@article {pmid42525357,
year = {2026},
author = {Sklinda, K and Bocianski, J and Budlewski, T and Kobylecka, M and Dorobek, M and Gorecki, A and Mruk, B and Błaszczak, M and Walecki, J},
title = {Perfusion as a biomarker of brain dysfunction in dementia (AD, DLB, FTD/PPA, PDD): comparison of CT, MRI (ASL/DSC/DCE), SPECT, and PET with interpretive pitfalls - a narrative review.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42525357},
issn = {2240-2993},
abstract = {The term 'brain perfusion' is applied in clinical practice to a family of neuroimaging techniques that measure, in reality, quite different physiological quantities in the brain circulation. CT perfusion (CTP) and DSC-MRI track a contrast bolus to derive semi-quantitative haemodynamic parameters. ASL-MRI estimates cerebral blood flow (CBF) without contrast, but the result is sensitive to arterial transit time, haematocrit, and the patient's haemodynamic state on the day of the scan. DCE-MRI quantifies blood-brain barrier (BBB) permeability, a property of the neurovascular unit rather than a flow measurement. Perfusion SPECT provides a relative, normalisation-dependent CBF map that is distorted by cortical atrophy. [[18]F]FDG-PET reflects synaptic glucose metabolism, but not blood flow. Because these techniques answer different physiological questions, their results are not interchangeable, and applying a threshold or pattern derived from one modality to interpret another is methodologically unsound - yet this conflation occurs with regularity in clinical practice. This narrative review synthesises the clinical applications, diagnostic performance, and interpretive pitfalls of each technique in Alzheimer's disease (AD)/mild cognitive impairment (MCI-AD), dementia with Lewy bodies (DLB)/Parkinson's disease dementia (PDD), frontotemporal dementia (FTD)/primary progressive aphasia (PPA), and mixed dementia with vascular pathology. Recognised limitations include the narrative study design and the small number of head-to-head multi-modal studies in pathologically confirmed cohorts. A comparative table and practical minimum reporting elements are provided.},
}

@article {pmid42525901,
year = {2026},
author = {Zheng, J and Lip, GYH and Zhang, Z and Lee, SWR},
title = {Association of Sugar Restriction in Utero Through Age 2 Years on Dementia Risk Later in Life.},
journal = {Neurology},
volume = {107},
number = {4},
pages = {e218313},
doi = {10.1212/WNL.0000000000218313},
pmid = {42525901},
issn = {1526-632X},
mesh = {Humans ; Female ; *Dementia/epidemiology/etiology/diagnostic imaging ; *Prenatal Exposure Delayed Effects/epidemiology ; Pregnancy ; Male ; Middle Aged ; United Kingdom/epidemiology ; Developmental Origins of Health and Disease ; Risk Factors ; Dementia, Vascular/epidemiology ; Magnetic Resonance Imaging ; Alzheimer Disease/epidemiology ; Brain/diagnostic imaging ; Aged ; Adult ; Infant ; },
abstract = {BACKGROUND AND OBJECTIVES: Excess sugar intake in early life may affect long-term brain health, but evidence for dementia is limited. We used the abrupt end of UK sugar rationing in September 1953 as a natural experiment to test whether exposure to sugar rationing during different windows within the first 1,000 days from conception was associated with adult risk of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD).

METHODS: We analyzed UK Biobank participants born around the end of UK sugar rationing. Exposure was classified as rationing in utero only, in utero plus the first year of life, in utero plus 1-2 years of life, or no exposure. Incident dementia was identified from linked ICD-10 records. MRI of the brain and cognitive function were assessed in the imaging subcohort. Adjusted Cox and Gompertz models estimated HRs and 95% CIs, Fine-Gray models accounted for competing risk, and mediation analyses evaluated type 2 diabetes and hypertension.

RESULTS: Among 64,737 participants included in the analysis, the mean age at recruitment was 54.6 years, and 56.4% were women; 40,963 were exposed to sugar rationing during fetal and/or early-childhood life, and 23,774 were unexposed. Compared with unexposed individuals, sugar rationing in utero plus the first year of life was associated with lower hazards of all-cause dementia (HR, 0.79; 95% CI 0.66-0.94) and AD (HR, 0.77; 95% CI 0.59-1.00). Similar or slightly stronger associations were observed for exposure in utero plus 1-2 years (all-cause dementia: HR, 0.77; 95% CI 0.63-0.95; AD: HR, 0.72; 95% CI 0.53-0.98). Exposure in utero plus 1-2 years was associated with delayed onset of all-cause dementia by 2.55 years, AD by 2.87 years, and VaD by 2.49 years. Early-life sugar rationing was also associated with higher total gray matter volume (β, 3.27; 95% CI 0.46-6.07), lower white matter hyperintensity volume (β, -0.64; 95% CI -0.97 to -0.31), and better performance in processing speed and reasoning. Incident type 2 diabetes and hypertension jointly mediated 25.5% of the association.

DISCUSSION: Sugar restriction in the first 1,000 days was associated with lower dementia hazards, delayed onset, and more favorable brain-health profiles. These results support early-life sugar reduction as a potential strategy for dementia prevention.},
}

Humans
Female
*Dementia/epidemiology/etiology/diagnostic imaging
*Prenatal Exposure Delayed Effects/epidemiology
Pregnancy
Male
Middle Aged
United Kingdom/epidemiology
Developmental Origins of Health and Disease
Risk Factors
Dementia, Vascular/epidemiology
Magnetic Resonance Imaging
Alzheimer Disease/epidemiology
Brain/diagnostic imaging
Aged
Adult
Infant

@article {pmid42526376,
year = {2026},
author = {Hu, H},
title = {Interpreting plasma p-tau217 discordance in real-world memory clinics.},
journal = {Journal of the neurological sciences},
volume = {489},
number = {},
pages = {126117},
doi = {10.1016/j.jns.2026.126117},
pmid = {42526376},
issn = {1878-5883},
}

@article {pmid42526554,
year = {2026},
author = {Peng, B and Zou, S and Shi, Y and Zhu, X and Liu, M and Li, H and Zhang, Y},
title = {Fluorescence imaging-based investigation of tau-mediated promotion of U1 small nuclear ribonucleoprotein 70 kDa co-phase separation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153818},
doi = {10.1016/j.ijbiomac.2026.153818},
pmid = {42526554},
issn = {1879-0003},
abstract = {Neurofibrillary tangles formed by Tau protein are a core pathological hallmark of Alzheimer's disease (AD). Although liquid-liquid phase separation (LLPS) of Tau is thought to induce its aggregation, and the basic-acidic dipeptide (BAD) domain-containing protein U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) abnormally co-localizes with Tau tangles in AD brains, the molecular mechanism underlying their co-aggregation remains unclear. In this study, we found that Tau co-phase separates with two low-complexity domains (LC1/LC2). Both LC1 and LC2 promote the gelation of Tau droplets and the formation of pathological Tau aggregates under the conditions tested. Furthermore, under cellular stress, Tau and U1-70K exhibit aberrant cytoplasmic co-localization, suggesting a functional link between them under pathological conditions and providing new insights into the molecular basis of Tau pathology in AD.},
}

@article {pmid42526715,
year = {2026},
author = {Bang, KY and Walenga, R and Chopski, S and Luke, MC and Blinova, K and Zhao, L and Guo, S},
title = {Intranasal drug delivery to the brain for neurodegenerative diseases: Current efforts and challenges in delivery platforms and modeling.},
journal = {Advanced drug delivery reviews},
volume = {},
number = {},
pages = {115938},
doi = {10.1016/j.addr.2026.115938},
pmid = {42526715},
issn = {1872-8294},
abstract = {Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), globally pose a significant challenge with an aging population. Despite the presence of various therapeutic agents, AD and PD treatments with small molecules currently only address the symptoms; certain biologic agents for AD have been approved for their disease-modifying effects, but the risk of intracerebral hemorrhage severely limits their use. Moreover, the bioavailability of orally administered agents in the brain is challenged by the blood-brain barrier, complicating brain-targeted drug development. Extensive efforts are currently underway to develop intranasal platforms with nanoparticles for direct nose-to-brain drug delivery. Additionally, various in vitro designs involving brain organoids, and in vivo models, such as rodents and zebrafish, have been explored to improve the efficiency and accuracy of preclinical models. Efforts to develop sophisticated computational modeling of intranasal drug delivery, including computational fluid dynamics (CFD) deposition and physiologically based pharmacokinetics (PBPK) modeling, also continue to advance the intranasal drug delivery research and potentially improve the feasibility of developing clinically relevant intranasal platforms for neurodegenerative disease.},
}

@article {pmid42527124,
year = {2026},
author = {Li, J and Wang, Y and Shi, L and Zheng, Z and Wu, Y and Jiang, N},
title = {Global Perspectives on Social Relationships and Cognitive Decline in Older Adults: Insights From Cohort Studies in the U.S., Mexico, England, and China.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261470866},
doi = {10.1177/07334648261470866},
pmid = {42527124},
issn = {1552-4523},
abstract = {BackgroundThis research aimed to explore associations between social relationships and annual cognitive decline in older adults globally.MethodsHarmonized data from 4 longitudinal aging cohorts across the U.S., Mexico, England, and China were included. Participants (aged ≥55) with social relationship data and repeated cognitive assessments were analyzed, excluding dementia cases. Linear mixed models assessed associations between social relationship markers and annual rate of cognitive decline, with effects pooled via two-stage random-effects meta-analysis.ResultsAmong 29,805 participants, living with others was associated with slower decline in episodic memory (b = 0.086, 95%CI: 0.013 to 0.158) and global cognition (b = 0.025, 95%CI: 0.013 to 0.038). Felt loneliness was associated with faster decline in episodic memory (b = -0.087, 95%CI: -0.140 to -0.034) and global cognition (b = -0.023, 95%CI: -0.040 to -0.006).ConclusionsGood social relationships were associated with slower cognitive decline, while poor social relationships with faster decline.},
}

@article {pmid42527215,
year = {2026},
author = {Ahmad, M and Irshad, A and Ahmed, MA and Ahmed, FK and Noor, S and Irshad, H},
title = {Demographic, gender and ethnic disparities in COPD associated mortality trends among older adults (>55 years) with Alzheimer's disease in the United States, 1999-2020: a 20 year retrospective analysis using CDC WONDER database.},
journal = {Journal of the National Medical Association},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jnma.2026.06.021},
pmid = {42527215},
issn = {1943-4693},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the 3rd leading cause of global deaths. COPD and AD have a bi-directional positive relationship, increasing the interrelated mortality.

OBJECTIVES: To analyze the mortality trends associated with COPD in Alzheimer's disease among older adults (>55 years of age) in the United States, using CDC WONDER data from 1999 to 2020.

METHODS: A retrospective analysis using the CDC WONDER database was conducted to analyse the mortality trends due to COPD in Alzheimer's disease patients, stratified by sex, race/ethnicity, census region, states and urbanization status.

RESULTS: A total of 58,495 deaths due to COPD-associated Alzheimer's disease occurred among older adults (aged >55 years). Overall mortality increased from an AAMR of 2.04 per 100,000 in 1999 to 5.19 per 100,000 in 2020 (AAPC=4.31%, p < 0.05). Men exhibited higher mortality than women (AAMR 4.00 vs. 3.58 per 100,000). Non-Hispanic Whites had the highest mortality (AAMR 4.04), followed by Hispanics (AAMR; 2.58) and Non-Hispanic Blacks (AAMR; 2.39). The mortality was highest in the Western region (AAMR; 4.3), followed by Southern region (AAMR; 4.14), Midwestern region (AAMR; 3.94) and least in Northeastern region (AAMR; 2.26). Non-Metropolitan areas exhibit higher AAMR (4.62) than Metropolitan areas (AAMR; 3.52). Tennessee, Kentucky, and Washington were the top 3 states with the highest mortality. Significant increases in mortality were observed across most demographic groups (p < 0.05).

CONCLUSION: These findings highlight the increasing COPD-related mortality among Alzheimer's patients and reveal significant disparities by sex, race, and urbanization status. Systemic inflammation, oxidative stress, and COPD-induced hypoxia may contribute to cognitive impairment and dementia. These results underscore the urgent need for targeted healthcare strategies and further research to address these disparities.},
}

@article {pmid42527300,
year = {2026},
author = {Luppi, JJ and Koomen, AP and Stam, CJ and Scheltens, P and de Haan, W},
title = {Connectome-guided personalization of optimal tDCS intervention selection in Alzheimer's disease: A modeling study.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0407-25.2026},
pmid = {42527300},
issn = {2373-2822},
abstract = {Transcranial direct current stimulation (tDCS) could reduce the neurophysiological effects in Alzheimer's disease (AD), but progress is hampered by variable outcomes across studies, likely related to both methodological and individual differences. We recently described a virtual brain network simulation method for optimizing tDCS interventions and now propose a method for further personalizing this approach. We now personalized the model for 6 female and 4 male biomarker-confirmed AD patients based on their brain structure and functional connectivity, by using individual structural magnetic resonance imaging (MRI) data and amplitude envelope correlation (AEC)-based connectivity matrices extracted from magnetoencephalography (MEG) scans, respectively. We then assessed a set of previously established stimulation strategies based on their ability to improve relevant neurophysiological outcome parameters in each personalized model, while undergoing AD damage. Personalized tDCS strategies were able to delay neurophysiological deterioration, but while the general model favored posterior anodal stimulation targeting the precuneus region, the personalized models favored frontal anodal stimulation targeting the dorsolateral prefrontal cortex (dlPFC) region in 90% of the cases. This may be explained by higher connectivity levels of frontal regions in the personalized connectivity matrices, as anodal stimulation of highly connected regions produced more beneficial effects. In this methodological study we propose several ways to improve personalized computational tDCS stimulation prediction modeling. We conclude that connectome-guided personalization of tDCS effects lead to different strategies with potentially better intervention outcomes. For external validation of this model-guided tDCS approach, model predictions are being tested in an ongoing clinical tDCS-MEG trial in AD patients.Significance statement Our aim is to improve the efficacy of transcranial direct current stimulation (tDCS) in Alzheimer's disease (AD) through the use of a personalized modeling approach. This is beneficial since results of tDCS remain variable across groups, and therefore a systematic approach to choosing the stimulation parameters such as placement of electrodes is required. Modeling of tDCS allows us to do this while assessing multiple possible approaches without necessitating a considerable burden on patients across multiple trials. Furthermore, personalizing the model can enable more accurate selection of target regions for stimulation, for example by locating highly connected brain regions without too much damage in each patient, thus increasing the potential for recovery.},
}

@article {pmid42527361,
year = {2026},
author = {Persson, J and Geffre, G},
title = {Mind Matters: South Dakota's Public Health Response to Dementia.},
journal = {South Dakota medicine : the journal of the South Dakota State Medical Association},
volume = {79},
number = {6},
pages = {262-264},
pmid = {42527361},
issn = {0038-3317},
mesh = {Humans ; South Dakota/epidemiology ; *Dementia/diagnosis/therapy/epidemiology ; *Public Health ; Caregivers ; },
abstract = {Alzheimer's disease and related dementias pose a growing health and societal challenge in South Dakota, where dementia ranks as the fourth leading cause of death. The burden extends beyond patients to families and caregivers, many of whom report significant emotional, financial, and physical strain. In response, the South Dakota Department of Health introduced the South Dakota Healthy Brain Initiative. This statewide effort aims to improve brain health across the lifespan, promote earlier detection, strengthen caregiver support, and prepare the state's workforce to better respond to the needs of people living with dementia. The initiative promotes routine cognitive assessment, distributes clinical toolkits to assist with diagnosis and care planning, and expands access to community-based services. A core focus of the initiative is health equity, particularly for rural, tribal, and underserved communities that face significant barriers to care. Through strengthened partnerships among public health, healthcare systems, and aging services, the Healthy Brain Initiative seeks to reduce disparities, support caregivers, and improve outcomes for individuals and families affected by dementia across South Dakota.},
}

Humans
South Dakota/epidemiology
*Dementia/diagnosis/therapy/epidemiology
*Public Health
Caregivers

@article {pmid42527385,
year = {2026},
author = {Postuma, RB},
title = {Amyloid Co-Pathology and Clinical Heterogeneity of Parkinson's Disease.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70459},
pmid = {42527385},
issn = {1531-8257},
}

@article {pmid42527552,
year = {2026},
author = {Dan, X and Croteau, DL and Liu, W and Chu, X and McDevitt, RA and Robbins, PD and Bohr, VA},
title = {Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42527552},
issn = {1546-1726},
support = {U19 AG056278 and U54 AG079754//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Dysfunctional mitophagy is proposed as a key component of Alzheimer's disease (AD) pathology, yet direct in vivo evidence and mechanistic insights are still lacking. Here we show that AD model mice expressing a mitophagy reporter (APP/PSEN1/mt-Keima) develop large accumulation of acidic and neutral mitochondria within neuronal processes that form a previously unrecognized pathological structure termed mitochondrial plaques (MPs). The development of MPs is driven by abnormal mitochondrial buildup and lysosomal recruitment occurs as a delayed response to promote mitochondrial degradation. However, degradation through mitophagy is incomplete due to impaired lysosomal functions, resulting in accumulation of both neutral and acidic mitochondria. MPs frequently codevelop with amyloid to form mixed plaques but can also emerge independently at early stages of disease. Notably, MPs were also identified in the 5xFAD AD mouse model and postmortem human AD brains. These findings establish MPs as a new pathological entity in AD.},
}

@article {pmid42527710,
year = {2026},
author = {Le Bras, A},
title = {Metabolomics atlas of Alzheimer's disease models.},
journal = {Lab animal},
volume = {55},
number = {8},
pages = {283},
doi = {10.1038/s41684-026-01782-x},
pmid = {42527710},
issn = {1548-4475},
}

@article {pmid42527713,
year = {2026},
author = {Jiang, M and Lin, Y and Wang, L and Ou, K},
title = {LncRNA DLX6-AS1 Regulates the Pathological Process Related to Alzheimer's Disease via miR-204-5p.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42527713},
issn = {1559-1174},
mesh = {Humans ; *Alzheimer Disease/pathology/genetics/blood/metabolism ; *MicroRNAs/physiology/genetics/biosynthesis/blood ; tau Proteins/metabolism ; Female ; Male ; Amyloid beta-Peptides/pharmacology/toxicity ; Phosphorylation ; *RNA, Long Noncoding/physiology/blood/genetics ; Cell Line, Tumor ; Aged ; Animals ; *Homeodomain Proteins/physiology/genetics ; Peptide Fragments/pharmacology/toxicity ; Aged, 80 and over ; Mice ; Brain/pathology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive neuronal damage. Incidence rises with age, and early diagnosis is difficult. This study examined DLX6-AS1 clinical relevance and regulatory mechanism in AD, and its interaction with miR-204-5p in AD pathology. It offers new insights into early diagnosis and treatment. A total of 133 AD patients and 105 healthy controls were selected. Their serum levels of DLX6-AS1 and miR-204-5p were analyzed using quantitative polymerase chain reaction. β-amyloid (Aβ)1-42-induced SH-SY5Y neuronal injury and okadaic acid (OA)-induced Neuro-2a tau abnormal phosphorylation models were constructed. The role/function of DLX6-AS1/miR-204-5p axis was then investigated using cell counting kit-8, flow cytometry, western blotting, enzyme-linked immunosorbent assay and a dual-luciferase reporter gene assay. AD patients had higher serum DLX6-AS1 and lower miR-204-5p levels. DLX6-AS1 showed an AUC of 0.838 for AD diagnosis. DLX6-AS1 levels were negatively associated with cognitive function, brain structural integrity, and benign pathology-and positively associated with disease severity, functional impairment, and pathological markers. In AD cell models, DLX6-AS1 was upregulated. Silencing it promoted cell proliferation, reduced apoptosis and oxidative stress, improved mitochondrial and synaptic function, decreased tau phosphorylation, and enhanced microtubule stability and axonal transport. Dual-luciferase assays confirmed direct binding between DLX6-AS1 and miR-204-5p. Co-inhibition reversed the protective effects of DLX6-AS1 silencing. Serum DLX6-AS1 is a potential biomarker for early diagnosis and assessment of AD. It regulates Aβ-induced neuronal damage and tau phosphorylation by targeting miR-204-5p, offering a new mechanism target for AD molecular therapy.},
}

Humans
*Alzheimer Disease/pathology/genetics/blood/metabolism
*MicroRNAs/physiology/genetics/biosynthesis/blood
tau Proteins/metabolism
Female
Male
Amyloid beta-Peptides/pharmacology/toxicity
Phosphorylation
*RNA, Long Noncoding/physiology/blood/genetics
Cell Line, Tumor
Aged
Animals
*Homeodomain Proteins/physiology/genetics
Peptide Fragments/pharmacology/toxicity
Aged, 80 and over
Mice
Brain/pathology

@article {pmid42527781,
year = {2026},
author = {Salvador, GLO and Park, JW and Schmidt, TS and Park, Y and Jeon, K and You, SC and Nagy, P and Dewey, B and , },
title = {Advancing the FAIRness of Multimodal Imaging Research Through the OMOP MI-CDM Framework: A Case Replication Study in Alzheimer's Disease.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
pmid = {42527781},
issn = {2948-2933},
abstract = {The objective of this study is to demonstrate an end-to-end approach for operationalizing the Findable, Accessible, Interoperable, and Reusable (FAIR) principles in multimodal medical imaging research using standardized data models and reproducible computational workflows, illustrated by reproducing the design and directional findings of a published Alzheimer's disease (AD) imaging study. Clinical and imaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI-4) were harmonized within the Observational Medical Outcomes Partnership Common Data Model and its Medical Imaging extension (OMOP MI-CDM). MRI acquisition metadata (DICOM) were extracted and mapped to standardized concepts, while clinical variables were integrated via reproducible extract-transform-load processes. Interoperable phenotypes were defined using OHDSI tools. Hippocampal volumes were derived from T1-weighted MRI using a fully automated machine learning segmentation pipeline (OpenMap-T1). Imaging attributes and derived measurements were stored as structured, provenance-preserving records in OMOP MI-CDM. We replicated a reference study evaluating hippocampal volume differences across AD, mild cognitive impairment (MCI), and cognitively normal controls, stratified by age and sex. We included 289 participants and 545 MRI studies. Across age- and sex-stratified cohorts, mean hippocampal volumes showed consistent directional reductions in AD compared with controls, with intermediate values in MCI, matching trends reported in the replication study. FAIR principles can be operationalized across the full imaging research pipeline using OMOP MI-CDM and automated analysis workflows. This framework enables transparent cohort definition, reproducible image processing, and interoperable reuse of machine learning-derived imaging features to support scalable validation and reproducible multimodal imaging research.},
}

@article {pmid42527810,
year = {2026},
author = {Marois, B and Leger, P and Petit, Y and Le Vot, R and Le Naveaux, F and Benoit, D and Aumeras, R and Wagnac, E},
title = {A Novel Video-Based Method to Estimate American Football Helmet Pad Deformation During Impact Testing.},
journal = {Annals of biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {42527810},
issn = {1573-9686},
support = {ETS-124//Axelys/ ; },
abstract = {PURPOSE: American football is among the sports with the highest incidence of mild traumatic brain injuries (mTBI), associated with long-term neurological consequences including cognitive impairment, chronic traumatic encephalopathy, and Alzheimer's disease. Despite recent rule changes and stricter National Football League (NFL) safety guidelines, mTBI remains common, underscoring the need for improved helmet design and evaluation. Current helmet testing protocols, such as the NFL's, measure head kinematics to derive performance scores but do not characterize helmet component behavior during impact. This study proposes a novel approach through the Pad Deformation Index (PDI)-a quantitative metric estimating compressive deformation of helmet pads during impact.

METHODS: Standard helmet impact tests were conducted at the Side Upper location, at three velocities (5.5, 7.4, and 9.3 m/s). Complementary mechanical tests on isolated pads using a drop tower at equivalent velocities linked helmet-level outcomes with localized pad response. High-speed videos enabled frame-by-frame reconstruction of the headform-impactor interaction and calculation of the minimum distance between the two rigid bodies, from which PDI was derived.

RESULTS: Higher PDI values generally coincided with reduced peak linear acceleration (PLA), Head Injury Criterion (HIC), DAMAGE, HARM, and partial Helmet Performance Score (HPS), supporting the use of PDI as an indicator connecting impact performance metric to pad deformation. Furthermore, pads exhibiting later densification within high-PDI range produced the lowest performance scores, underscoring the critical role of delayed densification.

CONCLUSION: PDI offers a practical tool for identifying absorption mechanisms and guiding helmet design.},
}

@article {pmid42527889,
year = {2026},
author = {Li, W and Suarez-Farinas, M and Shuster, A and Mednick, S and Figueiro, MG},
title = {Home-Based Tailored Light Therapy for Sleep, Mood, and Cognitive Outcomes in Mild Cognitive Impairment: A Randomized Trial.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261474211},
doi = {10.1177/07334648261474211},
pmid = {42527889},
issn = {1552-4523},
abstract = {BackgroundLight offers a promising approach to sleep and circadian disturbances in mild cognitive impairment (MCI).ObjectiveTest a home-based lighting intervention in people living with MCI.MethodsIn a randomized, placebo-controlled trial, 61 participants received active or placebo light for 24 weeks, with assessments for cognition, sleep, depression, and quality of life at baseline, week 13, 25, and, post-intervention, at week 37. Light exposure was measured as area under the curve (AUC) for morning circadian stimulus (CS).ResultsActive light participants (mean age 69.7 years; 52% male; mean MoCA 21.4) showed greater improvement in ADAS-Cog memory scores than placebo (p = 0.035), higher morning CS AUC by week 25 (0.021 vs -0.030; p = 0.025), and better sleep percent (-0.21 vs -1.29; p = 0.042), wake percent (-0.10 vs 1.19; p = 0.023), and wake after sleep onset (2.19 vs 8.23 min; p = 0.031).},
}

@article {pmid42527927,
year = {2026},
author = {Hu, X and Yu, Y and Luo, H and Li, J and Zhang, X and Wang, G and Li, J and Li, J and Chen, H and Qiu, Y},
title = {Transaldolase 1 contributes to pentose phosphate pathway disruption and synaptic dysfunction in Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42527927},
issn = {2047-9158},
support = {82373844//National Natural Science Foundation of China/ ; ZXY25001//Shanghai Jiao Tong University School of Medicine High level Local University Construction of Integrated Traditional Chinese and Western Medicine Research Platform Construction Project/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *Pentose Phosphate Pathway/physiology ; Animals ; Humans ; Mice ; *Transaldolase/metabolism/genetics ; Male ; *Synapses/metabolism/pathology ; Glucose/metabolism ; Neurons/metabolism ; Female ; Proteomics ; Mice, Transgenic ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Increasing evidence suggests that impaired glucose utilization is a major contributor to AD pathogenesis. Neurons preferentially use glucose through the pentose phosphate pathway (PPP). In AD, the flux through the PPP is significantly reduced; however, the underlying mechanism is still elusive. This study was aimed to elucidate how PPP was affected in AD and its contribution to the AD pathogenesis.

METHODS: Proteomic analyses of temporal cortex synaptosomes from AD patients and controls were conducted to identify dysregulated pathways and significantly affected proteins. Functional analysis was performed by knockdown or restoration of protein expression in primary cultured neurons, as well as in wild-type and 5 × FAD mice. Pseudotargeted metabolomics and biochemical, molecular, electrophysiological and behavioral assessments were performed to evaluate metabolic characteristics, redox status, mitochondrial function, synaptic plasticity and cognition.

RESULTS: Proteomic analysis of synaptic compartments identified glucose metabolism as the most significantly dysregulated functional network in AD. Further, transaldolase 1 (TALDO1), a rate-limiting enzyme in the PPP, was identified as a key enzyme affected in AD. TALDO1 was markedly downregulated at the early stage of AD. Downregulation of TALDO1 reduced glucose metabolism by inhibiting the PPP, TCA cycle and oxidative phosphorylation, causing broad metabolic collapse. Further, downregulation of TALDO1 depleted the nicotinamide adenine dinucleotide phosphate and glutathione pools, weakening antioxidant defense, thus resulting in mitochondria impairment and reduced energy supply. These collectively drive synaptic dysfunction and cognitive decline. Conversely, restoring TALDO1 expression in 5 × FAD mice improved glucose uptake, mitigated oxidative stress, restored metabolic homeostasis, and rescued neuronal and cognitive functions.

CONCLUSION: These findings identify TALDO1 as a key regulator of the impaired PPP in AD and may represent a promising therapeutic target for restoring neuronal metabolic homeostasis and function.},
}

*Alzheimer Disease/metabolism/pathology
*Pentose Phosphate Pathway/physiology
Animals
Humans
Mice
*Transaldolase/metabolism/genetics
Male
*Synapses/metabolism/pathology
Glucose/metabolism
Neurons/metabolism
Female
Proteomics
Mice, Transgenic

@article {pmid42528450,
year = {2026},
author = {Dewhurst, HE and Jorda, L and Aranda, A and Chunduri, B and Lopez, OL and Patira, R and Gogniat, MA},
title = {Multi-case review of posterior cortical atrophy in a neuropsychology clinic.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13554794.2026.2710636},
pmid = {42528450},
issn = {1465-3656},
abstract = {Posterior Cortical Atrophy (PCA) is a neurodegenerative syndrome defined by occipital atrophy that results in visuospatial deficits, often caused by Alzheimer's disease (AD) pathology. Patients with PCA are younger than typical AD patients and can present with anxiety. A rare and atypical variant of AD, the variable presentation of PCA has left it understudied, misdiagnosed, and with few in-depth examinations of cognitive profiles. This project reviews three patients referred for neuropsychological evaluation who were determined to have probable PCA. A comprehensive neuropsychological battery examined learning and memory, executive function, language, attention and processing speed, and visuospatial ability. Cases were examined based on cognitive complaints, daily functioning based on informant report, neuropsychological test performance, and neurodiagnostic work-up. Striking visuospatial deficits were observed in visuospatial construction tests (all patients scored < 1 percentile), and performance was impaired on most tests with visual components. Memory scores were impaired on some tests, but scores were slightly better on a contextualized verbal task compared to a word list. Patients had trouble functioning related to vision (e.g. object finding, reading) and tested positive for AD biomarkers. These cases highlight key aspects of the neuropsychological work-up for suspected PCA, including visuospatial deficits, AD biomarkers, and cognitive complaints.},
}

@article {pmid42528496,
year = {2026},
author = {Boeriu, AI and Andrews, SJ and Hoang, T and Bae, S and Yaffe, K},
title = {Epigenetic Clock Trajectories and Brain Health in Midlife.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.16.26358251},
pmid = {42528496},
abstract = {BACKGROUND: Accelerated biological aging can be assessed with DNA methylation (DNAm)-based epigenetic clocks. Research suggests that greater DNAm is associated with faster cognitive decline and risk of Alzheimer disease (AD) and other dementias. However, most studies have relied on single-time-point measurements of clocks, rather than evaluating dynamic changes over time. We examined the association between 15-year epigenetic aging trajectories and brain health outcomes in midlife.

METHODS: We analyzed 2,833 middle-aged adults (mean baseline age 40 years, 59% female and 44% Black) with ≥ 3 DunedinPACE (a recently developed epigenetic clock) measurements, collected over 15 years. Using mixed-effects modeling, we derived individual-specific slopes of epigenetic aging trajectories and categorized participants as Fast Agers (slopes > 1 SD above the mean), Slow Agers (slopes < 1 SD below the mean), or Typical Agers (within ±1 SD of the mean). We examined associations between trajectory group and cognition on five cognitive domains as well as on plasma AD biomarkers (NfL, p-tau217, Aβ42/Aβ40), all assessed 15-20 years post-baseline. Models were adjusted for demographics, education, physical activity and APOE *ε4 carrier status (with additional adjustments for eGFRcr for biomarker outcomes).

RESULTS: Epigenetic aging trajectories were associated with multiple domains of cognition and AD biomarkers (Figure 1). Compared to Typical Agers, Fast Agers showed worse processing speed, memory, executive function, and global cognition (all p<0.05), with no difference in verbal fluency. Slow Agers had better performance on memory and global cognition (both p < 0.05). Fast Agers also exhibited significantly lower Aβ42/Aβ40 levels (p = 0.011) compared to Typical agers; no significant associations with p-tau217 or NfL were observed in either group.

CONCLUSION: Middle-aged adults with faster 15-year epigenetic aging trajectories demonstrated worse cognitive performance, whereas those with slower biological aging trajectories exhibited cognitive resilience and more favorable AD biomarker profiles. By examining long-term trajectories rather than single timepoints, these findings identify individuals at differential risk for brain health outcomes.},
}

@article {pmid42528498,
year = {2026},
author = {Moradi, E and Dahnke, R and Gaser, C and Rikkonen, T and Kröger, H and Väänänen, S and Solomon, A and Sund, R and Tohka, J and , },
title = {Elevated BrainAGE precedes cognitive impairment and improves prediction of future cognitive decline.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42528498},
abstract = {Magnetic Resonance Imaging (MRI) derived brain age varies substantially between individuals, but it remains unclear whether early deviations from normal brain ageing precede future cognitive decline and whether they provide predictive value beyond conventional MRI measures. Here, we investigated whether MRI-derived brain age gap estimation (BrainAGE) identifies early structural brain ageing differences among cognitively normal individuals who later develop mild cognitive impairment (MCI) or dementia. We analysed longitudinal structural MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and replicated the main findings in the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE). Individuals who later converted to MCI or dementia had higher BrainAGE values several years before diagnosis and, in ADNI, showed steeper longitudinal increases than stable individuals. Elevated BrainAGE values were also associated with increased risk of future conversion to MCI in cognitively healthy individuals and faster subsequent memory decline. Cross-sectional differences and the association between BrainAGE and risk of future conversion were replicated in OSTPRE. Importantly, adding BrainAGE to models including demographic, APOE4, cognitive, and MRI-derived measures consistently improved prediction of future cognitive outcomes, with the greatest benefit observed for individuals who converted after longer follow-up. These findings show that structural brain ageing begins to diverge years before the onset of MCI. BrainAGE captures this early divergence, providing complementary information beyond conventional structural MRI measures that may improve the early identification of cognitively normal individuals at increased risk of future cognitive decline when integrated with other biomarkers.},
}

@article {pmid42528526,
year = {2026},
author = {Noble, JM and Nadkarni, NK and Martinez, D and Temprosa, M and Bowers, A and Carmichael, O and Doherty, L and Febres, GJ and Sanchez, D and Goldberg, TE and Sherif, H and Shah, V and Luchsinger, JA and , },
title = {Implementation of a standardized Video-based Asynchronous Neurological Examination (VANE) in a multi-center observational study of Alzheimer's disease (AD) and AD related dementias.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42528526},
abstract = {INTRODUCTION: The Diabetes Prevention Program Outcomes Study (DPPOS) is an established cohort of aging persons with pre-diabetes and type 2 diabetes with 25 years of median follow-up. In 2022 DPPOS added Alzheimer's disease (AD), and AD related dementias (ADRD) phenotyping using the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDSv3), which included a standardized neurological examination across 25 clinical sites, administered by clinical staff and interpreted centrally by clinicians.

METHODS: A DPPOS video-based asynchronous neurological examination (DPPOS-VANE) was developed iteratively through consensus from research clinicians and staff feedback to harmonize with UDSv3 to identify common neurological diagnoses aside from dementia including diabetic cranial neuropathies, stroke and parkinsonism. DPPOS-VANE was designed to be conducted without direct participant contact by the examiner, reproducible, and independent of clinical skills of PCs. An iPad™ camera recorded the video exam, comprised of assessments of extraocular and facial movements, visual fields, speech, gross motor strength, pronator drift, praxis and parkinsonism. A 10-minute training video demonstrated the examination step-by-step with scripts and instructions in English and Spanish. Site-specific performance review, feedback, and staff certification preceded central reading of video recordings by physicians.After two years of implementation, 1286 DPPOS-VANEs led to 1284 examination reviews. Of these, 1204 (93%) were completed by having the examiner follow the standard script. Overall, 1237 examinations (96%) were delivered as planned, 41 (3%) had minor errors but were still usable, and 6 (0.4%) had major deviations in exam technique; two additional recorded evaluations were not usable as recorded videos were inaccessible due to technical errors. Each examination was completed within 10-15 minutes. Each site on average completed 51.4 examinations (range 14-92).

DISCUSSION: Engaging 55 research staff across 25 sites and 3 physician-reviewers, this study is the first to demonstrate feasibility of a VANE as an efficient neurological examination model enabled by commonly used devices. Such a multisite standardized VANE represents a novel paradigm for large epidemiological studies.},
}

@article {pmid42528531,
year = {2026},
author = {Okorie, M and Jiang, X and Tolosa-Tort, P and Sharma, RU and Clark, AL and Yaffe, K and Yokoyama, JS and Andrews, S and , },
title = {Orthogonal Contributions of Genetic, Clinical, and Social Determinants of Health Risk Burdens on Alzheimer's Disease Pathophysiology.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.07.26357509},
pmid = {42528531},
abstract = {IMPORTANCE: Alzheimer's disease (AD) arises from complex interactions among genetic, clinical, and social determinants of health (SDoH) risk factors, yet their independent contributions to underlying AD pathophysiology remain elusive.

OBJECTIVE: To quantify the effects of risk factors across amyloid (Aβ)/tau, neurodegeneration, and cognition.

DESIGN: Cross-sectional analysis using structural equation modeling (SEM).

SETTING: Health and Aging Brain Study-Health Disparities (HABS-HD), a community-based cohort study.

PARTICIPANTS: A total of 2,276 participants with demographics, genetic, clinical, and biomarker data from the baseline visit.

EXPOSURES: APOE ε4 carrier status, AD polygenic risk score (AD-PRS), clinical risk score (CogDRisk), and a social determinants of health (SDoH) latent score derived using factor analysis.

MAIN OUTCOMES AND MEASURES: Latent variables representing Aβ/tau pathology (plasma pTau 181 , plasma pTau 217 /Aβ 42 , amyloid PET positivity, and global standardized uptake value ratio), neurodegeneration (plasma neurofilament light, cortical thickness, hippocampal volume), and cognition (memory, executive, and language tests) were modeled and regressed on AD latent variables using SEM adjusted for age, sex, genetic principal components, and spoken language.

RESULTS: The total analytic sample included 2,276 participants (mean age: 65.3 ± 8.7; non-Hispanic White: 43.0%, non-Hispanic Black: 16.2%, and Latinx/Hispanic adults: 40.8%). APOE ε4 was strongly associated with worse Aβ/tau latent variable (β=0.31; p<0.001), with smaller but significant associations with neurodegeneration (β=0.085; p<0.001) and cognition (β=0.083; p<0.001). Higher AD-PRS was modestly associated with worse Aβ/tau (β=0.075; p<0.01) but was not associated with neurodegeneration or cognition. A higher clinical risk score was significantly associated with worse neurodegeneration (β=0.16; p<0.001) but not with Aβ/tau or cognition. Adverse SDoH was associated with worse neurodegeneration (β=0.071; p<0.05) and strongly associated with worse cognition (β=0.22; p<0.001), with no associations with Aβ/tau.

CONCLUSION AND RELEVANCE: Genetic risks were primarily associated with Aβ and tau pathology, clinical risks with neurodegeneration, and SDoH risks with cognition, suggesting that risk factors exert differential effects on AD pathophysiology. Future studies investigating additional risk factors and their longitudinal associations with AD pathophysiological changes are warranted.

KEY POINTS: Questions: Do Alzheimer's disease (AD) risk factors differentially influence underlying AD pathophysiological processes, and do these associations vary across demographic subgroups?Findings: Genetic and genomic risk burdens demonstrated the strongest associations with amyloid and tau pathology; clinical risk burden with neurodegeneration; and adverse social determinants of health with cognition.Meaning: Because of the differential effects of risk factors on the underlying AD pathophysiology, a one-size-fits-all approach to AD risk prediction and prevention is insufficient. AD risk assessment should leverage multidomain frameworks incorporating genomic, clinical, and social determinants of health information to better inform disease development and progression.},
}

@article {pmid42528554,
year = {2026},
author = {De Carli, D and Sudati, A and Dercole, F},
title = {Explainable Machine Learning Models for Alzheimer's Diagnosis Using Routine and Low-Cost Clinical Data.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.10.26357720},
pmid = {42528554},
abstract = {Emerging as a significant global health challenge, Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that causes memory loss and cognitive decline. Despite the ever-increasing waiting time for a specialist diagnosis, the need for a cost-effective and fast diagnostic technique is evident. This study explores the development of an explainable deep learning model to diagnose AD using only routine and low-cost clinical data, including demographic information, patient history, and results of neuropsychological tests (limited to those that can be automatically acquired). The analysis was carried out using a dataset provided by the National Alzheimer's Coordinating Center, comprising 167,364 observations and 1,024 features. The findings demonstrate diagnostic performance comparable, and slightly superior, to that of clinicians when evaluated under similar informative constraints. This study introduces two classification models to discriminate whether the presumptive etiological cause of cognitive impairment is Alzheimer's disease. The deep neural network achieved an accuracy of 90% with an area under the receiver operating characteristic curve (ROC-AUC) of 0.96, whereas the Light Gradient Boosting Machine reached the same accuracy with a ROC-AUC of 0.97.},
}

@article {pmid42528566,
year = {2026},
author = {Lopez, FV and Gillis, M and Lee, S and Sakamoto, MS and Zhang, R and , and Sherva, R and Logue, MW and Merritt, VC},
title = {Curation of Mini Mental State Examination (MMSE) Scores in the VA Million Veteran Program (MVP): Applications for Cognitive Aging Research.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.26358064},
pmid = {42528566},
abstract = {BACKGROUND: Electronic health record (EHR)-linked biorepositories provide opportunities to advance epidemiological research in Alzheimer's disease (AD) and related dementias.

OBJECTIVE: Evaluate the extraction, curation, and associative validity of Mini Mental State Examination (MMSE) scores from the VA EHR for participants in the VA Million Veteran Program (MVP).

METHODS: The sample (N = 49,555; 7.4% women) included a multiethnic cohort (European [68.3%], African [20.4%], Hispanic [9.0%]) with EHR-extracted MMSE scores; 30.7% were apolipoprotein E (APOE) ε4 carriers, and 25.8% had multiple scores. Linear regressions examined cross-sectional associations between ε4 dosage (0, 1, 2) and first and lowest MMSE scores. MMSE scores were also evaluated against MVP dementia diagnostic algorithms in participants aged ≥65 years.

RESULTS: Among participants of European ancestry, there was a significant ε4 dose-response relationship (p s < .001) with MMSE scores. Homozygote carriers scored lower than heterozygote carriers (M diff : first = -0.5; lowest = -0.9), who scored lower than non-carriers (M diff : first = -0.4; lowest = -0.6). Among Veterans of African and Hispanic ancestry, no dose-response relationship was observed, although ε4 carriers had lower scores than non-carriers (p s ≤ .04). MMSE scores corresponded strongly with dementia case/control status across phenotypes: mild impairment on the MMSE was strongly associated with AD (odds ratio [OR] = 11.48), with more severe MMSE impairment showing stronger associations (moderate OR = 17.95; severe OR = 27.83).

CONCLUSION: This study demonstrated MMSE scores can be systematically extracted and curated from the VA EHR. Findings offer a scalable framework for future studies on risk stratification, highlighting the potential for harnessing MVP to explore genetic and clinical factors contributing to cognitive and dementia outcomes in diverse samples.},
}

@article {pmid42528609,
year = {2026},
author = {Ayubcha, C and Dennis, E and Bhattacharyya, U and John, J and Lam, M and Lencz, T and Ge, T and Chen, CY},
title = {Characterizing the impact of plasma protein levels on human brain structure and disorders leveraging integrative multi-omics analysis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.13.26358006},
pmid = {42528609},
abstract = {With recent advances in high-throughput proteomic technologies, population-scale plasma proteomics datasets, often linked to extensive genetic and phenotypic information, have become increasingly accessible. Yet the relationships between circulating protein levels, brain imaging phenotypes, and risk for neurological and psychiatric disorders remain largely unexplored. Proteome-wide association studies offer a promising approach for elucidating biological mechanisms that connect genetic variation to complex brain-related traits and diseases. In this study, we integrated protein quantitative trait loci (pQTLs) from the two largest plasma proteomic resources (the UK Biobank Pharma Proteomics Project [UKB-PPP] and Ferkingstad et al. [deCODE]) with genome-wide association studies of brain imaging-derived phenotypes in UK Biobank using Mendelian randomization and colocalization analyses. We identified 120 cis and 20 trans associations between plasma proteins and imaging phenotypes and validated these findings using brain tissue-derived proteomic and transcriptomic datasets. Multivariable Mendelian randomization revealed eleven plasma proteins (coding genes APOE, ARL3, MICB, NSF, RHOC, RSPO3, ENPP2, BTN2A1, EIF2AK3, MRVI1, and OPLAH) with significant direct effects on the risk of Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, and schizophrenia. Single-cell expression and pathway enrichment analyses further revealed cell-type-specific effects and distinct biological processes underlying these protein- disease associations. Together, these findings demonstrate robust links between plasma protein variation and brain structure, delineate protein-disease pathways, and highlight the cellular and molecular mechanisms that contribute to neurobiological diversity and pathology.},
}

@article {pmid42528719,
year = {2026},
author = {Yang, M and Gao, Z and Zhao, Z and Niu, X and Xue, F and Zhang, J and Sun, H and Shen, Y and Liu, G},
title = {The dual pathological roles and targeted therapy of PGE2: from receptor signaling networks to disease microenvironment modulation.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1810417},
pmid = {42528719},
issn = {1663-9812},
abstract = {Prostaglandin E2 (PGE2) is a pleiotropic lipid mediator that exerts context-dependent effects via four G protein-coupled receptors (EP1-EP4), playing a pivotal role in the pathogenesis of diverse disorders, including neurodegenerative, cardiovascular, neoplastic, and chronic inflammatory diseases. In this review, we systematically delineate the dualistic functions and mechanisms of PGE2 across these diseases. In neurodegenerative conditions such as Alzheimer's and Parkinson's diseases, PGE2 exacerbates neuroinflammation and neuronal injury in part through EP1 and EP2 in specific cell types, whereas EP4 signaling can confer neuroprotection in certain disease-stage and cellular contexts. Within the tumor microenvironment, PGE2 can drive immunosuppression, angiogenesis, and tumor progression via the EP2/EP4 axis, particularly in colorectal carcinoma, lung adenocarcinoma, and melanoma where this axis is best characterized. In cardiovascular and metabolic diseases, PGE2 exhibits both protective (EP4-mediated) and detrimental (EP3-mediated) effects. Building on this mechanistic framework, we highlight emerging therapeutic strategies designed to overcome the limitations of conventional non-steroidal anti-inflammatory drugs (NSAIDs). These include modulating key enzymes involved in PGE2 synthesis and degradation, developing subtype-selective EP receptor modulators for context-specific intervention, and synergistically targeting downstream pathogenic signaling pathways (e.g., PI3K/Akt/mTOR). By integrating mechanistic and translational perspectives, this review aims to advance next-generation therapies targeting the PGE2 signaling network.},
}

@article {pmid42528726,
year = {2026},
author = {Kelley, AR and Sackinger, E and Frischman, M and Thomas, N and Kim, K and Scuderi, G and Labut, EM and MacMurchy, D and Ikea-Mario, T and Rauenhorst, J and Neitzel, E and Vu, T and Liko, L and Hoff, A and Hoff, A and Wallace, O and Harry, WKE and Hagen, B and Bihun, AZ and Abou-Seada, IA and Lee, K and Butler, J and Nigussie, F and Ebrahimi, A and Lee, PY and Marney, LC and Maier, CS and Magnusson, KR and Hagen, TM},
title = {Pre-plaque glutamatergic hyperexcitability, mitochondrial dysfunction, and dendritic remodeling in the hippocampus of one-month-old 5xFAD mice.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1804332},
pmid = {42528726},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and stereotyped neuropathology, yet the earliest cellular events that precede overt plaque burden and measurable behavioral impairment remain incompletely defined. Here, we tested the hypothesis that synaptic hyperexcitability and subcellular metabolic dysfunction emerge early in the 5xFAD mouse model and contribute to region-specific neuronal vulnerability before substantial amyloid plaque deposition. Using the 5xFAD heterozygous mouse, we first established the onset of transgene expression and the timing of plaque accumulation. Robust transgene expression was detected by postnatal day 15 and statistically significant plaque accumulation in the CA1 stratum radiatum by 4 months of age. Hippocampal slice electrophysiology revealed an early hyperexcitable phenotype at 1 month of age, including both increased AMPA receptor-mediated transmission and N-methyl-D-aspartate receptor signaling associated with the GluN2B subunit. Given the tight coupling between glutamatergic hyperactivity, oxidative stress, calcium dysregulation, and mitochondrial health, we assessed mitochondrial structure and function at this pre-plaque stage. Mitochondrial abnormalities consistent with impaired bioenergetic homeostasis were evident within hippocampal synaptic processes. Morphological analyses demonstrated that these early changes were associated with altered dendritic architecture in the CA1 and dentate gyrus regions, revealing hippocampal subregional susceptibility. Finally, spatial transcriptomics identified regionally enriched molecular signatures consistent with differential vulnerability. The CA1 subregion exhibited pronounced downregulation of mitochondria-related transcripts, and single-cell deconvolution resolved this transcriptomic suppression specifically to CA1 pyramidal neurons (CA1.ProS); CA3 and dentate gyrus did not show equivalent mitochondrial pathway suppression. Together, these findings define a pre-plaque window in 5xFAD mice marked by GluN2B-linked glutamatergic hyperexcitability, early mitochondrial disruption, and selective dendritic and transcriptional vulnerability. Mitochondrial transcriptomic suppression was anatomically restricted to CA1 pyramidal neurons, establishing a cell-type-specific bioenergetic signature at 1 month of age, well before overt amyloid pathology. While the observations herein are descriptive in nature and detailed mechanisms have yet to be established, nevertheless, the integrated timeline suggests that synaptic and metabolic dysfunctions arise before substantial plaque deposition and may represent tractable early targets for intervention in AD.},
}

@article {pmid42528828,
year = {2026},
author = {Serra, L and Bonarota, S and Caruso, G and Mancini, M and Sperati, S and Di Domenico, C and Tamigi, FM and Di Lorenzo, F and Ricci, F and Caltagirone, C and Koch, G and Giove, F and Bozzali, M and Petrosini, L},
title = {Stage-dependent effects of cognitive reserve on memory and brain structural integrity across the spectrum from healthy aging to Alzheimer's disease.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1830181},
pmid = {42528828},
issn = {1662-5161},
abstract = {INTRODUCTION: Cognitive reserve (CR) has been proposed as a key factor explaining inter-individual variability in cognitive performance despite comparable neuropathology. However, its role across the Alzheimer's disease (AD) continuum remains unclear. This study investigates stage-dependent effects of CR on the relationship between memory performance and brain structural network integrity across healthy subjects (HS), individuals with subjective cognitive decline (SCD), and patients with amnestic mild cognitive impairment (a-MCI), and AD dementia.

MATERIALS AND METHODS: A total of 209 participants underwent a comprehensive neuropsychological assessment and 3T MRI. Source-based morphometry identified three grey matter structural covariance networks, involving orbitofrontal-temporal-insular regions (OTIN), precuneus-posterior cingulate cortex (PreCiN), and cingulate-hippocampal regions (CHiN). A composite memory score was derived using factor analysis. Regression and moderation models examined the predictive and moderating effects of CR (operationalized as years of education) and network integrity on cognitive performance within each group.

RESULTS: OTIN and PreCiN showed progressive structural vulnerability along the AD continuum, whereas CHiN showed no significant between-group differences. Across the sample, OTIN and PreCiN integrity significantly predicted cognitive performance. In HS, CR was positively associated with memory performance independently of structural network integrity, suggesting an additive protective role of cognitive reserve in healthy aging. In the SCD group, CR was not directly associated with memory, and only limited effects emerged, indicating early alterations in reserve-related processes. In a-MCI patients, the significant interaction between CR and OTIN integrity suggested patterns consistent with compensatory mechanisms, with higher reserve supporting memory despite structural decline. In AD patients, CR and its interaction with structural networks no longer predicted cognitive outcomes, suggesting a possible exhaustion of reserve capacity.

CONCLUSION: These findings support a stage-dependent model of CR, characterized by an additive protective role in healthy aging, patterns consistent with compensatory recruitment in early cognitive decline, and a possible loss of reserve effectiveness beyond a critical neuropathological threshold. Distinct network vulnerabilities and stage-specific CR effects highlight potential windows for reserve-enhancing interventions across the AD continuum.},
}

@article {pmid42528992,
year = {2026},
author = {Ren, C and Zhu, J and Huang, L and Hu, T and Guan, Y and Xie, F and Jin, J and Guo, Q},
title = {Dual decline in gait and cognition as a high-risk clinical phenotype: differential associations with cerebral amyloid-β deposition and the apolipoprotein E ε4 allele and implications for integrated assessment.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1845747},
pmid = {42528992},
issn = {1663-4365},
abstract = {BACKGROUND: Gait slowing and cognitive impairment often coexist in older adults, yet their relationship with core Alzheimer's disease (AD) biomarkers remains incompletely understood.

OBJECTIVE: To investigate the associations of isolated and combined slow gait (SG) and cognitive impairment subtypes with cerebral amyloid-β (Aβ) deposition and the apolipoprotein E ε4 (APOE ε4) allele in Chinese older adults.

METHODS: This cross-sectional study included 1,753 participants (mean age 65.9 years). Based on gait speed and cognitive status, participants were classified into six groups: normal, slow gait alone (SG-A), subjective cognitive decline alone (SCD-A), mild cognitive impairment alone (MCI-A), SCD with slow gait (SCD-SG), and MCI with slow gait (MCI-SG). 687 individuals underwent 18F-florbetapir positron emission tomography (PET) scans, 654 participants were examined for Apolipoprotein E (APOE) genotyping, and 618 participants had all relevant information recorded.

RESULTS: The MCI-SG group exhibited the most pronounced physical decline (slowest gait speed and weakest handgrip strength) and the highest burden of AD pathology, with a significantly higher prevalence of Aβ positivity (38%) and APOE ε4 carriage (32%) compared with other groups. While overall Aβ positivity rates across the six groups were not significantly different, logistic regression analyses revealed specific, strong associations. Aβ positivity was significantly associated with both SCD-SG (OR = 1.78, 95% CI: 1.03-3.08) and MCI-SG (OR = 1.85, 95% CI: 1.07-3.21) compared with the normal group. In contrast, APOE ε4 carriage was specifically and more strongly linked to MCI-SG (OR = 3.21, 95% CI: 1.41-7.31) compared with the SCD-A group. These combined gait-cognitive impairment phenotypes showed consistently stronger associations with AD biomarkers than isolated impairments across multiple reference groups. The risk was greatest for MCI-SG in individuals who were both Aβ positive and APOE ε4 carriers (OR = 2.27, 95% CI: 1.19-5.15).

CONCLUSION: The co-occurrence of slow gait and mild cognitive impairment (MCI-SG) represents a distinct high-risk clinical phenotype strongly linked to AD pathology. Aβ and APOE ε4 show differential associations across the gait-cognitive spectrum. Integrated assessment of gait and cognition improves risk stratification in older adults and may guide early intervention strategies.},
}

@article {pmid42529009,
year = {2026},
author = {Zhou, H and Jiang, N and Bernheim, S and Paik, P and Zhou, Q and Kurabayashi, K and Ray, K},
title = {Wearable monitoring during music-based interventions in dementia: physiological and behavioral observations from a pilot study.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1854021},
pmid = {42529009},
issn = {1662-5161},
abstract = {INTRODUCTION: Music-based interventions (MBIs) are widely used in dementia care, but objective methods for characterizing participant responses during intervention sessions remain limited. Synchronized datasets combining wearable physiological signals and behavioral observations are particularly scarce.

METHODS: We conducted a pilot feasibility study involving five individuals with Alzheimer's disease and related dementias (ADRD) who participated in 13 formal MBI sessions. Physiological signals, including photoplethysmography (PPG), electrodermal activity (EDA), skin temperature (TEMP), and accelerometry (ACC), were collected using a wrist-worn wearable sensor and synchronized with intervention playlists and time-stamped behavioral observations. Exploratory analyses examined physiological responses across intervention phases, participant-specific response patterns, time-of-day effects, and music-preference effects.

RESULTS: The dataset contains 13 intervention sessions, 99 music segments, and 248 behavioral observations. PPG, ACC, TEMP, and behavioral observations were available for all sessions, while EDA quality varied because of sensor-contact challenges. Behavioral responses were highly heterogeneous across participants, with engagement and calm behaviors observed most frequently. Physiological responses also showed substantial inter-individual variability, and case studies demonstrated that physiological and behavioral responses were not always concordant.

CONCLUSION: This study demonstrates the feasibility of collecting synchronized physiological, behavioral, and intervention-context data during MBIs in people living with dementia. The resulting publicly available multimodal dataset provides a foundation for future investigations of participant-specific responses and adaptive music-based interventions.},
}

@article {pmid42529064,
year = {2026},
author = {Swann, P and Malpetti, M and Chouliaras, L and White, SR and Mak, E and Surendranathan, A and Jones, PS and Su, L and Savulich, G and Kigar, S and McKeever, A and Fryer, T and Hong, YT and Aigbirhio, FI and Rowe, JB and O'Brien, JT},
title = {Peripheral and central inflammation associated with progressive cognitive decline in dementia with Lewy bodies.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag274},
pmid = {42529064},
issn = {2632-1297},
abstract = {Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia, pathologically defined by the presence of Lewy bodies. Peripheral and central inflammation are increasingly recognized in DLB in clinical, post-mortem and animal studies. Finding clinically relevant biomarkers of inflammation in DLB will support the identification of novel pathways for disease-modifying therapies or use in clinical trials of immunomodulatory agents. Whilst there are cross-sectional studies of inflammation markers in DLB, there is limited evidence on the association between these markers and cognitive decline over time. Twenty participants with DLB underwent blood sampling for serum inflammatory markers, paired with PET imaging of the translocator protein (TSPO) and up to 4 years of longitudinal cognitive testing. Thirty participants with Alzheimer's disease-comprising both Alzheimer's dementia and/or mild cognitive impairment with biomarker evidence of amyloid pathology (AD/MCI+)-and 28 controls were also recruited for group comparisons. Data from 42 baseline cytokine immunoassays and TSPO PET were used as predictors of longitudinal cognitive scores in linear mixed-effects models. Partial least squares regression was used to test the association between peripheral and central inflammation. Using peripheral inflammatory markers as single predictors, we identified 14 associated with either a slower or faster rate of cognitive decline in DLB, whilst no single marker was predictive of decline in AD/MCI+. As many inflammatory markers were highly correlated, we used principal component analysis to identify a cytokine component associated with reduced cognitive decline in both DLB and AD/MCI+, that overlapped with the single markers identified in the previous analysis. A separate component was associated with cognitive decline in AD/MCI+ or DLB with Alzheimer's dementia co-pathology (ascertained by amyloid PET). Widespread TSPO binding was associated with reduced cognitive decline in DLB, whilst a fronto-temporal pattern was associated with more rapid cognitive decline in both DLB and AD/MCI+. There were associations between peripheral cytokines and TSPO PET in AD/MCI+, but these were not significant in DLB. Overall, peripheral and central inflammation predicted cognitive decline in DLB. Specific patterns associated with both faster and slower rates of decline were identified. These profiles had both overlapping and contrasting associations when compared to AD/MCI+. Collectively, these data add to a body of evidence suggesting clinically relevant levels of inflammation in DLB. Future studies in larger, multi-site cohorts with multiple biomarker sampling points are required to understand the impact and dynamics of inflammation across all stages of the disease.},
}

@article {pmid42529168,
year = {2026},
author = {McCool, S and Jain, A and Smith, JC and Van Hook, MJ},
title = {Plaque-associated microglial polarization in visual brain regions of the 5xFAD mouse model.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1824891},
pmid = {42529168},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD), a neurodegenerative disorder associated with amyloid beta (Aβ) plaque deposition, leads to cognitive decline in affected individuals. Vision changes are among the reported symptoms in AD with studies showing both decline in functions performed by the visual system as well as associations between vision loss and cognitive impairment in AD patients. Due to the increasing number of individuals diagnosed with AD and its early impact on vision, we sought to provide an in-depth analysis of how Aβ, a primary pathology typically preceding many other AD-associated pathologies, affects visual regions of the brain and how microglia, key immune regulators of the brain's environment, respond to this AD-like pathology.

METHODS: Amyloid pathology was examined in histological sections containing the dorsolateral geniculate nucleus (dLGN), and the primary visual cortex (V1), suprachiasmatic nucleus (SCN), and superior colliculus (SC) of 5xFAD mice using thioflavin-S and anti-amyloid staining. Microglia morphology was analyzed in Iba1 antibody-stained sections and phagocytic activity was evaluated with CD68 co-staining.

RESULTS: We found that in the pathway for image-forming vision, including the dLGN and V1, there was significant Aβ pathology, shifts in microglial morphology to an amoeboid state, localization of microglia around plaques, and increased Iba1/CD68 co-labeling. However, in non-image-forming visual brain regions such as the SC and SCN, there was minimal Aβ pathology, ramified microglial morphology, and minimal phagocytic activity.

CONCLUSION: Overall, Aβ plaque deposition was related to brain-region-specific differences in microglial responses, indicating that visual brain regions are differentially affected by AD pathology in the 5xFAD mouse model of amyloidosis.},
}

@article {pmid42529199,
year = {2026},
author = {Lin, Y and Cheng, L and Zhang, Z and Cui, L and Li, W and Guo, Q and Miao, Y},
title = {Blood transcriptomic signatures link β-amyloid deposition to molecular pathways across SCD, MCI, and dementia.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1816733},
pmid = {42529199},
issn = {1663-4365},
abstract = {INTRODUCTION: Brain β-amyloid (Aβ) accumulation is a hallmark of Alzheimer's disease, but noninvasive detection remains challenging. Blood transcriptomics may provide accessible biomarkers associated with Aβ pathology.

METHODS: We integrated peripheral blood transcriptomic profiling and MRI-derived structural metrics from 48 individuals across the cognitive continuum, including subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia, stratified by Aβ-PET status. Predictive models were constructed using leave-one-out cross-validation (LOOCV), and selected genes were validated by qRT-PCR.

RESULTS: Cross-stage analysis identified RUNX1T1 and COL14A1 as consistently downregulated in Aβ-positive individuals regardless of clinical stage. A predictive model incorporating these two genes demonstrated moderate discrimination of Aβ-PET status in internal leave-one-out cross-validation (LOOCV) evaluation (AUC = 0.81). In addition, COL14A1 expression was associated with cortical thickness and hippocampal volume, whereas RUNX1T1 was primarily associated with hippocampal structure. Among individuals with MCI or dementia, HCN1 and NRG3 were upregulated, whereas KCNMB2 was downregulated in Aβ-positive subjects. A three-gene model based on these markers achieved an LOOCV AUC of 0.79.

DISCUSSION: These findings indicate that peripheral blood transcriptomic alterations are associated with Aβ pathology across clinical groups. RUNX1T1 and COL14A1 represent candidate peripheral biomarkers associated with Aβ pathology, while the observed molecular signatures and their associations with brain structural measures provide a basis for further validation in larger, longitudinal cohorts and mechanistic studies.},
}

@article {pmid42529446,
year = {2026},
author = {Hakhverdyan, S and Hansson, S and Kadej, P and Orlovsky, SB and Hladkou, S and Viirman, B and Nilsson, A and Lord, M and Cologna, SM and Mohr, JT and Syvänen, S and Andrén, PE and Michno, W},
title = {Spatially Resolved Free Fatty Acid Profiling Reveals Region- and Age-Dependent Remodeling of Alzheimer's Disease Plaques.},
journal = {JACS Au},
volume = {6},
number = {7},
pages = {4153-4165},
pmid = {42529446},
issn = {2691-3704},
abstract = {Free fatty acids (FFAs) are bioactive mediators of inflammation, energy metabolism, and membrane remodeling, yet their spatial organization within the Alzheimer's disease (AD) brain and at individual amyloid-β (Aβ) plaques has remained inaccessible. We developed a novel, chemically tailored MALDI workflow that enables simultaneous, spatially resolved detection of nearly 30 FFAs alongside over 100 complex lipid species within the same tissue section. Applying this approach to a transgenic AD mouse model across brain regions and disease stages, and combining it with single-plaque microenvironment analysis (SPMA) that treats each plaque as an individual analytical object, we uncover two previously inaccessible dimensions of plaque-associated lipid biology. FFA distributions form highly structured spatial compartments reflecting regional cytoarchitecture, with distinct enrichment of saturated, monounsaturated, and polyunsaturated species across cortical layers. Within Aβ plaques, nearly 75% of detected FFAs are significantly remodeled, with reciprocal enrichment of short saturated and highly unsaturated species alongside depletion of long-chain monounsaturated FFAs. This pattern is consistent with concurrent disruption of ELOVL-mediated elongation and FADS-mediated desaturation, including opposing enrichment of pro-inflammatory arachidonic acid and pro-resolving docosahexaenoic acid. Machine learning of single-plaque profiles reveals that FFA composition alone classifies plaque age with high accuracy, demonstrating that lipid remodeling continues after Aβ peptide composition has stabilized. Together, these findings establish spatial FFA profiling as a new analytical dimension in neurodegeneration research, revealing that Aβ plaques are dynamic lipid-metabolic microenvironments that continue to remodel long after Aβ deposition has stabilized.},
}

@article {pmid42529466,
year = {2026},
author = {Shi, B and Wang, Z and Lian, J and Yang, Z and Zuo, X},
title = {APLG-Net: an anatomy-guided local-global hybrid network with progression-aware supervision for structural MRI-based NC/MCI/AD classification.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1885491},
pmid = {42529466},
issn = {1664-2295},
abstract = {INTRODUCTION: Structural MRI-based Alzheimer's disease classification remains challenging due to subtle anatomical variations and the intermediate nature of mild cognitive impairment (MCI).

METHODS: We propose APLG-Net, an anatomy-guided local-global hybrid network with progression-aware supervision for NC/MCI/AD classification. The model integrates a global whole-brain encoder and a local ROI-based encoder, followed by cross-attention fusion and vector-gated integration. An ordinal supervision strategy is introduced to model disease progression.

RESULTS: On the ADNI dataset, APLG-Net achieves 87.1% accuracy, 86.4% balanced accuracy, 86.8% Macro-F1, and 85.6% MCI F1, outperforming CNN-based, Transformer-based, and hybrid baselines.

DISCUSSION: The results demonstrate that incorporating anatomical priors, local-global feature interaction, and ordinal supervision significantly improves MCI discrimination and overall classification robustness.},
}

@article {pmid42529533,
year = {2026},
author = {Kummer, N and Cihova, M and Nirmalraj, PN},
title = {Antiamyloid Antibody Effects on Aβ-42 Protein Aggregates Profiled Using Nanospectroscopy.},
journal = {Chemical & biomedical imaging},
volume = {4},
number = {7},
pages = {1379-1389},
pmid = {42529533},
issn = {2832-3637},
abstract = {Anti-amyloid-β (Aβ) monoclonal antibodies are designed to selectively target protein biomarkers and promote amyloid clearance in Alzheimer's disease. Yet the effects of antibodies on individual Aβ protein aggregates remain to be fully clarified. The work presented here employs nanospectroscopy (atomic force microscopy combined with infrared spectroscopy) to resolve morphological and secondary structural changes in Aβ-42 protein aggregates upon treatment with aducanumab and lecanemab antibodies (biosimilars). The treatment of Aβ-42 peptides with aducanumab resulted in reduction of oligomer prevalence and formation of larger-diameter fibril bundles confirmed from the AFM height maps and infrared spectral readouts recorded at nanometer-scale spatial resolution. Conversely, lecanemab treatment of Aβ-42 peptides did not suppress oligomer generation but was observed to preferentially bind along the full length of the nodular-shaped protofibril surface. Importantly, neither aducanumab nor lecanemab was observed to induce any surface adsorption-driven disassembly of Aβ-42 protofibrils or elongated mature fibrils. Thus, nanospectroscopy enables direct characterization of antibody-amyloid interfacial interactions and provides insights into the distinct modes of action of emerging anti-Aβ therapeutics through label-free chemical imaging.},
}

@article {pmid42529812,
year = {2026},
author = {Harkess-Murphy, E and Macrae, R and Brown, M and Hall, J},
title = {Trauma-Informed Support in a Dementia Helpline: Retrospective Mixed Methods Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e71746},
doi = {10.2196/71746},
pmid = {42529812},
issn = {2561-326X},
mesh = {Humans ; *Dementia/psychology ; Retrospective Studies ; *Hotlines/statistics & numerical data ; *Caregivers/psychology ; Male ; Female ; *COVID-19/psychology/epidemiology ; United Kingdom ; Qualitative Research ; Aged ; },
abstract = {BACKGROUND: People with dementia and their caregivers experience significant psychological distress, which may increase their vulnerability to trauma across the dementia diagnostic and caregiving trajectory. Specialist dementia helplines offer immediate emotional support, information, and signposting; however, little empirical evidence exists about how call handlers account for potential trauma in their responses.

OBJECTIVE: This study aimed to examine the extent to which call handlers' responses on the United Kingdom's only 24-hour dementia helpline reflected trauma-informed (TI) principles of safety, trust, choice, collaboration, and empowerment and to describe caller characteristics and reasons for contact during the COVID-19 pandemic.

METHODS: No participants were actively recruited. Instead, the study analyzed 198 anonymized, routinely collected helpline call logs (out of 200 randomly selected) drawn from 7357 calls received by Alzheimer Scotland's 24-hour helpline between April 2020 and April 2021. A retrospective deductive framework analysis mapped narrative summaries to 5 TI principles (safety, trustworthiness and transparency, choice, collaboration, and empowerment). Double‑coding and calibration were undertaken in line with established guidance on intercoder reliability for qualitative research. Descriptive statistics summarized caller characteristics and theme frequencies; no inferential testing was conducted due to the exploratory nature of the analysis, sample properties, and the subjective nature of theme ratings.

RESULTS: Most calls were made during daytime hours (159/198, 79.5%) and were made by carers, family members, or friends (n=179, 89.5%). Emotional support was the most frequently recorded reason for contact (91 instances), followed by carer stress (66 instances) and information on caring (51 instances). Across call handlers' responses, collaboration (126/179, 70.4%) and empowerment (108/179, 60.3%) were the most frequently observed TI principles, followed by safety (105/179, 58.7%), choice (66/179, 37.4%), and trust (56/179, 31.3%). Safety-focused responses were more prevalent in nighttime calls than daytime calls (76.9% vs 56%). Illustrative call log excerpts demonstrated empathetic listening, validation, shared problem-solving, and signposting practices aligned with TI principles.

CONCLUSIONS: In this exploratory retrospective evaluation, responses from a national dementia helpline commonly reflected TI principles, despite call handlers receiving primarily awareness-level TI content within their wider role preparation. Findings should be interpreted as descriptive and hypothesis-generating because they are based on call log summaries rather than recorded interactions and were obtained within the unique context of the COVID-19 pandemic. The results suggest that TI principles may be feasible and relevant in dementia helpline services and highlight the potential value of more structured approaches to TI workforce development. Future prospective research incorporating richer data sources such as recorded calls and call-reported outcomes is warranted to support service development and evaluation.},
}

Humans
*Dementia/psychology
Retrospective Studies
*Hotlines/statistics & numerical data
*Caregivers/psychology
Male
Female
*COVID-19/psychology/epidemiology
United Kingdom
Qualitative Research
Aged

@article {pmid42529883,
year = {2026},
author = {Li, X and Chen, H and Wang, X and Hu, Y and Yang, Z and Wei, M},
title = {Advances in biomarkers for Parkinson's disease: from molecular pathology to precision diagnostics.},
journal = {Journal of Zhejiang University. Science. B},
volume = {27},
number = {7},
pages = {736-760},
pmid = {42529883},
issn = {1862-1783},
support = {82101513//the National Basic Research Program of China/ ; 2019-ZD-0943//the Natural Science Foundation of Liaoning Province/ ; },
mesh = {Humans ; *Parkinson Disease/diagnosis/pathology/genetics ; *Biomarkers/analysis ; alpha-Synuclein ; *Precision Medicine ; Pathology, Molecular ; },
abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disorder, and continues to present significant challenges in early diagnosis, precise subtyping, and prognosis assessment. In recent years, the field of biomarker research has undergone a profound paradigm shift from static concentration measurements to functional activity detection. The most revolutionary breakthrough is the α-synuclein seed amplification assay (α-Syn-SAA), which enables ultrasensitive and specific detection of pathological α-Syn in both clinical and prodromal stages, thus providing an unprecedented window for early intervention. Substantial progress has also been made in the development of biomarkers such as neurofilament light chain (NfL), Alzheimer's disease-related biomarkers, and genetic biomarkers, as well as in detection technologies based on peripheral samples. The integrated application of cutting-edge technologies, such as real-time quaking-induced conversion (RT-QuIC), high-resolution mass spectrometry, and high-field magnetic resonance imaging (MRI), is advancing the field into a new stage characterized by a focus on pathological activity, multi-omics integration, and non- or minimally invasive approaches. In this review, we explore recent advances in PD biomarkers, focusing on core pathophysiological markers. We examine the potential of multi-omics and artificial intelligence (AI) to enhance diagnostic, subtyping, and prognostic accuracy, while also outlining the pivotal role and future directions of biomarkers in advancing precision medicine for PD.},
}

Humans
*Parkinson Disease/diagnosis/pathology/genetics
*Biomarkers/analysis
alpha-Synuclein
*Precision Medicine
Pathology, Molecular

@article {pmid42530031,
year = {2026},
author = {Benbaji, M and Raveh, B and Bassal, L and Elias, U and Gazit, L and Allali, G and Marshall, GA and Arzy, S},
title = {Alzheimer disease in the computational era: from a deterministic disease to a multifaceted disorder.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag248},
pmid = {42530031},
issn = {1460-2156},
abstract = {The definition of Alzheimer disease (AD) keeps changing over the years, which is critical for studying it, understanding it, and developing treatments. Here we first review the different definitions proposed for AD from its original characterization by Kraepelin in 1908, to the recent Alzheimer's Association revised criteria in 2024. We describe these definitions in parallel to the new knowledge gained, demonstrating how they vacillate between restricted and circumscribed clinicopathological characterizations and wider clinical and pathological ones. Then, we describe AD multifaceted clinical presentations, including very early subtle cognitive and behavioural changes, alongside its pathological multifactorial variability of core-pathologies, co-pathologies and risk factors, encompassing changes in various cortical and subcortical brain regions, and its genetic complex landscape. We suggest that all potential factors among the different levels should be considered to provide a patient-tailored clinical profile. To address the richness and complexity of the data, we outline a metamodeling-based computational framework that allows diverse sources of evidence to be integrated without forcing them into a single monolithic model. Specifically, different data subsets are first used to construct partial models, each addressing selected domains and factors; these models are then converted into probabilistic surrogate models with shared variables and parameters; finally, the latent variables inferred from the surrogate models are related via a probabilistic coupling layer to create predictions of individual patients' trajectories and intervention effects, staging, clinical stratification and attribution maps. Taken together, the computational and data revolutions may enable us to expose the complexity of AD through large-scale patients' data, computational metamodeling, and hypothesis-free analyses, leading to reconceptualization of AD from a monolithic diagnostic category into a stratified, mechanistically interpretable nosology, with practical implications at the individual patient level.},
}

@article {pmid42530037,
year = {2026},
author = {Skondra, M and Papadopoulos, L and Kougioumtzoglou, T and Kandilakis, CL and Konidari, E and Papalexiou, V and Marouli, I and Malagkoniari, LM and Kostakiotis, A and Veskoukis, T and Peritogiannis, V and Economou, P and Felemegkas, P and Alexopoulos, P},
title = {Anticholinergic Burden and Cognitive Function, Depressive Symptoms, and Functional Performance in Individuals With Neurocognitive Disorders: Real-World Evidence.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {7},
pages = {51135},
doi = {10.31083/JIN51135},
pmid = {42530037},
issn = {0219-6352},
mesh = {Humans ; Female ; Male ; Aged ; *Depression/chemically induced/physiopathology ; Aged, 80 and over ; *Activities of Daily Living ; *Cholinergic Antagonists/adverse effects ; *Neurocognitive Disorders/physiopathology ; *Cognition/drug effects ; *Cognitive Dysfunction/physiopathology/chemically induced ; *Functional Status ; },
abstract = {BACKGROUND: Despite their negative effects on cognitive function and cognitive decline risk, drugs with anticholinergic properties are commonly prescribed, particularly in older individuals. In this observational study we aimed to shed light on the relationships between anticholinergic burden (ACB) and depressive symptoms and cognitive and functional performance in a real-world clinical setting.

METHODS: The study included individuals seeking care at the old-age psychiatry outpatient clinic of Patras University Mental Health Services. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale; cognitive function was tapped using the Cognitive Telephone Screening Instrument, the Montreal Cognitive Assessment, and the Mini-Mental State Examination; and functional performance was assessed using the Bristol Activities of Daily Living Scale. Differences in demographic and clinical variables across the four diagnostic groups were analyzed. Regression analyses were performed to examine the associations between ACB, cognitive and non-cognitive symptoms, and demographic variables. In addition, clustering analyses were conducted to identify distinct, naturally occurring examinee subgroups and to assess if ACB differed across them.

RESULTS: The study sample consisted of individuals without cognitive impairment (N = 301), people with mild neurocognitive disorder (MiND, N = 264), major neurocognitive disorder caused by Alzheimer's disease (ADMaND, N = 114), or other diseases (nonADMaND, N = 63). Significant associations were detected between ACB and depressive symptoms (0.72, p < 0.001), short-term memory (-0.11, p = 0.017), long-term memory (-0.24, p < 0.001), working memory (-0.24, p = 0.001), attention/concentration (-0.13, p = 0.004), verbal fluency (-0.57, p = 0.003), inductive reasoning (-0.17, p = 0.002), basic activities of daily living (0.29, p = 0.001), and instrumental activities of daily living (0.58, p < 0.001). The clustering analyses indicated that in the cluster including individuals with more advanced cognitive decline, poorer functional status, and more severe depressive symptoms, ACB was higher compared with the second group identified by the analyses (p < 0.001).

CONCLUSIONS: ACB is related to different aspects of the clinical phenotype of cognitive decline. Despite the lack of solid evidence regarding causal relationships and need for further research, minimizing ACB in clinical settings may embody a potential pragmatic strategy in managing cognitive decline in ageing.},
}

Humans
Female
Male
Aged
*Depression/chemically induced/physiopathology
Aged, 80 and over
*Activities of Daily Living
*Cholinergic Antagonists/adverse effects
*Neurocognitive Disorders/physiopathology
*Cognition/drug effects
*Cognitive Dysfunction/physiopathology/chemically induced
*Functional Status

@article {pmid42530040,
year = {2026},
author = {Shi, Q and Pradhan, AK and Dong, S and Rammes, G and Wang, X},
title = {Sevoflurane and Aβ1-42 Oligomers Synergistically Induce Morphological Changes of Astrocytes in the Hippocampus of Male Mice.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {7},
pages = {50442},
doi = {10.31083/JIN50442},
pmid = {42530040},
issn = {0219-6352},
support = {2024MZFS003//Open Fund Program of the Key Laboratory of Anesthesiology and Resuscitation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/pharmacology ; *Sevoflurane/pharmacology ; *Peptide Fragments/pharmacology/administration & dosage ; *Astrocytes/drug effects/pathology/metabolism ; Male ; *Hippocampus/drug effects/pathology/metabolism ; Glial Fibrillary Acidic Protein/metabolism/drug effects ; *Anesthetics, Inhalation/pharmacology/administration & dosage ; Mice ; },
abstract = {BACKGROUND: Reactive gliosis serves as a characteristic feature of the pathophysiology of Alzheimer's disease (AD). Nevertheless, the influence of anesthetics on the morphological dynamics of astrocytes remains ambiguous.

METHODS: Employing ex vivo hippocampal slices, in this study, we explored the impacts of sevoflurane and Amyloid-β peptide 1-42 (Aβ1-42) oligomers on astrocytic morphology. The primary outcomes encompassed the fluorescence intensity of glial fibrillary acidic protein (GFAP), the levels of a 38-kDa GFAP breakdown product (a marker of astroglial injury), and quantitative morphometric analyses (cell volume, surface area, branch complexity, and Sholl intersections).

RESULTS: Co-exposure to sevoflurane and Aβ1-42 led to an elevation of the 38-kDa GFAP breakdown product and a significant reduction in the mean fluorescence intensity of GFAP. Moreover, it resulted in a decrease in astrocytic volume, surface area, branch complexity, and Sholl intersections. These synergistic alterations were not observed when either treatment was administered alone.

CONCLUSIONS: These findings imply that sevoflurane aggravates Aβ1-42-induced astrocytic dysfunction, which has implications for perioperative management in patients with AD or those at risk of developing AD.},
}

Animals
*Amyloid beta-Peptides/pharmacology
*Sevoflurane/pharmacology
*Peptide Fragments/pharmacology/administration & dosage
*Astrocytes/drug effects/pathology/metabolism
Male
*Hippocampus/drug effects/pathology/metabolism
Glial Fibrillary Acidic Protein/metabolism/drug effects
*Anesthetics, Inhalation/pharmacology/administration & dosage
Mice

@article {pmid42530050,
year = {2026},
author = {Sheng, J and Lin, J and Zhang, Q and Gong, Z and Zhang, R and Wu, M and Cheng, Y and Zhu, X and Sun, Z},
title = {A Multi-Frequency Self-Supervised Fusion Model for EEG-Based Dementia Classification.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {7},
pages = {50737},
doi = {10.31083/JIN50737},
pmid = {42530050},
issn = {0219-6352},
support = {LZ24F010007//Key Program of Natural Science Foundation of Zhejiang Province/ ; 62271177//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnosis/classification ; *Electroencephalography/methods ; *Frontotemporal Dementia/diagnosis/physiopathology/classification ; *Supervised Machine Learning ; *Brain Waves/physiology ; Classification Algorithms ; },
abstract = {BACKGROUND: Brain source localization technology enables precise characterization of the spatial distribution of neural activity, serving as a crucial tool for exploring the pathological mechanisms underlying dementia. However, effectively integrating complementary diagnostic information from source localization features across multiple frequency bands remains a major challenge to enhancing classification performance and model interpretability.

METHODS: An attention-based multi-frequency self-supervised fusion model (AM-SSF) is proposed to address this issue. Independent contrastive self-supervised encoders are trained for the θ (4-8 Hz), α (8-13 Hz), β (13-30 Hz), and γ (30-48 Hz) frequency bands to learn band-specific latent representations. Then, an attention-guided adaptive fusion module is introduced to dynamically allocate band weights through cross-entropy-based supervised optimization, thereby achieving effective cross-band information integration. Finally, a random forest classifier is employed to evaluate the model's performance in distinguishing Alzheimer's disease (AD) from frontotemporal dementia (FTD).

RESULTS: Experimental results show that the proposed framework achieves a classification accuracy of 93.1% under five-fold cross-validation, significantly outperforming baseline methods such as single-band self-supervised learning (SSL) and average pooling fusion. Further analysis of the attention weight distributions revealed that the θ and β bands contributed most to model decision-making, providing interpretability regarding frequency-specific effects.

CONCLUSIONS: In summary, the proposed AM-SSF model enhances AD and FTD classification performance while offering valuable insights into the discriminative roles of frequency band features.},
}

Humans
*Alzheimer Disease/physiopathology/diagnosis/classification
*Electroencephalography/methods
*Frontotemporal Dementia/diagnosis/physiopathology/classification
*Supervised Machine Learning
*Brain Waves/physiology
Classification Algorithms

@article {pmid42530052,
year = {2026},
author = {Shcheblykina, OV and Kostina, DA and Pokrovskii, MV and Korokin, MV},
title = {Neurotrophic Factors in Stroke, Traumatic Brain Injury, and Neurodegeneration: A Convergent Pathophysiological and Translational Perspective.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {7},
pages = {51543},
doi = {10.31083/JIN51543},
pmid = {42530052},
issn = {0219-6352},
support = {FZWG-2026-0003//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {Humans ; *Brain Injuries, Traumatic/metabolism/therapy/physiopathology ; Animals ; *Stroke/metabolism/therapy/physiopathology ; *Nerve Growth Factors/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/physiopathology ; },
abstract = {Neurotrophic factors (NTFs), including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), and vascular endothelial growth factor (VEGF), play a central role in neuronal survival, plasticity, and regeneration. Despite their distinct etiologies and temporal profiles, stroke (both ischemic and hemorrhagic), traumatic brain injury (TBI), and neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), converge on a common pathophysiological phenotype characterized by excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal apoptosis. Neurotrophic factors modulate these pathological cascades through tropomyosin receptor kinase (Trk) receptors, p75 neurotrophin receptor (p75NTR), and related signaling pathways, thereby supporting neuroprotection, neurogenesis, and synaptogenesis. Experimental evidence from preclinical models demonstrates robust beneficial effects of neurotrophin-based interventions in stroke, TBI, AD, and PD across protein, gene, and cell-based strategies. However, clinical translation remains severely limited. Early-phase clinical trials of adeno-associated virus (AAV)-mediated GDNF and neurturin gene therapy for PD, ex vivo NGF gene therapy for AD, and BDNF gene therapy for AD have confirmed acceptable safety profiles but yielded modest or inconsistent efficacy, largely due to constraints in brain delivery, the need for invasive neurosurgical procedures, restricted target coverage, suboptimal control of expression, and marked patient heterogeneity. Consequently, the principal barrier to clinical success is not biological validity, but the lack of safe, effective and scalable delivery platforms capable of bypassing or functionally modulating the BBB. In this review we synthesize shared pathophysiological mechanisms linking stroke, TBI and NDDs; examine the biology, receptor systems, and signaling pathways of key neurotrophic factors; summarize preclinical evidence for their therapeutic potential; and critically evaluate current delivery strategies, including viral vectors, lipid nanoparticles, exosomes, cell-based therapies, small-molecule mimetics, and intranasal administration. We conclude that overcoming delivery barriers through development of improved viral and non-viral platforms, minimally invasive administration routes, controllable expression systems, and rational patient stratification based on disease stage and biomarkers will be essential to fully realize the neuroprotective and neuroregenerative potential of neurotrophin-based therapies for acute and chronic brain disorders.},
}

Humans
*Brain Injuries, Traumatic/metabolism/therapy/physiopathology
Animals
*Stroke/metabolism/therapy/physiopathology
*Nerve Growth Factors/metabolism
*Neurodegenerative Diseases/metabolism/therapy/physiopathology

@article {pmid42530076,
year = {2026},
author = {Li, Y and Gong, J and Yang, L and Jin, L and Peng, R and Wang, F and Wang, L},
title = {Investigating the Therapeutic Mechanism of Ginkgo Biloba Extract in Alzheimer's Disease via Integrated Network Pharmacology and Molecular Docking.},
journal = {Die Pharmazie},
volume = {81},
number = {7},
pages = {51748},
doi = {10.31083/Pharmazie51748},
pmid = {42530076},
issn = {3053-691X},
support = {232102311152//Scientific and Technological Project in Henan Province/ ; },
mesh = {Animals ; Molecular Docking Simulation ; *Ginkgolides/pharmacology ; *Ginkgo biloba/chemistry ; *Alzheimer Disease/drug therapy/genetics ; *Plant Extracts/pharmacology/chemistry ; Mice ; Ginkgo Extract ; Molecular Dynamics Simulation ; Network Pharmacology ; Humans ; Amyloid beta-Peptides ; Protein Interaction Maps/drug effects ; Cell Line ; Disease Models, Animal ; },
abstract = {OBJECTIVE: This study aimed to investigate the mechanisms through which ginkgolides in Ginkgo biloba extract (GBE) may protect against Alzheimer's disease (AD).

METHODS: Candidate ginkgolide constituents and their putative targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SwissTargetPrediction. AD-associated genes were retrieved from OMIM and GeneCards. Overlapping targets were used to construct component-target-disease and protein-protein interaction (PPI) networks for hub target screening. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using DAVID. AutoDock Vina was used for molecular docking, and molecular dynamics simulations were conducted to evaluate ligand-target stability. The predicted mechanisms were further examined in APP/PS1 mice and Aβ1-42-treated HT22 cells.

RESULTS: A total of 27 active ginkgolide-related constituents and 336 intersecting targets were identified. Ginkgolides B and M were identified as the major active compounds, whereas MAPK3, HIF-1α, and AKT1 emerged as important targets. Enrichment analysis indicated a close association with the PI3K-Akt pathway. Docking analysis showed that ginkgolides B and M bound strongly to MAPK3 and HIF-1α with binding energies ranging from -9.34 to -8.41 kcal/mol. Molecular dynamics simulations supported the stable formation of these complexes. In vivo and in vitro experiments showed that ginkgolides B and M alleviated synaptic protein damage, decreased HIF-1α expression, and improved cognitive deficits.

CONCLUSIONS: Ginkgolides B and M may contribute to anti-AD effects in experimental models, partly through modulation of HIF-1α-related stress responses and PI3K-Akt-associated survival pathways.},
}

Animals
Molecular Docking Simulation
*Ginkgolides/pharmacology
*Ginkgo biloba/chemistry
*Alzheimer Disease/drug therapy/genetics
*Plant Extracts/pharmacology/chemistry
Mice
Ginkgo Extract
Molecular Dynamics Simulation
Network Pharmacology
Humans
Amyloid beta-Peptides
Protein Interaction Maps/drug effects
Cell Line
Disease Models, Animal

@article {pmid42530129,
year = {2026},
author = {Monge-García, V and Lorenzo-García, S and Bernal-Soriano, MC and Torrella-Esteban, P and Monge-García, S and Sánchez-Payá, J and Monge-Argilés, JA},
title = {Validation of Plasma p-tau217 as a Biomarker of Prodromal Alzheimer's Disease.},
journal = {Revista de neurologia},
volume = {81},
number = {7},
pages = {50619},
doi = {10.31083/RN50619},
pmid = {42530129},
issn = {1576-6578},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/cerebrospinal fluid ; *tau Proteins/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; Female ; Male ; Aged ; Cognitive Dysfunction/blood/cerebrospinal fluid/diagnosis ; Reproducibility of Results ; Prodromal Symptoms ; Middle Aged ; Sensitivity and Specificity ; },
abstract = {BACKGROUND: Plasma phosphorylated tau 217 protein (p-tau217p) has recently been proposed as a useful biomarker for the early diagnosis of Alzheimer's disease (AD). However, local validation is recommended because of the potential influence of clinical, analytical, and preanalytical factors on assay performance.

METHODS: Between 2021 and 2024, we evaluated patients with amnestic mild cognitive impairment (aMCI) through clinical history, neurological and neuropsychological examination, blood sampling for biobanking, brain imaging, and lumbar puncture, among other diagnostic tests. In September 2025, p-tau217p levels were measured simultaneously using the LUMIPULSE immunoassay (Fujirebio). The diagnostic validity, reproducibility, receiver operating characteristic (ROC) curve performance, correlation with cerebrospinal fluid (CSF) biomarkers, and influence of clinical and analytical variables were evaluated in this study.

RESULTS: Among the 108 aMCI patients included, 66 met the criteria for clinic-biological AD, while the remainder had alternative clinical diagnoses. Using a two-threshold approach, p-tau217p levels ≥0.19 yielded a sensitivity of 88% and a positive predictive value of 83% for identifying AD. Levels ≥0.39 showed a specificity of 91% and a positive predictive value of 90% for the same purpose. Intermediate values (0.20-0.38) achieved a specificity of 83%. The intraclass correlation coefficient for the assay reproducibility was 0.97. The ROC curve for p-tau217p demonstrated an area under the curve of 0.86 for diagnosing AD. P-tau217p correlated more strongly with CSF p-tau181 (ρ = 0.63; p < 0.01) than with CSF Aβ1-42 (ρ = -0.40; p < 0.01). Finally, a reduced glomerular filtration rate was associated with a significant increase in p-tau217p levels (p < 0.006).

CONCLUSIONS: In our setting, p-tau217p measurement showed a high validity for the diagnosis of prodromal AD, which is consistent with the recent neurological literature. The assay showed high reproducibility, although results may be influenced by renal function. P-tau217p correlated more strongly with CSF p-tau181 than with CSF Aβ1-42.},
}

Humans
*Alzheimer Disease/blood/diagnosis/cerebrospinal fluid
*tau Proteins/blood/cerebrospinal fluid
Biomarkers/blood/cerebrospinal fluid
Female
Male
Aged
Cognitive Dysfunction/blood/cerebrospinal fluid/diagnosis
Reproducibility of Results
Prodromal Symptoms
Middle Aged
Sensitivity and Specificity

@article {pmid42530130,
year = {2026},
author = {Li, P and Wang, Y},
title = {AI-Enabled Modeling for Alzheimer's Disease Risk Prediction and Validation.},
journal = {Revista de neurologia},
volume = {81},
number = {7},
pages = {49220},
doi = {10.31083/RN49220},
pmid = {42530130},
issn = {1576-6578},
mesh = {Humans ; *Alzheimer Disease/diagnosis/genetics/cerebrospinal fluid ; Female ; Retrospective Studies ; Risk Assessment/methods ; Male ; Aged ; Random Forest ; Boosting Machine Learning Algorithms ; Predictive Learning Models ; Risk Factors ; Prediction Algorithms ; *Artificial Intelligence ; Amyloid beta-Peptides/cerebrospinal fluid ; Apolipoprotein E4/genetics ; Biomarkers/cerebrospinal fluid ; },
abstract = {BACKGROUND: To investigate the multimodal clinical influencing factors of Alzheimer's disease (AD) onset, and to establish and test a risk prediction tool derived from these determinants and additional clinical measures, thus facilitating early intervention and risk classification in individuals at high risk for AD.

METHODS: A retrospective cohort of 502 high-risk individuals for AD (exhibiting cognitive decline or family history) who visited our hospital was included. A total of 502 participants were randomly split into a training cohort (n = 350) and a validation cohort (n = 152) in a 7:3 proportion. Demographic characteristics, clinical indicators, biomarkers, and genetic markers were collected. In the training set, univariate analysis and least absolute shrinkage and selection operator (LASSO) regression were first applied for variable screening, followed by multivariate logistic regression to pinpoint independent influencing factors. Random forest (RF), XGBoost, and deep learning models were constructed using Python, with performance evaluated using area under the curve (AUC). The optimal model was selected, and feature importance was analyzed.

RESULTS: Between the training and validation sets, no statistically significant baseline characteristic differences were found (p > 0.05). Multivariate logistic regression identified the apolipoprotein E epsilon 4 allele (APOE ε4) genotype, cerebrospinal fluid (CSF) p-tau181/amyloid-beta 42 (Aβ42) ratio, and diabetes as independent risk factors for AD (p < 0.05), while serum folate levels, Mini-Mental State Examination (MMSE) scores, and Montreal Cognitive Assessment (MoCA) scores served as independent protective factors (p < 0.05). In the validation set, the RF model achieved the highest AUC (0.879), followed by XGBoost (0.869) and deep learning (0.844), with the CSF p-tau181/Aβ42 ratio identified as the most predictive feature.

CONCLUSION: The RF model, based on integrated multimodal clinical influencing factors and clinical indicators, demonstrates potential for AD risk stratification in high-risk populations when evaluated on a validation cohort.},
}

Humans
*Alzheimer Disease/diagnosis/genetics/cerebrospinal fluid
Female
Retrospective Studies
Risk Assessment/methods
Male
Aged
Random Forest
Boosting Machine Learning Algorithms
Predictive Learning Models
Risk Factors
Prediction Algorithms
*Artificial Intelligence
Amyloid beta-Peptides/cerebrospinal fluid
Apolipoprotein E4/genetics
Biomarkers/cerebrospinal fluid

@article {pmid42530254,
year = {2026},
author = {Stepenko, Y and Shcheblykina, O and Zhunusov, N and Shmigerova, V and Kozin, S and Mitkevich, V and Radchenko, A and Kuzubova, E and Khalzov, L and Korokin, M},
title = {Peripheral Administration of isoD7-Aβ Exacerbates Motor Deficits and Tau Pathology in P301S Mice.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {7},
pages = {53279},
doi = {10.31083/FBL53279},
pmid = {42530254},
issn = {2768-6698},
support = {FZWG-2026-0003//Program of Fundamental Research in the Russian Federation/ ; 124031800075-1//Program of Fundamental Research in the Russian Federation/ ; },
mesh = {Animals ; *tau Proteins/metabolism/genetics ; Mice ; *Amyloid beta-Peptides/administration & dosage ; Mice, Transgenic ; Male ; *Alzheimer Disease/pathology/metabolism ; Brain/metabolism/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Mice, Inbred C57BL ; Signal Transduction ; Disease Models, Animal ; Glycogen Synthase Kinase 3 beta/metabolism ; Apoptosis ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to dementia, disability, and premature death. Beta-amyloid (Aβ) and tau pathology are considered key components of its pathogenesis; however, the role of peripheral amyloid load in modulating pre-existing tau pathology remains understudied. We hypothesized that peripheral amyloid load could exacerbate tau pathology through mechanisms potentially linked to the disruption of the Akt/glycogen synthase kinase-3β-associated signaling pathway, which could lead to increased behavioral deficits and progression of neurodegenerative changes.

OBJECTIVE: To evaluate the effect of double peripheral (retro-orbital) administration of the Aβ isoform D7 on the behavioral phenotype, morphological signs of tau pathology, and the expression of genes related to Akt/GSK-3β-associated signaling, neuroinflammation, and apoptosis in the brains of P301S transgenic mice.

MATERIALS AND METHODS: The study included 12-week-old male P301S transgenic mice (Tg(Thy1-MAPT*P301S)2541Godt) (n = 20, biological duplication) and wild-type C57Black6/J mice (n = 10). P301S mice received two retro-orbital injections of isoD7-Aβ into the venous sinus at a dose of 100 µg (n = 10) with a 1-month interval; control P301S mice received an equivalent volume of water for injection (n = 10). Behavioral testing ("open field", "novel object recognition", "vertical pole", "inverted screen") was performed at 16 and 20 weeks of age. Tau pathology was assessed immunohistochemically using AT-8 (pSer202/pThr205) antibodies in the frontal cortex and brainstem, and amyloid deposits were assessed histologically using Congo red staining in the entorhinal cortex and hippocampus. The expression of Akt1, Gfap, Mapt, Cdk5, Casp3, Bax, and Bcl2 genes in brain tissue was analyzed by quantitative real-time PCR.

RESULTS: Two peripheral administrations of isoD7-Aβ were not associated with further deterioration of performance in the "open field" and "novel object recognition" tests compared to the control P301S group, which likely reflects the already established deficit characteristic of this transgenic line. In contrast, in motor coordination tests ("vertical pole", "inverted screen"), motor impairments in the P301S+Aβ group emerged by week 16, whereas in P301S mice without amyloid load, they appeared only by week 20. Immunohistochemical analysis revealed an increase in AT-8-positive staining in the brainstem, whereas no statistically significant differences were found between groups in the frontal cortex. Histological analysis did not reveal amyloid plaques in the entorhinal cortex and hippocampus of P301S+Aβ mice and control P301S mice. At the molecular level, the P301S+Aβ group showed decreased Akt1 expression, increased Gfap and Bax expression, and decreased Bcl2 expression, with no significant changes in Mapt, Casp3, and Cdk5. This pattern is consistent with dysregulation of Akt/GSK-3β-associated signaling, enhanced glial activation, and a pro-apoptotic shift.

CONCLUSIONS: Two peripheral administrations of isoD7-Aβ to P301S mice were associated with earlier development of motor impairments, increased tau protein phosphorylation, and changes in gene expression consistent with a disrupted Akt/GSK-3β-associated signaling pathway. These findings support the hypothesis that peripheral amyloid load can exacerbate tauopathy manifestations, and the observed transcriptional changes are consistent with the possible involvement of the Akt/GSK-3β-associated signaling pathway, which may represent a potential therapeutic target in AD.},
}

Animals
*tau Proteins/metabolism/genetics
Mice
*Amyloid beta-Peptides/administration & dosage
Mice, Transgenic
Male
*Alzheimer Disease/pathology/metabolism
Brain/metabolism/pathology
Proto-Oncogene Proteins c-akt/metabolism
Mice, Inbred C57BL
Signal Transduction
Disease Models, Animal
Glycogen Synthase Kinase 3 beta/metabolism
Apoptosis

@article {pmid42530260,
year = {2026},
author = {Kravtsov, A and Kozin, S and Kondratenko, R and Lyasota, O and Dorohova, A and Leontyeva, O and Hernandez-Caceres, JL and Dzhimak, S},
title = {Neuroprotective Properties and Molecular Mechanisms of Action of 4H-Pyran-Based Acids.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {7},
pages = {48552},
doi = {10.31083/FBL48552},
pmid = {42530260},
issn = {2768-6698},
support = {075-15-2025-283//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {Humans ; *Neuroprotective Agents/pharmacology/chemistry ; Animals ; Signal Transduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Pyrans/pharmacology/chemistry ; Pyrones/pharmacology/chemistry ; Antioxidants/pharmacology ; },
abstract = {The development of effective neuroprotective agents remains one of the most urgent and complex challenges in modern medical and biological research, given the increasing prevalence of neurodegenerative diseases and the limited efficacy of existing therapeutic options. In recent years, compounds belonging to the 4H-pyran chemical class have attracted significant attention due to their pronounced antioxidant, anti-inflammatory, and cytoprotective properties. These molecules exhibit structural versatility, enabling modulation of multiple molecular targets involved in neuronal survival, redox homeostasis, and mitochondrial function. This review provides a comprehensive analysis of the pharmacological activity and molecular mechanisms of action of five 4H-pyran-based compounds-maltol, kojic acid, chelidonic acid, comenic acid, and meconic acid. Special attention is paid to their effects on signaling pathways that play a central role in maintaining neuronal integrity and resistance to stress factors. In particular, the review examines how these compounds regulate key intracellular cascades such as nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response element (ARE), Nrf2/PTEN-induced putative kinase 1 (PINK1)/Parkin, nuclear factor-kappa B (NF-κB), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), which are critically involved in controlling oxidative stress, mitochondrial autophagy, inflammation, and neuronal plasticity. The integrated evaluation of these mechanisms demonstrates that 4H-pyran-based acids can act as multitarget neuroprotective agents capable of influencing both primary metabolic processes and secondary signaling responses to neurotoxic stimuli. Their pleiotropic action highlights the promise of these compounds as molecular scaffolds for the development of novel drugs aimed at preventing or delaying the progression of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.},
}

Humans
*Neuroprotective Agents/pharmacology/chemistry
Animals
Signal Transduction/drug effects
*Neurodegenerative Diseases/drug therapy/metabolism
*Pyrans/pharmacology/chemistry
Pyrones/pharmacology/chemistry
Antioxidants/pharmacology

@article {pmid42530543,
year = {2026},
author = {Pan, Y and Cho, B and Stallings-Smith, S},
title = {Sex and racial/ethnic patterns in subjective cognitive concerns-related functional difficulties among middle-aged and older adults: A multi-year cross-sectional analysis of a population-based U.S. adult sample in 2015-2022.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261472887},
doi = {10.1177/13872877261472887},
pmid = {42530543},
issn = {1875-8908},
abstract = {BackgroundExperiencing subjective cognitive concerns (SCC) marks a potential risk stage for Alzheimer's disease.ObjectiveThis study examined sex and racial/ethnic patterns in the prevalence of functional difficulties among U.S. adults with SCC.MethodsData for 32,105 adults aged ≥45 years who experienced SCC in the past year were sourced from the Behavioral Risk Factor Surveillance System in 2015-2022. Individuals reporting SCC-related functional difficulties in daily or social life activities always/usually/sometimes (versus rarely/never) in the past year were considered having each of the functional difficulties. Weighted binomial logistic regression analyses were conducted to examine the association of sex (male or female) and race/ethnicity (non-Hispanic White [NHW], non-Hispanic Black [NHB], Hispanic, or non-Hispanic Other [NHO]) with SCC-related daily and social life difficulties, adjusting for all covariates.ResultsOverall, a decreasing trend in SCC-related functional difficulties was observed in both sexes, while female adults had higher prevalence. Trends in these functional difficulties varied by race/ethnicity, with NHW adults exhibiting the most stable and lowest prevalence. Female adults had significantly higher odds of experiencing SCC-related daily life (adjusted odds ratio [AOR] = 1.28, 95% confidence interval [CI] = 1.15, 1.41) and social life difficulties (AOR = 1.12, 95% CI = 1.01, 1.24) than male adults. NHB, Hispanic, and NHO groups had higher odds of experiencing SCC-related daily and social life difficulties compared to NHW participants.ConclusionsFemale and racial/ethnic minority individuals experienced higher levels of SCC-related functional difficulties. Public health interventions are warranted to alleviate such challenges for vulnerable populations.},
}

@article {pmid42530559,
year = {2026},
author = {Manzine, PR and Carrasco, M and Antonia Alves Fernandes, T and Santos Alves, S and Guzman, L and Driouech, L and Millet, M and Garcia Cairasco, N and Olloquequi, J and Juan, ME and Ettcheto, M and Cominetti, MR and Camins, A},
title = {Cognitive-enhancing drugs in Phase II clinical trials for Alzheimer's disease: emerging therapeutic candidates.},
journal = {Expert opinion on investigational drugs},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543784.2026.2710112},
pmid = {42530559},
issn = {1744-7658},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is biologically defined by amyloid-β (Aβ) and tau pathology but clinically manifests as progressive synaptic dysfunction and cognitive decline. Although anti-amyloid and anti-tau therapies modestly slow disease progression, they do not directly restore cognition or synaptic function.

AREAS COVERED: Phase II trials of cognition‑enhancing therapies in AD and prodromal AD were reviewed to identify factors behind success or failure. Trials from ClinicalTrials.gov and the EU Clinical Trials Register with cognitive endpoints were assessed by mechanism, design, population, and outcomes. Strategies included synaptic, inflammatory, metabolic, vascular, and regenerative approaches.Most therapies showed limited or inconsistent cognitive effects, and many trials did not demonstrate clear efficacy.

EXPERT OPINION: Phase II cognition‑enhancing trials in AD show biological plausibility but remain methodologically limited. Cognitive signal detection depends on the fit between mechanism, disease stage, and trial design, and on the statistical approach used to capture subtle change. Outcome variability highlights the need for sensitive cognitive measures and adequate power. Progress will require precision‑enriched designs, with biomarker‑defined populations, cognitive‑trajectory modeling, and integrated cognitive and functional endpoints.},
}

@article {pmid42530714,
year = {2026},
author = {Asgari, M and Mousavi, SE and Zaeifi, D and Ehsani, E},
title = {Maternal Traumatic Brain Injury Increases Fetal Brain Cis p-tau Levels: Evidence for Potential Transplacental Effects in a Murine Model.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42530714},
issn = {1559-1166},
support = {1402-2-209-67616//Experimental Medicine Research Center, Tehran University of Medical Sciences/ ; },
mesh = {Animals ; Female ; Pregnancy ; *tau Proteins/metabolism/genetics ; *Brain Injuries, Traumatic/metabolism ; Mice ; *Brain/metabolism/embryology ; Mice, Inbred BALB C ; *Maternal-Fetal Exchange ; },
abstract = {Traumatic brain injury (TBI) is a well-established risk factor for Alzheimer's disease-related tauopathy. However, whether maternal TBI can lead to transgenerational transmission of pathogenic tau to offspring remains unknown. This study examines whether maternal Traumatic brain injury (TBI) induces pathogenic tau transfer to offspring, impairing fetal brain development. TBI was induced in pregnant Balb/C mice prior to pregnancy using a weight-drop model, while the sham group underwent anesthesia without injury, and the fetal brains were analyzed for cis p-tau using immunofluorescence (IF) and Western blotting (WB). Maternal anxiety post-TBI was assessed via the Elevated Plus Maze (EPM). Compared with the sham group, maternal TBI resulted in 4.25 and 5.81-fold increase in cis p-tau aggregation in embryonic and fetal brains, respectively (F(2,12) = 68.45, p < 0.001; F(2,12) = 102.34, p < 0.0001), and protein levels showed 3.13- and 6.79-fold increases (F(2,12) = 45.12, p < 0.001; F(2,12) = 89.67, p < 0.0001). This was accompanied by a significant increase in apparent transfer efficiency of p-tau to fetal brains (t(8) = 12.50, p < 0.0001). EPM assessment revealed that TBI-induced dams spent significantly more time in the open arms compared with sham (t(8) = 2.65, p = 0.029), suggesting reduced anxiety-like behavior or increased risk-taking. Maternal serum p-tau181 and fetal cis p-tau showed a positive but non-significant correlation (r(3) = 0.78, p = 0.120). These changes were associated with IL-6 and TNF increased by 2.8-fold (t(8) = 4.22, p = 0.003) and 1.8-fold (t(8) = 2.45, p = 0.040), respectively. These findings demonstrate a significant increase in apparent p-tau transfer efficiency from maternal serum to fetal brain following maternal TBI, although the correlation between maternal serum p-tau181 and fetal brain cis p-tau did not reach statistical significance.},
}

Animals
Female
Pregnancy
*tau Proteins/metabolism/genetics
*Brain Injuries, Traumatic/metabolism
Mice
*Brain/metabolism/embryology
Mice, Inbred BALB C
*Maternal-Fetal Exchange

@article {pmid42530851,
year = {2026},
author = {},
title = {RETRACTION: The Preventive Effects of Edible Folic Acid on Cardiomyocyte Apoptosis and Survival in Early Onset Triple-transgenic Alzheimer's Disease Model Mice.},
journal = {Environmental toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1002/tox.70167},
pmid = {42530851},
issn = {1522-7278},
abstract = {K. Lin, C. Chiu, W. Kuo, D. Ju, C. Shen, R. Chen, C. Lin, V. P. Viswanadha, J. Liu, R. S. Huang, and C. Huang, "The Preventive Effects of Edible Folic Acid on Cardiomyocyte Apoptosis and Survival in Early Onset Triple-transgenic Alzheimer's Disease Model Mice," Environmental Toxicology 33, no. 1 (2017): 83-92, https://doi.org/10.1002/tox.22498. The above article, published online on 25 October 2017 in Wiley Online Library (https://wileyonlinelibrary.com), has been retracted by agreement between the journal's Editor-in-Chief, April Rodd, and Wiley Periodicals LLC. A third party reported on PubPeer [1] that bands in Figures 2, 3, and 4 appeared to have been duplicated in other articles and preprints [Chiang et al. 2016 (https://doi.org/10.3402/fnr.v60.31417); Bai et al. 2019 (https://doi.org/10.1101/823088); and Asokan et al. 2019 (https://doi.org/10.1186/s12906-019-2700-8)]. Each article describes these bands as different samples and many show additional blots that were not included in this article. Additionally, the GAPDH control bands in Figures 2 and 3 in this article also appear to have been duplicated. The retraction has been agreed to because the evidence of data duplication and manipulation fundamentally compromises the editors' confidence in the results presented in this article. The authors were informed of the retraction. Reference [1] René Aquarius, Comments on "The preventive effects of edible folic acid on cardiomyocyte apoptosis and survival in early onset triple-transgenic Alzheimer's disease model mice," PubPeer, April 2026. https://pubpeer.com/publications/76A62C91CAA2ABA60C4A9E31783C55.},
}

@article {pmid42530901,
year = {2026},
author = {Li, TY and Yu, ZM},
title = {Opposing effects of uric acid and triglycerides on cognitive decline cancel within a metabolic oxidative composite: Longitudinal evidence from CHARLS and cross-sectional replication in NHANES.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471903},
doi = {10.1177/13872877261471903},
pmid = {42530901},
issn = {1875-8908},
abstract = {BackgroundComposite metabolic-oxidative scores have shown inconsistent associations with cognitive outcomes, yet whether their components move in the same direction remains unexamined.ObjectiveTo test whether Metabolic Oxidative Risk Score (MORS) tracks cognitive change, and to decompose MORS to assess whether component effects on cognitive slope are concordant or opposing.MethodsWe constructed a four-component MORS (uric acid, triglycerides, fasting glucose, reverse-scored HDL; range 4-20) and examined its association with cognitive change across four waves (2011-2018) in CHARLS (N = 7,300, age ≥ 45 years) using linear mixed models. Equivalence testing distinguished null findings from insufficient power. Components were decomposed individually and simultaneously. Cross-sectional triangulation used NHANES 2011-2014 (N = 1,340, age ≥ 60 years).ResultsThe adjusted MORS × time interaction was β = -0.00046 SD/year (95% CI -0.00185 to 0.00093; p = 0.516); equivalence testing rejected any clinically meaningful effect (p = 0.0002). Component decomposition revealed opposing effects: higher uric acid predicted steeper decline (β = -0.0055; p = 0.003) while higher triglycerides predicted attenuated decline (β = + 0.0042; p = 0.045), with near-perfect cancellation at the composite level. In NHANES, the MORS-cognition association reversed sign after socioeconomic adjustment and showed a significant non-linear association (p = 6 × 10[-4]); leave-one-out analysis identified uric acid as the dominant signal carrier.ConclusionsAn equal-weight metabolic-oxidative composite does not track cognitive decline because its components exert opposing effects that cancel. Uric acid emerges as an independent, potentially modifiable risk factor with implications for Alzheimer's disease prevention research.},
}

@article {pmid42530906,
year = {2026},
author = {Novotný, JS and Thatcher, A and Shatti, D and Mofardin, S and Rakuša, M and Kolenc, M and Zupan, M and Frol, S and Popović, KŠ and Oblak, JP and Bossert, I and Kuruvilla, T and Lyburn, I and Trifiro, G and Stokin, GB},
title = {Evaluation of the Addenbrooke's Cognitive Examination-Revised in a routine cognitive outpatient clinic.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471428},
doi = {10.1177/13872877261471428},
pmid = {42530906},
issn = {1875-8908},
abstract = {BackgroundThe Addenbrooke's Cognitive Examination-Revised (ACE-R) is a widely used multidomain cognitive screening instrument. However, its performance in routine cognitive outpatient clinics with heterogeneous, diagnostically unselected populations remains insufficiently characterized.ObjectiveTo evaluate the diagnostic accuracy and clinical utility of ACE-R across the spectrum of cognitive impairment in a real-world cognitive outpatient setting.MethodsThis retrospective observational study included 348 consecutive patients attending a cognitive outpatient clinic. Diagnostic accuracy was assessed using binary and multiclass classification, and longitudinal cognitive trajectories were analysed using multilevel modelling.ResultsACE-R reliably differentiated dementia from non-dementia and distinguished Alzheimer's disease from mild cognitive impairment. Discrimination between subjective cognitive impairment and normal cognition was limited, consistent with the absence of objective cognitive deficits in subjective cognitive impairment. The instrument demonstrated greater sensitivity for cortical dementias than for subcortical conditions. Longitudinal analyses showed significant cognitive decline in Alzheimer's disease.ConclusionsACE-R is a practical and clinically useful screening tool for routine outpatient settings, particularly for dementia detection. However, limited sensitivity in early-stage impairment and restricted ability to differentiate dementia subtypes support its use within a multimodal diagnostic framework rather than as a standalone instrument.},
}

@article {pmid42530934,
year = {2026},
author = {Calderón-Garcidueñas, L and Stommel, EW and Hernández-Luna, J and Clouston, SAP and Muñoz, MJ and Loera-Barba, BA and Torres-Jardón, R and Nalbantoglu, OU},
title = {Abnormal eye movements reflect early cortical and volumetric brain changes in apparently healthy, PM2.5-exposed urban youth.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471048},
doi = {10.1177/13872877261471048},
pmid = {42530934},
issn = {1875-8908},
abstract = {BackgroundEye movement dysfunction plays an important role in understanding the pathology of neurodegenerative disorders. Fine particulate matter (PM2.5) exposures are associated with hallmark proteins diagnostic of Alzheimer's and Parkinson's diseases in Metropolitan Mexico City (MMC) ≤ 40-year-old residents.ObjectiveTo assess oculomotor function with neuroanatomical correlates using magnetic resonance imaging (MRI) region of interest analysis in young urbanites.MethodsVideo-based eye-tracking was used to explore oculomotor dysfunction and structural brain MRI changes in two highly exposed PM2.5 cohorts. We assessed fixation stability, smooth pursuit, pro-saccades, and anti-saccades using the Eyelink 1000-plus eye-tracker, in 80 volunteers' age 33 ± 11 years from MMC and Cuernavaca. Forty-five MMC subjects age 31.2 ± 14.7 years with oculomotor assessment had brain MRIs. Measurements of saccadic accuracy, latency, and smooth pursuit gain and square wave jerk frequency were collected.ResultsOculomotor variables did not reach statistically significant differences in MMC versusCuernavaca. Abnormal antisaccades, low gain pursuit, and square wave jerks were documented more often in MMC residents. Correlational analysis between oculomotor function and structural MRI data revealed statistical cortical and subcortical changes at frontal-temporal-parietal regions, hippocampus, thalamus, caudate, amygdala, habenula, nucleus accumbens, and cerebellum. Involved regions potentially reveal the location and severity of neurodegeneration processes via altered saccade parameters.ConclusionsOur findings suggest that simple oculomotor test batteries may provide a useful tool to monitor and/or measure the impact of pollution on neurodevelopment and early neurodegeneration. The integration of ocular movement parameters into the Continuum model of neurodegeneration offers a promising approach for neuroprotection decision-making and rigorous emissions control in polluted settings.},
}

@article {pmid42530937,
year = {2026},
author = {Tanaka, K and Ogawa, S and Suzuki, H and Fujiwara, Y and Nobuhara, T and Kato, H and Kawamoto, R and Kimura, E and Miyake, Y},
title = {Association between number of teeth and functional tooth units and prevalence of mild cognitive impairment in Japan: Baseline data from the Aidai Cohort Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470790},
doi = {10.1177/13872877261470790},
pmid = {42530937},
issn = {1875-8908},
abstract = {BackgroundEpidemiological studies have suggested a possible association between tooth loss and dementia, yet evidence regarding mild cognitive impairment (MCI) remains limited.ObjectiveWe examined the association between the number of remaining teeth and functional tooth units (FTUs) and the prevalence of MCI.MethodsA total of 8697 adults aged 20-95 years (3786 men and 4911 women) were included. Dental status was assessed visually, excluding third molars. MCI was defined as a score of less than 26 on the Japanese version of the Montreal Cognitive Assessment. Participants were categorized into five groups based on the FTUs of natural teeth (n-FTUs) and total FTUs: n-FTUs ≥10; n-FTUs 6-9 and total FTUs ≥10; n-FTUs 6-9 and total FTUs <10; n-FTUs <6 and total FTUs ≥10; and n-FTUs <6 and total FTUs <10.ResultsThe prevalence of MCI was 35.5%. A reduced number of teeth was significantly associated with the higher prevalence of MCI (p for trend <0.0001). Compared with having n-FTUs ≥10, having n-FTUs <6 and total FTUs ≥10, and having n-FTUs <6 and total FTUs <10 were independently associated with a higher prevalence of MCI. There was no association between having 6-9 n-FTUs, regardless of total FTUs, and the prevalence of MCI.ConclusionsEven when occlusal function is maintained through prosthodontic restorations, a reduced number of natural teeth is independently associated with MCI, underscoring the importance of preserving natural dentition for maintaining cognitive health.},
}

@article {pmid42531044,
year = {2026},
author = {Li, Y and Wang, S and Xie, K and Qian, S and Ma, M and Zhang, H},
title = {Burden trends of Alzheimer's disease and other dementias in China, 1990-2023: Sex, age, and risk-attributable patterns.},
journal = {Annals of the Academy of Medicine, Singapore},
volume = {},
number = {},
pages = {},
doi = {10.47102/annals-acadmedsg.2026146},
pmid = {42531044},
issn = {2972-4066},
abstract = {INTRODUCTION: China's population has aged rapidly in recent decades, accompanied by a steady rise in Alzheimer's disease and other dementias (ADOD). Understanding long-term national trends is important for anticipating future healthcare needs.

METHOD: The authors analysed Global Burden of Disease (GBD) 2023 estimates for China from 1990 to 2023, following the Guidelines for Accurate and Transparent Health Estimates Reporting, with STROBE used as a secondary reporting reference. Deaths, disability-adjusted life years (DALYs), incidence, and prevalence were examined together with crude rates, age-standardised rates (ASRs), and average annual percentage changes. Results were evaluated and stratified by sex and broad age group. Modelled risk-attributable burden was assessed for selected GBD risk factors-ambient particulate matter pollution, high fasting plasma glucose, smoking, and household air pollution from solid fuels.

RESULTS: Over the study period, the number of people affected increased markedly. Deaths rose from 122,411 in 1990 to 586,002 in 2023, while DALYs and prevalent cases more than tripled. In contrast, ASR showed only modest upward changes. Women had higher ASRs in 2023, although mortality- and DALY-related rates increased more quickly among men. The burden remained concentrated in those aged 75 years and older. Among the selected exposures, ambient particulate matter pollution accounted for the largest attributable share in 2023, whereas household air pollution declined over time.

CONCLUSION: The marked increase in absolute ADOD burden, together with smaller changes in ASR, is consistent with demographic ageing being an important contributor to rising dementia-related service needs in China. The risk-attributable estimates suggest changing population-level patterns for selected environmental and metabolic exposures, but they should not be interpreted as individual-level causal effects.},
}

@article {pmid42531071,
year = {2026},
author = {Le Bars, S and Soudy, M and Glaab, E},
title = {XYomics: detecting sex-dependent molecular mechanisms in omics data.},
journal = {Nucleic acids research},
volume = {54},
number = {14},
pages = {},
doi = {10.1093/nar/gkag759},
pmid = {42531071},
issn = {1362-4962},
support = {//Luxembourg Fondation Wivine/ ; INTER/JPND23/17999421/AD-PLCG2//Luxembourg National Research Fund/ ; INTER/22/17104370/RECAST//Luxembourg National Research Fund/ ; INTER/EJP RD22/17027921/PreDYT//Luxembourg National Research Fund/ ; C24/BM/18865990/AsynIntact//Luxembourg National Research Fund/ ; },
mesh = {Humans ; *Software ; Male ; *Sex Characteristics ; *Alzheimer Disease/genetics/metabolism ; Female ; *Computational Biology/methods ; Genomics/methods ; Single-Cell Analysis ; },
abstract = {Understanding sex-dependent differences in disease risk, manifestation, and treatment response is essential for precision medicine. While funding agencies now mandate consideration of Sex as a Biological Variable (SABV), existing bioinformatics tools lack systematic approaches to characterize sex-related molecular mechanisms. Current practices frequently treat sex as a confounding variable, which may obscure important biological differences such as sex-specific alterations, sex-dimorphic changes (opposite effects between sexes), and sex-modulated changes (different effect magnitudes). We present XYomics, an open-source R package for systematic analysis of sex-dependent alterations in biomedical omics data. The software identifies sex-specific, sex-dimorphic, and sex-modulated changes at both individual feature and systems levels. XYomics implements dual analytical modes: sex-disease interaction term modeling for adequately powered datasets and sex-stratified analysis with robust non-significance filtering for smaller sample sizes. Using single-cell RNA sequencing data from Alzheimer's disease patients, we demonstrate how XYomics identifies sex-dimorphic genes largely undetected by standard sex-averaged analyses. By integrating statistical categorization with pathway enrichment and network analysis using a curated hormone signaling interactome, the software facilitates discovery of sex-specific biomarkers and disease mechanisms frequently obscured in sex-aggregated analyses.},
}

Humans
*Software
Male
*Sex Characteristics
*Alzheimer Disease/genetics/metabolism
Female
*Computational Biology/methods
Genomics/methods
Single-Cell Analysis

@article {pmid42520619,
year = {2026},
author = {Zhao, H and Zhang, T and Liu, L and Zhang, S and Ma, W},
title = {The management of daily topics in conversations with individuals with Alzheimer's disease in Chinese residential care.},
journal = {Social science & medicine (1982)},
volume = {406},
number = {},
pages = {119617},
doi = {10.1016/j.socscimed.2026.119617},
pmid = {42520619},
issn = {1873-5347},
abstract = {BACKGROUND: Individuals with Alzheimer's Disease (AD) often experience difficulties managing topics in daily interactions, which can hinder their participation in interactions and affect their social engagement. There is a gap in exploring the interactional dynamics and the maintenance of personhood when interacting with individuals with AD in asymmetric institutional settings.

OBJECTIVES: This study aims to examine the interactional competence of individuals with AD and how their vulnerabilities are managed in daily-topic interactions within institutional healthcare settings.

METHODS: This study adopts Conversation Analysis (CA) to examine video-recorded conversations between a trained researcher and individuals with mild cognitive impairment due to AD residing in two residential care facilities in China.

FINDINGS: Individuals with mild AD demonstrate agency within asymmetric interactions by reshaping conversational frames, preserving face, and situating themselves within relational contexts to maintain their personhood. This agency emerges only when interlocutors actively engage, providing validation and recognition while accommodating temporary incoherence. These findings underscore the collaborative nature of sustaining identity in dementia care and highlight the particular significance of such interactional practices within the Chinese cultural context.

IMPLICATIONS: Conversation partners can support agency in individuals with AD by ratifying frame reconfigurations, sustaining topics, acknowledging repetitions, and responding flexibly to disengagement. Care facilities are also expected to create more opportunities for residents to engage in casual conversation.},
}

@article {pmid42520739,
year = {2026},
author = {Jafari, M and Tang, Z and Acharya, UR and Li, Y},
title = {Applications of quantum AI in brain disorder diagnosis: A systematic review.},
journal = {Computer methods and programs in biomedicine},
volume = {286},
number = {},
pages = {109565},
doi = {10.1016/j.cmpb.2026.109565},
pmid = {42520739},
issn = {1872-7565},
abstract = {BACKGROUND AND OBJECTIVE: Brain disorder diagnosis and prediction remain challenging because neuroimaging, electrophysiological, behavioral, and multimodal data are high-dimensional, noisy, heterogeneous, and limited by small clinical cohorts. This systematic review synthesised applications of quantum artificial intelligence (QAI) for brain disorder diagnosis, prediction, detection, and monitoring.

METHODS: Following PRISMA guidelines, studies published from 2016 to 13 January 2026 were retrieved from Scopus, Web of Science, and IEEE Xplore. After screening, 36 studies met the eligibility criteria and were qualitatively analysed according to disorder category, data modality, QAI method, implementation setting, validation strategy, and performance.

RESULTS: At the broader disease-group level, neurodegenerative disorders were the most frequently investigated, followed by mental health and psychiatric disorders. At the individual level, Parkinson's disease and schizophrenia were the leading applications, followed by depression, anxiety, Alzheimer's disease, and stress-related tasks. MRI-based modalities were the most frequently used data source, followed by multimodal data and EEG. Methodologically, primary QAI approaches were dominated by quantum neural and QDL architectures, followed by quantum-inspired optimization or feature-selection methods and quantum-kernel/conventional QML classifiers. Qiskit/IBM Quantum and PennyLane were the most frequently reported quantum software frameworks. However, most studies relied on simulators, classical quantum-inspired implementations, or unclear implementation settings, with limited real-hardware evaluation.

CONCLUSIONS: QAI shows emerging potential for brain disorder analysis, particularly through hybrid quantum-classical learning, quantum neural architectures, quantum-kernel methods, and quantum-inspired optimization. Nevertheless, current evidence remains preliminary and requires larger datasets, subject-level and external validation, fair classical benchmarking, noise-resilient circuits, real quantum hardware evaluation, explainability, and clinical validation.},
}

@article {pmid42520782,
year = {2026},
author = {Persson, J and Voss, G},
title = {Anti-Amyloid Therapies for Early Alzheimer's Disease: Evidence-Based Recommendations.},
journal = {South Dakota medicine : the journal of the South Dakota State Medical Association},
volume = {79},
number = {1},
pages = {35-39},
pmid = {42520782},
issn = {0038-3317},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; Evidence-Based Medicine ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in older adults and represents a growing public health burden. Traditional therapies offer only symptomatic relief without modifying disease progression. Recently approved anti-amyloid monoclonal antibodies, donanemab and lecanemab, represent a shift toward disease-modifying treatment in patients with mild cognitive impairment (MCI) or mild AD with confirmed amyloid pathology.

METHODS: This review synthesizes current evidence from key clinical trials, real-world safety considerations, and expert-driven appropriate use recommendations (AURs) to guide the safe and effective use of donanemab and lecanemab.

RESULTS: Both agents demonstrate statistically significant and clinically meaningful slowing of cognitive and functional decline in early symptomatic AD. Key differences exist in their mechanisms of action, dosing schedules, and treatment duration. Safety monitoring, particularly for amyloid-related imaging abnormalities (ARIA) and apolipoprotein E (APOE) ε4 genotyping, is an essential component of care.

CONCLUSION: Anti-amyloid therapies offer a meaningful step forward in AD management, but their use requires careful patient selection, biomarker confirmation, and adherence to safety protocols. As long-term outcomes and comparative effectiveness remain uncertain, continued surveillance, patient education, and equitable access will be important in optimizing the clinical impact of anti-amyloid therapies.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal/therapeutic use
Evidence-Based Medicine
Cognitive Dysfunction/drug therapy

@article {pmid42520805,
year = {2026},
author = {Savignac, C and St-Onge, F and Villeneuve, S and Badhwar, A and Gagliano Taliun, SA and Farhan, S and Geddes, M and Iturria Medina, Y and Poirier, J and Spreng, RN and Bzdok, D and , },
title = {Parent-of-origin effects in Alzheimer's liability dissociate neurocognitive and cardiovascular traits in at-risk individuals.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102943},
doi = {10.1016/j.xcrm.2026.102943},
pmid = {42520805},
issn = {2666-3791},
abstract = {Alzheimer's disease (AD) has a higher prevalence in women than men and is more frequently inherited from mothers than fathers. Yet, while neuroimaging and biomarker studies link maternal family history to stronger AD-related alterations, epidemiological studies suggest that paternal history confers comparable or even greater risk. Here, we leverage the deeply profiled PREVENT-AD cohort to derive three intermediate phenotypes of AD susceptibility. Drawing on nearly 1,000 individual study visits, we quantify how these intermediate phenotypes vary as a function of maternal versus paternal AD lineage. We show that lineage-specific differentiation, including both maternal and paternal biases, is reflected in the brain structure and phenome of adult children of AD patients. Cognitive and cardiovascular risk markers, together with associated genetic variants, show the strongest differentiation along the parental-lineage spectrum of disease susceptibility relative to other correlates of AD burden. Our cross-generational analysis ultimately delineates multidimensional parent-of-origin effects in AD genealogy.},
}

@article {pmid42520915,
year = {2026},
author = {Xing, S and Ren, P and Chen, Z and Fu, Y},
title = {Non-transgenic rodent models associated with Alzheimer's disease: applications, evaluation, and perspectives.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.063},
pmid = {42520915},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Familial AD accounts for less than 1% of cases, while sporadic AD (SAD) accounts for over 95%. Mild cognitive impairment (MCI) is the critical transition phase from normal aging to AD dementia. Understanding the pathological progression from MCI to AD and the mechanisms underlying SAD is essential. Rodent models, including transgenic and non-transgenic models, are vital tools for developing effective AD therapies. However, transgenic models primarily mimic familial AD and poorly replicate MCI and the complex pathological features of SAD. Non-transgenic models address these limitations by incorporating genetic, environmental, and aging factors, thereby better simulating SAD complexity. In addition, non-transgenic models are valuable for studying the compensatory mechanisms within neural networks that preserve cognitive function despite early pathology during MCI. In this review, we provide a comprehensive summary of non-transgenic rodent models used in AD and MCI research. First, we detail modeling strategies, including agents, administration routes, and dosages. Next, we discuss evaluation methods, such as behavioral and molecular assessments. We emphasize the importance of electrophysiological data, such as long-term potentiation, for evaluating cognition. Finally, we discuss the advantages and limitations of these non-transgenic models. This review may serve as a reference for selecting models to study the progression from MCI to AD and to develop related therapeutics. Combining non-transgenic and transgenic models more accurately replicates the complex, multifactorial pathology of the disease.},
}

@article {pmid42521027,
year = {2026},
author = {de Sevilla, LP and Majumdar, S and Recio, B},
title = {The Human Retina in Alzheimer's Disease: Pathology, Mechanisms, and Biomarkers.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103275},
doi = {10.1016/j.arr.2026.103275},
pmid = {42521027},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration and synaptic dysfunction that begins decades before clinical symptoms emerge. While AD research has traditionally focused on the brain, increasing evidence suggests that the retina undergoes pathological remodeling that shares features with cerebral changes. Advances in retinal imaging, including optical coherence tomography (OCT), OCT angiography, and hyperspectral approaches, have identified structural, vascular, and functional abnormalities in individuals with mild cognitive impairment (MCI) and early-stage AD. This supports the potential utility of the retina as a non-invasive biomarker for detecting neurodegenerative processes. Furthermore, postmortem studies have demonstrated accumulation of amyloid-β and phosphorylated tau, increased vulnerability of retinal ganglion cells (RGC), synaptic alterations in the inner plexiform layer (IPL), and significant activation of glial cells and complement-mediated inflammatory pathways. Melanopsin RGCs appear to be selectively affected, suggesting a mechanistic link between retinal pathology and the circadian or sleep disturbances commonly observed in AD. This review synthesizes human clinical data from imaging, histopathological, and proteomic studies supporting retinal involvement in AD, with emphasis on convergent mechanisms, including mitochondrial dysfunction, oxidative stress, microglial activation, and synaptic degeneration. Key limitations and sources of variation in current retinal biomarker studies, including cohort heterogeneity, comorbid ocular disease, and methodological variability, are discussed, and future directions are outlined to strengthen retinal diagnostics and therapeutic monitoring of visual system dysfunction in AD.},
}

@article {pmid42521029,
year = {2026},
author = {Virlley, M and Spooner, RK and Wilson, TW and Pruitt, T and Davenport, EM and Maldjian, JA and Proskovec, AL},
title = {Gating of Somatosensory Neural Oscillations Across the Lifespan: A Narrative Review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103276},
doi = {10.1016/j.arr.2026.103276},
pmid = {42521029},
issn = {1872-9649},
abstract = {Healthy and pathological aging are associated with progressive changes in cortical inhibition, yet the underlying neural mechanisms remain incompletely understood. Somatosensory gating (SG), the brain's suppression of redundant tactile input, provides a pre-attentive marker of inhibitory function. Paired-pulse paradigms concurrent with noninvasive magnetoencephalography (MEG) provide a millisecond portrayal of the neural dynamics underlying somatosensory processing and the gating of such responses with excellent spatial resolution. This narrative review synthesizes SG research focusing on neural oscillations, with a particular emphasis on gamma-band activity which is linked to GABAergic inhibitory processes. SG oscillatory metrics are sensitive to both healthy chronological aging and biological stressors such as allostatic load and epigenetic aging and offer insight beyond neural evoked responses. We also examine aberrant presentations of SG oscillatory metrics in age-related neuropathologies, including Alzheimer's disease and HIV-associated neurocognitive disorder, sensorimotor pathologies, and psychiatric conditions. Finally, we outline methodological considerations and propose future directions to refine SG oscillatory metrics as markers of inhibitory decline or potential compensatory mechanisms, situating the existing findings within prominent theories of neurocognitive aging. Collectively, this review underscores how an oscillatory perspective to brain function reveals frequency-specific somatosensory and inhibitory mechanisms, highlighting their differential sensitivity to healthy aging and pathology.},
}

@article {pmid42521030,
year = {2026},
author = {Kechko, OI and Moskalev, AA and Franceschi, C and Mitkevich, VA and Makarov, AA},
title = {Is amyloid beta peptide a driver of inflammaging?.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103280},
doi = {10.1016/j.arr.2026.103280},
pmid = {42521030},
issn = {1872-9649},
abstract = {Inflammaging, the chronic subclinical systemic inflammation accompanying aging, represents a critical pathogenetic mechanism underlying age-related neurodegenerative diseases. While amyloid beta (Aβ) peptides are established contributors to neuroinflammation in Alzheimer's disease, their role in aging-related subclinical inflammation remains insufficiently elucidated. In humans, Aβ exhibits dual functions: it supports neuronal activity, survival, and protection against neurotrauma, while also promoting inflammation and central nervous system dysfunction. This review highlights the beneficial effects of Aβ, including its antioxidant and antipathogenic properties, and synthesizes current knowledge of the molecular mechanisms driving Aβ-associated inflammaging. We structure this analysis across distinct brain cell types - microglia, astrocytes, oligodendrocytes, neurons, pericytes, and endothelial cells - and consider additional factors influencing Aβ-related neuroinflammation. Finally, we examine strategies to counteract the detrimental effects of Aβ, focusing on Aβ physiological clearance via the blood-brain barrier and glymphatic system, as well as therapeutic interventions. Understanding Aβ-driven inflammaging mechanisms offers new therapeutic avenues for early intervention in age-related neurodegenerative diseases, particularly in genetically susceptible populations. Targeting Aβ-associated inflammaging reframes Aβ not solely as a pathological marker but also as a context-dependent contributor to inflammatory processes during brain aging.},
}

@article {pmid42521309,
year = {2026},
author = {Moncion, K and Rodrigues, L and Bon, A and Sutoski, A and Sikorska, K and Allison, EY and Abreu, J and Golchi, S and Arbour, N and Gauthier, C and Paquette, C and Rosa-Neto, P and Leppert, I and Rowley, C and Tardiff, CL and Thiel, A and Al-Khazraji, B and Tang, A and Roig, M},
title = {Protecting the brain from post-stroke cognitive impairment and dementia with multimodal exercise training: study protocol for a Bayesian adaptive trial (PROTECT).},
journal = {BMJ open},
volume = {16},
number = {7},
pages = {e123336},
doi = {10.1136/bmjopen-2026-123336},
pmid = {42521309},
issn = {2044-6055},
mesh = {Humans ; *Stroke/complications ; *Stroke Rehabilitation/methods ; *Cognitive Dysfunction/prevention & control/etiology ; *Dementia/prevention & control/etiology ; Bayes Theorem ; *Exercise Therapy/methods ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase III as Topic ; Resistance Training/methods ; Brain ; Multicenter Studies as Topic ; Biomarkers/blood ; Cognition ; Neuroimaging ; },
abstract = {INTRODUCTION: Stroke triggers acute vascular and inflammatory mechanisms that predispose the brain to rapid neurodegeneration. Up to 52% of stroke survivors develop cognitive impairment within 6 months and 20% receive a clinical diagnosis of dementia within 5 years. The subacute phase (<6 months) represents a critical window in which the brain may be most responsive to neuroprotective interventions. Multimodal aerobic and resistance training improves cognition in chronic stroke, but whether it improves cognition, neuroimaging markers and blood biomarkers of dementia risk when delivered during this early window remains unknown. The PROTECT trial will compare the effects of 12 weeks of multimodal exercise (moderate-to-high-intensity resistance and aerobic training) versus a low-intensity exercise comparator on cognition, neuroimaging outcomes, blood biomarkers of cognitive decline and dementia risk in people with subacute stroke.

METHODS AND ANALYSIS: The PROTECT trial is a 12-week, Phase 3, assessor-blinded, multisite Bayesian adaptive randomised controlled trial (RCT) following a two-arm parallel group sequential design with 6-month and 12-month follow-up (NCT07445841). Participants will be randomised to multimodal training or the comparator using concealed allocation with permuted blocks of varying sizes. The primary outcome is cognition, measured using the 13-item Alzheimer's Disease Assessment Scale-Cognitive assessment (ADAS-Cog-13). Secondary outcomes include ADAS-Cog-Plus, structural and perfusion neuroimaging and blood biomarkers of inflammation and neurodegeneration. Tertiary outcomes include cardiorespiratory fitness, functional mobility, muscle strength, body composition, neuropsychological status, patient-reported cognition, quality of life, fatigue and healthcare utilisation. Outcomes will be assessed at baseline, post-intervention (primary endpoint) and at 6-month and 12-month follow-up. Sample size was estimated via 20 000 Monte Carlo simulations using an ADAS-Cog effect size of Cohen's d=0.63 from a previous exercise RCT. The target was ≥80% power to detect this treatment effect at a one-sided type I error rate of 2.5%, using a weakly informative prior centred at zero with a variance of 100. The minimum required was 45 completers per arm (N=90) and accounting for 25% attrition, up to 120 participants (60 per arm) will be enrolled. Pre-planned adaptive features include: (1) two interim analyses at 50% and 75% of completers; (2) early stopping for efficacy and futility; and (3) sample size re-estimation.

ETHICS AND DISSEMINATION: Ethical approval to conduct this study has been granted by the Centre de recherche interdisciplinaire en réadaptation du Montréal métropolitain (CRIR MP-50-2025-2294) and Hamilton Integrated Research Board (HIREB 19222). Any protocol amendments will be submitted to the appropriate ethics boards. Written informed consent to participate in this study will be obtained from all participants by study coordinators or assistants. Study results will be published and reported in peer-reviewed journal following Adaptive Designs Consolidated Standards of Reporting Trials extension guidelines.

TRIAL REGISTRATION NUMBER: NCT07445841.},
}

Humans
*Stroke/complications
*Stroke Rehabilitation/methods
*Cognitive Dysfunction/prevention & control/etiology
*Dementia/prevention & control/etiology
Bayes Theorem
*Exercise Therapy/methods
Randomized Controlled Trials as Topic
Clinical Trials, Phase III as Topic
Resistance Training/methods
Brain
Multicenter Studies as Topic
Biomarkers/blood
Cognition
Neuroimaging

@article {pmid42521490,
year = {2026},
author = {Jung, WH and Oh, ST and Choe, MS and Kwon, YJ and Kim, SJ and Jeon, YS and Baek, KM and Chang, W and Lim, KS and Kim, JS and Yun, SP and Lee, MY},
title = {A Cerebral Organoid Model of Familial Alzheimer's Disease Using Amyloid Precursor Protein Mutation, Val669Leu (APP[Seoul]).},
journal = {International journal of stem cells},
volume = {},
number = {},
pages = {},
doi = {10.15283/ijsc25044},
pmid = {42521490},
issn = {2005-3606},
abstract = {Various animal and cellular Alzheimer's disease (AD) models harboring familial AD (fAD) mutations have been developed and widely used for AD research. In this study, we established an AD cerebral organoid (CO) model using a novel Val669Leu (APP[Seoul]) mutation in the APP gene. We generated a human embryonic stem cell (hESC) line overexpressing APP[Seoul], referred to as the fAD-S hESC line. Using this line, we produced COs and confirmed robust AD-associated pathologies, including amyloid-β (Aβ) accumulation and tau phosphorylation. In addition, increased expression of β-secretase was observed in this model. Based on these findings, we investigated the effects of BACE1 inhibitor IV, a β-secretase inhibitor, in the CO model. Treatment with BACE1 inhibitor IV significantly reduced Aβ levels and tau phosphorylation. Furthermore, we differentiated the fAD-S hESC line into cortical neurons (fAD-S neurons) to establish a 2D cellular AD model. Consistent with the CO results, fAD-S neurons exhibited elevated levels of Aβ and phosphorylated tau, which were also significantly attenuated by BACE1 inhibitor IV treatment. Collectively, these results demonstrate the successful establishment of hESC-derived 2D and 3D AD models based on the APP[Seoul] fAD mutation.},
}

@article {pmid42521537,
year = {2026},
author = {da Silva, AMP and Haddad-Santos, D and de Siqueira Lima, DV and Cardoso, LJC and Moura, CB and Høilund-Carlsen, PF and Perry, G and Kishi, T and Barbosa, BJAP and Anghinah, R},
title = {Bayesian Reanalysis of a Pilot Randomized Clinical Trial of Low-Dose Lithium in Mild Cognitive Impairment: A Probabilistic Re-Expression of the LATTICE Trial.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.06.014},
pmid = {42521537},
issn = {1545-7214},
abstract = {OBJECTIVE: The LATTICE pilot randomized clinical trial found no statistically significant effect of low-dose lithium on 6 coprimary outcomes in mild cognitive impairment (MCI). We aimed to re-express these results in Bayesian terms and estimate the probability of benefit, negligible difference, or harm across cognitive, neuroimaging, biomarker, and safety outcomes.

METHODS: We conducted a Bayesian reanalysis of published aggregate data from LATTICE, a single-site, randomized, double-blind, placebo-controlled 2-year trial of low-dose lithium carbonate versus placebo. The trial randomized 83 older adults with MCI, of whom 80 initiated treatment. Outcomes included verbal and visuospatial delayed recall, Preclinical Alzheimer Cognitive Composite, hippocampal and cortical volume measures, brain-derived neurotrophic factor, and serious adverse events. Posterior means, 95% credible intervals (CrI), and posterior probabilities were estimated using weakly informative priors.

RESULTS: Lithium was associated with a posterior mean standardized effect of 0.38 SD for CVLT-II delayed recall (95% CrI, -0.03 to 0.80), corresponding to a 96.5% probability of benefit and an 80.6% probability of exceeding 0.20 SD. The raw between-group difference was 1.47 points (95% CrI, 0.18-2.75). Bayesian re-expression of the intention-to-treat model showed an annualized CVLT-II treatment-by-time effect of 0.69 points per year (95% CrI, 0.02-1.35). BVMT-R remained near null. Hippocampal outcomes were directionally favorable but imprecise. Other cognitive, biomarker, imaging, and safety outcomes showed no robust signal.

CONCLUSIONS: This Bayesian reanalysis supports an inconclusive interpretation of LATTICE, while identifying a probabilistic signal for verbal delayed recall-not seen in the other outcomes-that warrants testing in adequately powered trials.},
}

@article {pmid42521539,
year = {2026},
author = {Bassiouni, W and Ye, E and Colson, TL and Ferguson, SSG and Abd-Elrahman, KS},
title = {M1 muscarinic receptor modulation drives sex-specific alterations of Alzheimer's pathophysiology in APPswe/PSEN1ΔE9 mice.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {},
number = {},
pages = {104980},
doi = {10.1016/j.jpet.2026.104980},
pmid = {42521539},
issn = {1521-0103},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, where females account for 60% of diagnosed cases. AD is featured by β-amyloid deposition, which influences the activity of M1 muscarinic acetylcholine receptors (M1 mAChRs) that are essential for memory and learning. We previously demonstrated that VU0486846, a M1 mAChR positive allosteric modulator, improves cognitive function in AD mice by ameliorating β-amyloid pathology. However, it remains unclear how changes in M1 mAChR signaling and subcellular localization in AD brain influences its mechanism and how this differs between sexes. Nine-month-old male and female APPswe/PSEN1ΔE9 (APP/PS1) and wild-type mice were treated with VU0486846 (10 mg/kg/day) or vehicle via drinking water for 8 weeks. Elevated extracellular signal-regulated kinase 1/2 signaling, a plausible driver for β-amyloid pathology, was observed in female but not male APP/PS1 mice cortices, whereas VU0486846 mitigated this change. Additionally, VU0486846 enhanced the phosphorylation of the neuronal transcription factor cAMP response element-binding protein and increased the level of c-Fos, which regulate neuronal survival, in female wild-type and APP/PS1 mice only. In contrast, only male APP/PS1 mice exhibited increased levels of p62/SQSTM1 and decreased glycogen synthase kinase-3β activity, indicative of impaired autophagic flux, a change that was ameliorated by VU0486846 treatment. In subcellular fractions obtained from mice cortices, VU0486846 only increased cytosolic M1 mAChR level in female wild-type and APP/PS1 mice but not in males. Our findings indicate that M1 mAChR signaling is disrupted in APP/PS1 mice in a sex-dependent manner. VU0486846 enhances prosurvival signaling in females, potentially by increasing the cytosolic pool of M1 mAChRs, while modulating autophagy pathways in males, highlighting a sex-specific mechanism of action and underscoring its therapeutic potential. SIGNIFICANCE STATEMENT: The study highlights the sex-specific role of M1 muscarinic acetylcholine receptor (M1 mAChR) in Alzheimer's disease (AD) pathophysiology, providing evidence that the ability of M1 mAChR positive allosteric modulation to alleviate β-amyloid pathology occurs through distinct mechanisms. It rescues neuronal activity in females, which could be linked to enhanced cytosolic receptor pooling, while restoring autophagic flux in males. The study also reinforces the therapeutic potential of M1 mAChR positive allosteric modulators and supports the development of sex-tailored interventions for AD.},
}

@article {pmid42521649,
year = {2026},
author = {Na, HK and Sun, Y and Park, CW and Lee, JH and Choi, YY and Vo, QP and Chung, SJ and Yoo, HS and Lyoo, CH and Sohn, YH and Hong, JY and Lee, PH},
title = {Greater Motor and Nonmotor Burden at Diagnosis Is Associated With Amyloid Copathology in Parkinson's Disease.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70446},
pmid = {42521649},
issn = {1531-8257},
support = {2024ER100200//Korean National Institute of Health/ ; RS-2026-25498013//National Research Foundation of Korea/ ; },
abstract = {BACKGROUND: Concurrent Alzheimer's disease pathology is increasingly recognized as a poor prognostic factor in Parkinson's disease (PD), yet reliable clinical indicators for early identification of AD copathology remain poorly established.

OBJECTIVE: To investigate baseline motor and nonmotor symptom profiles associated with amyloid-β (Aβ) copathology in newly diagnosed PD.

METHODS: Among patients with PD who underwent Aβ imaging, we retrospectively identified 152 patients who completed the Cross-Cultural Smell Identification Test (CC-SIT), autonomic function tests, neuropsychological assessment, and Neuropsychiatric Inventory Questionnaire (NPI-Q) at drug-naive state. Predictors of Aβ positivity were identified using stepwise multivariable logistic regression and validated with Random Forest classifiers employing Boruta feature selection.

RESULTS: Compared with Aβ-negative counterparts (n = 93), Aβ-positive (Aβ + PD, n = 59) patients demonstrated greater olfactory dysfunction (CC-SIT, P = 0.002), dysautonomia (Composite Autonomic Severity Scale [CASS], P < 0.001), and mood disturbance (NPI-Q-mood, P < 0.001) and higher prevalence of probable rapid eye movement sleep behavior disorder (P = 0.009) and neurogenic orthostatic hypotension (P = 0.006). Aβ + PD patients showed greater motor disability (Unified Parkinson's Disease Rating Scale Part III [UPDRS-III], P < 0.001) despite comparable striatal dopamine transporter uptake. Logistic regression identified lower CC-SIT scores (odds ratio [OR] = 0.821, 95% confidence interval [CI95%]: 0.703-0.959), higher CASS scores (OR = 1.380, CI95%: 1.144-1.666), higher NPI-Q-mood scores (OR = 1.057, CI95%: 1.005-1.111), higher UPDRS-III (OR = 1.080, CI95%: 1.030-1.132), and APOE ε4 carrier status (OR = 3.643, CI95%: 1.479-8.969) as independent predictors of Aβ positivity, which were also confirmed as important variables by Boruta feature selection.

CONCLUSIONS: Our findings suggest that greater motor and nonmotor symptom burden at diagnosis, characterized by olfactory/autonomic dysfunction, mood disturbance, and motor deficits disproportionate to dopaminergic denervation, was associated with Aβ positivity in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}

@article {pmid42521874,
year = {2026},
author = {Vanderlip, CR and Stark, CEL},
title = {Modernizing cognitive assessment in Alzheimer's disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42521874},
issn = {2662-8465},
support = {T32AG00096//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG066683/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; },
}

@article {pmid42521895,
year = {2026},
author = {Abidar, S and Nhiri, M and Bianchi, V},
title = {Suicide in neurodegenerative diseases: a systematic review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42521895},
issn = {1590-3478},
mesh = {Humans ; *Neurodegenerative Diseases/psychology ; *Suicide/psychology/statistics & numerical data ; Amyotrophic Lateral Sclerosis/psychology ; Multiple Sclerosis/psychology ; },
abstract = {BACKGROUND AND OBJECTIVE: Suicide is a public health issue, which differs from suicidality, the continuum from suicidal ideation to the suicidal act, including suicide attempts and completed suicide. The main goal of the present study is to determine the relationship between Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with suicidality.

METHODS: This is a systematic review aiming to determine the relationship between AD, PD, ALS, and MS with suicidality following PRISMA 2020 guidelines by collecting cross-sectional, case-control, and cohort studies; case series; case reports; and retrospective and prospective studies from Google Scholar, PubMed, and Cochrane Library. The protocol of this systematic review was registered on PROSPERO; the registration number is CRD420261422354.

RESULTS: From 2247 records identified from electronic databases, only 24 articles were included: three studies focusing on AD, nine on PD, and six studies focusing on ALS and MS, respectively. These studies exhibited moderate to low risk of bias. Despite the broad differences regarding the neurochemistry, pathophysiology, diagnosis, symptoms, and treatments of the selected diseases, patients are at a higher risk of suicidality. Depression and low social connectivity are the most prevalent risk factors. Suicidality is mainly detected during the first years post-diagnosis in PD, ALS, and MS patients, while the results in AD are confusing.

CONCLUSIONS: Data about this topic is scarce and largely varying. Further research is required to elucidate this paradigmatic realm, fostering awareness, enhancing therapies, and providing explanations and interpretations of the mechanisms involved.},
}

Humans
*Neurodegenerative Diseases/psychology
*Suicide/psychology/statistics & numerical data
Amyotrophic Lateral Sclerosis/psychology
Multiple Sclerosis/psychology

@article {pmid42522048,
year = {2026},
author = {Wang, QQ and Sun, QQ and Guo, YS and Yin, S and Zhou, JW},
title = {Neuroinflammation in Alzheimer's and Parkinson's diseases: pathogenic mechanisms and therapeutic strategies.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42522048},
issn = {2047-9158},
support = {82301629//National Natural Science Foundation of China/ ; ZR2024MH129//Natural Science Foundation of Shandong Province/ ; 2021ZD0200900//STI2030-Major Projects/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/therapy/metabolism/immunology ; *Parkinson Disease/pathology/therapy/metabolism/immunology ; *Neuroinflammatory Diseases/pathology/therapy/metabolism ; Animals ; Inflammation/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neuroinflammation is increasingly recognized as a key contributor and amplifier associated with the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). Neuroinflammation occurs throughout various stages of these diseases with expanding complexity. Currently, no effective therapies exist that specifically target neuroinflammatory processes in these disorders. In this review, we synthesize current understanding of central and peripheral inflammatory mechanisms implicated in both diseases. We illustrate how endogenous pathological triggers, such as amyloid-β (Aβ) peptide, hyperphosphorylated tau, and α-synuclein, activate glial cells, contributing to chronic neuroinflammation that exacerbates neurodegeneration. Additionally, peripheral factors, including systemic inflammation, environmental exposures, and gut-brain axis interactions, are discussed for their roles in modulating neuroinflammatory responses. Notably, the underappreciated roles of oligodendrocyte precursor cells and oligodendrocytes in neuroimmune crosstalk are also highlighted. Advanced methodologies, including glial cell imaging, single-cell transcriptomics, and human induced pluripotent stem cell-derived organoid models, are providing unprecedented insights into the molecular and cellular mechanisms underlying neuroinflammation. Finally, we evaluate emerging therapeutic strategies and ongoing clinical trials targeting neuroinflammatory pathways and analyze the potential of immunomodulatory approaches to slow disease progression. This comprehensive review emphasizes that precise targeting of neuroinflammation represents a tractable strategy for developing effective disease‑modifying treatments for AD and PD.},
}

Humans
*Alzheimer Disease/pathology/therapy/metabolism/immunology
*Parkinson Disease/pathology/therapy/metabolism/immunology
*Neuroinflammatory Diseases/pathology/therapy/metabolism
Animals
Inflammation/pathology
Amyloid beta-Peptides/metabolism

@article {pmid42522051,
year = {2026},
author = {Souza, MR and Alvarenga, TA and Mazaro-Costa, R and Tufik, S and Andersen, ML},
title = {Reproductive neuroendocrine pathways as modulators of sleep-related sex differences in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71699},
doi = {10.1002/alz.71699},
pmid = {42522051},
issn = {1552-5279},
support = {2020/13467-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Associação Fundo de Incentivo à Pesquisa/ ; },
}

@article {pmid42522056,
year = {2026},
author = {Wear, D and Morrone, CD and Yu, WH},
title = {Refining our understanding of sleep impairment and connection to Alzheimer's disease in preclinical models.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71700},
doi = {10.1002/alz.71700},
pmid = {42522056},
issn = {1552-5279},
support = {A2022016F//BrightFocus Foundation/ ; //Ontario Ministry of Colleges and Universities/ ; 11020222023Q2412//Natural Sciences and Engineering Research Council of Canada/ ; AG080781//Foundation for the National Institutes of Health/ ; },
}

@article {pmid42522059,
year = {2026},
author = {Okorie, M and Jonson, C and Oddi, AP and Castruita, PA and Fulton-Howard, B and Yaffe, K and Yokoyama, JS and Udeh-Momoh, C and Andrews, SJ and , },
title = {Cross-ancestry polygenic risk scores enhance Alzheimer's disease risk prediction in multiethnic cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71529},
doi = {10.1002/alz.71529},
pmid = {42522059},
issn = {1552-5279},
support = {ZIAAG000534//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; R01AG062588//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; R01AG057234//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; P30AG062422//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; P01AG019724//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; U19AG079774//NIH Intramural Center for Alzheimer's and Related Dementias (CARD)/ ; U24AG072122//National Alzheimer's Coordinating Center/ ; U54NS123985/NS/NINDS NIH HHS/United States ; U19AG079774/AG/NIA NIH HHS/United States ; //Rainwater Charitable Foundation/ ; //Bluefield Project to Cure Frontotemporal Dementia/ ; /ALZ/Alzheimer's Association/United States ; //Global Brain Health Institute/ ; //Genentech/ ; //French Foundation/ ; //Mary Oakley Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Genetic Risk Score ; Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Amyloid beta-Peptides/cerebrospinal fluid ; Bayes Theorem ; *Multifactorial Inheritance/genetics ; Female ; Cohort Studies ; tau Proteins/cerebrospinal fluid ; White People/genetics ; Male ; },
abstract = {INTRODUCTION: Genome-wide association studies (GWAS) have identified 80+ genetic loci associated with Alzheimer's disease (AD), enabling the development of polygenic risk scores (PRS). However, the predictive accuracy of PRS in diverse populations remains low. Here, we evaluated the predictive accuracy of single-, multi-, and cross-ancestry AD-PRS models across multi-ancestral populations.

METHODS: We used AD GWAS summary statistics from European, African, Admixed American, and East Asian populations to construct AD-PRS for each target population. Model performance was assessed by estimating odds ratios, R[2], and area under the curve.

RESULTS: The cross-ancestry Bayesian PRS model demonstrated the highest predictive performance in non-European populations. It was significantly associated with poorer cognitive function, lower Aβ42 cerebrospinal fluid levels, and the most severe category of Aβ and tau neuropathological burden.

DISCUSSION: Inclusive genetic datasets and cross-ancestry PRS models are needed to enhance the transportability of AD-PRS across multi-ancestral populations.},
}

Humans
*Alzheimer Disease/genetics
Genetic Risk Score
Genome-Wide Association Study
*Genetic Predisposition to Disease
Amyloid beta-Peptides/cerebrospinal fluid
Bayes Theorem
*Multifactorial Inheritance/genetics
Female
Cohort Studies
tau Proteins/cerebrospinal fluid
White People/genetics
Male

@article {pmid42522069,
year = {2026},
author = {Okorie, M and Jiang, X and Yaffe, K and Yokoyama, JS and Andrews, SJ and , },
title = {Associations of dementia polyexposure scores to Alzheimer's disease endophenotypes in a diverse population.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71567},
doi = {10.1002/alz.71567},
pmid = {42522069},
issn = {1552-5279},
support = {U24AG072122//National Alzheimer's Coordinating Center/ ; //Mary Oakley Foundation/ ; //French Foundation/ ; //Genentech/ ; //Global Brain Health Institute/ ; /ALZ/Alzheimer's Association/United States ; //Rainwater Charitable Foundation/ ; U54NS123985/NS/NINDS NIH HHS/United States ; U19AG079774/AG/NIA NIH HHS/United States ; R01AG057234/AG/NIA NIH HHS/United States ; P30AG062422/AG/NIA NIH HHS/United States ; P01AG019724/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Endophenotypes ; *Alzheimer Disease/epidemiology/diagnosis/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Female ; Male ; Aged ; tau Proteins/metabolism ; *Dementia/epidemiology/diagnosis ; Risk Factors ; Positron-Emission Tomography ; Aged, 80 and over ; Peptide Fragments ; },
abstract = {INTRODUCTION: Dementia clinical risk scores (CRSs) provide accessible tools for identifying individuals at risk for Alzheimer's disease (AD) and related dementias, yet their performance across diverse populations and relationships to AD endophenotypes remains unclear.

METHODS: We evaluated four CRSs, modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia (mCAIDE), Washington Heights-Inwood Columbia Aging Project (WHICAP), Lifestyle for Brain Health (LIBRA), and Cognitive Dementia Risk (CogDRisk), in relation to cognitive impairment (CI) and AD endophenotypes, including tau phosphorylated at threonine 217 (pTau217)/amyloid beta 42 (Aβ42) positivity defined using a Youden index-derived cutoff for amyloid positron emission tomography (PET) positivity. Logistic and linear regression models stratified by self-reported race/ethnicity were used to assess the associations of CRS with endophenotypes and CI and to evaluate predictive performance.

RESULTS: CogDRisk showed the strongest and most consistent performance across endophenotypes, pTau217/Aβ42 positivity, and CI, with mCAIDE performing the worst and lacking associations with plasma biomarkers. Higher CRS were consistently associated with increased odds of dementia across all races/ethnicities.

CONCLUSIONS: CRSs capture AD-related risk across diverse populations and modestly reflect underlying biological endophenotypes, supporting their utility in community-based risk assessment.},
}

Humans
*Endophenotypes
*Alzheimer Disease/epidemiology/diagnosis/diagnostic imaging
Amyloid beta-Peptides/metabolism
Female
Male
Aged
tau Proteins/metabolism
*Dementia/epidemiology/diagnosis
Risk Factors
Positron-Emission Tomography
Aged, 80 and over
Peptide Fragments

@article {pmid42522110,
year = {2026},
author = {Quigley, DD and Walsh, S and Kassner, CT and Dhingra, L and Dick, AW},
title = {Private Equity Ownership in Hospice Care: A Systematic Review (2012-2026).},
journal = {The American journal of hospice & palliative care},
volume = {},
number = {},
pages = {10499091261471107},
doi = {10.1177/10499091261471107},
pmid = {42522110},
issn = {1938-2715},
abstract = {Hospice care is associated with improved end-of-life outcomes. Recent shifts in hospice utilization highlight several key trends. Alzheimer's disease and related dementias (ADRD) (25%) have surpassed cancer (23%) as the leading primary diagnosis. Concurrently, industry ownership has transitioned from predominantly nonprofit to for-profit (70%) and private equity (PE) ownership has grown dramatically from 3% to 15%. To date, no study has synthesized evidence on PE ownership in hospice care. We conducted a systematic review of English-language, peer-reviewed studies published 2012-2026, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of 630 screened articles, 114 underwent full-text review and 6 met inclusion criteria. All studies used national data; sample sizes ranged from 80 to 536 PE-owned hospices. Three studies examined PE prevalence and market trends; two assessed caregiver-reported care experiences, and one evaluated financial outcomes by PE ownership. The evidence regarding PE ownership of hospices remains limited. It highlights the increasing role of PE in hospice markets. It consistently found (across two studies) worse care experiences at PE-owned hospices vs nonprofit hospices, except for emotional and religious support which was similar across ownership type. The evidence suggests PE ownership is associated with complex, often worse patterns related to market structure, care experiences, and financial allocation. Additionally, it underscores the limited evidence base to inform policy development. Research is needed to examine associations between PE ownership and hospice care quality, both overall and among vulnerable populations. Research should clarify modifiable factors influencing hospice quality and better characterize evolving ownership structures.},
}

@article {pmid42522301,
year = {2026},
author = {Ishak, NI and Siran, R and Mohamad Zain, WNIW and Azme, N},
title = {Endothelial-to-mesenchymal Transition at the Blood-brain Barrier: Molecular Mechanisms and Pathological Roles Across Brain Diseases.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273485479260721072747},
pmid = {42522301},
issn = {1996-3181},
abstract = {Endothelial-to-Mesenchymal Transition (EndMT) is a significant contributor to Blood- Brain Barrier (BBB) dysfunction in various brain diseases. The majority of current therapies, aimed at reducing BBB dysfunction, focus on preventing inflammation or stabilizing tight junctions. In most cases, these therapies do not provide adequate or long-lasting vascular protection. Endothelial cells undergo phenotypic programming, losing their barrier-forming capacity and developing features of mesenchymal and extracellular matrix-producing cells as the disease progresses. The change leads to chronic vascular leakage, neuroinflammation, microvascular fibrosis, and dysfunctional neurovascular coupling. Several upstream stimuli, including inflammatory cytokines, TGF-β/BMP-Smad signaling, and oxidative damage, converge to drive EndMT within the distinctive, specialized environment of the brain endothelium. Ischemic stroke, multiple sclerosis, cerebral cavernous malformations, arteriovenous malformations, glioblastoma, brain metastasis, and Alzheimer's disease indicate that EndMT is not a rare or unique process but a shared and common pathologic process that may result in disease progression and eventual resistance to treatment. Recent single-cell and spatial transcriptomic data have shown that partial EndMT states exist and may be precursors to irreversible microvascular remodeling. It is necessary to identify therapeutic approaches that go beyond short-term stabilization of the BBB and target the molecular programs underlying the loss of endothelial identity. This review synthesizes mechanistic, disease-related, and therapeutic evidence indicating that EndMT is a leading cause of BBB failure and highlights therapeutic opportunities for targeting this endothelial plasticity in brain diseases.},
}

@article {pmid42522305,
year = {2026},
author = {Paliwal, D and Thakur, A},
title = {Exploring the Therapeutic Potential of Chalcones in Alzheimer's Disease: Mechanistic Insights and SAR Perspectives.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575457432260717112508},
pmid = {42522305},
issn = {1875-5607},
abstract = {Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by amyloid- β aggregation, oxidative stress, neuroinflammation, tau hyperphosphorylation, and cholinergic dysfunction. The limited efficacy of current therapies has driven the development of multitargetdirected ligands (MTDLs). Chalcones represent a versatile scaffold for modulating multiple ADrelated targets. This review provides a concise analysis of the structure-activity relationship (SAR) of chalcone derivatives, highlighting the effects of hydroxylation, methoxylation, halogenation, and heterocyclic hybridization on biological activity. Electron-withdrawing substituents (e.g., halogens, -CF3) enhance enzyme inhibition and MAO-B selectivity, whereas electron-donating groups (e.g., hydroxyl and methoxy groups) contribute to antioxidant activity, metal chelation, and hydrogen bonding interactions. Scaffold hybridization and optimized linker design further improve multitarget engagement, including AChE/BuChE inhibition, MAO-B modulation, and anti-amyloid activity. However, despite promising in vitro and in silico findings, translational limitations remain due to insufficient in vivo validation and pharmacokinetic constraints. Overall, chalcone-based MTDLs provide a rational framework for the development of next-generation anti-Alzheimer agents.},
}

@article {pmid42522313,
year = {2026},
author = {Tian, J and Yao, R and Shen, L and Jiao, B and Luo, SL},
title = {PP2A: Decoding Its Structure, Regulation and Therapeutic Applications in Neurological Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X482496260716074148},
pmid = {42522313},
issn = {1875-6190},
abstract = {Protein phosphatase 2A (PP2A) is a highly conserved serine/threonine phosphatase that plays a pivotal role in maintaining cellular homeostasis by counterbalancing kinase activity. As a heterotrimeric enzyme composed of scaffolding, regulatory, and catalytic subunits, PP2A achieves extraordinary functional diversity through the dynamic assembly of more than 80 holoenzyme variants. This structural versatility allows PP2A to regulate a wide range of biological processes, including cell cycle progression, apoptosis, DNA damage response, and major signaling pathways such as MAPK and Wnt. Dysregulation of PP2A, through altered subunit expression, post-translational modification, or inhibition by endogenous suppressors like CIP2A and SET, has been implicated in diverse diseases, notably neurodegenerative disorders, cancers, and metabolic syndromes. In neurological disorders such as Alzheimer's and Parkinson's diseases, impaired PP2A activity contributes to pathogenic protein hyperphosphorylation, neurofibrillary tangle formation, and neuroinflammation. Recent advances have fundamentally reshaped our understanding of PP2A biology. High-resolution structural studies have revealed the molecular basis of holoenzyme assembly and substrate recruitment, while accumulating evidence suggests that PP2A activity is dynamically regulated across tissues and cell types, largely driven by differential expression of regulatory subunits and post-translational modifications. Despite these advances, current knowledge remains fragmented, and a comprehensive synthesis linking PP2A structural dynamics, regulatory mechanisms, and its roles in pathophysiology, particularly in the context of neurological disorders, is still lacking. This review deciphers the structural complexity and regulatory mechanisms of PP2A, elucidates its multifaceted roles in neural physiology and pathology, and examines current and emerging therapeutic strategies targeting PP2A modulation to intervene in neurological disease.},
}

@article {pmid42522580,
year = {2026},
author = {Park, CW and Choi, Y and Lee, HS and Jeong, SH and Lee, PH and Kim, YJ and Sohn, YH and Lee, J and Chung, SJ},
title = {Amyloid-linked trajectories of cerebral hypoperfusion and dopamine loss in dementia with Lewy bodies.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag264},
pmid = {42522580},
issn = {1460-2156},
abstract = {Dementia with Lewy bodies (DLB) is clinically heterogeneous, and the evolutionary trajectories of cortical dysfunction, nigrostriatal dopaminergic degeneration, and amyloid accumulation, as well as the interactions among them, remain poorly understood. This study enrolled 83 patients with DLB who underwent dual-phase 18F-FP-CIT PET and 18F-FBB PET scans at initial assessment. Fifteen standardised imaging biomarkers capturing cerebral perfusion (early-phase 18F-FP-CIT PET images), striatal dopamine depletion (late-phase 18F-FP-CIT PET images), and amyloid burden (18F-FBB PET images) were entered into a Subtype and Stage Inference (SuStaIn) model. The SuStaIn analysis delineated two subtypes of DLB with distinct evolutionary trajectories: Subtype 1 (n = 37) was characterized by early amyloid accumulation, followed by cerebral hypoperfusion progressing from the posterior cingulate cortex to other cortical and limbic regions, and later diffuse striatal dopamine depletion; Subtype 2 (n = 36) initially presented with selective dopamine loss in the putamen, with subsequent dopaminergic deficits in other striatal subregions, followed by amyloid accumulation and cerebral hypoperfusion progressing from the precuneus to other cortical and limbic regions. The remaining 10 patients with DLB did not have sufficiently abnormal imaging findings to be categorized into a defined subtype (Subtype 0). Subtype 1 exhibited more severe Alzheimer's disease (AD)-like cortical atrophy and lower cingulate island sign ratios on early-phase 18F-FP-CIT PET images. Patients in Subtype 2 had a higher prevalence of rapid eye movement sleep behavior disorder and visual hallucinations than those in Subtype 1. In conclusion, we delineate two distinct multimodal imaging progression patterns in DLB: an early nigrostriatal dopamine depletion-linked trajectory with more typical DLB characteristics and an early amyloid deposition-linked trajectory characterised by an inverse cingulate island sign and AD-like cortical atrophy. These findings highlight the clinical and biological heterogeneity within DLB.},
}

@article {pmid42522648,
year = {2026},
author = {Wei, Z and Qian, H and Dai, C and Wu, J and Li, Y and Yin, K and Li, M and Yang, H},
title = {Global Research Trends of Protein Post-translational Modifications in Alzheimer's Disease: A Bibliometric Analysis.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X457922260717112524},
pmid = {42522648},
issn = {1875-6190},
abstract = {BACKGROUND: In recent years, a considerable body of research has increasingly underscored the critical roles that protein Post-Translational Modifications (PTMs) play in the pathogenesis of Alzheimer's Disease (AD). However, a comprehensive bibliometric analysis of this field is still lacking. This study aims to systematically map research trends and hotspots and to identify promising directions for future work.

METHODS: The data in this study were extracted from the Web of Science Core Collection (WOSCC) and visualized using CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel 2016 to analyze bibliometric indicators including countries, institutions, authors, journals, citations, production categories, and keywords.

RESULTS: A collection of 1,170 articles was retrieved, spanning the publication period from January 1, 1990, to December 31, 2024. The top three countries in terms of publications were the United States, China, and Germany. The most productive institution was the University of California System in the United States, contributing 57 articles. The leading authors identified were Mitkevich Vladimir, Perry George, and Makarov Alexander A. The Journal of Alzheimer's Disease was the top-ranked journal in terms of published papers. The most frequently cited article was "The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation," published in the International Journal of Molecular Sciences. Finally, the most prolific research category was neuroscience, with 432 papers published. High-frequency keywords included Alzheimer's disease, phosphorylation, tau, and neurodegeneration.

DISCUSSION: The study's findings suggest that PTM research in AD continues to revolve around the core pathological hallmarks represented by Aβ and tau protein. At the same time, some studies have reported aberrant modifications of α-synuclein and its potential role in AD. By systematically cataloging diverse PTM types and the molecular mechanisms involving Aβ and tau throughout AD progression, this analysis paves the way for a reassessment of AD pathogenesis from a "modification-function-pathology" perspective and provides a basis for identifying potential PTM-related targets and intervention strategies.

CONCLUSION: This bibliometric analysis highlights the growing scholarly attention devoted to the relationship between PTMs and AD. The significant contributions and emerging trends emphasize the pivotal role of PTMs in the pathogenesis of AD, which may guide future biomarker discovery.},
}

@article {pmid42522708,
year = {2026},
author = {Li, H and Khang, TF},
title = {SIEVEseq: Unified differential expression, variability, and skewness analyses using RNA-Seq data.},
journal = {DNA research : an international journal for rapid publication of reports on genes and genomes},
volume = {},
number = {},
pages = {},
doi = {10.1093/dnares/dsag012},
pmid = {42522708},
issn = {1756-1663},
abstract = {RNA-Seq data analysis is commonly biased towards detecting differentially expressed genes and insufficiently conveys the complexity of gene expression changes between biological conditions. This bias arises because discrete count models cannot fully and independently parameterize the mean, variance, and skewness of gene expression distributions. Therefore, a unified statistical framework that simultaneously tests differential expression, variability, and skewness is needed. We present SIEVEseq, a statistical methodology that provides such a framework. SIEVEseq embraces a compositional data analysis strategy to transform discrete RNA-Seq counts into continuous form with a distribution well-fitted by the skew-normal distribution. Both parametric and nonparametric simulations show that SIEVEseq better controls the false discovery rate and Type II error than existing differential expression methods. Analysis of the Mayo RNA-Seq dataset for Alzheimer's disease demonstrates that gene sets with significant differences in mean, variance, and skewness between control and disease groups strongly predict disease state. Furthermore, functional enrichment analysis indicates that relying solely on differentially expressed genes identifies only part of the biological spectrum, whereas incorporating genes with differential variability and skewness reveals additional disease-related aspects. Cross-data and cross-methodology validation suggest the detected biological signals are genuine. The SIEVEseq R package is available at https://cran.r-project.org/web/packages/SIEVEseq.},
}

@article {pmid42523103,
year = {2026},
author = {Dey, C and Pal, P and Khan, A and Dey, SG},
title = {Heme-copper-Aβ mediated dopamine oxidation through self-sustaining redox cycling.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cc03615e},
pmid = {42523103},
issn = {1364-548X},
abstract = {Alzheimer's disease is characterized by progressive neurodegeneration, with Aβ peptides playing a critical role in disease pathology. Beyond their aggregation into plaques, Aβ peptides can interact with redox-active cofactors such as copper and heme, forming complexes capable of catalyzing ROS generation. While Cu-Aβ is known to oxidise catecholamines like dopamine through redox cycling, the functional implications of ternary heme-Cu-Aβ assemblies remain poorly understood. In this study, we demonstrate that the heme-Cu-Aβ complex catalyzes dopamine oxidation more efficiently than Cu-Aβ alone, driven by a self-sustaining cooperative redox cascade involving Cu-mediated H2O2 generation and subsequent heme-mediated peroxidase-like activity in the presence of the endogenously produced H2O2. Moreover, kinetic analysis and mutant studies reveal the critical contributions of Arg5 in modulating the redox behavior of the complex. These findings establish the heme-Cu-Aβ complex as a potent catalytic assembly capable of altering dopamine homeostasis under oxidative stress, offering new insights into Aβ-mediated neurotoxicity in Alzheimer's disease.},
}

@article {pmid42523146,
year = {2026},
author = {Vellone, D and Leon, R and Goodarzi, Z and Forkert, ND and Smith, EE and Ismail, Z},
title = {Mild behavioral impairment-apathy and Alzheimer's disease plasma phosphorylated tau biomarker levels.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470257},
doi = {10.1177/13872877261470257},
pmid = {42523146},
issn = {1875-8908},
abstract = {BackgroundMild behavioral impairment (MBI), characterized by later-life emergence of persistent neuropsychiatric symptoms (NPS), is an early clinical indicator of dementia risk. Global MBI has been associated with Alzheimer's disease (AD) pathology; studies have also explored MBI domains. Prior work has linked MBI-apathy to AD cerebrospinal fluid (CSF) biomarkers, but whether associations are detectable using plasma-based biomarkers such as phosphorylated tau (p-tau) is unknown. Establishing such relationships is critical, as plasma biomarkers are more accessible than CSF.ObjectiveTo explore cross-sectional and longitudinal associations between MBI-apathy and plasma p-tau181 levels using Alzheimer's Disease Neuroimaging Initiative data.MethodsOlder adults with normal cognition or mild cognitive impairment were categorized as MBI-apathy (n = 69), non-MBI NPS (n = 112), and no-NPS (n = 215) based on Neuropsychiatric Inventory scores and symptom persistence over one year. Linear regression modelled cross-sectional associations between NPS group and plasma p-tau181, adjusting for age, sex, education, apolipoprotein E4 status, and Mini-Mental State Examination score. Hierarchical linear mixed-effects modelling assessed associations over two and three years, including time-by-NPS group interactions.ResultsMBI-apathy was associated with significantly higher plasma p-tau181 levels at baseline (24.05% [6.06-45.08%]; adjusted p = 0.014), and over two (26.46% [7.24-49.12%]; adjusted p = 0.012) and three years (29.28% [10.17-51.72%]; adjusted p = 0.004) compared to no-NPS. No significant associations were observed for non-MBI NPS. In sensitivity analyses, non-MBI apathy was not associated with plasma p-tau181 at baseline (-9.96% [-32.69-20.44%]; unadjusted p = 0.478).ConclusionsMBI-apathy is associated with elevated plasma p-tau181 cross-sectionally and longitudinally, supporting MBI-apathy as a potential proxy marker of tau pathology for early AD detection.},
}

@article {pmid42523149,
year = {2026},
author = {Mosquera-Heredia, MI and Vidal, OM and Barceló, E and Morales, LC and Silvera-Redondo, C and Bolívar, DA and Allegri, R and Arcos-Burgos, M and Garavito-Galofre, P and Vélez, JI},
title = {Novel blood lncRNA biomarkers associated with clinical severity and specific cognitive dimensions in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470430},
doi = {10.1177/13872877261470430},
pmid = {42523149},
issn = {1875-8908},
abstract = {BackgroundDifferential expression of long non-coding RNAs (lncRNAs) in brain, serum, and blood show strong potential to distinguish Alzheimer's disease (AD) from healthy controls.ObjectiveTo explore whether lncRNA signatures delineate AD pathology and map to distinct, multidimensional cognitive domains, enhancing specificity in assessing AD severity and progression.MethodsWe profiled 29,603 lncRNAs transcripts in blood samples from 15 AD patients and 15 healthy controls, alongside comprehensive neuropsychological assessments. Generalized Linear Models and Predictive Power Score analyses, with statistical prioritization, identified lncRNAs associated to AD neuropsychological architecture.ResultsSeveral lncRNAs share strongly associated with cognitive performance and AD severity, mapping to genes involved in key AD-related molecular processes, including synaptic and neurotransmitter regulation (e.g., EPHB1, CHRNA4, TEAD1), protein homeostasis and Aβ pathology (e.g., FBXL2, FAM221A, APP), mitochondrial function and cellular stress (e.g., VDAC3, PPT2-EGFL8), neuroinflammation and immune regulation (e.g., TEAD1, EMX2OS, LY6E-DT), epigenetic and transcriptional control (e.g., PRDM2, DLEU1, FIRRE), neuronal excitability (e.g., KCNJ14), and neuroprotection and synaptic plasticity (e.g., SIL1). Novel associations included ferroptosis, DNA stability, microtubule dynamics, and dendritic orientation (e.g., BTB3, DICER1, GNG7, IBA57, NEAT1, POT1, SRD5A3).ConclusionsWe identify candidate lncRNA signatures that may serve as potential biomarkers and enhance our understanding of the molecular basis of the cognitive architecture in AD, opening new avenues for biomarker identification and targeted therapeutic strategies development. Validation in larger, diverse cohorts is essential to confirm their mechanistic contributions to AD.},
}

@article {pmid42523152,
year = {2026},
author = {Oliveira, MPB and Da Silva, SLA and Cezar, NOC and Lima-Truax, CR and Truax, BD and Brito-Costa, S and Takahashi, ACM and Serrão, PRMDS and Andrade, LP},
title = {Exploring the relationship between Alzheimer's disease and lower extremity isokinetic muscle strength in community-dwelling older adults: A cross-sectional observational study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471888},
doi = {10.1177/13872877261471888},
pmid = {42523152},
issn = {1875-8908},
abstract = {BackgroundOlder adults diagnosed with Alzheimer's disease (AD) often experience diminished muscle strength, highlighting the continued importance of evaluating muscle function in this population.ObjectiveTo examine the relationship between AD and isokinetic lower limb muscle strength in older adults.MethodsA cross-sectional observational study was conducted to examine the association between AD and lower limb isokinetic muscle strength in community-dwelling older adults. AD diagnosis was the independent variable; dependent variables included peak torque, average peak torque, and total work. A standardized isokinetic protocol adapted for older adults with cognitive impairment was used to assess knee (flexion/extension at 60°/s and 180°/s) and ankle (dorsiflexion/plantar flexion at 30°/s) strength. Crude and adjusted linear regression models evaluated statistical associations, with significance set at p ≤ 0.05.ResultsA total of 80 older adults were included, 50% of whom had a diagnosis of AD. The crude model's analysis showed an association between AD and all knee and ankle isokinetic measurements. When the models were adjusted, the association was maintained only for ankle peak torque (β1 = -16.23; p < 0.048) and ankle average peak torque (β1 = -13.65; p < 0.049) at 30°/s (plantar flexion).ConclusionsAlzheimer's disease is associated with lower ankle plantar flexors isokinetic muscle strength in community-dwelling older adults. No significant associations between AD and knee (flexors and extensors) and ankle (dorsiflexors) isokinetic muscle strength were found.},
}

@article {pmid42523300,
year = {2026},
author = {Flores, S and Wilpitz, A and Ojeda-Juarez, D and Wang, J and Danque, G and Sumowski, P and Funk, G and Malik, A and Pizzo, D and Richards, E and Iliff, JJ and Sigurdson, CJ},
title = {Aquaporin-4 mislocalization from astrocyte endfeet prolongs survival in a prion-cerebral amyloid angiopathy model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.13.732468},
pmid = {42523300},
issn = {2692-8205},
abstract = {Aquaporin 4 (AQP4) water channels are polarized to astrocytic endfeet at blood vessel interfaces, and lose polarity in vascular diseases, including stroke, chronic traumatic encephalopathy, and Alzheimer's disease. AQP4 modulates water influx and efflux in the interstitial fluid, yet how AQP4 localization impacts cerebral amyloid angiopathy (CAA) remains poorly understood. Here we show that astrocytic end feet and AQP4 are displaced from amyloid-bearing vessels in a prion-CAA mouse model that expresses GPI-anchorless PrP [C] . Displacing AQP4 genetically through deleting alpha-syntrophin (Snta1 [-/-]) led to a marked prolongation in survival, together with reduced microglial inflammation and C1q, in prion-CAA-affected mice. Additionally, synaptic structural proteins were better maintained. Finally, the level and distribution of prion aggregates were similar among the mice, indicating that prion conversion and spread was not affected. These results suggest that reducing AQP4 water channel function slows the decline in a vascular amyloid disease by reducing neuroinflammation.},
}

@article {pmid42523318,
year = {2026},
author = {Wisch, JK and Jiao, Z and Millar, PR and McKay, NS and Beric, A and Lin, W and Baker, B and Stauber, J and Preminger, S and Jucker, M and R Barthélemy, N and Chhatwal, J and Ryan, NS and Schindler, SE and Morris, JC and Cruchaga, C and Benzinger, TLS and Karch, CM and Bateman, RJ and McDade, E and Llibre-Guerra, J and , and , and Gordon, BA and Ances, BM and Ibanez, L},
title = {Biomarker Variability Limits Individualized Amyloid Time Estimation in Alzheimer Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.08.737258},
pmid = {42523318},
issn = {2692-8205},
abstract = {OBJECTIVE: Disease progression modeling (DPM) or "amyloid time" is increasingly used to stage Alzheimer disease (AD). DPM performance depends on within-individual heterogeneity in rates of pathological accumulation as well as test-retest reliability of the biomarker. The relative contributions of these variabilities have not been systematically assessed. This would be particularly relevant if extrapolations from DPM were to be used to make individual-level predictions for research, clinical trials, or potentially future clinical practice.

METHODS: We conducted simulation studies incorporating empirically-derived noise properties from amyloid biomarkers to assess the contributions of inter- and intra-individual variability. Findings generalized in an autosomal dominant AD cohort with amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and plasma biomarkers and in a sporadic AD cohort with both amyloid PET and plasma biomarkers. We assessed group level DPM performance via mean average error (MAE) and root mean squared error (RMSE). At the individual level, we evaluated distinctness of distributions of biomarker levels associated with specific disease timings.

RESULTS: Inter-individual variability was the dominant source of error in temporal estimates. Intra-individual variability reduced estimate stability. Optimal performance occurred in biomarkers with positive average accumulation rates where a subset of individuals had exceptionally high levels of accumulation. In research study data, amyloid PET outperformed CSF and plasma biomarkers.

INTERPRETATION: DPM is fundamentally constrained by dynamic range, variability, and test-retest reliability of the biomarker of interest. Current DPM approaches are more robust at the group level, particularly when applied to biomarkers with more than 10-15% variability like fluid biomarkers.

FUNDING: National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korean Ministry of Health & Welfare and Ministry of Science and ICT, Spanish Institute of Health.},
}

@article {pmid42523335,
year = {2026},
author = {Vrba, SM and Limkar, AR and Keil-Steitz, K and Nirschl, JJ and Laaker, CJ and Bansal, D and Ordonez, SFW and Brooks, EG and Helgager, J and Pehar, M and Sandor, M and Ricke, WA and Fabry, Z},
title = {Amyloid-beta is present in the spinal cord of APP/PS1 mice and may contribute to neuropathology manifesting as lower urinary tract dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.09.737006},
pmid = {42523335},
issn = {2692-8205},
abstract = {Urinary incontinence (UI) is a common and debilitating comorbidity in Alzheimer's disease (AD), yet its underlying pathophysiology remains poorly defined. While UI in dementia has traditionally been attributed to functional impairment, emerging clinical and urodynamic data suggest that neurologic mechanisms may contribute to lower urinary tract dysfunction in this population. Here, we investigated urinary function and neuropathological changes in aged APP/PS1 mice (AD mice), a widely used model of amyloid pathology. Using functional voiding assays, we identified a pattern of urinary dysfunction characterized by increased urinary frequency, small-volume voiding, shortened void duration, and reduced bladder compliance in the absence of bladder outlet obstruction or gross changes in bladder or prostate morphology. These findings are most consistent with a storage-phase abnormality accompanied by impaired voiding coordination rather than classic detrusor overactivity or underactivity. We examined spinal cord and peripheral components involved in bladder innervation and identified amyloid-beta deposition throughout the thoracolumbar and lumbosacral spinal cord, dorsal root ganglia, ventral roots, cauda equina, and associated meningeal structures in AD mice. Importantly, amyloid deposition was accompanied by reduced expression of vesicular acetylcholine transporter and decreased neuronal activation in bladder-innervating pathways, without evidence of increased apoptosis. Taken together, these data demonstrate that AD mice develop a mixed lower urinary tract dysfunction phenotype associated with amyloid-beta deposition and altered neuronal signaling within the spinal cord and peripheral micturition pathways. These findings support a neurogenic contribution to urinary dysfunction in AD and highlight the spinal cord as a novel site of pathology that may influence urinary symptoms in Alzheimer's dementia.},
}

@article {pmid42523338,
year = {2026},
author = {Gutierrez-Kuri, E and Marie Garcia-Rogers, JL and Perez, J and Smith, S and Kenwood, MR and Archuleta, KS and Xiao, Y and Campos, G and Barannikov, S and Wang, H and Pardo, S and Romsdahl, TB and Miller, H and Stowe, AM and William, R and Goldberg, M and Han, X and Bieniek, KF and Weintraub, ST and Griffith, AV and Hopp, SC and Palavicini, JP},
title = {PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.13.738356},
pmid = {42523338},
issn = {2692-8205},
abstract = {BACKGROUND: Phospholipase C gamma-2 (PLCγ2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP 2) to form diacylglycerol (DAG) and inositol trisphosphate (IP 3), feeding into diverse downstream signaling pathways. PLCG2 polymorphisms have been associated with reduced and/or increased risk of Alzheimer's disease (AD) and related dementias, longevity, autoinflammation, and immune disorders. In the brain, PLCγ2 is expressed in microglia, and other neuroimmune and vascular interface populations, yet its role in brain homeostasis remains incompletely defined.

METHODS: We analyzed the brains of three-month-old Plcg2 wild-type (WT), heterozygous (Het KO) and homozygous knockout (Homo KO) littermate mice modeling human PLCG2 loss-of-function risk alleles linked to AD risk using a multiomic approach that included lipidomics, metabolomics, proteomics, and transcriptomics, together with immunofluorescence, as well as flow-cytometric profiling of peripheral and brain-draining immune compartments.

RESULTS: Plcg2 deficiency substantially impaired early survival and produced splenomegaly without increasing total spleen cellularity, instead shifting spleen composition toward myeloid/innate-enriched cells and away from B cells, with expansion of age-associated B-cell (ABC-like) subsets and parallel reductions in CD4 and CD8 regulatory T cells in spleen and cervical lymph nodes. Brain lipidomics revealed selective depletion of PIP 2 , despite very low bulk PLCγ2 protein abundance relative to other PLC family members. PLCγ2 loss led to significant reductions in myelin-enriched lipid classes and myelin/paranode-associated proteins, accompanied by compensatory upregulation of oligodendrocyte/myelin genes, and modest shifts in microglial, lysosomal, complement, and oxidative metabolism pathways by NanoString and DIA-MS. Targeted acylcarnitine profiling demonstrated reprogramming of brain oxidative metabolism, with increased short-, medium-, and long-chain acylcarnitines and enrichment of mitochondrial matrix fatty-acid and amino-acid catabolic enzymes in Homo KO brains.

CONCLUSIONS: Loss of PLCγ2 installs a coordinated program that compromises systemic immune tolerance and subtly erodes central myelin and phosphoinositide homeostasis while enhancing brain oxidative metabolism, effects that extend beyond microglial phagocytic signaling and may underlie increased vulnerability to AD pathology and aging, providing a mechanistic framework for how PLCG2 variation may link systemic immune regulation, white-matter integrity, and neurodegenerative risk.

LIMITATIONS: Because constitutive Plcg2 Homo KO mice display high early mortality and intestinal vascular abnormalities, observed phenotypes may reflect developmental compensation and may not fully recapitulate protective human PLCG2 variants.},
}

@article {pmid42523383,
year = {2026},
author = {Matsumoto, N and Choi, H and Freda, PJ and Hernandez, ME and Wang, ZP and Moore, JH},
title = {EcoXAI: Autonomous Agentic Ecosystem for Explainable Artificial Intelligence and Biomedical Discovery.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.08.737358},
pmid = {42523383},
issn = {2692-8205},
abstract = {MOTIVATION: As biomedical datasets and knowledge graphs continue to grow in size, complexity, and heterogeneity, navigating and extracting actionable insights from them presents a major bottleneck for researchers. There is a clear need for autonomous analytical solutions that can utilize recent advancements in agentic AI such as agent harnessing and loop engineering without introducing hallucination or workflow fragmentation. Researchers, regardless of technical expertise, need tools that streamline complex data analysis and deliver meaningful, actionable insights grounded in both data and established biomedical knowledge. EcoXAI addresses this by introducing a modular, customizable, containerized multi-agent system that structures analysis into explicit pipeline execution stages, lowering the computational barrier for clinical and translational researchers.

RESULT: EcoXAI replaces monolithic AI text interfaces with an autonomous execution-driven framework with specialized bioinformatics agents for delivering proactive, data-driven insights grounded in established biological knowledge. Unlike purely LLM-driven or less integrated AI solutions prone to hallucinations or biologically implausible outcomes, EcoXAI's multi-agent framework, which leverages modern agentic management and explicit knowledge graph integration, provides greater transparency and verifiability in its reasoning. In our use case in drug repurposing for Alzheimer's Disease, EcoXAI evaluated 103 drug candidates and identified 79 novel candidates whose predictive models exceeded a randomized baseline, including the CCR5 antagonist Maraviroc, whose generated hypothesis was subsequently supported by the literature. These results demonstrate the potential of knowledge graph-grounded AI agents to accelerate hypothesis-driven biomedical research.

EcoXAI is available on GitHub at: https://github.com/EpistasisLab/EcoXAI .

CONTACT: jason.moore@csmc.edu.},
}

@article {pmid42523480,
year = {2026},
author = {Goate, A and Romero-Molina, C and Gomez-Gutierrez, R and See, WY and Patel, T and Davtyan, H and Ma, J and Xu, Q and Sewell, M and Allton, K and McReynolds, M and Calderon, O and Lightfoot, Y and Bommer, G and Cruchaga, C and Blurton-Jones, M and Ray, W and Marcora, E},
title = {Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine and reduced Alzheimer's disease risk.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10216155/v1},
pmid = {42523480},
issn = {2693-5015},
abstract = {Lactamase β (LACTB) is a serine β-lactamase-like mitochondrial enzyme genetically associated with obesity, kidney disease, and hyperlipidemia. LACTB is located in an Alzheimer's Disease (AD) risk locus and its expression in the brain has been genetically associated with AD susceptibility. The aim of this study was to investigate LACTB function and genetic link to AD in myeloid cells, due to their central role in modulating AD risk. Our Mendelian randomization analyses revealed that lower LACTB expression in myeloid cells is genetically associated with reduced disease susceptibility and increased succinylcarnitine, a metabolite independently associated with AD risk. We identified LACTB as a primary enzyme responsible for succinylcarnitine hydrolysis. In human macrophages and microglia, LACTB loss promoted enhanced oxidative phosphorylation, reduced protein synthesis and altered lipid homeostasis. LACTB expression was upregulated following interferon or TNF stimulation, and LACTB loss modified efferocytosis-related functions under inflammatory conditions. In vivo , xenotransplanted human LACTB knockout microglia showed enhanced association with amyloid plaques in the mouse brain. Together, these findings experimentally validated the genetic association between reduced LACTB expression and elevated succinylcarnitine and identified LACTB as an inflammation-responsive regulator of myeloid cell metabolism and function that may contribute to its protective genetic association with AD. Given its druggability and potential to use succinylcarnitine as a genetically-validated endophenotype and target engagement biomarker, LACTB represents a promising therapeutic target for AD.},
}

@article {pmid42523500,
year = {2026},
author = {Kim, Y and Heo, W and Park, SJ and Kim, Y and Cho, YE},
title = {Astrocytic lactate shuttle disruption and the energy-starved lysosome in Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42523500},
issn = {2693-5015},
abstract = {Lysosomal dysfunction is central to Alzheimer's disease (AD), yet why structurally intact vacuolar H[+]-ATPase (V-ATPase) proton pumps fail to maintain lysosomal pH remains unresolved. Because V-ATPase activity depends on continuous ATP supply, we hypothesized that disruption of the astrocyte-neuron lactate shuttle imposes a cross-cellular energy deficit-an "energy-starved lysosome" (ESL) state. Integrating single-nucleus transcriptomics (SEA-AD; 1.3 million nuclei, 84 donors) with cerebrospinal fluid proteomics (ADNI Emory; n = 1,105), we found that astrocytic lactate-export genes, led by MCT4 (- 43%), declined far faster than V-ATPase, and that astrocytic MCT4 was coupled to neuronal V-ATPase independently of disease stage (donor-level partial r = + 0.466). At the protein level, V-ATPase V1A abundance was preserved across diagnostic groups-consistent with structural pump integrity-while, at the individual level, glycolytic capacity (hexokinase-1, HK1) tracked Tau pathology; this glycolysis-Tau coupling reproduced on an independent proteomic platform and against immunoassay Tau, whereas an apparent CSF V1A-Tau correlation did not survive distribution-robust analysis or validation against immunoassay Tau and is not interpreted as an individual-level marker. These findings position cross-cellular metabolic decoupling, rather than structural pump loss, as a candidate upstream constraint on lysosomal acidification, defining a candidate intervention window.},
}

@article {pmid42523505,
year = {2026},
author = {Salomón-Cruz, ID and Agudelo-Castrillon, SC and Barbosa-Carvajal, JP and Lozano-Trujillo, LA and Ríos, MH and Trujillo-Chacón, LM and Villegas, A and Osorio, E and Fernandez, GJ and Area-Gómez, E and Cardona-Gómez, GP},
title = {APOE3 Christchurch is associated with sphingolipids recycling and glial lipid remodeling in autosomal dominant Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10297182/v1},
pmid = {42523505},
issn = {2693-5015},
abstract = {Alzheimer's disease is characterized by profound disturbances in brain lipid metabolism, which regulate membrane integrity, connectivity, immune response, and cell survival. However, the mechanisms by which the protective APOE3 Christchurch variant modulates lipid homeostasis in autosomal dominant AD remain poorly understood. Here, we investigated lipid changes in postmortem brains carriers of PSEN1-E280A mutation, including APOE3Ch variant. Using a multimodal approach integrating thin-layer chromatography lipid profiling, enzymatic activity assays, digital PCR, immunofluorescence, flow cytometry, and single-nucleus RNA sequencing, we characterized lipid composition and transcriptional expression in the cerebral cortex. Familial and sporadic AD brains exhibited extensive remodeling of lipid pathways, including depletion of structural phospholipids and marked alterations in sphingolipid metabolism. Notably, APOE3Ch carriers displayed reduced cholesterol and phospholipid content, preservation of ceramide pools, and enrichment of specific ganglioside fractions, accompanied by increased sphingomyelinase activity and coordinated downregulation of genes involved in sphingolipid biosynthesis and remodeling. Single-nucleus transcriptomic analyses further revealed cell-type-specific alterations across glial populations, including reduced pruning of differentiated oligodendrocytes and suppression of lipid metabolic process in astrocytes and microglia. Together, these findings suggest that APOE3Ch promotes a reduced de novo biosynthesis of cholesterol and a distinct sphingolipid metabolic state characterized by enhanced lipid recycling, potentially attenuating lipid-driven neuroinflammatory responses.},
}

@article {pmid42523517,
year = {2026},
author = {Diaz, CS and Baghirova, N and Vu, DT and Can, DC and Allali, G and Ryvlin, P and Chén, OY},
title = {Imputation-free transformer learning enables robust Alzheimer's disease prediction and calibrated uncertainty quantification across heterogeneous clinical cohorts.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42523517},
issn = {2331-8422},
abstract = {Accurate diagnostic classification and disease-severity prediction for Alzheimer's disease are hampered by the incompleteness and heterogeneity of real-world clinical data. Left unaddressed, these barriers prevent reliable disease modelling and hinder effective clinical evaluation. Conventional imputation strategies introduce systematic bias, distort inter-feature relationships, and yield overconfident predictions, limitations especially consequential in diagnostic settings. Here, we propose NITROGEN, an imputation-free transformer that jointly models within-patient feature dependencies and between-patient relational structure through masked and intersample attention, enabling robust multimodal learning directly from partially observed records. We trained NITROGEN on ADNI (N=7858 scans), and evaluated it on two independent cohorts: OASIS-3 (N=2675 scans) and AIBL (N=1286 scans). Across cohorts and diagnostic and cognitive score prediction tasks, NITROGEN showed robust calibration and uncertainty quantification advantages over tree-based ensemble methods, while maintaining competitive discriminative performance. Cross-cohort and cross-method analyses identified cortical thickness in the temporal pole, age, and APOE genotype as important, though not individually sufficient, features for AD classification. We further introduced a modality-aware uncertainty adjustment that augments predictive uncertainty proportionally to the importance of absent modalities, enabling calibrated confidence when diagnostic information is unavailable. Together, our results show that imputation-free attention learning preserved meaningful discrimination under cohort shift, revealing expected degradation on more distributionally different cohorts, and demonstrate that evaluating models along calibration, interpretability, and cross-cohort reliability, not accuracy alone, is essential for clinical deployment.},
}

@article {pmid42523519,
year = {2026},
author = {Chen, X and Munoz-Mayorga, D and Lyu, X and Jati, S and Zhang, J and Rossitto, LA and Tao, Y and Zhao, S and Hui, E and Kauffman, A and Zhu, B},
title = {A non-canonical androgen signaling pathway drives microglial activation and tau pathology in females.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42523519},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) disproportionately affects women, who exhibit greater vulnerability to Tau pathology and neuroinflammation. The precise mechanisms underlying this vulnerability remain elusive, although sex hormones are thought to play a pivotal role. Here, we report that supplementation with the non-aromatizable androgen dihydrotestosterone (DHT) exacerbates Tau pathology in female tauopathy models, with microglia as the main driver of this effect. DHT treatment upregulates proinflammatory gene expression in microglia and promotes the disease-associated microglia (DAM) phenotype in a Trem2-dependent manner. Surprisingly, these effects are independent of the canonical androgen receptor (AR) and instead depend on the orphan nuclear receptor TR4, which mediates DHT-driven effects by transcriptionally regulating Trem2 in microglia. Moreover, TR4 protein levels are elevated in postmortem brain tissue from Braak stage 6 female AD patients and correlate with p-Tau levels. Together, our findings uncover a non-canonical DHT-TR4- Trem2 signaling axis in microglia and identify TR4 as a key regulator of neuroinflammation in female neurodegeneration, providing mechanistic insight into female-specific vulnerability to AD.},
}

@article {pmid42523523,
year = {2026},
author = {Estrella, LD and Dasgupta, S and Gundavelli, A and Li, H and Yang, SH and Chancellor, S and Pastika, T and Abdourahman, A and Tamm, J and Yanamandra, K and Romanul, N and Liao, F and Zhao, K and Lin, G and Srinivasa, P and Wang, X and Martin, A and Asque, E and Doering, A and Ried, JS and Talanian, RV and Kwon, T and Woodbury, ME and Grinberg, YY and Agastra, E and Oakley, DH and Hyman, BT and Serrano-Pozo, A and Zwang, T and Das, S and Bennett, RE},
title = {Cerebrovascular Single-Nucleus RNA-Seq Reveals Heat Shock Activation and Vascular Remodeling in Alzheimer's Disease and Primary Tauopathies.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42523523},
issn = {2693-5015},
abstract = {Cerebrovascular alterations are widely observed in both Alzheimer's Disease (AD) and primary tauopathies. Here, we hypothesized that mechanisms of cerebrovascular alterations are shared between AD and primary tauopathies. We performed single-nucleus RNA sequencing of postmortem human inferior temporal gyrus to characterize transcriptomic changes across cerebrovascular cell types in AD and primary tauopathies (Corticobasal Degeneration, Pick's disease, and Progressive Supranuclear Palsy). Differential gene expression analyses revealed disease-specific transcriptional programs across vascular cell populations. However, genes involved in the heat-shock response were consistently upregulated across all diseases, suggesting a conserved cerebrovascular stress response during neurodegeneration. We further identified marked cerebrovascular remodeling in AD relative to primary tauopathies, along with dysregulation of genes mapping to AD risk loci in endothelial cells. Transcriptomic findings were validated using tissue clearing, light-sheet microscopy, and immunofluorescence quantification of vascular markers. These results define a conserved vascular stress program alongside AD-specific remodeling, highlighting the vasculature as a therapeutic target in neurodegeneration.},
}