@article {pmid42996291,
year = {2026},
author = {Badea, A and Xu, J and Laskowitz, DT and Badea, CT},
title = {APOE ε4 Modifies the Association of Left Atrial Remodeling With Brain Aging.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42996291},
support = {RF1 AG057895/AG/NIA NIH HHS/United States ; N01 HC025195/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; R01 CA302738/CA/NCI NIH HHS/United States ; 75N92025D00012/HL/NHLBI NIH HHS/United States ; R01 HL107385/HL/NHLBI NIH HHS/United States ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; R56 AG066184/AG/NIA NIH HHS/United States ; R01 AG066184/AG/NIA NIH HHS/United States ; R01 AG070149/AG/NIA NIH HHS/United States ; U19 AG023122/AG/NIA NIH HHS/United States ; R01 HL179758/HL/NHLBI NIH HHS/United States ; },
abstract = {INTRODUCTION: Whether APOE ε4 modifies relationships between subclinical cardiac phenotypes and brain structure is unknown.

METHODS: In Framingham Heart Study Offspring participants, we related antecedent echocardiographic remodeling (Examinations 4-6) to repeated brain MRI, and cardiac magnetic resonance phenotypes to regional cortical morphometry, testing cardiac × APOE ε4 interactions with false-discovery-rate (FDR) correction and permutation testing of the regional screen.

RESULTS: APOE ε4 modified the association between antecedent left atrial (LA) remodeling and subsequent lateral ventricular expansion (β=-0.00858, P=1.45×10[-4], q=0.0023; N=1,305; 3,787 MRI observations), the only FDR-significant result of 16 longitudinal tests, including with participant-specific MRI-time slopes (q=0.034); it weakened when intracranial volume × MRI time was modeled. Four regional ventricular cardiac × APOE ε4 interactions met within-family FDR criteria, but their number was consistent with chance (permutation P=0.70). Maximum LA volume index showed an APOE ε4-dependent association with left middle-occipital cortical-thickness variability (whole-brain q=0.017; permutation P=0.041) that persisted after ventricular adjustment. Cardiac phenotypes and trajectories showed no FDR-significant APOE ε4-dependent associations with plasma Aβ42/40, p-tau181, GFAP, or NfL, and adjustment for these biomarkers changed the regional interactions by at most 3.2%. Allen Human Brain Atlas data showed cholesterol-biosynthesis enrichment in the right superior frontal cortex, implicated by the LV end-systolic volume interaction, but without convergent pathway evidence.

DISCUSSION: APOE ε4 modified atrial-brain relationships, with the strongest evidence linking antecedent atrial remodeling to later ventricular expansion. Replication with prespecified models is needed.},
}

@article {pmid43020063,
year = {2026},
author = {Daniel, SF and Lee, C and Mollenkopf, T and Lee, M and Arbuckle, J and Fiabane, E and Gabitto, MI and Johansen, N and Kapen, I and Kraft, AW and Lai, HY and Li, SY and McGinty, R and Miller, JA and Welch-Moosman, S and Otto, S and Sawyer, L and Shepard, N and Thompson, CL and Tjärnberg, A and Waters, J and Zhen, X and Macosko, E and Lein, E and Ng, L and Zeng, H and Mufti, S and Yao, Z and Hawrylycz, M},
title = {MapMyCells: High-performance mapping of cell-by-gene data to reference brain taxonomies.},
journal = {Cell reports methods},
volume = {},
number = {},
pages = {101650},
doi = {10.1016/j.crmeth.2026.101650},
pmid = {43020063},
issn = {2667-2375},
abstract = {Single-cell reference mapping is increasingly central to translating heterogeneous datasets into consistent representations of cell identity. As cell-type atlases expand in scale and complexity, mapping new data to shared references enables reproducible annotation, cross-study integration, and accumulation of biological knowledge. We present MapMyCells, an open-source, high-performance framework for mapping diverse single-cell omics datasets to hierarchical reference taxonomies with minimal preprocessing. MapMyCells currently supports six diverse brain references spanning whole mouse and human brain, Alzheimer's disease and aging cohorts, developing mouse cortex, and a cross-species basal ganglia taxonomy. Across these references, MapMyCells accurately recovers cell identities at broad and intermediate taxonomic levels, remains robust with reduced informative gene panels, and supports transcriptomic, epigenomic, and spatial datasets. Benchmarking shows competitive accuracy with substantially lower computational requirements, enabling datasets and taxonomies containing thousands of cell types to be analyzed on standard workstations. MapMyCells provides a scalable framework for unified, extensible brain cell atlases.},
}

@article {pmid43020064,
year = {2026},
author = {Wang, N and Cardenas, C and Nieto-Caballero, VE and Turner, D and Feinberg, H and Yuan, D and Scott, N and DeBerardine, M and Dan, S and Caceres, L and Schembri, J and Chang, WJ and Yao, Z and Lee, C and Pillow, JW and Krienen, FM},
title = {PIANO enables generative modeling of gene expression and scales multi-omics integration to 100 million cells.},
journal = {Cell reports methods},
volume = {},
number = {},
pages = {101661},
doi = {10.1016/j.crmeth.2026.101661},
pmid = {43020064},
issn = {2667-2375},
abstract = {Single-cell RNA technologies enable the routine acquisition of transcriptomic atlases. However, these molecular profiles are influenced by overlapping sources of variation. Since these covariates confound comparisons, data integration is the first step in most analyses. Three challenges remain: correcting strong batch effects, scaling to millions of cells, and modeling how covariates influence gene expression. To address these challenges, we developed PIANO, probabilistic inference autoencoder networks for multi-omics, a deep learning framework whose central feature is a generative model of gene expression data. Additionally, PIANO achieves robust integrations and trains 10× faster than previous methods. PIANO accurately integrates single-cell data across species and across single-cell and spatial transcriptomics modalities. As practical applications, PIANO models spatially resolved gene expression during Alzheimer's disease progression in human brains and integrates over 100 million cancer cells to model drug perturbations. In summary, PIANO's integration and generative modeling capabilities will empower novel insights for a wide range of future studies.},
}

@article {pmid43020165,
year = {2026},
author = {Yan, M and Tian, L and Gao, W},
title = {Modular nanoplatforms for precision diagnosis and therapy of Alzheimer's disease.},
journal = {Nanomedicine : nanotechnology, biology, and medicine},
volume = {},
number = {},
pages = {103047},
doi = {10.1016/j.nano.2026.103047},
pmid = {43020165},
issn = {1549-9642},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder whose pathological heterogeneity and restrictive blood-brain barrier (BBB) limit conventional diagnosis and therapy. This review presents a pathology- and function-oriented framework for modular AD nanotheranostics, linking key biomarkers and pathological processes to molecular recognition, brain delivery, therapeutic intervention, responsive release, and treatment monitoring. Major BBB-crossing strategies are critically evaluated, emphasizing the distinction between endothelial uptake and genuine brain-parenchymal delivery. Closed-loop nanoplatforms are organized into sensing, BBB-crossing, lesion-targeting, therapeutic, stimuli-responsive, imaging/monitoring, and feedback-adjustment modules, with representative material systems compared according to these functions. Most current platforms remain monitoring-enabled theranostic systems rather than true closed-loop systems. Clinical translation will require simplified biodegradable designs, rigorous verification of parenchymal delivery, standardized manufacturing, long-term safety evaluation, biomarker-guided patient selection, and predefined feedback rules linking treatment response to therapeutic adjustment.},
}

@article {pmid43020291,
year = {2026},
author = {Anbar, HS and Lozon, Y and Khodr, V and Jabr, R and Elnazier, M and Zarzour, T and Nasir, R and Ahmed, S and Malahifci, R and El Gamal, MI and Abdullatif, M and Ahmed, M and Dohle, W and Potter, BVL and Hassan, HM},
title = {Irosustat and STX140 improve cognitive function and modulate amyloid, oxidative stress, and inflammatory pathways in experimental Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118618},
doi = {10.1016/j.bcp.2026.118618},
pmid = {43020291},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) is currently the most prevalent neurodegenerative disorder affecting the geriatric population. The pathology of AD has been described as neuronal loss caused by the accumulation of beta-amyloid plaques and the formation of neurofibrillary tangles resulting from tau protein phosphorylation. This study aimed to investigate the therapeutic potential of steroid sulfatase inhibition using two drugs, the clinical steroid sulfatase inhibitor Irosustat and the multi-targeting preclinical candidate STX140, in scopolamine-induced AD in male Wistar rats compared to Donepezil as a standard drug. Behavioral tests such as the Open Field Test, Elevated Plus Maze Test, and Morris Water Maze Test were conducted to confirm the disease state and assess any improvement. At the end of the study, the animals were dissected to collect blood and brain samples for morphological, histological, immunohistochemical, biochemical, quantitative polymerase chain reaction and western blotting analyses. Treatment with Irosustat or STX140 improved learning, memory, and cognitive function compared with the disease group. The treated groups showed lowered brain tissue Aβ-40 & 42 levels, acetylcholinesterase activity, oxidative stress, and inflammatory markers. Morphological assessments showed that the drugs protected against brain atrophy and neuronal loss. Irosustat and STX140 are therefore promising therapeutic candidates for the management of Alzheimer's Disease.},
}

@article {pmid43020849,
year = {2026},
author = {Lee, J and Nichols, E and Adar, SD and Knapp, D and Atshan, S and Avendano, M and Bindas, A and Brauer, M and Brook, JR and Chang, HH and Chiang, YY and Choi, H and Doiron, D and Flood, S and Fransz-Myers, MM and Gross, AL and Hayes-Larson, E and Claus Henn, B and Hicken, M and Keller, KP and Kezios, KL and Kieny, C and Lane, KJ and Luben, TJ and Meijer, E and Narayanan, S and Shih, RA and Szpiro, AA and Thorpe, LE and Van Riper, D and Weerman, B and Weiss, J and Wellenius, GA and Weuve, J},
title = {Understanding the exposome across the life course to promote healthy aging: consensus recommendations from the Gateway Exposome Coordinating Center.},
journal = {Nature aging},
volume = {6},
number = {11},
pages = {2379-2392},
pmid = {43020849},
issn = {2662-8465},
support = {U24AG088894//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
mesh = {Humans ; Aging ; Consensus ; *Environmental Exposure ; *Exposome ; *Healthy Aging ; },
abstract = {Healthy aging is shaped by the exposome-the accumulation of exposures experienced across the life course arising from intersections of the natural, physical, social, community and policy environments in which people age. This Consensus Statement reports recommendations from the Gateway Exposome Coordinating Center to accelerate life-course research on the exposome's impacts on healthy aging, including Alzheimer's disease and related dementias. Recommendations centered on five themes are presented: the promotion of interdisciplinary collaboration; the integration of life-course perspectives on the timing, accumulation and sequencing of exposures; systematically quantifying and incorporating broader contexts of time and place into health research; the adoption of mechanistic thinking to develop pathway-relevant exposure metrics; and leveraging new data streams, including wearable sensors, administrative records and remote sensing, to improve exposure measurement. These priorities emphasize harmonized measures, transparent methods and attention to bias, with the goal of identifying actionable intervention and policy targets across diverse populations that can shape individuals' exposures, lived experiences, behaviors and, ultimately, health as they age.},
}

Humans
Aging
Consensus
*Environmental Exposure
*Exposome
*Healthy Aging

@article {pmid43021327,
year = {2026},
author = {Son, HJ and Lee, NH and Kim, H and Myeong, SH and Kang, JH and Lee, NK and Lee, SY and Jang, H and Seo, SW and Chang, JW and Na, DL and Kim, HJ},
title = {Ethionamide preconditioning enhances the therapeutic efficacy of human mesenchymal stromal cells in an Alzheimer's disease model.},
journal = {Stem cell research & therapy},
volume = {17},
number = {1},
pages = {},
pmid = {43021327},
issn = {1757-6512},
support = {RS-2026-25485281//National Research Foundation of Korea (NRF)/ ; SMX1250981, SMO1264024//Samsung Medical Center/ ; RS-2022-KH127216//the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare/ ; },
mesh = {*Alzheimer Disease/therapy/pathology/metabolism ; Animals ; Humans ; *Mesenchymal Stem Cells/drug effects/metabolism/cytology ; *Mesenchymal Stem Cell Transplantation/methods ; Disease Models, Animal ; Mice ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Microglia/metabolism/drug effects/pathology ; },
abstract = {BACKGROUND: Mesenchymal stromal cells (MSCs) are promising therapeutic candidates for neurodegenerative diseases, including Alzheimer's disease (AD). However, their limited survival and functionality in pathological environments hinder their therapeutic efficacy. The primary objective of this study was to evaluate the therapeutic efficacy of ethionamide (ETH)-preconditioned MSCs (ETH-MSCs) in mitigating AD pathology.

METHODS: Wharton's jelly-derived MSCs (WJ-MSCs) were preconditioned with ethionamide, and their therapeutic efficacy was evaluated in both in vitro and in vivo AD models. In vitro, ETH-MSCs were assessed for their ability to modulate microglial inflammation and promote amyloid-β (Aβ) clearance under AD-like conditions. For in vivo studies, ETH-MSCs were injected into the lateral ventricles of 5xFAD transgenic mice. The effects of ETH-MSC administration on glial activation (GFAP and Iba1 expression) and Aβ deposition were evaluated.

RESULTS: In vitro, ETH-MSCs reduced pro-inflammatory cytokine secretion by microglia and enhanced Aβ clearance in neurons. In vivo, ETH-MSCs treatment significantly decreased GFAP and Iba1 expression, indicating reduced astroglial and microglial activation, and reduced amyloid plaque burden in 5xFAD mice. Repeated ETH-MSCs injections further boosted Aβ clearance, demonstrating a cumulative therapeutic benefit.

CONCLUSIONS: Ethionamide preconditioning significantly enhances the neuroprotective and amyloid-clearing capabilities of WJ-MSCs. These findings suggest the potential of ETH-MSCs as an effective therapeutic strategy for AD, with superior efficacy compared to naïve MSCs in both in vitro and in vivo models.},
}

*Alzheimer Disease/therapy/pathology/metabolism
Animals
Humans
*Mesenchymal Stem Cells/drug effects/metabolism/cytology
*Mesenchymal Stem Cell Transplantation/methods
Disease Models, Animal
Mice
Amyloid beta-Peptides/metabolism
Mice, Transgenic
Microglia/metabolism/drug effects/pathology

@article {pmid43021380,
year = {2026},
author = {Zattoni, M and Aigner, L},
title = {Disentangling the role of adaptive immunity in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {43021380},
issn = {1750-1326},
mesh = {*Alzheimer Disease/immunology ; Humans ; *Adaptive Immunity/immunology ; Animals ; Immunity, Innate ; },
abstract = {Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by progressive synaptic and neuronal loss, amyloid-β deposition, hyperphosphorylated tau accumulation, and chronic neuroinflammation, traditionally attributed primarily to the innate immune system. Increasing evidence, however, implicates the adaptive immune system as an active contributor to AD pathogenesis and progression. This emerging perspective has stimulated the development of immunomodulatory strategies aimed at mitigating cognitive decline and neuropathological hallmarks of the disease. In this review, we examine how adaptive immune responses change throughout the course of AD, integrating findings from both human studies and animal models while emphasizing the temporal dynamics of these alterations. We critically evaluate areas of consensus and controversy in the field, highlighting how differences in experimental models, disease stages, and methodological approaches contribute to divergent findings. Finally, we assess current therapeutic strategies targeting adaptive immunity, discussing their potential mechanisms of action and identifying key therapeutic windows and routes of administration that may maximize efficacy. By providing a comprehensive overview of adaptive immune involvement in AD, this review aims to inform the development of more precise and effective immunomodulatory interventions.},
}

*Alzheimer Disease/immunology
Humans
*Adaptive Immunity/immunology
Animals
Immunity, Innate

@article {pmid43021430,
year = {2026},
author = {Lees, AJ},
title = {Love in the time of Alzheimer: Gabriel García Márquez's pact with solitude.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag402},
pmid = {43021430},
issn = {1460-2156},
}

@article {pmid43021519,
year = {2026},
author = {Triposkiadis, F and Xanthopoulos, A},
title = {EXPRESS: The Medin-Aorta-Brain Axis: Linking Vascular Aging to Alzheimer's Disease.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261508312},
doi = {10.1177/0271678X261508312},
pmid = {43021519},
issn = {1559-7016},
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of cerebral amyloid-β (Aβ). Medin amyloid is present in the aging aorta and has been linked to cerebrovascular dysfunction. We hypothesize that medin contributes to AD pathogenesis through a systemic aorta-brain axis. Aortic medin may promote aortic stiffening, thereby increasing cerebral pulsatile load and impairing perivascular clearance. Furthermore, cerebral medin co-localizes with Aβ, exacerbating neurovascular injury. This hypothesis requires validation. We outline falsifiable predictions, a staged biomarker framework, and the interpretation of circulating medin levels. Medin targeting may be a strategy to maintain vascular compliance and reduce Aβ aggregation, pending safety studies.},
}

@article {pmid43021531,
year = {2026},
author = {Verma, A and Kundu, S and Jaiswal, S and Khanna, P},
title = {Vegetarian dietary patterns are not associated with lower odds of noncommunicable diseases among patients presenting to a tertiary care center in North India: a cross-sectional survey.},
journal = {Clinical nutrition research},
volume = {15},
number = {4},
pages = {253-260},
doi = {10.7762/cnr.2025.0010},
pmid = {43021531},
issn = {2287-3732},
abstract = {OBJECTIVE: Noncommunicable diseases (NCDs) present a huge global burden, accounting for approximately 7.3 trillion cases and 43.8 million deaths in 2021. In India, 68% of all deaths are caused by NCDs. Carbohydrate intake has been associated with NCD development. Standard Indian diets mainly comprise carbohydrates. In this study, we aimed to analyze the association of vegetarian versus omnivorous diets with the odds of developing NCDs in patients visiting the emergency department.

METHODS: Over 18 months, a cross-sectional epidemiological survey-based study was conducted among patients aged >18 years presenting to our department with documented comorbid conditions (e.g., diabetes mellitus [DM], hypertension, heart disease, hypothyroidism, Alzheimer disease, and cancer). These patients completed a 32-item questionnaire survey regarding dietary and lifestyle choices. Associations between comorbidity status and dietary variables were evaluated by bivariate analysis. Additionally, unadjusted odds ratio (OR) and adjusted OR for DM, hypertension, and heart disease were calculated.

RESULTS: This study included 11,011 patients, of which 55.31% were males and 68.91% were >55 years old. Furthermore, 65.87% were vegetarians, whereas 28.97% were omnivores. Hypertension, DM, and heart disease were found in 62.6%, 49.9% and 26.0%, respectively, while 58% had combinations of NCDs. Adjusted for age, sex, smoking, sugar, alcohol, exercise, and packaged food, OR (omnivore vs. vegetarian) was 0.94 (95% confidence interval [CI], 0.86-1.03; P=0.180), 0.91 (95% CI, 0.83-1.00; P=0.052) and 1.02 (95% CI, 0.92-1.13; P=0.690) for DM, hypertension, and heart disease, respectively.

CONCLUSION: Most patients with NCDs followed a vegetarian dietary pattern, which was not associated with lower odds of developing NCDs.},
}

@article {pmid43021542,
year = {2026},
author = {Makarios, SN and Shukla, R and Yadav, H and Jain, S},
title = {Periodontitis as a Modifiable Risk Factor for Dementia: Mechanistic Pathways Linking Oral Inflammation to Neurodegeneration.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-8},
doi = {10.1017/cjn.2026.10704},
pmid = {43021542},
issn = {0317-1671},
abstract = {Emerging evidence increasingly implicates chronic periodontal disease as a contributor to age-related cognitive decline and dementia, including Alzheimer's disease (AD). Periodontitis is defined by persistent oral microbial dysbiosis, ulcerated gingival epithelium, repeated bacteremia and sustained systemic inflammatory signaling - factors that plausibly influence neuroimmune pathways and cerebrovascular integrity. This review synthesizes findings from epidemiological studies, systematic reviews, mechanistic analyses and experimental models to examine the biological links between oral inflammation and neurodegeneration. Collectively, the literature suggests a stepwise oral-brain axis: first gingival inflammation promotes local and systemic pro-inflammatory cytokine release, second repeated bacteremia allows oral pathogens and microbial byproducts to enter circulation, third these signals and agents access and compromise the blood-brain barrier, then fourth microglia in the brain become primed and hyper-reactive and at last enhanced neuroinflammation accelerates amyloid-β and tau pathology. Although causal inference remains limited by the predominance of observational data, emerging intervention studies and mechanistic evidence suggest that periodontal health is a potentially modifiable factor in dementia prevention strategies.},
}

@article {pmid43021763,
year = {2026},
author = {Sun, YZ and Yi, Y and He, Y and Chen, DD and Liu, MX and Zhang, XL},
title = {Dual Roles of Cathepsins in Neuroinflammation: From Pathogenic Mediators to Therapeutic Targets in Neurological Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X505934261026094642},
pmid = {43021763},
issn = {1875-6190},
abstract = {Neurological diseases are a series of disorders that affect the brain, spinal cord, and peripheral nervous system, posing a significant threat to human health. Persistent neuroinflammation is a critical factor in the occurrence of neurological diseases, although the underlying mechanisms are highly complex. Recent evidence increasingly demonstrates that cathepsins play an important role in the initiation and progression of neuroinflammation. Significant alterations in the expression, activity, and intracellular localization of cathepsins occur during the pathogenesis of neurological disorders. Therefore, the pathophysiological roles of cathepsins have attracted considerable attention in neuroscientific research. This review provides a critical overview of current knowledge on cathepsins in neurological diseases, with particular attention to their roles in neuroinflammation. Besides, this review highlights the interplay between cathepsins and key neural cells in the nervous system (including microglia, astrocytes, oligodendrocytes, and neurons) as well as signaling molecules as a mechanistic framework. This study elucidates the mechanism of cathepsin-mediated neuroinflammation and details their roles in different types of neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury, and multiple sclerosis (MS). Although treatments are available for some neurological disorders, this review will examine cathepsin-mediated neuroinflammation in depth to assess its potential as a clinically significant therapeutic target.},
}

@article {pmid43021770,
year = {2026},
author = {Jiang, P and Guo, X and Wang, L and Huang, W and Xie, H and Gao, X},
title = {Under-recognized Autoimmune Encephalitis in Patients with Alzheimer's Disease: A Case Series Emphasizing EEG Screening.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050509968261027101230},
pmid = {43021770},
issn = {1875-5828},
abstract = {INTRODUCTION: AD and AE present overlapping cognitive decline, often causing misdiagnosis and delayed immunotherapy. AD has an insidious onset and slow progression with typical Aβ and tau abnormalities, while AE manifests subacute neuropsychiatric symptoms and inflammatory imaging or CSF changes. Rapid cognitive decline in AD patients with superimposed AE is easily misdiagnosed as simple neurodegeneration. EEG is a convenient non-invasive test that can serve as a screening tool to trigger further autoimmune evaluation in AD patients with unexplained rapid deterioration. This case series reports two verified AD patients complicated with anti-LGI1 encephalitis and probable seronegative AE. It adds to the literature on the pathological coexistence and interaction of AD and AE, highlights the underutilized diagnostic value of EEG, and supports routine EEG screening for rapidly progressive AD cognitive decline.

CASE PRESENTATION: Two biomarker-confirmed AD female patients with comorbid AE were included. The 75-year-old patient had 4 years of cognitive decline (baseline MMSE=10), with typical AD imaging and biomarker abnormalities, positive anti-LGI1 IgG and abnormal EEG, diagnosed with AD combined with LGI1 encephalitis. She received IVIg, rituximab, anti-amyloid and anti-dementia treatment. MMSE improved from 10 to 18 at 1 month but fluctuated thereafter (MMSE 11-12, MoCA 3-9) with treatment pause and irregular adherence; serum LGI1 antibody and AD biomarkers remained normal throughout. The 62-year-old patient had 7 years of cognitive decline, personality changes, and hallucinations (MMSE=0, MoCA=0). She was diagnosed with probable seronegative AE complicated with AD based on AD imaging changes, positive CSF indicators, and positive TBA findings. Treatment with telitacicept and lecanemab was associated with modest cognitive improvement (MMSE +3, MoCA +2) at short-term follow-up.

CONCLUSION: Rapid cognitive exacerbation in AD patients should not be attributed to natural neurodegeneration. Routine EEG is an essential noninvasive tool for cognitive evaluation in AD. EEG abnormalities in AD patients require comprehensive autoimmune examinations. Concurrent AE is a reversible and treatable factor worsening AD cognitive impairment. Combined immunotherapy and anti-amyloid treatment can significantly improve patient cognition and biomarkers. EEG should be a routine screening item for rapidly progressive AD. Autoimmune inflammation may accelerate AD progression, providing new insights for AD immunological pathogenesis and targeted therapy research.},
}

@article {pmid43021771,
year = {2026},
author = {Akter, H and Siddique, MAB and Tufael, and Debnath, A and Debnath, N},
title = {Impact of Nursing Interventions on Cognitive Decline and Quality of Life in Alzheimer's Disease: A Comprehensive Mini-Review.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050514304261027040607},
pmid = {43021771},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive worsening with severe cognitive impairment and poor quality of life. The nursing interventions of cognitive stimulation, medication management, and holistic care are significant for cognitive outcomes and the emotional well-being of AD patients. The purpose of this mini-review is to determine the efficacy of nursing interventions in slowing cognitive decline and improving quality of life experienced by people with Alzheimer's. An extensive literature search was carried out, including works that affected cognitive functioning, psychological well-being, and life satisfaction as a whole. Cognitive stimulation therapy (CST), medication adherence, and family-centered care were key interventions that were shown to have a significant effect on cognitive performance, helping decrease neuropsychiatric symptoms (anxiety and depression) and encouraging social interaction and independence. The results presented in the evidence indicate that holistic models of care that incorporate emotional and social support are highly effective in improving patients' cognitive and psychological health. Nevertheless, resource shortages, staff training, and caregiver burnout continue to be serious impediments to the successful implementation of these interventions. Nursing interventions play a critical role in enhancing cognitive and emotional health among AD patients. These interventions should be refined, and their benefits and long-term effects studied to inform best practices in AD care in future research.},
}

@article {pmid43021956,
year = {2026},
author = {Zhang, X and Wu, Y and Han, J and Zhao, Z and Yao, Y and Sun, Y and Wang, X},
title = {Recent advances in the pharmacological effects and mechanisms of borneol and borneol-containing formulations in central nervous system diseases.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1950139},
pmid = {43021956},
issn = {1663-9812},
abstract = {Borneol is an aromatic medicinal agent widely used in traditional Chinese medicine, both as a standalone component and as an ingredient in multi-herb formulations. Its pharmacological relevance to central nervous system (CNS) disorders has attracted increasing attention, particularly in Alzheimer's disease, Parkinson's disease, epilepsy, ischemic stroke, and glioma. Accumulating evidence indicates that borneol may influence multiple pathophysiological processes, including brain-barrier function and drug delivery, neuroinflammation and oxidative stress, neurotransmitter homeostasis and neuronal excitability, cellular injury and death, and the clearance of pathological substances and post-injury repair. Here, we integrate and compare these mechanisms across disease contexts. Notably, although several actions of borneol appear to converge across CNS disorders, others are strongly disease- and context-dependent; for example, its effects on brain-barrier permeability, oxidative stress, and cell death may differ in direction according to disease pathology and therapeutic intent. Pharmacokinetic studies support measurable brain exposure to borneol, yet direct comparative evidence of pharmacological activity, brain disposition, and human pharmacokinetics among borneol preparations of different botanical origins and stereochemical configurations remains scarce. Borneol-containing formulations also exhibit multi-level pharmacological effects; however, because most studies lack borneol-alone, borneol-depleted, or add-back controls, these effects cannot be unequivocally attributed to borneol itself. Overall, the current evidence base remains dominated by cellular and animal studies, with several proposed mechanisms inferred primarily from changes in molecular expression or computational predictions. Robust causal validation, high-quality clinical evidence, and long-term safety data are still limited. Future studies should therefore define the dose-exposure-response relationships and disease-specific therapeutic windows of different borneol preparations, establish the independent contribution of borneol within complex formulations, and determine its genuine therapeutic value and long-term safety through rigorous mechanistic and clinical investigation.},
}

@article {pmid43021970,
year = {2026},
author = {Gau, SY and Lo, SW and Hsu, C and Tu, YF and Su, YJ and Chen, CC and Wu, MC and Mitsukura, Y and Chang, HC},
title = {PCSK9 inhibitor use and risk of dementia and neurodegenerative diseases in adults aged 50 Years and older: a global electronic health record study.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1942691},
pmid = {43021970},
issn = {1663-9812},
abstract = {BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors achieve profound lipid lowering, yet their long-term neurocognitive effects remain uncertain. Evidence from randomized trials is limited by short follow-up and lack of dedicated neurodegenerative endpoints.

METHODS: We performed a retrospective target trial emulation using the TriNetX Global Collaborative Network. Adults aged ≥50 years with hyperlipidemia initiating PCSK9 inhibitors or comparator lipid-lowering therapies between 2015 and 2024 were included. Active-comparator cohorts were constructed against statins, ezetimibe, and fenofibrate or cholestyramine with mutual exclusion of prior exposure. Propensity score matching at a 1:1 ratio balanced demographics, body mass index, socioeconomic indicators, healthcare utilization, and cardiometabolic comorbidities. Outcomes included incident all-cause dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, and other neurodegenerative disorders. Sensitivity analyses incorporated lag periods, varying follow-up durations, alternative matching strategies, and intention-to-treat analyses. Cross-dataset validation was additionally conducted using the US Collaborative Network to assess reproducibility under independent data settings. Hazard ratio along with 95% confidence interval were evaluated in each analysis.

RESULTS: Among 31,604 matched PCSK9 inhibitor-statin pairs, PCSK9 inhibitor use was associated with lower risks of all-cause dementia (HR 0.454; 95% CI 0.394-0.522), Alzheimer's disease (HR 0.553; 95% CI 0.433-0.705), vascular dementia (HR 0.536; 95% CI 0.402-0.714), Parkinson's disease (HR 0.686; 95% CI 0.544-0.865), and other neurodegenerative disorders (HR 0.730; 95% CI 0.645-0.825). Results were consistent across comparator therapies, cross-dataset validation and sensitivity analyses.

CONCLUSION: PCSK9 inhibitor use was associated with lower observed risks of neurodegenerative outcomes across multiple analyses and datasets. These findings support a potential association but do not establish causality and require confirmation in prospective trials.},
}

@article {pmid43022016,
year = {2026},
author = {Bednorz, A and Religa, D},
title = {Sex-specific personality metatrait profiles and their associations with APOE, PICALM variants, and cognitive performance in healthy middle-aged adults: a cluster-based analysis.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1933176},
pmid = {43022016},
issn = {2673-6217},
abstract = {INTRODUCTION: APOE ε4 is the strongest common genetic risk factor for late-onset Alzheimer's disease, while PICALM rs3851179 has been associated with amyloid-β clearance. Personality can be summarized into two higher-order metatraits: Stability, reflecting emotional and behavioral regulation, and Plasticity, reflecting cognitive flexibility. This study examined whether genetic associations with episodic memory and fluid intelligence differ across Stability-Plasticity personality clusters in cognitively healthy middle-aged adults.

MATERIAL AND METHODS: The sample comprised 192 participants. NEO-FFI personality traits were standardized to derive the metatraits Stability and Plasticity. Sex-stratified agglomerative hierarchical clustering (Ward's linkage) identified two personality profiles characterized by relatively higher or lower levels of both metatraits. Cognitive outcomes included the California Verbal Learning Test (CVLT) and Raven's Progressive Matrices (RPM). Sex-stratified regression models examined associations between APOE ε4 carrier status, PICALM rs3851179 GG genotype, age, education, and cognitive performance.

RESULTS: After false discovery rate correction, significant associations were observed only in females. In the low Stability-low Plasticity cluster, the APOE × age interaction was negatively associated with CVLT Recognition performance (pFDR = 0.019; R[2] = 0.254). In the high Stability-high Plasticity cluster, models incorporating APOE and/or PICALM status were significantly associated with CVLT Recognition performance (R[2] = 0.583-0.619, pFDR = 0.010-0.019). For fluid intelligence, significant negative APOE × age and APOE × age × education interactions, as well as a negative APOE × PICALM × age interaction, were observed in the respective models (R[2] = 0.553-0.696, pFDR = 0.001-0.019).

CONCLUSION: Personality metatraits were associated with variability in APOE-related cognitive outcomes, particularly among females. These findings suggest that personality structure can contribute to individual differences in cognitive aging pathways associated with genetic risk. However, the results should be interpreted considering the cross-sectional design and limited sample size.},
}

@article {pmid43022197,
year = {2026},
author = {Khan, SH and Iqbal, R and Alqahtani, S and Shan, RU and Alhefdhi, A and Alkhamees, B and Gasmi, K and Ali, A},
title = {Efficient neuroanalytic local-global learning with dual-branch CNN-lightweight Swin Transformer for Alzheimer's disease analysis.},
journal = {Frontiers in computational neuroscience},
volume = {20},
number = {},
pages = {1972923},
pmid = {43022197},
issn = {1662-5188},
abstract = {Alzheimer's disease (AD) is one of the main causes of dementia, where early detection is critical for postponing the progression of the disease and timely treatment. Recent computer-aided diagnosis using deep learning with structural MRI has shown optimal performance; however, the rising number of model parameters and high computational requirements make the deployment challenging in resource-limited environments. This study proposes an efficient deep learning framework named "NeuroCST" based on a dual-branch network architecture incorporating an enhanced EfficientNet-based CNN and a Lightweight Swin Transformer working independently to capture local and global information of AD. The enhanced Efficient Convolution branch extracts fine-grained morphological features using depthwise separable convolution and residual learning for texture capturing. Consequently, the customized SwinLite Transformer branch models global contextual dependencies using Efficient SwinLite Transformer blocks with attention, shifted-window partitioning, and MLP. These dual-branch diverse feature vectors are then concatenated and processed by a spatial attention mechanism, NeuroCST-SA, for optimal pixel selection to reduce redundancy and discriminate minor contrast and texture inter-class variation. The proposed NeuroCST is evaluated on the public Kaggle AD dataset, which contains 6,400 original and 33,984 augmented MRI images (40,384 in total) in four classes: Mild Demented, Moderate Demented, Non-Demented, and Very Mild Demented. The NeuroCST-SA performs better on diverse experimental setups, both augmented and original, than existing CNNs and ViTs, achieving 98.42% accuracy, 98.50% sensitivity, 98.60% precision, and an F1-score of 98.55% (mean, with a standard deviation of 2.49% across holdout cross-validation). The base NeuroCST model has 15.3 million parameters and 5.2 GFLOPs, and the NeuroCST-SA variant has 14.8 million parameters, 4.9 GFLOPs, and a processing time of 11.4 ms per image. The performance demonstrates the effective integration of CNN and transformer in capturing diverse local-global features for robust AD classification.},
}

@article {pmid43022201,
year = {2026},
author = {Singaravel, V},
title = {Optogenetics in neurobiology and neurodegenerative disorders: from neural circuit mechanisms to precision neuromodulation.},
journal = {Frontiers in medical technology},
volume = {8},
number = {},
pages = {1958917},
pmid = {43022201},
issn = {2673-3129},
abstract = {Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and stroke, are characterized by progressive neuronal dysfunction, synaptic impairment and neural circuit degeneration, leading to severe cognitive and motor deficits. Although considerable progress has been made in understanding their molecular pathology, the circuit level mechanisms driving disease onset and progression remain incompletely understood. Optogenetics, which combines microbial opsins, genetic engineering and optical stimulation, enables reversible, cell-specific control of neuronal activity with millisecond precision and has transformed neuroscience from observational analysis to causal investigation of neural circuits. This review summarizes recent advances in the molecular basis of optogenetics, microbial opsins, gene delivery strategies and optical stimulation technologies, together with their applications in basic neurobiology and neurodegenerative disease research. We discuss how optogenetics has advanced understanding of neural circuit organization, synaptic plasticity, memory, neurodevelopment, sleep regulation, protein aggregation, synaptic dysfunction, neuroinflammation, mitochondrial impairment, oxidative stress and regulated cell death. Although these studies have generated important mechanistic insights and demonstrated functional improvements in experimental models, translation into human therapies remains investigational due to challenges associated with gene delivery, long-term opsin expression, immune compatibility and optical accessibility. Emerging therapeutic strategies, including closed-loop neuromodulation, wireless photostimulation, artificial intelligence-assisted neural decoding, nanotechnology enabled light delivery and brain computer interfaces, are critically evaluated with emphasis on their current evidence status, translational challenges and limitations for clinical implementation. Collectively, optogenetics provides an unprecedented platform for deciphering disease mechanisms and evaluating circuit-based neuromodulation strategies, while continued technological and biological validation will determine its future role in precision therapies for neurodegenerative disorders.},
}

@article {pmid43022223,
year = {2026},
author = {Liu, W and Xu, B and Yang, C and Li, G and Yang, X},
title = {Xanthohumol promotes cognitive function-associated neuroprotein changes in two mouse models of Alzheimer's disease.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {1113-1121},
pmid = {43022223},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that progressively impairs cognitive function for which there is no effective treatment. Natural dietary compounds such as xanthohumol (Xn) potentially offer a new therapeutic approach in AD. We aim to employ quantitative proteomic techniques to investigate the effects of Xn on cognitive impairment in two established murine models of AD. Treatment with 0.5 mg/kg Xn significantly improved the ability of stimulating learning and memory and cognitive function of 3 ×Tg AD mice while 5 mg/kg Xn ameliorated cognitive decline in APP/PS1 mice. We identified two common differential proteins and 12 pathways in the hippocampi of 3 ×Tg AD mice and 70 common differential proteins and 22 pathways in APP/PS1 mice. Moreover, Nine common signaling pathways mainly involved in energy metabolism, neurodegenerative disease, cardiovascular disease and cancer. So multi high-throughput proteomic analyses of hippocampus add to the scientific basis for development of effective drugs for AD, one candidate of which is Xn.},
}

@article {pmid43022324,
year = {2026},
author = {Bayram, E and Carter, DJ and Litvan, I},
title = {Sex differences in clinical profile across Lewy body disease pathology stages.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100175},
pmid = {43022324},
issn = {2589-9589},
abstract = {BACKGROUND: Sex impacts clinical profile for people with limbic, neocortical LB pathology, and AD pathology contributes to heterogeneity. Amygdala, olfactory, and brainstem LB can also underlie LB disease and sex differences for these pathology stages are unclear.

METHODS: Data were obtained from National Alzheimer's Coordinating Center for 198 females and 314 males with LB pathology and available data on AD pathology staging. Main and interaction effects of sex and LB pathology group for clinical diagnosis, cognitive, behavioral, and motor outcomes were assessed with logistic and linear regression models, with and without AD pathology staging as a covariate. Sex differences within individual LB pathology groups were also assessed.

RESULTS: Females were less likely to have spouses/partners as informants, had less advanced LB pathology stage, and more advanced ADNC stage. Females were less likely to have RBD and a clinical diagnosis of LB dementia, including after adjustment for AD pathology stage. Advancing LB pathology was associated with a greater reduction in the likelihood of clinical AD diagnosis and a greater increase in the likelihood of auditory hallucinations in males than females, after adjustment for AD pathology stage. Females with neocortical LB pathology were less likely than males to have RBD.

CONCLUSIONS: Lower likelihood of RBD in females was particularly evident at the neocortical LB pathology stage. Clinical correlates of LB pathology may differ by sex, and these sex differences may not be fully explained by AD co-pathology. Considering sex and co-pathology is important for both diagnostic and therapeutic approaches to LB disease.},
}

@article {pmid43022368,
year = {2026},
author = {Taouili, R and Lefebvre, C and Oosterlynck, M and Bouillet, T and Eddarkaoui, S and Musiol, D and Formentin, C and Accart, B and Maurage, CA and Colin, M and Buée, L and Halliez, S},
title = {Deciphering early tau pathology events using an Alzheimer's disease-seeded organotypic hippocampal slice culture model.},
journal = {iScience},
volume = {29},
number = {11},
pages = {118083},
pmid = {43022368},
issn = {2589-0042},
abstract = {In Alzheimer's disease, the spreading of the tau pathology through the brain is assumed to rely on pathological species of tau acting as seeds. To better understand the underlying mechanisms, we need models allowing us to study tau seeding in a brain-like environment. We developed an ex vivo model based on organotypic hippocampal slice cultures prepared from transgenic mouse pups expressing human pro-aggregative mutant tau. We show for the first time that human brain-derived tau seeds are able to potentiate tau pathology in such cultures. Moreover, tau seeds are generated ex vivo, completing the validation of the model. Then, we shed light on the initial events of tau seeding: tau pathology appears sequentially, first in neurites and then in cell bodies, and misfolding (MC1+) precedes pathological phosphorylation (pS422, pT217). Altogether, this makes the present model a highly valuable bioassay to decipher the molecular and cellular mechanisms leading to tau pathology development.},
}

@article {pmid43022413,
year = {2026},
author = {Shan, Q and Li, J and Wang, Y and Gupta, S and Song, L and Zhang, W and Su, F and Guo, Y},
title = {Brain-computer interfaces for neurodegenerative diseases: A comprehensive review of closed-loop systems from diagnosis to neural rehabilitation.},
journal = {iScience},
volume = {29},
number = {11},
pages = {118073},
pmid = {43022413},
issn = {2589-0042},
abstract = {Brain-computer interface (BCI) technology serves as an important bridge between the nervous system and external devices and has shown considerable promise for the diagnosis and treatment of neurodegenerative diseases, whose global burden continues to increase: in 2021, more than 57 million people were living with dementia worldwide, with Alzheimer's disease (AD) accounting for approximately 60-70% of cases, while an estimated 11.77 million people were living with Parkinson's disease (PD) in 2021, according to the Global Burden of Disease Study 2021. This growing disease burden, together with the progressive loss of cognitive, motor, and communicative functions, highlights the need for more precise approaches to early detection, functional assistance, and individualized intervention. Conventional diagnostic and therapeutic approaches remain poorly suited to early detection and timely intervention. This paper analyzes the development of BCI technology, from the first detection of electroencephalogram (EEG) signals to the parallel development of invasive and non-invasive systems, and outlines the basic principles of signal acquisition, processing, and decoding, together with the relative advantages and limitations of different approaches. It then focuses on the use of BCI in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), covering early diagnosis, functional reconstruction, and neuromodulation. The article also discusses the difficulties encountered by BCI technology in terms of technological realization, clinical translation, and ethical considerations, as well as several future research directions, including multimodal fusion, adaptive algorithms, closed-loop control systems, and personalized treatment so as to drive the applications of BCI in precision medicine and in neurological diseases.},
}

@article {pmid43022451,
year = {2026},
author = {Ma, T and Li, Y and Ding, Y and Liu, S and Gao, C and Li, X and Tong, Z and Lv, Y},
title = {Correction: New insight into Alzheimer's disease: small molecule-Aβ in the brain transport and peripheral organ clearance.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {2029384},
doi = {10.3389/fragi.2026.2029384},
pmid = {43022451},
issn = {2673-6217},
abstract = {[This corrects the article DOI: 10.3389/fragi.2026.1921485.].},
}

@article {pmid43022618,
year = {2026},
author = {Jiang, Y and Wu, L and Li, W and Li, L and Huang, Z and Gui, Y and Wang, JZ and Liu, R and Jing, CH and Wang, X},
title = {Tau spread plays an etiopathogenic connection between seizures and Alzheimer's disease.},
journal = {iScience},
volume = {29},
number = {11},
pages = {117747},
pmid = {43022618},
issn = {2589-0042},
abstract = {Patients with Alzheimer's disease (AD) display heightened seizure susceptibility, in which neuronal hyperactivity during seizures correlates with exacerbated Tau pathology and cognitive impairment. This study integrated public transcriptomic datasets with machine learning approaches, suggesting Tau spread as a key biological association between seizure activity and AD. We validated activity-dependent Tau release under epileptic stimulation using primary neurons and human induced pluripotent stem cells (hiPSC)-derived neuronal models. Further validation in an AAV-based mouse Tau propagation model revealed robust bidirectional interactions: pathological Tau overexpression worsened seizure outcomes, while seizures accelerated Tau propagation across brain regions, inducing neuronal loss and gliosis. This study characterizes the activity-regulated interplay between epileptic activity and AD-associated Tau pathology, offering a potential therapeutic target for AD comorbid with epilepsy.},
}

@article {pmid43022635,
year = {2026},
author = {Liu, Y and Yang, R and Chang, H},
title = {Neurovascular-immune-clearance remodeling in brain aging.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1950144},
pmid = {43022635},
issn = {1664-3224},
mesh = {Humans ; *Aging/immunology/pathology ; *Brain/immunology/blood supply/metabolism/pathology ; Animals ; Blood-Brain Barrier/immunology/metabolism ; Glymphatic System/immunology/metabolism ; Neuroimmunomodulation ; Biomarkers ; Cellular Senescence ; },
abstract = {Brain aging involves concurrent changes in cerebral vessels, immune regulation, and waste clearance, yet these processes are often studied separately. This fragmented approach limits understanding of how dysfunction in one system influences the others and contributes to age-related neurological disorders. This review summarizes current evidence on the neurovascular-immune-clearance axis, focusing on neurovascular unit deterioration, impaired glymphatic and meningeal lymphatic transport, neuroimmune remodeling, and the cell-specific mechanisms that connect these processes. We further compare their shared and disease-dependent roles in Alzheimer's disease, vascular cognitive impairment, and late-life depression. Available imaging, fluid, proteomic, and epigenetic biomarkers are evaluated for their ability to measure different components of this axis, and emerging interventions are organized according to their predominant effects on vascular support, clearance function, immune signaling, and cellular senescence. Current evidence indicates that brain aging is characterized by interacting and partially compensable functional bottlenecks rather than a single linear pathological pathway. Integrating these mechanisms provides a framework for interpreting heterogeneous aging phenotypes, selecting complementary biomarkers, and developing mechanism-guided interventions. Future progress will depend on longitudinal human validation and direct demonstration that target engagement produces durable neurological benefit.},
}

Humans
*Aging/immunology/pathology
*Brain/immunology/blood supply/metabolism/pathology
Animals
Blood-Brain Barrier/immunology/metabolism
Glymphatic System/immunology/metabolism
Neuroimmunomodulation
Biomarkers
Cellular Senescence

@article {pmid43022642,
year = {2026},
author = {Wang, L and Lai, W and Wei, T and Zhang, Y and Wen, Y},
title = {Physical activity in preclinical Alzheimer disease: current evidence and implications for multimodal longitudinal research.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1978500},
pmid = {43022642},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnosis/metabolism ; *Exercise/physiology ; Longitudinal Studies ; Biomarkers ; Gait/physiology ; },
abstract = {Alzheimer disease (AD) pathology may be detectable years before cognitive symptoms, but biomarker testing of cognitively unimpaired people is not recommended for routine clinical use. Objective physical activity (PA), gait, and rest-activity measures are attractive research signals because they are repeatable and relatively inexpensive; however, none are specific to AD. This narrative review examined evidence linking PA, gait, and rest-activity measures to AD-related outcomes and considered their role in multimodal longitudinal research within biomarker-characterized cohorts. Targeted searches of PubMed, Scopus, and IEEE Xplore were conducted from inception through 25 August 2026, and reference lists of pivotal studies and guidance documents were hand-searched. Priority was given to guidelines, longitudinal cohorts, randomized trials, studies using objective behavior measures and AD biomarkers, and externally evaluated prediction models. Observational evidence links higher activity with lower dementia risk, but reverse causation remains plausible. In biomarker-characterized cohorts, greater baseline step count has been associated with slower amyloid-related tau accumulation and slower cognitive and functional decline, not with lower amyloid burden. Rest-activity fragmentation has shown cross-sectional and prospective associations with amyloid-related measures, whereas a 1-year aerobic-exercise trial did not reduce amyloid accumulation. Recent multimodal AI studies demonstrate that non-PET (positron emission tomography) data can estimate amyloid and tau status. Yet, they do not establish the incremental value of free-living PA in cognitively unimpaired community samples. We therefore outline a framework for longitudinal behavioral research in cohorts whose biomarker status has been characterized independently of PA-based selection. Its primary purpose is to examine associations between behavioral measures and subsequent cognitive, functional, and tau trajectories. Whether PA improves individual prediction beyond clinical information and baseline biomarkers remains a separate, unresolved question. PA is considered a contextual behavioral measure, and the framework does not propose using it to determine eligibility for biomarker testing or research recruitment.},
}

Humans
*Alzheimer Disease/physiopathology/diagnosis/metabolism
*Exercise/physiology
Longitudinal Studies
Biomarkers
Gait/physiology

@article {pmid43022806,
year = {2026},
author = {Shan, Q and Zheng, W and Yao, W and Bai, Y and Ding, W and Wang, J and Bai, F},
title = {Developing precision nanoparticle-based drug delivery systems for Alzheimer's disease therapy.},
journal = {Materials today. Bio},
volume = {41},
number = {},
pages = {103789},
pmid = {43022806},
issn = {2590-0064},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease that has thus far suffered from unsatisfactory therapeutic outcomes. Despite ongoing research into AD pathogenesis and related drugs, few disease-modifying therapies are currently available. Moreover, efficient drug delivery is significantly hindered by low permeability of the blood-brain barrier (BBB) and non-specific distribution within the brain, further limiting the efficacy of existing anti-AD medications. Nanotechnology has recently emerged as a promising approach to overcome these challenges. This review aims to offer a comprehensive overview of recent advances in precision nanoparticle-based drug delivery systems for AD therapy. First, we outline the multiple pathological mechanisms and representative pathogenesis-inspired therapies of AD. Next, we summarize various types of nanoparticles that have been utilized in AD drug delivery, including polymeric, lipid-based, inorganic, and biomimetic nanocarriers. Subsequently, we highlight the nanoparticle-mediated strategies for cascaded precision drug delivery at different levels, focusing on both the BBB and specific pathologies or cell populations within AD lesions. Finally, we discuss potential challenges and prospects in employing precision delivery systems, aiming to accelerate the development and clinical translation of nanoparticle-based therapies for AD.},
}

@article {pmid43022882,
year = {2026},
author = {Lee, N and Youn, K and Kwon, H and Kim, DH and Ho, CT and Jun, M},
title = {Correction: Fucoxanthin attenuates carbonyl stress and neuroinflammation by modulating MGO/RAGE/NF-κB axis in Aβ-induced models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {2023015},
doi = {10.3389/fphar.2026.2023015},
pmid = {43022882},
issn = {1663-9812},
abstract = {[This corrects the article DOI: 10.3389/fphar.2026.1811183.].},
}

@article {pmid43023022,
year = {2026},
author = {Huang, H and Bao, X and Deng, Q},
title = {Long-Term Neutrophil Depletion and Flow Cytometric Analysis of Brain Neutrophils in the 5xFAD Mouse Model.},
journal = {Bio-protocol},
volume = {16},
number = {21},
pages = {e5864},
pmid = {43023022},
issn = {2331-8325},
abstract = {Neutrophils are the most abundant circulating leukocytes in human blood and have been implicated in the progression of Alzheimer's disease (AD). Elevated neutrophil numbers have been observed in the blood and brain parenchyma of AD patients and mouse models, yet their precise pathological role remains poorly understood. A major barrier to progress is the lack of validated protocols for long-term neutrophil depletion and reliable recovery of brain-infiltrating neutrophils for characterization. Here, we describe a step-by-step protocol for sustained neutrophil depletion in the 5xFAD mouse model using intraperitoneal injection of an anti-Ly6G antibody for six weeks. We used a dose-escalation strategy to maintain depletion efficiency, as neutrophil regeneration increases over time. We also applied a previously established flow cytometry method to monitor neutrophil depletion in peripheral blood, using an antibody panel designed to avoid interference from the depleting anti-Ly6G clone. Furthermore, we present an optimized brain tissue processing workflow that combines mechanical dissociation with Percoll density gradient centrifugation to collect brain-infiltrating neutrophils for downstream flow cytometric analysis. Here, this workflow was applied and validated in the 5xFAD mouse model but is not specific to AD brain tissue and may be applicable to other mouse models. Key features • Depletion of circulating neutrophils in mice. • Assessment of neutrophil depletion efficiency in mouse blood. • Processing of mouse brain parenchyma and recovery of brain-infiltrating neutrophils. • Flow cytometric analysis of neutrophils isolated from mouse brain tissue.},
}

@article {pmid43023262,
year = {2027},
author = {Chen, H and Ding, T and Zhu, Y and Yang, M and Wang, F and Chen, P and Lin, H and Kang, H and Hu, M and Zhou, J and Wang, X},
title = {Metabolic syndrome and Alzheimer's disease: Mechanistic links and precision prevention (Review).},
journal = {International journal of molecular medicine},
volume = {59},
number = {1},
pages = {},
doi = {10.3892/ijmm.2026.6051},
pmid = {43023262},
issn = {1791-244X},
mesh = {Humans ; *Alzheimer Disease/prevention & control/metabolism/etiology/pathology ; *Metabolic Syndrome/complications/metabolism/prevention & control ; Animals ; Brain/metabolism ; *Precision Medicine ; Oxidative Stress ; },
abstract = {Metabolic syndrome (MetS) is associated with increased risk of Alzheimer's disease (AD), however, the majority of previous studies regard MetS as an isolated risk factor and focus on single pathways, lacking systematic understanding of combined effects among multiple metabolic components. The present review systematically summarizes the multifaceted mechanisms by which MetS promotes AD pathology, including insulin resistance and cerebral energy dysregulation, oxidative stress and mitochondrial dysfunction, neuroinflammation and glial cell activation, vascular dysfunction and dysregulation of the renin‑angiotensin system, as well as the central convergent signaling pathway involving glycogen synthase kinase‑3β. The present review further highlights emerging regulatory mechanisms involving the gut‑brain axis, epigenetic reprogramming, sex differences and hormonal effects and senescent microenvironment. By emphasizing the peripheral‑central crosstalk and interactive amplification of MetS components, the present review aimed to position AD as a central manifestation of systemic metabolic disorders in the brain and propose a multi‑domain precision strategy integrating lifestyle intervention, metabolic drug repurposing, gut microbiota regulation, anti‑aging therapy and biomarker‑guided subtype classification for intervention against MetS‑associated AD.},
}

Humans
*Alzheimer Disease/prevention & control/metabolism/etiology/pathology
*Metabolic Syndrome/complications/metabolism/prevention & control
Animals
Brain/metabolism
*Precision Medicine
Oxidative Stress

@article {pmid43023264,
year = {2026},
author = {de Moraes, RF and Athanasio, BDS and Carmona, KC and Gambogi, LB and Belotto, LGF and Resende, EPF and Caramelli, P and de Souza, LC},
title = {Cerebral perfusion SPECT in the diagnostic framework of degenerative dementias: still useful after all these years.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {},
doi = {10.1159/ndd/aduag010},
pmid = {43023264},
issn = {1660-2862},
abstract = {INTRODUCTION: The clinical distinction between the different types of dementia is a clinical challenge and establishing an accurate diagnosis is essential for guiding treatment. We aimed to investigate the diagnostic value of cerebral perfusion SPECT in the diagnostic framework of dementias.

METHODS: We included patients with cognitive disorders who underwent a cerebral SPECT between 2013-2019. Medical data for all participants were collected, and clinical diagnosis were established independently of the SPECT findings. All SPECT images were blindly analysed, by describing the topographical patterns of hypoperfusion.

RESULTS: We included 51 patients: typical Alzheimer's disease (AD; n=24), behavioral variant frontotemporal dementia (bvFTD, n=15), primary progressive aphasia (PPA, n=6), and atypical AD (logopenic aphasia and behavioral/dysexecutive variant AD, n=6). SPECT achieved 72% and 66% for distinguishing typical AD from bvFTD and AD (typical and atypical cases) from FTD (PPA and bvFTD), respectively. Compared to bvFTD, hypoperfusion in inferior parietal (p < 0.002), in the superior parietal (p < 0.01) and in the lateral temporal (p < 0.018) regions were more frequent in the typical AD group. Considering all AD cases (typical and atypical presentations) and FTD (PPA and bvFTD), hypoperfusion in the anterior temporal (p < 0.03) and in basal ganglia (p < 0.026) were more frequent in the FTD group. On the contrary, hypoperfusion in inferior parietal (p < 0.0001), in the superior parietal (p < 0.004) and in the lateral temporal (p < 0.03) cortex were more common in AD than in FTD patients.

CONCLUSION: The diagnostic value of a SPECT for differentiating dementias is limited, but specific topographical patterns of hypoperfusion may be useful for distinguishing AD from bvFTD.  .},
}

@article {pmid43023272,
year = {2026},
author = {Pal, T and Singh, P},
title = {Oleandrin-mediated Neuroprotection: BDNF/TrkB Activation, CREB Modulation, and Implications for Neurovascular Degeneration.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026489314261028110331},
pmid = {43023272},
issn = {1875-5739},
abstract = {INTRODUCTION: Oleandrin, a cardiac glycoside derived from Nerium oleander, has been identified for its neuroprotective potential. This review article will discuss the broad molecular mechanisms by which oleandrin targets neurovascular degeneration and its potential to influence critical signaling pathways that regulate oleandrin-related neuronal survival, plasticity, and inflammation.

METHODS: These data come from studies using models of ischemic stroke, oxygen-glucose deprivation, excitotoxicity, and neurodegenerative diseases. The literature search was conducted using relevant scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar. Keywords such as oleandrin, Nerium oleander, BDNF, TrkB, CREB, neuroprotection, and cerebral ischemia were used sequentially. Oleandrin's influence on the BDNF-TrkB, MAPK/ERK, PI3K/Akt, and PLC-γ signaling cascades, CREB phosphorylation, and NF-κB inactivation were used to make the hypotheses.

RESULTS: Oleandrin increases endogenous BDNF expression and activates TrkB receptors, which triggers signaling cascades such as MAPK/ERK, PI3K/Akt, and PLC-γ. Oleandrin also increases phosphorylation of CREB protein on serine 133, thereby increasing neuroprotective gene expression and suppressing NF-κB-driven inflammation.

DISCUSSION: Oleandrin's neuroprotective effect suggests the possibility of developing a bifunctional drug that targets both CREB and BDNF-TrkB signaling for the treatment of central nervous system disorders. However, the major challenge associated with the use of oleandrin in therapy is its delivery mechanism for the treatment of stroke and other brain diseases, such as Alzheimer's.

CONCLUSION: Oleandrin has significant neuroprotective properties via its anti-inflammatory and neuroprotective mechanisms. Oleandrin is a therapeutic candidate, showing neurovascular protection and efficacy in animal models. More work is needed in clinical studies and drug design.},
}

@article {pmid43023278,
year = {2026},
author = {Wang, Z and Li, T and Li, K},
title = {Targeting Long Non-Coding RNAs in Tau Phosphorylation: A New Paradigm for Diagnosis and Therapy in Tauopathies.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X524281261028113749},
pmid = {43023278},
issn = {1875-6190},
abstract = {Tau phosphorylation is a critical regulatory process in neuronal physiology, and its dysregulation is a hallmark of tauopathies, including Alzheimer's disease. While canonical protein kinases and phosphatases have been extensively studied as regulators of tau phosphorylation, long non-coding RNAs (lncRNAs) have recently emerged as key epigenetic and post-transcriptional modulators of this process. This review comprehensively synthesizes current evidence on the mechanistic roles of lncRNAs in regulating tau phosphorylation. This study describes four primary mechanisms through which lncRNAs influence tau phosphorylation: (1) acting as competing endogenous RNAs (ceRNAs) to sponge microRNAs that target tau or tau-modifying enzymes, (2) functioning as natural antisense transcripts that modulate the expression of tau kinases, (3) modulating gene expression through epigenetic and transcriptional regulation, and (4) influencing protein activity and mRNA stability. This study further examines the cellular clearance of hyperphosphorylated tau via the ubiquitin-proteasome and autophagy-lysosomal pathways and identifies the unexplored role of lncRNAs in these degradation processes as a critical knowledge gap. Finally, we discuss the translational potential of lncRNAs as non-invasive diagnostic biomarkers detectable in biofluids and as promising therapeutic targets for tauopathies. Understanding the intricate regulatory networks of lncRNAs in tau phosphorylation provides novel mechanistic insights into tau pathology and opens new avenues for diagnosis and therapeutic intervention in neurodegenerative diseases.},
}

@article {pmid43023279,
year = {2026},
author = {Henderson, H and Crain, N and Xie, JY},
title = {Which Modality of Physical Exercise is More Effective at Treating and Preventing Alzheimer's Disease: Aerobic or Anaerobic?.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050510461261027055519},
pmid = {43023279},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) is a chronic neurological disease that causes memory loss and progressive cognitive decline, resulting in severe disability and eventual death. AD presents significant difficulties to patients, their families, and the healthcare system. Currently, there is no cure for this disease. Available treatment options focus on addressing symptomatology and have mixed efficacy, along with considerable adverse effects. We aim to review the current literature proposing exercise as an intervention and preventive strategy for AD and to compare aerobic vs. anaerobic exercise to determine which is most beneficial for this purpose.

METHODS: A literature search was conducted in the PubMed database using the following terms: exercise, physical activity, Alzheimer's disease, prevention, aerobic, anaerobic, endurance training, and resistance training. Selected studies were written in English and published between 2000 and 2026.

RESULTS AND DISCUSSION: A thorough review of recently published literature suggests that exercise is indeed an effective strategy to address and prevent cognitive decline associated with AD. It may also play a role in preventing the onset of disease altogether, though more research is needed to confirm this. Both aerobic and anaerobic exercise appear to be effective and beneficial for AD patients. However, the biochemical changes elicited by these two forms of exercise are largely different.

CONCLUSION: Both aerobic and anaerobic exercises are beneficial for AD. A combination of both types of exercise may yield optimal results due to their distinct biochemical effects.},
}

@article {pmid43023336,
year = {2026},
author = {Gan, Y and Yang, M and Li, J and Tan, H and Wang, Q and Xu, D and Liang, S and Xiao, Z and Tian, S and Wang, Z and Zeng, Y and Liu, Q and Yao, K and Lin, Y and Ning, Y and Chen, B and Zhong, X},
title = {Olfactory network variability is associated with odor identification and cognitive performance in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261502862},
doi = {10.1177/13872877261502862},
pmid = {43023336},
issn = {1875-8908},
abstract = {BackgroundOdor identification impairment is an early marker of Alzheimer's disease pathology and predicts dementia conversion in mild cognitive impairment (MCI). However, the pathophysiological role of dynamic functional connectivity (dFC) variability within olfactory networks remains unclear.ObjectiveTo characterize seed-based dFC variability across olfactory pathways in MCI with odor identification impairment (MCI-OII) and examine its associations with olfactory and cognitive performance.MethodsNinety-seven patients with MCI were recruited and subdivided into MCI-OII and those without odor identification impairment (MCI-NOII), along with 97 age-matched healthy controls (HC). All participants underwent neuropsychological assessment, olfactory testing, and resting-state functional magnetic resonance imaging. Seed-based dFC variability was computed using a sliding window approach. Correlation and exploratory mediation analyses examined associations among abnormal dFC, odor identification, and cognition.ResultsCompared to MCI-NOII and HC, MCI-OII exhibited increased dFC variability between the left piriform cortex/right insula and right caudate nucleus, and between the left insula and left middle frontal gyrus. For the connection between the left insula and left cerebellar lobule VI, dFC variability showed a graded pattern from MCI-OII to HC to MCI-NOII. Increased caudate-centered dFC variability was associated with poorer odor identification, memory, and executive performance. Furthermore, exploratory mediation analyses suggested indirect associations involving odor identification, caudate-centered dFC variability, and memory or executive function.ConclusionsMCI-OII is characterized by increased olfactory-network dFC variability, particularly in caudate-centered pathways. These findings suggest that dFC variability may serve as a candidate network-level marker of concurrent olfactory impairment and cognitive dysfunction in MCI.},
}

@article {pmid43023339,
year = {2026},
author = {Dajani, I and Alsheik, N and Chaari, A},
title = {Multimodal neuroimaging in Alzheimer's disease: A practical, case-illustrated review of quantitative MRI and molecular PET.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261505047},
doi = {10.1177/13872877261505047},
pmid = {43023339},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) accounts for 60-70% of dementia cases worldwide. Current diagnostic pathways rely on structural magnetic resonance imaging (MRI) to exclude secondary causes, amyloid positron emission tomography (PET) to confirm pathology, and tau PET for disease staging. However, these approaches are limited by subjectivity, cost, accessibility, and variability in interpretation. Quantitative imaging tools such as volumetric MRI and NeuroQuant offer reproducible metrics that may enhance diagnostic precision and standardization. This review synthesizes literature published between 2000 and 2026 evaluating structural MRI, quantitative volumetric MRI, amyloid PET, tau PET, FDG PET, and emerging adjunctive imaging techniques, supplemented by illustrative clinical cases demonstrating multimodal integration in practice. Particular emphasis is placed on the role of NeuroQuant in standardized atrophy quantification and its integration with molecular imaging modalities. Volumetric MRI enhances PET-based diagnosis and staging by contextualizing amyloid and tau pathology within patterns of selective neurodegeneration. Quantitative metrics correlate with cognitive decline and disease progression. Multimodal imaging strategies improve diagnostic specificity, longitudinal monitoring, and phenotypic stratification across the AD. Multimodal imaging provides a comprehensive framework for AD management. Quantitative MRI using NeuroQuant bridges structural and molecular domains, supporting standardized assessment and integration with emerging precision diagnostic approaches.},
}

@article {pmid43023441,
year = {2026},
author = {Singh, V and Mishra, R and Mazumder, R and Mazumder, A and Rani, A},
title = {Emerging Nanoparticle Therapeutic Approaches for Alzheimer's Disease: Target Sites and Mechanistic Insights.},
journal = {Recent patents on nanotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118722105513615261105103058},
pmid = {43023441},
issn = {2212-4020},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a progressive neurodegenerative condition and the most frequent cause of dementia among the elderly. AD is characterized by extracellular accumulation of amyloid plaques, neurofibrillary tangles, and glial responses, which result in neuronal and synaptic loss. The ongoing research into therapeutic interventions has shifted from symptomatic management toward disease-modifying strategies, including approaches targeting amyloid aggregation, tau pathology, neuroinflammation, and synaptic repair.

METHODS: The manuscript presents a thorough analysis of the targeted strategy, with particular emphasis on the application of nanoparticle-based systems for improve the management of Alzheimer's disease. Studies examining the role of tau protein, Amyloid Beta (Aβ), and other peptides in forming the pathological framework of Alzheimer's disease were included in the analysis.

RESULTS: Recent findings indicate that nanoparticle-based approaches have enhanced therapeutic efficacy through targeted drug delivery, improved penetration across the blood-brain barrier, and attenuation of neuroinflammation, thereby offering promising benefits in the management of Alzheimer's disease. The growing interest in nanotechnology-based interventions for Alzheimer's disease is reflected in a substantial number of patented innovations, including liposomal formulations, cerium oxide nanoparticles, and natural nanoparticle-pharmaceutical compositions.

DISCUSSION: Nanoparticle-based therapeutics demonstrate multifaceted efficacy in addressing Alzheimer's disease pathology. By directly inhibiting the accumulation and expression of key pathogenic targets-such as amyloid-beta and hyperphosphorylated tau-while simultaneously modulating microglial activity and neuroinflammatory cascades, nanotechnology targets mechanisms that traditional therapies often fail to resolve.

CONCLUSION: Moving beyond conventional symptom-focused care, nano-enabled delivery systems offer a scalable strategy to enhance drug efficacy and cross the blood-brain barrier. Future research should prioritize translating these preclinical nanotherapeutic platforms into standardized clinical applications.},
}

@article {pmid43023504,
year = {2026},
author = {Joshi, KD and Pathak, D and Dave, A and Prajapati, O and Barmade, MA and Yadav, MR and Murumkar, PR},
title = {Therapeutic Potential of Pyrazole-based Molecules in Alzheimer's Disease: A Review of Progress and Prospects.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575478631261027032241},
pmid = {43023504},
issn = {1875-5607},
abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disease involving many pathophysiological factors in its genesis. While its complex etiology poses significant therapeutic challenges, it also presents opportunities to develop novel drugs that modulate specific biological targets involved in its pathogenesis. Pyrazole is a privileged scaffold present in various molecules with the potential to ameliorate multiple diseases and disorders. Several pyrazole -containing molecules have cleared clinical trials and are currently available on the market, highlighting the pyrazole ring as a promising scaffold for drug design. Researchers have designed, synthesized, and evaluated an array of biologically active pyrazole derivatives, targeting different pathways in AD, reporting promising lead molecules with potent activities. This review comprehensively covers the literature on pyrazole-containing compounds as Anti-AD agents capable of targeting key pathophysiological hallmarks, such as cholinergic esterase enzymes (AChE/BuChE inhibitors), amyloid (Aβ40-42 aggregation inhibitors), tau protein (GSK3β inhibitors), biometals (metal chelators, antioxidants, and ROS scavengers), and certain newer targets like MAO (MAO-A/B inhibitors) and PDE (PDE 1-10 inhibitors).},
}

@article {pmid43023509,
year = {2026},
author = {Javid, S and Mardani, Z},
title = {Beta-Amino Alcohols as Key Frameworks in Drug Discovery: A Review of Medicinal Applications and Biological Profiles.},
journal = {Medicinal chemistry (Shariqah (United Arab Emirates))},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734064529260261104134338},
pmid = {43023509},
issn = {1875-6638},
abstract = {Beta-Amino alcohols, as pivotal frameworks in organic and medicinal chemistry, play a prominent role in drug design and development. This comprehensive review evaluates the therapeutic potential of β-amino alcohols, highlighting their significance in the management of a broad spectrum of human pathologies, including cancer, bacterial infections, malaria, and viral diseases. Furthermore, the efficacy of these molecules in cardiovascular, respiratory, and ocular disorders is assessed. Alongside their therapeutic applications, the epoxide ring-opening process, the primary and most established synthetic pathway for constructing β-amino alcohol cores, is critically discussed and integrated with structure activity relationship (SAR) insights to demonstrate how specific chemical modifications dictate pharmacological potency. The consolidated findings reveal that β-amino alcohols exert their therapeutic effects through diverse molecular mechanisms. These pathways encompass the suppression of malignant cell proliferation, potent bactericidal activity against resistant Staphylococcus aureus strains, inhibition of Plasmodium species in malaria, targeting the main protease (Mpro) of SARS-CoV-2 for COVID-19 therapeutics, and functioning as dual-binding cholinesterase inhibitors for Alzheimer's disease management. Additionally, these derivatives have been reported to modulate adrenergic receptors, highlighting their potential relevance to cardiovascular, respiratory, and ocular therapeutic research, including conditions such as hypertension, asthma, and glaucoma. Overall, this review provides an up-to-date analysis of β-amino alcohol-based therapeutic applications and offers a new perspective on the potential role of these compounds in modern medicinal chemistry, which may contribute to the rational design of novel drug candidates.},
}

@article {pmid43023511,
year = {2026},
author = {Bhanja, SS and Tripathy, S and Sharma, DK},
title = {Therapeutic Potential of Liposomes in Targeting Neurodegenerative Diseases: Mechanistic Insights and a Future Perspective.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026509056261030055920},
pmid = {43023511},
issn = {1875-5739},
abstract = {INTRODUCTION: Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are progressive disorders with limited disease-modifying treatments. Poor drug bioavailability, systemic toxicity, and restricted Blood-Brain Barrier (BBB) penetration remain major therapeutic challenges. Although previous reviews have discussed liposomal delivery, an updated mechanistic and translational assessment is needed.

METHODS: This review analyzed relevant studies on liposome-based drug delivery for neurodegenerative diseases, focusing on BBB penetration, targeting strategies, formulation characteristics, therapeutic mechanisms, and translational challenges.

RESULTS: Liposomes improve drug solubility, stability, bioavailability, and brain delivery through passive transport, receptor-mediated transcytosis, adsorptive-mediated transport, and ligandassisted targeting. Functionalization with transferrin, lactoferrin, peptides, antibodies, and other ligands can enhance BBB transport and site-specific delivery. Liposomal systems target key pathological mechanisms, including amyloid-β aggregation, oxidative stress, neuroinflammation, mitochondrial dysfunction, and dopaminergic neuronal degeneration. Major gaps include limited clinical validation, long-term safety data, BBB-targeting efficiency, formulation stability, and manufacturing scalability.

DISCUSSION: Compared with earlier reviews, this review integrates recent advances in liposome engineering with disease-specific mechanisms, BBB-targeting strategies, therapeutic outcomes, and translational barriers, providing a comprehensive perspective on the progression from preclinical development toward clinical application.

CONCLUSION: Liposomes represent a promising platform for targeted therapy of neurodegenerative diseases. Standardized evaluation, scalable manufacturing, long-term safety assessment, and well-designed clinical trials are essential for establishing their therapeutic efficacy and facilitating clinical translation.},
}

@article {pmid43023513,
year = {2026},
author = {Zhang, H and Li, X and Yang, M and Chu, B and Shang, Q and Feng, Z and Li, W and Bai, X and Wang, F},
title = {Neuroinflammation and Brain Network Remodeling in Alzheimer's Disease: Integrating DTI, fMRI, TSPO-PET, and Fluid Biomarkers.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050507382261028073350},
pmid = {43023513},
issn = {1875-5828},
abstract = {In Alzheimer's disease (AD), how neuroinflammation triggers white-matter injury and remodels functional networks remains a core unresolved question. This narrative review surveys research progress, technical approaches, and outstanding challenges of multimodal neuroimagingincluding diffusion tensor imaging (DTI), functional MRI (fMRI), translocator protein PET (TSPOPET), and fluid biomarkers-in elucidating neuroinflammation in AD. Five themes are discussed: molecular and fluid biomarkers of neuroinflammation; DTI-characterized signatures of white matter damage; fMRI-demonstrated functional network reorganization; alterations in structure-function coupling; and machine learning-enhanced multimodal data fusion strategies. Future multicenter longitudinal studies with standardized acquisition and analysis protocols are needed to dissect the causal chain of "inflammation → microstructural injury → network collapse → cognitive decline" and to establish an integrated imaging-biology framework for early screening and longitudinal monitoring of AD.},
}

@article {pmid43023698,
year = {2026},
author = {Gobbo, S and Amati, V and Tosi, G and , },
title = {Neuropsychiatric symptoms in MCI, AD, and healthy older adults: a network analysis perspective.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13607863.2026.2761610},
pmid = {43023698},
issn = {1364-6915},
abstract = {OBJECTIVES: Alzheimer's Disease (AD), while traditionally classified as a cognitive disorder, is also characterized by neuropsychiatric symptoms (NPS). Despite their clinical relevance, NPS are often under-assessed or rarely examined in conjunction with cognitive symptoms. Here, we aimed to explore the dynamic interplay between cognitive and neuropsychiatric symptoms across the AD continuum.

METHOD: We applied moderated Mixed Graphical Models (mMGMs) to a large sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including Normal Controls (NC), individuals with Mild Cognitive Impairment (MCI), and patients with AD.

RESULTS: Moderation analyses showed that diagnosis significantly influenced key relationships, such as those between visual hallucinations and visuoconstructive or memory functions, and between delusions and semantic fluency. Centrality analyses identified bridging symptoms-such as apathy, semantic fluency, and MMSE performance linking cognitive and psychiatric domains, highlighting their clinical relevance. In addition, diagnosis-specific patterns of symptom interaction were found, with AD patients displaying a denser and more interconnected network between cognitive and neuropsychiatric domains compared to the other groups.

CONCLUSIONS: These findings support a more integrated conceptualization of AD pathology, where cognitive and neuropsychiatric symptoms co-evolve. Early identification and treatment of NPS may therefore be critical to improve quality of life and for informing comprehensive diagnostic and therapeutic strategies.},
}

@article {pmid43024001,
year = {2026},
author = {Castro-Fonseca, E and Meireles, F and Monteiro, M and Guimarães, DM and Morais, V and Freitas, J and de Lima, CVF and de Moraes, FHP and Bramati, I and Vianna-Barbosa, R and Wollner, J and da Silva, CG and Mello-Neto, AF and Oliveira, LE and Andrade-Moraes, CH and Oliveira-Pinto, AV and Sudo, FK and Assunção, N and Alho, AT and Ferretti-Rebustini, REL and Leite, REP and Suemoto, CK and Rodriguez, RD and Jacob-Filho, W and Nitrini, R and Pasqualucci, CA and Grinberg, LT and Mattos, P and Tovar-Moll, F and Lent, R},
title = {Microstructural alterations of human medial temporal lobe in dementia: volumetric and DTI findings correlate with cell number and neuropathology.},
journal = {Brain structure & function},
volume = {231},
number = {9},
pages = {},
pmid = {43024001},
issn = {1863-2661},
mesh = {Humans ; *Temporal Lobe/pathology/diagnostic imaging ; Male ; *Diffusion Tensor Imaging ; Female ; Aged ; *Alzheimer Disease/pathology/diagnostic imaging ; Cell Count ; Aged, 80 and over ; *Cognitive Dysfunction/pathology/diagnostic imaging ; Middle Aged ; Magnetic Resonance Imaging ; *Dementia/pathology ; Anisotropy ; },
abstract = {Volumetric and diffusion tensor imaging (DTI) alterations in medial temporal lobe (MTL) regions are consistently reported in Alzheimer's disease (AD). However, their biological basis remains poorly understood. We combined Magnetic Resonance Imaging (MRI) metrics with cellular quantification and neuropathological burden assessment to investigate microstructural substrates underlying MTL imaging alterations in human donors with known cognitive and neuropathological status. Absolute cell numbers were quantified in a cohort of 54 brain donors using the isotropic fractionator, and postmortem MRI was performed on a subset of 18 fixed brain hemispheres. To assess microstructural brain alterations associated with disease progression, in vivo volumetric and DTI metrics were analyzed in 39 cognitively unimpaired controls (CU), 31 individuals with mild cognitive impairment (MCI), and 14 patients with clinical AD dementia. In the postmortem cohort, MTL diffusivity metrics showed moderate negative correlations with total cell numbers. Mean, axial, and radial diffusivity positively correlated with Braak stage, whereas fractional anisotropy (FA) correlated negatively with CERAD score, linking diffusion alterations to AD-related pathology. In vivo MTL analyses revealed increased mean, axial, and radial diffusivity, and reduced FA in AD patients compared with both CU and MCI individuals. The MCI group exhibited intermediate alterations in diffusivity. Differences between in vivo and postmortem diffusion values were consistent with tissue fixation, temperature, and variations in acquisition protocols. Our findings suggest that diffusion MRI alterations in the MTL are associated with reduced cellularity and neuropathological burden, supporting the biological relevance of DTI metrics as markers of microstructural degeneration in AD.},
}

Humans
*Temporal Lobe/pathology/diagnostic imaging
Male
*Diffusion Tensor Imaging
Female
Aged
*Alzheimer Disease/pathology/diagnostic imaging
Cell Count
Aged, 80 and over
*Cognitive Dysfunction/pathology/diagnostic imaging
Middle Aged
Magnetic Resonance Imaging
*Dementia/pathology
Anisotropy

@article {pmid43024124,
year = {2026},
author = {Huixuan, H and Ruizhe, W and Chunrong, H and Na, W and Tianwai, D and Ludan, Y and Wenzhe, L and Xiaofang, S},
title = {PPARγ at the Nexus of Lipid Metabolism and Neuroinflammation in Alzheimer's Disease: A Longitudinal Multi-omics Analysis.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {43024124},
issn = {1559-1166},
support = {PL2025H042//Natural Science Foundation of Heilongjiang Province/ ; 20240303100228//Science and Technology Department, Heilongjiang Province/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism ; *PPAR gamma/metabolism/genetics ; *Lipid Metabolism ; Animals ; Multiomics ; },
abstract = {Peroxisome proliferator-activated receptor gamma (PPARγ) has emerged as an important regulator linking lipid metabolism and neuroimmune responses in Alzheimer's disease (AD). Increasing evidence suggests that disruption of the lipid-immune axis contributes to disease progression and may underlie the heterogeneous therapeutic responses observed with PPARγ-targeted interventions. Experimental studies indicate that PPARγ activation influences multiple biological processes relevant to AD, including lipid homeostasis, mitochondrial function, inflammatory signaling, and amyloid-β clearance. However, the translation of these findings into consistent clinical benefit remains limited by challenges such as poor blood-brain barrier penetration, systemic adverse effects, and disease stage-dependent therapeutic responses. Recent advances in multi-omics technologies and single-cell transcriptomics have provided new insights into the context-dependent roles of PPARγ in different neural cell populations, highlighting dynamic interactions between lipid metabolism, neuroinflammation, and cellular function throughout AD progression. These findings suggest that PPARγ-associated pathways may represent an important regulatory interface linking metabolic and inflammatory processes, while emphasizing the complexity of their temporal and cell-specific regulation. This review synthesizes current evidence from experimental studies, human multi-omics investigations, and clinical research to provide an updated perspective on the role of PPARγ in coordinating lipid metabolism and neuroinflammation in AD. In addition, we discuss the major translational challenges and emerging therapeutic strategies, including selective PPARγ modulation, improved central nervous system delivery, and precision treatment approaches tailored to disease stage.},
}

Humans
*Alzheimer Disease/metabolism
*PPAR gamma/metabolism/genetics
*Lipid Metabolism
Animals
Multiomics

@article {pmid43024222,
year = {2026},
author = {Singh, M and Ghosh, P and Rati, S and Jaganathan, BG and Iyer, PK},
title = {A chemometrically validated discriminative sensing strategy combining biomolecular specificity with data-driven classification of Aβ1-40 fibrils.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6nr03146c},
pmid = {43024222},
issn = {2040-3372},
abstract = {Achieving selective and sensitive early detection of amyloid-β (Aβ1-40) fibrils, the hallmark of neurodegenerative disease, in the presence of monomers and abundant serum proteins remains a long-standing major challenge for detecting the disease at its preclinical stage. Here, we report a rationally designed fluorescent probe that exhibits a pronounced 585 nm emission enhancement, enabling rapid and selective identification of Aβ1-40 fibrils with minimal background interference, highlighting its potential for detecting Aβ1-40 fibrils. The probe shows negligible response toward monomers and common proteins, including human serum albumin (HSA), bovine serum albumin (BSA), and lysozyme, demonstrating high selectivity to Aβ1-40 fibrils. Mechanistic studies using NMR (Nuclear Magnetic Resonance), FTIR (Fourier-Transform Infrared), CD (Circular Dichroism), and UV-visible spectroscopy reveal that the sensing response arises from specific probe-fibril interactions, including site-dependent binding and π-π stacking with β-sheet structures. CD and FTIR analyses confirm fibril formation and structural integrity, while NMR provides molecular-level evidence of binding-induced perturbations. Chemometric analysis, including principal component analysis (PCA), hierarchical cluster analysis (HCA), k-nearest neighbours (kNN), and partial least squares discriminant analysis (PLS-DA), enables clear classification of fibrils, monomers, and protein interferents with an accuracy of 88.8% and 90%, using fluorescence and absorbance, respectively, validating the potential of the sensing platform. This work establishes a chemometrically validated sensing strategy that combines molecular specificity with data-driven classification via both absorbance and emission spectroscopy, offering a scalable approach for the selective detection of Aβ1-40 fibrils relevant to Alzheimer's disease (AD) diagnostics.},
}

@article {pmid43024304,
year = {2026},
author = {Chen, X and Cao, M and Chen, H},
title = {Association between depression and cognitive function in adults aged 50 years and older: A cross-sectional study of NHANES 2011-2014.},
journal = {Medicine},
volume = {105},
number = {46},
pages = {e51213},
doi = {10.1097/MD.0000000000051213},
pmid = {43024304},
issn = {1536-5964},
mesh = {Humans ; Cross-Sectional Studies ; Middle Aged ; Female ; Male ; *Depression/epidemiology ; Aged ; Nutrition Surveys ; *Cognition/physiology ; *Cognitive Dysfunction/epidemiology ; Neuropsychological Tests ; United States/epidemiology ; Prevalence ; },
abstract = {Cognitive impairment and depression frequently coexist in older adults. This study examined their association among adults aged ≥50 years using nationally representative National Health and Nutrition Examination Survey (NHANES) data. This cross-sectional study analyzed NHANES 2011 to 2014 data from adults aged ≥50 years. Depression was defined as a Patient Health Questionnaire-9 (PHQ-9) score ≥10, and cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease Word Learning, Animal Fluency Test, and Digit Symbol Substitution Test (DSST). Weighted multivariable linear regression models accounting for the NHANES complex sampling design were used to examine the association between depression status and standardized cognitive performance. Cognitive test scores were converted to Z-scores before regression analysis. Among 2729 participants, 671 had depression (weighted prevalence, 24.59%). Participants with depression performed significantly worse across all cognitive assessments (all P < .01). In fully adjusted models, depression was significantly associated with lower standardized cognitive performance across all domains, including delayed word recall (β = -0.089, 95% confidence interval [CI]: -0.145--0.034, P = .003), total word recall (β = -0.033, 95% CI: -0.055--0.010, P=.006), Animal Fluency Test performance (β = -0.044, 95% CI: -0.066- - 0.021, P < .001), and Digit Symbol Substitution Test performance (β = -0.031, 95% CI: -0.042--0.019, P < .001). Depression status was associated with poorer cognitive performance across multiple domains in adults aged ≥50 years. Longitudinal studies are needed to clarify the temporal relationship between depression and cognitive decline.},
}

Humans
Cross-Sectional Studies
Middle Aged
Female
Male
*Depression/epidemiology
Aged
Nutrition Surveys
*Cognition/physiology
*Cognitive Dysfunction/epidemiology
Neuropsychological Tests
United States/epidemiology
Prevalence

@article {pmid43024495,
year = {2026},
author = {Pitopoulou, M and Dimitriou, NK and Sabbidou, E and Gryparis, A and Manouilidou, C and Petri, M and Panagea, E and Nousia, A and Dardiotis, E and Messinis, L and Nasios, G},
title = {Cultural adaptation and discriminative validity of the Arizona Battery of Communication Disorders -Second Edition (ABCD-2) in neurodegenerative disorders.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/23279095.2026.2761603},
pmid = {43024495},
issn = {2327-9109},
abstract = {OBJECTIVE: The study aimed to translate and culturally adapt the ABCD-2 into Greek and investigate its discriminative ability in four neurodegenerative-disorder groups against healthy controls.

METHODS: About 315 participants, assigned into five diagnostic groups [Parkinson's Disease (PD, n = 57), Alzheimer's Disease (AD, n = 62), Mild Cognitive Impairment (MCI, n = 67), Mixed Dementia (MD, n = 18), and a Control Group (CG, n = 111)], were assessed with the ABCD-2 and Addenbrooke's Cognitive Examination-Revised (ACE-R) for convergent-validity comparison.

RESULTS: Kruskal-Wallis tests showed significant group differences across all cognitive-communication domains (p < 0.001). The ABCD-2 Total Score showed excellent discrimination between patients and controls (AUC = 0.935, 95% CI 0.909-0.960; sensitivity = 85.8%, specificity = 89.2% at a cutoff of 25.2). Differential diagnostic accuracy was moderate-to-good for AD (AUC = 0.783) and MCI (AUC = 0.788), but limited for PD (AUC = 0.530) and MD (AUC = 0.620). Language Expression (AUC = 0.916) and Episodic Memory (AUC = 0.888) showed the highest diagnostic utility. The Total Score correlated strongly with the ACE-R (ρ = 0.888, p < 0.001), with excellent inter-rater reliability (ICC(2,1) = 0.997, 95% CI 0.989-0.999) and high internal consistency (Cronbach's α = 0.92).

CONCLUSIONS: The Greek version of the ABCD-2 is a reliable and valid battery for identifying cognitive-communication deficits in neurodegenerative conditions. Its discriminative validity may support the detection and individualized management of cognitive-communication disorders in these populations. Subgroup-specific and unadjusted cutoff scores should be regarded as exploratory pending external validation.},
}

@article {pmid43024589,
year = {2026},
author = {Villarejo-Galende, A and García-Arcelay, E and Almagro, M and Balasa, M and Piñol-Ripoll, G and Landete, L and Abellan, I and Berbel, A and Espejo, B and Baquero, M and Marin, J and Franco-Macias, E and Viñuela Fernández, F and Feria-Vilar, I and Perez-Vieitez, C and Rodríguez-Espinosa, N and Puig-Pijoan, A and Bargay Pizarro, E and Rodríguez-Rodríguez, E and Rodrigo, J and Boada, M and Sánchez-Juan, P and Manzano, S and Maurino, J},
title = {Psychological resilience among informal care partners of individuals with mild cognitive impairment.},
journal = {PloS one},
volume = {21},
number = {11},
pages = {e0362079},
doi = {10.1371/journal.pone.0362079},
pmid = {43024589},
issn = {1932-6203},
mesh = {Humans ; Female ; *Resilience, Psychological ; Male ; Aged ; *Cognitive Dysfunction/psychology ; *Caregivers/psychology ; Cross-Sectional Studies ; Middle Aged ; Quality of Life ; Spain ; },
abstract = {BACKGROUND: Care partners of individuals with mild cognitive impairment (MCI) encounter unique psychosocial and operational challenges. While dementia research traditionally focuses on advanced cognitive decline, the factors underlying positive psychological adaptation during the early MCI window remain poorly characterized. This study aimed to evaluate the prevalence of psychological resilience among informal care partners of individuals with MCI and identify independent multivariable correlates of high adaptive capacity.

METHODS: We conducted a multicenter, cross-sectional study across 19 specialized memory clinics in Spain in collaboration with the Spanish Confederation of Alzheimer's Disease and Other Dementias (CEAFA). Psychological resilience was quantified using the 14-Item Resilience Scale (RS-14). Secondary outcomes included health-related quality of life, caregiver strain, psychological distress, dyadic relationship quality, and perceived affiliate stigma. Multivariable logistic regression was employed to identify independent predictors of moderate-to-high resilience (RS-14 score >81).

RESULTS: We analyzed 196 care partners (mean age: 63.5 [SD 13.1] years, 62.8% women). Overall, 63.3% (n = 124) demonstrated moderate-to-high resilience. In bivariate analyses, higher resilience correlated with superior quality of life, greater sense of competence, and enhanced relationship quality between care partners and care recipients. In multivariable logistic regression, only robust perceived social support (OR=2.37, 95% CI 1.78-3.14, p < 0.001) and lower affiliate stigma (OR=0.09, 95% CI 0.03-0.23, p < 0.001) remained independently associated with moderate-to-high resilience (model fit: Hosmer- Lemeshow x2  = 5.039, p = 0.753; Nagelkerke R2 = 0.319).

CONCLUSIONS: Psychological resilience strongly aligns with care partner well-being prior to the onset of overt care-recipient dependency. Early psychosocial interventions designed to reinforce functional social support networks and mitigate internalized stigma may offer a valuable framework for supporting care partner well-being.},
}

Humans
Female
*Resilience, Psychological
Male
Aged
*Cognitive Dysfunction/psychology
*Caregivers/psychology
Cross-Sectional Studies
Middle Aged
Quality of Life
Spain

@article {pmid43024710,
year = {2026},
author = {Tao, Q and Luo, T and Wang, P and Jiang, M and Lai, Z and Jin, B and Liu, Y and He, Y and Wei, Y and Gao, Y and Zhu, L and Du, H and Wang, L and Peng, Y and Hou, Y and Liu, S and Liu, L and Zhang, J and Han, L},
title = {Single-nucleus multiomic profiling uncovers epigenetic dysregulation driving hippocampal vulnerability in Alzheimer's disease.},
journal = {Science advances},
volume = {12},
number = {46},
pages = {eaee4760},
doi = {10.1126/sciadv.aee4760},
pmid = {43024710},
issn = {2375-2548},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Epigenesis, Genetic ; *Hippocampus/metabolism/pathology ; Multiomics ; Kruppel-Like Factor 4 ; Animals ; Microglia/metabolism ; *Cell Nucleus/metabolism/genetics ; Gene Regulatory Networks ; Gene Expression Profiling ; Neurons/metabolism ; Transcriptome ; Astrocytes/metabolism ; },
abstract = {Alzheimer's disease (AD) exhibits region- and cell-type-specific vulnerability, yet the underlying regulatory mechanisms remain poorly defined. We performed integrated single-nucleus RNA-seq and ATAC-seq of human hippocampus to resolve gene regulatory architecture in AD. By linking chromatin accessibility to transcription, we identified more than 1000 disease-associated cis-regulatory interactions, highlighting coordinated epigenomic-transcriptomic remodeling. Excitatory cornu ammonis (EX.CA) neurons exhibited disproportionate regulatory disruption, characterized by increased chromatin accessibility coupled to activation of apoptosis-related gene programs, whereas dentate gyrus (EX.DG) neurons remained comparatively resistant. In glial cells, regulatory network inference revealed activation of transcription factor modules centered on SPI1/KLF4 in microglia and STAT3 in astrocytes, defining epigenetic programs that are highly associated with inflammatory and metabolic state transitions. Comparative evaluation with the prefrontal cortex uncovered conserved inflammatory activation alongside region-specific immune regulatory divergence, indicating spatially distinct microglial responses. Furthermore, cross-species integration demonstrated that a substantial fraction of AD-associated regulatory elements are human-specific, with AD-risk variants enriched in microglial cis-regulatory elements at loci including BIN1 and APOE. Together, these results provide a mechanistic framework linking chromatin remodeling to cell-type-specific dysfunction and reveal human-specific regulatory architecture as a crucial factor to AD vulnerability and translational limitation.},
}

Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Epigenesis, Genetic
*Hippocampus/metabolism/pathology
Multiomics
Kruppel-Like Factor 4
Animals
Microglia/metabolism
*Cell Nucleus/metabolism/genetics
Gene Regulatory Networks
Gene Expression Profiling
Neurons/metabolism
Transcriptome
Astrocytes/metabolism

@article {pmid43024960,
year = {2026},
author = {Park, Y and Han, JW and Kim, KW},
title = {A narrow-bandwidth resonance-gated Kuramoto model of individualized gamma entrainment.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/aec200},
pmid = {43024960},
issn = {1741-2552},
abstract = {We examined whether frequency mismatch between fixed 40 Hz Gamma ENtrainment Using Sensory Stimulation (GENUS) and an assigned local resonance centre reduces simulated entrainment, and what this implies for individualized stimulation. Approach. A forced Kuramoto population received stimulation through an assumed Gaussian resonance gate. Unforced and ungated controls separated gate effects from oscillator dynamics. We tested bandwidth (BW), coupling, amplitude, gate shape, swept stimulation and a delayed modular network. BW denotes the input gate's standard deviation. Existing event-related synchronization (ERS) and within-visual connectivity-strength data were analyzed with separate observation templates. Main results. Predictions were conditional on the imposed gate. At BW=0.5 Hz, a 2 Hz mismatch reduced stimulus-referenced phase-locking value (PLV_stim) by 95.0%, from 0.508 to 0.026. At BW=2-3 Hz, reductions were 31.0-46.9% at default coupling and 29.9-51.9% across couplings. Narrow-gate attenuation persisted under tested supercritical coupling. Compensation depended on gate tails and amplitude; finite Gaussian gain permitted compensation at sufficiently large internal drive. Among 200 simulated subjects, matched stimulation yielded 13.71-fold higher PLV_stim than fixed 40 Hz. Sweeps produced transient resonance capture with little subsequent locking. In the delayed network, collective frequencies fell below nodal frequencies, while raw selectivity depended on gate placement and unforced reference locking. Empirical ERS and connectivity strength did not uniquely identify physiological gate BW or validate 0.5 Hz. Significance. The model quantifies consequences of a narrow-gate hypothesis rather than establishing narrow biological tuning. Results motivate measuring individual stimulation-response curves, including network outcomes, but do not establish an optimal individualized GENUS protocol or support frequency prescription from a resting gamma peak alone. .},
}

@article {pmid43025006,
year = {2026},
author = {Kumar, ANL and Vetukuri, VS and Gupta, VMNSSVKR and Reddy, SS and Swaroop, CR},
title = {Systematic review of machine and deep learning in EEG Alzheimer's detection.},
journal = {Psychiatry research. Neuroimaging},
volume = {365},
number = {},
pages = {112371},
doi = {10.1016/j.pscychresns.2026.112371},
pmid = {43025006},
issn = {1872-7506},
abstract = {Alzheimer's disease is the most prevalent neurodegenerative disease, resulting in progressive memory loss in people. It has a significant impact on the population and the global healthcare system. Disease acquisition is a major concern due to the absence of pre-existing treatment options. The growth of machine learning and deep learning-based algorithms is effective in analyzing EEG data for diagnosing Alzheimer's disease. This systematic literature review investigates existing primary studies that focus on applying ML and DL in the identification of Alzheimer's disease, with emphasis on pre-processing, feature extraction, and classification. In doing so, it assesses the results produced by varying algorithms and addresses the problems encountered while deploying these systems. The review's objective is to offer a current situation and potential solutions for practitioners and scholars interested in healthcare service issues.},
}

@article {pmid43025073,
year = {2026},
author = {Deng, L and Sun, S and Tian, D and Xue, L and Lei, Y and Chu, J and Wang, Q and Xie, M},
title = {Borneol-incorporated liposomes enhance nose-to-brain delivery of N-acetylcysteine/tea polyphenol-derived carbon dots for multitarget intervention in Alzheimer's disease.},
journal = {Journal of colloid and interface science},
volume = {730},
number = {},
pages = {141964},
doi = {10.1016/j.jcis.2026.141964},
pmid = {43025073},
issn = {1095-7103},
abstract = {The functional performance of colloidal nanomaterials depends on the interplay between precursor chemistry, colloidal assembly, and interfacial behavior, yet how these factors can be coordinated through material design remains poorly understood. We hypothesized that precursor composition and lipid-interface engineering could jointly regulate carbon-dot surface chemistry and colloidal behavior, thereby influencing their biological functions. Here, tea polyphenols (TP) and N-acetylcysteine (NAC) were co‑carbonized to generate N/S-enriched carbon dots (NTCDs), which were subsequently encapsulated in borneol-containing liposomes to construct borneol-modified liposomes encapsulating NTCDs (NTCDs@Bor-Lipid). In vitro, NTCDs showed stronger antioxidant and metal-ion chelation activities than NAC-free carbon dots, while liposomal encapsulation largely preserved these activities. The resulting formulation exhibited a Z-average hydrodynamic diameter of 96.5 ± 1.4 nm, with less than 8% variation over 7 days in physiologically relevant media, and showed an encapsulation efficiency of 69.28% and a loading capacity of 6.48%. Borneol incorporation enhanced cellular uptake and transepithelial transport, accompanied by increased brain accumulation after intranasal administration. In APP/PS1 mice, NTCDs@Bor-Lipid reduced cerebral Aβ plaque burden, oxidative stress, and neuroinflammation, and improved cognitive performance. Overall, this work links precursor composition and lipid-interface engineering with carbon-dot surface chemistry and colloidal behavior, providing a physicochemical basis for understanding the functional performance of the nanosystem in nose-to-brain delivery and Alzheimer's disease-related models.},
}

@article {pmid43025540,
year = {2026},
author = {Lin, Y and He, J and Gong, J and Chen, J and Ke, Z and Cai, F},
title = {Neuroprotective actions of GLP-1 receptor agonists in Neurodegeneration: From mechanisms to clinical translation.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.11.016},
pmid = {43025540},
issn = {1873-7544},
abstract = {BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been explored as potential therapeutics for neurodegenerative disorders, yet a comprehensive integration of their neuroprotective mechanisms across Alzheimer's disease (AD), Parkinson's disease (PD), and related conditions remains to be consolidated. This review examines the multimodal effects of GLP-1RAs on neuroinflammation, autophagy, mitochondrial function, and protein aggregation, with a focus on translational relevance and alignment between preclinical findings and clinical evidence.

METHODOLOGY: A systematic synthesis of preclinical and clinical studies investigating GLP-1RA administration in neurodegenerative disease models and populations was conducted. Studies reporting neuroprotective outcomes and mechanistic pathways were included, and clinical trial data and real-world evidence for AD, PD, Huntington's disease, stroke, diabetic encephalopathy, and peripheral neuropathy were systematically evaluated.

RESULTS: Preclinical evidence revealed that GLP-1RAs modulate key pathogenic processes, including amyloid-β and tau pathology, α-synuclein accumulation, neuroinflammatory cascades, oxidative stress, mitochondrial dynamics, endoplasmic reticulum stress, autophagy, and synaptic plasticity. Clinical data provided variable support, with emerging real-world evidence suggesting potential benefits. Novel strategies-such as dual GIP/GLP-1 receptor agonists, enhanced blood-brain barrier penetration, and sustained-release formulations-were identified as promising approaches to improve efficacy, although significant gaps remain between preclinical promise and clinical outcomes.

CONCLUSION: This review consolidates evidence that GLP-1RAs exert broad neuroprotective effects through multiple mechanisms, but clinical translation is still evolving. The potential of GLP-1-based therapies as disease-modifying interventions for neurodegeneration warrants further investigation, with particular attention to bridging preclinical and clinical findings and optimizing drug delivery strategies.},
}

@article {pmid43025541,
year = {2026},
author = {Verma, A and Khan, MA and Anwer, T and Alam, O and Sharma, M},
title = {Beyond conventional neurodiagnostic: quantum-enabled mapping of AGE-RAGE dynamics in type 3 diabetes.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.11.015},
pmid = {43025541},
issn = {1873-7544},
abstract = {Type 3 Diabetes (T3D) is a conceptual framework used to describe the association between cerebral insulin resistance, metabolic dysfunction and neurodegenerative processes, particularly those associated with Alzheimer's disease (AD). The advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE) axis has been implicated in oxidative stress, inflammatory signaling and neuronal dysfunction. However, conventional biochemical approaches often provide endpoint measurements and may not fully resolve the spatial and temporal dynamics of these processes. Advances in quantum sensing and nanotechnology offer potential tools for detecting selected physicochemical signals in biological systems, although their demonstrated capabilities vary substantially across platforms. This review examines the biological relevance of the AGE-RAGE axis in neurodegeneration and discusses the principles and types of quantum sensing technologies, including nitrogen-vacancy centers in diamond and quantum dots, alongside other nanomaterial-based sensing approaches. Particular attention is given to probe functionalization, bioconjugation, signal transduction and experimental platforms that could support future investigations of AGE-RAGE-associated processes. Importantly, direct, real-time quantum sensing of AGE-RAGE interactions in living neuronal systems remain to be experimentally established. Accordingly, proposed applications involving receptor activation, downstream signaling, brain organoids, brain-on-chip systems and in vivo imaging are considered in terms of their potential, limitations and validation requirements. Challenges relating to target specificity, biological interference, biocompatibility, spatial and temporal resolution and translational feasibility are also discussed. This review outlines a prospective framework for investigating AGE-RAGE-associated signaling dynamics while distinguishing established sensing capabilities from applications that require further experimental validation.},
}

@article {pmid43025603,
year = {2026},
author = {Paul, S and Bhardwaj, J and Sharma, S and Swalih, M and Koul, D and Bk, B},
title = {Lepr Haploinsufficiency Accelerates Alzheimer-like Neurodegeneration via CDK5 Hyperactivation.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113749},
doi = {10.1016/j.jbc.2026.113749},
pmid = {43025603},
issn = {1083-351X},
abstract = {Leptin receptor (LEPR) signaling plays a critical role in neuronal survival and synaptic function and is increasingly implicated in Alzheimer's disease (AD) pathogenesis. Beyond its metabolic actions, leptin regulates β-amyloid homeostasis, tau phosphorylation, and synaptic plasticity. While the neurological consequences of homozygous leptin receptor (Lepr) mutations are well characterized, the impact of heterozygous Lepr deficiency on brain aging and neurodegeneration remains unclear. To address this, we analyzed heterozygous leptin receptor mutant (db/+) mice at 6 and 12 months of age using metabolic, behavioral, biochemical, neuropathological, and transcriptomic approaches. Young db/+ mice were comparable to controls, whereas aged db/+ mice developed obesity, impaired glucose tolerance, and insulin resistance, accompanied by deficits in spatial learning and motor coordination. Aged db/+ brains exhibited elevated amyloid-β42 levels, increased CDK5 kinase activity, and hyperphosphorylation of tau at Ser396 and Thr231. Although total LEPR protein levels were unchanged, phosphorylation of STAT3 at Tyr705 was significantly reduced, indicating impaired downstream LEPR signaling. Transcriptomic profiling revealed downregulation of genes involved in synaptic signaling and plasticity, including Gabrb2, Brsk1, Camk2a, Syn1, and Syngap1, along with alterations in neurotransmitter and oxidative phosphorylation pathways. Collectively, these findings demonstrate that leptin receptor haploinsufficiency promotes age-dependent metabolic dysfunction, synaptic failure, and CDK5-mediated tauopathy, leading to Alzheimer-like neurodegeneration and identifying LEPR as a potential genetic risk factor and therapeutic target.},
}

@article {pmid43025659,
year = {2026},
author = {Marrocco, N and Bardelli, F and Fratini, M and Politano, A and Cloetens, P and Balducci, C and Gianoncelli, A and Bonanni, V and Meneghini, C and Moresi, V and Bukreeva, I and Massimi, L and Palermo, F and Cedola, A},
title = {Three-Dimensional Structural and Elemental Organization of Amyloid Plaques Revealed by Correlative Synchrotron Imaging.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103596},
doi = {10.1016/j.neuro.2026.103596},
pmid = {43025659},
issn = {1872-9711},
abstract = {Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles, accompanied by dysregulation of brain elemental and ionic homeostasis. Abnormal accumulation of biometals, such as Fe, Cu and Zn, as well as sodium (Na) imbalance have been reported in AD brain tissue, yet their spatial relationship with plaque morphology is still poorly characterized. Here, we present a correlative multiscale synchrotron-based imaging approach applied to brain tissue from the APP23 transgenic mouse model of AD (B6-Tg/Thy1APP23Sdz). Low-energy Synchrotron X-ray fluorescence spectroscopy provided high-resolution distribution maps of Na in plaques and surrounding AD brain tissue samples. X-ray fluorescence tomography (XRFT) was exploited to extend the elemental analysis to transition biometals, and to three dimensions on bulk, non-sectioned tissue samples. Nano-scale X-ray phase-contrast tomography (XPCT) of the same volumes was performed, and the data were co-registered with the XRFT ones. This correlative XPCT/XRFT strategy allows for rigorous distinction between true elemental enrichment and apparent signal variations influenced by local tissue electron density. Additionally, micro-XPCT enabled multiscale visualization of amyloid deposits from the whole-brain level down to individual plaque morphology. Our results show that Aβ plaques are chemically heterogeneous structures, with distinct distribution of Mn, Fe, Cu, Zn, and Na, correlated with specific morphological plaque compartments.},
}

@article {pmid43014985,
year = {2027},
author = {Verma Saluja, K and Jindal, S and Benzinger, TLS},
title = {Molecular Neuroimaging in Alzheimer's Disease.},
journal = {Neuroimaging clinics of North America},
volume = {37},
number = {1},
pages = {51-67},
doi = {10.1016/j.nic.2026.07.003},
pmid = {43014985},
issn = {1557-9867},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Neuroimaging/methods ; *Molecular Imaging/methods ; Positron-Emission Tomography/methods ; Brain/diagnostic imaging ; Biomarkers/metabolism ; tau Proteins/metabolism ; },
abstract = {Molecular neuroimaging in Alzheimer's disease has shifted from a confirmatory diagnostic adjunct to a decision-defining clinical tool that informs diagnosis, treatment eligibility, and longitudinal therapeutic monitoring. Driven by global therapeutic approvals of anti-amyloid monoclonal antibodies and high-precision fluid biomarkers, molecular imaging now adjudicates diagnostic certainty and governs progression to disease-modifying therapy. While high-precision plasma biomarkers increasingly serve as scalable screening tools, they frequently require adjudication by amyloid or tau PET to resolve indeterminate results and enable treatment decisions. 18F-FDG PET remains an important diagnostic tool for patients with more advanced dementia presenting with complex syndromes.},
}

Humans
*Alzheimer Disease/diagnostic imaging
*Neuroimaging/methods
*Molecular Imaging/methods
Positron-Emission Tomography/methods
Brain/diagnostic imaging
Biomarkers/metabolism
tau Proteins/metabolism

@article {pmid43014987,
year = {2027},
author = {Minoshima, S and Anzai, Y and Thientunyakit, T and Ngam, PI and Cliatt Brown, CJ and Drzezga, A},
title = {Dementia and Neurodegenerative Disease: Emerging Neurodegenerative Diseases-Limbic-predominant age-related TDP-43 encephalopathy/Hippocampal Sclerosis, Argyrophilic Grain Disease, Primary Age-Related Tauopathy, and Frontotemporal Dementia Fused in Sarcoma.},
journal = {Neuroimaging clinics of North America},
volume = {37},
number = {1},
pages = {89-101},
doi = {10.1016/j.nic.2026.07.005},
pmid = {43014987},
issn = {1557-9867},
mesh = {Humans ; *Tauopathies/diagnostic imaging/pathology ; Hippocampal Sclerosis/diagnostic imaging ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; *Frontotemporal Dementia/diagnostic imaging ; *TDP-43 Proteinopathies/diagnostic imaging ; *Dementia/diagnostic imaging ; Brain/diagnostic imaging ; Diagnosis, Differential ; Magnetic Resonance Imaging/methods ; },
abstract = {Limbic-predominant age-related TAR DNA-binding protein 43 encephalopathy, hippocampal sclerosis-aging, primary age-related tauopathy, argyrophilic grain disease, and frontotemporal lobar degeneration fused in sarcoma are increasingly recognized neurodegenerative disorders that frequently mimic Alzheimer's disease (AD) and commonly coexist with AD pathology in older adults. As disease-modifying therapies emerge, accurate identification of these non-AD and mixed pathologies has become clinically important. This article reviews current clinicopathologic concepts and highlights the role of MR imaging and molecular PET imaging in differentiating limbic-predominant and frontotemporal neurodegeneration, estimating concurrent AD pathology, and interpreting complex multietiology dementia patterns.},
}

Humans
*Tauopathies/diagnostic imaging/pathology
Hippocampal Sclerosis/diagnostic imaging
*Neurodegenerative Diseases/diagnostic imaging/pathology
*Frontotemporal Dementia/diagnostic imaging
*TDP-43 Proteinopathies/diagnostic imaging
*Dementia/diagnostic imaging
Brain/diagnostic imaging
Diagnosis, Differential
Magnetic Resonance Imaging/methods

@article {pmid43015086,
year = {2026},
author = {Rivera-Ramirez, N and O'Malley, JJ and Jagirdar, R and Campbell, JR and Silva-Pérez, M and Stephens, GS and Chin, J and Beierlein, M},
title = {Thalamic Reticular Nucleus Excitability and Cholinergic Signaling are Disrupted in a Mouse Model of Alzheimer's Disease Neuropathology.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1320-26.2026},
pmid = {43015086},
issn = {1529-2401},
abstract = {The thalamic reticular nucleus (TRN) forms powerful GABAergic connections with thalamic nuclei that regulate sleep, attention, and sensory processing. TRN neurons receive dense cholinergic innervation from the basal forebrain and brainstem, dynamically shaping TRN function across brain states. We previously showed reduced TRN activity and sleep deficits in amyloid precursor protein transgenic mice (APP mice), implicating TRN dysfunction as an early contributor to Alzheimer's disease (AD) pathophysiology. Here, using slice electrophysiology in mice of both sexes, we determined whether changes in intrinsic membrane properties or cholinergic synaptic transmission contribute to TRN hypoactivity in APP mice. We found that TRN neurons located in the inner core and outer shell regions undergo substantial increases in excitability after the first postnatal month. In mature animals, core neurons exhibited higher firing rates and diverse firing patterns, including persistent firing, whereas shell neurons fired at lower rates and displayed more homogeneous firing patterns without persistent activity. Firing diversity in core neurons was mediated in part by low-threshold T-type Ca[2+] channels. Cholinergic synaptic activation, mediated predominantly by basal forebrain afferents, produced biphasic excitatory-inhibitory postsynaptic responses in both core and shell neurons, with the ratio of postsynaptic excitation and inhibition varying across postsynaptic targets. Overall, cholinergic activation suppressed TRN firing. In APP mice, core neurons showed reduced intrinsic excitability and cholinergic afferents evoked postsynaptic responses with a larger muscarinic receptor-mediated inhibitory component, leading to delayed TRN firing. Together, these findings identify both intrinsic and cholinergic synaptic mechanisms that may contribute to TRN dysfunction during early AD.Significance Statement Alzheimer's disease (AD) is typically diagnosed after cognitive symptoms emerge when treatments are less effective, highlighting the need to understand preclinical disease mechanisms. Cholinergic signaling and slow-wave sleep are disrupted before symptom onset, but the mechanisms underlying these changes remain poorly understood. Because the thalamic reticular nucleus (TRN) receives strong cholinergic input and mediates sleep-related rhythms, it is well positioned to contribute to early AD pathophysiology. We previously found reduced TRN activity and disrupted sleep in an AD mouse model. Here, we show that intrinsic excitability and cholinergic synaptic signaling are altered in TRN neurons during preclinical AD. These changes may contribute to thalamic dysfunction and sleep disturbances, providing a potential circuit mechanism linking early AD pathology to disease progression.},
}

@article {pmid43015247,
year = {2026},
author = {Xie, Z and Yang, Q and Liu, L and Chu, M and Quan, Z and Yang, L and Bai, Z and Yang, K and Nakanishi, H and Wu, L and Qing, H and Ni, J},
title = {Targeting peripheral cathepsin E restricts CD8[+] T-cell neuroinvasion and ameliorates Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
pmid = {43015247},
issn = {1552-5279},
support = {8260053790//National Natural Science Foundation of China/ ; 82230042//National Natural Science Foundation of China/ ; 32070954//National Natural Science Foundation of China/ ; 2026JJ60267//Natural Science Foundation of Hunan Province/ ; 2026JJ50069//Natural Science Foundation of Hunan Province/ ; 25B0375//Research Foundation of Education Bureau of Hunan Province/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/immunology/metabolism ; *CD8-Positive T-Lymphocytes/metabolism/immunology ; Mice ; Humans ; *Cathepsin E/metabolism/antagonists & inhibitors ; Disease Models, Animal ; Mice, Transgenic ; Brain/pathology/metabolism ; Cell Movement ; Adoptive Transfer ; },
abstract = {BACKGROUND: CD8[+] T-cell-mediated neuroimmune activation increases with aging and contributes to Alzheimer's disease (AD), yet the molecular cues that drive their recruitment into the brain remain largely undefined.

METHODS: We quantified Cathepsin E (CatE) expression in CD8[+] T cells from 5×FAD mice and clinical samples from patients with AD. The functional necessity of CatE in T-cell trafficking was assessed through 4D-data-independent acquisition (4D-DIA) proteomics, microfluidic migration assays under physiological flow, and adoptive transfer experiments. Finally, we evaluated the therapeutic efficacy of a brain-impermeable CatE inhibitor in mitigating AD-related pathology.

RESULTS: CatE is selectively and age-dependently upregulated in peripheral CD8[+] T cells in both AD mice and patients. Adoptive transfer of AD-derived CD8[+] T cells significantly accelerated promoted soluble Aβ₁- 4 2 accumulation, glial activation, and memory deficits in 5-month-old recipient mice. Mechanistically, CatE is associated with elevated expression of vinculin and fibronectin in CD8[+] T cells, accompanied by enhanced activation of β1-integrins that stabilizes adhesion to brain endothelial cells. Pharmacological suppression of peripheral CatE effectively restricted T-cell infiltration, attenuated neuroinflammation, and restored cognitive function in AD models.

DISCUSSION: These results identify CatE as a key cell-intrinsic regulator of CD8[+] T-cell migratory competence. Targeting the peripheral CatE-integrin axis offers a promising immunotherapeutic strategy to limit pathogenic neuroinflammation in AD while circumventing the challenges of blood-brain barrier penetration.},
}

Animals
*Alzheimer Disease/pathology/immunology/metabolism
*CD8-Positive T-Lymphocytes/metabolism/immunology
Mice
Humans
*Cathepsin E/metabolism/antagonists & inhibitors
Disease Models, Animal
Mice, Transgenic
Brain/pathology/metabolism
Cell Movement
Adoptive Transfer

@article {pmid43015270,
year = {2026},
author = {Feng, Y and Chen, X and Song, W and Yang, X and Dou, L and Bonakdarpour, B and Jamshidi, P and Castellani, RJ and Mao, Q and Chu, X and Gao, H and Liu, Y and Xu, J and Hou, Y and Martin, W and Nelson, PT and Leverenz, JB and Hu, M and Li, YE and Pieper, AA and Cummings, J and Flanagan, ME and Cheng, F},
title = {A single-nucleus multiome map of the human cerebellum with Alzheimer's disease and related dementias.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {43015270},
issn = {2041-1723},
support = {R01AG082118//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U24 AG021886/AG/NIA NIH HHS/United States ; RF1 AG048083/AG/NIA NIH HHS/United States ; R56 AG057478/AG/NIA NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG092591/AG/NIA NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; R33 AG083003/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; R01 AG092462/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 NS133812/NS/NINDS NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; P20 GM109025/GM/NIGMS NIH HHS/United States ; U01 NS093334/NS/NINDS NIH HHS/United States ; R01 AG053798/AG/NIA NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology ; *Cerebellum/metabolism/pathology ; Female ; *Cell Nucleus/metabolism/genetics ; Male ; Purkinje Cells/metabolism ; *Dementia/genetics/metabolism/pathology ; Transcriptome ; Multiomics ; Aged ; Frontal Lobe/metabolism/pathology ; Gene Regulatory Networks ; },
abstract = {Although cerebellum is neuropathologically affected in Alzheimer's disease (AD) and AD-related dementia (ADRD), the cell type-specific genomic and epigenomic changes remain poorly understood. Here, we present single-nucleus multiome (RNA-seq and ATAC-seq) analysis of 103,861 nuclei isolated from both the cerebellum and frontal cortex of diseased individuals and cognitively healthy controls. We identify 431,834 significant peak-to-gene linkages across cell subtypes, revealing cis-regulatory elements linked to cell type-specific and disease-associated transcriptomic and regulatory network changes. Differential trajectory analysis pinpoints disease-associated genes in cerebellar granule cells, such as STMN1 and CLU. Integrating epigenomic, genetic, and three-dimensional genome data, we pinpoint two likely causal variants linked to SEZ6L2 in Purkinje cells and KANSL1 in granule cells. Through CRISPR interference in patient-derived cerebellar organoids, we show that silencing the variant-containing regulatory elements suppresses SEZ6L2 and KANSL1 expression, which perturbs neurodegeneration-associated gene programs. This cell type-specific regulatory landscape provides genomic and epigenomic insights into the pathological role of the cerebellum in AD/ADRD.},
}

Humans
*Alzheimer Disease/genetics/metabolism/pathology
*Cerebellum/metabolism/pathology
Female
*Cell Nucleus/metabolism/genetics
Male
Purkinje Cells/metabolism
*Dementia/genetics/metabolism/pathology
Transcriptome
Multiomics
Aged
Frontal Lobe/metabolism/pathology
Gene Regulatory Networks

@article {pmid43015435,
year = {2026},
author = {Basu, M},
title = {New culprit in early Alzheimer's: Blood-brain barrier blocks protective proteins.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {43015435},
issn = {1476-4687},
}

@article {pmid43015511,
year = {2026},
author = {Daly, T},
title = {Broadening the scope of multimodal precision prevention in Alzheimer's disease research.},
journal = {Discover mental health},
volume = {6},
number = {1},
pages = {},
pmid = {43015511},
issn = {2731-4383},
abstract = {INTRODUCTION: Within the last decade, translational research into Alzheimer's disease and related dementias (ADRD) has embraced the complexity of disease mechanisms and pluralistic approaches to therapeutics. As part of this broader shift, the "multimodal precision prevention paradigm" has emerged as an actionable approach to reduce the public health burden of ADRD.

OBJECTIVE: To provide an overview of the definitions, scope, and limitations of the multimodal precision prevention paradigm for ADRD and propose a broader definition of translational research in ADRD research and policy.

METHODS: This article performs a critical analysis of leading proposals by different international research initiatives working on multimodal precision medicine for ADRD prevention.

MAIN RESULTS: Within the multimodal precision prevention paradigm, two overlapping approaches are distinguished on a continuum: on one hand, researchers predominantly from the global North propose a multimodal therapy approach. On the other hand, authors from the global South are proposing a "multimodal diversity" approach stressing the need for a deeper understanding of, and action against, broader contributors to risk of ADRD. It is argued that the complexity of multimodal diversity requires extending the scope of what is typically called "translational research" beyond the "bench-to-bedside" metaphor to include broader policy entry points for prevention (such as action against the social determinants of ADRD).

CONCLUSIONS: Translational research into ADRD faces a choice between narrow and broader policy entry points. This article suggests a broader definition of translational research as follows: translational research in Alzheimer's disease and Alzheimer's disease-related dementias should promote a multi-directional interaction between, and multimodal integration of, laboratory-based and diverse population research to achieve a robust, global understanding of brain health and disease that can inspire equitable public health policy and advance precision medicine.},
}

@article {pmid43015644,
year = {2026},
author = {Liu, X and Guo, Z and Fu, B and Jia, X and Mao, C and Zhang, Z and , },
title = {An impaired excitatory-inhibitory balance in the right inferior temporal gyrus of patients with Alzheimer's disease correlated with executive function.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {43015644},
issn = {1471-2318},
support = {U19 AG024904/AG/NIA NIH HHS/United States ; 2020KY182//the General Project of the Department of Science and Technology of Zhejiang Province/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/psychology/metabolism ; Female ; *Temporal Lobe/physiopathology/diagnostic imaging ; Male ; Aged ; *Executive Function/physiology ; Magnetic Resonance Imaging/methods ; Cognitive Dysfunction/physiopathology/psychology ; Aged, 80 and over ; Cohort Studies ; },
abstract = {BACKGROUND: Preliminary research indicates that an imbalance between excitation and inhibition may be an early pathological feature of Alzheimer's disease. However, the relevant brain networks, neurotransmitters and genetic mechanisms are still unclear.

METHODS: This study enrolled 27 patients with Alzheimer's disease (AD), 86 patients with mild cognitive impairment MCI, and 85 healthy controls (HC), all aged 65 or older, from the ADNI3 cohort in May 2024. We employed analysis of covariance to compare abnormalities in the excitation-inhibition balance across the three groups. We performed a transcriptomic analysis of abnormal excitation-inhibition imbalance. To elucidate the characteristics of the underlying brain networks, we extracted brain regions exhibiting differences in the balance of excitation and inhibition for seed-based functional connectivity analysis.

RESULTS: Compared to the HC group, AD exhibits a significant putative excitatory-inhibitory imbalance in the right inferior temporal gyrus and superior orbital frontal gyrus. The Hurst exponent of the right inferior temporal gyrus was significantly correlated with executive function. Transcriptomic analysis revealed that the abnormal excitation-inhibition imbalance observed in AD patients is significantly associated with GABA and mGluR5 receptors, as well as with genes that are enriched in the GABAergic synapse pathway. Functional connectivity analysis using the right inferior temporal gyrus as a seed point revealed significant abnormalities in the frontoparietal control network in AD patients.

CONCLUSIONS: Our findings suggest that an imbalance between excitation and inhibition in the inferior temporal gyrus is a potential pathological mechanism underlying AD. This imbalance also leads to functional abnormalities in the frontoparietal control network associated with executive functions.},
}

Humans
*Alzheimer Disease/physiopathology/psychology/metabolism
Female
*Temporal Lobe/physiopathology/diagnostic imaging
Male
Aged
*Executive Function/physiology
Magnetic Resonance Imaging/methods
Cognitive Dysfunction/physiopathology/psychology
Aged, 80 and over
Cohort Studies

@article {pmid43015714,
year = {2026},
author = {Pérez-de la Cruz, S},
title = {From technique to sensitivity: the transformation of clinical and ethical reasoning in physiotherapy students in the context of chronic neurodegenerative diseases.},
journal = {BMC medical education},
volume = {26},
number = {1},
pages = {},
pmid = {43015714},
issn = {1472-6920},
mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Physical Therapy Specialty/education/ethics ; Qualitative Research ; *Clinical Reasoning ; Male ; Female ; Spain ; *Physical Therapists/education ; Attitude of Health Personnel ; Chronic Disease ; Curriculum ; },
abstract = {BACKGROUND: The evolution of Physiotherapy requires a shift from the biomedical model towards bioethical and humanistic approaches. This study explores how final-year students perceive their professional role when dealing with patients with complex neurodegenerative conditions, where traditional technical success is challenged by the irreversibility of the deterioration.

METHODS: Qualitative research based on interpretative description. Thirty final-year students from the University of Almería (Spain) took part, divided into five working groups. Three training sessions and discussions were held on Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, stroke and Rett syndrome. The data were analysed using thematic analysis and triangulation by researchers external to the study, with reflexivity ensured through logbooks.

RESULTS: A shift in clinical reasoning was identified, with sensitivity taking precedence over technique. Students redefined therapeutic success in terms of "comfort" and support, valuing "microscopic achievements" such as the preservation of dignity and the alleviation of distress. Of particular note is the ability to adapt ethical principles according to the patient's cognitive integrity (autonomy in ALS versus protection in Alzheimer's) and the integration of the carer as an inseparable part of the therapeutic process.

CONCLUSION: Future physiotherapists perceive humanization and the empathetic interpretation of non-verbal cues as essential therapeutic tools. Unlike previous studies focused on clinical experience, this research explores pre-clinical ethical maturation, offering a unique perspective on the educational foundation and humanistic predisposition of future graduates prior to their immersion in the healthcare system. It is imperative that academic curricula formally integrate competencies in bioethics, palliative care and emotional management to prepare graduates for extreme vulnerability and prevent early professional burnout.},
}

Humans
*Neurodegenerative Diseases/therapy
*Physical Therapy Specialty/education/ethics
Qualitative Research
*Clinical Reasoning
Male
Female
Spain
*Physical Therapists/education
Attitude of Health Personnel
Chronic Disease
Curriculum

@article {pmid43015837,
year = {2026},
author = {Capdevila-Bayo, M and Rossi, R and de Rojas, I and Puerta, R and Guzmán, L and Carrasco, M and Muñoz-Morales, Á and Olivé, C and Montrreal, L and García-González, P and Bayón-Buján, P and Miguel-Romero, A and Calm, B and Sotolongo-Grau, O and Tatinya, N and Alegret, M and Sanz-Cartagena, P and Fernández, V and Marquié, M and Valero, S and Montalban, X and Camins, A and Ramírez, A and Martí, M and Pividori, MI and Boada, M and Sánchez-Luengo, MÁ and Mañes, S and Ruiz, A and Ettcheto, M and Cano, A},
title = {A peripheral proteomic signature of Alzheimer's disease is identified in the plasma extracellular vesicles of mild cognitive impairment patients from a memory clinic: the BIOPEXAL study.},
journal = {Journal of nanobiotechnology},
volume = {24},
number = {1},
pages = {},
pmid = {43015837},
issn = {1477-3155},
support = {Projectes de recerca jove i emergent 2024 grant 24S05876-001//Barcelona City Council/ ; Predocs-UB grant//University of Barcelona/ ; Pre-doctoral grant FI24/00029//Instituto de Salud Carlos III (ISCIII)/ ; Sara Borrell grant CD22/00125//Instituto de Salud Carlos III (ISCIII)/ ; STAR Award, the Keith M. Orme and Pat Vigeon Orme Endowed Chair in Alzheimer's and Neurodegenerative Diseases (2024-2025) and Patricia Ruth Frederick Distinguished Chair for Precision Therapeutics in Alzheimer's and Neurodegenerative Diseases (2025-2028)//University of Texas, National Institute of Aging, National Institutes of Health/ ; Assistant professor Serra Hunter contract (UB-LE-9115)//Generalitat de Catalunya/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/metabolism/diagnosis ; *Cognitive Dysfunction/blood/metabolism ; *Extracellular Vesicles/metabolism ; Female ; Male ; *Proteomics/methods ; Aged ; Biomarkers/blood ; *Proteome/analysis ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; Middle Aged ; },
abstract = {AIMS: Alzheimer's disease (AD) is commonly diagnosed when neuronal damage is already established and irreversible. Achieving an accurate differential diagnosis in the preclinical and mild cognitive impairment (MCI) stage is one of the greatest challenges nowadays. Nanotechnological analysis of plasma extracellular vesicles (pEVs) are gaining attention as a promising tool for the early detection of AD pathology. This study aims to evaluate the proteomic profile of pEVs from patients with MCI and AD dementia to explore their potential as AD screening tools.

METHODS: pEVs were isolated by ultracentrifugation from 144 patients with MCI A-T-, MCI A+T+, and AD dementia. Nanoparticle tracking analysis and cryo-TEM were used to characterize the pEVs. CSF, serum and pEVs proteomics were carried out by using the multiplex PEA technology of Olink® proteomics, Inflammation and Neurology Explore 384 panels (768 proteins).

RESULTS: Characterization results showed that isolated plasma fraction corresponded in shape, size and concentration to EVs. Many pEVs neurology proteins involved in AD pathology significantly correlated (r > ± 0.30, p < 0.05) with their CSF homonyms, but not with their serum's. pEVs' proteome correlated with common AD signatures (CSF Aβ42 and pTau181, plasma pTau181, MMSE, NBACE, and Qalb) showing similar patterns to those observed with CSF biomarkers. Several pEVs neurology proteins didn't exhibit differences between the MCI A+T+ and AD dementia groups, whilst they did with MCI A-T-. Proteins in pEVs showed strong correlations with several measures of brain atrophy in MRI. Several neurology pEV proteins predicted conversion from MCI to AD dementia. Moreover, some of these showed a significant diagnostic accuracy of AD pathology.

CONCLUSION: Preliminary results suggest that EVs biomarker signature could reflect AD pathology in the prodromal stages of AD continuum. However, further experiments are still needed for a better understanding of EVs' role in AD development and pathology dissemination.},
}

Humans
*Alzheimer Disease/blood/metabolism/diagnosis
*Cognitive Dysfunction/blood/metabolism
*Extracellular Vesicles/metabolism
Female
Male
*Proteomics/methods
Aged
Biomarkers/blood
*Proteome/analysis
Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
Middle Aged

@article {pmid43015898,
year = {2026},
author = {Millar, PR and Doering, S and Adeyemo, B and Jindal, S and McKay, NS and Strain, JF and Wisch, JK and An, GZ and Canfield, P and Flores, S and Metcalf, NV and Roman, J and Cruchaga, C and Hassenstab, JJ and Holtzman, DM and Morris, JC and Gordon, BA and Ances, BM and Benzinger, TL},
title = {Network connectivity and amyloid-β align with tau in atypical Alzheimer disease subtypes.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {43015898},
issn = {1758-9193},
support = {K01-AG090753/AG/NIA NIH HHS/United States ; P01-AG026276/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P30-AG066444/AG/NIA NIH HHS/United States ; AARF-22-972678/ALZ/Alzheimer's Association/United States ; K01 AG090753/AG/NIA NIH HHS/United States ; A2022014F//BrightFocus Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology/classification ; *tau Proteins/metabolism ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/metabolism/pathology ; Female ; Aged ; Male ; Magnetic Resonance Imaging ; Neural Pathways/diagnostic imaging/metabolism ; Aged, 80 and over ; Retrospective Studies ; },
abstract = {BACKGROUND: Spatiotemporal patterns of tau accumulation differ between Alzheimer disease (AD) subtypes in brain networks related to clinical manifestations. Converging evidence suggests that accumulation may be driven by spreading through network connections and/or interactions with amyloid-β (Aβ). Persons with atypical AD presentations might carry pre-existing network-specific vulnerabilities, which might predispose these areas to tau pathology. However, it is unknown if regional patterns of Aβ and network connectivity differ between tau-defined subtypes and whether these patterns precede tau accumulation.

METHODS: We used Subtype-and-Stage-Inference (SuStaIn) to identify subtypes in 919 tau-PET scans from 709 participants in the Knight ADRC. We tested group differences between tau-defined subtypes in regional Aβ-PET and resting-state-functional-connectivity (RSFC) seed maps to early-stage tau epicenter regions using retrospective imaging data preceding the tau-PET scans by up to 14 years, including across stages of AD progression.

RESULTS: Most participants were tau-negative (N = 522). Among tau-positive participants, we identified three tau-PET subtypes. Limbic tau was the most common subtype (N = 136, 73.9%), resembling amnestic AD. Participants with the posterior tau subtype (N = 25, 13.6%) had specific cognitive deficits on visuospatial-dominant tasks, resembling posterior cortical atrophy. Participants with the medial-temporal-lobe-sparing (MTL-sparing) tau subtype (N = 23, 12.5%) were younger and more severely impaired, resembling early-onset dysexecutive AD. Subtype-specific Aβ-PET elevations colocalized with regions of tau accumulation, including in preliminary retrospective analyses of scans preceding tau positivity. RSFC was elevated between subtype-specific regions of tau spreading. Specifically, connectivity was elevated between occipital regions in the posterior tau subtype and was elevated between temporal and frontal regions in the MTL-sparing subtype. In preliminary retrospective analyses, these patterns were detectable in small subsets of scans acquired when participants were Aβ-negative or cognitively unimpaired, before they would later exhibit atypical tau patterns, and extended with disease progression.

CONCLUSIONS: Regional patterns of Aβ, tau, and functional connectivity align in subtype-specific brain networks. Elevated connectivity between tau spreading regions might indicate network-specific vulnerabilities that predispose these regions to tau aggregation, possibly preceding Aβ positivity. These results suggest a temporal sequence of disease progression in brain networks, which might inform explanations of clinico-pathological heterogeneity and the development of precision medicine tools for early detection, prognosis, and treatment of atypical AD.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/pathology/classification
*tau Proteins/metabolism
Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
*Brain/diagnostic imaging/metabolism/pathology
Female
Aged
Male
Magnetic Resonance Imaging
Neural Pathways/diagnostic imaging/metabolism
Aged, 80 and over
Retrospective Studies

@article {pmid43016032,
year = {2026},
author = {Liu, J and Li, Y and Xia, D},
title = {Association between urinary flow rate and cognition in the elderly: a cross-sectional study.},
journal = {The Canadian journal of urology},
volume = {33},
number = {5},
pages = {1313-1325},
pmid = {43016032},
issn = {1488-5581},
support = {2024C03198//"Pioneer" and "Leading Goose" R&D Program of Zhejiang/ ; },
mesh = {Humans ; Female ; Cross-Sectional Studies ; Aged ; Male ; *Cognition/physiology ; Nutrition Surveys ; *Cognitive Dysfunction/physiopathology/epidemiology ; Middle Aged ; *Urination/physiology ; United States ; },
abstract = {BACKGROUND: Urinary abnormalities and cognitive impairment are common in older adults, but their relationship remains incompletely understood. We examined the association between urinary flow rate (UFR) and cognitive performance in this population.

METHODS: We analyzed data from 2700 participants aged ≥60 years in the 2011-2014 U.S. National Health and Nutrition Examination Survey (NHANES). Cognitive performance was assessed using the Digit Symbol Substitution Test (DSST), Animal Fluency Test (AFT), and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) immediate- and delayed-recall tests. Multivariable linear regression evaluated associations between UFR and cognitive scores, and segmented regression assessed potential nonlinear threshold effects.

RESULTS: The mean age was 69.58 years, and 51.48% were women. In the fully adjusted model, higher UFR was associated with higher DSST scores (β = 1.77, 95% CI: 0.74-2.81; p = 0.0008). Participants in the highest UFR tertile had a 2.41-point higher DSST score than those in the lowest tertile (β = 2.41, 95% CI: 0.90-3.92; p = 0.0018; p for trend = 0.0051). Segmented regression identified inflection points of 1.46 mL/min for AFT, 1.30 mL/min for DSST, 0.69 mL/min for CERAD immediate recall, and 0.80 mL/min for CERAD delayed recall. Below these points, higher UFR was significantly associated with better cognitive scores, whereas no significant associations were observed above them. The UFR-DSST association was stronger among participants with BMI ≤30 kg/m2 (p for interaction = 0.0106).

CONCLUSIONS: Lower UFR was associated with poorer cognitive performance in older adults, with a nonlinear pattern. Prospective longitudinal and mechanistic studies are needed to confirm these findings and clarify their clinical relevance.},
}

Humans
Female
Cross-Sectional Studies
Aged
Male
*Cognition/physiology
Nutrition Surveys
*Cognitive Dysfunction/physiopathology/epidemiology
Middle Aged
*Urination/physiology
United States

@article {pmid43016101,
year = {2026},
author = {Bhardwaj, M and Singh, AP and Sharma, BM},
title = {Cyclovirobuxine D: Pharmacological and Bioanalytical Perspectives and Therapeutic Insights.},
journal = {Drug metabolism and bioanalysis},
volume = {19},
number = {3},
pages = {234-245},
pmid = {43016101},
issn = {3117-3861},
mesh = {Humans ; Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use/pharmacokinetics/chemistry ; Signal Transduction/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use/pharmacokinetics ; Antineoplastic Agents/pharmacology/therapeutic use/pharmacokinetics ; },
abstract = {Cyclovirobuxine D (CVB-D) is a steroidal alkaloid extracted from Buxus microphylla, widely used in traditional Chinese medicine for cardiovascular diseases. It has demonstrated significant pharmacological activities, including anti-arrhythmic, cardioprotective, neuroprotective, antiinflammatory, and anti-cancer effects. CVB-D modulates key signaling pathways, such as PI3K/Akt, NF-κB, MAPK, and calcium channel regulation, contributing to its therapeutic potential. Studies indicate that CVB-D induces apoptosis, inhibits cell proliferation, and suppresses tumor metastasis, particularly in lung, gastric, colorectal, and hepatocellular cancers. Additionally, its neuroprotective properties suggest potential applications in neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Beyond its benefits, CVB-D poses challenges related to toxicity, bioavailability, and long-term safety. Reported side effects include hepatotoxicity, nephrotoxicity, and cardiovascular risks, necessitating further clinical investigations. Despite its promising pharmacological profile, preclinical and clinical trials are essential to determine its optimal dosage and therapeutic window. This review provides a comprehensive analysis of CVB-D, including its mechanisms of action, pharmacokinetics, therapeutic potential, and limitations. A deeper understanding of its molecular interactions and safety profile will help guide future drug development and clinical applications.},
}

Humans
Animals
*Drugs, Chinese Herbal/pharmacology/therapeutic use/pharmacokinetics/chemistry
Signal Transduction/drug effects
Neuroprotective Agents/pharmacology/therapeutic use/pharmacokinetics
Antineoplastic Agents/pharmacology/therapeutic use/pharmacokinetics

@article {pmid43016150,
year = {2026},
author = {Al-Jehani, H and Al-Kuraishy, HM and Eliwa, D and Batiha, GE},
title = {Platelets in Alzheimer's disease: pathogenic mechanisms and therapeutic implications.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/01616412.2026.2762288},
pmid = {43016150},
issn = {1743-1328},
abstract = {OBJECTIVES: This review examines the role of platelets, the primary peripheral source of amyloid precursor protein (APP) and amyloid-beta (Aβ), in Alzheimer's disease (AD) pathogenesis, focusing on the bidirectional feedback loop between peripheral platelet over-activation and central neuropathology, alongside potential antiplatelet therapies.

METHODS: A narrative review was conducted evaluating literature on platelet biological functions, pathological shifts in platelet APP processing in AD, mechanisms of blood-brain barrier (BBB) breakdown, and the therapeutic potential of antiplatelet agents (e.g. aspirin, clopidogrel) and adenosine A2A receptor modulators.

RESULTS: In AD patients, platelet APP expression is markedly upregulated, shifting toward amyloidogenic processing via decreased α-secretase and increased β-secretase activity. Activated platelets breach the BBB, release pro-inflammatory mediators into the brain parenchyma, and promote cerebral Aβ deposition. Reciprocally, central AD pathology further drives systemic platelet activation, creating a self-reinforcing disease loop.

CONCLUSIONS: A clear, bidirectional relationship may exist between activated platelets and AD neuropathology. Because peripheral platelets actively fuel central amyloid accumulation and neuroinflammation, targeting platelet activation may be a viable strategy to mitigate AD risk and slow disease progression.},
}

@article {pmid43016267,
year = {2026},
author = {Afridi, S and Choudhary, F and Sharma, P and Mustafa, M and Farooqi, H},
title = {Ubiquitin-Proteasome System: Key Insights into Neurological Disorder Mechanisms.},
journal = {Current aging science},
volume = {19},
number = {4},
pages = {406-420},
pmid = {43016267},
issn = {1874-6128},
mesh = {Humans ; *Proteasome Endopeptidase Complex/metabolism ; *Ubiquitin/metabolism ; Animals ; Ubiquitin-Protein Ligases/metabolism ; *Neurodegenerative Diseases/drug therapy/enzymology/physiopathology/pathology/metabolism ; Autophagy ; Proteostasis ; Proteolysis ; Proteotoxic Stress ; Signal Transduction ; },
abstract = {The ubiquitin-proteasome system (UPS) is crucial for maintaining protein homeostasis in the central nervous system. Dysfunction of the UPS leads to the accumulation of neurotoxic aggregates, including amyloid, tau, alpha-synuclein, SOD1, and TDP-43, which are hallmark features of various neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Agerelated decline in the UPS and autophagy-lysosomal pathways results in compromised proteostasis and progressive neuronal damage. Current literature from diverse databases provides insights emphasizing the clinical relevance of UPS-targeted interventions. Strategies such as targeted degradation of misfolded proteins, modulation of PINK1/Parkin-mediated mitophagy, and the use of enzyme activators or allosteric modulators show potential in restoring brain homeostasis. This review discusses UPS-mediated proteolytic mechanisms, molecular disruptions associated with disease progression, and emerging therapeutic approaches aimed at enhancing protein clearance.},
}

Humans
*Proteasome Endopeptidase Complex/metabolism
*Ubiquitin/metabolism
Animals
Ubiquitin-Protein Ligases/metabolism
*Neurodegenerative Diseases/drug therapy/enzymology/physiopathology/pathology/metabolism
Autophagy
Proteostasis
Proteolysis
Proteotoxic Stress
Signal Transduction

@article {pmid43016268,
year = {2026},
author = {Rejitha, C and Babu, L},
title = {Animal and Cell Models in Alzheimer's and Parkinson's Disease: Current Innovations Reviewed.},
journal = {Current aging science},
volume = {19},
number = {4},
pages = {448-463},
pmid = {43016268},
issn = {1874-6128},
mesh = {Animals ; *Parkinson Disease/genetics/metabolism/pathology/physiopathology/drug therapy ; *Disease Models, Animal ; Humans ; *Alzheimer Disease/genetics/metabolism/pathology/physiopathology/drug therapy ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) remain major global health challenges due to their complex pathology and lack of curative therapies. Advancing therapeutic strategies requires reliable experimental models that recapitulate disease mechanisms. This review summarizes recent developments in animal and in vitro models for AD and PD, with emphasis on their translational relevance and applications. Transgenic mice (APP/PS1, 3xTg-AD), α-synuclein and LRRK2-based models for PD, rat 6- OHDA systems, zebrafish, and non-human primates provide valuable insights into amyloid deposition, tau aggregation, synaptic dysfunction, and motor impairment, though each presents limitations in faithfully mimicking human disease. Complementary in vitro approaches using neuronal and glial cell lines enable targeted studies on oxidative stress, inflammation, amyloid-beta (Aβ) toxicity, tau pathology, and dopaminergic degeneration. Emerging platforms such as CRISPR/Cas9-based editing, induced pluripotent stem cell (iPSC)-derived organoids, and artificial intelligence-driven drug discovery are further expanding the preclinical landscape. Together, these integrated strategies enhance understanding of neurodegenerative processes and hold promise for the development of effective disease-modifying therapies.},
}

Animals
*Parkinson Disease/genetics/metabolism/pathology/physiopathology/drug therapy
*Disease Models, Animal
Humans
*Alzheimer Disease/genetics/metabolism/pathology/physiopathology/drug therapy
Amyloid beta-Peptides/metabolism

@article {pmid43016269,
year = {2026},
author = {Mehrabadi, S and Samarghandian, S},
title = {Glymphatic Dysfunction in Alzheimer's Disease: Mechanisms, Biomarkers, and Emerging Therapeutic Perspectives.},
journal = {Current aging science},
volume = {19},
number = {4},
pages = {464-472},
pmid = {43016269},
issn = {1874-6128},
mesh = {Humans ; *Alzheimer Disease/physiopathology/therapy/metabolism/cerebrospinal fluid ; *Glymphatic System/physiopathology/metabolism ; Animals ; Biomarkers/metabolism/cerebrospinal fluid ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Sleep ; Cognition ; *Brain/metabolism/physiopathology/pathology ; Sleep Wake Disorders/physiopathology/therapy/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, with hallmark pathological features including amyloid-beta plaques, tau tangles, and neuronal loss. The glymphatic system, a recently discovered network responsible for brain waste clearance, plays a crucial role in maintaining cerebral homeostasis by facilitating the removal of neurotoxic metabolites, including amyloid-beta. Disruption of glymphatic function has emerged as a key factor in AD pathophysiology, contributing to the accumulation of toxic proteins and accelerating neurodegenerative processes. This narrative review explores the complex interplay between glymphatic dysfunction and AD. We discuss the mechanisms of the glymphatic system, emphasizing its reliance on cerebrospinal fluid (CSF) and interstitial fluid flow to clear metabolic waste, and how this process is closely linked to sleep cycles. In AD, impaired glymphatic function, exacerbated by aging and sleep disturbances, accelerates the buildup of amyloid-beta and tau, driving neurodegeneration. Furthermore, sleep disturbances commonly observed in AD patients further hinder glymphatic activity, creating a vicious cycle that exacerbates cognitive decline. Emerging therapeutic approaches aimed at enhancing glymphatic function-including sleep regulation, pharmacological agents, and lifestyle interventions-are promising, but most findings remain preliminary and largely based on animal studies or early clinical observations. These strategies should therefore be considered exploratory until validated in large-scale human trials. By restoring efficient waste clearance, such interventions may offer novel avenues for slowing or preventing AD progression.},
}

Humans
*Alzheimer Disease/physiopathology/therapy/metabolism/cerebrospinal fluid
*Glymphatic System/physiopathology/metabolism
Animals
Biomarkers/metabolism/cerebrospinal fluid
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Sleep
Cognition
*Brain/metabolism/physiopathology/pathology
Sleep Wake Disorders/physiopathology/therapy/metabolism

@article {pmid43016645,
year = {2026},
author = {Zhong, J and Li, J and Mo, Z and Zeng, Y and Peng, J and Zhu, P and Wang, H and Mo, C and Liu, Y and Tu, Y},
title = {Cerebrospinal fluid MMP-2 and TIMP-2 reflect blood-cerebrospinal fluid barrier dysfunction in Guillain-Barré syndrome and CIDP.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1993595},
pmid = {43016645},
issn = {1664-2295},
mesh = {Humans ; *Guillain-Barre Syndrome/cerebrospinal fluid/blood/physiopathology ; Female ; *Matrix Metalloproteinase 2/cerebrospinal fluid/blood ; Male ; *Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/cerebrospinal fluid/blood/physiopathology ; *Tissue Inhibitor of Metalloproteinase-2/cerebrospinal fluid/blood ; Middle Aged ; Aged ; Prospective Studies ; Biomarkers/cerebrospinal fluid/blood ; *Blood-Brain Barrier/physiopathology/metabolism ; Matrix Metalloproteinase 9/cerebrospinal fluid/blood ; Adult ; },
abstract = {BACKGROUND: This study aimed to investigate patterns of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). It also examined how these patterns relate to dysfunction of the blood-cerebrospinal fluid barrier (BCB).

METHODS: This prospective observational study enrolled 86 participants: 33 patients with GBS, 34 with CIDP, and 19 with Alzheimer's disease (AD) as controls. Enzyme-linked immunosorbent assay (ELISA) quantified MMP-2, MMP-9, TIMP-1, and TIMP-2 levels in blood and cerebrospinal fluid (CSF). Analyses included group comparisons, multivariable logistic regression, ROC curve analysis, and multivariable linear regression to assess classification value and association with CSF protein (CSF-Pro).

RESULTS: Compared to controls, patients with immune-mediated peripheral neuropathies had lower blood MMP-2 and TIMP-2 levels and higher blood MMP-9 levels. CSF MMP-2 and TIMP-2 levels were higher in CIDP than in GBS. Multivariable logistic regression showed CSF MMP-2 was associated with disease classification. ROC analysis revealed CSF MMP-2 moderately distinguished CIDP from GBS (AUC = 0.700). Multivariable linear regression showed CSF TIMP-2 was independently and negatively associated with CSF-Pro levels.

CONCLUSION: The MMP-2/TIMP-2 axis may contribute to BCB dysfunction in immune-mediated peripheral neuropathies. CSF MMP-2 levels are associated with disease classification, while elevated CSF TIMP-2 levels may alleviate barrier damage. These biomarkers may serve as potential reference indicators for assessing barrier dysfunction and could provide a basis for differentiating GBS from CIDP.},
}

Humans
*Guillain-Barre Syndrome/cerebrospinal fluid/blood/physiopathology
Female
*Matrix Metalloproteinase 2/cerebrospinal fluid/blood
Male
*Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/cerebrospinal fluid/blood/physiopathology
*Tissue Inhibitor of Metalloproteinase-2/cerebrospinal fluid/blood
Middle Aged
Aged
Prospective Studies
Biomarkers/cerebrospinal fluid/blood
*Blood-Brain Barrier/physiopathology/metabolism
Matrix Metalloproteinase 9/cerebrospinal fluid/blood
Adult

@article {pmid43016785,
year = {2026},
author = {Shir, D and Piura, YD and Graff-Radford, NR and Aduen, P and Jain, MK and Schecter, L and Vemuri, P and Day, GS and Lachner, C},
title = {Modifiable dementia risk factors and socioeconomic differences in a diverse aging cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70493},
pmid = {43016785},
issn = {2352-8729},
abstract = {BACKGROUND: Black and Hispanic/Latino Americans experience higher risk of Alzheimer's disease and related dementias (ADRD). Modifiable biological and social risk factors may contribute to this risk but remain underrecognized.

METHODS: In this cross-sectional study, we evaluated 105 cognitively normal Black and Hispanic/Latino-White adults in a Northeast Florida longitudinal cohort. Assessments included clinical exams, objective cardiometabolic/laboratory testing, brain magnetic resonance imaging, and amyloid and tau positron emission tomography (PET) imaging. We compared subjective versus objective risk factors and explored potential associations with prespecified neuroimaging biomarkers.

RESULTS: Participant median age was 64.2 years, and 63% were female. Nearly all participants (98%) had at least one modifiable ADRD risk factor; 58% had at least three. Objective testing identified higher prevalence of abnormal hemoglobin A1C and vitamin B12 deficiency than self-report. Black participants had greater white matter hyperintensity burden than Hispanic-White participants, whereas PET measures were similar. Measured risk factors were not clearly associated with neuroimaging biomarkers.

DISCUSSION: Potentially modifiable ADRD risk factors were common and underrecognized in this modest-sized cohort of Black and Hispanic/Latino Americans. These findings reinforce the importance of objective assessment of modifiable risk factors to inform early prevention strategies while emphasizing the need to validate these preliminary findings in larger, representative cohorts.},
}

@article {pmid43016791,
year = {2026},
author = {Cáceres-Palomo, L and Alfonso-Triguero, M and Belloso-Iguerategui, A and Santiago-Mujika, E and Mirón-Alcalá, M and Arranz, AM},
title = {Chimeric models of neurodegenerative diseases: from disease mechanisms to regenerative therapies.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {51},
pmid = {43016791},
issn = {3059-4944},
abstract = {Human-rodent chimeric CNS models provide a unique platform for investigating human-specific aspects of neurodegeneration within the physiological environment of the living CNS. These models are generated by transplanting human pluripotent stem cell-derived neurons, astrocytes, microglia, oligodendrocytes, or neural or glial progenitor cells into the CNS of permissive host animals. Following transplantation, human cells mature, functionally integrate within host tissue, and retain key species-specific molecular and cellular features. Here, we review recent advances in the use of chimeric models to investigate disease mechanisms in Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and demyelinating disorders. We highlight the unique insights these models have provided into human-specific cellular vulnerabilities, genotype-dependent phenotypes, glial responses, and neuroimmune interactions in vivo. We also discuss emerging translational applications, including cell replacement therapies, engineered glial delivery platforms, and remyelination strategies, some of which have progressed toward clinical translation. Finally, we outline the current limitations and future directions for developing next-generation multi-lineage humanized models with enhanced disease fidelity and translational potential.},
}

@article {pmid43017153,
year = {2026},
author = {Feng, Y and Sha, Y and Xu, L and Tian, J and Gao, Y and Zhou, R and Liu, G},
title = {Integrated gut microbiome and fecal metabolome profiling identifies taurine-associated microbial dysbiosis across the Alzheimer's disease clinical spectrum.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1981076},
pmid = {43017153},
issn = {1663-4365},
abstract = {BACKGROUND: Gut microbiome alterations have been associated with Alzheimer's disease (AD), but how microbial composition, fecal metabolites, and cognitive function relate across the cognitive impairment spectrum-from subjective cognitive decline (SCD) through mild cognitive impairment (MCI) to AD-remains unclear. We integrated microbiome and metabolome profiles across this clinical spectrum.

METHODS: Fecal samples from 84 participants [10 healthy controls (HC), 22 SCD, 23 MCI, 29 AD] underwent 16S rRNA V3-V4 sequencing and untargeted LC-MS metabolomics. Profiles were integrated via Procrustes analysis, sparse canonical correlation, MIMOSA2 community-metabolism modeling, and mediation analysis. Differential abundance was assessed by Kruskal-Wallis, ANCOM-BC2, and LinDA.

RESULTS: Microbial composition differed across groups (ANOSIM R = 0.111, p = 0.001; Adonis R [2] = 0.070, p = 0.002). Cross-method validation confirmed 8 differentially abundant genera in AD vs. HC with 100% directional concordance between ANCOM-BC2 and LinDA, including depletion of butyrate-producing Lachnospiraceae (Blautia, Dorea, Fusicatenibacter) and enrichment of opportunistic pathobionts (Klebsiella, Escherichia-Shigella). Taurine showed the highest MIMOSA2 community-prediction R [2] (0.129; n = 62) and was positively associated with MMSE scores (r = 0.45, BH-FDR Q = 0.0005). A multi-omic random forest model (5 genera + 5 metabolites + age + sex) discriminated AD-clinical spectrum participants from HC with AUC = 0.86 (95% CI 0.82-0.90), although pairwise differences from the age + sex baseline (AUC = 0.75) did not reach statistical significance. Statistical mediation analysis was consistent with a Blautia → taurine → MMSE statistical mediation [ACME = 0.21, p = 0.008; 54% proportion mediated, bootstrap 95% CI (9%, 58%)].

CONCLUSION: Integrated multi-omic profiling reveals coordinated microbiome-metabolome dysregulation across the AD clinical spectrum, with taurine as a candidate microbial-metabolic node linking gut dysbiosis to cognitive performance. Microbial and metabolic alterations are detectable at the SCD stage, before objective cognitive impairment. These findings warrant validation in larger, age-matched cohorts and higher-resolution metagenomic studies.},
}

@article {pmid43017199,
year = {2026},
author = {Gan, X and Zhou, X and Yan, S and Yang, S and Li, Z},
title = {Sleep and circadian disturbances in Alzheimer's disease: clinical assessment, treatable syndromes, and limits of biomarker inference.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1998439},
pmid = {43017199},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/complications/physiopathology ; *Sleep Wake Disorders/diagnosis/etiology/physiopathology/therapy ; Biomarkers ; Polysomnography ; Animals ; *Chronobiology Disorders/diagnosis/therapy/etiology/physiopathology ; Circadian Rhythm/physiology ; },
abstract = {Sleep and circadian disturbances in Alzheimer's disease (AD) affect patients and caregivers, but clinical action depends on the syndrome, measurement, and outcome under consideration. This narrative review links sleep assessment to indication-based care while distinguishing symptomatic benefit, physiological target engagement, and disease modification. A purposive literature search was supplemented by targeted checks of PubMed-indexed and original publisher records through 4 October 2026. Selected studies are described by population, AD ascertainment, comparator, and measured endpoint rather than assigned formal evidence-certainty grades. Actigraphy characterizes behavioral rest-activity patterns; melatonin timing and temperature rhythms address endogenous circadian physiology under controlled conditions. Polysomnography and quantitative electroencephalography characterize respiratory events, sleep architecture, and oscillatory activity. These measurements inform different questions and do not independently assign AD etiology or cognitive-functional stage. Clinical priorities include confirmed obstructive sleep apnea, cognition-adapted insomnia care, irregular sleep timing, medication-related effects, parasomnias, limb symptoms, and excessive daytime sleepiness. Interpretation incorporates hypoxemia, treatment exposure, comorbidity, caregiver support, and competing diagnoses. Randomized sleep benefits remain distinct from observational cognitive associations or exploratory imaging and cerebrospinal fluid changes. Human and animal studies of arousal circuits, protein dynamics, inflammation, and fluid transport provide mechanistic context, with conflicting results interpreted according to the actual experimental endpoint. The review provides a clinically organized account of selected evidence, not a comprehensive treatment ranking. Sleep care and cognitive-etiologic assessment should proceed in parallel, with follow-up matched to patient function, safety, and the specific treatment goal.},
}

Humans
*Alzheimer Disease/complications/physiopathology
*Sleep Wake Disorders/diagnosis/etiology/physiopathology/therapy
Biomarkers
Polysomnography
Animals
*Chronobiology Disorders/diagnosis/therapy/etiology/physiopathology
Circadian Rhythm/physiology

@article {pmid43017209,
year = {2026},
author = {Bai, X and Ji, Y and Ruan, H and Zhang, W and Ma, Y and Jiang, X and Liu, X and Wang, F},
title = {Acupuncture-related brain network findings across clinical stages of the Alzheimer's disease continuum: a critical review of functional MRI evidence.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1977763},
pmid = {43017209},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/therapy/diagnostic imaging/physiopathology ; *Magnetic Resonance Imaging ; *Acupuncture Therapy ; *Brain/diagnostic imaging/physiopathology ; *Cognitive Dysfunction/therapy/diagnostic imaging/physiopathology ; *Nerve Net/diagnostic imaging/physiopathology ; Disease Progression ; },
abstract = {Brain network abnormalities are observed across the Alzheimer's disease (AD) continuum, but the relationship between clinical stage, acupuncture-related functional brain changes, and cognitive outcomes remains unclear. This review examined clinical blood oxygen level-dependent functional MRI studies of acupuncture in subjective cognitive decline (SCD), mild cognitive impairment (MCI, including amnestic MCI [aMCI]), and AD dementia. PubMed, Web of Science Core Collection, and China National Knowledge Infrastructure (CNKI) were searched for relevant studies. The evidence was synthesized narratively by clinical stage, with attention to study design, acupuncture protocols, control conditions, imaging methods, brain-cognition associations, biomarker status, and possible cohort overlap. In SCD, the limited available evidence mainly involved changes in regional spontaneous activity, hippocampal connectivity, and network organization. In MCI, including aMCI, reported changes involved memory- and limbic-related regions, DLPFC-ACC connectivity, and locus coeruleus-related pathways. In AD dementia, reported changes mainly involved the hippocampus and posterior medial memory-related regions, with earlier studies mainly examining short-term responses and two longitudinal cohorts assessing changes over a treatment course. Across the reviewed literature, findings in MCI, including aMCI, involved a broader range of brain regions and networks, whereas those in AD dementia were more often centered on the hippocampus and posterior medial memory-related regions. These differences are difficult to attribute to clinical stage alone, given substantial differences across studies in acupuncture protocols, control conditions, imaging methods, sample size, biomarker confirmation, and follow-up. Larger longitudinal studies with biomarker confirmation where possible and complementary imaging modalities are needed to determine whether the observed differences are related to clinical stage and how the imaging changes relate to cognitive outcomes.},
}

Humans
*Alzheimer Disease/therapy/diagnostic imaging/physiopathology
*Magnetic Resonance Imaging
*Acupuncture Therapy
*Brain/diagnostic imaging/physiopathology
*Cognitive Dysfunction/therapy/diagnostic imaging/physiopathology
*Nerve Net/diagnostic imaging/physiopathology
Disease Progression

@article {pmid43017342,
year = {2026},
author = {Zhou, S and Chen, Y and Yang, X and Xiang, L and Li, B and Qiu, L and Liu, Z and Zhang, T and Liu, F and Zeng, L and Mao, G},
title = {Noncoding RNA control of neuroinflammation in Alzheimer's disease: from immune cell states to precision therapeutics.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1998588},
pmid = {43017342},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/genetics/therapy/metabolism ; Animals ; *Neuroinflammatory Diseases/genetics/immunology/therapy ; *RNA, Untranslated/genetics ; Precision Medicine ; MicroRNAs/genetics ; Microglia/immunology/metabolism ; },
abstract = {Neuroinflammation is an active and heterogeneous component of Alzheimer's disease, shaped by dynamic interactions among microglia, astrocytes, neurons, and brain-interface compartments. Noncoding RNAs, including microRNAs, long noncoding RNAs, circular RNAs, and emerging small-RNA species, regulate innate immune sensing, interferon responses, phagocytosis, metabolic adaptation, inflammasome activity, and neuronal stress. Their effects are strongly context dependent: the same noncoding RNA can exert different or even opposing functions according to cell identity, intracellular or extracellular localization, disease stage, and dose. Extracellular vesicles and extracellular RNA sensing further extend noncoding RNA activity beyond cell-autonomous regulation, creating intercellular circuits that couple neuronal stress to glial immune states. Noncoding RNA-regulated inflammation intersects with amyloid-β production and clearance, tau-associated stress, synaptic dysfunction, mitochondrial impairment, and regulated cell death. Rather than acting as isolated inflammatory switches, noncoding RNAs appear to tune the strength of pathological feedback networks that determine whether proteotoxic and inflammatory stress is contained or progressively amplified. The translational value of individual noncoding RNAs depends on the convergence of causal evidence, mechanistic resolution, human relevance, and therapeutic tractability. Human brain, cerebrospinal fluid, patient-derived extracellular vesicles, and induced pluripotent stem cell models are beginning to bridge experimental mechanism and human disease, while antisense oligonucleotides, engineered extracellular vesicles, targeted nanoparticles, and synthetic circular RNAs provide emerging therapeutic routes. Pleiotropy, cell-type specificity, disease-stage dependence, endosomal trafficking, and innate RNA sensing remain major barriers. Context-resolved noncoding RNA regulatory nodes that control defined neuroimmune states may ultimately enable precision neuroimmune reprogramming while preserving protective immune functions.},
}

Humans
*Alzheimer Disease/immunology/genetics/therapy/metabolism
Animals
*Neuroinflammatory Diseases/genetics/immunology/therapy
*RNA, Untranslated/genetics
Precision Medicine
MicroRNAs/genetics
Microglia/immunology/metabolism

@article {pmid43017368,
year = {2026},
author = {Luo, D and Lv, X and Mu, H and Tao, X and Chen, H and Cui, Z and Gao, P},
title = {The role of vascular factors in Alzheimer's disease: from cerebrovascular pathological mechanisms to blood biomarkers.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1997082},
pmid = {43017368},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is the most common dementia, and post-mortem and imaging studies consistently demonstrate that vascular pathology coexists with plaques and tangles in most AD brains. Vascular risk factors-hypertension, diabetes, dyslipidaemia, and atrial fibrillation-damage the neurovascular unit, disrupt the blood-brain barrier, and induce chronic hypoperfusion, thereby promoting β-amyloid (Aβ) deposition, tau hyperphosphorylation, and neuroinflammation. Cerebral small vessel disease, amyloid angiopathy, and carotid stenosis are overrepresented in AD and accelerate cognitive decline. Ultrasensitive blood assays now enable plasma Aβ42/40, phosphorylated tau isoforms, glial fibrillary acidic protein, and neurofilament light chain to approach the diagnostic accuracy of cerebrospinal fluid and PET, while endothelial injury markers such as vascular endothelial-cadherin and soluble adhesion molecules are emerging. Against this background, this review contends that AD diagnostics must move beyond a single-pathology framework toward an integrated model that combines neurodegenerative and vascular injury biomarkers. Reliance on Aβ and tau alone cannot capture clinical heterogeneity nor guide vascular-targeted interventions. A multidimensional blood panel reflecting pericyte loss, endothelial dysfunction, and blood-brain barrier compromise may offer improved stratification and ultimately help identify whether a biomarker-defined subgroup could benefit from vascular interventions-a hypothesis that remains to be tested prospectively. This review traverses the entire cascade from risk factors through cerebrovascular mechanisms to surgical considerations and blood biomarkers, aiming to provide a clinically actionable reference for multidisciplinary dementia care.},
}

@article {pmid43017408,
year = {2026},
author = {Li, X and Gozes, I},
title = {AI-enabled drug repurposing in Alzheimer's disease: from computational nomination to pharmacological proof.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1999276},
pmid = {43017408},
issn = {1663-9812},
abstract = {Artificial intelligence (AI) has expanded the scale and speed of drug repurposing in Alzheimer's disease (AD). Transcriptomic signature matching, network-based systems pharmacology, real-world data pharmacoepidemiology and multi-omics machine learning have generated hundreds of candidate drugs, while repurposed agents account for 35% (56 of 158) of drugs and 42% (15 of 36) of Phase 3 agents in the 2026 AD pipeline. Clinical translation, however, remains unproven. Randomised trials of GLP-1 receptor agonists illustrate the gap between prioritisation and therapeutic proof: semaglutide did not slow clinical progression in evoke and evoke+, while liraglutide did not improve the primary FDG-PET endpoint in ELAD. We examine four complementary evidence domains, defining what each can and cannot establish, and position large language models as a cross-cutting tool for evidence synthesis and knowledge-graph reasoning rather than an independent source of biological evidence. Rather than cataloguing methods and candidates, we appraise leading drugs at the individual-molecule level and propose explicit criteria for progression from computational nomination to clinical testing. The framework defines seven requirements for clinical progression: disease-stage matching, adequate site-of-action exposure, including CNS exposure for central mechanisms, mechanistic validation in human-relevant models, biomarker-stratified trial design, convergence across independent evidence domains, causal inference with explicit boundary conditions, and mechanism-aligned endpoints with predefined stopping rules. AI has improved candidate prioritisation in AD, but clinical value will depend on converting ranked hypotheses into pharmacologically plausible and prospectively testable programmes.},
}

@article {pmid43017556,
year = {2026},
author = {Huang, X and Zhang, X and Zhu, Q},
title = {Microbiome-targeted strategies for Alzheimer's disease: multi-omics signatures, mechanistic links, and intervention evidence.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1828118},
pmid = {43017556},
issn = {1664-302X},
abstract = {Alzheimer's disease (AD) is increasingly studied in relation to gut microbial mechanisms because microbial metabolism, mucosal barrier function, and peripheral immune activation may influence neuroinflammation and host metabolic stress. This review evaluates microbiome-linked evidence in AD with emphasis on studies that combine metagenomics, metabolomics, inflammatory markers, neuroimaging, cerebrospinal fluid or blood biomarkers, and cognitive phenotyping. Current data support several recurring but not yet causal axes, including bile acid transformation, short-chain fatty acid (SCFA) production, trimethylamine N-oxide (TMAO), bacterial product-related inflammatory signaling, and barrier dysfunction. We also review microbiome-targeted interventions, including diet and prebiotics, strain-specified probiotics and synbiotics, oligosaccharide-based agents, gut-restricted antimicrobials, and fecal microbiota transplantation (FMT). The strength of evidence differs substantially across these strategies: sodium oligomannate has been tested in a phase 3 trial, whereas many probiotic, antimicrobial, and FMT approaches remain early clinical, preclinical, or mechanism-generating. Future trials should define a priori microbial, metabolite, immune, and brain biomarker endpoints; control diet, medication, and comorbidity confounding; and validate candidate signatures across independent cohorts before using microbiome profiles for screening or treatment selection.},
}

@article {pmid43017560,
year = {2026},
author = {Stellingwerf, A and Schreuder, FHBM and Kuiperij, HB and Van Der Kolk, AG and Backes, WH and Claassen, JAHR and Verbeek, MM},
title = {Longitudinal amyloid-beta measurements and blood-brain barrier dysfunction in cerebral amyloid angiopathy as part of the Mechanisms Of DEMentia project: protocol of the MODEM-LAMBDA-C study.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1949765},
pmid = {43017560},
issn = {1664-2295},
mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging/physiopathology/metabolism/complications ; *Blood-Brain Barrier/metabolism/diagnostic imaging/physiopathology ; Female ; Longitudinal Studies ; Male ; Magnetic Resonance Imaging ; Aged ; Peptide Fragments/cerebrospinal fluid ; *Dementia/cerebrospinal fluid/etiology ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-beta (Aβ) peptides within the cerebral vasculature and is a major cause of lobar intracerebral haemorrhage, cognitive impairment, and dementia. Vascular Aβ aggregates are enriched in shorter peptides (Aβ38 and Aβ40) whereas neuritic plaques, as observed in Alzheimer's disease pathology, predominantly contain longer Aβ peptides (Aβ42 and Aβ43). These pathological signatures are reflected by reduced cerebrospinal fluid (CSF) Aβ levels. However, the longitudinal dynamics of CSF Aβ peptides in CAA and their relationship with blood-brain barrier (BBB) dysfunction remain poorly understood.

METHODS: The MODEM-LAMBDA-C study is a longitudinal observational study including participants with CAA and age- and sex-matched control participants. At baseline, participants undergo clinical assessment, cognitive testing, blood pressure measurement, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the brain, blood sampling, and lumbar puncture to obtain CSF. At 2 years of follow-up, all assessments except MRI are repeated. Longitudinal changes in CSF Aβ peptide concentrations will be examined and related to cognitive performance, baseline MRI markers of cerebral small vessel disease and DCE-MRI-derived measures of BBB leakage. Additionally, CSF biomarkers of BBB dysfunction will be quantified and correlated with DCE-MRI markers of BBB dysfunction.

CONCLUSION: By integrating biochemical and imaging markers of Aβ pathology and BBB dysfunction, the MODEM-LAMBDA-C study aims to provide a comprehensive understanding of disease mechanisms underlying CAA, potentially contributing to improved diagnosis and prognostic strategies.

CLINICAL TRIAL REGISTRATION: https://onderzoekmetmensen.nl/en, identifier: NL85709.091.23.},
}

Humans
*Amyloid beta-Peptides/cerebrospinal fluid
*Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnostic imaging/physiopathology/metabolism/complications
*Blood-Brain Barrier/metabolism/diagnostic imaging/physiopathology
Female
Longitudinal Studies
Male
Magnetic Resonance Imaging
Aged
Peptide Fragments/cerebrospinal fluid
*Dementia/cerebrospinal fluid/etiology

@article {pmid43017601,
year = {2026},
author = {Xiao, Z and Qin, Y and Dong, M and Wei, S and Ma, Q and Luo, C and Li, Y and Chen, F and Wu, G and Wei, P and Hu, R and Huang, Z and Liu, C},
title = {Multi-Omics Mendelian Randomization Identifies DDX17 as a Potential Mediator Linking Gut Microbiota-Immune-Metabolism Axis to Alzheimer's Disease.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {652037},
pmid = {43017601},
issn = {1178-7074},
abstract = {INTRODUCTION: The gut microbiota-immune-metabolism axis has been implicated in Alzheimer's disease (AD) pathogenesis; however, the key host molecular targets linking peripheral dysregulation to central neurodegeneration remain elusive.

METHODS: In this study, we systematically integrated large-scale GWAS data covering 1,903 gut microbiota taxa, 14,696 immune cell features, and 34,843 metabolite features with AD GWAS summary statistics, using two-sample Mendelian randomization (MR) to identify causal genes. These genes were intersected with differentially expressed genes from three GEO datasets, followed by protein-protein interaction network construction using four Cytoscape algorithms (MCC, EPC, DMNC, Degree) and feature selection via three machine learning methods (Support Vector Machine, Random Forest, LASSO). Single-cell transcriptomics (GSE188545) localized key gene expression, Support Vector Machine virtual knockout (scTenifoldKnk) analyzed downstream regulatory networks, with in vitro validation performed in okadaic acid-treated SH-SY5Y cells using RT-qPCR and Western blotting.

RESULTS: MR analysis revealed multiple causal associations among microbial taxa, immune phenotypes, metabolites, and AD. Integration of MR causal genes with DEGs, PPI network analysis, and machine learning refinement prioritized six key genes: BYSL, DDX17, HSPA6, RRN3, C4B, and NCKAP1L. Among them, only DDX17 showed robust expression in AD-associated neuronal populations in single-cell transcriptomics, whereas the other five genes showed low expression and may act through non-cell-autonomous mechanisms. Virtual knockout predicted that the PI3K/AKT pathway was the most significantly enriched downstream of DDX17 perturbation. In vitro, DDX17 was significantly upregulated in an OA-induced AD cell model, and siRNA-mediated knockdown partially reversed tau hyperphosphorylation (total P-tau and P-tau Thr217), while restoring AKT phosphorylation at Thr308 and Ser473.

CONCLUSION: These findings suggest that DDX17 is a potential downstream host candidate linking peripheral dysregulation to tau pathology in AD, partially through PI3K/AKT pathway modulation. However, these results are primarily hypothesis-generating, and direct mechanistic and in vivo validation remain essential.},
}

@article {pmid43017815,
year = {2026},
author = {Williams, DM and Mukadam, N and Davies, NM and Anderson, EL},
title = {Understanding apolipoprotein E as a predominant cause of Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag395},
pmid = {43017815},
issn = {1460-2156},
abstract = {The full contribution of apolipoprotein E (APOE) to Alzheimer's disease burden in populations may have been overlooked. This is due, in large part, to a lack of recognition that the most common allele of the APOE gene, ε3, increases risk of Alzheimer's disease relative to the ε2 allele. When the impact of both ε3 and ε4 alleles of APOE are considered, the majority of late-onset Alzheimer's disease appears to be attributable to differences in APOE function or expression in populations of European ancestry and in other ethnic groups for which we have reliable data. Moreover, most sporadic early-onset Alzheimer's disease might not occur without the contributions of APOE ε3 and ε4, and the two alleles may be component causes of most forms of Alzheimer's disease arising from highly penetrant genetic mutations and trisomy 21. Taken together, these lines of epidemiological evidence suggest that APOE is a predominant cause of Alzheimer's disease, spanning the aetiologies of many forms of the disease. Consequently, almost all prospective cases of Alzheimer's disease might benefit from the development of therapies to modulate APOE's role in the disease's pathophysiology.},
}

@article {pmid43017840,
year = {2026},
author = {Drapała, N and Barańska, I and Kliś-Kalinowska, A and Szczerbińska, K},
title = {Factors associated with self-reported stress by informal caregivers providing care for older adults.},
journal = {International journal of occupational medicine and environmental health},
volume = {},
number = {},
pages = {},
doi = {10.13075/ijomeh.1896.02855},
pmid = {43017840},
issn = {1896-494X},
abstract = {OBJECTIVES: The aim of this study was to assess the prevalence of self‑reported stress among informal caregivers of older adults living at home and to identify key factors associated with caregiving-related stress.

MATERIAL AND METHODS: Between April 2024 and May 2025, a cross-sectional survey was conducted among 338 informal caregivers of individuals aged ≥60 years. Data were collected using the interRAI-Self-Reported Carer Needs (SCaN) tool. Logistic regression analyses were used to identify key stress-related factors.

RESULTS: Factors that significantly increase the odds of experiencing stress associated with caregiving include: being employed while providing care (OR = 3.03, 95% CI: 1.61-5.70), caring for a person with Alzheimer's disease or other dementia (OR = 2.38, 95% CI: 1.24-4.54), lack of access to respite services (OR = 3.53, 95% CI: 1.92-6.49), spending >35 h/week on caregiving (OR = 2.27, 95% CI: 1.08-4.77), and the presence of mood-disorder symptoms in the carer (OR = 3.53, 95% CI: 1.92-6.49). Caregivers who felt their relatives' needs were unmet were nearly 6 times more likely to report stress compared to those who felt otherwise (OR = 5.84, 95% CI: 1.48-23.01).

CONCLUSIONS: Caregiver stress is a multifaceted phenomenon associated with numerous factors. This cross-sectional study identifies factors associated with the prevalence of caregiving stress, underscoring the need for a multidimensional approach to strengthen and optimize support systems for informal caregivers and the individuals they care for. Int J Occup Med Environ Health. 2026;39(6).},
}

@article {pmid43017915,
year = {2026},
author = {Singh, R and Reuben, S and Oyelami, M and Adeleye, A and Marshall, E},
title = {In vivo biomarkers for limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC): A scoping review of proposed measures.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261505301},
doi = {10.1177/13872877261505301},
pmid = {43017915},
issn = {1875-8908},
abstract = {BackgroundLimbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common cause of late-life amnestic dementia that mimics Alzheimer's disease but lacks a validated in vivo biomarker.ObjectiveThe authors sought to map the in vivo biomarker candidates for LATE-NC, characterize the type and quality of evidence for each, highlight their validation against postmortem TDP-43 staging and map their performance in both pure LATE-NC and mixed pathology.MethodsFive databases were searched (PubMed/MEDLINE, EMBASE, Web of Science, Cochrane Library, Scopus). Eligible studies investigated in vivo biomarkers for LATE-NC in adults with mean age above 65. Two reviewers independently screened all records; a third adjudicated disagreements. Data were extracted across 24 fields and synthesized narratively.Results43 studies covering structural MRI (19), FDG-PET (8), plasma (7), diffusion MRI (4), multimodal MRI (1), CSF (2), TDP-43 PET (1), and linguistic markers (1) were reviewed. The most replicated signal was medial temporal lobe atrophy and hypometabolism. Several studies framed their candidate as a diagnostic validation against autopsy; yet only three reported formal performance metrics with stated cut-off values. A handful of studies (12%) tested in an independent cohort and the corpus contains only one study from outside North America and Europe (Japan).ConclusionsImaging evidence is well-anchored but mostly exploratory or surrogate validated at this stage. Plasma TDP-43 elevation is consistent but no commercial assay has a validated cut-point. Clinical translation requires external validation, cut-point-anchored diagnostic accuracy, and cohort diversification.},
}

@article {pmid43017921,
year = {2026},
author = {Wilson, L and Toomey, M and Pachana, NA and Dawes, P},
title = {Impact of Hearing and Vision Loss on Quality of Life in Older Adults Living With Cognitive Impairment: A Scoping Review.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261506165},
doi = {10.1177/14713012261506165},
pmid = {43017921},
issn = {1741-2684},
abstract = {Previous reviews have established that hearing and vision impairments are common among people living with cognitive impairment and that these comorbidities can exacerbate effects of cognitive impairments on cognitive, social and functional outcomes. This scoping review aimed to extend on this knowledge, by identifying and evaluating evidence regarding the effect of hearing and vision impairment on quality of life among older adults living with cognitive impairment, to: (i) determine if a compounding effect exists between hearing and/or vision and cognitive impairments; (ii) compare the effects on hearing, vision and health-related quality of life, and (iii) evaluate quality of life outcomes for hearing and vision interventions for this population. Seven electronic databases were searched systematically from inception to February 2026 for studies reporting quality of life outcomes among older adults living with cognitive impairment and hearing and/or vision impairment. Results were summarised then categorised by aim. Thirteen studies met inclusion criteria. The limited evidence suggests that (i) individuals living with comorbid vision and cognitive impairments may have substantially worse quality of life than those with either impairment alone, (ii) the effect is similar in size across different quality of life outcomes and (iii) sensory support interventions, involving counselling and assistance with device use, appear to be a more promising method of improving quality of life among this population. Further research is necessary to understand the relationship between hearing and vision impairments and quality of life among people living with cognitive impairment. Recommendations for future research include focusing on dual sensory impairment, utilising mixed methods approaches and inclusive selection criteria for people living with dementia. Further development and implementation of sensory support programs, codesigned with individuals with lived experience, is also recommended for improving the quality of life for people living with dementia globally.},
}

@article {pmid43018301,
year = {2026},
author = {Saha, G and Bandyopadhyay, S},
title = {Molecular Insights into the Aβ-42 Tetramer-Induced Disruptive Effects on a Model Phospholipid Membrane.},
journal = {The journal of physical chemistry. B},
volume = {130},
number = {45},
pages = {12014-12027},
doi = {10.1021/acs.jpcb.6c04108},
pmid = {43018301},
issn = {1520-5207},
support = {NA//Anusandhan National Research Foundation/ ; NA//Indian Institute of Technology Kharagpur/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Molecular Dynamics Simulation ; *Lipid Bilayers/chemistry ; *Peptide Fragments/chemistry/metabolism ; *1,2-Dipalmitoylphosphatidylcholine/chemistry ; *Phospholipids/chemistry ; Temperature ; Protein Multimerization ; },
abstract = {Formation of pores in neuronal membranes by amyloid-β (Aβ) oligomers is believed to be the origin behind neurotoxicity in Alzheimer's disease (AD). However, despite significant efforts, high-resolution characterizations of the pore-forming Aβ oligomers from experimental studies have been hindered due to structural heterogeneity of such aggregated oligomers. Consequently, efforts have been made to characterize the aggregated oligomers that develop within a membrane environment. Attempts have been made in this study to probe the microscopic properties of the three-dimensional structure of an Aβ oligomer, specifically an Aβ-42 tetramer present in a membrane-mimicking environment. The tetramer comprises of eight antiparallel β strands forming an Aβ-42 barrel. Atomistic molecular dynamics simulations at constant temperature and pressure (NPT) have been carried out on a fully hydrated liquid-crystalline lamellar phase of dipalmitoylphosphatidylcholine (DPPC) lipid bilayer with an Aβ-42 tetramer embedded into it forming a pore. The results were compared with that of a fully hydrated pure DPPC bilayer system. Based on the calculations, we have been able to successfully quantify the disruptions in the bilayer structure caused by the peptide tetramer through conformational rearrangements of the lipid hydrocarbon chains. We believe that the results presented can quantitatively provide fundamental molecular-level insights into the detrimental effects of pore-forming Aβ-42 on membrane environment, which in turn, may have important implications on Alzheimer's disease.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Molecular Dynamics Simulation
*Lipid Bilayers/chemistry
*Peptide Fragments/chemistry/metabolism
*1,2-Dipalmitoylphosphatidylcholine/chemistry
*Phospholipids/chemistry
Temperature
Protein Multimerization

@article {pmid43018660,
year = {2026},
author = {Wang, Y and Zhao, H and Kong, M and Qin, K and Teng, Y and Zhu, Z and Li, Y and Liu, D and Cui, L and Sun, Y},
title = {Epigenetic regulation of the complement system in age-related chronic inflammation: mechanisms and therapeutic prospects.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {43018660},
issn = {1573-4978},
support = {#82371153 and #82571317//the National Natural Science Foundation of China/ ; #ZR2022QH073 and #ZR2025MS1188//the Natural Science Foundation of Shandong Province/ ; #ZR2025LZ044//Natural Science Foundation of Yantai/ ; },
mesh = {Humans ; *Epigenesis, Genetic ; *Inflammation/genetics/immunology ; *Aging/genetics/immunology ; *Complement System Proteins/genetics/metabolism ; Animals ; DNA Methylation/genetics ; Alzheimer Disease/genetics/immunology ; Complement Activation/genetics ; Macular Degeneration/genetics ; Chronic Disease ; },
abstract = {Aging is accompanied by progressive changes in epigenetic regulation, immune function, and tissue homeostasis, which may contribute to chronic low-grade inflammation and age-related disease. The complement system is an important component of innate immunity and participates in immune surveillance, tissue homeostasis, and inflammatory regulation. Increasing evidence suggests that DNA methylation, histone modifications, and non-coding RNAs can influence the expression of complement components and regulatory proteins, while complement-associated inflammatory signaling may reciprocally affect cellular epigenetic states. In this review, we summarize current evidence linking epigenetic regulation with complement biology during aging and discuss how this relationship varies across tissues and disease contexts. Particular attention is given to the central nervous system, where complement-dependent synaptic remodeling can support physiological circuit refinement but may become excessive or dysregulated under pathological conditions. We further examine the epigenetic-complement relationship in Alzheimer's disease, age-related macular degeneration, and atherosclerosis, and consider age-associated clonal hematopoiesis as a potential modifier of myeloid and inflammatory states. Rather than proposing a uniform linear pathway from epigenetic aging to complement activation and disease, we propose a context-dependent framework in which age-associated epigenetic remodeling may coexist with physiological adaptation or, under specific genetic, metabolic, environmental, cellular, and tissue contexts, contribute to reduced regulatory reserve and persistent complement-associated inflammation. This framework highlights the potential of cell-, tissue-, and disease-stage-specific strategies targeting the epigenetic-complement axis while preserving physiological complement functions.},
}

Humans
*Epigenesis, Genetic
*Inflammation/genetics/immunology
*Aging/genetics/immunology
*Complement System Proteins/genetics/metabolism
Animals
DNA Methylation/genetics
Alzheimer Disease/genetics/immunology
Complement Activation/genetics
Macular Degeneration/genetics
Chronic Disease

@article {pmid43018803,
year = {2026},
author = {Jenkins, MR and Hickey, EJ and Greenlee, JL and Brothers, CE and Yoon, DM and Barry, AM and Schworer, EK and Handen, BL and Hom, CL and Bodde, AE and Ptomey, LT and Hartley, SL},
title = {Adverse life experiences, mood symptoms, and quality of life in adults with down syndrome.},
journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation},
volume = {35},
number = {12},
pages = {},
pmid = {43018803},
issn = {1573-2649},
mesh = {Humans ; *Down Syndrome/psychology ; *Quality of Life/psychology ; Adult ; Female ; Male ; Middle Aged ; *Mood Disorders/psychology ; *Life Change Events ; Affect ; },
abstract = {PURPOSE: Life expectancy for people with Down syndrome (DS) has increased, creating a need to understand how to optimize later-life quality of life (QOL). In the general population, adverse life experiences (ALES) are thought to alter QOL via several mechanisms, including the presence of mood disorders. Little is known about whether ALES predict later-life QOL in adults with DS and, if so, whether this association is driven by increased mood symptoms.

METHODS: Data came from 133 adults with DS (Mage = 38.58 years, SD = 8.61) without dementia enrolled in the Alzheimer Biomarker Consortium-Down Syndrome. We used hierarchical linear regression to predict the effect of ALES and mood symptoms on QOL. We conducted an ordinary least squares path analysis to quantify the direct effect of ALES on QOL and the indirect effect through mood symptoms using 5000 bootstrap samples.

RESULTS: ALES was not a significant predictor of QOL. Mood symptoms were significantly negatively associated with QOL. The path analysis indicated that adults with DS who experienced more ALES also had more mood symptoms, and mood symptoms were associated with lower QOL. The confidence interval for the indirect effect was below zero, indicating that mood symptoms significantly affected the relationship between ALES and QOL. The direct effect of ALES on QOL was not significant.

CONCLUSION: Mood symptoms are not simply a correlate of early adversity but an intervening variable through which the psychological and neurobiological effects of ALES may be expressed as poorer later-life QOL.},
}

Humans
*Down Syndrome/psychology
*Quality of Life/psychology
Adult
Female
Male
Middle Aged
*Mood Disorders/psychology
*Life Change Events
Affect

@article {pmid43018819,
year = {2026},
author = {Alsamman, AM and Ibrahim, MS and Mousa, KH and Ibrahim, SM and Mokhtar, MM and Saedwi, AM and Khaled, R and Allali, AE and Zayed, H},
title = {NeuroBase: A Web-Based Transcriptomic Resource and R Package for Cross-Disorder Analysis of Neurodegenerative and Neuropsychiatric Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {43018819},
issn = {1559-1182},
mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Internet ; *Mental Disorders/genetics ; *Transcriptome/genetics ; *Databases, Genetic ; Gene Expression Profiling ; Principal Component Analysis ; },
abstract = {Neurodegenerative and neuropsychiatric disorders, including Alzheimer's disease, autism spectrum disorder, bipolar disorder, Parkinson's disease, and schizophrenia, are highly prevalent and biologically complex conditions that remain difficult to diagnose and treat. This study aimed to develop NeuroBase, a web-based transcriptomic resource that supports exploratory comparison of shared and disorder-specific gene expression features across these disorders. Fourteen human brain bulk RNA sequencing datasets (262 total samples) were processed using a standardized pipeline, followed by differential gene expression analysis with DESeq2, edgeR and limma-voom for broad exploratory discovery, complemented by a multi-method sensitivity analysis to define a method-concordant core gene set, protein-protein interaction network analysis using STRING with downstream exploration in Cytoscape, and functional enrichment analysis. Principal component analysis and clustering-based visualizations were used to summarize similarities and differences in transcriptomic patterns among disorders. Differential expression analysis identified dataset-level significant genes within each disorder using DESeq2 for one dataset per disorder (FDR ≤ 0.05), including 38 genes in Alzheimer's disease, 6,704 in autism spectrum disorder, 3,559 in bipolar disorder, 687 in Parkinson's disease, and 2,750 in schizophrenia; a stricter multi-method intersection analysis yielded method-concordant Core Intersection sets in the most informative datasets (983 core DEGs in autism spectrum disorder, 505 in bipolar disorder, 281 in schizophrenia, and 234 and 151 in two Parkinson's disease datasets; only two core genes (SPP1 and CHST3) were found in Alzheimer's disease). A unified strict-threshold reanalysis (FDR ≤ 0.05, |log2FC|≥ 1) revealed disorder-level DEG burdens ranging from 34 (Alzheimer's disease) to 2,812 (autism) deduplicated genes, but only 24 genes were reproducible across independent cohorts of the same disorder, highlighting the limited cross-cohort reproducibility characteristic of bulk brain transcriptomics. Enrichment analyses identified significantly enriched signaling pathways in autism spectrum disorder and nominally enriched synapse-related pathways in Alzheimer's disease. Representative high-signal genes included SPP1 in Alzheimer's disease, NRGN in one Parkinson's disease dataset, and BEST1 in autism spectrum disorder. Cross-disorder comparison identified 465 differentially expressed genes shared between the neurodegenerative and neuropsychiatric disorder groups, and principal component analysis showed that sample variation was dominated by dataset and tissue of origin. NeuroBase is a publicly accessible, web-based transcriptomic database and companion R package (neurobaseR) that enables standardized, cross-disorder exploration of bulk brain gene expression profiles across neurodegenerative and neuropsychiatric disorders, supporting comparative analysis, programmatic data access, and hypothesis generation through interactive visualization and pathway-level summaries.},
}

Humans
*Neurodegenerative Diseases/genetics
*Internet
*Mental Disorders/genetics
*Transcriptome/genetics
*Databases, Genetic
Gene Expression Profiling
Principal Component Analysis

@article {pmid43018845,
year = {2026},
author = {Chakraborty, W and Roy, KK},
title = {Precision Neurology in Alzheimer's Disease: Genomics to Drug Optimization for Effective Therapeutic Intervention.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {43018845},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy/therapy ; *Genomics/methods ; *Precision Medicine/methods ; *Neurology/methods ; Pharmacogenetics ; Animals ; },
abstract = {Alzheimer's disease (AD) exhibits high clinical and biological heterogeneity, which complicates the development of one-size-fits-all therapeutic strategies. Standard trial designs can mask subgroup-specific effects, highlighting the need to move towards precision neurology entailing multisystem genomics, biomarkers, and artificial intelligence (AI) integrative signals. The aim of the study is to critically synthesize and evaluate emerging strategies for drug optimization and individual therapeutic algorithms informed by genomic architecture, pharmacogenomics (PGx), and polygenic risk scores (PRS) with the opinion to resolve the controversy and unanswered question. Amplify the convergence into amyloid processing, lipid metabolism, and innate immunity seen from monogenic mutations and over 80 GWAS risk loci. Genotyping of CYP2D6 and CYP2C19 variants permits pharmacogenomic stratifications for the optimization of cholinesterase inhibitor and psychotropic dosing, thereby reducing adverse events. Variants of the alleles APOE ε4 and immune-related factors (e.g., FCGR3A) are significant in predicting the effects of ARIA associated with amyloid on anti-amyloid immunotherapy outcomes. PRS and deep phenotyping (including digital and fluid-based biomarkers) allow for the identification of unique biological endotypes (e.g., tau-dominant vs. vascular-inflammatory) that improve clinical trial enrichment and prognostication. This framework delineates molecular endotypes and translates CYP2D6 or APOE stratification into drug dosing and ARIA risk predictions. These biomarker-driven strategies shift AD management from a passive, reactive therapeutic scheme to an active, personalized one. Utilization of high-dimensional data streams via AI-driven learning health systems converts AD management from a reactive, symptom-based model to that which is proactive and hallmark biomarker-driven precision.},
}

Humans
*Alzheimer Disease/genetics/drug therapy/therapy
*Genomics/methods
*Precision Medicine/methods
*Neurology/methods
Pharmacogenetics
Animals

@article {pmid43018890,
year = {2026},
author = {Moore, SJ and Murphy, GG},
title = {Acarbose ameliorates age-related spatial learning and memory deficits in a mouse model of normal aging but not Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {43018890},
issn = {2509-2723},
support = {AG081981/AG/NIA NIH HHS/United States ; AG074552/AG/NIA NIH HHS/United States ; AWD016559//Glenn Foundation for Medical Research/ ; },
abstract = {INTRODUCTION: Declines in function occur in both "normal" aging (in the absence of disease) and age-related pathological contexts, like Alzheimer's disease (AD). Whether "anti-aging" interventions (that extend lifespan) also promote cognitive function in aging and AD remains largely unexplored.

METHODS: We assessed the effect of acarbose (1000 ppm from 4 months of age) on spatial learning and memory using the Morris water maze in young adult (6 mo), mid-aged (12 mo), or aged (24 mo) cohorts of normal aging (Ntg-HET3) and AD-relevant (5xFAD-HET3) genetically heterogeneous mice.

RESULTS: In middle-aged and aged Ntg-HET3 mice, acarbose (ACA) treatment moderately improved age-related deficits in spatial learning and robustly ameliorated impairments in spatial memory, maintaining performance at levels equivalent to young adults, with a progressively greater effect at older ages. Conversely, ACA failed to improve progressively worsening AD-related cognitive impairments in 5xFAD-HET3 mice.

DISCUSSION: This work demonstrates that anti-aging interventions can also promote cognitive longevity in normal aging. Further, it highlights that AD does not simply reflect an accelerated aging process and requires therapies beyond anti-aging interventions that target its unique molecular and cellular drivers.},
}

@article {pmid43019091,
year = {2026},
author = {Iglesias, JE and Johnson, IP and Williams-Ramirez, J and Zemlyanker, D and Tian, L and Gopinath, K and Olchanyi, M and Farnan, AD and Demopoulos, A and Rosen, MS and Sheth, KN and de Havenon, A and Kimberly, WT and Sorby-Adams, A},
title = {On the accuracy of nonlinear image registration in portable low-field 3D brain MRI.},
journal = {Scientific reports},
volume = {16},
number = {},
pages = {34965},
pmid = {43019091},
issn = {2045-2322},
mesh = {*Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging ; Humans ; Algorithms ; *Imaging, Three-Dimensional/methods ; *Image Processing, Computer-Assisted/methods ; Signal-To-Noise Ratio ; Nonlinear Dynamics ; },
abstract = {Portable low-field MRI offers an affordable and mobile alternative to conventional high-field scanners, enabling imaging in point-of-care and resource-limited settings. However, its lower signal-to-noise ratio, reduced resolution, and acquisition artifacts raise concerns about the accuracy of standard image registration methods. Reliable nonlinear registration is critical for a wide range of emerging applications, including frequent brain monitoring, assessment of neurodegenerative disease progression, and evaluation of treatment effects such as those associated with Alzheimer's therapeutics. In this work, we systematically evaluated state-of-the-art registration approaches on simulated low-field scans (obtained by downsampling high-field images) and on real low-field brain MRI data. We compared three approaches that are representative of current registration methods: classical optimization (NiftyReg), learning-based registration (SynthMorph), and synthesis-based registration (SynthSR+NiftyReg). Using downsampled high-field scans, all methods performed well, achieving high Dice scores and smooth deformation fields, indicating that reduced resolution alone does not hinder registration. In contrast, real low-field data exhibited lower accuracy, primarily due to geometric distortion and other acquisition-specific artifacts. Among the tested approaches, the synthesis-based pipeline achieved the most robust performance across subjects and modalities. Overall, existing algorithms can accommodate resolution limitations, however, future methods could further enhance coregistration by explicitly addressing the distortions present in low-field MRI scans.},
}

*Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging
Humans
Algorithms
*Imaging, Three-Dimensional/methods
*Image Processing, Computer-Assisted/methods
Signal-To-Noise Ratio
Nonlinear Dynamics

@article {pmid43019186,
year = {2026},
author = {De Francisci, M and Faggionato, E and Dalla Man, C and Lee, JJ and Metcalf, N and Raichle, ME and Morris, JC and Benzinger, TLS and Vlassenko, AG and Bertoldo, A and Goyal, MS},
title = {Full-compartmental modeling of [[18]F]FDG PET suggests divergent brain metabolism trajectories from healthy aging to early Alzheimer disease.},
journal = {Scientific reports},
volume = {16},
number = {},
pages = {35963},
pmid = {43019186},
issn = {2045-2322},
mesh = {*Alzheimer Disease/metabolism/diagnostic imaging/pathology ; Humans ; *Positron-Emission Tomography/methods ; *Fluorodeoxyglucose F18 ; *Brain/metabolism/diagnostic imaging ; Female ; Glucose/metabolism ; Male ; *Aging/metabolism ; Aged ; Radiopharmaceuticals ; Aged, 80 and over ; },
abstract = {UNLABELLED: Within the Alzheimer disease (AD) spectrum, metabolic alterations occur in addition to proteinopathies. While hypometabolism is frequently observed in the late symptomatic stages, characterizing the metabolic changes during early AD stages might aid in both understanding its pathophysiology and in patient selection for future treatments. In this study, we conduct an exploratory, data-driven analysis aimed at better understanding the timing and specificity of the metabolic changes in early AD. Using kinetic analysis of [[18]F]FDG PET brain imaging data coming from 223 individuals, including 33 preclinical individuals and 19 symptomatic individuals, we find new evidence of a more complex spatiotemporal trajectory of glucose metabolism in early AD, which includes a paradoxical regional increase in glucose phosphorylation during preclinical AD. These findings suggest that the pathologic phases of AD parallel changes in brain glucose metabolism, which is readily assessable with [[18]F]FDG PET imaging. Moreover, they may indicate that metabolic interventions may work differently during preclinical AD as compared to the early symptomatic phase.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-64573-x.},
}

*Alzheimer Disease/metabolism/diagnostic imaging/pathology
Humans
*Positron-Emission Tomography/methods
*Fluorodeoxyglucose F18
*Brain/metabolism/diagnostic imaging
Female
Glucose/metabolism
Male
*Aging/metabolism
Aged
Radiopharmaceuticals
Aged, 80 and over

@article {pmid43019187,
year = {2026},
author = {Milicic, L and Vacher, M and Bourgeat, P and Doré, V and Shishegar, R and Maruff, P and Masters, CL and Rowe, CC and Villemagne, VL and Porter, T and Laws, SM and , and , },
title = {Peripheral DNA methylation of candidate Alzheimer's disease risk genes and its associations with cognition, brain volume and amyloid-β burden.},
journal = {Scientific reports},
volume = {16},
number = {},
pages = {35889},
pmid = {43019187},
issn = {2045-2322},
mesh = {Humans ; *DNA Methylation ; *Alzheimer Disease/genetics/pathology/metabolism/diagnostic imaging ; *Amyloid beta-Peptides/metabolism ; *Cognition ; *Brain/pathology/metabolism/diagnostic imaging ; Female ; Male ; Aged ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Magnetic Resonance Imaging ; CpG Islands ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {UNLABELLED: Alzheimer's disease (AD) is a growing major public health issue, affecting millions of people worldwide. Genome-wide association studies (GWAS) have identified over 50 loci associated with late-onset AD risk. However, most disease-associated variants are located in noncoding regions of the genome, making it difficult to elucidate exactly how disease risk is affected. Variants within noncoding regions can modulate disease risk through mechanisms such as gene expression regulation, which can be regulated by DNA methylation, which has, in recent years, been implicated in dementia and AD. This study utilised data from two well-characterised longitudinal studies, the Australian Imaging, Biomarker and Lifestyle (AIBL) study (n = 565) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 533), and aimed to investigate the association between peripheral blood DNA methylation at CpG sites located in previously implicated AD-risk genes and cognition, MRI volumetric measures and brain Aβ-amyloid (Aβ) burden. Analyses were undertaken across the preclinical to prodromal population as well as within subsets classified by clinical diagnosis and Aβ burden using two methods: all CpG sites within a candidate gene and a representative site from each gene region with the greatest variance (mean absolute deviation; MAD). We identified numerous associations in the AIBL cohort that remained significant after correction for the false discovery rate, although only one novel site was validated in the ADNI cohort. This was located within the gene body region of CR1 (cg00416522) and was associated with ventricle volume in cognitively unimpaired individuals with high brain Aβ burden. While this study's results contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related traits, they suggest that there are limited associations of peripheral DNA methylation with cognitive and neuroimaging traits in the a priori AD-risk genes that were screened in this study. Future meta-analyses across studies with larger cohort sizes and phenotypically rich datasets will help to confirm this finding and potentially elucidate further associations, while unbiased approaches are warranted and may uncover novel peripheral DNA methylation associations.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-64935-5.},
}

Humans
*DNA Methylation
*Alzheimer Disease/genetics/pathology/metabolism/diagnostic imaging
*Amyloid beta-Peptides/metabolism
*Cognition
*Brain/pathology/metabolism/diagnostic imaging
Female
Male
Aged
Genetic Predisposition to Disease
Genome-Wide Association Study
Magnetic Resonance Imaging
CpG Islands
Aged, 80 and over
Longitudinal Studies