDs) pose clinical challenges due to their complexity and molecular heterogeneity. Here, we present a pan-neurodegeneration atlas (PanNDA) from multilayer, deep proteomic analysis of 2,279 human brain samples spanning 6 major NDs: Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal lobar degeneration with TDP-43 pathology, progressive supranuclear palsy with tau pathology, vascular dementia, and Parkinson's disease. PanNDA integrates data from whole proteome, detergent-insoluble proteome, and posttranslational modifications (phosphorylation and ubiquitination), enabling intra- and inter-disease comparisons. Intra-disease analyses uncover distinct molecular subtypes (e.g., three in AD and four in LBD), reveal dysregulated pathways, and prioritize top-ranked proteins. Inter-disease comparisons identify shared alterations in NDs, such as GPNMB in microglial and lysosomal activation and NPTX2 in synaptic regulation, alongside disease-specific changes and hub regulators within protein networks. Overall, PanNDA provides a systems-level framework for understanding ND mechanisms and serves as a foundational resource that is accessible via an interactive website: https://penglab.shinyapps.io/pannda.},
}

@article {pmid41876030,
year = {2026},
author = {Suswidiantoro, V and Tang, KS and Rahman, K and Puteri, MU and Wahyuni, T and Ariestanti, DM and James, RJ and Yan, CC and Kato, M and Saputri, FC},
title = {Metabolic Drivers of Alzheimer's Disease: Integrating brain Hypometabolism, insulin Resistance, and systemic dysregulation.},
journal = {Frontiers in neuroendocrinology},
volume = {},
number = {},
pages = {101248},
doi = {10.1016/j.yfrne.2026.101248},
pmid = {41876030},
issn = {1095-6808},
abstract = {The repeated failure of amyloid therapies highlights a core misunderstanding of Alzheimer's disease (AD) origins. A new metabolic paradigm now positions impaired brain metabolism-not protein accumulation-as the central, early driver. Key evidence shows cerebral glucose hypometabolism emerges decades before symptoms, linked to brain insulin resistance ("type 3 diabetes") and mitochondrial dysfunction. The APOE ε4 allele worsens lipid defects thereby, accelerating the progression of AD pathology. These disruptions-alongside gut-brain axis issues-create a self-reinforcing cycle that fuels amyloid β (Aβ), tau, neuroinflammation, and synaptic loss. This framework integrates with the neuron-centric model, explaining disease heterogeneity and the inadequacy of single-target drugs. This review particularly highlights the metabolic perspective in AD, underscoring the need for a radical therapeutic shift: from late stage protein clearance strategies to early, multimodal interventions that restore metabolic homeostasis and disrupt the entire pathogenic continuum.},
}

@article {pmid41876051,
year = {2026},
author = {Chu, AJ and Erlandsson, A and Williams, JM},
title = {Amyloid precursor protein derivatives differentially alter the microRNA cargo of astrocyte-derived extracellular vesicles.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.03.036},
pmid = {41876051},
issn = {1873-7544},
abstract = {Alterations to the protein and microRNA cargo of extracellular vesicles (EVs) occur in Alzheimer's disease (AD) and may contribute to disease progression. We previously showed that ingestion of amyloid-beta (Aβ) by both murine and human astrocytes leads to alterations to the protein cargo of EVs that induce significant neuronal impairment and apoptosis. Here, we hypothesised that pathological changes to the microRNA cargo of astrocyte-derived EVs (ADEVs) would also occur following exposure of astrocytes to Aβ, whereas treatment of astrocytes with the neuroprotective protein secreted amyloid precursor protein-alpha (sAPPα) would induce neuroprotective changes in microRNA expression in ADEVs. Primary murine astrocytes were treated with vehicle, 0.1 μM Aβ protofibrils (AβPF), 1 nM sAPPα, or 1 nM sAPPα in conjunction with 0.1 μM AβPF (sAPPα + AβPF). Differentially expressed microRNA in ADEVs were detected by RT-qPCR using highly sensitive TaqMan Advanced microRNA arrays representing 168 neurodegeneration-associated microRNA. ADEVs from AβPF-exposed astrocytes contained significantly higher amounts of let-7c-5p, miR-29a-3p and miR-34a-5p, while miR-99b-5p and miR-181d-5p were significantly increased in ADEVs from sAPPα- and sAPPα + AβPF-treated astrocytes, respectively. Bioinformatic analysis revealed that gene targets of microRNA upregulated in ADEVs following astrocytic exposure to either AβPF or sAPPα + AβPF were enriched in numerous pathways with known links to AD pathology, with gene targets of the sAPPα + AβPF group also enriched in immune system-related pathways. In contrast, gene targets of miR-99b-5p are known to directly target pathways that are involved in AD, suggesting that ADEVs secreted by sAPPα-treated astrocytes have neuroprotective potential.},
}

@article {pmid41876052,
year = {2026},
author = {Harutyunyan, H and Minasyan, R and Kalueff, AV and Yenkoyan, KB},
title = {Neurobiological links between Alzheimer's disease and reward system dysfunction.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.03.028},
pmid = {41876052},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a highly prevalent progressive neurodegenerative disorder with unclear etiology, complex symptoms, and limited treatment options. Early pathological processes in AD emerge long before the onset of overt cognitive and motor symptoms and involve the accumulation of amyloid-β oligomers and neurofibrillary tangles, accompanied by neuroinflammation and neuronal loss. Importantly, the brain reward system comprises cortical and subcortical structures that share neurochemical pathways and reciprocal connectivity with regions affected during AD progression. Consistent with this overlap, reward-related behavioral deficits, including apathy, anhedonia, and motivational impairments, are frequently observed in both patients with AD and experimental models of the disease. Here, we discuss the neuroanatomical, neurochemical, and molecular overlap between AD pathology and reward-related neural circuits and propose that dysfunction of the reward system may represent an important pathogenetic endophenotype of AD. A better understanding of these multilevel interactions may help refine the conceptual framework of AD and support the development of novel therapeutic strategies targeting reward-related circuits and their underlying molecular mechanisms.},
}

@article {pmid41866337,
year = {2026},
author = {Lindbohm, JV and Stražar, M and Lee, HM and Ashenberg, O and Mars, N and Sipilä, PN and Ripatti, S and Graham, D and Kivimäki, M and Xavier, RJ},
title = {Population and single-cell analyses reveal immune cell-specific expression profiles associated with Alzheimer's disease risk.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71282},
doi = {10.1002/alz.71282},
pmid = {41866337},
issn = {1552-5279},
support = {339568//Research Council of Finland/ ; 350426//Research Council of Finland/ ; 331671//Research Council of Finland/ ; 355567//Research Council of Finland/ ; //Päivikki and Sakari Sohlberg foundation/ ; 221854/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; R01AG056477/AG/NIA NIH HHS/United States ; MR/R024227/1/MRC_/Medical Research Council/United Kingdom ; MR/Y014154/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Alzheimer Disease/genetics/immunology ; Genome-Wide Association Study ; Single-Cell Analysis ; Brain/immunology/metabolism ; Mendelian Randomization Analysis ; Transcriptome ; Genetic Predisposition to Disease ; Quantitative Trait Loci ; },
abstract = {INTRODUCTION: Dysregulation of the peripheral immune system may increase Alzheimer's disease (AD) risk, but the underlying cell type-specific mechanisms remain unclear.

METHODS: We conducted Mendelian randomization and colocalization analyses of 4489 genes using single-cell expression quantitative trait locus data from unstimulated and stimulated peripheral immune cells, integrated with an AD genome-wide association study (N = 455,258). Spatial transcriptomics of brain tissue samples was used to identify brain-infiltrating immune cells.

RESULTS: Thirteen genes were associated with AD risk. Expression of BIN1, CTSW, CTSH, HLA-DRB1, TSTD1, PLEKHA1, and SCIMP increased AD risk, while EPHA1-AS1, FCER1G, FIBP, KAT8, STX4, and HLA-DQA1 reduced it. These associations were peripheral immune cell type and state specific. PLEKHA1 and TSTD1 were upregulated and FIBP downregulated in natural killer and T cells in AD brain tissue.

DISCUSSION: These findings link immune cell-specific gene expression to AD risk across activation states and within brain-infiltrating immune cells, highlighting potential targets for immune-based AD prevention and treatment.},
}

Humans
*Alzheimer Disease/genetics/immunology
Genome-Wide Association Study
Single-Cell Analysis
Brain/immunology/metabolism
Mendelian Randomization Analysis
Transcriptome
Genetic Predisposition to Disease
Quantitative Trait Loci

@article {pmid41866365,
year = {2026},
author = {Guo, G and Song, W and Wang, A and Cui, Q and Yang, X and Wang, Y and Ma, Y and Han, H and Li, Z and Zhang, Z and Meng, W and Wang, S and Shi, F},
title = {Sensitivity comparison of longitudinal cognitive function indicators of Alzheimer's disease after mild cognitive impairment: a prospective cohort study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-44192-2},
pmid = {41866365},
issn = {2045-2322},
support = {81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 81872719//National Natural Science Foundation of China/ ; 81803337//National Natural Science Foundation of China/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; 2019-6-156, Lu-Jiao//Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; ZR2023MH313//Shandong Provincial Natural Science Foundation/ ; },
abstract = {Accurate prediction of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is critical for early intervention. Many existing models lack the ability to capture the nonlinear nature of cognitive decline and individual heterogeneity. This study employed a semi‑parametric joint model to analyze longitudinal cognitive trajectories and identify robust predictors of conversion. Data from 596 participants (184 AD converters, 412 stable MCI) were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Longitudinal assessments included ADAS‑Cog13, ADAS‑Cog11, CDR‑SB, FAQ, RAVLT‑IR, RAVLT‑L, and MMSE. A semi‑parametric joint model combining B‑splines for the longitudinal process with a Cox survival submodel was fitted for each cognitive measure. Model performance was evaluated using AIC, BIC, intraclass correlation coefficient (ICC), time‑dependent C‑index, dynamic AUC, and calibration curves. Subgroup analyses were conducted by APOE‑ε4 carrier status. In multivariable joint models, APOE‑ε4 carriage was a consistent risk factor (HR range: 1.38-1.77). Higher scores on ADAS‑Cog13 (HR = 3.71 per SD), ADAS‑Cog11 (HR = 2.71), CDR‑SB (HR = 3.79), and FAQ (HR = 2.85) increased the hazard of conversion, whereas higher scores on RAVLT‑IR (HR = 0.23), RAVLT‑L (HR = 0.14), and MMSE (HR = 0.53) were protective. All models showed high ICCs (0.94-0.98) and moderate‑to‑good predictive accuracy over 2, 5, and 8 year horizons (C‑index: 0.585-0.668). CDR‑SB and FAQ exhibited the strongest effect sizes and clearest dose‑dependent trajectories across APOE‑ε4 subgroups. Calibration curves demonstrated good agreement between predicted and observed survival. The semi‑parametric joint model effectively captures nonlinear cognitive‑functional decline and provides validated predictions of AD risk. APOE‑ε4 genotype combined with longitudinal monitoring of CDR‑SB and FAQ offers a robust framework for stratifying progression risk in clinical MCI management.},
}

@article {pmid41866449,
year = {2026},
author = {Wang, Z and He, F and Li, L and Wang, W and Zhang, L and Tang, J and Le, W},
title = {Sleep Disorders in Neurodegenerative Diseases: Pathological Correlations and Underlying Mechanisms.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41866449},
issn = {1995-8218},
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and others, represent an escalating public health burden in aging populations. NDDs are characterized by progressive neuronal loss and misfolded protein aggregation. Despite distinct clinical heterogeneity, these diseases universally present with debilitating non-motor symptoms, among which sleep-wake disorders are highly prevalent. Once considered secondary to neuronal damage, growing evidence now highlights a bidirectional interplay: sleep disruption is not only a consequence of neurodegeneration but also exacerbates its progression. This review synthesizes this complex interplay, outlining sleep phenotypes across major NDDs, dissecting key underlying mechanisms (impaired protein homeostasis, glymphatic dysfunction, chronic neuroinflammation, sleep-regulatory nucleus vulnerability, and circadian dysregulation), and summarizing current pharmacotherapeutic and non-pharmacological interventions. Attenuating sleep disorders may therefore provide symptomatic relief and disease‑modifying effects for NDDs.},
}

@article {pmid41866584,
year = {2026},
author = {Zhou, J and Zhang, X and Yin, S and Xue, S and He, Q and Chen, S and Xue, X},
title = {Molecular mechanisms of exercise-induced improvements in Alzheimer's disease: a focus on lipid homeostasis.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {41866584},
issn = {2047-9158},
support = {ZR2025QC303//Natural Science Foundation of Shandong Province/ ; 23TYJ03//Shandong Province Social Science Planning Research Project/ ; },
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *Lipid Metabolism/physiology ; *Exercise/physiology ; *Homeostasis/physiology ; Animals ; *Exercise Therapy/methods ; },
abstract = {Alzheimer's disease (AD) is the most prevalent type of dementia, and its pathophysiological mechanisms involve multiple factors, including genomic factors, metabolomic factors, and environmental factors. Lipid dysregulation occurs both centrally and peripherally in patients with AD, and the severity is closely associated with disease progression. Applied studies based on genome-wide association studies, genomic analyses, lipidomic analyses, mass spectrometry, and machine learning, have identified lipids as a key potential target for early diagnosis and intervention in AD. However, due to the complexity of AD pathogenesis and the considerable structural and functional diversities of lipids, pharmacological therapies that target lipid homeostasis have shown limited effectiveness in ameliorating AD pathology and are often accompanied by side effects. In contrast, exercise, a holistic intervention with multitarget effects, can modulate the levels of multiple lipids simultaneously and slow the progression of AD with minimal side effects. However, the mechanisms require further clarification. This review summarizes alterations and mechanisms of action of lipids-including fatty acids, triglycerides, glycerophospholipids, sphingolipids, and cholesterol-in AD and further outlines the possible molecular mechanisms through which exercise influences AD through modulation of lipid metabolism. We also review the recent clinical research on lipid-targeting drugs for AD, and propose a hypothesis that lipids may act as a mediator of the peripheral-central crosstalk between exercise and AD. Additionally, how different apolipoprotein E genotypes may affect the response to exercise in AD is explored. These insights provide a theoretical basis for nonpharmacological interventions for AD and offer an important reference for the development of lipid-related therapeutic targets.},
}

*Alzheimer Disease/metabolism/therapy
Humans
*Lipid Metabolism/physiology
*Exercise/physiology
*Homeostasis/physiology
Animals
*Exercise Therapy/methods

@article {pmid41866640,
year = {2026},
author = {Corrada, BR and Speth, RC},
title = {Is Alzheimer's an Autoimmune Disease?.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41866640},
issn = {1559-1182},
support = {1R15AG091199-01/GF/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/immunology/pathology/therapy ; Humans ; *Autoimmune Diseases/immunology/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease is defined as a progressive neurodegenerative disorder characterized by a gradual decline in cognitive and functional abilities [1]. Although debate continues with respect to its exact pathology, several hypotheses have been proposed to explain its underlying mechanisms. The two primary pathological factors of Alzheimer's disease are the accumulation of amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau and neurofilament protein [1, 2]. It should be noted that our use of the descriptor hyperphosphorylated tau is done to conform with current nomenclature; it should not be construed as indicating saturation of all the amino acids capable of being phosphorylated. Emerging clinical evidence proposes that some variants of Alzheimer's disease may be caused by an autoimmune process rather than a purely neurodegenerative one. The purpose of this paper is to review and evaluate evidence supporting and challenging the autoimmune hypothesis of Alzheimer's disease, as well as to explore its implications for future therapeutic strategies within the framework of the disease.},
}

*Alzheimer Disease/immunology/pathology/therapy
Humans
*Autoimmune Diseases/immunology/pathology
Animals
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid41866791,
year = {2026},
author = {Verma, K and Kumar, S},
title = {From autopsy to PET to cerebrospinal fluid to blood: Quantifying reference-standard dependence in Alzheimer's disease amyloid biomarker validation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430858},
doi = {10.1177/13872877261430858},
pmid = {41866791},
issn = {1875-8908},
abstract = {BackgroundBlood-based biomarkers are increasingly used as scalable front-line tools for Alzheimer's disease amyloid evaluation, but most are validated against amyloid positron emission tomography (PET) and/or cerebrospinal fluid (CSF) rather than neuropathology. In a chained validation cascade (neuropathology→PET→CSF→blood), reported performance may depend strongly on the comparator and on how "gray-zone" (indeterminate) results are handled.ObjectiveTo quantify benchmark dependence and gray-zone policy sensitivity in amyloid biomarker validation and characterize plasma-to-neuropathology performance inference from imperfect proxies.MethodsWe assembled a fully auditable evidence core spanning the amyloid cascade with reconstructable 2 × 2 tables. We recomputed positive percent agreement (PPA) and negative percent agreement (NPA) with 95% Wilson confidence intervals under a prespecified primary policy (exclude indeterminates) and two sensitivity policies (indeterminate→negative; indeterminate→positive). Reference-swap drift across benchmarks was summarized with Monte Carlo uncertainty intervals. For plasma-to-neuropathology inference, we combined plasma-PET agreement with tracer-specific PET-autopsy anchors and reported (i) chained-proxy point implications under conditional independence and (ii) partial-identification bounds without conditional independence across prevalence scenarios (π = 10-50%).ResultsUnder the primary policy, Lumipulse plasma pTau217/Aβ42 showed similar agreement across PET, CSF, and composite comparators (PPA 0.97-0.98; NPA ≈0.91), with drift intervals spanning zero. Indeterminates were frequent (∼19-20%) and dominated apparent shifts: indeterminate→negative reduced PPA by 0.13-0.21, whereas indeterminate→positive reduced NPA by 0.17-0.21. Chained-proxy implications for plasma versus neuropathology varied by PET tracer anchor (sensitivity 0.86-0.96; specificity 0.81-0.91), while bounds were wider (sensitivity 0.83-1.00; specificity 0.81-0.98).ConclusionsGray-zone policy is a first-order driver of reported blood-test performance, and proxy-to-proxy agreement does not uniquely identify plasma-to-neuropathology accuracy without explicit assumptions.},
}