@article {pmid42026254,
year = {2026},
author = {Nakagawa, T and Xie, JL and Park, K and Cao, K and Savadkohighodjanaki, M and Zhang, YJ and Jun, H and Ichii, A and Lee, JY and Soma, S and Medhat, YK and Saido, TC and Igarashi, KM},
title = {Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42026254},
issn = {1546-1726},
support = {A2019380S//BrightFocus Foundation (BrightFocus)/ ; A2022018F//BrightFocus Foundation (BrightFocus)/ ; BRFSG-2017-04//Brain Research Foundation (BRF)/ ; JPMJPR2481//MEXT | Japan Science and Technology Agency (JST)/ ; AARF-22-923955/ALZ/Alzheimer's Association/United States ; },
abstract = {The entorhinal cortex is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer's disease (AD). The entorhinal cortex therefore has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. Here we show that dopamine neurons projecting their axons to the lateral entorhinal cortex (LEC), critical for memory formation in healthy brains, become dysfunctional from the early pathological stage and cause associative memory impairments in amyloid precursor protein knock-in mice. Dopamine dysfunction led to the disruption of associative memory encoding of LEC layer 2/3. Optogenetic reactivation of LEC dopamine fibers rescued associative learning behavior. L-DOPA treatment restored memory encoding of LEC neurons and associative memory of amyloid precursor protein knock-in mice. These results suggest early dysfunction of LEC-projecting dopamine neurons underlie memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in patients with AD.},
}

@article {pmid42026315,
year = {2026},
author = {Manco, C and Righi, D and Sangiorgio, AR and Pucci, B and De Stefano, N and Plantone, D},
title = {Comparison of TDP-43, NfL, and GFAP in cerebrospinal fluid and serum in Alzheimer's disease.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42026315},
issn = {1433-8491},
}

@article {pmid42026319,
year = {2026},
author = {Bdair, M and Zahran, A and Jallad, H and Barham, I and Qubbaj, A and AbuRabi'e, M and Jarrar, B and Aburajab, J and Alsafareeni, Z and Mansor, A and Ghannam, S and Daor, A and Daralbarmeel, A and Awwad, AR and Khader, M and Awawdeh, A},
title = {National trends and disparities in Alzheimer disease's mortality (1999-2023) with scenario projections and a data-driven LSTM sensitivity analysis to 2043.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42026319},
issn = {1433-8491},
}

@article {pmid42026378,
year = {2026},
author = {Boregowda, G and Sharif, O and Gutierrez Iii, D and Simmons, A and Pujo-Menjouet, L and Oraby, T and Lindstrom, MR},
title = {Theory and simulations of delayed stochastic and deterministic models of prion diseases.},
journal = {Journal of mathematical biology},
volume = {92},
number = {5},
pages = {},
pmid = {42026378},
issn = {1432-1416},
support = {2316952//National Science Foundation/ ; 2150478//National Science Foundation/ ; ANR-21-CE15-0011//Agence National de la Recherche/ ; },
mesh = {*Prion Diseases/metabolism/etiology/pathology/physiopathology ; Humans ; Stochastic Processes ; Mathematical Concepts ; Computer Simulation ; *Models, Biological ; Brain/metabolism ; Animals ; Connectome ; Disease Progression ; PrPSc Proteins/metabolism ; Models, Neurological ; Prion Proteins ; },
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's, Parkinson's, and prion diseases, are characterized by the dynamical spread of toxic proteins through the brain. In prion diseases, cellular prion protein (PrP C), produced by neurons, misfolds into a toxic form, known as scrapie prion protein (PrP Sc). PrP Sc induces neuronal stress which ultimately leads to cell death. In this paper, we develop mathematical models for the progression of prion diseases, incorporating a cellular defense mechanism that introduces a delay term affecting protein translation and a volatility term accounting for unaccounted biological factors influencing the system. We also extend the model to capture the spatial spread of toxic proteins over the brain connectome. Our first objective is to establish the existence and uniqueness of a global positive solution to the prion disease models. Afterwards, we analyze the asymptotic behavior of the models by identifying regimes of persistence and extinction of toxic proteins. For the deterministic delayed systems, we perform a stability analysis for the persistence and demonstrate that the system undergoes a Hopf bifurcation. We also study the intensity of fluctuations of the equilibrium state of the stochastic model. Additionally, we present numerical simulations to illustrate the model dynamics using biologically relevant parameters.},
}

*Prion Diseases/metabolism/etiology/pathology/physiopathology
Humans
Stochastic Processes
Mathematical Concepts
Computer Simulation
*Models, Biological
Brain/metabolism
Animals
Connectome
Disease Progression
PrPSc Proteins/metabolism
Models, Neurological
Prion Proteins

@article {pmid42026585,
year = {2026},
author = {Choi, H and Hong, SB and Kim, Y and Joung, H and Choi, Y and Cha, J and Park, JY and Lee, YS and Choi, H and Han, JW and Kim, KH and Shin, CH and Lee, DY and Mook-Jung, I},
title = {Tryptophan-kynurenine metabolic reprogramming along the gut-brain axis alleviates Alzheimer's pathology.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03796-1},
pmid = {42026585},
issn = {1742-2094},
support = {RS-2022-KH128705//Korea Dementia Research Center/ ; RS-2020-KH106747//Korea Dementia Research Center/ ; RS-2023-00273634//National Research Foundation of Korea/ ; },
}

@article {pmid42026650,
year = {2026},
author = {Gabb, VG and Blackman, J and Morrison, HD and Turner, N and Heslegrave, A and Coulthard, E},
title = {Mind the gap: obtaining reliable sleep estimates and the diagnostic value of sleep discrepancy in individuals with Alzheimer's disease and Lewy body disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71377},
doi = {10.1002/alz.71377},
pmid = {42026650},
issn = {1552-5279},
support = {//Bristol and Weston Hospitals Charity/ ; //BRACE/ ; //Alzheimer's Research UK/ ; //Margaret Jost Fellowship/ ; //David Telling Charitable Trust/ ; //Don Thoburn Memorial Scholarship/ ; //S Scobie and A Graham/ ; //NIHR Bristol Biomedical Research Centre/ ; },
mesh = {Humans ; *Lewy Body Disease/complications/diagnosis ; *Alzheimer Disease/complications/diagnosis ; Male ; Female ; Aged ; Actigraphy ; *Sleep Wake Disorders/diagnosis/etiology ; Cognitive Dysfunction/complications ; Aged, 80 and over ; Sleep Quality ; },
abstract = {INTRODUCTION: Objective sleep disturbances, including short and fragmented sleep, are observed in neurodegenerative diseases. However, subjective sleep disturbances are inconsistently reported. Improved understanding of objective and subjective sleep estimation is needed to tailor sleep interventions.

METHODS: Baseline subjective habitual sleep was compared to objective sleep measured by actigraphy averaged over 8 weeks in 20 patients with mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD) or Lewy body disease (LBD) and 20 healthy older adults. Discrepancies between objective and subjective sleep parameters were used to predict cohort membership (AD, LBD, or control).

RESULTS: Participants with AD and LBD estimated lower sleep disturbance than actigraphy. Subjective sleep quality was poorest in LBD and highest in AD. Subjective sleep and subjective-objective sleep discrepancy discriminated between cohorts with 80% accuracy.

DISCUSSION: Subjective and objective sleep differ and both should be measured in MCI and dementia. Sleep discrepancy may have diagnostic utility.},
}

Humans
*Lewy Body Disease/complications/diagnosis
*Alzheimer Disease/complications/diagnosis
Male
Female
Aged
Actigraphy
*Sleep Wake Disorders/diagnosis/etiology
Cognitive Dysfunction/complications
Aged, 80 and over
Sleep Quality

@article {pmid42026653,
year = {2026},
author = {Acarsoy, C and Bos, D and Mooldijk, SS and Ikram, MA and Ikram, MK},
title = {Migraine and the Risk of Dementia in the General Population.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71386},
doi = {10.1002/alz.71386},
pmid = {42026653},
issn = {1552-5279},
support = {//Erasmus Medical Center and Erasmus University/ ; //Organization for Scientific Research/ ; //Netherlands Organization for Health Research and Development/ ; //Research Institute for Diseases in the Elderly/ ; //Netherlands Genomics Initiative/ ; //Ministry of Education, Culture and Science/ ; //Ministry for Health, Welfare and Sports/ ; //European Commission/ ; //Municipality of Rotterdam/ ; },
mesh = {Humans ; *Migraine Disorders/epidemiology ; Female ; Male ; *Dementia/epidemiology ; Aged ; Prospective Studies ; Risk Factors ; Middle Aged ; Netherlands/epidemiology ; Alzheimer Disease/epidemiology ; Surveys and Questionnaires ; },
abstract = {INTRODUCTION: Migraine and dementia are prevalent disorders with high societal impact; however, research regarding their association remains inconsistent.

METHODS: We analyzed 6888 participants from the prospective Rotterdam Study. Migraine status was assessed (2006-2011) via validated questionnaire. Participants were followed for a median of 9.4 years until January 2020. Dementia diagnoses were confirmed through in-person screenings and medical record linkages, including neuroimaging.

RESULTS: At baseline, 1041 participants (15.1%) had migraine. Over 62,180 person-years, 491 participants developed dementia (379 [77.2%] with Alzheimer's). Cox models revealed that migraine was associated with a lower risk of dementia (hazard ratio [HR] 0.70, 95% confidence interval [CI]: 0.51-0.95) and Alzheimer's disease (HR 0.58, 95% CI: 0.40-0.85).

DISCUSSION: This study suggests that migraine is associated with a reduced risk of dementia, including Alzheimer's disease. Whether this reflects biological neuroprotection or methodological factors is currently unclear, necessitating further investigation.},
}

Humans
*Migraine Disorders/epidemiology
Female
Male
*Dementia/epidemiology
Aged
Prospective Studies
Risk Factors
Middle Aged
Netherlands/epidemiology
Alzheimer Disease/epidemiology
Surveys and Questionnaires

@article {pmid42026661,
year = {2026},
author = {Kuppens, A and Rogister, B and Neirinckx, V},
title = {Pharmacological modulation of CXCL12/CXCR4/ACKR3 for brain disorders - an overview.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02877-1},
pmid = {42026661},
issn = {1478-811X},
support = {7.6518.24//Fonds De La Recherche Scientifique - FNRS/ ; },
}

@article {pmid42026868,
year = {2026},
author = {Huang, J and Wang, YB and Wu, J and Qian, PJ and Shao, J and Cao, DD and Liu, Y and Luo, ZG},
title = {SEC62-mediated ER-Phagy activation alleviates Alzheimer's disease pathology and restores cognitive function in 5×FAD mice.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2026.04.037},
pmid = {42026868},
issn = {1525-0024},
abstract = {Alzheimer's disease (AD) is a common age-related neurodegenerative disorder. Previous studies have shown that patients with AD exhibit dysregulation of endoplasmic reticulum (ER) homeostasis in the brain, such as ER stress and ER damage. As a type of selective autophagy that specifically clears damaged ER, ER-phagy (endoplasmic reticulum-phagy) plays a key role in ER quality control, but the role in AD progression remains elusive. In this study, we found that ER homeostasis is severely disrupted in the pathological state of AD, characterized by enhanced ER stress response, the presence of ER damage, and concurrent defects in ER-phagy function. Notably, some receptors mediating ER-phagy were decreased in neurons differentiated from induced pluripotent stem cells (iPSCs) derived from AD patients and in 5×FAD mouse samples. Interestingly, overexpression of the ER-phagy receptor SEC62 in the brain of 5×FAD mice via intrathecal AAV injection markedly alleviated disease phenotypes, including β-amyloid (Aβ) plaque deposition, neuroinflammation, and cognitive impairment. These results indicate that restoring ER-phagy activity provides a potential strategy for the treatment of AD.},
}

@article {pmid42027189,
year = {2026},
author = {Aaltonen, A and Saari, TT and Urjansson, M and Palviainen, T and Paajanen, TI and FinnGen, and Palotie, A and Runz, H and Kaprio, J and Julkunen, V and Vuoksimaa, E},
title = {Cross-sectional assessment of telephone- and computer-administered instruments in detection of cognitive impairment.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/13803395.2026.2661625},
pmid = {42027189},
issn = {1744-411X},
abstract = {OBJECTIVE: We investigated the associations of telephone- and computer-administered cognitive screening instruments for Alzheimer's disease with in-person measurement in a population-based sample of individuals without a prior diagnosis of dementia-causing neurodegenerative disease.

METHOD: We studied 202 TWINGEN participants (126 female) who had in-person administered Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-nb) data. The participants were aged 65-85 years and of European ancestry. Telephone-administered instruments were telephone assessment for dementia (TELE) and modified version of Telephone Tnterview for Cognitive Status, and computer-administered instrument was web-based cCOG. We utilized correlation analyses, areas under the receiver operating characteristic curves (AUC) and hierarchical linear mixed-effects models in main analyses.

RESULTS: Screening instruments exhibited moderate to high correlations with CERAD-nb, with the strongest correlation between cCOG and CERAD-nb (r = .62). Despite exclusion criteria, 20 participants had cognitive impairment according to the CERAD-nb total score. When evaluating the instruments' ability to distinguish between participants with and without cognitive impairment, AUCs ranged from .65 (95% CI [.53, .78]) for TELE to .76 (95% CI [.67, .86]) for cCOG. All instruments predicted in-person CERAD-nb score in linear mixed-effects models, when controlling for demographic factors. Including both telephone- and computer-administered measures as predictors resulted in better accuracy compared to including only one modality as a predictor.

CONCLUSIONS: Performance in telephone- and computer-administered cognitive screening instruments was associated with performance in in-person neuropsychological battery designed for early detection of Alzheimer's disease. The results indicate validity of the computerized and telephone-administered tests at the population level.},
}

@article {pmid42027251,
year = {2026},
author = {Alghamdi, M and von Wegner, F and Chan, DKY and Green, M and , },
title = {Brain atrophy and clinical diagnosis independently predict default mode network failure across the Alzheimer's disease continuum.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70343},
pmid = {42027251},
issn = {2352-8729},
abstract = {INTRODUCTION: This study examined the link between default mode network (DMN) functional connectivity, cerebral small vessel disease (CSVD), brain atrophy, and plasma Alzheimer's disease (AD) biomarkers.

METHODS: We analyzed the Alzheimer's Disease Neuroimaging Initiative database (N = 279), examining the relationships between DMN functional integrity (network failure quotient [NFQ]), gray and white matter fractions (GMF, WMF), white matter hyperintensities (WMHs), plasma phosphorylated tau (p-tau)217 and amyloid beta (Aβ)42/Aβ40 ratio, and clinical assessments. Statistical associations were tested using one-way analysis of variance and univariate and multivariate regression models.

RESULTS: The AD group showed increased NFQ values (P < 0.001). Significant univariate associations were found between NFQ and WMH, gray and white matter atrophy, Aβ ratio, and p-tau217 (P < 0.05). Atrophy markers (GMF, WMF) and AD diagnosis were the only independent predictors of NFQ in multivariate models (P < 0.05).

DISCUSSION: Our study identifies markers of brain atrophy as independent predictors of DMN failure, unlike AD plasma biomarkers and magnetic resonance imaging markers of CSVD.},
}

@article {pmid42027297,
year = {2026},
author = {Chen, W and Li, R and Zhang, J and Lei, J and Jiang, X and Sun, X},
title = {From metabolic substrate to epigenetic regulation: roles and mechanisms of lactylation in brain health and disease.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1779468},
pmid = {42027297},
issn = {1662-5099},
abstract = {Lactate, traditionally regarded as a metabolic byproduct of glycolysis, is now recognized as a critical signaling molecule in the central nervous system. Emerging evidence indicates that lactate participates in a dynamic metabolic-epigenetic regulatory network through protein lactylation, a post-translational modification capable of modulating chromatin structure and gene transcription. We summarize the physiological roles of lactate in neuronal-glial metabolic coupling and highlight cell-type-specific functions of the lactate-lactylation axis under both normal and pathological conditions. Particular emphasis is placed on its involvement in ischemic stroke, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Available findings indicate that this axis is integral to synaptic plasticity, neuroinflammatory balance, and metabolic homeostasis. Under pathological conditions, excessive lactate accumulation promotes aberrant lactylation patterns that may drive persistent inflammation, metabolic reprogramming, and neuronal dysfunction by reshaping chromatin accessibility and transcriptional landscapes. Collectively, the lactate-lactylation axis represents a unifying mechanistic framework linking metabolic flux to epigenetic regulation in neurological disorders and may serve as a promising source of diagnostic biomarkers and precision therapeutic targets.},
}

@article {pmid42027568,
year = {2026},
author = {Feng, ZT and Zhang, YY and Xue, CX},
title = {Bioactive compounds and exercise in aging and neurodegeneration: mechanistic insights from the gut-brain-metabolic axis.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1781176},
pmid = {42027568},
issn = {2296-861X},
abstract = {Aging and neurodegenerative disorders are associated with impaired hippocampal plasticity, yet existing literature largely examines exercise, nutrition, or metabolic regulation in isolation. This review synthesizes emerging evidence supporting an integrative neuro-nutritional-metabolic framework in which bioactive compounds and physical exercise converge to modulate hippocampal neurogenesis, synaptic plasticity, and cognitive resilience. Recent investigative efforts elucidate the neuro-nutritional-metabolic axis as a pivotal interface that integrates bioactive compounds derived from diet, systemic metabolic processes, and neuronal functionality. In this review, the term 'neuro-nutritional-metabolic axis' refers to an integrative framework describing the bidirectional interactions among dietary bioactive compounds, systemic metabolic regulation, and central nervous system plasticity. This concept extends established models such as the microbiota-gut-brain axis and muscle-brain communication by emphasizing their convergence on metabolic and neurotrophic signaling pathways relevant to hippocampal function. Simultaneously, physical exercise is acknowledged as a significant modulator of neurotrophic signaling pathways, mitochondrial performance, and neuroinflammatory responses. This review synthesizes mechanistic evidence derived predominantly from preclinical studies alongside emerging but comparatively limited clinical findings to evaluate how bioactive compounds and physical exercise interact to influence hippocampal plasticity and cognitive function. We examine the convergence of these interventions on essential molecular pathways, as well as antioxidant and anti-inflammatory cascades, to facilitate neuronal survival, synaptic reorganization, and cognitive resilience. Moreover, we investigate their potential to mitigate metabolic dysfunction, oxidative stress, and chronic inflammation, which are pivotal factors contributing to cognitive deterioration in the context of aging and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. Comprehending these synergistic interactions lays the groundwork for formulating tailored, multimodal interventions that specifically address the neuro-nutritional-metabolic axis to enhance memory retention, optimize learning processes, and support cognitive resilience and may contribute to the modulation of risk factors associated with neurodegenerative conditions.},
}

@article {pmid42027570,
year = {2026},
author = {Zhang, H and Liu, C and Yuan, X and Yin, H},
title = {The role of nutrition and multimodal lifestyle interventions in Alzheimer's prevention and management: a mini-review.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1818913},
pmid = {42027570},
issn = {2296-861X},
abstract = {Alzheimer's disease (AD) is a progressive and currently incurable neurodegenerative disorder, which is driving a paradigm shift in research focus toward preventive and disease-modifying strategies. This mini-review synthesizes current evidence on dietary and lifestyle interventions for AD prevention and management from randomized controlled trials (RCTs) and observational studies. Current findings indicate that multidomain approaches, such as the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet and the Finnish Geriatric Intervention Study (FINGER) model, which integrate nutrition, physical activity, and cognitive training, consistently demonstrate efficacy in slowing cognitive decline and reducing brain atrophy in at-risk elderly populations. The evidence for specific nutritional supplements is mixed; however, certain combinations like omega-3 fatty acids paired with carotenoids, B vitamins (folate/B12), and probiotics show promise, particularly for improving memory and reducing inflammation. Intervention outcomes are significantly influenced by genetic factors, especially the APOE4 carrier status, which modulates nutrient metabolism and amyloid response, thereby underscoring the critical need for personalized approaches. Key targeted biological pathways include oxidative stress, phospholipid metabolism, and neuro-inflammation. Despite promising data, several limitations persist, such as inconsistent results, short trial durations, and a lack of standardized protocols. Future research must prioritize long-term, genetically stratified trials alongside mechanistic studies to validate efficacy, optimize personalization, and translate findings into clinically actionable, scalable guidelines for diverse populations.},
}

@article {pmid42027686,
year = {2026},
author = {Jeon, JY and Lee, H and Ji, M and Kim, JS and Ahn, DH},
title = {Personalized audiovisual gamma stimulation enhances neural connectivity and entrainment beyond fixed 40 Hz protocols.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1787255},
pmid = {42027686},
issn = {1662-4548},
abstract = {BACKGROUND: Conventional 40 Hz gamma stimulation is applied across individuals, potentially overlooking inter-individual neural variability.

OBJECTIVE: This study evaluated conversation gamma frequency (CGF)-a personalized gamma frequency derived from task engagement-against the fixed 40 Hz and individual gamma frequency (IGF) derived from auditory responses.

METHODS: In Experiment 1, gamma center frequencies were measured under resting, reading, and conversation conditions. In Experiment 2, EEG was used to compare neural entrainment effects across CGF, 40 Hz, and IGF conditions.

RESULTS: Conversation gamma frequency stimulation induced stronger neural activation and functional connectivity in the frontal, temporal, and parietal cortices compared to 40 Hz or IGF. Theta-gamma coupling analysis revealed significantly increased phase synchronization under CGF compared to 40 Hz with enhanced connectivity. However, entrainment declined as the frequency difference between CGF, and 40 Hz increased, emphasizing the limitation of fixed-frequency stimulation.

CONCLUSION: These findings provide EEG-based mechanistic evidence that individualized gamma stimulation may represent a hypothesis-generating strategy for future neurorehabilitation research in aging and neurodegenerative conditions.},
}

@article {pmid42027759,
year = {2026},
author = {Han, Y and Luo, G and Huang, Y and Cai, Z and Su, W and Kuang, X and Huang, L and Wei, L and Ming, F and He, Z and Yang, Z and Wang, J and Jiang, W and Xiao, C and Hu, Q and Yan, J},
title = {Research progress on Alzheimer's disease vaccines: from Aβ-targeted approaches to clinical translation.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1794820},
pmid = {42027759},
issn = {2673-6217},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive impairment, with the β-amyloid protein (Aβ) aggregation as a core pathological driver. As global aging intensifies, AD poses a severe public health burden, highlighting the urgency of developing effective immunotherapies. This review aims to systematically summarize the research progress of Aβ-targeted AD vaccines, from first-generation approaches to next-generation strategies, and discuss key challenges and future directions for clinical translation.

METHODS: A comprehensive literature search was conducted across PubMed, Web of Science, the Cochrane Library, EMBASE, and Google Scholar up to 14 November 2025. Relevant studies were selected using predefined eligibility criteria, focusing on Aβ-targeted AD vaccines' development, mechanisms, preclinical efficacy, and clinical outcomes. Review articles and meta-analyses were included, while case reports and non-Aβ-targeted studies were excluded. Data extraction and synthesis focused on vaccine strategies, immune mechanisms, and translational challenges.

RESULTS: First-generation Aβ vaccine (e.g., AN-1792) showed preclinical promise but failed clinically due to autoimmune complications. Next-generation vaccines, including peptide/epitope vaccines, DNA vaccines, viral vector vaccines, and protein self-assembling vaccines, have been developed to induce protective Th2-biased immune responses while avoiding harmful T-cell reactions. Preclinical studies demonstrate reduced Aβ deposition and improved cognitive function, with several candidates advancing to clinical trials showing favorable safety and immunogenicity. Key mechanisms include Fc receptor-mediated phagocytosis, antibody-mediated fibril disaggregation, and the peripheral Aβ sink effect.

CONCLUSION: Aβ-targeted AD vaccines have evolved toward safer and more effective designs, with multiple strategies showing translational potential. Challenges remain, including blood-brain barrier (BBB) penetration, immune response modulation, and defining optimal therapeutic time windows. Future research should focus on personalized vaccines, combination therapies, and novel antigen delivery platforms to fully realize the clinical potential of AD immunotherapies.},
}

@article {pmid42027884,
year = {2026},
author = {Naik, DR and Savyanavar, DA},
title = {Comparative Analysis of Deep Learning Techniques in Alzheimer's Disease Diagnosis: Trends, Challenges, and Future Directions.},
journal = {MethodsX},
volume = {16},
number = {},
pages = {103844},
pmid = {42027884},
issn = {2215-0161},
abstract = {Alzheimer's disease is a slow, progressive neurological disorder that impacts the brain tissue and causes cells to die, the most common reason for dementia. It typically reduces brain volume, subsequently impairing several cognitive functions. We explored the phases of Alzheimer's disease diagnosis by thoroughly analysing the paper and highlighting the significance of pre-processing methods. Artificial intelligence progress has transformed medical image analysis by enabling automatic, precise identification of Alzheimer's disease through hybrid architectures, convolutional neural networks, and transfer-learning-based models. This article includes applications of Alzheimer's disease based on datasets, Artificial Intelligence models, limitations, pre-processing methods, challenges, and current research in this area. The article lists various medicinal modalities, risk factors for Alzheimer's disease, the disease's progression stages, and different criteria for evaluating the performance of Artificial Intelligence models. Accuracy, precision, confusion matrix, AUC, F1-score, ROC, recall, and MCC are some of the metrics covered in this paper. The paper discusses the number of comparisons of various deep learning techniques for Alzheimer's, new trends, limitations, recommendations, and future directions. Finally, the paper shows the ongoing practical outcomes and difficulties in Alzheimer's situations. Building on the analysis, this survey helps to cover different dimensions of Alzheimer's disease that have not been previously considered.},
}

@article {pmid42027916,
year = {2026},
author = {Xu, F and Zhang, Y and Tan, D and He, Y and Fei, Q and Xu, K},
title = {Effects of exercise on cognitive function in older patients with Alzheimer's disease: a meta-regression and meta-analysis.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1793973},
pmid = {42027916},
issn = {2296-2565},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Cognition/physiology ; Aged ; *Exercise/psychology/physiology ; *Exercise Therapy/methods ; Middle Aged ; Male ; Randomized Controlled Trials as Topic ; Female ; },
abstract = {OBJECTIVE: This study aimed to systematically evaluate the effects of exercise intervention on cognitive function in AD patients through meta-analysis, specifically investigating the dose-response relationships and moderating effects of various exercise prescription parameters including frequency, single-session duration, weekly total duration, total intervention duration, type, and intensity-on the magnitude of cognitive improvement. The findings are expected to provide scientific and actionable empirical evidence for designing precise and individualized exercise programs.

METHODS: Relevant literatures were systematically retrieved from eight databases up to August 2025, including PubMed, Web of Science, Embase, Emcare, Scopus, Cochrane Library, Ebsco, and SPORTDiscus. All included trials were randomized controlled trials (RCTs) involving adults aged 60 years and above. These studies examined the effects of exercise intervention on cognitive function in AD patients, compared with passive control groups without exercise. A multilevel meta-analysis was used to assess the impact of exercise on cognitive function outcomes in AD patients. Additionally, multivariate meta-regression analysis was employed to identify the exercise frequency (sessions per week) that maximizes cognitive improvement, as well as key moderating factors.

RESULTS: Data from 23 studies, involving 1,868 adults, were included. Exercise intervention significantly improved global cognitive function in AD patients (g = 0.22, 95% CI: 0.02-0.41, p < 0.001). Patient age, single-session duration, and total weekly exercise duration did not significantly affect outcomes (p > 0.05). However, the cognitive benefits of exercise were significantly enhanced with increased weekly exercise frequency, with a notable strengthening trend observed when sessions exceeded five per week.

CONCLUSION: Exercise intervention can effectively improve cognitive function in AD patients. "To optimize intervention outcomes, exercise prescription should consider higher frequency (e.g., more than five sessions per week may be associated with greater cognitive benefits) and the cumulative effect during the initial intervention phase (e.g., sustained beyond 12 weeks may represent a critical window for short-term improvement). In addition, a potential plateau in long-term benefits suggests the need for periodic program adjustments and multimodal exercise strategies. These findings should be interpreted as exploratory dose-response associations rather than definitive clinical prescriptions.

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=1012816, identifier CRD420251012816.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Cognition/physiology
Aged
*Exercise/psychology/physiology
*Exercise Therapy/methods
Middle Aged
Male
Randomized Controlled Trials as Topic
Female

@article {pmid42028071,
year = {2026},
author = {Sun, X and Yang, L and Wang, X},
title = {Traditional Chinese Medicine for Alzheimer's Disease: Current Evidence and Chemometric Approaches for Multi-Target Evaluation.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {590661},
pmid = {42028071},
issn = {1176-6328},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is currently no therapy that can fundamentally change the disease course. The limitations of single-target drugs have led the scientific community to turn to multi-target intervention strategies. In this context, traditional Chinese medicine (TCM) demonstrates potential in addressing the complex pathology of AD due to its "multi-component, multi-target, multi-pathway" overall regulatory characteristics. This review systematically reviews the current research status of TCM in the treatment of AD, with a particular focus on the evidence of its effects through multiple mechanisms such as reducing Aβ deposition, inhibiting excessive phosphorylation of Tau protein, regulating the cholinergic system, and alleviating neuroinflammation. Additionally, this article highlights how to utilize the "spectral efficacy relationship" combined with chemometrics methods (such as multiple regression, partial least squares regression, artificial neural networks, etc) to establish quantitative correlations between TCM chemical components and efficacy/clinical endpoints, thereby providing a methodological framework for evaluating the synergistic effects of TCM's multi-component interactions. The article also summarizes the evidence grades of currently commonly used TCM preparations in clinical practice and points out that future research needs to continuously deepen in areas such as standardized clinical endpoints, strict trial design, systematic safety assessment, and data-driven efficacy analysis. This review aims to provide theoretical references and research directions for integrating the holistic view of TCM with modern system analysis methods and promoting the development of multi-target treatment strategies for AD.},
}

@article {pmid42028213,
year = {2026},
author = {Medina-Rioja, R and Llorente-Vidrio, A and Ruiz-Garcia, R and Rodríguez-Violante, M},
title = {From clinical judgment to biology: a clinician's opinion on the use of blood-based biomarkers in Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1804163},
pmid = {42028213},
issn = {1664-2295},
}

@article {pmid42028229,
year = {2026},
author = {Zhu, Y and Singh, RK and Bekena, S and Brown, DC and Chen, C and Blake, M and Trani, JF and Babulal, GM},
title = {Lost before forgetting: objective driving metrics track navigation deficits tied to preclinical Alzheimer's disease.},
journal = {Innovation in aging},
volume = {10},
number = {5},
pages = {igag013},
pmid = {42028229},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: Navigation is a complex, multisensory process in which subtle changes may emerge before the onset of symptomatic Alzheimer's disease (AD). This study investigated whether navigation abilities were associated with amyloid and tau pathology in cognitively normal older adults.

RESEARCH DESIGN AND METHODS: Among 285 cognitively unimpaired older adults, navigation and objective driving behaviors were assessed using the self-reported Santa Barbara Sense of Direction Scale (SBSOD) and a datalogger, respectively. Amyloid and tau burden were quantified using PET-MRI 2 years post-initial driving data collection. Linear mixed-effects models were used to evaluate the associations between biomarker status and longitudinal navigation changes.

RESULTS: At baseline, there were no significant differences in SBSOD, trip chaining, or entropy, a metric that quantifies the variability in one's driving patterns based on PET biomarker status. Over 6.1 years (SD = 3.3), compared to amyloid- participants, amyloid+ participants experienced faster declines in SBSOD and entropy and increases in trip chain counts and percentages of chained trips/distances, indicating more deliberate compensatory planning for subtle deficits. Conversely, tau+ participants exhibited slower declines in SBSOD and greater increases in driving unpredictability (i.e., higher entropy, greater percentages of chained trips/distances) across 5.6 years (SD = 2.9), but not in total trip counts compared to tau- participants.

DISCUSSION AND IMPLICATIONS: Changes in navigation may reflect the accumulation of amyloid (compensatory planning) and tau (diminished planning, increased randomness) in distinct brain regions. These findings highlight the promise of driving and navigation metrics as sensitive, noninvasive markers of preclinical AD, underscoring a critical window for intervention.},
}

@article {pmid42028802,
year = {2026},
author = {Chan, CK and Glover, CM and Parker, M and Grill, JD and Langbaum, JB and Morhardt, DJ and Okonkwo, O and Farrar-Edwards, D and Wang, S},
title = {Outreach, Recruitment and Engagement Cores of NIA-designated Alzheimer's Disease Research Centers: Current strategies and future directions.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71238},
doi = {10.1002/alz.71238},
pmid = {42028802},
issn = {1552-5279},
support = {P30AG072959 (C.K.C.)//National Institutes of Health/National Institute on Aging/ ; P30AG072976 (S.W.)//National Institutes of Health/National Institute on Aging/ ; 5P50AG016573 (C.M.G.)//National Institutes of Health/National Institute on Aging/ ; P30AG066511 (M.P.)//National Institutes of Health/National Institute on Aging/ ; P30AG072980 (J.B.L.)//National Institutes of Health/National Institute on Aging/ ; P30AG066519 (J.D.G.)//National Institutes of Health/National Institute on Aging/ ; P30AG013854 (D.J.M.)//National Institutes of Health/National Institute on Aging/ ; P30AG062715 (O.O. D.F.E.)//National Institutes of Health/National Institute on Aging/ ; },
mesh = {Humans ; *Alzheimer Disease ; United States ; *National Institute on Aging (U.S.) ; *Patient Selection ; *Biomedical Research ; },
abstract = {Populations at higher risk for Alzheimer's disease and related dementias (ADRD) are often not proportionally represented in research. These populations include but are not limited to individuals from wide-ranging ethnic and racial backgrounds, those with lower education, and those with limited health-care access. Addressing disparities in research participation will be essential to improving our understanding of the varied causal mechanisms, risks and protective factors, and responses to interventions to find generalizable solutions to improve health outcomes in ADRD. The goals of this perspective are to (1) review obstacles and facilitators to recruitment and retention of populations at higher risk for ADRD, (2) provide an overview of data-driven actionable items, ongoing strategies, and proposed initiatives for the recruitment and retention of these populations in National Institute on Aging-funded Alzheimer's Disease Research Centers; and (3) highlight the roles of Outreach, Recruitment and Engagement Cores and the National Alzheimer's Coordinating Center in achieving these goals.},
}

Humans
*Alzheimer Disease
United States
*National Institute on Aging (U.S.)
*Patient Selection
*Biomedical Research

@article {pmid42028856,
year = {2026},
author = {Wang, J and Xu, L and Shen, Q and Tang, Y},
title = {GABAB receptors in glial cells: from physiological regulation to pathological implications.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag141},
pmid = {42028856},
issn = {1460-2156},
abstract = {The GABAB receptor, a metabotropic receptor for the inhibitory neurotransmitter γ-aminobutyric acid, is essential for the proper functioning of inhibitory neurons. Previous studies have shown that GABAB receptors are primarily expressed at presynaptic or postsynaptic membranes of inhibitory or excitatory neurons, where they play a critical role in regulating synaptic signaling. Interestingly, a growing body of evidence indicates that GABAB receptors are also expressed in various types of glial cells and can significantly influence their functions, ultimately contributing to the regulation of multiple processes in the central nervous system. In this review, we first summarize the structure of GABAB receptors and their common downstream signaling pathways in neuronal and glial cells. We then highlight recent research progresses about how GABAB receptors in different glial cell types participate in regulating various important physiological processes, such as excitatory/inhibitory balance, synaptic pruning, and myelination. Furthermore, we provide a comprehensive overview of the significant roles played by glial GABAB receptors in the pathogenesis of neurological disorders, including epilepsy, inflammatory diseases, Alzheimer's disease, major depressive disorder, cerebrovascular diseases, and multiple sclerosis. Accumulating evidence indicates that glial GABAB receptors play a pivotal role in both health and disease, highlighting their potential as therapeutic targets for a variety of neurological conditions. By comprehensively outlining the multiple physiological and pathological processes mediated by GABAB receptors in brain glial cells, this review seeks to broaden the functional scope of glial cells and enhance the comprehension of neuron-glia crosstalk.},
}

@article {pmid42029167,
year = {2026},
author = {Huo, M and Tran, RT and Meyer, OL and Lyons, KS and Mroz, EL},
title = {Spousal Discrepancies in Perceived Needs of People Living with Alzheimer's Disease: A Mixed-Methods Study of Caregivers' Perspective Taking and Dyadic Communication.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261446038},
doi = {10.1177/07334648261446038},
pmid = {42029167},
issn = {1552-4523},
abstract = {People living with Alzheimer's disease (PLWD) often face unmet care needs, which may arise as caregivers and PLWD differ in their perceptions of PLWD's needs. To understand how these discrepancies vary by caregivers' perspective taking (i.e., their ability to understand PLWD's thoughts and feelings), we conducted a sequential mixed-methods study with 67 couples managing Alzheimer's disease. Both spouses completed semi-structured interviews to describe PLWD's needs and discussed how they communicated about needs. Caregivers' perspective taking was negatively associated with discrepancies in PLWD's needs. Thematic analysis of a subgroup parallel sample demonstrated that, when caregivers reported high perspective taking, couples described navigating PLWD's needs through open dialogue and caregivers adopted respectful communication practices. When caregivers reported low perspective taking, couples described misaligned expectations and communication efforts; caregivers initiated communication to identify PLWD needs and acknowledged employing insensitive language. Findings can inform interventions to improve the quality of dementia care and promote health.},
}

@article {pmid42029189,
year = {2026},
author = {Furman, S and Zayou, L and Tsourmas, KI and Javonillo, DI and Olivarria, GM and Cheng, Y and Pachow, C and Fernandez, K and Le, L and Edwards, RA and Nicholas, DA and Sanchez, GP and Baric, RS and Green, KN and Lane, TE},
title = {Infection of 5xFAD mice with a mouse-adapted SARS-CoV-2 does not alter Alzheimer's disease neuropathology yet induces widespread changes in gene expression across diverse cell types.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71394},
doi = {10.1002/alz.71394},
pmid = {42029189},
issn = {1552-5279},
support = {R35NS116835//National Institutes of Health (NIH-National Institute of Neurological Disorder and Stroke [NINDS])/ ; R01AG081599//NIH-National Institute on Aging (NIA)/ ; U54 AG054349/AG/NIA NIH HHS/United States ; R01 AI110700/AI/NIAID NIH HHS/United States ; 5P30CA062203-26//NIH-National Cancer Institute (NCI)/ ; U01AI180164//NIH-National Cancer Institute (NCI)/ ; 1F31NS141599//NIH-National Cancer Institute (NCI)/ ; T32 NS121727/NS/NINDS NIH HHS/United States ; 5T32 AI007319-33//NIH-National Cancer Institute (NCI)/ ; T32 AG00096//NIH-NIA Training/ ; U54 AG054349/AG/NIA NIH HHS/United States ; T32 NS121727/NS/NINDS NIH HHS/United States ; 105190/ALZ/Alzheimer's Association/United States ; },
mesh = {Animals ; *Alzheimer Disease/pathology/genetics/virology/metabolism ; Mice ; *COVID-19/pathology/genetics ; Mice, Transgenic ; *Brain/pathology/metabolism/virology ; *SARS-CoV-2 ; Disease Models, Animal ; Plaque, Amyloid/pathology ; Neuroglia/metabolism ; Neurons/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Humans ; Gene Expression ; },
abstract = {INTRODUCTION: The COVID-19 pandemic underscored the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on worsening the severity of Alzheimer's disease (AD) neuropathology and disease progression.

METHODS: Aged 5xFAD and wild-type (WT) mice were infected with a mouse-adapted SARS-CoV-2 (MA10), and extensive characterization of molecular and cellular changes within the brains was carried out.

RESULTS: MA10 infection induced acute viral pneumonia. Viral RNA was undetectable within the brains of infected mice, and there was no evidence of glial activation or neuroinflammation. MA10 infection did not affect amyloid beta (Aβ) plaque volume or numbers in 5xFAD mice compared to uninfected mice. Spatial transcriptomics revealed altered expression of genes associated with homeostatic function in neurons, glia, and vascular endothelial cells.

DISCUSSION: Collectively, these findings demonstrate that while MA10 infection did not affect AD neuropathology, there were numerous downstream effects on gene expression associated with resident central nervous system cell functions that may impact neurologic disease.},
}

Animals
*Alzheimer Disease/pathology/genetics/virology/metabolism
Mice
*COVID-19/pathology/genetics
Mice, Transgenic
*Brain/pathology/metabolism/virology
*SARS-CoV-2
Disease Models, Animal
Plaque, Amyloid/pathology
Neuroglia/metabolism
Neurons/metabolism/pathology
Amyloid beta-Peptides/metabolism
Humans
Gene Expression

@article {pmid42029395,
year = {2026},
author = {Deng, W and Xie, Y},
title = {Beyond AUC: Clinical interpretability of depression-MRI-machine learning analyses in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71435},
doi = {10.1002/alz.71435},
pmid = {42029395},
issn = {1552-5279},
}

@article {pmid42029407,
year = {2026},
author = {Wearn, A and Onuska, KM and Shanks, HRC and Gaurav, R and Lehéricy, S and Baracchini, G and Hughes, C and Tremblay-Mercier, J and Narayanan, S and Breitner, J and Poirier, J and Schmitz, TW and Turner, GR and Spreng, RN and , },
title = {Locus coeruleus degeneration is associated with cortical tau deposition and cognitive decline in older adults at familial risk of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71427},
doi = {10.1002/alz.71427},
pmid = {42029407},
issn = {1552-5279},
support = {R01(RNS: AG068563)/AG/NIA NIH HHS/United States ; RNS: AARG-22-927100/ALZ/Alzheimer's Association/United States ; AW #317644 CSH: #320680 RNS//Fonds de Recherche du Québec-Santé/ ; CSH: #181831/CAPMC/CIHR/Canada ; //McGill University: JeanneTimminsCostelloPostdoctoralFellowship(AW)/ ; },
mesh = {Humans ; *Locus Coeruleus/pathology/diagnostic imaging/metabolism ; *Alzheimer Disease/pathology/diagnostic imaging/genetics/metabolism ; Male ; Female ; *tau Proteins/metabolism ; Aged ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Longitudinal Studies ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Aged, 80 and over ; Middle Aged ; Melanins ; },
abstract = {INTRODUCTION: The locus coeruleus (LC) is among the first sites of tau pathology in Alzheimer's disease (AD) and may seed neocortical tau.

METHODS: We used longitudinal neuromelanin-sensitive MRI to assess LC integrity in vivo in a cohort of cognitively unimpaired older adults with familial risk of AD in relation to tau and amyloid positron emission tomography (PET) and long-term cognitive trajectories.

RESULTS: We showed that both LC integrity at baseline and its rate of degeneration over time independently predicted a neocortical pattern of tau deposition. In keeping with the known function of the LC, neuropsychological tests showed that LC integrity at baseline predicted changes in attention. Finally, we found that longitudinal LC degeneration correlated with memory decline in people with elevated neocortical amyloid burden.

DISCUSSION: Our findings underscore the importance of LC in AD pathogenesis. Longitudinal measurement of LC degeneration may help distinguish trajectories of age-related cognitive decline and early AD.},
}

Humans
*Locus Coeruleus/pathology/diagnostic imaging/metabolism
*Alzheimer Disease/pathology/diagnostic imaging/genetics/metabolism
Male
Female
*tau Proteins/metabolism
Aged
Positron-Emission Tomography
Magnetic Resonance Imaging
Neuropsychological Tests
Longitudinal Studies
*Cognitive Dysfunction/diagnostic imaging/pathology
Aged, 80 and over
Middle Aged
Melanins

@article {pmid42029420,
year = {2026},
author = {James, TA and Zhao, L and Xu, H and Wu, J and Schweidel, DA and Goldstein, FC and Levey, AI and Qiu, D and Loring, DW and Hanfelt, JJ and Lah, JJ},
title = {Visual memory correlates with AD biomarkers in cognitively unimpaired individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71417},
doi = {10.1002/alz.71417},
pmid = {42029420},
issn = {1552-5279},
support = {R01-AG070937/AG/NIA NIH HHS/United States ; IIS RD004723//Roche Diagnostics/ ; },
mesh = {Humans ; Male ; Female ; Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; *Alzheimer Disease/cerebrospinal fluid ; Neuropsychological Tests ; Aged ; Middle Aged ; tau Proteins/cerebrospinal fluid ; *Memory/physiology ; Hippocampus/pathology/diagnostic imaging ; Adult ; Brain/diagnostic imaging/pathology ; Factor Analysis, Statistical ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) pathology evolves silently for many years prior to disease, and early identification of individuals at greatest risk is critical for improving outcomes.

METHODS: We conducted exploratory factor analysis (EFA) using neuropsychological testing of 1697 healthy adults. Factor scores were submitted as predictors for structural magnetic resonance imaging, functional connectivity, and cerebrospinal fluid (CSF) biomarkers.

RESULTS: The EFA model identified five latent factors. Factor 1, Verbal Memory, included high loadings from Rey Auditory Verbal Learning Test, and Factor 2, Visual Memory, included high loadings from Rey Complex Figure Test (RCFT). Factor 2 positively correlated with hippocampal volume, precuneus and posterior salience network connectivity, and negatively with CSF tau. Factor 1 correlated with hippocampal volume but not with network connectivity or CSF biomarkers.

DISCUSSION: Results demonstrate a significant relationship of visual memory with AD biomarkers. RCFT may be an important assessment for evaluating and tracking individuals during the earliest stages of AD pathology.},
}

Humans
Male
Female
Biomarkers/cerebrospinal fluid
Magnetic Resonance Imaging
*Alzheimer Disease/cerebrospinal fluid
Neuropsychological Tests
Aged
Middle Aged
tau Proteins/cerebrospinal fluid
*Memory/physiology
Hippocampus/pathology/diagnostic imaging
Adult
Brain/diagnostic imaging/pathology
Factor Analysis, Statistical

@article {pmid42029424,
year = {2026},
author = {Clark, AL and Hamlin, AM},
title = {Life course neighborhood conditions and change: a 20-year examination of neighborhood context and associations with Alzheimer's disease biomarkers in late life.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71382},
doi = {10.1002/alz.71382},
pmid = {42029424},
issn = {1552-5279},
support = {R03 AG085241/AG/NIA NIH HHS/United States ; P30AG066614//Center on Aging and Population Sciences at The University of Texas at Austin/ ; DGE-2137420//National Science Foundation Graduate Research Fellowship Program/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/epidemiology ; Biomarkers/blood ; Male ; Female ; Aged ; Glial Fibrillary Acidic Protein/blood ; *Amyloid beta-Peptides/blood ; Neurofilament Proteins/blood ; Longitudinal Studies ; Middle Aged ; *Residence Characteristics ; *Neighborhood Characteristics/statistics & numerical data ; Aged, 80 and over ; Peptide Fragments/blood ; },
abstract = {INTRODUCTION: Life course models of Alzheimer's disease (AD) suggest that both long-term exposure to neighborhood conditions and changes in neighborhood context may shape dementia risk. This study examined the impact of mid- and late-life levels of neighborhood segregation, as well as longitudinal change in segregation, on plasma AD biomarkers.

METHODS: Participants were 119 racially/ethnically diverse (60% Black/Latino) adults. Residential addresses were geocoded to temporally harmonized US Census tracts, and the dissimilarity index quantified segregation. Plasma neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid beta (Aβ) 42/40 were measured.

RESULTS: Generalized estimating equations adjusting for individual-level sociodemographic and health characteristics revealed mid-life, but not late-life, levels of segregation were significantly associated with NfL. Increasing segregation across 10- and 20-year periods was associated with higher levels of GFAP and NfL, respectively.

DISCUSSION: Mid-life levels of segregation and longitudinal change in segregation were linked to plasma markers of neurodegeneration and astroglial activation.},
}

Humans
*Alzheimer Disease/blood/epidemiology
Biomarkers/blood
Male
Female
Aged
Glial Fibrillary Acidic Protein/blood
*Amyloid beta-Peptides/blood
Neurofilament Proteins/blood
Longitudinal Studies
Middle Aged
*Residence Characteristics
*Neighborhood Characteristics/statistics & numerical data
Aged, 80 and over
Peptide Fragments/blood

@article {pmid42029761,
year = {2026},
author = {Tekin, N and Şahin, F and Şahin, B and Kaya, ZZ and Yılmaz, A and Graham, SF and Serteser, M and Baykal, AT},
title = {A perspective for alzheimer disease from gut microbiota-associated NMR-based fecal metabolomics: a study with 5XFAD mice.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42029761},
issn = {1573-7365},
}

@article {pmid42029781,
year = {2026},
author = {Zhao, M and Abbasi, AA and Li, P and Lu, P},
title = {Mitochondrial dysfunction in sleep deprivation.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42029781},
issn = {1573-7365},
support = {202401-06//Joint Innovation Team for Clinical & Basic Research/ ; 092-200012 PL//the Academic Promotion Program of Shandong First Medical University/ ; },
}

@article {pmid42029826,
year = {2026},
author = {Kwon, G and Kim, H and Kim, H and Lee, J},
title = {Generative Synthesis of Fractional Anisotropy Maps from T1 MRI Using Transfer Learning for White Matter Assessment in Stroke.},
journal = {Brain topography},
volume = {39},
number = {3},
pages = {},
pmid = {42029826},
issn = {1573-6792},
support = {RS-2023-00265824//Ministry of Science and ICT, South Korea/ ; RS-2026-25483830//National Research Foundation of Korea/ ; },
mesh = {Humans ; *White Matter/diagnostic imaging/pathology ; Male ; Female ; Aged ; Anisotropy ; Diffusion Tensor Imaging/methods ; *Magnetic Resonance Imaging/methods ; Middle Aged ; *Stroke/diagnostic imaging ; *Brain/diagnostic imaging ; Aged, 80 and over ; Neuroimaging/methods ; },
abstract = {Assessment of white matter integrity is critical for predicting functional recovery after ischemic stroke. However, conventional magnetic resonance imaging (MRI) cannot capture tract-specific microstructural changes, and diffusion tensor imaging (DTI) is limited by prolonged acquisition times. This study aimed to synthesize fractional anisotropy (FA) maps from routinely acquired T1-weighted (T1) MRI using 2.5D inputs within a generative adversarial network (GAN) framework. Specifically, our primary objective was to evaluate the relative efficacy of a proposed transfer learning strategy compared to single-domain training approaches. T1-FA paired data from 375 cognitively normal participants (832 images) from the Alzheimer's Disease Neuroimaging Initiative served as the non-lesion dataset, while longitudinal MRI data from 69 ischemic stroke patients (236 images) were from a single-center cohort. Three models were evaluated: the non-lesion-trained (NLT) model trained on non-lesion data, the lesion-trained (LT) model trained on stroke data, and the NLT model further fine-tuned on the stroke dataset (NLT + LF). Model performance was evaluated using voxel-wise errors (mean absolute error (MAE) and root mean square error (RMSE)), structural similarity (peak signal-to-noise ratio (PSNR) and structural similarity index measure (SSIM)), spatial overlap (Dice coefficient (Dice)), and distributional similarity (Kullback-Leibler divergence). Bonferroni-corrected paired t-tests showed that NLT + LF showed significantly better performance than NLT across all evaluated regions, including the whole brain, white matter, and lesions (all p < 0.001). Compared with LT, NLT + LF showed superior performance for all metrics at p < 0.001, except for lesion-region Dice and RMSE, which remained significant at p < 0.01. The preservation of lesion-relevant features and anatomical fidelity, together with the capture of degeneration patterns, accompanied these gains. Overall, the proposed NLT + LF approach improved lesion-specific representation and established that high-fidelity FA maps can be reliably synthesized from T1 MRI. This transfer learning framework offers a practical alternative to DTI for clinical stroke assessment.},
}

Humans
*White Matter/diagnostic imaging/pathology
Male
Female
Aged
Anisotropy
Diffusion Tensor Imaging/methods
*Magnetic Resonance Imaging/methods
Middle Aged
*Stroke/diagnostic imaging
*Brain/diagnostic imaging
Aged, 80 and over
Neuroimaging/methods

@article {pmid42029989,
year = {2026},
author = {Sariaslani, A and Abrishami Moghaddam, H and A Ardekani, B and , },
title = {Corpus Callosum Segmentation on Structural MRI Using Multi-atlas Deformable Registration.},
journal = {Neuroinformatics},
volume = {24},
number = {2},
pages = {},
pmid = {42029989},
issn = {1559-0089},
}

@article {pmid42030001,
year = {2026},
author = {von Wegner, F and Hermann, G and Tödt, I and Todtenhaupt, IK and Laufs, H},
title = {A Quantitative Comparison of Two Methods for Higher-Order EEG Microstate Syntax Analysis.},
journal = {Brain topography},
volume = {39},
number = {3},
pages = {},
pmid = {42030001},
issn = {1573-6792},
mesh = {Humans ; *Electroencephalography/methods ; Entropy ; *Alzheimer Disease/physiopathology ; *Brain/physiopathology ; Markov Chains ; Male ; Female ; Aged ; Signal Processing, Computer-Assisted ; },
abstract = {Entropy rate (ER) and sample entropy (SE) are two metrics that have been used to quantify the syntactic complexity of electroencephalography (EEG) microstate sequences. We here present a theoretical and numerical comparison of these two metrics and apply them to a resting-state EEG dataset from individuals with Alzheimer's disease (AD) and a control group. We first derive theoretical ER and SE estimates for first-order discrete Markov processes, providing a null hypothesis for statistical testing of higher-order syntax properties. Under the first-order syntax null hypothesis, we find a close mathematical relationship between both metrics that can be expressed by the microstate transition probability matrix. An inequality is derived that shows ER to be an upper bound to SE under the Markov approximation. We quantify accuracy and precision of the theoretical ER and SE estimates on EEG microstate sequences from the healthy control group. We then show that ER and SE identify significant higher-order syntax properties in microstate sequences from the control and AD groups. We investigate continuous and jump microstate sequences. In the former, each time point is labelled with the best matching microstate label, and in the latter, duplicate labels are removed, exclusively retaining transitions between non-identical microstates. Group comparison demonstrates that continuous microstate sequences from the AD group have lower entropy values (ER, SE), whereas jump sequences from the AD group have higher entropy values compared to control. Finally, we introduce a new syntax metric that normalizes ER and SE values with respect to their first-order syntax levels, to assess differences that only depend on syntax order. This metric revealed no differences between control and AD groups for either continuous or jump microstate sequences. This study provides further insights into higher-order microstate syntax and how it can be quantified with respect to the underlying first-order syntax. Similarities and differences between ER and SE as syntax metrics are highlighted and exemplified on experimental data. Our results show that (i) EEG microstate sequences from control and AD subjects show higher-order syntax properties across the tested syntax levels, (ii) continuous and jump sequences from control and AD groups are syntactically different, and (iii) differences between the control and AD groups disappear when higher-order syntax properties are normalized to the group-specific Markov level.},
}

Humans
*Electroencephalography/methods
Entropy
*Alzheimer Disease/physiopathology
*Brain/physiopathology
Markov Chains
Male
Female
Aged
Signal Processing, Computer-Assisted

@article {pmid42030244,
year = {2026},
author = {do Carmo, JM and Hall, JE and Ladnier, E and Dai, X and Wang, Z and Mouton, AJ and Omoto, ACM and Jorge, L and da Silva, AA},
title = {Parental obesity exacerbates cognitive dysfunction and cardiac vulnerability in offspring of an Alzheimer disease model.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpheart.00047.2026},
pmid = {42030244},
issn = {1522-1539},
support = {P30 GM149404/GM/NIGMS NIH HHS/United States ; U54 GM115428/GM/NIGMS NIH HHS/United States ; R01 DK121411/DK/NIDDK NIH HHS/United States ; R01 HL163076/HL/NHLBI NIH HHS/United States ; },
abstract = {Alzheimer disease (AD) is a growing health problem characterized by neurocognitive and cardiovascular dysfunction. Although parental obesity programs adverse cardiometabolic complications, including obesity, hypertension and cardiorenal dysfunction in their offspring, whether parental obesity worsens cardiac, metabolic, and cognitive function in lean offspring that are susceptible to AD (3xTg-AD mice) remains unclear. Male and female offspring from control diet-fed or high fat diet (HFD)-fed parents were examined at 26-28 weeks of age. Cognitive function was assessed by Morris Water Maze and New Object Recognition (NOR) tests, cardiac function by echocardiography and invasive hemodynamic measurements, and mitochondrial (MT) function by high-resolution respirometry in isolated cardiac fibers and brain cortex. AD offspring from obese parents (HFD-Offs) exhibited worse memory retention compared to AD offspring from lean parents (ND-Offs), whereas recognition memory assessed by NOR was not significantly different between groups although there was greater variability in HFD-Offs. Although systolic function by echocardiography was similar between groups, male HFD-Offs showed impaired diastolic relaxation with prolonged isovolumetric relaxation time (IVRT), while E/e' remained unchanged. Left ventricular catheterization showed reduced indices of contractility and relaxation, including maximal and minimal rates of pressure changes: dP/dtmax (8,038±1011 vs. 18,704±183 mmHg/sec), dP/dtmin (-7,724±471 vs. -13,634±1139) and prolonged Tau (4.0±0.1 vs. 2.9±0.1) in HFD-Offs compared to ND-Offs. Male HFD-Offs exhibited reduced MT glucose and fatty acid oxidation in heart and brain. These findings indicate that parental obesity exacerbates AD-related cognitive decline and cardiac dysfunction in a sex-specific manner, suggesting parental metabolic status as an important determinant of AD-related cardiometabolic vulnerability.},
}

@article {pmid42030370,
year = {2026},
author = {Panda, SR and Soni, U and Panja, P and Rajdev, B and Singh, M and Kundu, S and Ranade, A and Pawar, SD and Acharya, R and Naidu, VGM},
title = {Modulation of Mitochondrial Dynamics by Loganic Acid Ameliorates Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00012},
pmid = {42030370},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly, which refers to forgetting facts and experiences. Apart from being a classical neuropathological hallmark, AD is connected with pronounced mitochondrial fragmentation, although the exact contribution of mitochondrial dynamics in AD progression is poorly defined. Therefore, this study is aimed at investigating the role of loganic acid (LGA) in mitochondrial dynamics, hippocampal plasticity, and cognitive deficits in the scopolamine (SC)-induced cognitive impairment model. The results showed significant decline of p-Drp1 protein and elevation of Mfn2 proteins in LGA-treated SC-induced mice, indicating reduced mitochondrial fragmentation and restoration of mitochondrial dynamics. In addition, LGA treatment promotes the reduction of fragmented and spherical-shaped mitochondria in SC-induced mice. LGA treatment alleviated reactive oxygen species (ROS) production and elevated mitochondrial membrane potential, reducing neurodegeneration in SC mice. Moreover, the decline of inflammatory cytokines (TNF-α and IL-1β) and downregulation of NF-kB expression in LGA-treated SC-induced mice suggested improved neuronal health. In parallel, LGA also increased the regulation of the cytoskeleton within neuronal dendrites, synaptic plasticity, and neuronal dendrites outgrowth, which was validated with increased expression of MAP2. In conclusion, the present study findings suggest that LGA exerts neuroprotection via preserving the mitochondrial ultrastructure and modulating the mitochondrial dynamics. All of these changes further restore neuronal cell density and myelination, leading to the mitigation of neurodegeneration, and restore cognitive deficits and spatial memory in SC-induced C57BL/6 mice.},
}

@article {pmid42030634,
year = {2026},
author = {Reyna-Sevilla, A and Rodríguez-Bolaños, R and Palacios-Rodríguez, OA and Gámez-Ortiz, R and Galarde-López, M and Ortega Ibarra, IH},
title = {Mental health conditions in Mexico: Diagnosis trends based on hospital records.},
journal = {Atencion primaria},
volume = {58},
number = {7},
pages = {103501},
doi = {10.1016/j.aprim.2026.103501},
pmid = {42030634},
issn = {1578-1275},
abstract = {OBJECTIVE: Analyze spatiotemporal trends in mental disorder diagnoses in Mexico between 2019 and 2023.

DESIGN: An ecological study was conducted based on records of mental disorder diagnoses in the population aged ≥21 years with social security coverage. SITE: Mexico, based on data from the National Open Data Platform on primary care units of the Mexican Social Security Institute (IMSS).

PARTICIPANTS: A total of 12,561,531 records obtained from diagnoses of mental disorders in the population aged ≥21 years with social security coverage during the period 2019-2023.

INTERVENTIONS: Rates were estimated, adjusted for sex and age. Spatio-temporal trends were evaluated using Moran's I index.

MAIN MEASURES: Classification of mental disorder, sex, age, entity, year.

RESULTS: At the national level, the mental disorder rate rose from 2419 per 100,000 population in 2019 to 7192 in 2023. Anxiety and obsessive-compulsive disorders, substance use disorders, and depressive episodes were the main diagnosis in both sexes. The data show a growing trend in mental disorders of various etiologies, in addition to depression and anxiety, which are treated by healthcare services. These disorders exhibited regional and gender-based variations during the study period.

CONCLUSIONS: It is recommended to expand health service coverage to strengthen the detection and diagnosis of mental disorder, reinforce primary care in regions at greatest risk, and incorporate prevention strategies for disorders that may increase in magnitude (dementias, Alzheimer's disease, schizophrenia, and delusional disorders).},
}

@article {pmid42030894,
year = {2026},
author = {Facci, L and Chemello, C and Marcolin, E and Franceschini, D and Scarin, N and Pagetta, A and Giusti, P and Moro, S and Zusso, M},
title = {Serum amyloid A1 directly engages TLR4/MD-2 to trigger neuroinflammatory signaling in microglia cultures.},
journal = {International immunopharmacology},
volume = {180},
number = {},
pages = {116710},
doi = {10.1016/j.intimp.2026.116710},
pmid = {42030894},
issn = {1878-1705},
abstract = {INTRODUCTION: Serum amyloid A1 (SAA1) is an inducible acute-phase protein produced in the liver and released in response to environmental and inflammatory stimuli, making it a reliable clinical biomarker of acute inflammation. In addition to its hepatic origin, SAA1 has been detected in axonal myelin sheaths in multiple sclerosis and Alzheimer's disease, suggesting that it may influence cells of the central nervous system (CNS) through several receptors, including Toll like receptors (TLRs).

AIM: We aimed to clarify the role of TLR4 in mediating SAA1-induced inflammation in CNS cells and to elucidate the molecular mechanisms of SAA1 interaction with the TLR4/MD-2 complex.

METHODS: We used an engineered TLR4 reporter cell system to assess TLR4 activation by SAA1. In primary microglia cultures, we evaluated the effects of SAA1 on pro-inflammatory mediators, with or without pharmacological inhibitors, including the TLR4 inhibitor CLI-095, curcumin, and L48H37. Biochemical and computational approaches were used to investigate direct interactions between SAA1 and the TLR4/MD-2 complex.

RESULTS: SAA1 activates the TLR4/MD-2 complex in a concentration-dependent manner. This effect was abolished by the TLR4 inhibitor CLI-095. Curcumin and L48H37, which bind to the hydrophobic pocket of MD-2, reduced SAA1-induced release of interleukin-1β, tumor necrosis factor-α, and nitric oxide, as well as NF-κB activation in microglia. Biochemical and computational studies confirmed a direct interaction between SAA1 and TLR4/MD-2.

CONCLUSIONS: SAA1 directly engages TLR4/MD-2 to trigger neuroinflammatory responses. Targeting this axis may attenuate SAA1-driven neuroinflammation and offers potential therapeutic strategies for neurodegenerative disorders.},
}

@article {pmid42030932,
year = {2026},
author = {Carnevale, LN and Banerjee, P and Zhang, X and Navarro, J and Raspur, CK and Patel, P and Nakamura, T and Schahrer, E and Scott, H and Lang, N and Diedrich, JK and Roberts, AJ and Yates, JR and Lipton, SA},
title = {Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer's disease brain.},
journal = {Cell chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.chembiol.2026.03.017},
pmid = {42030932},
issn = {2451-9448},
abstract = {Aberrant activation of innate immune signaling is known to contribute to neuroinflammation in age-related neurological disorders, but the mechanisms underlying this activation remain unclear. Here, we discovered that protein S-nitrosylation, a redox-based posttranslational modification, regulates the stimulator of interferon genes (STING) protein in Alzheimer's disease (AD). Using a combination of redox chemical biology and mass spectrometry, we identified S-nitrosylation at cysteine 148 as a critical modification facilitating STING oligomerization and triggering excessive type I interferon signaling in a causal fashion. This modification was observed in human AD postmortem brain tissue, in human induced pluripotent stem cell (hiPSC)-derived innate immune cells exposed to AD-related protein aggregates, and in a transgenic AD mouse model. Our findings reveal a novel molecular link between nitrosative stress and dysregulated innate immunity that drives neuroinflammation and synaptic loss in AD. Targeting this redox-sensitive cysteine presents a promising therapeutic strategy to modulate neuroinflammation and potentially slow disease progression.},
}

@article {pmid42030987,
year = {2026},
author = {Li, X and Zhang, C and Ni, H and Sun, P and Ren, J and Huang, S},
title = {MMP9 as a shared immune-related gene in Alzheimer's and Huntington's diseases: a cross-tissue transcriptomic analysis.},
journal = {Artificial cells, nanomedicine, and biotechnology},
volume = {54},
number = {1},
pages = {316-331},
doi = {10.1080/21691401.2026.2644164},
pmid = {42030987},
issn = {2169-141X},
mesh = {Humans ; *Huntington Disease/genetics/immunology ; *Matrix Metalloproteinase 9/genetics/immunology ; *Alzheimer Disease/genetics/immunology ; *Gene Expression Profiling ; Male ; *Transcriptome ; Organ Specificity/genetics ; Female ; Aged ; },
abstract = {Alzheimer's disease (AD) and Huntington's disease (HD) share neuroinflammatory mechanisms, yet their specific immune microenvironments remain poorly understood. Integrating transcriptomic profiles of peripheral blood and frontal cortex tissues with 2,160 immune-related genes, we analysed their shared immunopathology. Differential analysis identified 64 peripheral and 159 central consistently dysregulated immune genes, intersecting to isolate 10 co-expressed all-immune genes. Functional enrichment highlighted neutrophil and monocyte activation, alongside IL-17 and T-cell receptor signalling pathways. Machine learning (LASSO and Boruta) robustly pinpointed MMP9 as the core shared immune hub gene. External validation revealed MMP9 exhibited modest diagnostic performance in peripheral blood (AD AUC = 0.616; HD AUC = 0.619) but stronger predictive accuracy in brain tissues (AD AUC = 0.825; HD AUC = 0.876). Furthermore, MMP9 expression positively correlated with neutrophil and M0 macrophage infiltration. While modest peripheral accuracy limits its standalone diagnostic utility, this cross-tissue analysis establishes MMP9 as a consistently upregulated candidate molecular indicator of shared neuroinflammation, offering a valuable target for future mechanistic research.},
}

Humans
*Huntington Disease/genetics/immunology
*Matrix Metalloproteinase 9/genetics/immunology
*Alzheimer Disease/genetics/immunology
*Gene Expression Profiling
Male
*Transcriptome
Organ Specificity/genetics
Female
Aged

@article {pmid42031063,
year = {2026},
author = {Shi, C and Jia, K and Guo, Y and Qian, S and Wang, B and Qiu, Y and Dan, L and Dang, Z and Xue, K and Gao, F and Zhao, L},
title = {Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116242},
doi = {10.1016/j.bbr.2026.116242},
pmid = {42031063},
issn = {1872-7549},
abstract = {Disulfidptosis is a recently identified form of regulated cell death driven by disulfide stress and cytoskeletal collapse under conditions of impaired reducing capacity. Neurodegenerative diseases (NDs), including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by oxidative stress, mitochondrial dysfunction, metabolic impairment, protein aggregation, and cytoskeletal instability-features that may provide a permissive intracellular context for disulfidptosis. However, its occurrence and pathological relevance in these disorders remain incompletely understood. In this review, we examine the potential involvement of disulfidptosis in neurodegenerative diseases from a disease-centered perspective. We emphasize that current evidence is largely indirect and based on mechanistic overlap rather than direct experimental validation in neural systems. Accordingly, we distinguish between direct evidence, indirect mechanistic support, and pathophysiological plausibility. We further discuss cell-type-specific susceptibility across neurons and glial cells, analyze its relationship with other cell death pathways, and consider potential therapeutic implications. Overall, disulfidptosis is best regarded as a context-dependent and emerging mechanism that may contribute to neuronal vulnerability under specific metabolic and redox constraints. Clarifying its disease relevance will be essential for determining its significance in neurodegeneration and its potential as a therapeutic target.},
}

@article {pmid42031084,
year = {2026},
author = {Segura, AH and Illán, IÁ and de Inestrosa, JRP and Román, FS and Martínez Murcia, FJ and Levin, J and Górriz Sáez, JM and , },
title = {Robust validation of neuroimaging and clinical models via the SAR method: A case study based on the ADNI dataset.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121917},
doi = {10.1016/j.neuroimage.2026.121917},
pmid = {42031084},
issn = {1095-9572},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and substantial brain atrophy. Early and accurate prediction of disease progression and staging is crucial for timely intervention and effective treatment planning. Previous studies, including those based on artificial intelligence techniques, have employed neuroimaging, biomarkers and clinical data to model AD progression; however, many of these approaches rely on strong parametric assumptions or lack robust statistical guarantees regarding model validity. To bridge this gap, this study proposes a novel framework for validating predictive and staging models of disease using a statistically agnostic methodology. The objective is to take the advantages of an unconventional method for robust validation of ML models related to AD. Validation is performed using the Statistical Agnostic Regression (SAR) methodology applied to the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. The method tests for a linear relationship by resampling and estimating an upper bound on the expected risk (R) via a Bayesian bound under the worst-case scenario. The SAR power assesses the likelihood of detecting a true linear relationship using the test statistic R, via Monte Carlo simulations under the null distribution. Three predictive models related to structural neuroimaging are assessed: one for the Mini Mental State Examination (MMSE) score, another for the concentration of amyloid beta 1-42 protein in the cerebrospinal fluid, and a third for age. In addition, a model for staging based on Alzheimer's-related clinical groups is explored through the joint analysis of segmented gray matter and white matter images. The findings indicate that the SAR methodology not only facilitates robust validation of predictive ML models related to neuroimaging and AD but also enables an effective staging of the AD continuum. This SAR-proposed framework opens new perspectives for the validation of ML models for early diagnosis and provides a solid foundation for future research in computational neuroscience.},
}

@article {pmid42031119,
year = {2026},
author = {Ferré-González, L and Peña-Bautista, C and López-Nogueroles, M and Durand, T and Baquero, M and Cháfer-Pericás, C},
title = {Sex-Specific lipid peroxidation profile and clinical features in a cognitive impairment cohort.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.04.143},
pmid = {42031119},
issn = {1873-4596},
abstract = {BACKGROUND: Alzheimer's disease (AD) displays a sex imbalance; women represent two-thirds of cases and often progress faster. Lipid peroxidation contributes to AD neurotoxicity from the oxidation of fatty acids can. However, how sex modulates plasma lipid peroxidation across clinical stages remains poorly characterized. This study examines sex- and AD clinical stage-related patterns in these plasma compounds.

METHODS: Plasma lipid peroxidation compounds were quantified by liquid chromatography/mass spectrometry in a clinical cohort stratified into 6 groups (cognitively unimpaired (without AD (n = 93), with AD (n=27)), mild cognitive impairment (due to AD (n = 105), not due to AD (n = 45)), mild dementia (due to AD (n = 84), not due to AD (n = 34))).

RESULTS: Across clinical groups, women showed a more severe clinical profile, while men showed higher neurofilament light chain (NfL) levels in several groups. Specifically, 10 lipid peroxidation compounds showed impaired levels in women with AD, while only 2 compounds in men. Notably, significant positive correlations were observed between certain lipid peroxidation compounds and cerebrospinal fluid (CSF) biomarkers exclusively in women. Positive correlations were observed between isoprostanes / neuroprostanes and some neuropyschological tests (CDR, MMSE, ADCS-ADL-MCI) in women, as well as mixed correlations between lipid peroxidation compounds and two tests (RBANS, FAQ) in men. Furthermore, multivariate analysis confirmed that clinical diagnosis was the main determining factor rather than biological sex, with 4 lipid peroxidation compounds (10-epi-10-F4t-NeuroP, 17-epi-17-F2t-dihomo-IsoP, total IsoP and total NeuroP) showing differences among clinical groups with distinct patterns of progression, specifically men showing higher levels in preclinical stages, while women showed more complex fluctuations throughout AD progression.

CONCLUSIONS: Plasma lipid peroxidation follows sex-dependent biological patterns across clinical stages of AD, highlighting a wider variety of altered biomarkers in women, which underscores the need to evaluate sex-stratified approaches for the diagnosis and AD staging.},
}

@article {pmid42031321,
year = {2026},
author = {Basha, S and Nadkarni, PP and Pai, AR and Mahato, KK},
title = {Co-Aggregation of Amyloidogenic Proteins in Age-Related Neurodegenerative Diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103148},
doi = {10.1016/j.arr.2026.103148},
pmid = {42031321},
issn = {1872-9649},
abstract = {Age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and related dementias, are increasingly understood as multifactorial proteinopathies involving co-aggregation of amyloidogenic proteins such as Tubulin-associated unit protein (Tau), α-synuclein (α-syn), amyloid-β (Aβ), and TAR DNA-binding protein 43 (TDP-43). Rather than acting independently, these proteins often cross-seed, co-localize, and modulate each other's aggregation dynamics and toxicity. This review critically examines the mechanistic and pathological underpinnings of heterotypic protein co-aggregation, integrating biophysical, cellular, animal, and human data. Further, this review proposes a conceptual framework that views neurodegeneration as a network of interacting misfolded proteins shaped by ageing-related changes in lipid membranes, redox balance, proteostasis, and genetic factors. Emphasis is placed on translational opportunities: co-aggregation-specific biomarkers in cerebrospinal fluid and extracellular vesicles, and emerging multi-targeted therapies including immunotherapy, proteostasis modulators, and autophagy-inducing chimeras. This review also discusses the clinical implications of co-pathology in mixed dementias and overlapping disorders. It is therefore time to move beyond the classical one protein-one disease paradigm and embrace models that explicitly incorporate heterotypic co-aggregation, mixed pathologies, and shared vulnerability pathways across ageing-related disorders. By reframing co-aggregation as a central pathogenic mechanism, this review highlights the need for diagnostics and therapeutics that address the interconnectivity of protein misfolding in ageing brains.},
}

@article {pmid42031360,
year = {2026},
author = {Li, X and Li, J and Sun, Y and Yao, T and Lu, Y and Liu, S and Li, H and Shi, Y and Chen, L and Zhao, Y and Jiang, W and Li, Z and Zhou, Z and Wang, B and Zhang, S and Yu, H and Lai, Y and Lu, Q and Li, Y and Li, H and Xu, Z and Wang, G and Zhu, Z},
title = {Challenges and delivery strategies for PROTACs in central nervous system therapeutics.},
journal = {Advanced drug delivery reviews},
volume = {},
number = {},
pages = {115876},
doi = {10.1016/j.addr.2026.115876},
pmid = {42031360},
issn = {1872-8294},
abstract = {The drug development for central nervous system (CNS) disorders, particularly neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, faces formidable challenges. While proteolysis-targeting chimeras (PROTACs) represent a paradigm-shifting modality by redefining target engagement mechanisms, their clinical translation remains hindered by limited blood-brain barrier (BBB) permeability and suboptimal pharmacokinetic profiles. In recent years, diverse CNS-targeted delivery strategies have emerged, driving PROTAC research toward translatable therapeutic potential. This Review highlights recent advances and persistent challenges in noninvasive BBB-penetrant delivery systems, including viral vectors, engineered exosomes, functionalized nanocarriers, and cell membrane-derived biomimetic vehicles, with a particular emphasis on intranasal administration as a direct route to the brain. Parallel progress in rational molecular engineering, encompassing E3 ligase selection, linker polarity and rigidity modulation, and optimization of target-binding ligands, has further enhanced PROTAC drug-likeness and BBB transport efficiency. Current CNS-directed PROTAC designs increasingly incorporate cell-penetrating peptides, nanoparticles, and prodrug formulations to balance stability, selectivity, and brain exposure. Future advanced PROTAC delivery platforms require integrating multifunctional nanocarriers with rational structural optimization to enhance BBB permeability. Further artificial intelligence-accelerated molecular design and targeted protein degradation technologies offer novel avenues for addressing undruggable CNS targets.},
}

@article {pmid42031363,
year = {2026},
author = {Gerwert, G and Mann, M and Langenhoff, L and Woitzik, N and Hubert, D and Duman, D and Höveler, A and Budde, S and Simon, J and Beyer, L and Schuler, M and Weber, S and Mollenhauer, B and Kötting, C and Güldenhaupt, J and Gerwert, K},
title = {An Immuno-Infrared Sensor Detects Preclinical Alzheimer's and Parkinson's Disease by Protein Misfolding.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.6c00433},
pmid = {42031363},
issn = {1520-5207},
abstract = {The immuno-infrared sensor (iRS) detects misfolding of biomarker proteins in blood and provides thereby a very early and easily accessible diagnosis of Alzheimer's and Parkinson's disease. Only in early stages recently approved therapeutic Alzheimer's drugs work efficiently. In symptom-free stages, lifestyle change can largely delay the disease progression, and the drugs may even block the disease progression. Population screening by a simple blood test will therefore be a game changer in the fight against neurodegenerative diseases. This was made possible by the new iRS platform. In the iRS platform, antibodies as catcher molecules concentrate the target protein biomarker on the functionalized attenuated total reflection crystal surface. A blocking layer prevents unspecific binding. A quantum cascade laser is used to measure the amide I absorbance maximum as a readout, indicating the degree of the biomarker misfolding and thereby disease progression.},
}

@article {pmid42031657,
year = {2026},
author = {Kaur, A and Singh, S and Singh, M and Silakari, P and Mannan, A and Vishwas, S and Kumar, P and Subramaniyan, V and Singh, TG},
title = {Corrigendum to "Demethyleneberberine attenuates combined cognitive and metabolic dysfunctions in an insulin-resistance-induced Alzheimer's disease rat model: Synthesis, in-silico and in-vivo insights" [Experimental Neurology, 398 (2026) 115634].},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115774},
doi = {10.1016/j.expneurol.2026.115774},
pmid = {42031657},
issn = {1090-2430},
}

@article {pmid42031881,
year = {2026},
author = {Asiry, O and El-Gawady, A and Eltoukhy, MM and Mohamed, MF},
title = {LASSO-HHO two-stage hybrid gene selection framework for accurate Alzheimer's disease diagnosis.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42031881},
issn = {2045-2322},
support = {UJ-23-AKSPE-14//University of Jeddah/ ; },
mesh = {*Alzheimer Disease/diagnosis/genetics ; Humans ; Algorithms ; Gene Expression Profiling/methods ; *Computational Biology/methods ; Databases, Genetic ; },
abstract = {Selecting informative genes is essential for building accurate and efficient diagnostic models, especially for high-dimensional gene expression data such as those related to Alzheimer's disease. These datasets typically involve thousands of genes with limited samples, increasing the risk of overfitting and computational complexity. To address this, we propose a LASSO-HHO Gene Selection (LHGS) framework. LASSO is first applied to reduce dimensionality by filtering irrelevant genes. A conditional HHO-based optimization stage is then applied only when the LASSO-selected subset does not achieve sufficient accuracy or remains relatively large. Otherwise, the LASSO-selected features are directly used without further optimization. Experimental results show that the proposed method reduces the number of selected genes by up to 99.9% while maintaining high performance. The experimental results indicate that 100% accuracy can be achieved on specific datasets. In particular, GSE48350 and GSE36980 achieved 100% accuracy using LASSO alone, whereas GSE118553 and GSE132903 required the full LHGS framework to achieve the same performance. The framework also improves computational efficiency within a consistent experimental setup by reducing the optimization search space after LASSO filtering. Overall, LHGS provides a practical and efficient solution for gene selection in high-dimensional biomedical data.},
}

*Alzheimer Disease/diagnosis/genetics
Humans
Algorithms
Gene Expression Profiling/methods
*Computational Biology/methods
Databases, Genetic

@article {pmid42032039,
year = {2026},
author = {Dong, Y and Xiao, X and Zhuang, XX and Wu, W and Wang, ZY and Zhang, S and Li, JT and Zhang, K and Fu, WY and Chen, JM and Xiong, SH and Deng, S and Li, K and Ma, C and Jin, W and Jin, X and Cai, Q and Shen, HM and Li, M and Su, H and Wan, JB and Yu, H and Ouyang, D and Ye, K and Fang, EF and Tan, CSH and Yang, G and Niu, Z and Lu, JH},
title = {DeepDrugDiscovery identifies blood-brain barrier permeable autophagy enhancers for Alzheimer's disease.},
journal = {Nature biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {42032039},
issn = {2157-846X},
support = {0040/2024/RIB1//Fundo para o Desenvolvimento das Ciências e da Tecnologia (Science and Technology Development Fund)/ ; },
abstract = {Dysfunctional autophagy, a key cellular cleaning process, is a key driver of brain ageing and neurodegenerative diseases such as Alzheimer's disease (AD). However, developing effective treatments by enhancing autophagy has been challenging, as most known compounds act through the broad mTOR pathway, risking side effects, and few can effectively penetrate the brain. To address this, we developed DeepDrugDiscovery-a mechanism-aware, AI-powered screening platform incorporating ADMET and blood-brain barrier penetrability predictions. Here we show that this platform successfully identified novel, mTOR-independent autophagy enhancers, with two lead compounds demonstrating an ability to cross the blood-brain barrier, clear AD-related protein aggregates and restore memory function in worm and mouse AD models. By releasing DeepDrugDiscovery as an open-source, modular tool, we offer a user-friendly AI platform that enables customized therapeutic screening. Our work establishes a scalable, AI-driven pipeline that integrates cross-species validation to rapidly discover mechanism-based therapeutics for diseases with high unmet medical need.},
}

@article {pmid42032173,
year = {2024},
author = {Hasan, WU and Zaman, KT and Wang, X and Li, J and Xie, B and Tao, C},
title = {Empowering Alzheimer's caregivers with conversational AI: a novel approach for enhanced communication and personalized support.},
journal = {npj biomedical innovations},
volume = {1},
number = {1},
pages = {},
pmid = {42032173},
issn = {3005-1444},
support = {2218046//National Science Foundation/ ; 2218046//National Science Foundation/ ; 2218046//National Science Foundation/ ; 2218046//National Science Foundation/ ; 2218046//National Science Foundation/ ; 2218046//National Science Foundation/ ; },
abstract = {Alzheimer's disease and related dementias (ADRD) place a significant burden on caregivers. To address this, we developed ADQueryAid, a conversational AI system designed to empower ADRD caregivers. Built on a Large Language Model and enriched with ADRD knowledge, ADQueryAid uses Retrieval-Augmented Generation to provide personalized and informative support. A user study comparing ADQueryAid to a baseline model (ChatGPT 3.5) demonstrated its superior usability, offering contextually relevant information and emotional support. This study highlights the potential of tailored AI systems to enhance the caregiving experience, paving the way for future research on their long-term impact.},
}

@article {pmid41814062,
year = {2026},
author = {Margarian, S and Chen, Y and Waheed, J and Rezaeimanesh, P and Chiang, VS and Takehara-Nishiuchi, K},
title = {Cost-effective, open-source, automated apparatus for testing transitive inference in mice.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41814062},
issn = {2045-2322},
abstract = {Transitive inference is a form of reasoning that relies on prior knowledge and benefits survival in diverse species. While initially designed for humans, the transitive inference task has been adapted for mice, allowing for integration with various state-of-the-art manipulation and monitoring tools for mechanistic investigations. Existing paradigms, however, rely on manually presented stimuli, making them time-consuming, labor-intensive, and error-prone. Here, we introduce AutoTI, a fully automated behavioral apparatus that precisely controls the timing of task events and logs timestamps for events and responses. The automation also enables continuous, undisturbed monitoring of spontaneous behavior, allowing for detailed analyses of movement trajectory beyond basic accuracy metrics. Using AutoTI, we developed a robust training protocol that reliably achieved high success rates on transitive tests in mice. Notably, mice exhibited hallmark behavioral patterns seen in humans, including the symbolic distance effect and the serial position effect. AutoTI provides a cost-effective and scalable system for investigating the neurobiological basis of inferential reasoning. It also holds promise for translational research targeting its impairment in autism, schizophrenia, and Alzheimer’s disease, as well as advancing the reasoning capabilities of artificial intelligence.},
}

@article {pmid42020180,
year = {2026},
author = {Tong, FF and Huang, RQ and Gao, Y and Luo, QQ and Chen, YP and Xu, GZ},
title = {[Epidemiological studies of the association between dyslipidemia and Alzheimer's disease].},
journal = {Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi},
volume = {47},
number = {4},
pages = {767-774},
doi = {10.3760/cma.j.cn112338-20250727-00528},
pmid = {42020180},
issn = {0254-6450},
mesh = {*Alzheimer Disease/epidemiology ; Humans ; *Dyslipidemias/epidemiology/complications ; Risk Factors ; },
abstract = {Alzheimer's disease (AD), as the representative type of dementia among neurodegenerative diseases, has become a major challenge in the field of global public health. Dyslipidemia is considered an acquired risk factor for AD, and both are progressive diseases with long developmental periods, making dyslipidemia a potential predictor of future AD occurrence. Therefore, preventing dyslipidemia is of great significance for the prevention and treatment of AD. Given the global epidemiological background of AD, this article aims to systematically review the association between dyslipidemia and AD, providing theoretical support for the prevention and control of both conditions.},
}

*Alzheimer Disease/epidemiology
Humans
*Dyslipidemias/epidemiology/complications
Risk Factors

@article {pmid42020356,
year = {2026},
author = {Zou, Z and Chen, J and Li, J and Chen, Y},
title = {The iron-energy metabolism axis in Alzheimer's pathogenesis: from mechanisms to interventions.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03034-w},
pmid = {42020356},
issn = {2058-7716},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with a complex, multifactorial pathogenesis. Growing evidence implicates disturbances in cellular energy metabolism and iron dyshomeostasis as interlinked contributors to pathology. Within this framework, iron accumulation may act as an upstream regulator in certain contexts and stages, while in others it emerges downstream and amplifies ongoing injury. As iron is an essential cofactor for mitochondrial respiration and the tricarboxylic acid cycle, iron imbalance can compromise ATP production and disrupt glucose metabolism, exacerbating neuronal energy deficits. The interplay among iron accumulation, oxidative stress, and neuroinflammation can create vicious cycles that reprogram cellular metabolism and disrupt the critical metabolic coupling between neurons and glial cells. This review synthesizes recent advances in understanding the iron-energy metabolism axis in AD, delineates mechanisms by which iron imbalance precipitates mitochondrial dysfunction and glucose metabolic impairments, and evaluates how these deficits synergize with neuroinflammation and proteinopathy across disease stages. Finally, we appraise emerging therapeutic strategies targeting iron overload and metabolic pathways, discuss their stage-dependent risks and benefits, and outline the need for biomarker-guided approaches to optimize patient selection and treatment timing.},
}

@article {pmid42020486,
year = {2026},
author = {Ahn, JW and Yoon, EJ and Kim, HS and Choi, Y and Jeong, J and Damodar, K and Yoo, YM and Park, D and Joo, SS},
title = {HSN G1 demonstrates multifaceted therapeutic strategy against Alzheimer disease in APP PS1 mouse model.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49541-9},
pmid = {42020486},
issn = {2045-2322},
abstract = {Current therapeutic approaches for Alzheimer's disease (AD) demonstrate limited efficacy and fail to address disease progression. In the present study, we present HSN-G1, a novel ginsenoside-enriched pharmaceutical formulation that employs a dual-target mechanism through the modulation of amyloid clearance pathways and cholinergic neurotransmission. HSN-G1 demonstrates a reproducible ginsenoside profile enriched with Re (33.27 mg/g), Rd (25.00 mg/g), and Rg3 stereoisomers (12.18 mg/g), ensuring pharmaceutical-grade reproducibility. HSN-G1 enhanced amyloid-beta (Aβ) clearance in microglial cells, with significantly greater effects observed in SRA-overexpressing cells, suggesting SRA-dependent clearance mechanisms. In APP/PS1 transgenic mice, six-week oral administration of HSN-G1 (100-400 mg/kg) elicited significant dose-dependent improvements in cognitive performance. Male mice exhibited more stable and consistent enhancements in both passive avoidance and spatial memory tests compared to vehicle controls (p < 0.001), while both sexes demonstrated comparable reductions in brain Aβ levels (approximately 45%) and differential increases in acetylcholine (73% in males; 55% in females, p < 0.01). HSN-G1 administration enhanced the expression of neurotrophic factors, with NGF upregulation predominantly observed in males, whereas BDNF, CNTF, and GDNF were consistently elevated across both sexes. These findings establish HSN-G1 as a promising disease-modifying agent with standardized composition and therapeutic efficacy, surpassing the limitations of conventional single-target approaches. The superior efficacy of HSN-G1 compared to existing treatments validates its potential for clinical development, highlighting the significance of sex-specific therapeutic responses in future AD therapeutics.},
}

@article {pmid42020643,
year = {2026},
author = {Liu, G and Xie, B and Zhao, J and Lv, L},
title = {LINC00926 promotes microglial M1 polarization and neuroinflammation by sponging miR-383-3p in Alzheimer's disease: a potential diagnostic and therapeutic target.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42020643},
issn = {2240-2993},
}

@article {pmid42020711,
year = {2026},
author = {Liu, Q and Parrish, RL and Tang, S and Tasaki, S and Bennett, DA and Seyfried, NT and De Jager, PL and Menon, V and Buchman, AS and Yang, J},
title = {Cell-type-aware transcriptome-wide association studies identify 91 independent risk genes for Alzheimer's disease dementia.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10030-4},
pmid = {42020711},
issn = {2399-3642},
support = {R35GM138313//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01AG089703//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Most existing transcriptome wide association studies (TWASs) of Alzheimer's Disease (AD) dementia only use bulk RNA-seq data and a single statistical method. Here, we utilize an omnibus TWAS (TWAS-O) pipeline that leverages multiple complementary statistical methods to integrate the snRNA-seq dataset (n = 415) of the dorsolateral prefrontal cortex (DLPFC) and the latest GWAS data of AD dementia. We fine-map TWAS risk genes by gene-based conditional analysis and conducted validation analyses by the analogous omnibus proteome-wide association studies (PWAS-O) using bulk proteomics data of DLPFC (n = 716). We identify 223 unique cell-type-aware TWAS risk genes from 350 associations across six major brain cell-types, including 91 fine-mapped independent associations, 11 of which are novel. By PWAS-O, we identify 21 significant PWAS risk genes, including 13 independent associations, which validated 31.9% independent cell-type-aware TWAS associations. By protein-protein interaction network analyses, our novel cell-type-aware TWAS findings are linked to established AD risk genes such as APOE, BIN1, and MAPT.},
}

@article {pmid42020790,
year = {2026},
author = {Ferreira, AFF and Feng, ZP and Sun, HS and Britto, LRG},
title = {Inhibiting the transient receptor potential melastatin 2 channel in microglia: current evidence and therapeutic potential in neurological disorders.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {42020790},
issn = {1745-7254},
abstract = {Microglia, the resident immune cells of the central nervous system, play a pivotal role in neuroinflammation and is a key contributor to the onset and progression of various neurological and neurodegenerative diseases. The Transient Receptor Potential Melastatin 2 (TRPM2), a non-selective calcium channel, has emerged as a sensor linking oxidative stress responses and calcium influx. It is expressed in many tissues and cells, including neurons, astrocytes, and microglia. TRPM2 represents one of the molecular mediators regulating microglial activity and function, cytokine production, and microglia-neuron communication. Growing evidence suggests that TRPM2 contributes to the pathological mechanisms underlying diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, epilepsy, and neuropathic pain. However, most of the studies mainly explored the TRPM2 involvement in cell death, which has been reviewed by some other authors. In this review, we compile and discuss findings from in vivo and in vitro studies evaluating the role of TRPM2, with a specific focus on its influence over microglial function and neuroinflammatory responses, a field that has been poorly explored. We gathered information from studies reporting, in stroke models, that both pharmacological inhibition and genetic deletion of TRPM2 reduced infarct volume, improved behavioral outcomes, and diminished glial reactivity. In models of neurodegeneration, TRPM2 modulation shows promising effects on neuronal survival and microglial phenotype. In neuropathic pain models, TRPM2 was found to mediate microglial activation and the release of pro-inflammatory mediators, contributing to pain hypersensitivity. However, findings in epilepsy models reveal a more complex picture, with TRPM2 deficiency producing either neuroprotective or deleterious outcomes, highlighting the need for further studies. Although most studies to date support a pathogenic role for TRPM2 in microglia-mediated neuroinflammation, some limitations were highlighted, as the non-selective pharmacological inhibitors available, the inclusion of only males in the majority of studies, and the use of a global TRPM2 knockout. Only two studies employed conditional genetic models to promote specific TRPM2 deletion from microglia, with promising findings. Overall, current evidence indicates TRPM2 as a promising modulator of microglia, with broad implications for the treatment of neurological disorders characterized by chronic inflammation.},
}

@article {pmid42020886,
year = {2026},
author = {Çelik, H and Dalkılınç, E and Aydın, Ş and Çelik, O and Küçükler, S and Topal, A and Akay, R and Gönüllü, S and Yıldız, MO and Alım, B and Özdemir, S},
title = {Delivery of miR-25802 via Small Vesicles Protects Against Mitochondrial Injury, Oxidative Stress, and Neuroinflammation in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42020886},
issn = {1559-1182},
mesh = {*Oxidative Stress/drug effects ; *MicroRNAs/administration & dosage ; *Alzheimer Disease/pathology/metabolism/genetics ; *Mitochondria/metabolism/pathology/drug effects ; Humans ; Cell Line, Tumor ; Amyloid beta-Peptides/metabolism/toxicity ; *Neuroinflammatory Diseases/pathology/metabolism ; *Extracellular Vesicles/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Mitochondrial dysfunction, oxidative stress, and neuroinflammation play a critical role in the occurrence and progression of Alzheimer's disease (AD). MicroRNAs (miRNAs) have been studied recently as potential therapeutic approaches for AD. In this study, we examined the function and underlying mechanism of microRNA-25802 (miR-25802), a newly discovered miRNA in an AD model. In order to evaluate the levels of oxidative stress, mitochondrial damage and neuroinflammation in neuroblastoma cells, four experimental groups were created: control group (neuroblastoma cells, SH-SY5Y), amyloid beta (Aβ)-induced neuroblastoma cells (SY5Y-Aβ), small extracellular vesicles (sEVs)-only group and miR-25802-loaded small extracellular vesicles (sEV-miR25802) administered group. Neuroinflammation, oxidative stress, mitochondrial damage, tau hyperphosphorylation, and Aβ accumulation were evaluated in Aβ-induced neuroblastoma cells. Oxidative stress was analyzed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and glutathione peroxidase 1 (GPX1). Inflammatory markers such as tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule 1 (ICAM1), and brain-derived neurotrophic factor (BDNF) mRNA levels, a neurotrophic factor, were evaluated by RT-qPCR. Neurofilament light chain (NfL), vascular endothelial growth factor-A (VEGF-A), macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1) and cytochrome c (Cyt-c), mitochondrial transcription factor A (TFAM), PTEN-induced kinase 1 (PINK1) and dynamin-1-like protein (DNM1L) protein levels were determined by ELISA. Mechanistically, sEV-miR25802 were shown to provide anti-inflammatory and neuroprotective effects by regulating neuroinflammation, mitochondrial dysfunction, and oxidative stress. These findings reveal the regulatory role of miR-25802 on neuroinflammation, mitochondrial damage, and oxidative stress and suggest that it may be a potential therapeutic target for AD.},
}

*Oxidative Stress/drug effects
*MicroRNAs/administration & dosage
*Alzheimer Disease/pathology/metabolism/genetics
*Mitochondria/metabolism/pathology/drug effects
Humans
Cell Line, Tumor
Amyloid beta-Peptides/metabolism/toxicity
*Neuroinflammatory Diseases/pathology/metabolism
*Extracellular Vesicles/metabolism
Reactive Oxygen Species/metabolism

@article {pmid42020929,
year = {2026},
author = {Ng, B and Kodosaki, E and Veleva, E and Keshavan, A and Schott, JM and Heslegrave, AJ and Fox, NC and Zetterberg, H},
title = {Aging-related matrix metallopeptidase 10 and osteopontin levels are associated with pathology, cognitive decline, and age at onset in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71082},
pmid = {42020929},
issn = {1552-5279},
support = {//National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; },
mesh = {Humans ; *Osteopontin/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/pathology ; Female ; Male ; Aged ; *Aging/cerebrospinal fluid/pathology ; Age of Onset ; Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; *Matrix Metalloproteinase 10/cerebrospinal fluid ; Aged, 80 and over ; *Cognitive Dysfunction/cerebrospinal fluid/pathology ; Middle Aged ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Aging is the strongest risk factor for Alzheimer's disease (AD) characterized by amyloid-β (Aβ) plaques and tau tangles in the brain. We aim to compare biological aging-related biomarkers among AD, non-neurodegenerative control (NDC) and non-AD neurodegenerative (Non-AD) individuals to evaluate their clinical utility.

METHODS: We included 137 participants (37 NDC, 67 AD, 33 Non-AD) from the University College London (UCL) Dementia Research Centre and measured matrix metallopeptidase 10 (MMP-10), osteopontin (OPN), neurofilament-light, and glial fibrillary acidic protein in cerebrospinal fluid (CSF) in addition to Aβ/pTau and clinical parameters.

RESULTS: Elevated MMP-10 associated with poorer cognition and later onset specifically in AD, whereas elevated OPN associated with Aβ and tau pathology. MMP-10 and OPN levels improved the differentiation of AD from NDC, and AD from Non-AD, respectively.

DISCUSSION: Our study provides evidence on potential clinical utility of CSF MMP-10 and OPN in diagnosis and supports taking biological aging into consideration in AD research.

HIGHLIGHTS: Elevated osteopontin and matrix metallopeptidase 10 (MMP-10) levels in Alzheimer's disease (AD) cerebrospinal fluid. MMP-10 levels are linked to age at onset and cognitive decline. Osteopontin levels are linked to AD pathologies in the cerebrospinal fluid. MMP-10 levels improved discrimination of AD from non-neurodegenerative controls. Osteopontin levels improved discrimination of AD from other neurodegenerative cases.},
}

Humans
*Osteopontin/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/pathology
Female
Male
Aged
*Aging/cerebrospinal fluid/pathology
Age of Onset
Amyloid beta-Peptides/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
*Matrix Metalloproteinase 10/cerebrospinal fluid
Aged, 80 and over
*Cognitive Dysfunction/cerebrospinal fluid/pathology
Middle Aged
Glial Fibrillary Acidic Protein/cerebrospinal fluid
Neurofilament Proteins/cerebrospinal fluid

@article {pmid42021299,
year = {2026},
author = {Xie, S and Liang, Y and Pang, Y and Li, Y and Cao, S and Li, Y and Wang, Q and Moghekar, A and Albert, M and Jia, J and , },
title = {Plasma biomarker trajectories across Alzheimer's clinical onset: a 17-year prospective study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02045-0},
pmid = {42021299},
issn = {1758-9193},
}

@article {pmid42021305,
year = {2026},
author = {Shippy, DC and Sande, ML and Ulland, TK},
title = {Type-1 interferons associated with microglial-mediated neuroinflammation in Alzheimer's disease.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03828-w},
pmid = {42021305},
issn = {1742-2094},
support = {R01AG070973/AG/NIA NIH HHS/United States ; },
}

@article {pmid42021321,
year = {2026},
author = {Xi, R and Zheng, X and Zhao, J and Fu, Y},
title = {The SHIP1-inflammatory-lipid axis in Alzheimer's disease: from genetic risk to spatiotemporal mechanistic insights.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03819-x},
pmid = {42021321},
issn = {1742-2094},
support = {32400821//the National Natural Science Foundation of China/ ; 82471322//the National Natural Science Foundation of China/ ; SR21500123//the Jiangsu Specially Appointed Professor Program/ ; ZXL2024390//the Gusu Leading Talents in Innovation and Entrepreneurship Program/ ; LG-ADB510202//the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Lingang Laboratory/ ; B202306//the Startup Foundation for Hundred-Talent Program of Zhejiang University/ ; SMIDF-150-2025A4//the Brain Health Youth Fund/ ; },
}

@article {pmid42021347,
year = {2026},
author = {Wang, L and Han, L and Liu, S},
title = {Dysfunction of the neurovascular unit as a temporal driver in Alzheimer's pathogenesis.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42021347},
issn = {2047-9158},
support = {32530027//National Natural Science Foundation of China/ ; 2021ZD0204400//National Science and Technology Major Project/ ; 2021YFA0805100//Key Technologies Research and Development Program/ ; },
mesh = {*Alzheimer Disease/pathology/physiopathology/metabolism ; Humans ; Animals ; *Brain/pathology/metabolism/blood supply ; *Neurovascular Coupling/physiology ; },
abstract = {Extensive studies have shown that cerebrovascular dysfunction is a critical factor in the onset and progression of Alzheimer's disease (AD). Neurovascular unit (NVU) is impaired in AD brains, including damage of tight junction between endothelial cells, degeneration of pericytes, activation of astrocytes and microglia, and apoptosis of neurons. As decreased cerebral blood flow is observed before amyloid-beta (Aβ) generation, it is supposed that NVU dysfunction may precede and exacerbate the pathological state of AD neural system, and that the events of NVU dysfunction and Aβ deposition synergistically promote AD progression. Technological breakthroughs of three-dimensional NVU organoids, spatial transcriptomics with single-cell resolution, and development of artificial intelligence technology, such as machine learning and deep learning, offer the possibility of constructing accurate functional structural models. Here we systematically review the NVU dysfunction during AD progression as well as the applications of spatial transcriptomics and organoid technology in NVU studies.},
}

*Alzheimer Disease/pathology/physiopathology/metabolism
Humans
Animals
*Brain/pathology/metabolism/blood supply
*Neurovascular Coupling/physiology

@article {pmid42021568,
year = {2026},
author = {Li, Z and Ge, R and Zhao, Z and Xiao, H and Du, C and Lai, Y and Wang, L},
title = {From Bio-Interface Materials to Neural Integration: The Next-Generation Brain-Machine Interfaces Powered by Hydrogels.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e23422},
doi = {10.1002/adma.202523422},
pmid = {42021568},
issn = {1521-4095},
support = {22322803//National Natural Science Foundation of China/ ; 22375047//National Natural Science Foundation of China/ ; 22361162607//International Cooperation and Exchanges NSFC/ ; 20240305028YY//Key Research Development Program of Jilin Province/ ; 2022YFB3804905//National Key Research and Development Program of China/ ; 2022YFB3804900//National Key Research and Development Program of China/ ; //Graduate Innovation Fund of Jilin University/ ; FZ2025038//State Key Laboratory of New Textile Materials and Advanced Pro- cessing/ ; },
abstract = {Brain-machine interfaces (BMIs), which serve as revolutionary tools for neural recording, modulation, and rehabilitation, are highly dependent on the biocompatibility and mechanical suitability of their electrode materials. Although traditional metal electrodes possess excellent conductivity, their inherent rigidity causes a substantial mechanical mismatch with soft neural tissue, leading to chronic inflammatory responses and poor long-term stability. The emergence of hydrogel electrodes has provided a breakthrough solution to this fundamental limitation. Hydrogels, characterized by their softness, high ionic conductivity, and tissue-like compliance, offer a viable solution to mitigate these issues. This review systematically explores the material properties of hydrogel-integrated BMIs, providing an in-depth investigation of key hydrogel characteristics, including toughness, adhesion, conductivity, and biocompatibility. Additionally, hydrogel-based BMIs are categorized into non-invasive and invasive systems, each defined by its characteristic operational principles and signal-acquisition mechanisms. The study further reviews critical issues, including surgical implantation strategies, multimodal data fusion, integration of artificial intelligence, as well as system integration and clinical translation. From a therapeutic perspective, this work highlights the application of BMIs in treating neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, neuropathic pain, and depression. Furthermore, this review critically examines the persistent challenges faced by hydrogel-based BMIs and proposes innovative strategies for future development. Ultimately, it outlines a developmental roadmap for next-generation hydrogel-based biotherapeutic technologies aimed at achieving high-fidelity, stable and clinically translatable BMI systems.},
}

@article {pmid42021589,
year = {2026},
author = {Karakasli, AA and Karahan, S and Ayhan, Y},
title = {Response to Commentary on "Clinical Predictors of Alzheimer's Disease-Like Brain Atrophy in Individuals With Memory Complaints".},
journal = {Brain and behavior},
volume = {16},
number = {4},
pages = {e71412},
doi = {10.1002/brb3.71412},
pmid = {42021589},
issn = {2162-3279},
}

@article {pmid42021611,
year = {2026},
author = {Wong, C and Piersol, CV and Chew, F and Lekovitch, C and Shier, V and Morris, M and Martínez, J and Britton, J and Leland, NE},
title = {Lessons Learned From the Implementation of a Pragmatic Trial Evaluating Non-Pharmacological Approaches to Dementia Care in US Nursing Homes.},
journal = {Journal of evaluation in clinical practice},
volume = {32},
number = {3},
pages = {e70451},
pmid = {42021611},
issn = {1365-2753},
support = {IHS-1608-35732/PCORI/Patient-Centered Outcomes Research Institute/United States ; },
mesh = {Humans ; *Nursing Homes/organization & administration ; United States ; *Dementia/therapy ; *Pragmatic Clinical Trials as Topic ; Comparative Effectiveness Research ; },
abstract = {RATIONALE: The consistent delivery of effective evidence into nursing home practice has been shown to enhance quality of care and residents' outcomes. Pragmatic trials enable the evaluation of efficacious interventions in a real-world context, including care of residents living with Alzheimer's Disease and Related Dementias (ADRD). Yet, there are limited pragmatic trials conducted in nursing homes and even less evidence on the strategies to successfully conduct such research in this setting.

OBJECTIVE: To identify the lessons learned from a pragmatic trial and provide recommendations for future successful studies in United States (US) nursing homes.

METHODS: Drawing on a case example of a recently completed pragmatic trial, we used the Comparative Effectiveness Research Framework to guide the thematic analysis of study documentation to identify challenges, strategies used, and recommendations for future pragmatic trials in US nursing homes.

RESULTS: Five themes emerged from this case example: 1) establish and sustain community partner collaboration, 2) context analysis and appropriate implementation plan, 3) study adaptability, 4) data collection in a 'real world' setting, and 5) broad dissemination. Within each theme, strategies we used, challenges we encountered, and recommendations for future studies were identified. Examples of recommendations include empowering community partners to be engaged in the research, co-design with community partners, account for the dynamic nature of the nursing home setting, and maintain communication with organization leaders.

CONCLUSIONS: Successful completion of pragmatic trials in US nursing homes requires active engagement of community partners throughout the research process. The emergent lessons learned and recommendations highlight the complex nature of this care setting, the need to be proactive in implementation planning, and the pivotal role of community partners. Moving forward, there is a need for greater emphasis on systematically sharing experiences more broadly to advance the science of pragmatic trials in US nursing homes.},
}

Humans
*Nursing Homes/organization & administration
United States
*Dementia/therapy
*Pragmatic Clinical Trials as Topic
Comparative Effectiveness Research

@article {pmid42021771,
year = {2026},
author = {Bednorz, A and Religa, D},
title = {Schizophrenia and dementia across the lifespan: epidemiological links, cognitive trajectories, and the pathophysiological interplay.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1779076},
pmid = {42021771},
issn = {1664-2295},
abstract = {BACKGROUND: Schizophrenia is a severe psychiatric disorder characterized by persistent cognitive impairment across multiple domains and is increasingly associated with elevated risk of late-life dementia. However, the nature of this association and its underlying mechanisms remain unclear.

OBJECTIVE: This mini-review synthesizes current evidence on dementia risk in schizophrenia, focusing on epidemiology, cognitive trajectories, biological mechanisms, and differential relationships with Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD).

RESULTS: Epidemiological studies consistently indicate a two- to threefold increased risk of dementia among individuals with schizophrenia, although estimates vary due to diagnostic and ascertainment biases. Cognitive trajectories are heterogeneous: many patients remain cognitively stable over time, while subgroups demonstrate gradual or accelerated decline associated with negative symptoms, medical comorbidities, and social factors. Current evidence does not support a uniform progression toward Alzheimer-type neurodegeneration. Biomarker, neuropathological, and neuroimaging findings suggest distinct biological profiles, with reduced cognitive reserve, neurodevelopmental vulnerability, accelerated aging processes, and vascular and metabolic burden contributing to dementia risk. Genetic overlap between schizophrenia and AD appears modest, whereas partial clinical and molecular convergence is observed with FTD. Screening tools such as MMSE and MoCA may overestimate dementia prevalence due to longstanding baseline cognitive deficits. Sex differences, late-onset psychosis, and cardiometabolic comorbidities further modify risk trajectories.

CONCLUSION: Dementia risk in schizophrenia likely reflects the interaction of lifelong neurodevelopmental vulnerability with aging-related and modifiable factors rather than a disorder-specific neurodegenerative pathway. Longitudinal biomarker-informed studies and tailored diagnostic frameworks are needed to improve differentiation between chronic cognitive impairment and true neurodegeneration.},
}

@article {pmid42021966,
year = {2026},
author = {Tabi, YA and Meyer, EC},
title = {Autoimmune diseases are associated with increased neurodegenerative and cerebrovascular risk, while systemic corticosteroid exposure shows limited neurodegenerative and modest vascular associations.},
journal = {IBRO neuroscience reports},
volume = {20},
number = {},
pages = {596-608},
pmid = {42021966},
issn = {2667-2421},
abstract = {Systemic autoimmune diseases (AIDs), characterized by chronic peripheral inflammation and frequent vascular comorbidity, are increasingly linked to adverse central nervous system (CNS) outcomes; however, comparative evidence across diverse AIDs and clarification of the roles of vascular burden, inflammatory activity, and immunomodulatory therapy remain limited. Using the TriNetX Global Collaborative Network, we conducted a sequence of retrospective, propensity score-matched cohort experiments in adults aged 50-85 years to quantify incident Parkinson's disease (PD), Alzheimer's disease (AD), transient ischemic attack (TIA), and ischemic stroke across 22 AIDs and to evaluate therapy- and inflammation-stratified risk patterns. In the primary disease-control analysis (Experiment 1 A), AID diagnosis was associated with broadly elevated neurodegenerative and cerebrovascular risk, with stronger and more consistent associations for TIA and ischemic stroke than for PD and AD. To probe robustness, we repeated analyses under tighter control of baseline vascular burden (Experiment 1B: additional matching on circulatory-system diagnoses) and under treatment balancing (Experiment 1 C: additional matching on immune-suppressant exposure). Vascular matching substantially attenuated many associations, particularly for AD, whereas immune-suppressant matching did not materially erase the pervasive cerebrovascular excess. Within-disease CRP stratification (Experiment 2; low vs elevated CRP) did not yield a uniform neurodegenerative gradient but identified a disease-dependent ischemic vulnerability axis in selected inflammatory phenotypes. In treatment substudies, systemic cortisone exposure (Experiment 3) showed little association with PD/AD risk but a modest, heterogeneous increase in TIA/ischemic stroke. Medication-specific strata (Experiment 4) revealed stronger but directionally variable separations, consistent with confounding by indication and severity. Together, these findings position systemic autoimmunity as a robust marker of heightened cerebrovascular risk and a more phenotype-dependent correlate of neurodegenerative risk, supporting intensified vascular surveillance in high-risk AID populations and mechanistic work disentangling inflammation, comorbidity, and treatment.},
}

@article {pmid42022292,
year = {2026},
author = {Llorente-Saguer, I and Gabriele, R and Bradshaw, TY and Leckey, CA and Belder, CRS and Chávez-Gutiérrez, L and de Silva, R and Fox, NC and Wray, S and Oxtoby, NP and Arber, C},
title = {Unbiased data-driven analysis of five amyloid-beta peptides for biomarker investigations in familial Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag105},
pmid = {42022292},
issn = {2632-1297},
abstract = {Changes to the relative abundance of amyloid-beta (Aβ) peptides are hallmarks of Alzheimer's disease. Induced pluripotent stem cell (iPSC)-derived neurons offer a physiological model of Aβ production. We employed unbiased, data-driven analyses to investigate combinations of Aβ peptides as Alzheimer's disease biomarkers and the relative contribution of peptides to Alzheimer's disease pathogenesis. We measured Aβ37, Aβ38, Aβ40, Aβ42 and Aβ43 in 10 iPSC-neuronal cultures from PSEN1 mutation carriers. We combined these data with published cell model data and used linear weighted combinations to (i) distinguish Alzheimer's disease from controls, and (ii) predict age-at-onset for PSEN1 mutations. Data-driven approaches distinguished Aβ42 and Aβ43 from shorter peptides, providing unbiased evidence for a greater association of Aβ42 and Aβ43 to disease pathogenesis, compared with shorter peptides (Aβ37, Aβ38 and Aβ40). Weighted linear combinations of Aβ peptides outperform Aβ42/40 and provide insights into relative peptide contribution as biomarkers. A representative weighted composite value ratio (wCVR) derived from all data, balancing both disease classification and age-at-onset prediction, was (21 ⋅ A β 37 + 10 ⋅ A β 38 + 69 ⋅ A β 40) / (94 ⋅ A β 42 + 6 ⋅ A β 43) . This work suggests a practical non-parametric harmonization approach to employing Aβ ratios as biomarkers for Alzheimer's disease, from multiple sites and assays. Building on this foundation, we applied a new model using weighted composite value ratios, which outperform existing biomarkers across all tasks. This underscores the value of integrating multiple peptides and assigning optimized weightings. The study confirms the association of Aβ42 and Aβ43 with Alzheimer's disease pathogenesis in a data-driven manner. Peptide weights further provide mechanistic insights into the relative contribution of each peptide to disease, such as a greater contribution of Aβ37 compared to Aβ38. The algorithm used herein can be further refined to improve biomarkers for Alzheimer's disease.},
}

@article {pmid42022333,
year = {2026},
author = {Poisnel, G and Lhérault, M and Palix, C and Turpin, AL and Felisatti, F and Vrillon, A and Paquet, C and Chocat, A and Coulbault, L and De La Sayette, V and Gonneaud, J and Chételat, G and , },
title = {Physical activity attenuates the association between allostatic load and early Alzheimer's disease-related biomarkers in older adults.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70248},
pmid = {42022333},
issn = {2352-8737},
abstract = {INTRODUCTION: Allostatic load (AL), an index of cumulative physiological dysregulation from chronic stress, may contribute to Alzheimer's disease (AD) pathophysiology by accelerating brain aging. Higher AL has been associated with AD-related biomarkers, suggesting a mechanistic connection. Lifestyle factors influence both AL and AD vulnerability, but their moderating role in AL-AD biomarker associations remains unclear.

METHODS: We included 111 cognitively unimpaired older adults from the baseline visit of the Age-Well trial. AL was computed as a composite score of 18 biomarkers spanning neuroendocrine, immune, metabolic, cardiovascular-respiratory, and anthropometric systems. Plasma biomarkers included amyloid beta (Aβ)42, Aβ40, phosphorylated-tau (p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Physical activity, Mediterranean diet adherence, and cognitive activity were assessed using validated questionnaires. Multiple linear regressions tested associations between AL and (1) AD-related biomarkers and (2) lifestyle factors, as well as their interactions, controlling for age, sex, education, apolipoprotein E ε4 (APOE ε4) status, and glomerular filtration rate (GFR).

RESULTS: Higher AL was associated with higher Aβ42/Aβ40 ratio (b = 0.004, 95% CI [0.001, 0.007], p = 0.010, false discovery rate [FDR] = 0.040) and lower NfL levels (b = -0.035, 95% CI [-0.063, -0.008], p = 0.013, FDR = 0.026). AL correlated negatively with physical activity (b = -0.899, 95% CI [-1.568, -0.230], p = 0.009, FDR = 0.027). A significant interaction was observed between physical activity and AL in relation to the p-tau231/Aβ42 ratio (b = -0.339, 95% CI [-0.588, -0.091], p = 0.008, FDR = 0.032), such that higher AL was associated with lower p-tau231/Aβ42 ratio among more physically active individuals compared with less active individuals.

DISCUSSION: Regular physical activity was associated with a weaker relationship between AL and early AD-related biomarkers in this cross-sectional sample. Longitudinal studies should confirm whether maintaining physical activity attenuates stress-related physiological dysregulation and reduces AD vulnerability.},
}

@article {pmid42022334,
year = {2026},
author = {Bhagunde, P and Penner, N and Willis, BA and Bell, R and Sachdev, P and Charil, A and Irizarry, MC and Hersch, S and Reyderman, L},
title = {Pharmacokinetic/pharmacodynamic analyses of plasma pathophysiology biomarkers in subjects with early Alzheimer's disease following lecanemab treatment.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70246},
pmid = {42022334},
issn = {2352-8737},
abstract = {INTRODUCTION: Lecanemab, a novel monoclonal antibody targeting both neurotoxic amyloid beta (Aβ) protofibrils and Aβ plaques, substantially reduces markers of amyloid and significantly slows clinical decline on multiple measures of cognition and function in early AD in Phase 2 (Study 201) and Phase 3 (Study 301; Clarity AD) studies. In these clinical studies, several plasma biomarkers showed improvements comparing lecanemab with placebo. Herein, we utilized modeling and simulation to evaluate the long-term effects of lecanemab on pathophysiology biomarkers in plasma.

METHODS: Plasma Aβ42/40 ratio, tau phosphorylated at threonine 181 (p-tau181), and glial fibrillary acidic protein (GFAP) data were pooled from lecanemab Phase 2 and 3 studies. Individual serum lecanemab exposure estimated using a population pharmacokinetic model was correlated with plasma biomarker concentrations using indirect response pharmacokinetic/pharmacodynamic (PK/PD) models. Simulations were conducted to evaluate the effect of lecanemab (10 mg/kg IV every 2 weeks, LEC10-BW) after 4 years of continuous treatment, discontinuation after 18 months of treatment or transitioning to less frequent dosing at 18, 24, or 30 months.

RESULTS: PK/PD models describing the change in plasma biomarker levels over time in response to lecanemab treatment were developed, and simulations demonstrated that plasma biomarkers reverted toward pretreatment baseline after cessation of lecanemab treatment, with an average re-accumulation half-life of approximately 1 to 1.5 years, which was faster than amyloid plaque re-accumulation measured by positron emission tomography. Simulations illustrated transitioning to a lecanemab monthly dosing regimen was sufficient to stabilize plasma biomarker concentrations at levels consistent with ongoing inhibition of amyloid pathology and neuroinflammation.

DISCUSSION: PK/PD model simulations demonstrated that plasma biomarkers serve as early indicators of amyloid accumulation and downstream effects. Plasma biomarker simulations suggest the need for ongoing lecanemab treatment even after amyloid plaque clearance. Transition to a less frequent monthly IV regimen at 18 months was shown to maintain the changes in plasma biomarker levels consistent with lecanemab efficacy.},
}

@article {pmid42022545,
year = {2026},
author = {Kruger, K and van der Veen, H and Beigy, M and O'Donovan, SD and van Riel, N and Remie, LB and Aarts, E and Steegenga, W and Smeets, PAM and van Trijp, MPH and de Groot, LCPGM and Vermeiren, Y},
title = {Gut-brain health effects of PREbiotics in older adults with suspected COgnitive DEcline: design of the PRECODE randomised placebo-controlled trial.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1738622},
pmid = {42022545},
issn = {2296-861X},
abstract = {UNLABELLED: Global lifespan is rising, alongside increasing age-related conditions. Cognitive disorders such as dementia, are projected to triple in number by 2050. Currently, no cure is available for Alzheimer's disease (AD), the most common form of dementia, and the need for preventative strategies is paramount. Subjective cognitive decline plus (SCD+) lies on the AD continuum, with increased risk of accelerated cognitive decline, providing an ideal target group for early intervention. The microbiota-gut-brain axis (MGBA) is an emerging avenue for prevention, as dietary fibres may beneficially modulate microbiota and microbial metabolites, such as short chain fatty acids and tryptophan-indoles, resulting in improved gastrointestinal and cognitive functioning. PRECODE is a four-armed, randomised, double-blinded, placebo-controlled trial in 164 older adults (60-79 years) with SCD+ and additional "LIfestyle for BRAin Health" (LIBRA) risk factors. The study aims to investigate 26 weeks of supplementation with chicory inulin, resistant dextrin, and seaweed polysaccharide compared to placebo (maltodextrin) on the MGBA. The primary outcome is effects on neurocognition, assessed by brain activation during working memory load measured with blood-oxygen level dependant functional magnetic resonance imaging (BOLD fMRI) and performance during 2-back task. The secondary outcomes include cognition by neuropsychological test battery, brain and intestinal health parameters, and immune and metabolic markers. Findings may guide new preventative modalities in preclinical AD and provide mechanistic insights into the MGBA in individuals at risk for cognitive decline.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT06433037.},
}

@article {pmid42022552,
year = {2026},
author = {Jiang, H and Pang, X},
title = {Luteolin as a dietary flavonoid for brain health: modulating neuroinflammation and cognitive decline in neurodegenerative disorders.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1774416},
pmid = {42022552},
issn = {2296-861X},
abstract = {Luteolin, a flavonoid naturally present in a variety of fruits, vegetables, and medicinal plants, has been recognized as a potentially effective neuroprotective nutraceutical because of its remarkable anti-inflammatory, antioxidant, and neurotrophic properties. Increasing evidence suggests that neuroinflammation and oxidative stress are major contributors to cognitive decline and neuronal degeneration in several prominent neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). Luteolin significantly inhibits microglial activation, reduces pro-inflammatory cytokine production, modulates the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and enhances Nrf2-mediated antioxidant mechanisms. Furthermore, it promotes synaptic plasticity through brain-derived neurotrophic factor (BDNF)-associated pathways and mitigates the aggregation of pathological proteins, including Aβ, tau, α-synuclein, and mutant huntingtin. Preclinical studies consistently demonstrate substantial improvements in cognitive function, motor performance, demyelination, and neuronal viability in models of AD, PD, MS, and HD. Preliminary clinical observations also indicate prospective advantages for cognitive function, regulation of inflammatory responses, and alleviation of symptoms, particularly concerning AD and MS. Notwithstanding these encouraging outcomes, obstacles persist due to luteolin's restricted bioavailability, ideal dosing parameters, and the translational discrepancies between experimental models and human pathophysiological conditions. In summary, luteolin emerges as a noteworthy candidate for nutraceutical-oriented approaches designed to alleviate neuroinflammation and cognitive deterioration in the context of neurodegenerative diseases.},
}

@article {pmid42022560,
year = {2026},
author = {Ríos, V and Linares-Pipón, C and Maulén, C and Castro-Álvarez, A and Bradshaw, B and Romero-Parra, J and Cuellar, MA and Martínez-Cifuentes, M and Parra, C},
title = {Conformationally locked 7-aryl tetrahydroisoquinolines as dual acetylcholinesterase inhibitors and antioxidants: role of intramolecular hydrogen bonding and aryl electronics.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1797738},
pmid = {42022560},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which cholinergic dysfunction and oxidative stress act as synergistic contributors to cognitive decline and neuronal damage. Multitarget-directed ligands (MTDLs) capable of modulating both acetylcholinesterase (AChE) activity and oxidative stress pathways are promising candidates for disease-modifying therapies.

METHODS: A series of conformationally locked 7-aryl tetrahydroisoquinoline derivatives was synthesized via a tandem cross-metathesis/Michael/annulation strategy. These compounds feature a stable intramolecular O-H···O=C hydrogen bond that enforces a quasi-planar geometry and modulates the electronic properties of the aryl substituent. The compounds were evaluated for their AChE inhibitory activity using Ellman's assay and for antioxidant capacity using the oxygen radical absorbance capacity (ORAC) assay. Molecular docking studies were performed to analyze binding modes within AChE's aromatic gorge, while density functional theory (DFT) calculations were conducted to assess the thermodynamics of hydrogen atom transfer (HAT) and ionization potential (IP) related to antioxidant behavior.

RESULTS: All derivatives exhibited micromolar AChE inhibition (IC50 = 33-54 µM), with structure-activity relationships driven by the electronic nature and π-polarizability of the 7-aryl ring. Docking results revealed a conserved, π-dominated binding pose within the enzyme's active site. ORAC measurements showed substituent-dependent radical-scavenging activity consistent with the electronic trends observed in enzyme inhibition. DFT calculations indicated a thermodynamic preference for hydrogen atom transfer (HAT) from benzylic C-H over phenolic O-H cleavage, supporting the observed antioxidant profile.

CONCLUSION: This study identifies 7-aryl tetrahydroisoquinolines as a novel, mechanistically coherent scaffold for the development of dual-acting neuroprotective agents targeting both cholinergic dysfunction and oxidative stress in Alzheimer's disease. Their tunable electronic properties and preorganized geometry offer a promising foundation for further optimization within the multitarget therapeutic framework.},
}

@article {pmid42022571,
year = {2026},
author = {Patil, VS and Khanal, P and Harish, DR},
title = {Editorial: Targeted drug delivery and mode of action of small molecules in neuroinflammation.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1782890},
doi = {10.3389/fphar.2026.1782890},
pmid = {42022571},
issn = {1663-9812},
}

@article {pmid42022623,
year = {2026},
author = {Gao, Q and Sun, Z and Wang, Y},
title = {Association of Urinary Perchlorate and Thiocyanate With Cognitive Function in Older Adults: A Cross-Sectional Study.},
journal = {Health science reports},
volume = {9},
number = {3},
pages = {e71965},
pmid = {42022623},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: It is well-known that perchlorate, nitrate, and thiocyanate are thyroid-disrupting chemicals. Evidence regarding the cognitive correlates of thyroid-disrupting anions in older adults remains scarce, particularly in population-based studies assessing multiple cognitive domains. Our study aimed to explore the associations between urinary levels of perchlorate, nitrate, and thiocyanate and cognitive function.

METHODS: Participants were obtained from the National Health and Nutritional Examination Survey (NHANES). Urinary levels of perchlorate, nitrate, and thiocyanate were measured by ion chromatography coupled with electrospray tandem mass spectrometry. Cognitive function was evaluated using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test, the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Logistic regression analyses were conducted to examine the association between urinary levels of the chemicals and cognitive function.

RESULTS: A total of 993 adults were included with a mean age of 69.5 ± 6.6 years. In multivariable-adjusted logistic regression models, urinary perchlorate was inversely associated with low cognitive function evaluated through the AFT [OR: 0.78; 95% CI (0.63, 0.96); p < 0.05], and urinary thiocyanate was negatively related to low cognitive function assessed by CERAD [OR: 0.70; 95% CI (0.50, 0.97); p < 0.05] and AFT [OR: 0.69; 95% CI (0.50, 0.94); p < 0.05].

CONCLUSION: A relative low urinary perchlorate and thiocyanate were associated with low cognitive function. Higher levels of perchlorate and thiocyanate may be inverse cross-sectional associations in cognitive function.},
}

@article {pmid42022738,
year = {2026},
author = {Makridis, A and Kazeli, K and Katsipis, G and Tzekaki, EE and Pantazaki, AA and Bosch, C and Simon-Carbajo, R and Angelakeris, M},
title = {Biomarker-targeted functionalized magnetic nanoparticles: synthesis and aptamer conjugation optimization toward Alzheimer's disease biosensing.},
journal = {Nanoscale advances},
volume = {},
number = {},
pages = {},
pmid = {42022738},
issn = {2516-0230},
abstract = {Magnetic-plasmonic hybrid nanoparticles are gaining prominence in biomedical diagnostics due to their dual functionality, combining magnetic manipulation and signal enhancement. A major challenge remains the reproducible synthesis of core-shell nanostructures with controlled size, composition, and stability. In this work, we present a robust two-step aqueous co-precipitation method to produce gold/magnetite nanoparticles, for early Alzheimer's disease diagnosis, based on biomarker's aptamer-based biosensing. Magnetite nanoparticles were first synthesized with high saturation magnetization, followed by controlled gold shell growth via citrate-assisted reduction. Systematic tuning of gold precursor ratios and washing steps enabled precise control over the shell structure and surface properties. The nanoparticles were extensively characterized using X-ray diffraction, dynamic light scattering, zeta potential analysis, vibrating sample magnetometry, ultraviolet-visible spectroscopy, and inductively coupled plasma measurements, outlining optimal characteristics: distinct core-shell morphology, ferrimagnetic behavior, strong localized surface plasmon resonance, and high colloidal stability. Beyond synthesis and characterization of nanoparticles, this study also introduces an innovative aptamer conjugation protocol tailored for maximizing their binding efficiency, thereby enhancing early recognition of certain neurodegenerative biomarkers: Aβ-40, Aβ-42, TBA and GFAP. The tailored features of the gold/magnetite nanoparticles allow fine control over particle size and aptamer loading, making this work a valuable tool for designing structurally, magnetically, and physicochemically optimized carriers for neurodegenerative disease diagnostics. Collectively, these results establish a scalable and functional platform suitable for next-generation biosensing applications in the early detection of Alzheimer's disease.},
}

@article {pmid42022743,
year = {2026},
author = {Dai, D and Chen, J and Guo, X and Sun, J and Yi, H},
title = {Mechanistic research on the vestibular-hippocampal pathway in neurodegenerative diseases: an integrative perspective from molecular to behavioral levels.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1779268},
pmid = {42022743},
issn = {1662-4548},
abstract = {This paper systematically reviews the pivotal role and bidirectional regulatory mechanisms of the Vestibular-hippocampal pathway in the onset and progression of neurodegenerative diseases (such as Alzheimer's disease), focusing on the common comorbidity of vestibular dysfunction and cognitive decline. Evidence spanning molecular to behavioral levels indicates that vestibular signal loss can induce hippocampal atrophy and spatial memory impairment through neuroinflammation, impaired synaptic plasticity, and disrupted theta rhythms. Conversely, hippocampal degeneration further impairs vestibular information integration, creating a vicious cycle. Intervention approaches such as vestibular rehabilitation, cognitive training, and neurostimulation show potential for slowing co-morbidity progression. Future research should focus on developing animal models simulating vestibular-neurodegenerative co-morbidity, conducting longitudinal clinical validation using multimodal imaging and electrophysiology techniques, and optimizing neuromodulation strategies and targeted molecular interventions to advance this mechanism toward early diagnosis and precision treatment.},
}

@article {pmid42022958,
year = {2026},
author = {Chien, SC and Chien, YC and Wang, HJ and Chen, JC},
title = {A ZIF-8-modified electrochemical biosensor for sensitive Aβ aggregation monitoring and Alzheimer's disease drug screening.},
journal = {RSC advances},
volume = {16},
number = {23},
pages = {20855-20865},
pmid = {42022958},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder driven by the abnormal aggregation of β-amyloid (Aβ) into oligomers, fibrils, and plaques. Current therapeutic strategies primarily alleviate symptoms but struggle to prevent aggregation due to the dynamic nature of Aβ species and prolonged drug development cycles. Sensitive and real-time monitoring of Aβ structural transitions is therefore essential for understanding disease progression and evaluating potential inhibitors. In this study, we developed a ZIF-8-modified electrochemical biosensor capable of translating Aβ42 conformational changes into quantifiable current signals, providing a promising platform for monitoring dynamic aggregation. The aggregation behavior of Aβ42 was systematically characterized using dynamic light scattering (DLS), electrochemical measurements, and Thioflavin T (ThT) fluorescence combined with ultrafiltration. A critical transition from the lag to the growth phase was observed at 24 h, with aggregates exceeding ∼60 nm undergoing irreversible fibrillization. The ZIF-8-modified electrochemical sensor detected early-stage structural rearrangements with superior sensitivity compared to conventional ThT fluorescence, revealing subtle oligomer formation. Quantitative current measurements allowed continuous monitoring of aggregation kinetics, highlighting the temporal resolution of the platform. Validation experiments with curcumin treatment demonstrated strong inhibitory effects between 18 and 24 h, delaying fibrillization, reducing late-stage β-sheet accumulation, and decreasing aggregate size by approximately 25%. In addition, the sensor successfully distinguished minor differences in structural transitions under varying inhibitor concentrations, demonstrating its capability for high-resolution, real-time assessment of aggregation dynamics and drug efficacy. This ZIF-8-modified electrochemical biosensor provides high-sensitivity, dynamic monitoring of Aβ42 aggregation and drug-induced inhibition, offering a valuable tool for mechanistic studies of protein aggregation pathology. By enabling early detection of structural transitions and real-time evaluation of inhibitors, this platform has the potential to accelerate therapeutic screening and improve the development of effective interventions for AD.},
}

@article {pmid42023255,
year = {2026},
author = {Valle, ML and Arienzo, D},
title = {Preclinical advances in antibodies against N-terminal Aβ4-x species for Alzheimer's disease and cerebral amyloid angiopathy.},
journal = {Ibrain},
volume = {12},
number = {1},
pages = {52-64},
pmid = {42023255},
issn = {2769-2795},
abstract = {Alzheimer's disease (AD) pathogenesis is characterized by the accumulation of amyloid beta (Aβ) deposits in the cerebral parenchyma and vasculature, a condition referred to as cerebral amyloid angiopathy (CAA). Besides the full-length form, Aβ deposits showed a highly heterogenous composition due to the action of different proteolytic enzymes. N-terminal Aβ peptides have shown higher aggregation propensity and toxicity compared to the other truncated forms, with species starting at residue phenylalanine 4 (Aβ4-x) being more neurotoxic than the others. Thus, Aβ4-x species have drawn attention in AD pathogenesis, potentially offering novel therapeutic targets to halt or reverse disease progression. Antibodies targeting specifically Aβ4-x species were designed with the aim of preventing their aggregation and promoting their clearance counterbalancing their neurotoxic effect. This work provides an update on monoclonal and polyclonal antibodies developed to specifically target Aβ4-x species in AD and CAA preclinical studies (in vitro and in vivo models).},
}

@article {pmid42023276,
year = {2026},
author = {Kuan, JH and Raghavan, RS and Koh, DLW and Tan, WY and Iezhitsa, I and Agarwal, R},
title = {Navigating the cholesterol maze: Key insights on use of statins in neurodegenerative disorders.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {1},
pages = {30-47},
pmid = {42023276},
issn = {2770-730X},
abstract = {Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and multiple sclerosis (MS) involve progressive neuronal loss driven by dysregulated neurotransmission, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Cholesterol metabolism has emerged as a critical factor involved with both central and peripheral dysregulation contributing to pathology. This review synthesizes current evidence on cholesterol's role in neurodegeneration and evaluates the therapeutic potential of statins, which act via cholesterol-dependent and other pleiotropic mechanisms. A PubMed search covering 1985-2025 publications was conducted using terms related to neurodegenerative diseases, statins, cholesterol metabolism, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuroprotection. Studies were selected to highlight mechanistic insights into cholesterol regulation in the nervous system and clinical data on statin use. Neuronal loss in neurodegeneration is driven by processes including excitotoxicity, inflammation, and mitochondrial dysfunction. Excessive reactive oxygen species activate apoptotic pathways involving BAX, BAK, and p53. Dysregulated cholesterol metabolism is a significant contributor: In AD, the ApoE allele ε4 (ApoE4) links elevated cholesterol to amyloid-β (Aβ) accumulation and cognitive decline; in PD, cholesterol shows mixed effects, with some studies suggesting protection and others linking high levels to α-synuclein aggregation and mitochondrial impairment. In HD reduced cholesterol biosynthesis correlates with neuronal loss, while MS associates with elevated cholesterol and cognitive dysfunction. Statins, widely used cholesterol-lowering agents, reduce Aβ production, enhance its clearance, and improve synaptic function. Beyond lipid lowering, they exert anti-inflammatory, antioxidant, and anti-apoptotic effects. Clinical outcomes remain mixed, with benefits influenced by statin type, dose, treatment duration, disease stage, and patient genetics. Statins show multifaceted neuroprotective potential through cholesterol-dependent and independent pathways. While preclinical data are encouraging, clinical evidence is heterogeneous. Long-term, stratified trials are needed to clarify efficacy, and tailoring therapy to disease-specific mechanisms may offer a viable strategy for mitigating neurodegeneration and enhancing neuronal survival.},
}

@article {pmid42023285,
year = {2026},
author = {Cao, B and Qi, Q and Hutchinson, S and Ferguson, D and Malhotra, P and Koychev, I and O'Brien, JT and Bridgeman, K and Ritchie, CW and Lawlor, B and Naci, L and , },
title = {The relative contribution of modifiable and non-modifiable factors for determining cognition in mid-life individuals at risk for late-life Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70303},
pmid = {42023285},
issn = {2352-8729},
abstract = {INTRODUCTION: It remains unknown whether cognitive reserve contributors can protect against dementia from mid-life, in the context of several modifiable and non-modifiable risk factors, including family history and inherited risk for late-life dementia.

METHODS: We leveraged PREVENT Dementia, a large multisite study of healthy mid-life at-risk individuals (N  =  700) and used canonical correlation analysis (CCA) to investigate multivariate associations between 13 cognitive tasks, 10 modifiable and four non-modifiable risks, and three reserve contributors.

RESULTS: The CCA identified a significant canonical mode (r = 0.486, p (FWE) < 0.001) between dementia risk, reserve contributors, and cognition. The key finding was that modifiable stimulating activities showed the strongest positive association with cognition. Depressive symptoms and traumatic brain injury were the top two modifiable risk factors negatively associated with cognition.

DISCUSSION: These results highlight the strong potential of early, cost-effective, and multifactorial dementia prevention interventions that target both modifiable risk reduction and boosting of cognitive reserve from mid-life.},
}

@article {pmid42023454,
year = {2026},
author = {Qi, W and Wang, J and Gao, X and Liu, Y},
title = {Impact of Sleep Quality on Cognitive Function in Elderly Patients With Alzheimer's Disease.},
journal = {Actas espanolas de psiquiatria},
volume = {54},
number = {2},
pages = {328-334},
doi = {10.62641/aep.v54i2.2126},
pmid = {42023454},
issn = {1578-2735},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/complications/physiopathology/psychology ; Aged ; Retrospective Studies ; *Sleep Quality ; Aged, 80 and over ; *Cognition/physiology ; *Cognitive Dysfunction/physiopathology ; Polysomnography ; Severity of Illness Index ; },
abstract = {OBJECTIVE: This study aimed to analyse the effect of sleep quality on cognitive function in elderly patients with Alzheimer's disease (AD).

METHODS: This retrospective study extracted clinical data from the hospital's electronic medical record system for elderly patients with AD admitted to the Departments of Neurology or Geriatrics between June 2022 and June 2024. Cognitive function was assessed using the MiniMental State Examination (MMSE), subjective sleep quality was evaluated with the Athens Insomnia Scale (AIS) and objective sleep architecture parameters were measured via overnight polysomnography (PSG). Participants were stratified into mild and moderate-to-severe cognitive impairment groups according to their MMSE scores. General characteristics and sleep-related indicators were compared between the two groups. A binary logistic regression model was employed to analyse independent factors influencing cognitive impairment severity. In this model, cognitive impairment severity served as the dependent variable, and PSG parameters and AIS score served as the core independent variables. Adjustments were made for potential confounding factors, including age, gender, years of education, disease duration, Hospital Anxiety and Depression Scale (HADS) scores and  Instrumental Activities of Daily Living Scale (IADL) scores.

RESULTS: The cohort comprised 61 (40.67%) moderate-to-severe and 89 (59.33%) mild impairment patients. Compared with the mild impairment group, the moderate-to-severe group showed significantly poorer subjective (higher AIS) and objective sleep profiles, including reduced total sleep time, efficiency, and N2/N3 sleep and increased N1 sleep, latency and awakenings (p < 0.05). Adjusted regression identified the N3 stage/total sleep time ratio as a protective factor (odds ratio [OR] = 0.720, 95% CI: 0.576-0.900, p = 0.004) and the AIS score (OR = 1.850, 95% CI: 1.405-2.434, p < 0.001) and number of awakenings (OR = 3.101, 95% CI: 1.879-5.116, p < 0.001) as independent risk factors.

CONCLUSION: In elderly patients with AD, impaired objective sleep architecture and subjective insomnia are significantly associated with poor cognitive function. This study highlighted sleep parameters as potential indicators for cognitive status assessment.},
}

Humans
Male
Female
*Alzheimer Disease/complications/physiopathology/psychology
Aged
Retrospective Studies
*Sleep Quality
Aged, 80 and over
*Cognition/physiology
*Cognitive Dysfunction/physiopathology
Polysomnography
Severity of Illness Index

@article {pmid42023459,
year = {2026},
author = {Zhou, H and Liu, Y and Li, K and Mou, S and Cao, X and Chen, Q},
title = {The Role of Exosome-miRNA as Biomarkers of Alzheimer's Disease: A Systematic Review of Case-Control and Longitudinal Studies.},
journal = {Actas espanolas de psiquiatria},
volume = {54},
number = {2},
pages = {556-567},
doi = {10.62641/aep.v54i2.2109},
pmid = {42023459},
issn = {1578-2735},
mesh = {Humans ; *Alzheimer Disease/diagnosis/genetics/blood ; *Exosomes/genetics/metabolism ; *MicroRNAs ; Biomarkers/blood ; Case-Control Studies ; Longitudinal Studies ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and its diagnosis emains challenging. Exosomal microRNAs (miRNAs), due to their stability, tissue specificity, and ability to cross the blood-brain barrier, show significant promise as ideal biomarkers for AD. The present study aimed to systematically elucidate the relationship between the exosomal miRNA expression changes and AD pathogenesis (including Aβ deposition, Tau protein phosphorylation, and neuroinflammation) and to evaluate their potential utility in clinical screening and therapeutic interventions. A systematic literature search was conducted in the PubMed and Web of Science databases to identify human case-control or cohort studies reporting expressions of mature exosomal miRNAs in the serum, plasma, cerebrospinal fluid, saliva, or central nervous system cells. After evaluating the quality of the studies using the National Institutes of Health quality assessment tool, the identified differentially expressed miRNAs were summarized and functionally integrated. Among the 390 screened records, 48 studies (n = 3046 AD patients) met the inclusion criteria. The analysis identified 120 exosomal miRNAs that are differentially expressed at different AD ages. Six miRNAs (miR-125b, miR-146a, miR-193b, miR-185-5p, miR-29b/c, miR-21-5p) were most consistently reported and showed significant correlation with AD pathology.},
}

Humans
*Alzheimer Disease/diagnosis/genetics/blood
*Exosomes/genetics/metabolism
*MicroRNAs
Biomarkers/blood
Case-Control Studies
Longitudinal Studies

@article {pmid42023593,
year = {2026},
author = {Li, Z and Chen, X and Liu, J and Mo, S and Yu, Y and Sun, Z and Gao, X and Su, D},
title = {Combining Engineered Probe Library with Tiered Screening for the Rational Discovery of Alzheimer's Diagnostic Probe with an Enhanced Signal-to-Noise Ratio.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c00088},
pmid = {42023593},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is neuropathologically defined by the deposition of β-amyloid (Aβ) plaques, a key diagnostic biomarker. However, current fluorescence probes targeting Aβ plaques are often limited by poor blood-brain barrier (BBB) penetration and short blood circulation half-lives, resulting in insufficient signal-to-noise ratios for in vivo imaging. To address this, we developed a rationally engineered near-infrared (NIR) fluorescent molecular probe library and implemented a tiered, closed-loop screening strategy for the discovery of probes, enabling high-fidelity in situ visualization of Aβ plaques. Through this integrated approach, we identified ADFP-2, which displays a high binding affinity for Aβ aggregates and exhibits a 34-fold fluorescence enhancement upon binding. Notably, ADFP-2 demonstrates optimal BBB penetrability and a prolonged circulation time, facilitating high-contrast in vivo imaging of Aβ deposits. This study not only provides a potent molecular tool for the early diagnosis of AD but also validates a systematic and efficient framework for probe discovery and optimization through engineered libraries and tiered screening.},
}

@article {pmid42023629,
year = {2026},
author = {Li, Y and Li, S and Ma, J and Zhao, J and Ning, N and Sun, J},
title = {The role of synaptic plasticity in Alzheimer's disease: from molecular mechanisms to therapeutic targets.},
journal = {Folia neuropathologica},
volume = {64},
number = {1},
pages = {1-11},
doi = {10.5114/fn.2025.156508},
pmid = {42023629},
issn = {1509-572X},
mesh = {*Alzheimer Disease/physiopathology/pathology/metabolism/therapy ; Humans ; *Neuronal Plasticity/physiology ; Animals ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by a complex pathophysiology, involving abnormal aggregation of amyloid b (Ab) and tau proteins, neuroinflammatory responses, and significant synaptic dysfunction, which collectively contribute to cognitive decline. This review offers a novel perspective by focusing on the pivotal role of synaptic plasticity in the pathogenesis of AD, underscoring its potential as a therapeutic target. The study uniquely synthesizes current molecular and clinical research to illustrate how Ab and tau pathologies disrupt synaptic signaling and structure, further exacerbated by neuroinflammation. We explore both pharmacological interventions, such as BACE1 inhibitors and tau stabilizers, and non-pharmacological strategies, including cognitive therapy and neuromodulation techniques, which have shown promise in modulating synaptic plasticity and slowing cognitive deterioration. Despite these advancements, the field faces significant challenges, including the complexity of AD's underlying mechanisms and limitations in early diagnosis. This review not only highlights the significance of synaptic plasticity in AD but also proposes future research directions that could lead to innovative therapeutic approaches, offering new hope for effective treatment strategies.},
}

*Alzheimer Disease/physiopathology/pathology/metabolism/therapy
Humans
*Neuronal Plasticity/physiology
Animals
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42023673,
year = {2026},
author = {Shofner, S and Morgan, K and Luu, P and Shusterman, R and Doncov, A and Heys, J and Ray, L and Lim, MM and Tucker, D},
title = {tES Synchronization of Slow Oscillations in N3 Sleep Decreases Brain Electrical Impedance: Implications for Improved Brain Waste Clearance.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsag079},
pmid = {42023673},
issn = {1550-9109},
abstract = {The age-related impairment of glial-lymph (glymphatic) mechanisms for brain waste clearance has been suspected as a causal factor in the accumulation of toxic metabolites, including amyloid beta and tau proteins in Alzheimer's Disease and alpha synuclein in Parkinson's Disease and Lewy Body Dementia. Because electrical current at low frequencies flows preferentially through extracellular space (ECS), measures of brain electrical impedance may track changes over time in ECS as a function of CSF dynamics that are important to brain waste clearance in sleep. We applied a single-frequency measure of electrical impedance in a study of transcranial electrical stimulation (tES) to enhance deep N3 sleep in healthy adults, using a novel method for estimating the intracranial impedance compartment through separately estimating and subtracting the electrode-skin impedance. The results suggest that, regardless of tES, brain impedance slowly decreases over the course of the night's sleep versus waking, with a marked decrease in REM. Furthermore, the therapeutic tES protocol (applied to synchronize and enhance slow oscillations of N3) resulted in significant brain impedance decreases in the transition from N2 to N3 (as well as in REM), consistent with the fast MRI evidence of respiration-linked CSF inflow at these intervals.},
}

@article {pmid42023677,
year = {2026},
author = {González, KA and Tarraf, W and Pa, J and Banks, SJ and Bangen, KJ and Galasko, D and Gallo, LC and Stickel, AM and Anita, NZ and Márquez, F and Filigrana, P and Isasi, CR and Daviglus, M and Testai, FD and Lamar, M and DeCarli, C and González, HM},
title = {Diabetes, hyperglycemia, and ATN blood biomarkers in Hispanic/Latino populations: SOL-INCA study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71223},
doi = {10.1002/alz.71223},
pmid = {42023677},
issn = {1552-5279},
support = {R01AG075758/AG/NIA NIH HHS/United States ; R56AG048642/AG/NIA NIH HHS/United States ; RF1AG054548/AG/NIA NIH HHS/United States ; RF1AG061022/AG/NIA NIH HHS/United States ; //National Science Foundation Graduate Research Fellowship Program/ ; //National Heart, Lung and Blood Institute/ ; HHSN268201300001I / N01-HC-65233//University of North Carolina/ ; HHSN268201300004I / N01-HC-65234//University of Miami/ ; HHSN268201300002I/N01-HC-65235//Albert Einstein College of Medicine/ ; HHSN268201300003I / N01- HC-65236//University of Illinois at Chicago/ ; HHSN268201300005I / N01-HC-65237//San Diego State University/ ; /MD/NIMHD NIH HHS/United States ; /DE/NIDCR NIH HHS/United States ; /DC/NIDCD NIH HHS/United States ; /NS/NINDS NIH HHS/United States ; /DK/NIDDK NIH HHS/United States ; //Office of Dietary Supplements/ ; },
mesh = {Humans ; Biomarkers/blood ; Male ; Female ; *tau Proteins/blood ; *Hispanic or Latino/statistics & numerical data ; *Amyloid beta-Peptides/blood ; *Diabetes Mellitus/blood/ethnology ; Neurofilament Proteins/blood ; Aged ; Middle Aged ; *Hyperglycemia/blood/ethnology ; Glycated Hemoglobin/metabolism ; Glial Fibrillary Acidic Protein/blood ; Peptide Fragments/blood ; White ; },
abstract = {INTRODUCTION: Research studying associations between plasma amyloid-tau-neurodegeneration (ATN) biomarkers and vascular factors, such as diabetes, is limited. We sought to examine associations between diabetes status and plasma ATN biomarkers in diverse Hispanic/Latino individuals.

METHODS: We used data from the Hispanic Community Health Study/Study of Latinos and the Study of Latinos-Investigation of Neurocognitive Aging ancillary studies. Our exposures included diabetes status and hemoglobin A1c (HbA1c) percentage. Outcomes included amyloid beta (Aβ) 42/40 ratio, phosphorylated tau 181 (p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP).

RESULTS: The final analytic sample was N = 6264. Diabetes, but not prediabetes, was associated with higher NfL and p-tau181 and lower Aβ42/40 ratio. Elevated HbA1c percentage was associated with higher NfL, p-tau181, and GFAP and lower Aβ42/40.

DISCUSSION: Diabetes was associated with plasma biomarkers of Alzheimer's disease pathology and non-specific neurodegeneration. Reducing diabetes prevalence could be beneficial for lowering dementia risk in this population.},
}

Humans
Biomarkers/blood
Male
Female
*tau Proteins/blood
*Hispanic or Latino/statistics & numerical data
*Amyloid beta-Peptides/blood
*Diabetes Mellitus/blood/ethnology
Neurofilament Proteins/blood
Aged
Middle Aged
*Hyperglycemia/blood/ethnology
Glycated Hemoglobin/metabolism
Glial Fibrillary Acidic Protein/blood
Peptide Fragments/blood
White

@article {pmid42024020,
year = {2026},
author = {Chun, H and Lee, HW and Hong, SB and Ha, SS and Yoon, KJ},
title = {Home-based transcranial photobiomodulation improves cognitive function in mild cognitive impairment due to Alzheimer's disease: A randomized, double-blind, placebo-controlled confirmatory trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443973},
doi = {10.1177/13872877261443973},
pmid = {42024020},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder in which early bioenergetic dysfunction is increasingly implicated in its pathogenesis. Transcranial photobiomodulation (tPBM), a non-invasive neuromodulation using near-infrared light, has shown promise in improving cerebral metabolism and cognitive function.ObjectiveTo assess the safety and efficacy of a home-administered tPBM intervention in individuals with mild cognitive impairment (MCI) due to AD.MethodsIn this randomized clinical trial, 80 participants meeting the NIA-AA criteria for MCI due to AD were recruited. Participants self-administered a tPBM device emitting 808 nm near-infrared light over the bilateral dorsolateral prefrontal cortex, six times weekly for 12 weeks. The primary outcome was the change in MoCA-K score from baseline to week 13. Secondary outcomes included K-MMSE2, CERAD-K, and GDepS scores.ResultsActive tPBM significantly improved cognitive performance compared with the placebo. Mean MoCA-K scores increased by 3.87 ± 2.51 points in the active group versus a 0.74 ± 2.85 point decline in the placebo group (p < 0.001). K-MMSE2 scores improved significantly (p < 0.001). CERAD-K showed a significant between-group difference at week 13 (p < 0.001), while GDepS scores remained unchanged. No device-related adverse events occurred, and adherence to home-based treatment was high.Conclusions12 weeks of home-administered tPBM safely and significantly improved cognitive function in individuals with MCI due to AD. The observed benefits are consistent with enhanced mitochondrial metabolism, cerebral perfusion, and synaptic efficiency. These findings support tPBM as a promising, non-pharmacological treatment for MCI due to AD and as a preventative strategy against AD.Trial RegistrationKorean Clinical Research Information Service (CRiS), https://cris.nih.go.kr, KCT0011155.},
}

@article {pmid42024038,
year = {2026},
author = {Horakova, H and Jester, DJ and Vohradkova, T and Sheardova, K and Ondrej, J and Matuskova, V and Fendrych Mazancova, A and Nikolai, T and Andel, R and Lerch, O and Laczó, J and Hort, J and Vyhnalek, M},
title = {Evaluating self- and informant-reported complaints as predictors of cognitive progression in subjective cognitive decline: A clinically-based evaluation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443656},
doi = {10.1177/13872877261443656},
pmid = {42024038},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive complaints (SCCs) in cognitively normal older adults are associated with increased dementia risk. However, it remains uncertain which complaints best predict cognitive decline and whether predictive value differs between patient and informant reports.ObjectiveTo examine associations between self- and informant-reported total scores and individual items from the Questionnaire of Cognitive Complaints (QPC) and longitudinal cognitive decline in individuals with subjective cognitive decline (SCD).Methods261 individuals with SCD from the prospective Czech Brain Aging Study were followed longitudinally (mean 4.2-year follow-up). Linear mixed-effects models (random intercepts), adjusted for age, sex, and education, were estimated separately for self- and informant-reported QPC-total scores and for individual QPC-items to examine associations with change over time in global cognition, memory, and executive function/processing speed cognitive composites.ResultsHigher QPC-total scores predicted steeper decline across all cognitive composites in both self- and informant-reports, with modest effects. At the item level, after Bonferroni correction, informant-reported impressions of memory change and worse memory compared with peers were associated with a more pronounced decline across all cognitive composites exceeding the predictive value of the QPC-total score. Several other memory- and non-memory-related complaints showed associations in the same direction but did not consistently remain significant after correction.ConclusionsIn older adults with SCD, focusing on specific SCCs, particularly informant-reported memory complaints, rather than relying solely on global SCC score, allows more targeted identification of individuals whose complaints are most consistently associated with longitudinal cognitive decline. Structured assessments integrating informant perspective may improve early risk stratification.},
}

@article {pmid42024046,
year = {2026},
author = {Rodriguez-Reyes, RF and Guo, H and Luongo, M and Gomez-Isaza, L and Pletnikova, O and Troncoso, JC and Morris, M},
title = {Amyloid plaques associated with shift in patterns of hippocampal tau pathology in middle age.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443643},
doi = {10.1177/13872877261443643},
pmid = {42024046},
issn = {1875-8908},
abstract = {BackgroundTau pathology begins to accumulate in the medial temporal lobe in many individuals in middle age. Some individuals develop amyloid pathology, more advanced tau pathology (Braak stage), and higher levels of CA1 hippocampal tau pathology in the context of Alzheimer's disease. Others never develop significant amyloid pathology; in these cases, hippocampal tau pathology can be CA2-predominant and tends not to accumulate past intermediate stages. But factors associated with the early formation of these tau patterns is unclear.ObjectiveThe objective of this study is to examine demographic, genetic (APOE), and pathologic factors associated with the emergence of hippocampal tau pathology patterns in middle age.MethodsWe identified 89 individuals with hippocampal tau pathology ages 65 and younger. These cases were assessed for tau stage, amyloid plaques, and APOE4 status. Hippocampal tau pathology in CA1 and CA2 was scored semi-quantitatively.ResultsIn a younger aging population, tau pathology initially deposits at low levels in CA1 and CA2. In the presence of amyloid, tau pathology is increased in both CA1 and CA2, but with a shift toward a greater proportion of cases with higher tau pathology in CA1.ConclusionsPatterns of tau pathology in middle age are strongly associated with amyloid plaques, including increased CA1 and CA2 pathology and a greater proportion of CA1-predominant cases. In the absence of amyloid, tau pathology shows a normal (Gaussian) distribution between CA1 and CA2. These tau pathology distributions at younger ages are similar to the patterns seen at older ages in AD and PART.},
}

@article {pmid42024081,
year = {2026},
author = {Song, JH and Kim, HJ and Son, M and Kim, HR and Kim, SH and Kim, HS},
title = {The association between hemoglobin level and risk of developing dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443702},
doi = {10.1177/13872877261443702},
pmid = {42024081},
issn = {1875-8908},
abstract = {BackgroundHemoglobin levels are key indicators of health and may be associated with dementia risk. This study examined this association in a Korean population, stratified by sex.ObjectiveThis study aimed to evaluate the association between hemoglobin levels and the incidence of all-cause and subtype-specific dementia in a nationwide Korean cohort and to determine whether these associations differed by sex.MethodsFrom the National Health Insurance Service-National Health Screening Cohort, 316,542 adults aged ≥40 years were followed from 2004-2005 until 2019. Hemoglobin levels were divided into sex-specific quintiles. Dementia was defined by International Classification of Diseases, 10th Revision codes and prescriptions for anti-dementia medications. Risks of all-cause, Alzheimer's, and vascular dementia were analyzed using Cox proportional hazards models.ResultsCompared to the reference group (4th quintile), both the lower and higher hemoglobin quintiles were associated with an increased all-cause dementia risk (adjusted HR 1.16 [95% CI, 1.11-1.22] for Q1 and 1.07 [95% CI, 1.02-1.13] for Q5). Alzheimer's risk rose only in the lower quintiles, while vascular dementia risk rose at both extremes. These associations were stronger in women.ConclusionsAbnormal hemoglobin levels, particularly in women, were linked to an increased risk of dementia. Managing hemoglobin levels and correcting anemia may help prevent dementia.},
}

@article {pmid42024083,
year = {2026},
author = {Ye, Z and Zai, A and Wang, B and Bennett, A and Guilarte-Walker, YG and Wong, K and Zai, AH and Erban, S and Lin, H},
title = {Leveraging routine clinical data for dementia risk prediction using machine learning.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443945},
doi = {10.1177/13872877261443945},
pmid = {42024083},
issn = {1875-8908},
abstract = {BackgroundEarly diagnosis of dementia is essential for enabling timely interventions that may slow disease progression, improve patient outcomes, and reduce healthcare costs. This study aims to develop machine learning models to predict dementia risk using longitudinal electronic health record (EHR) data.ObjectiveThis research aims to develop and evaluate machine learning models for dementia risk prediction using longitudinal EHR data from routine clinical care and to identify key clinical features associated with elevated dementia risks.MethodsWe conducted an incidence-based case-control study using EHR data from the UMass Memorial Health system (2017-2024) to develop a dementia risk prediction model.ResultsThis study included 5622 dementia cases and 44,976 controls. The XGBoost model achieved the highest AUC (0.802), with top predictors included thyroid-stimulating hormone (TSH), vitamin B12, and HDL cholesterol. Model performance was consistent across sexes and remained robust in multiple sensitivity analyses.ConclusionsMachine learning models that integrate comorbid conditions and longitudinal laboratory test patterns show their potential in predicting dementia risk. These findings highlight the promise of routinely collected EHR data as a scalable, low-cost resource for identifying individuals at elevated risk for dementia.},
}

@article {pmid42024084,
year = {2026},
author = {Xie, M and Niu, X and Sun, F and Shi, L},
title = {Transcriptome-based identification and experimental validation of a key gene in Alzheimer's disease using dermal fibroblasts.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443968},
doi = {10.1177/13872877261443968},
pmid = {42024084},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by progressive cognitive impairment and neuronal damage. The pathogenesis of AD is complex and involves multiple pathological processes. Currently, effective methods for early diagnosis and treatment are lacking.ObjectiveTo identify key pathogenic genes and investigate their roles in Alzheimer's disease, we analyzed transcriptomic data from dermal fibroblasts of AD patients, aiming to assess their potential as novel biomarkers and therapeutic targets.MethodsTranscriptomic data from AD patient and control-derived dermal fibroblasts (DFs) were analyzed to identify differentially expressed genes. Key genes were screened using bioinformatics and a random forest algorithm. ceRNA analysis was performed to explore miRNA-mRNA interactions. The candidate gene SRSF5 was validated via overexpression and knockdown, followed by qPCR, western blotting, and reactive oxygen species (ROS) assays. The role of SRSF5 in endoplasmic reticulum (ER) stress was evaluated by measuring ER stress markers and cellular stress responses.ResultsTranscriptomic analysis revealed significant upregulation of SRSF5 in AD DFs. ceRNA analysis identified miRNAs regulating SRSF5 in AD. Overexpression of SRSF5 led to reduced neuronal proliferation, increased apoptosis, elevated ROS levels, and activation of ER stress markers (CHOP, GRP78, XBP1). SRSF5 knockdown alleviated these effects.ConclusionsSRSF5 may drive AD pathogenesis via ER and oxidative stress, serving as a potential biomarker and therapeutic target for early diagnosis and intervention.},
}

@article {pmid42024087,
year = {2026},
author = {Peck, MR and Chapman, JE and Hill, T and Quinn, K and Ikiz, ED and Lopez, A and Hascup, ER and Bae, C and Hascup, KN},
title = {D-methionine improves spatial navigation and attenuates oxidative stress and amyloid pathology in a sex-specific manner.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444307},
doi = {10.1177/13872877261444307},
pmid = {42024087},
issn = {1875-8908},
abstract = {BackgroundOxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimer's disease (AD) and represent therapeutic targets beyond amyloid-centered approaches.ObjectiveTo determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD models.MethodsMale and female APP/PS1 and APP[NL-F] mice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic, and inflammatory markers, and hippocampal microglial phenotypes were evaluated.ResultsD-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APP[NL-F] mice. APP[NL-F] males exhibited improved Morris water maze learning. Amyloid pathology was region-specifically reduced, including decreased hippocampal plaque size in male APP[NL-F] mice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-β (Aβ)42 in male APP/PS1 mice. Lipid peroxidation was reduced only in female APP[NL-F] mice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue IL-6 expression in female APP[NL-F] mice. In the hippocampus, D-Met decreased microglial activation, with female APP[NL-F] mice showing reduced Iba1 and disease-associated microglial markers and increased Axl expression.ConclusionsShort-term D-Met acts as a metabolic and redox modulator with amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APP[NL-F] mice.},
}

@article {pmid42024089,
year = {2026},
author = {Lazaar, N and Rirash, AF and Papma, JM and Mattace Raso, FUS and Franzen, S},
title = {Beliefs, barriers, and behaviors: Exploring dementia prevention perspectives in culturally diverse populations in The Netherlands.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443983},
doi = {10.1177/13872877261443983},
pmid = {42024089},
issn = {1875-8908},
abstract = {BackgroundModifiable risk factors play a key role in preventing or delaying dementia, yet little is known about how culturally diverse populations in Europe perceive these risk factors.ObjectiveThis study aimed to: (1) explore lay perceptions of dementia and its risk factors, and (2) examine how these perceptions interact with social and structural determinants of health to shape dementia prevention behaviors.MethodsWe conducted a qualitative study guided by the I-Change model, using semi-structured interviews with 20 adults varying in cultural and linguistic background, education, and age. Interviews were conducted in Dutch, English, and Moroccan-Arabic (Darija), translated if needed and transcribed verbatim. Data analysis followed open, axial, and selective coding to identify themes.ResultsParticipants emphasized genetics and biological vulnerability over modifiable risk factors when discussing dementia risk. Socioeconomic status, physical ability, and (social) environment were perceived to shape opportunities for healthy aging. Peers, family, and cultural norms were both facilitators and barriers to health-promoting behaviors. Lived- and observed experiences of illness motivated general behavior change, not specifically linked to dementia and Alzheimer's disease. Stress, sleep, resilience, and discipline were viewed as influential for cognitive health. Participants often integrated personal, cultural, and social perspectives when interpreting dementia risk.ConclusionsPerceptions of dementia and Alzheimer's disease risk among culturally diverse individuals are shaped by biological beliefs, psychosocial influences, and social context. Knowledge of dementia and modifiable risk factors remains limited among minoritized populations. Public health initiatives might benefit from incorporating prevention messages in a community perspective to enhance engagement and motivation.},
}

@article {pmid42024093,
year = {2026},
author = {Levine, TF and Mashinchi, GM and Rodrigues, J and Cross, CL and Caldwell, JZK and , },
title = {Effect of sex on trajectories of verbal learning and memory and clinical symptoms in diverse Alzheimer's disease cohorts.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444759},
doi = {10.1177/13872877261444759},
pmid = {42024093},
issn = {1875-8908},
abstract = {BackgroundWomen continue to demonstrate a verbal learning and memory advantage compared to men even in the earliest stages of Alzheimer's disease (AD). However, the literature on sex differences in longitudinal AD trajectories is sparse, particularly in ethnically diverse samples.ObjectiveTo examine sex differences in verbal learning and memory, as well as clinical symptoms, in clinically normal non-Hispanic white (NHW) and Hispanic/Latino (HL) cohorts longitudinally.MethodsWe examined longitudinal sex effects on verbal learning and memory (Spanish-English Verbal Learning Test) and clinical symptoms (Clinical Dementia Rating Scale-Sum of Boxes) in NHW (n = 529) and HL (n = 439) participants with available AD biomarkers (plasma Aβ42/Aβ40 and hippocampal volume) who were clinically normal at baseline and completed follow-up assessment 18-24 months later.ResultsIn both cohorts, women demonstrated higher verbal learning and memory scores at baseline (ps < 0.001). In the NHW cohort, longitudinal sex differences were observed in verbal learning and memory, with women maintaining performance over time, whereas men's performance declined (p = 0.071 and p = 0.020, respectively). In the HL cohort, longitudinal sex differences were observed in clinical symptoms, with men demonstrating greater decline than women (p = 0.033). Trajectories of decline did not significantly differ between ethnic cohorts. AD biomarkers did not moderate observed effects.ConclusionsThis study highlights the potential impact of ethnicity on sex-based differences in cognitive decline in older adulthood. Future work is needed to determine best practices for tracking progression along the AD continuum, particularly within the preclinical phase.},
}

@article {pmid42024094,
year = {2026},
author = {Ye, Z and Teng, B and Wang, S and Zhu, J and Chen, J and Zhang, B and Cai, H and Wei, R and Li, B and Xie, X and Yu, X and Li, J and Huang, S and Weng, Y and Yang, D and , },
title = {Association of inflammation-related plasma proteins with vascular cognitive burden and Alzheimer's disease: A multi-method study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443713},
doi = {10.1177/13872877261443713},
pmid = {42024094},
issn = {1875-8908},
abstract = {BackgroundInflammation is implicated in the pathogenesis of dementia. However, its role in the vascular cognitive burden and the clinical stage of Alzheimer's disease (AD) remains controversial.ObjectiveThis study aimed to explore the association of plasma inflammatory proteins with vascular cognitive burden and clinical stage of AD by using a multi-method approach.MethodsWe included 330 individuals with complete plasma protein profiles, Hachinski Ischemia Scale scores, and cognitive function status between September 13, 2005, and October 24, 2007. We employed generalized linear models, restricted cubic splines, and the inverse variance weighting (IVW) method for two-sample Mendelian randomization (MR) to investigate the correlation between inflammatory biomarkers and dementia. We employed the random forest algorithm to build predictive models and utilized SHapley Additive exPlanations (SHAP) analysis for feature importance and interpretability.ResultsAD clinical stage exhibited significant associations with cortisol, C-peptide, tumor necrosis factor receptor-2 (TNFR-2) and interleukin-16 (IL-16, all p < 0.05). Similarly, the vascular cognitive burden was significantly correlated with C-peptide, carcinoembryonic antigen and TNFR-2 (all p < 0.05). These observational findings were corroborated by SHAP analysis. Subsequent MR analysis further revealed a weak negative causal relationship between AD and IL-16 (pIVW = 0.003; ORIVW = 0.981; 95% CI: 0.969-0.994).ConclusionsOur study identified several inflammatory proteins correlated with the vascular cognitive burden and AD clinical stage, providing exploratory evidence for future mechanistic and interventional research.},
}

@article {pmid42024095,
year = {2026},
author = {Kermel-Schiffman, I and Lifshitz, R and Carmel, S and Bachner, YG},
title = {Attitudes of older adults toward active euthanasia in advanced Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444353},
doi = {10.1177/13872877261444353},
pmid = {42024095},
issn = {1875-8908},
abstract = {BackgroundActive euthanasia by physicians involves administering a substance that directly causes a patient's death. In Alzheimer's disease, progressive cognitive decline and increasing dependence raise complex ethical and emotional dilemmas. Although legalized in some countries, active euthanasia remains controversial, with public attitudes shaped by multiple factors, particularly in advanced disease stages.ObjectiveThis study examined older adults' attitudes toward active euthanasia in advanced Alzheimer's disease from three perspectives: toward themselves, a family member, and an unknown individual. It also explored associations between sociodemographic and psychosocial variables and these attitudes.MethodsA quantitative study was conducted with 501 individuals aged 75+, recruited through day centers and snowball sampling. Attitudes were measured using hypothetical cases involving euthanasia decisions for oneself, a family member, and an unknown individual. Variables included self-efficacy, will to live, desire to prolong life, life satisfaction, fear of death, social support, and sociodemographic characteristics. Analyses employed mean comparisons and hierarchical linear regression models.ResultsParticipants reported the most favorable attitudes toward euthanasia when considering themselves (M = 3.61), followed by a family member (M = 3.22), with the least favorable attitudes expressed toward an unknown individual (M = 2.86). Lower desire to prolong life and higher self-efficacy predicted more positive attitudes across all cases, while lower will to live was positively associated only in personal and familial contexts. Female gender, higher education, and lower religiosity were linked to more favorable attitudes across all contexts.ConclusionsSociodemographic and personality characteristics should be considered when developing strategies aimed at increasing public awareness of active euthanasia, especially among older adults.},
}

@article {pmid42024098,
year = {2026},
author = {Pizzoni, L and Piero, AD and Blasutto, B and Casagrande, M and Piccardi, L and Guariglia, C},
title = {Accelerated long-term forgetting in Alzheimer's disease continuum: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443537},
doi = {10.1177/13872877261443537},
pmid = {42024098},
issn = {1875-8908},
abstract = {BackgroundAccelerated long-term forgetting (ALF), the disproportionate loss of information over days or weeks despite normal performance at standard delays, has been proposed as an early cognitive marker of Alzheimer's disease (AD).ObjectiveProvide a qualitative and quantitative synthesis of current evidence on ALF across the AD continuum.MethodsWe performed a systematic review and meta-analysis following the PRISMA 2020 guidelines. Eligible studies evaluated episodic memory with delays of at least 1 h in participants across the AD continuum compared to healthy controls. Risk of bias was assessed using the Joanna Briggs Institute (JBI) tools, and pooled effect sizes (Hedges' g) were calculated for delays of 1 day, 1 week, and 1 month or longer.ResultsTwenty-eight studies (n = 1399) were included; 16 entered quantitative analyses. The 1-day effect was nonsignificant (g = 0.55, 95% CI -0.03-1.12). At 1 week, ALF effect was robust (g = 0.63, 95% CI 0.40-0.87; I[2] = 0%) and evident in at-risk groups (g = 0.61, 95% CI 0.37-0.86) despite intact early retention. Both verbal (g = 0.74) and non-verbal (g = 0.53) tasks, as well as recall (g = 0.61) and recognition (g = 0.70), showed similar sensitivity. Effects persisted at ≥1 month but weakened in at-risk groups.ConclusionsALF is strongly detected in the preclinical stage of AD, especially at a 1-week delay across different materials and retrieval methods. Long-delay memory tests may enhance the sensitivity of neuropsychological assessments for detecting early cognitive issues in the early stages of the AD continuum.},
}