@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.},
}

@article {pmid41866837,
year = {2026},
author = {},
title = {Corrigendum to "Neuropsychiatric signs and symptoms clusters and regional amyloid on [18]F-FC119S PET in Alzheimer's disease".},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261423686},
doi = {10.1177/13872877261423686},
pmid = {41866837},
issn = {1875-8908},
}

@article {pmid41867027,
year = {2026},
author = {Weigand, AJ and Tsoy, E and Atkins, KJ and Jarrott, S and Farias, ST and Scheffler, AW and Brailow, T and Rankin, KP and Kramer, JH and Possin, KL},
title = {Classifying cognitive status with TabCAT Match and UDS executive function tests.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71299},
doi = {10.1002/alz.71299},
pmid = {41867027},
issn = {1552-5279},
support = {P30 AG062422/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; R35 AG072362/AG/NIA NIH HHS/United States ; U01 NS128913/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Executive Function/physiology ; Male ; *Neuropsychological Tests ; Female ; Aged ; *Cognitive Dysfunction/diagnosis/classification ; Aged, 80 and over ; ROC Curve ; Alzheimer Disease/diagnosis ; },
abstract = {INTRODUCTION: Tablet-based Cognitive Assessment Tool (TabCAT) Match, a digital neuropsychological test, was compared to measures of executive function from the National Alzheimer's Coordinating Center's Uniform Dataset (UDS).

METHODS: TabCAT Match data were available for 1792 clinically diverse older adults. Receiver operating characteristic curves and analyses of covariance examined classification of Clinical Dementia Rating Scale (CDR) stages based on Match and UDS executive function scores. Sensitivity analyses were conducted across education level and testing language groups.

RESULTS: All measures had utility in differentiating CDR stages, with Match displaying the highest classification accuracy (AUC = 0.862) for cognitively unimpaired (CDR 0, clinically normal) versus cognitively impaired (CDR ≥ 0.5, mild cognitive impairment/dementia). The advantages of Match were especially apparent in non-English tested groups relative to UDS tests.

DISCUSSION: The identification of efficient neuropsychological measures, such as TabCAT Match, that are easily administered, sensitive to impairment, and appropriate across demographic groups is critical for optimizing diagnosis and clinical monitoring.},
}

Humans
*Executive Function/physiology
Male
*Neuropsychological Tests
Female
Aged
*Cognitive Dysfunction/diagnosis/classification
Aged, 80 and over
ROC Curve
Alzheimer Disease/diagnosis

@article {pmid41867029,
year = {2026},
author = {Chatila, ZK and Duggan, MR and Silberberg, E and Fernandez, J and Auber, LA and Bradshaw, EM and Schultek, NM},
title = {Can we refute a role for infections in Alzheimer's disease pathogenesis?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71288},
doi = {10.1002/alz.71288},
pmid = {41867029},
issn = {1552-5279},
support = {R01AG076018-05//US National Institutes of Health, National Institute on Aging/ ; F30AG074618//US National Institutes of Health, National Institute on Aging/ ; R01AG067581-05//US National Institutes of Health, National Institute on Aging/ ; },
mesh = {*Alzheimer Disease/microbiology/genetics/immunology/etiology ; Humans ; Gene-Environment Interaction ; *Infections/complications ; },
abstract = {While a growing body of literature suggests a role for infections in Alzheimer's disease (AD), microbial contributions to AD remains a contentious topic, in part due to challenges in reconciling the positive evidence with studies reporting null findings. Here, we examine the evidence that argues against a role for infections in AD, while offering mechanistic hypotheses that may account for both the negative and positive findings, including dysregulated host immunity and gene-environment interactions of AD-associated genes.},
}

*Alzheimer Disease/microbiology/genetics/immunology/etiology
Humans
Gene-Environment Interaction
*Infections/complications

@article {pmid41867189,
year = {2026},
author = {Solis-Urra, P and Olvera-Rojas, M and García-Rivero, Y and Zeng, X and Chen, Y and Sehrawat, A and Shekari, M and Oberlin, LE and Erickson, KI and Karikari, TK and Gómez-Río, M and Ortega, FB and Esteban-Cornejo, I},
title = {Effects of a 24-week resistance exercise program on brain amyloid and Alzheimer's disease blood-based biomarkers: the AGUEDA randomized controlled trial.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.02.26347392},
pmid = {41867189},
abstract = {We examined whether a 24-week resistance training program influenced brain amyloid-β (Aβ) and Alzheimer's Disease (AD)-related blood-based biomarkers. Ninety cognitively normal, physically inactive older adults aged 65-80 years were randomly allocated to a 24-week resistance training program (three ∼60-min supervised sessions/week) or a wait-list control group. Primary analyses assessed exercise-induced changes in brain Aβ (Centiloid values) and plasma ptau217/Aβ1-42 IPMS ratio. Secondary analyses examined ptau217/Aβ42 SIMOA ratio, ptau217, ptau181 and Aβ42/40, as well as potential interactions with sex, age, education, apolipoprotein ε4 (APOE4) status, amyloid PET-positivity, and comorbidities. The intervention produced no significant differences on brain Aβ or AD-related blood-based biomarkers (p>0.05) compared to the control group. However, the ptau217/Aβ1-42 IPMS ratio showed a small, non-significant increase in the control group (SMD = 0.162; 95% CI: -0.159 to 0.483) while remaining stable in the exercise group (SMD = 0.01; 95% CI: -0.291 to 0.310) with a similar trend for ptau217/Aβ42 SIMOA. Moderator analyses indicated differential responses by amyloid PET-positivity and APOE4 status on brain Aβ (p for interaction<0.05), with increases observed in APOE4 carriers and amyloid PET-positive individuals in the control group, whereas those allocated to the exercise intervention reduced their levels. The specificity observed within our subgroups suggests that resistance exercise may serve as a targeted intervention to modulate AD pathophysiology, raising new questions regarding its broader role in the delay of the disease in vulnerable populations.},
}

@article {pmid41867210,
year = {2026},
author = {Choi, JJ and Engelman, CD and Lu, T},
title = {Multi-Omics Integration of Transcriptomics and Metabolomics with Machine Learning Uncovers Novel Risk Factors for Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.28.26347204},
pmid = {41867210},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, memory impairment, and functional deterioration. Its complex pathogenesis involves factors such as amyloid plaques, tau tangles, neuroinflammation, and synaptic dysfunction, but the precise mechanisms remain unclear, hindering effective treatment. Genetic, environmental, and lifestyle factors contribute to AD risk, yet their interactions are poorly understood. Recent advances in transcriptomics and metabolomics have shed light on the molecular underpinnings of AD, with gene expression alterations and metabolic disruptions implicated in disease progression. These multi-omics disruptions highlight the need for integrative analytical approaches to better characterize AD-relevant biology and advance biomarker discovery.

OBJECTIVES: To integrate genetically imputed whole blood transcriptomics and plasma metabolomics to predict cognitive performance (PACC3) and to identify risk genes and metabolites contributing to prediction, thereby characterizing molecular signatures associated with cognitive performance in AD.

METHODS: This study applies a machine learning algorithm to integrate genetically imputed whole blood transcriptomics and measured plasma metabolomics data to predict cognitive performance, as measured by PACC3 score, using data from the Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (N = 1,046). After training a machine learning model on WRAP, the predictive performance was evaluated using an independent dataset from the Wisconsin Alzheimer's Disease Research Center (ADRC) cohort (N = 85). Feature importance was assessed to identify genes and metabolites that may play a role as potential risk factors in AD.

RESULTS: The machine learning model achieved a normalized root mean squared error (NRMSE) of 0.743 ± 0.037 and an R² of 0.311 ± 0.016 across 5-fold holdout test folds in WRAP (p = 5.93 × 10 [-30]), and an NRMSE of 0.915 and an R² of 0.061 when applied to the Wisconsin ADRC cohort. Feature importance revealed transcriptomic biomarkers such as RIPK1 , IL6ST , and BIN1 whose higher imputed expression levels were associated with poorer cognitive performance whereas other potential biomarkers including UGP2 , NDUFB5 , and TMOD2 were associated with better cognitive performance, reflecting mitochondrial energy metabolism and molecular processes associated with cognitive resilience. Several predictive metabolites including benzoate, 3-phenylpropionate, and imidazolelactate also mapped to AD vulnerability signatures, while acyl-carnitine species such as hexanoylcarnitine (C6) and propionate-related metabolites aligned with metabolic resilience.

CONCLUSION: Integrated analysis of transcriptomics and metabolomics demonstrated potential utility for identifying candidate biomarkers associated with cognition in AD. Genes and metabolites reflecting inflammatory signaling, mitochondrial dysregulation, and lipid metabolism emerged consistently among the most influential contributors. These findings align with well-established AD vulnerability pathways and highlight convergent biology across two omics layers. Collectively, this supports the value of multi-omics integration for improving molecular characterization of AD and advancing biomarker prioritization for future mechanistic and translational studies.},
}

@article {pmid41867219,
year = {2026},
author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Showalter, J and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Streamlining Eligibility Assessment for Alzheimer's Disease-Modifying Therapies: Prediction of MMSE Scores Using the Digital Clock and Recall.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.03.26347542},
pmid = {41867219},
abstract = {INTRODUCTION: The eligibility of anti-amyloid disease-modifying therapies (DMTs) and their integration into clinical practice in some institutions requires a specific range of Mini-Mental State Examination (MMSE) scores. Reliance on this pencil-and-paper psychometric instrument imposes operational burdens and risks perpetuating health disparities due to the test's known educational and cultural biases. This study evaluates the efficacy of the Digital Clock and Recall (DCR™) - a rapid, FDA-listed digital cognitive assessment - to crosswalk to MMSE scores using machine learning, thereby offering a faster, scalable, and equitable mechanism for patient triage.

METHODS: We conducted a retrospective analysis using data from the multi-site Bio-Hermes-001 study (NCT04733989 , N=945). Participants were clinically classified as cognitively unimpaired, mild cognitive Impairment, or probable Alzheimer's dementia. We trained a Poisson elastic net regression model using age and multimodal digital features derived from the DCR (including drawing kinematics and voice acoustics) to predict MMSE scores. The model was tested for generalizability using an independent external validation cohort from the Apheleia study (NCT05364307 , N=238).

RESULTS: The machine learning model predicted MMSE scores with a root mean squared error (RMSE) of 2.31 in the training cohort. This error margin falls within the established test-retest reliability range of the manual MMSE itself (2-4 points), suggesting the prediction is statistically non-inferior to human administration. External validation in the Apheleia cohort demonstrated robust generalizability (RMSE = 2.62). Crucially, the model exhibited demographic fairness, maintaining consistent accuracy across Race (White RMSE = 2.34; Non-White RMSE = 2.14) and Ethnicity (Hispanic RMSE = 2.26; Non-Hispanic RMSE = 2.31).

DISCUSSION: Machine learning can leverage multimodal features from the DCR to accurately and equitably crosswalk to MMSE scores in support of current guidelines, transforming a time-intensive manual test into a rapid, automated assessment. By deploying this "digital triage" engine, where traditional assessments are still used for DMT eligibility, healthcare systems can streamline the identification of DMT-eligible patients, reduce specialist referral bottlenecks, and ensure that access to life-altering therapies is determined by pathology rather than demography.},
}

@article {pmid41867223,
year = {2026},
author = {Le Guen, Y and Peña-Tauber, A and Catoia Pulgrossi, R and Park, J and Orias, H and Greicius, MD},
title = {Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer's disease and Parkinson's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.03.26347540},
pmid = {41867223},
abstract = {Alzheimer's disease and related dementias (ADRD) [1] and Parkinson's disease and related disorders (PDRD) [2] have substantial genetic contributions, yet the role of rare damaging coding variants remains incompletely characterized at population scale [3-6] . We performed gene-based burden testing of rare loss-of-function and deleterious missense variants using whole-genome sequencing data from large population biobanks combined with disease-specific sequencing cohorts, leveraging proxy phenotypes to maximize statistical power for late-onset neurodegenerative diseases [7] . We confirmed rare variant burden in established ADRD genes (ABCA7, PSEN1, ADAM10, ATP8B4, GRN, SORL1, TREM2, SHARPIN) and PDRD genes (GBA1, LRRK2). We additionally identified novel associations in ADRD (IMPA2, PMM2, SYNE1, CHRNA4, FCGR1A) and PDRD (ANKRD27, CCL7, USP19, SKP1, KANSL3). The strongest signal was observed for ANKRD27 , where damaging variants clustered within domains mediating interactions with Rab GTPases and retromer components. Our results demonstrate the power of population-scale sequencing combined with proxy phenotypes to identify rare coding risk genes for neurodegenerative diseases.},
}

@article {pmid41867349,
year = {2026},
author = {Deng, Y and Zeng, D and Wang, Y},
title = {SEMIPARAMETRIC ANALYSIS OF INTERVAL-CENSORED DATA SUBJECT TO INACCURATE DIAGNOSES WITH A TERMINAL EVENT.},
journal = {The annals of applied statistics},
volume = {20},
number = {1},
pages = {623-640},
pmid = {41867349},
issn = {1932-6157},
abstract = {Interval-censoring frequently occurs in studies of chronic diseases where disease status is inferred from intermittently collected biomarkers. Although many methods have been developed to analyze such data, they typically assume perfect disease diagnosis, which often does not hold in practice due to the inherent imperfect clinical diagnosis of cognitive functions or measurement errors of biomarkers such as cerebrospinal fluid. In this work, we introduce a semiparametric modeling framework using the Cox proportional hazards model to address interval-censored data in the presence of inaccurate disease diagnosis. Our model incorporates sensitivity and specificity of the diagnosis to account for uncertainty in whether the interval truly contains the disease onset. Furthermore, the framework accommodates scenarios involving a terminal event and when diagnosis is accurate, such as through postmortem analysis. We propose a nonparametric maximum likelihood estimation method for inference and develop an efficient EM algorithm to ensure computational feasibility. The regression coefficient estimators are shown to be asymptotically normal, achieving semiparametric efficiency bounds. We further validate our approach through extensive simulation studies and an application assessing Alzheimer's disease (AD) risk. We find that amyloid-beta is significantly associated with AD, but Tau is predictive of both AD and mortality.},
}

@article {pmid41867350,
year = {2026},
author = {Cai, Z and Zeng, D and Marder, KS and Honig, LS and Wang, Y},
title = {DYNAMIC CLASSIFICATION OF LATENT DISEASE PROGRESSION WITH AUXILIARY SURROGATE LABELS.},
journal = {The annals of applied statistics},
volume = {20},
number = {1},
pages = {641-662},
pmid = {41867350},
issn = {1932-6157},
abstract = {Disease progression prediction based on patients' evolving health information is challenging when true disease states are unknown due to diagnostic capabilities or high costs. For example, the absence of gold-standard neurological diagnoses hinders distinguishing Alzheimer's disease (AD) from related conditions such as AD-related dementias (ADRDs), including Lewy body dementia (LBD). Combining temporally dependent surrogate labels and health markers may improve disease prediction. However, existing literature models informative surrogate labels and observed variables that reflect the underlying states using purely generative approaches, often posing unrealistic assumptions on the outcomes and suffering from misspecification thereof. We propose integrating the conventional hidden Markov model as a generative model with a time-varying discriminative classification model to simultaneously handle potentially misspecified surrogate labels and incorporate important markers of disease progression. We develop an adaptive forward-backward algorithm with subjective labels for estimation, and utilize the modified posterior and Viterbi algorithms to predict the progression of future states or new patients based on objective markers only. Importantly, the adaptation eliminates the need to model the marginal distribution of longitudinal markers, a requirement in traditional algorithms. Asymptotic properties are established, and significant improvements in finite samples are demonstrated via simulation studies. Analysis of the neuropathological dataset of the National Alzheimer's Coordinating Center (NACC) shows much improved accuracy in distinguishing LBD from AD.},
}

@article {pmid41867361,
year = {2026},
author = {Li, G and Yap, PT},
title = {A Large-scale Neural Model Inversion Framework for Effective Connectivity Estimation.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {15961},
number = {},
pages = {3-12},
pmid = {41867361},
abstract = {The development of a computational framework that can infer large-scale brain-wide effective connectivity (EC) based on resting-state functional MRI (rs-fMRI) represents a grand challenge to computational neuroimaging. Towards the goal of estimating full-scale, whole-brain EC, we developed a new computational framework termed Large-scale nEural Model Inversion (LEMI) by utilizing a linear neural mass model with an efficient Kalman-filter based gradient descent algorithm. Key advantages of LEMI include fast estimation of both intra-regional and inter-regional connection strengths for large-scale networks, allowing exploration of both intrinsic and external mechanisms in neuroscience problems. Using ground-truth simulations, we demonstrated that LEMI can accurately and efficiently recover model parameters in a large network (100 regions) within 90 minutes. We then applied the LEMI model to an empirical rs-fMRI dataset from the ADNI database and identified widespread reduced excitation-inhibition (E-I) ratio in patients with Alzheimer's disease (AD). Overall, LEMI provides an efficient and accurate computational framework to estimate large-scale EC and whole-brain E-I balance based on non-invasive neuroimaging data.},
}

@article {pmid41867506,
year = {2026},
author = {Mou, FS and Ahmed, T and Huda, MN and Nandi, AK},
title = {Artificial neural networks fighting real neural decline: a systematic review of AI in Alzheimer's research.},
journal = {Artificial intelligence review},
volume = {59},
number = {4},
pages = {124},
pmid = {41867506},
issn = {0269-2821},
abstract = {Alzheimer's disease (AD) is a major global health challenge, with Artificial Intelligence (AI) increasingly recognized as a transformative tool for early detection, disease progression modeling, and therapeutic discovery. This systematic review, conducted in accordance with PRISMA guidelines, analyzed 156 peer-reviewed studies published between 2010 and 2024, identified from four major databases (Scopus, PubMed, Web of Science, IEEE Xplore). A particular emphasis was placed on multimodal approaches that integrate neuroimaging, genetics, biomarkers, and clinical data to improve accuracy and translational value. To organize this fragmented field, we introduce a novel Layered Framework that categorizes AI applications into four domains: Early Detection, Disease Progression Modeling, Therapeutic Discovery, and Real-World Integration. In addition, we applied ARIMA-based forecasting to project research trajectories through 2030, which revealed generative models and transformer architectures as the fastest-growing and most promising methodologies. The review highlights substantial advances in early detection and multimodal fusion, particularly through deep learning, while also identifying persistent challenges such as limited model generalizability, ethical concerns, and underexplored clinical implementation. Addressing these barriers will require multi-cohort validation, interpretable AI, and equity-driven model development. By consolidating evidence and forecasting future directions, this review provides a roadmap for accelerating precision-driven innovations in Alzheimer's care.},
}

@article {pmid41867700,
year = {2026},
author = {Wu, C and Wu, C and Yin, X and Zhong, C},
title = {Serum Homocysteine as a Potential Dynamic Biomarker for Staging and Monitoring Progression in Alzheimer's Disease.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {553269},
pmid = {41867700},
issn = {1176-6328},
abstract = {BACKGROUND: Reliable biomarkers are urgently needed for the early diagnosis and dynamic monitoring of Alzheimer's disease (AD). Serum homocysteine (Hcy) has been increasingly investigated but with inconsistent association to AD severity.

OBJECTIVE: To investigate the correlation between serum Hcy levels and AD severity/cognitive function, and to evaluate its clinical utility as a dynamic monitoring indicator for the disease.

METHODS: This retrospective study enrolled 80 AD patients (stratified by Mini-Mental State Examination [MMSE] score: 40 mild, 28 moderate, 12 severe) and 80 healthy controls from the Cerebrovascular Disease outpatient and inpatient departments of our hospital between January 2022 and December 2024. Fasting serum Hcy was measured via chemiluminescent immunoassay. Correlation with cognitive scores and severity discrimination were analyzed.

RESULTS: Serum Hcy levels were significantly higher in the AD group than controls (21.2 ± 6.6 vs 14.5 ± 4.8 μmol/L, p < 0.05), increasing with severity (mild: 16.8 ± 3.2, moderate: 21.2 ± 4.5, severe: 25.6 ± 5.8 μmol/L, p < 0.001). A strong inverse correlation with MoCA scores was observed (r = -0.76, p < 0.01). ROC analysis showed an AUC of 0.87 for discriminating AD severity, with an optimal cut-off of 17.5 μmol/L (sensitivity 78%, specificity 72%). After 6 months of B-vitamin intervention, Hcy decreased significantly with cognitive improvement.

CONCLUSION: Serum Hcy correlates strongly with AD severity and cognitive decline, supporting its potential as a dynamic biomarker for monitoring progression and treatment response.},
}

@article {pmid41867790,
year = {2026},
author = {Cho, S and Gabr, MT},
title = {Aβ-Overlapping Ectodomain Binding of the Clinical-Stage TREM2 Agonist VG-3927.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.02.709194},
pmid = {41867790},
issn = {2692-8205},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immune receptor genetically and functionally linked to Alzheimer's disease (AD). VG-3927, the first clinical-stage small-molecule TREM2 agonist, has been proposed to function as a transmembrane molecular glue and positive allosteric modulator (PAM). Whether it directly engages the extracellular ligand-recognition surface of TREM2 remains unknown. Here, we used a deep learning-based blind docking algorithm to map potential VG-3927 binding sites across TREM2 and identified a binding site within the ectodomain hydrophobic groove, a ligand-recognition surface previously implicated in Aβ and apoE binding. Microscale thermophoresis (MST) confirmed direct interaction of VG-3927 with TREM2 under optimized PEG-400 buffer conditions and independently demonstrated binding of Aβ [1-42] to the receptor. Co-incubation with Aβ reduced the VG-3927 thermophoretic response, consistent with interference at an overlapping ectodomain binding surface. Consistently, Aβ induced a rightward shift in the VG-3927 dose-response curve in a Jurkat TREM2-DAP12 NFAT reporter assay and attenuated VG-3927-induced phospho-SYK signaling. Together, these findings support the presence of a previously unrecognized ectodomain interaction mode for VG-3927 and suggest that amyloid-associated ligand occupancy may modulate TREM2 agonist activity within the AD microenvironment.},
}

@article {pmid41867823,
year = {2026},
author = {Rahim, A and Zhan, X and Han, Q and O'Donnell, A and Jeong, A and Madugundu, GS and Pujari, S and Kruk, M and Luo, X and Li, L and Wu, TP and Tretyakova, NY},
title = {DNA Adenine Methylation Clock in Brain Aging and Alzheimer's Disease Progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.05.709867},
pmid = {41867823},
issn = {2692-8205},
abstract = {N [6] -methyldeoxyadenosine (N [6] medA) is a recently identified endogenous DNA modification widely found in bacteria, plants, and eukaryotes. In mammals, N [6] medA has been implicated in brain function, immunity, and response to environmental stress, but its relevance to gene regulation and mammalian aging remains controversial due to its extremely low abundance (< 1 per 10 million adenines) and an uncertainty regarding its genomic origin. We have developed and validated an ultrasensitive isotope dilution nano liquid chromatography-nanospray ionization Orbitrap mass spectrometry methodology to quantify N [6] medA in genomic DNA. Applying this approach to human prefrontal cortex tissues, we found that genomic N [6] medA levels increase linearly with chronological age (Pearson correlation coefficient, 0.95). Individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) exhibited a trend toward elevated cortical N [6] medA levels relative to age-matched controls. Genome-wide profiling of N [6] medA in human prefrontal cortex was conducted using two independent methods: NAME-Seq and MeDIP-Seq, which revealed age associated adenine methylation changes reminiscent of established epigenetic aging signatures such as the 5-methylcytosine clocks. N [6] medA mapping experiments identified a subset of genomic loci that were altered in MCI and AD. Pathway analysis of cross-validated adenine methylation sites revealed an enrichment of genes involved in neuronal function and age-related neurological processes, including glutamatergic synapse, axon guidance, and long-term depression. Finally, mass-spectrometry-based photoaffinity proteomics with synthetic DNA representing a region of the APP gene identified N [6] medA reader proteins with known roles in DNA repair, replication and transcription. Together, these findings identify N [6] medA as an age-associated DNA modification in the human brain and suggest that its accumulation and recognition by specific protein readers may contribute to molecular processes underlying brain aging and age-related neurodegeneration.},
}

@article {pmid41867862,
year = {2026},
author = {Bathini, P and Schilling, S and Rahfeld, JU and Holtzman, DM and Saido, TC and Lemere, CA},
title = {Early Binding of Anti-Amyloid Antibodies to CAA Drives Complement Activation, Inflammation and ARIA in Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.04.709591},
pmid = {41867862},
issn = {2692-8205},
abstract = {Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk.},
}

@article {pmid41867865,
year = {2026},
author = {Timinski, K and Neupane, K and Prince, A and Bhandari, N and Khan, MR and Sharma, S and Shiravand, Y and Traughber, CA and Raquepaw, Z and Gulshan, K},
title = {FDA-approved drug library screen identifies antidepressants, antimicrobials, anti-COPD, and anti-CVD agents as blockers of NLRP3 inflammasome and sepsis in a sex-dependent manner.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.05.709979},
pmid = {41867865},
issn = {2692-8205},
abstract = {The NLRP3 inflammasome pathway is central to host defense, but dysregulated activation of inflammasomes promotes diseases associated with metabolic syndrome (diabetes, obesity, CVD, MASLD), neurodegenerative diseases (Alzheimer's and Parkinson's), autoinflammatory conditions (CAPS, gout), and respiratory illnesses (asthma/COPD, and COVID-19). Therapeutic modulation of NLRP3 is challenging as it requires selective blockade of detrimental inflammasome activation without broadly suppressing innate immunity. Here, we used a phenotypic screen in THP-1 ASC-GFP monocytes to identify FDA-approved drugs that can block LPS-induced priming of NLRP3 inflammasome or inhibit NLRP3 assembly (ASC speck formation) without disrupting upstream priming. Various classes of drugs, such as antidepressants (Fluoxetine, Duloxetine), antihypertensives (Irbesartan, amlodipine, nebivolol), antidiabetics (Rosiglitazone), β-adrenergic agonists (Salmeterol), antimalarials (Mefloquine), antifungals (Azoles, ciclopirox), and antivirals (Saquinavir, Remdesivir), were identified as potent blockers of either priming or assembly of NLRP3 inflammasome. Hits were validated in several biochemical assays, including effect on release of proinflammatory cytokines, autophagy, lysosomal biogenesis, LPS binding, NF-kB nuclear localization, mitochondrial membrane potential, mitochondrial ROS, and biophysical properties of the cell membrane. A subset of identified drugs was tested in murine studies to probe effects on NLRP3 inflammasome assembly/activation and LPS-induced sepsis. Mice treated with ASC puncta blockers showed markedly reduced proinflammatory cytokines in peritoneal lavage and plasma. Mice treated with LPS-priming blockers showed a sex-specific increase in survival rate in the mouse model of LPS-induced mortality, validating the in vitro screen. Further studies in primary human cells and in vivo disease models are needed to assess the repurposing and therapeutic relevance of identified drugs.},
}

@article {pmid41867870,
year = {2026},
author = {Li, B and Hagy, KT and Safi, A and Beer, MA and Barrera, A and Geraghty, S and Rai, R and Pederson, AN and Reisman, SJ and Love, MI and Sullivan, PF and Eroglu, C and Crawford, GE and Gersbach, CA},
title = {Reprogramming of neuronal genome function and phenotype by astrocytes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.07.710282},
pmid = {41867870},
issn = {2692-8205},
abstract = {UNLABELLED: Heterotypic cell-cell interactions are critical to governing cellular physiology, disease progression, and responses to the environment and pharmacologic interventions. For example, neurons and astrocytes engage in intricate interactions that are essential for brain development and function [1-3] . However, the transformation of these extracellular signals into epigenomic regulation that governs cell function is poorly understood. Here, we report that weeks of co-culture between human induced pluripotent stem cell (hiPSC)-derived neurons and mouse cortical astrocytes extensively reprograms gene expression and the chromatin accessibility landscape in neurons, affecting thousands of genes and putative gene regulatory elements (REs), including many transcription factors (TFs). These genes are enriched for functions implicated in neuronal differentiation and maturation, and tend to be impacted in schizophrenia, and autosomal dominant Alzheimer's disease. Through complementary CRISPR interference and activation screens, we recapitulated hundreds of astrocyte-induced transcriptional and chromatin remodeling events in mono-cultured neurons at both promoters and distal regulatory elements (REs) of TF genes. We discovered functional REs for ∼50 astrocyte-responsive TF genes, providing a map of gene regulatory network control. Astrocyte-responsive TF genes fall into groups that exert independent or counter-balancing transcriptional effects, highlighting the complex coordination of the neuronal response to astrocytes. Functional effects of specific TFs, including POU3F2 and TFAP2E, on neurite morphology and neuronal electrophysiology are consistent with transcriptional effects, demonstrating the capacity of direct epigenetic control to mimic heterotypic cellular signals. This work illuminates the regulation of neurodevelopment-and disease-relevant gene modules by neuron-astrocyte interactions, and provides a blueprint for applying modern functional genomics to uncover the links between cell microenvironment and epigenomic programming.

HIGHLIGHTS: Neuronal gene expression and chromatin accessibility landscape are profoundly remodeled by astrocytes over weeks of co-cultureAstrocyte-responsive neuronal gene modules and neuron-responsive astrocytic gene modules are enriched for genes associated with schizophrenia and familial Alzheimer's DiseaseSingle-cell CRISPR interference and activation screens of astrocyte-responsive gene regulatory elements identified dozens of functional regulatory elements of TF genes in neuronsSingle-cell CRISPR interference and activation screens of >200 astrocyte-responsive TF genes uncovered discrete functional clusters that promote neuronal maturity or stemnessAstrocyte-responsive TF genes reprogram neuronal electrophysiology and neurite morphology.},
}

@article {pmid41867871,
year = {2026},
author = {Ho, V and Tjondropurnomo, R and Nguyen, J and Balkó, E and Depew, S and Chen, X and Singh, R and Van Veen, JE and Rácz, B and Golshani, P},
title = {Single-Nucleus Transcriptomics Reveals Cell Type-Specific Remodeling and Epilepsy-Associated Microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.04.709339},
pmid = {41867871},
issn = {2692-8205},
abstract = {Mesial temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy involving the hippocampus and is a frequent sequelae of head trauma. TLE is associated with refractory seizures and significant cognitive deficits. Yet, the gene expression patterns and cell types driving epileptogenesis and the associated cognitive deficits are poorly understood. To address this, we performed single nucleus RNA sequencing on hippocampal tissue from mice at 3 and 6 weeks following pilocarpine-induced status epilepticus, a robust model of TLE. At these early timepoints, epilepsy samples showed reductions in specific Cck and Lamp5-Lhx6 interneuron subclusters, alongside increases in Cajal-Retzius cells, dentate granule (DG) cell precursors, and a mature DG cell subcluster. Among glia, an astrocyte subcluster and a markedly expanded microglia sublcuster were increased. We term this microglia population epilepsy-associated microglia (EAM). The transcriptomic profile of EAM partially overlaps with microglia described in models of Alzheimer's disease and traumatic brain injury, with enrichment of genes including Myo1e and Igf1 . EAM display amoeboid morphology, can be found in dense clumps around pyramidal and granule cell body layers, and exhibit enlarged vesicles and mitochondria on electron microscopy. Cell-cell interaction analysis predict that DG cells are the main interaction partners of EAM. This dataset recapitulates known cellular alterations in TLE while defining their underlying transcriptomic programs, enabling mechanistic dissection of the key processes driving epileptogenesis.},
}

@article {pmid41867873,
year = {2026},
author = {Graber, DJ and Sentman, ML and Cook, WJ and Sentman, CL},
title = {5xFAD-NSG mice: a preclinical Alzheimer model for human cell therapy studies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.03.709048},
pmid = {41867873},
issn = {2692-8205},
abstract = {UNLABELLED: Cellular therapies are one class of medicine being developed to treat Alzheimer's disease (AD), a neurodegenerative disease with memory loss, aberrant protein accumulation in the brain, and neuroinflammation. One challenge for development of human cell therapeutics is to have preclinical animal models that allow the use of human cells without immune-mediated rejection of those cells. The 5xFAD transgenic mouse model is a robust disease model for AD that expresses human amyloid precursor protein and presenilin-1 with multiple familial AD mutations, develops microglia-mediated neuroinflammation, accumulates amyloid-beta (Aβ) in the brain, and shows behavior changes with age. To create a mouse model for AD that permits the transplantation of human cells without immune-mediated rejection, we bred the 5xFAD transgenes onto the NOD-SCID-IL-2Rγ-deficient (NSG) mouse model to create 5xFAD-NSG mice. We report that 5xFAD-NSG mice develop Aβ plaques in the brain, microgliosis, neuroinflammation, and behavior changes that increase with age. We demonstrate that injection of CAR engineered human T regulatory cells are detected in the cerebral cortex and spleen after eight days. This 5xFAD-NSG mouse model for AD will be helpful to develop human cell-based therapies for AD.

SIGNIFICANCE STATEMENT: 5xFAD transgenic NSG mice develop a progressive AD-like disease and are an in vivo model for testing human cell-based therapies for AD.},
}

@article {pmid41867897,
year = {2026},
author = {Halim, DO and Di Biase, E and Rajon, A and Jordi, L and Hallett, PJ and Isacson, O},
title = {APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons.},
journal = {PNAS nexus},
volume = {5},
number = {3},
pages = {pgag053},
pmid = {41867897},
issn = {2752-6542},
abstract = {Lipid abnormalities are emerging as key pathogenic mechanisms in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Lewy body dementia. Astrocytes in the brain provide apolipoprotein E (APOE) proteins and influence neuronal metabolism and health. Using live-cell imaging and objective neurite imaging techniques, we induced cellular lipid load (cholesterol and triglycerides) by inhibiting the lysosomal cholesterol transport protein NPC1 in human neuron-astrocyte cocultures and examined the effects of CRISPR-edited APOE3 and APOE4 human astrocytes on the rescue of dystrophic neurites, where axons and dendrites of nerve cells become disfigured. APOE3, but not APOE4 or APOE knockout, astrocytes prevented cholesterol- and lipid-induced neurite damage in APOE4 neurons. In the media of APOE3 neuron-astrocyte cocultures, high-density lipoprotein-like particles were larger and presumably more lipidated than those in equivalent APOE4 cocultures. This discovery highlights that living APOE3 astrocytes control key biological mechanisms by physiologically enhancing lipid cellular homeostasis and rescuing lipid-induced neurite structural abnormalities relevant to Alzheimer's disease and neurodegenerative diseases.},
}

@article {pmid41867912,
year = {2025},
author = {Noshin, K and Boland, MR and Hou, B and He, W and Lu, V and Shen, L and Zhang, A},
title = {Integrating Social Determinants of Health in a Multi-Modal Deep Clustering Survival Model for Injury-Risk in Alzheimer's and Related Dementia Patients.},
journal = {Proceedings of machine learning research},
volume = {281},
number = {},
pages = {155-164},
pmid = {41867912},
issn = {2640-3498},
abstract = {As our population ages, the prevalence of Alzheimer's Disease and Related Dementias (ADRD) and its associated burdens continue to rise. Social Determinants of Health (SDOH) significantly influence both ADRD development and progression. Using Electronic Health Records (EHR) from a quaternary care academic medical center in a diverse urban setting, we investigated SDOH's impact on multi-modal deep clustering survival machines. Our findings revealed that SDOH improved model performance across feature selection methods (DeepCox roll-out vs. SHAP DeepExplainer) and EHR clinical modalities (medication vs. laboratory). Additionally, Laboratory features proved more informative than medications for predicting injury-fall risk. Our results highlight SDOH's crucial role in ADRD progression, particularly regarding injury-fall risk. We found that feature importance varied by selection method when analyzing multi-modality EHR data, with education emerging as a key SDOH factor among our top 10 features, underscoring its significance in ADRD progression.},
}

@article {pmid41868131,
year = {2026},
author = {Liu, T and Ren, W and Geng, X and Liu, C},
title = {Uncaria rhynchophylla: an ethnopharmacological review integrating traditional Chinese medicine uses with phytochemical and pharmacological evidence.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1723499},
pmid = {41868131},
issn = {1663-9812},
abstract = {Uncaria rhynchophylla (Miq.) Jacks. (UR), a climbing shrub of the Rubiaceae family, has been a foundational remedy in traditional Chinese medicine for over 1,500 years, and has long been used to treat neurological disorders, hypertension, and inflammatory conditions associated with "Liver Wind" and "Liver Yang Rising." This review summarizes traditional ethnopharmacological knowledge by integrating it with scientific evidence related to UR's chemical composition, pharmacological mechanisms, and therapeutic potential. This systematic narrative review analyzed 78 studies from databases including PubMed, Web of Science, Scopus, CNKI, and Wanfang (2000-2025), focusing on peer-reviewed articles on UR's phytochemistry, pharmacology, and pharmacokinetics. The plant primarily contains monoterpenoid indole alkaloids, triterpenoids, flavonoids, and phenolics. Preclinical studies have demonstrated potential neuroprotective effects against Alzheimer's disease, Parkinson's disease, epilepsy, and depression, though these are largely limited to in vitro and rodent models with methodological flaws such as small sample sizes and lack of blinding. Its antihypertensive effects involve calcium channel antagonism and nitric oxide-mediated vasodilation, while its immunomodulatory, antiviral, and anti-inflammatory effects further extend its therapeutic scope. Pharmacokinetic studies show poor oral bioavailability due to first-pass metabolism via CYP3A4, as well as stereoselective elimination. Despite some evidence linking traditional applications to modern pharmacology, major challenges remain, including difficulties in standardization, poor bioavailability, and a lack of clinical validation. Prioritizing large-scale clinical studies, development of combined formulations, and identification of biomarkers will help advance UR into the realm of evidence-based therapeutics, addressing unmet needs in neurodegenerative and cardiovascular diseases.},
}

@article {pmid41868145,
year = {2026},
author = {Guo, J and Lin, K and Liang, R and Jiang, L and He, X and Chen, J and Zheng, M},
title = {Zebrafish study provides evidence for Porphyromonas gingivalis outer membrane vesicles eliciting Alzheimer's disease-like pathologies.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1761068},
pmid = {41868145},
issn = {2235-2988},
mesh = {Animals ; Zebrafish ; *Alzheimer Disease/pathology/microbiology/etiology ; *Porphyromonas gingivalis/pathogenicity/metabolism ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Brain/pathology/metabolism ; Larva ; Proteomics ; Acetylcholinesterase/metabolism ; Periodontitis/microbiology ; *Bacterial Outer Membrane/metabolism ; Peptide Fragments ; },
abstract = {INTRODUCTION: Periodontitis has been epidemiologically linked to an increased risk of Alzheimer's disease (AD), yet the mechanistic contribution of periodontal pathogens remains insufficiently understood. Building on our previous findings that Porphyromonas gingivalis outer membrane vesicles (OMVs) induce cardiovascular dysfunction, this study investigates whether these vesicles also drive AD-related pathology using the zebrafish model.

METHODS: We microinjected P. gingivalis OMVs into the common cardinal vein of zebrafish larvae to evaluate locomotor behavior, brain injury, and neuroinflammatory responses. Integrated proteomic and transcriptomic analyses were performed to identify alterations in AD-associated pathways, and acetylcholinesterase activity along with Aβ1-42 plaque accumulation were quantified to validate hallmark AD phenotypes.

RESULTS: OMV exposure resulted in significant neurotoxicity, locomotor deficits, and robust neuroinflammation, accompanied by pronounced dysregulation of AD-related molecular pathways. Notably, OMVs markedly increased acetylcholinesterase activity and promoted Aβ1-42 deposition in larval brains.

DISCUSSION: These findings demonstrate that P. gingivalis OMVs act as potent inducers of neuronal damage and AD-like pathological features in vivo, providing mechanistic insight into how periodontal pathogens may contribute to neurodegenerative disease progression.},
}

Animals
Zebrafish
*Alzheimer Disease/pathology/microbiology/etiology
*Porphyromonas gingivalis/pathogenicity/metabolism
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Brain/pathology/metabolism
Larva
Proteomics
Acetylcholinesterase/metabolism
Periodontitis/microbiology
*Bacterial Outer Membrane/metabolism
Peptide Fragments

@article {pmid41868184,
year = {2026},
author = {Liu, Z and Zhang, H and Wan, B and Yin, S and Yue, R},
title = {Advances and Therapeutic Potential of Anthraquinone Compounds in Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {580330},
pmid = {41868184},
issn = {1177-8881},
mesh = {Humans ; *Anthraquinones/pharmacology/chemistry/isolation & purification/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/isolation & purification ; Animals ; Rheum/chemistry ; },
abstract = {BACKGROUND: Rhubarb, traditionally used in China for neurological disorders, has recently attracted considerable scientific attention for its neuroprotective and cerebrovascular benefits. The main therapeutic components of rhubarb are anthraquinones, including emodin, aloe-emodin, chrysophanol, rhein, and physcion. Accumulating experimental evidence indicates that anthraquinones are of importance in neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. However, as a promising candidate for drug development, the mechanisms by which anthraquinones treat NDDs have not been systematically reviewed. Therefore, this article outlines the anti-neurodegenerative effects of anthraquinones, focusing on their molecular mechanisms.

OBJECTIVE: This article reviews recent research progress of anthraquinones in NDDs, focusing on their potential targets and pathways to provide new ideas for the intervention and treatment of NDDs.

METHODS: A comprehensive search of PubMed, Web of Science, and Google Scholar was conducted for articles on the intervention of anthraquinones in NDDs in the past 20 years. The collected information was then summarized and analyzed.

RESULTS: Anthraquinones ameliorate NDDs through multiple mechanisms. They exhibit antioxidant and anti-inflammatory effects, protect mitochondria, and regulate microglial polarization. Furthermore, anthraquinones inhibit pyroptosis, apoptosis, tau phosphorylation, Aβ/α-synuclein aggregation, and acetylcholinesterase activity, while restoring metal homeostasis, activating estrogen receptors, modulating gut microbiota, increasing BDNF levels, and preserving blood-brain barrier permeability. More notably, these compounds play a neuroprotective role by mediating multiple signaling pathways and targets, including Nrf2, ERK1/2, PI3K/mTOR, ROS/TXNIP, SIRT1/PCG-1α, NLRP3, PI3K/Akt, MAPK, TLR4-NFκB, CaM/CaMKIV, and Ca[2+]/EGFR/PLCγ.

CONCLUSION: The pleiotropic actions of anthraquinones highlight their potential as therapeutic candidates for NDDs, yet clinical validation remains essential. Future studies should emphasize rigorously designed clinical trials and optimized brain-targeted delivery platforms. This review consolidates current evidence to support their translational development.},
}

Humans
*Anthraquinones/pharmacology/chemistry/isolation & purification/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/chemistry/isolation & purification
Animals
Rheum/chemistry

@article {pmid41868274,
year = {2024},
author = {Hasan, SA and James, AW and Fazili, FM and Tarabishi, S and Sheikh, NM and Shah, ZA},
title = {Endoplasmic Reticulum Stress in Neurodegenerative Diseases.},
journal = {Journal of dementia and alzheimer's disease},
volume = {1},
number = {2},
pages = {87-97},
pmid = {41868274},
issn = {3042-4518},
abstract = {Endoplasmic reticulum (ER) stress is a detrimental cellular phenomenon in the cells and is activated by the accumulation of unfolded or misfolded proteins in the ER. The unfolded protein accumulation activates the unfolded protein response (UPR), an adaptive mechanism designed to mitigate cellular stress by enhancing the ER's protein-folding capacity and protecting cells from apoptotic stimuli in neuroinflammation and neurodegenerative diseases. However, chronic ER stress and prolonged activation of the UPR can have adverse effects, including the activation of pro-apoptotic and inflammatory signaling pathways, which contribute to the development and progression of neurodegenerative disorders. Neurodegenerative diseases are complex and devastating conditions with underlying pathogenesis that are not fully understood. Genetic mutations leading to the accumulation of misfolded or phosphorylated tau proteins and amyloid-beta in the ER can induce ER stress, resulting in neuroinflammation and neuronal death. Several studies have reported the involvement of increased ER stress and UPR signaling proteins in the pathogenesis and progression of neurodegenerative diseases. Thus, inhibiting ER stress and neuroinflammation and targeting their associated signaling pathways represent a significant area of research interest. This review discusses the critical signaling molecules involved in ER stress, their mechanisms in the progression of neurodegenerative diseases, and the latest developments in the available ER stress inhibitors. Despite the extensive development of ER stress inhibitors over the years, only a limited number have been approved as pharmaceutical drugs. There remains a critical need for effective ER stress inhibitors to provide efficient treatments for neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41868350,
year = {2026},
author = {Xu, L and Kuang, J and Liu, A and Liao, L and Yu, L and Tian, C},
title = {EPR spectroscopy reveals different Cu(ii) coordination in APP142-172 and APP145-170 peptide fragments of amyloid precursor protein.},
journal = {RSC advances},
volume = {16},
number = {17},
pages = {15504-15509},
pmid = {41868350},
issn = {2046-2069},
abstract = {Amyloid precursor protein (APP) is central to Alzheimer's disease pathogenesis, yet the coordination chemistry and functional impact of core peptide fragments within its copper binding domain (CuBD) remain elusive. Here, we characterised the copper coordination environments and redox properties of two CuBD fragments APP142-172 and APP145-170 using electron paramagnetic resonance (EPR) and UV-Vis spectroscopy. At physiological pH, Cu(ii)-APP142-172 adopted a single N2O2 coordination, whereas Cu(ii)-APP145-170 existed in two distinct coordination modes identified by spectral simulation: the same N2O2 form (component I) as in Cu(ii)-APP142-172, and a nitrogen-rich 4N form (component II). Moreover, EPR-monitored pH titrations revealed that the 4N species predominated at alkaline pH and the N2O2 species at acidic pH. Although both Cu(ii)-APP complexes could promote Fe(ii) oxidation, only the N2O2 species (component I) exhibited ferroxidase activity, whereas the 4N species (component II) was redox-silent. These observations demonstrate that subtle changes in peptide length act as a structural switch for Cu(ii) coordination and redox activity, thereby affecting the copper-mediated regulation of neuronal redox processes.},
}

@article {pmid41868427,
year = {2026},
author = {Kim, S and Jeon, S and Cho, K and Kang, S and Bang, S and Ye, BS and Lee, JM},
title = {Deep learning for FDG-PET classification in patients with Alzheimer's disease, dementia with Lewy bodies and their mixed pathology: a solution for diagnostic heterogeneity.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1780858},
pmid = {41868427},
issn = {1663-4365},
abstract = {INTRODUCTION: Mixed pathology of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are frequently observed in patients with cognitive impairment, and complicate clinical diagnosis. We aimed to develop a classification model using [18]F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to improve diagnostic accuracy for these challenging cases.

METHODS: We analyzed FDG-PET images from 277 participants who were categorized into AD, DLB, mixed disease, and healthy control (HC) groups. Deep learning-based classification models were trained on seven binary classification tasks and one multiclass classification task and subsequently integrated into an ensemble model to predict AD, DLB, mixed disease or HC groups.

RESULTS: The model achieved an AUROC of 0.73 (95% CI, 0.69-0.78) for AD, 0.90 (95% CI, 0.89-0.91) for DLB, 0.71 (95% CI, 0.66-0.75) for Mixed, and 0.87 (95% CI, 0.84-0.89) for HC.

DISCUSSION: The model represents the state-of-the-art in automatic FDG-PET-based classification of AD, DLB, Mixed, and HC. This study highlights the utility of FDG-PET as a biomarker for differentiating AD, DLB, Mixed, and HC groups, resolving diagnostic challenges caused by overlapping clinical features.},
}

@article {pmid41868495,
year = {2026},
author = {Chen, YJ and Xie, MR and Zhu, QQ and Zhou, SQ and Li, B and Yuan, H},
title = {Insulin-like growth factor 1 associated research in Alzheimer's disease: an exploratory trends analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1709559},
pmid = {41868495},
issn = {1664-2295},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and behavioral deterioration. In recent years, the role of the insulin-like growth factor-1 (IGF-1) signaling pathway in the pathological process of AD has received increasing attention. This study provides a visual analysis of the current research status, development trends, collaboration networks, and research hotspots related to IGF-1 and AD.

METHODS: Publications were retrieved from the Web of Science and Scopus databases. CiteSpace, VOSviewer, and Bibliometrix software were used for visual analysis.

RESULTS: A total of 632 publications were included in the study. The annual publications related to IGF-1 and AD exhibited an overall upward trend. Research was concentrated in North America, Asia, and Europe. The United States holds a dominant position in terms of output, influence, and international influence. The Consejo Superior de Investigaciones Científicas was the most active institution. Journal of Alzheimer's Disease was the journal with the highest number of publications. Dr. Ignacio Torres-Aleman was the most prolific author. High-frequency keywords included IGF-1, AD, brain, insulin, controlled study, metabolism, oxidative stress, animals, signal transduction, amyloid beta protein, dementia, aging, and neuroprotection. Transgenic mouse, risk, depression, and cognitive impairment were the most powerful keywords that have emerged in recent years.

CONCLUSION: Research on IGF-1 and AD has continued to grow. Studies in this field have formed a tightly interconnected network, centered on the AD pathological core-IGF-1-related molecular mechanisms-downstream signaling pathways. The research focus is shifting from superficial correlations to investigations into underlying mechanisms and potential therapeutic targets. Depression and cognitive impairment are likely to become promising frontiers for future research.},
}

@article {pmid41868603,
year = {2025},
author = {Pan, S and Zhou, Y and Wang, X and Tong, J and Li, Y and Huang, J and Chen, S and Cui, Y and Wang, Z and Tan, YL},
title = {miRNA-associated gene networks reveal potential candidate markers for Alzheimer's disease.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1699404},
pmid = {41868603},
issn = {2296-889X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory and cognitive decline. Recent studies highlight the significant role of microRNAs (miRNAs) in regulating genes related to AD. This research aims to develop miRNA-associated gene regulatory networks as candidate AD biomarkers.

METHODS: We recruited 85 AD patients and 74 healthy controls, conducting whole blood miRNA sequencing and applying machine learning to identify differentially expressed miRNAs, which were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). We used bioinformatics databases to predict target genes for these miRNAs and obtained gene expression data from the Gene Expression Omnibus (GEO) database (GSE122063 and GSE18309). Using the ggplot2 package in R, we discovered the overlap between miRNA target genes and differentially expressed genes (DEGs) from the GSE datasets. Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses of the DEGs were then conducted using the Metascape database. Key hub genes were pinpointed by constructing a protein-protein interaction (PPI) network with the Retrieval of Interacting Genes (STRING) database and analyzing it with cytoHubba. Drug-gene interactions were predicted and examined using the Drug-Gene Interaction database (DGIdb) (http://www.dgidb.org/).

RESULTS: qRT-PCR was used to confirm the expression of the hub genes. The results showed that four miRNAs (miR-192-5p, miR-484, miR-21-5p, and miR-24-2-5p) were downregulated, while two target RNAs (SLC32A1 and GAD1) were upregulated.

DISCUSSION: This regulatory network, which is strongly linked to AD, has been initially identified as a candidate biomarker for AD. Our research provides new insights into the pathogenic mechanisms of AD, potentially improving the understanding of miRNAs' role in the disease.},
}

@article {pmid41868623,
year = {2026},
author = {Alcantara-Gonzalez, D and Santiago, E and Peña-Ortega, F},
title = {Amyloid-β acute exposition affects the CA1 hippocampal network activity and its topological organization, evaluated with multielectrode arrays.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1738954},
pmid = {41868623},
issn = {2813-3919},
abstract = {INTRODUCTION: Neuronal networks enable brain's information processing through a well-coordinated activity. Disruptions in this activity can impair key brain functions such as synaptic plasticity and long-term memory. Such dysfunctions are relevant to the cognitive deterioration in Alzheimer's disease (AD). Neuronal circuit alterations in AD are associated with amyloid-β (Aβ) extracellular accumulation across multiple brain regions involved in cognitive regulation. Although several studies have analyzed network topology and examined anatomical, functional, and effective connectivity to understand their role in AD, the direct contribution of Aβ to local neuronal network disturbances has not been investigated.

METHODS: We assessed the CA1 hippocampal network structure after acute exposure to Aβ1-42 (30 nM) using an in vitro multielectrode array approach. We analyzed neuronal spiking activity recordings, evaluated the frequency of spontaneous synchronized events, and assessed functional connectivity to elucidate the functional alterations in the network. We also elucidated the statistical features of network topology using Graph Theoretical analysis, small-world network properties, and network classification using the Estrada index approach.

RESULTS: CA1 hippocampal neurons showed an average reduced firing frequency. However, some putative pyramidal neurons and interneurons increased their activity. These differences in activity are cell-type-specific, being the interneurons the cells that mainly reduce their firing in presence of Aβ. The number and magnitude of their functional links within the network were not different, but a synchronized firing pattern of different neurons was observed. These changes were associated with alterations to the network's topological structure, indicating the generation of highly connected nodes in the presence of Aβ.

CONCLUSION: The main change in the reconfiguration of the CA1 hippocampal network induced by acute exposure to Aβ involved the differential change in firing of different neurons, where the average reduction in firing was found, but some neurons increased their firing. This may constitute an adaptive mechanisms that compensate for neuronal connectivity and help maintain the level of activity. This is the first time the Estrada index has been used to elucidate alterations in the topological neuronal network in an ex vivo brain preparation, highlighting its greater sensitivity for detecting changes compared to other topological network analysis approaches.},
}

@article {pmid41868751,
year = {2026},
author = {Zhang, Z and Zhang, R and Yang, W and Lv, K and Wu, M and Xu, L},
title = {AD diagnosis model based on fusion of heterogeneous brain imaging and genomic data.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1719390},
pmid = {41868751},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder in the elderly population, and early screening can effectively delay the progression of the disease. Mild cognitive impairment (MCI) occurs prior to the onset of AD; however, the accuracy of existing MCI-to-AD prediction methods remains relatively low. Additionally, small sample sizes and high feature dimensions often lead to model overfitting, highlighting the need for effective early screening approaches. To address the aforementioned issues, this study integrated non-paired multi-modal features-including clinical indicators from the ADNI database, blood biomarkers, brain region volume features extracted from MRI, and genetic biomarkers from the GEO database-and proposed a gender-corrected random matching strategy. The Random Forest algorithm was adopted to evaluate this strategy, analyze feature importance, and compare the performance of 9 machine learning algorithms based on the top 40 ranked features. The predictive performance of multi-modal data was superior to that of single-modal data, and the proposed strategy achieved favorable results in early AD screening. 16 specific genetic features (e.g., IFI27, EDF1, RAP2A, KIF5C, SERPINA3, FBXW7, IFITM1, ISG15, PSMB3, APOE4, KCNB1, PSPH, HMGN2, S100A13, IFIT3, and CALM1) and 6 brain region volume features ranked high in terms of importance. When validated using paired datasets from ADNI across the 9 algorithms, ensemble learning models demonstrated significantly stronger fitting capabilities. The non-paired multi-modal fusion approach not only expands the sample size but also enhances the generalization ability and robustness of the model. This provides a theoretical basis for the application of this strategy in the field of small-sample medical research.},
}

@article {pmid41868828,
year = {2026},
author = {Falsitta, LV and Pikula, A},
title = {Plant-Based Dietary Patterns and Neuroimaging Biomarkers of Brain Health: A Scoping Review of Observational and Interventional Evidence.},
journal = {American journal of lifestyle medicine},
volume = {},
number = {},
pages = {15598276261434176},
pmid = {41868828},
issn = {1559-8284},
abstract = {Healthy dietary interventions are well established in cardiovascular disease prevention, but their effects on the brain remain underexplored. This scoping review aims to investigate how adherence to core components of a whole-food plant-based diet (WFPBD) may impact neuroimaging outcomes across different brain conditions. We searched PubMed and MEDLINE for studies published in the past 20 years evaluating the effects of a predominantly or exclusively WFPBD, alone or combined with other lifestyle factors, on neuroimaging biomarkers. Selected studies were grouped into three domains: (1) demyelinating disease, (2) dementia and Alzheimer's disease, (3) cognitive aging and cerebrovascular burden. The dataset comprised heterogeneous study designs and follow-up durations, including randomized-controlled trials (RCTs; n = 9; 14 days - 3 years), longitudinal observational studies (n = 7; 2-20 years), and cross-sectional studies (n = 6). Observational evidence suggests associations between plant-based dietary patterns and favorable neuroimaging outcomes, whereas RCTs have generally not confirmed these effects. Residual confounding and healthy user bias are potential limitations. Dietary patterns aligned with a WFPBD may be important components of broader lifestyle interventions supporting brain health. Confirming observational findings will require adequately powered randomized trials with standardized neuroimaging endpoints and well-designed dietary interventions.},
}

@article {pmid41869280,
year = {2026},
author = {Mitchell, K and Hebbern, C and Ferro, A and Olaniyan, T and Christidis, T and Cakmak, JD and Rouleau, M and Anastasopolos, AT and Popadic, I and Johnson, M and Zhao, N and Tjepkema, M and Cakmak, S},
title = {Sector-specific Long-term Associations Between Transportation, Industrial, and Residential Combustion Air Pollutant Mixtures (PM2.5, SO2, NO2, O3) and Neurological Disease-related Mortality in Canada.},
journal = {Environmental epidemiology (Philadelphia, Pa.)},
volume = {10},
number = {2},
pages = {e467},
pmid = {41869280},
issn = {2474-7882},
abstract = {BACKGROUND: Improving air quality requires addressing sector-specific air pollution (SSAP). This study examined the relationship between long-term SSAP and Alzheimer's disease and dementia mortality in Canada, and whether associations were modified by neighborhood greenness, educational attainment, and material deprivation.

METHODS: We used data from the 2006 Canadian Census Health and Environment Cohort with mortality follow-up through 2019, linked to the Canadian Vital Statistics-Death database. Annual exposures to ambient air pollutants (i.e., PM2.5, SO2, NO2, and O3) from multiple sectors were estimated using the Global Environmental Multiscale-Modelling Air Quality and Chemistry model (10 km resolution) with sector-specific contributions anchored to 2015 emissions profiles. Quantile g-computation models were used to estimate hazard ratios (HRs) for Alzheimer's disease and dementia per quartile increase in SSAP.

RESULTS: Alzheimer's disease mortality was most strongly associated with SSAP from residential fuel combustion (RES: HR = 1.29; 95% CI: 1.16, 1.43), and was also positively associated with emissions from on-road transportation (HR = 1.22; 95% CI: 1.12, 1.32), ore and mineral industries (ORE: HR = 1.17, 95% CI: 1.10, 1.24), air-marine-rail transportation (HR = 1.12; 95% CI: 1.06, 1.18), and manufacturing (MAN: HR = 1.06; 95% CI: 1.01, 1.11), while inverse associations were observed for the oil and gas sector (HR = 0.85; 95% CI: 0.81, 0.88). Dementia mortality was positively associated with oil and gas (HR = 1.06; 95% CI: 1.03, 1.09), and inversely associated with air-marine-rail transportation (HR = 0.88; 95% CI: 0.85, 0.92) and ORE (HR = 0.89; 95% CI: 0.85, 0.92). Associations were generally stronger in lower greenness areas and among individuals with lower educational attainment, although heterogeneity by sector was observed.

CONCLUSION: SSAP mixtures were associated with Alzheimer's disease and dementia mortality in Canada. The direction and magnitude of associations varied by sector and by environmental and sociodemographic context, supporting the value of targeted, sector-specific mitigation strategies to reduce neurodegenerative mortality risk.},
}

@article {pmid41869421,
year = {2026},
author = {Cai, Y and Dai, W and Liu, F and Li, Z and Liu, G},
title = {Causal Associations Between Chronic Inflammatory Skin Diseases and Alzheimer's Disease: A Bidirectional Two-Sample Mendelian Randomization Study.},
journal = {Clinical, cosmetic and investigational dermatology},
volume = {19},
number = {},
pages = {589176},
pmid = {41869421},
issn = {1178-7015},
abstract = {BACKGROUND: Inflammatory skin diseases (ISDs) and Alzheimer's disease (AD) share chronic immune activation, but their causal link remains unclear.

METHODS: We performed a bidirectional two-sample Mendelian randomization using GWAS summary data from Europeans. Instrumental SNPs were analyzed with inverse-variance weighted (IVW), weighted median, and MR-Egger methods, with sensitivity tests for pleiotropy and heterogeneity.

RESULTS: Forward MR revealed significant causal effects of ISDs on AD, including lichen planus (OR 1.318, p=0.005), psoriasis vulgaris (OR 1.126, p=0.004), psoriasis with arthropathy (OR 1.032, p=0.002), psoriatic arthritis (OR 1.053, p=0.016), psoriasis (OR 1.072, p=0.008), papulosquamous conditions (OR 1.046, p=0.007), and follicular cysts (OR 1.066, p=0.047). No heterogeneity or pleiotropy was detected. Reverse analysis showed no causal effect of AD on ISDs.

CONCLUSION: These findings support a potential causal role of chronic skin inflammation in AD risk, though effect sizes were modest and clinical implications remain exploratory. This suggests that neuroimmune mechanisms may represent potential targets for further investigation.},
}

@article {pmid41869564,
year = {2026},
author = {Chauhan, M and Singh, K and Sharma, P},
title = {Targeting of Itch by clomipramine or gene therapy improves cognitive defects related to Alzheimer's disease.},
journal = {iScience},
volume = {29},
number = {4},
pages = {115181},
pmid = {41869564},
issn = {2589-0042},
abstract = {We propose a therapeutic strategy against Alzheimer's disease (AD), which involves targeting E3 ubiquitin ligase AIP4 or Itch. Previous studies have shown that Itch is aberrantly activated in cortical neurons of a mouse model of AD and contributes to neuronal death. We used a two-pronged approach to target Itch in a mouse model for AD: (1) adeno-associated virus (AAV) expressing loss-of-function mutants of Itch and (2) clomipramine, a tricyclic antidepressant, which is an Itch inhibitor. Both treatments significantly improved learning and memory associated with AD mice. A reversal in neuronal apoptosis was observed in AD mouse brain, which explained the improvement in cognition. Clomipramine was able to inhibit Itch in neurons and prevent their apoptosis in response to Aβ42. Given that clomipramine is being used against psychiatric disorders, this drug may be repurposed for use against AD.},
}

@article {pmid41869698,
year = {2026},
author = {Koizia, LJ and Allott, VES and Harris, BHL},
title = {Unpacking uncertainty in polygenic risk scores: Playing "risk score roulette".},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261421230},
doi = {10.1177/13872877261421230},
pmid = {41869698},
issn = {1875-8908},
}

@article {pmid41870153,
year = {2026},
author = {Walker, E and Wu, F and Rundle, AG and Hua, S and Quinn, JW and Neckerman, KM and Afanasyeva, Y and Arslan, AA and Koenig, KL and Zeleniuch-Jacquotte, A and Chen, Y},
title = {The association between midlife neighbourhood walkability and Alzheimer's disease in women: a prospective nested case-control study.},
journal = {Age and ageing},
volume = {55},
number = {3},
pages = {},
doi = {10.1093/ageing/afag054},
pmid = {41870153},
issn = {1468-2834},
mesh = {Humans ; Female ; *Alzheimer Disease/epidemiology/prevention & control/psychology/diagnosis ; Middle Aged ; Case-Control Studies ; Aged ; Prospective Studies ; Adult ; Risk Factors ; *Walking ; *Neighborhood Characteristics ; Age Factors ; Women's Health ; },
abstract = {BACKGROUND: The role of modifiable environmental factors in Alzheimer's disease (AD) risk remains poorly understood. Built environment features such as neighbourhood walkability (NW) may influence long-term cognitive health among women.

METHODS: The New York University Women's Health Study recruited 14 273 cognitively healthy women aged 35-65 years between 1985 and 1991, with follow-up for over 30 years. We geocoded residential addresses for each participant to derive a validated four-item baseline NW measure and a two-item average annual NW index over the follow-up period. We conducted a nested case-control study of 1865 AD cases identified via linkage to Medicare claims during follow-up matched to 3730 controls on age, race/ethnicity and Medicare coverage using risk-set sampling. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals for AD in relation to tertiles of NW measures, adjusting for potential confounders. Subgroup analyses examined potential effect modification.

RESULTS: Compared with women living in areas with the lowest baseline NW, those in the middle and highest tertiles had lower odds of having a diagnosis of AD during follow-up, with an OR of 0.95 (0.82-1.11) and 0.83 (0.71-0.98), respectively (P-trend = .03). Results were similar when using average annual NW. The association did not differ appreciably by age, smoking status, education or body mass index.

CONCLUSIONS: Higher midlife NW was associated with reduced odds of AD later in life. These findings highlight the potential for built environment interventions to promote cognitive health and support healthy ageing in women.},
}

Humans
Female
*Alzheimer Disease/epidemiology/prevention & control/psychology/diagnosis
Middle Aged
Case-Control Studies
Aged
Prospective Studies
Adult
Risk Factors
*Walking
*Neighborhood Characteristics
Age Factors
Women's Health

@article {pmid41870255,
year = {2026},
author = {KamaliZonouzi, S and Amanollahi, M and Farshbafnadi, M and Dolatshahi, M and Raji, CA},
title = {Association between retinal neurodegeneration assessed by optical coherence tomography and PET-detected cerebral amyloid burden in Alzheimer's disease: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261433198},
doi = {10.1177/13872877261433198},
pmid = {41870255},
issn = {1875-8908},
abstract = {BackgroundRetinal imaging is proposed as a biomarker for Alzheimer's disease, but evidence linking retinal changes to cerebral amyloid remains inconsistent, particularly in preclinical populations.ObjectiveThis article evaluates whether retinal structural and microvascular changes measured by optical coherence tomography (OCT) and OCT-angiography (OCT-A) are associated with cerebral amyloid-β (Aβ) burden assessed by positron emission tomography (PET).MethodsPubMed, Embase, Scopus, and Web of Science were searched on November 10, 2025. Two reviewers independently did screening, extraction, and quality assessment. Extracted outcomes included macular and peripapillary retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness, vessel density, foveal avascular zone size, and PET tracers.ResultsTwenty-two studies including 1616 participants met inclusion criteria. Fifteen assessed OCT, five OCT-A, and two both. Among cognitively normal individuals, seven studies compared retinal nerve fiber layer thickness by Aβ status, with only one reporting a significant difference. Overall, OCT metrics showed no consistent differences by Aβ status. OCT-A results were similarly inconsistent, with one study linking larger foveal avascular zone to Aβ positivity. Substantial heterogeneity in imaging devices, segmentation methods, and PET quantification was observed, and few studies adjusted for these factors.ConclusionsCurrent evidence does not demonstrate a consistent relationship between retinal OCT or OCT-A metrics and cerebral Aβ burden measured by PET. Methodological heterogeneity, small sample sizes, and limited statistical rigor contribute to inconclusive results. Standardized imaging protocols and longitudinal studies are required to determine whether retinal imaging can serve as a reliable non-invasive biomarker for early Alzheimer's disease.},
}

@article {pmid41870257,
year = {2026},
author = {Zhou, C and Ji, Y and Wang, Y and Liang, Y and Cao, Y and Lin, L and Wang, Y and Yang, Z and Liu, S and Chen, H},
title = {Meta-analysis of the efficacy of interventions for persons living with Alzheimer's disease: The role of music therapy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261433196},
doi = {10.1177/13872877261433196},
pmid = {41870257},
issn = {1875-8908},
abstract = {BackgroundEmerging evidence supports the clinical utility of music therapy for Alzheimer's disease (AD), yet robust clinical evidence remains limited.ObjectiveThis study aimed to systematically evaluate the multidimensional effects of music therapy on individuals with AD and to identify optimal intervention parameters and cumulative duration thresholds to guide clinical implementation.MethodsWe conducted a systematic review using RevMan 5.4, analyzing 24 randomized controlled trials (n = 2316) from Chinese and English databases up to January 2025.ResultsCompared to controls, music therapy significantly improved cognition (MD = 2.14, 95%CI = 0.88∼3.41, p = 0.0009), reduced neuropsychiatric symptoms (SMD = -0.55, 95%CI = -0.99∼-0.12, p = 0.01) and anxiety (MD = -4.37, 95%CI = -6.68∼-2.06, p = 0.0002), enhanced quality of life (SMD = 0.51, 95%CI = 0.02∼1.01, p = 0.04), and alleviated caregiver burden (SMD = -0.75, 95%CI = -0.94∼-0.55, p < 0.00001). The optimal regimen involved: frequency >3 sessions/week (p = 0.002), duration <40 min/session (p = 0.03), and intervention period ≥12 weeks (p = 0.002). A staged care model progressing from individual to group-based approaches is recommended (all p < 0.05). Minimum cumulative intervention durations for symptom improvement were: ≥1440 min for quality of life, ≥1800 min for behavioral and psychological symptoms, and ≥3360 min for cognition (all p < 0.05).ConclusionsMusic therapy demonstrates multidimensional benefits for persons living with AD, with distinct cumulative dose thresholds required for improving specific clinical symptoms, providing valuable guidance for clinical practice.},
}

@article {pmid41870258,
year = {2026},
author = {Rissanen, JA and Kärkkäinen, S and Katisko, K and Vanninen, A and Luikku, AJ and Rauramaa, T and Musialowicz, T and Kokki, M and Julkunen, V and Portaankorva, AM and Haapasalo, A and Solje, E and Hartikainen, P and Leinonen, V and Kokkola, T and Herukka, SK},
title = {The performance of plasma pTau181 and pTau217 in distinguishing Alzheimer's disease from various neurodegenerative disorders, psychiatric disorders, and cognitively unimpaired controls.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431800},
doi = {10.1177/13872877261431800},
pmid = {41870258},
issn = {1875-8908},
abstract = {BackgroundPlasma phosphorylated tau isoforms 181 (pTau181) and 217 (pTau217) are promising Alzheimer's disease (AD) biomarkers.ObjectiveWe evaluated the performance of pTau181 and pTau217 in the differential diagnostics between AD, other neurodegenerative diseases and non-neurodegenerative participants.MethodsWe included 104 patients with neurodegenerative diseases (37 with AD, 21 with synucleinopathies [SYNU], 24 with frontotemporal dementia [FTD] and 22 with idiopathic normal-pressure hydrocephalus [iNPH]) and 50 participants without neurodegenerative disorders (33 individuals undergoing knee arthroplasty and 17 with psychiatric diagnoses). pTau181 and pTau217 were measured via single-molecule array.ResultspTau181 differentiated AD patients from psychiatric patients with an area under the curve (AUC) of 0.879 and AD patients from all other participants with an AUC of 0.685. pTau181 was higher in patients with AD compared to FTD, iNPH, and non-neurodegenerative (ND) patients. pTau217 differentiated AD patients from psychiatric patients, with an AUC of 0.998, and AD patients from all other groups, with an AUC of 0.835. pTau217 was higher in AD patients compared to ND, FTD, and SYNU patients, but it did not differ between AD and iNPH patients without adjustment for age as a covariate.ConclusionsOur prospective cohort data indicate that pTau217 differentiates AD patients from psychiatric patients, with an excellent AUC value in receiver operating characteristic analysis. Our study supports the use of pTau217 rather than pTau181 as a minimally invasive tool to differentiate AD from non-neurodegenerative diseases (e.g., psychiatric disorders). Further studies are needed to determine the nature of pTau217 in iNPH.},
}

@article {pmid41870260,
year = {2026},
author = {Tallapragada, B and Markovic, SJ and Marston, KJ and Brown, BM and Galna, B and Shishegar, R and Gross, A and Lim, YY and Fripp, J and Doecke, JD and Hassenstab, J and Masters, CL and Maruff, P and Martins, RN and Sohrabi, HR},
title = {Composite scores to detect and monitor cognitive dysfunction in preclinical and prodromal Alzheimer's disease: A narrative review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261433044},
doi = {10.1177/13872877261433044},
pmid = {41870260},
issn = {1875-8908},
abstract = {Cognitive composites combine scores from multiple neuropsychological tests and demonstrate greater sensitivity to Alzheimer's disease (AD) related cognitive changes than individual tests. This review examines the development, composition and validity of cognitive composites to detect AD-related cognitive changes. The included cognitive composites were evaluated using four criteria: cognitive domains assessed; neuropsychological tests used, the inclusion of non-neuropsychological measures (e.g., Mini-Mental State Examination) that produce a global score themselves; and statistical methods used to calculate the composite. Existing composites fall into two categories: domain-specific (e.g., episodic memory, executive function, attention) or general composites combining multiple cognitive domains while incorporating clinical and functional measures. Psychometric properties were not consistently reported across all the studies. Therefore, a standardized validation framework is proposed to address these inconsistencies. Future work should focus on systematically evaluating optimized weighting, including data from clinical and functional measures and consistent psychometric reporting for assessing and monitoring cognitive dysfunction in early AD.},
}

@article {pmid41870262,
year = {2026},
author = {Yoon, B and Lee, HJ and Chae, H and Oh, EJ and Hong, YJ and Jeong, JH and Park, KH and Kim, S and Wang, MJ and Choi, SH and Ryu, JS and Kang, S and Yang, DW},
title = {Plasma glial fibrillary acidic protein as a potential biomarker for differentiating amyloid-negative subjective cognitive decline and mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427806},
doi = {10.1177/13872877261427806},
pmid = {41870262},
issn = {1875-8908},
abstract = {BackgroundDifferentiating subjective cognitive decline (SCD) from mild cognitive impairment (MCI) in amyloid-negative (A-) individuals is clinically relevant for early evaluation along the Alzheimer's disease (AD) pathway.ObjectiveTo assess whether plasma biomarkers discriminate between A-SCD and A-MCI and compare their performance.MethodsWe studied 114 amyloid PET-negative participants (93 A-SCD, 21 A-MCI) aged ≥60 years from multicenter cohorts. Plasma Aβ42/Aβ40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and phosphorylated tau 181 (pTau181) were measured using Simoa. Associations with MCI were estimated with logistic regression; discrimination was assessed by ROC analysis with AUCs and pairwise AUC comparisons using 1000 bootstrap resamples.ResultsStandardized log (GFAP) was associated with MCI in univariate analysis (OR 2.32; 95% CI 1.35-4.00; p = 0.002) and after adjustment for age and sex (OR 2.45; 1.27-4.74; p = 0.008). GFAP showed moderate discrimination (AUC 0.71; 0.59-0.82), whereas Aβ42/Aβ40, NFL, and pTau181 did not. Pairwise AUC differences favored GFAP over Aβ42/Aβ40 (ΔAUC 0.34; p = 0.020), NFL (0.21; p = 0.032), and pTau181 (0.29; p = 0.005).ConclusionsIn this A- cohort, plasma GFAP was the most informative biomarker for distinguishing MCI from SCD, likely reflecting astrocytic activation. Given modest accuracy and limited disease specificity, GFAP may be most useful as part of a multimodal panel rather than a stand-alone test.},
}

@article {pmid41870302,
year = {2026},
author = {Stewart, PV and Boscarino, JJ},
title = {Non-linear demographic correction enhances the diagnostic utility of the Montreal Cognitive Assessment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431359},
doi = {10.1177/13872877261431359},
pmid = {41870302},
issn = {1875-8908},
abstract = {BackgroundThe Montreal Cognitive Assessment (MoCA) is widely used for cognitive screening. Despite numerous studies showing that MoCA scores are affected by demographic variables including age, education, and race, the instrument is typically evaluated using a raw score or simple one-point education correction in clinical practice.ObjectiveIn this study, we comprehensively evaluate the diagnostic accuracy of the MoCA in a large cohort of individuals being evaluated for mild cognitive impairment or dementia.MethodsWe used data from the National Alzheimer's Coordinating Center (NACC) database to examine diagnostic accuracy of the MoCA, using both raw scores and Z-scores subject to non-linear demographic correction. We present comprehensive accuracy statistics, concordance with APOE ε4 status, and predictive validity of a mild cognitive impairment classification for the subsequent development of dementia.ResultsWe find that non-linear demographic correction modestly enhances diagnostic performance for individuals with mild cognitive impairment and dementia and results in classifying a higher proportion of APOE ε4 homozygous participants as individuals with dementia as compared to MoCA raw scores.ConclusionsNon-linear demographic correction may improve the diagnostic accuracy of the MoCA and increase concordance with a major known risk factor for Alzheimer's disease (i.e., APOE ε4 status).},
}

@article {pmid41870419,
year = {2026},
author = {Zhang, R and Vidoni, E and Vongpatanasin, W and Kerwin, DR and Cullum, CM and Rossetti, H and Stowe, AM and Billinger, SA and Gupta, A and Hall, T and Scheel, N and Zhu, DC and Hynan, LS and Burns, JM and Keller, JN and Binder, EF},
title = {Effects of Exercise and Intensive Vascular Risk Reduction on Cognitive Function in Older Adults: A Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0359},
pmid = {41870419},
issn = {2168-6157},
abstract = {IMPORTANCE: Physical inactivity, hypertension, and hyperlipidemia are modifiable cardiovascular risk factors for age-related cognitive decline and dementia. It remains unknown whether exercise training combined with intensive pharmacological reduction of cardiovascular risk factors (IRVR) would have greater benefits on cognitive function than those of exercise or IRVR alone.

OBJECTIVE: To determine the effects of exercise, IRVR, and exercise combined with IRVR on cognitive function in older adults.

This single-blind, multicenter randomized clinical trial with a 2 × 2 factorial design and duration of 24 months was conducted at 4 clinical sites in the US. Enrollment began on February 2, 2017; the final study visit was on January 31, 2022. After screening, older adults without dementia and with hypertension, family history of dementia, and/or self-reported subjective cognitive decline were randomized. Data were analyzed from December 2022 through October 2024.

INTERVENTIONS: Participants were randomized with a 1:1:1:1 ratio to aerobic exercise training, IRVR (lowering of systolic blood pressure to <130 mm Hg and serum low-density lipoprotein cholesterol with atorvastatin), IRVR + exercise, and usual care.

MAIN OUTCOMES AND MEASURES: The primary outcome was change in global cognitive function at 24 months from baseline, assessed with the Preclinical Alzheimer Cognitive Composite (PACC) score. Secondary outcomes were changes in the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) fluid composite score and individual test scores.

RESULTS: A total of 3290 individuals were screened, and 513 older adults (aged 60-85 years) without dementia and with hypertension, family history of dementia, and/or self-reported subjective cognitive decline were randomized. Among 513 randomized participants (mean [SD] age, 68.7 [6.0] years; 323 female participants [63.0%]), 443 completed 24-month visits, and 480 were included in the primary data analysis. For the primary outcome, there were no statistically significant interactions between intervention groups and time of visits (P = .13). At 24 months, PACC scores increased by 0.2 units in the no-exercise group (95% CI, 0.1-0.3) and by 0.3 units in the exercise group (95% CI, 0.2-0.4), with no significant group differences (0.1 units; 95% CI, -0.1 to 0.2; P = .37). PACC scores also increased by 0.3 units in the no-IRVR group (95% CI, 0.2-0.4) and by 0.2 units in the IRVR group (95% CI, 0.1-0.3), with no significant group differences (0.1 units; 95% CI, -0.3 to 0.03; P = .12). Increases in the NIHTB-CB composite score and individual test scores with exercise or IRVR showed similar results.

CONCLUSIONS AND RELEVANCE: In this multicenter randomized clinical trial among older adults with family history of dementia and/or self-reported subjective cognitive decline, exercise, IRVR, or both did not result in statistically significant differences in improvements in cognitive function over 24 months.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02913664.},
}

@article {pmid41870450,
year = {2026},
author = {Shah, D and Patel, A and Patel, A},
title = {Novel multitargeted Imidazo[1,2-a]pyridine-1,3,4-oxadiazole hybrids: design, synthesis and biological evaluation as anti-Alzheimer's agents.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17568919.2026.2649001},
pmid = {41870450},
issn = {1756-8927},
abstract = {AIMS: To design, synthesize, and evaluate novel imidazo[1,2-a]pyridine derivatives as dual acetylcholinesterase (AChE) and β-secretase (BACE1) inhibitors for potential Alzheimer's disease (AD) therapy.

MATERIALS AND METHODS: A series of imidazo[1,2-a]pyridine derivatives (DS1-DS15) were synthesized via cyclization using various aryl and heteroaryl acids and characterized by MP, TLC, FTIR, MS, and [1]H/[13]C NMR spectroscopy. Molecular docking studies were performed against AChE (PDB ID: 4EY7) and BACE1 (PDB ID: 4ACU). Pharmacokinetic properties were predicted using pkCSM, and molecular dynamics simulations were conducted for the lead compound. In vitro inhibitory activities were determined by IC50 values. In vivo anti-AD activity was evaluated in male Sprague Dawley rats using biochemical assays and histological analysis.

RESULTS: Compound DS7 showed the highest binding affinity toward both targets with stable protein-ligand interactions. It exhibited potent AChE inhibition (IC50 = 0.054 µM) and significant BACE1 inhibition (IC50 = 5.67 µM). In vivo studies demonstrated significant reversal of AD-associated biochemical and histopathological alterations at high dose.

CONCLUSION: DS7 emerged as a promising dual AChE/BACE1 inhibitor and a potential lead candidate for further optimization in AD drug development.},
}

@article {pmid41870451,
year = {2026},
author = {Stites, SD and Dedhia, M and Kuz, C},
title = {Predictors of extreme future time perspective change in persons who learn an Alzheimer's disease biomarker test result.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/13607863.2026.2643904},
pmid = {41870451},
issn = {1364-6915},
abstract = {OBJECTIVES: Future Time Perspective (FTP) refers to how individuals perceive their future. FTP can be impacted when people learn their Alzheimer's disease (AD) biomarker test result. This study aimed to understand what factors explain change in FTP after people learn their AD biomarker result and whether large FTP changes, after learning an AD biomarker test result, can be predicted by clinical and demographic characteristics.

METHOD: Cognitively unimpaired adults (N = 4,340) screening for an AD prevention trial, completed the 10-item FTP scale pre- and post- disclosure of their amyloid test result. We conducted bivariate and multivariable analyses. We calculated FTP change between pre- and post- result disclosure to estimate bivariate mean effects for covariates. We used a mixed-effects model to estimate time-varying effects and polytomous regression to estimate the relative risk ratio (RRR) of predictors of a large FTP increase (4th quartile) or decrease (1st quartile) compared to no change (2nd and 3rd quartiles).

RESULTS: In the mixed-effects model, the mean FTP score increased by 0.13 points from time 1 to time 2 (p < 0.001). Global cognition was a predictor of a large FTP increase post-disclosure (RRR = 0.95, p = 0.003 while elevated amyloid was a predictor of a large decrease (RRR = 1.25, p = 0.01). Women were more likely than men to experience a large FTP change, either increase (RRR = 1.45, p < 0.001) or decrease (RRR = 1.26, p = 0.005).

CONCLUSION: Disclosure processes may interact with reactions to specific test results, which has implications for the wider dissemination of these diagnostics. Assessable characteristics predict large FTP changes post-biomarker disclosure, which may help identify individuals with atypical outcomes.},
}

@article {pmid41870677,
year = {2026},
author = {Some, A and Naskar, N and Thomas, DM and Jeengar, MK and Nassar, A},
title = {Senescence as a Central Node in Alzheimer's Disease: Molecular Triggers, Cellular Effectors, and RNA-Based Interventions.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41870677},
issn = {1573-6903},
mesh = {*Alzheimer Disease/metabolism/pathology/therapy ; Humans ; Animals ; *Cellular Senescence/physiology ; Brain/metabolism/pathology ; Oxidative Stress/physiology ; },
abstract = {Alzheimer's disease (AD) is the most frequent neurodegenerative disorder. It is characterized by the buildup of amyloid-β (Aβ) plaques, as well as of tangles made out of tau that increasingly damage and kill neurons while also impairing memory and thinking. Recent findings indicate that cellular senescence is implicated in the pathogenesis of AD. Senescence occurs when cells irreversibly stop dividing under stress. In the brain, it can be induced by chronic activation of astrocytes and microglia, Aβ toxicity, tau hyperphosphorylation and oxidative stress. Senescent cells secrete proinflammatory factors, i.e., the senescence-associated secretory phenotype (SASP). These molecules promote inflammation, destroy mitochondria and interfere with synapses in ways that speed up the progress of the disease. Blocking those senescent cells may offer a new approach to treatment. Approaches including VEGFR-1 and SIRT5 interference, senolytics or senomorphs drugs, NLRP3 antagonist, PAI-1 inhibitors and small vessels inhibitors (including aspirin, curcumin derivatives and sildenafil) have been suggested to promisingly mitigate brain injury. RNA based therapy (miRNAs- and lncRNAs-targeted) and exosomal derived biomarkers are also an optimistic approach. A clearer understanding of how senescence is implicated in AD would have implications regarding the design and application of novel treatments aimed at delaying disease onset, slowing down progression or preserving brain function.},
}

*Alzheimer Disease/metabolism/pathology/therapy
Humans
Animals
*Cellular Senescence/physiology
Brain/metabolism/pathology
Oxidative Stress/physiology

@article {pmid41870774,
year = {2026},
author = {Mahmoud, MH and Mjery, Y and Fatani, SH and Jan, A and Taymour, S and Abdelsalam, K and Nasif, WA and Mukhtar, MH and Eldein, MMN},
title = {Protective effects of watercress (Nasturtium officinale) leaf methanolic extract against dextran sodium sulfate induced colon inflammation in rats.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41870774},
issn = {1568-5608},
abstract = {Numerous factors can lead to inflammation and enlargement of the colon, posing a serious health risk. This study investigated the protective effects of watercress (Nasturtium officinale) leaf methanolic extract against dextran sodium sulfate (DSS)-induced colonic inflammation in rats. Phytochemical analysis showed high levels of polyphenols, flavonoids, and condensed tannins in the methanolic extract, which exhibited the strongest in vitro anti-diabetic (α-amylase and α-glucosidase enzymes; Inhib. % 72.61 and 62.36%, respectively), anti-Alzheimer (AChE; Inhib. % 65.86 ± 0.15%), and anti-arthritic activity (protein denaturation and the proteinase enzyme activity; Inhib. % 58.09 ± 0.14 and 55.39 ± 0.14%, respectively) and was therefore selected for the in vivo study. Oxidative stress and inflammatory responses in colon tissue were evaluated using biochemical tests, histopathological examination, and assessment of mRNA levels of inflammatory markers (NF-κB, IL-6, IL-1β) and antioxidant enzymes (SOD1, CAT, GPx1). Watercress extract treatment successfully reinstated antioxidant enzyme activity and decreased inflammatory indicators in both pre-treated and post-treated cohorts. Histopathological examinations demonstrated a significant enhancement in the architecture of colon tissue and a decrease in inflammatory lesions. Molecular assays confirmed normalization of mRNA expression of antioxidant enzymes and inflammatory markers disrupted by DSS administration (p ≤ 0.05). These findings indicate that the methanolic extract of watercress leaves exerts protective effects against DSS-induced colonic inflammation at biochemical, histological, and molecular levels, supporting its potential as a natural anti-inflammatory agent.},
}

@article {pmid41870777,
year = {2026},
author = {Mostafa, RE and Asaad, GF},
title = {Bridging the gaps in alzheimer's disease: a comprehensive review of current and emerging therapies.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41870777},
issn = {1568-5608},
}

@article {pmid41870813,
year = {2026},
author = {Upadhayay, S},
title = {Role of Pentacyclic Triterpenes in the Management of Neurological Disorders: An Insight into Molecular Mechanisms and Therapeutic Approaches.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41870813},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Pentacyclic Triterpenes/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Neurological disorders represent major public health concerns globally, as they profoundly affect motor function, memory, and cognitive abilities, thus compromising patients' independence and quality of life. Despite extensive research, current treatment approaches predominantly offer palliative care, failing to hinder disease progression. The rising incidence of these disorders underscores an urgent necessity for more efficacious and disease-modifying therapies. According to findings, pentacyclic triterpenoids exhibit neuroprotective properties by inhibiting neuronal oxidative stress, neuroinflammation, apoptosis, and degeneration, making them promising candidates for targeting the underlying causes of neurodegeneration. Therefore, in this review, we explore natural and synthetic pentacyclic triterpenoids that exhibit neuroprotective effects by modulating signaling pathways, such as HMGB1, TLR4, NLRP3, NF-κB, Nrf2, PI3K, Akt, and CREB, which play crucial roles in regulating cell proliferation, differentiation, and neuronal plasticity. The present literature survey is performed by searching various keywords with several combinations: "pentacyclic triterpenes", "neurological disorders", Parkinson's Disease", "Huntington's Disease", "Alzheimer's Disease", "Multiple sclerosis", "Amyotrophic Lateral Sclerosis" "Epilepsy", "mitochondria dysfunction", "oxidative stress", "preclinical studies", "molecular mechanisms", and "clinical studies". Studies indicates that pentacyclic triterpenoids have a wide range of therapeutic potentials, current findings summarizes existing knowledge and examines the neuroprotective properties and potential molecular mechanisms of pentacyclic triterpenoids related with health benefits and neurological diseases. Available evidence suggests that pentacyclic triterpenoids possess the capacity to impede disease progression and may be beneficial in the treatment of neurological disorders. This review strengthens the understanding of pentacyclic triterpenoids and their molecular mechanisms, while also facilitating pharmaceutical discovery and development for neurodegenerative disorders.},
}

Humans
Animals
*Nervous System Diseases/drug therapy/metabolism
*Pentacyclic Triterpenes/therapeutic use/pharmacology
*Neuroprotective Agents/therapeutic use/pharmacology
Signal Transduction/drug effects
Oxidative Stress/drug effects

@article {pmid41870902,
year = {2026},
author = {Kang, J and Du, X and Zhang, X and Li, Y and Wang, C and Sun, S},
title = {METTL3-mediated TIGAR m6A modification and its role in microglia activation related to Alzheimer's disease.},
journal = {Neuroreport},
volume = {37},
number = {5},
pages = {195-203},
doi = {10.1097/WNR.0000000000002253},
pmid = {41870902},
issn = {1473-558X},
mesh = {Humans ; *Microglia/metabolism ; *Alzheimer Disease/metabolism ; *Methyltransferases/metabolism/genetics ; *Apoptosis Regulatory Proteins/metabolism ; *Adenosine/analogs & derivatives/metabolism ; Amyloid beta-Peptides/pharmacology ; Cell Line ; Phosphoric Monoester Hydrolases ; },
abstract = {OBJECTIVE: This study focused on clarifying whether methyltransferase3 (METTL3) participates in the polarization and activation of microglia in Alzheimer's disease (AD) by mediating the N6-methyladenosine (m6A) modification level of TP53-induced glycolysis and apoptosis regulator (TIGAR).

METHODS: Human microglia HMC3 cells were transfected with overexpression or knockdown lentivirus of METTL3, TIGAR, or TIGAR before being induced by Aβ treatment to establish an in-vitro AD cell model. The expression of TIGAR and METTL3 was measured by real-time quantitative PCR and western blot. Microglial polarization was assessed by detecting the expression of M1 microglia marker CD86 and M2 marker CD206 using immunofluorescence and measuring the protein expression of M1-associated iNOS and IL-1β, and M2-associated Arg-1 and IL-10 using western blot. PAR-CLIP was employed to examine the binding of METTL3 to TIGAR mRNA, and MeRIP was used to measure the m6A level of TIGAR mRNA. The stability of TIGAR mRNA was evaluated by an actinomycin D assay.

RESULTS: In Aβ-induced HMC3 cells, both METTL3 and TIGAR expressions were reduced. Aβ treatment in HMC3 cells increased M1 polarization and decreased M2 polarization. But this effect was partially reversed by overexpression of either METTL3 or TIGAR. METTL3 binds to TIGAR mRNA and increases its m6A level, thereby promoting TIGAR mRNA stability.

CONCLUSION: METTL3 modulates the balance of Aβ-induced polarization and microglia activation in HMC3 cells by upregulating TIGAR, promoting polarization toward an anti-inflammatory profile.},
}

Humans
*Microglia/metabolism
*Alzheimer Disease/metabolism
*Methyltransferases/metabolism/genetics
*Apoptosis Regulatory Proteins/metabolism
*Adenosine/analogs & derivatives/metabolism
Amyloid beta-Peptides/pharmacology
Cell Line
Phosphoric Monoester Hydrolases

@article {pmid41870994,
year = {2026},
author = {Pan, Z and Han, Y and Wang, G and Zhang, S and Lu, X and Su, X and Liu, Z},
title = {Dual-tracer PET/CT Imaging using 18F-AV-45 and 18F-AV-1451 for the Diagnosis of Alzheimer's Disease.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {229},
pages = {},
doi = {10.3791/69479},
pmid = {41870994},
issn = {1940-087X},
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; *Carbolines/chemistry ; Humans ; *Positron Emission Tomography Computed Tomography/methods ; *Aniline Compounds/chemistry ; *Ethylene Glycols/chemistry ; *Radiopharmaceuticals/chemistry ; Fluorine Radioisotopes ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by an insidious onset and gradual deterioration. Clinically, it manifests as cognitive decline and behavioral changes rather than only as generalized dementia. Currently, the diagnostic accuracy of AD remains limited due to the nonspecific clinical manifestations and the low specificity of conventional examinations such as neuropsychological assessments, electroencephalography (EEG), computed tomography (CT), and magnetic resonance imaging (MRI). Positron emission tomography/computed tomography (PET/CT) provides detailed structural and functional information along with specific molecular distributions, making it increasingly valuable for the diagnosis and research of AD. We performed PET/CT scans using the radiotracers [18]F-AV-45 (florbetapir) and [18]F-AV-1451 (flortaucipir). The key distinction between these tracers lies in their molecular targets: [18]F-AV-45 binds to β-amyloid (Aβ), whereas [18]F-AV-1451 specifically targets tau protein. This study elaborates on the protocol for the combined use of both tracers in AD diagnosis, encompassing patient preparation procedures, image acquisition techniques, interpretation standards, and the clinical significance of their joint application. This dual-tracer protocol provides a sensitive, comprehensive, and non-invasive method for detecting both amyloid and tau pathology, enhancing early diagnosis, disease staging, and research on disease progression.},
}

*Alzheimer Disease/diagnostic imaging/metabolism
*Carbolines/chemistry
Humans
*Positron Emission Tomography Computed Tomography/methods
*Aniline Compounds/chemistry
*Ethylene Glycols/chemistry
*Radiopharmaceuticals/chemistry
Fluorine Radioisotopes
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid41871009,
year = {2026},
author = {Hallam, RD and Foran, G and Fletcher, NK and MacPherson, REK and Necakov, A},
title = {BDNF alters β-cleavage of APP and subcellular distribution of BACE1.},
journal = {American journal of physiology. Cell physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpcell.00642.2025},
pmid = {41871009},
issn = {1522-1563},
support = {PGS-D//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; PGS-D//NSERC | RES'EAU-WaterNET/ ; RGPIN-2017-03904//NSERC | RES'EAU-WaterNET/ ; RGPIN-2018-06781//NSERC | RES'EAU-WaterNET/ ; },
abstract = {The accumulation and deposition of amyloid-beta (Aß) peptides is detrimental to neuronal networks and is driven by the cleavage of amyloid precursor protein (APP) by beta-secretase 1 (BACE1). The proteolytic processing of APP is tightly regulated by the opposing activities of BACE1 and ADAM10, with the latter producing a truncated, non-amyloidogenic fragment. Maintaining this balance is critical for normal physiological function, as complete inhibition of BACE1 has proven detrimental owing to the important physiological roles of its many substrates. Brain-derived neurotrophic factor (BDNF), an important mediator of neuronal function and survival, has recently been shown to reduce BACE1 activity in neural tissue, but the mechanism for this remains unknown. Previous research suggests that BACE1 cleavage of APP is favoured at acidic intracellular compartments, whereas non-amyloidogenic processing preferentially occurs at the plasma membrane. Hence, we hypothesized that BDNF alters the subcellular distribution of BACE1, reducing ß-cleavage of APP. Here, we show that acute BDNF treatment of differentiated neural cells (SH-SY5Y) reduced levels of sAPPß, a product of BACE1 cleavage of APP. Using confocal microscopy and quantitative image analysis, we found that this reduction in sAPPß levels is coincident with increased BACE1 localization to the plasma membrane, and a concomitant reduction of BACE1 localization to early endosomes. This effect appears to be independent of clathrin-mediated endocytosis (CME), as inhibition of CME by PitStop2 treatment increased a-cleavage of APP but did not reduce ß-cleavage independent of BDNF treatment. Hence, BDNF may reduce production of Aß by altering BACE1 distribution and decreasing upstream ß-cleavage.},
}

@article {pmid41871202,
year = {2026},
author = {Wu, S and Xie, J and Zhao, X and Zhao, H and Sánchez, OF and Yu, S and Rochet, JC and Freeman, JL and Yuan, C},
title = {Predifferentiation Neurotoxicity of GenX Exposure on hiPSC-Derived Cortical Neurons.},
journal = {Environmental science & technology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.est.5c13193},
pmid = {41871202},
issn = {1520-5851},
abstract = {Hexafluoropropylene oxide dimer acid (HFPO-DA), commercially known as GenX, was introduced as a potentially safer substitute for an older type of per- and polyfluorinated substance (PFAS) named perfluorooctanoic acid (PFOA). Emerging evidence suggests that GenX may possess neurotoxicity comparable to or greater than that of PFOA, underscoring the need for evaluating its potential to induce adverse health effects on the central nervous system. Here, we performed a systematic evaluation of predifferentiation GenX exposure and its neurotoxic effects utilizing human induced pluripotent stem cell (hiPSC)-derived cortical neurons. Neurons exposed to 0.4 and 4 ppb GenX prior to differentiation possess altered neuronal characteristics including synaptic density and neural activity, accompanied by transcriptomic changes associated with neurodegeneration, including enriched differentially expressed genes (DEGs) in the Alzheimer's disease (AD) pathway and predicted dysregulation of amyloid processing. Consistent with the transcriptomic alterations, GenX exposure altered multiple APP processing readouts, including increased sAPPβ/sAPPα ratios and intracellular C99 accumulation, accompanied by reduced extracellular Aβ40 and Aβ42 levels. Hyperphosphorylation of tau was also observed along with lipid droplet accumulation and reduced global translational activity, indicating broader disruptions. Collectively, our findings suggest that GenX exposure prior to differentiation, mimicking developmental exposure, can lead to persistent molecular and functional alterations in human cortical neurons that resemble key features observed in neurodegenerative diseases.},
}