@article {pmid42602062,
year = {2026},
author = {Bréchet, L and Bouhour, C and Rochas, V and Mekrom, VA and Eshmawey, M and Unschuld, PG},
title = {Personalized, home-based transcranial alternating current stimulation for memory improvement in mild cognitive impairment: randomized, sham-controlled clinical trial protocol.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1882406},
pmid = {42602062},
issn = {1663-4365},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD) and represents a critical window for interventions aimed at slowing neurodegenerative progression. Disruptions in neural oscillatory activity are key contributors to memory dysfunction in MCI and AD. Transcranial alternating current stimulation (tACS) is a non-invasive neuromodulation technique that entrains neural oscillations at specific frequencies, potentially restoring network dynamics underlying memory.

METHODS: The MemStim study is a randomized, sham-controlled, parallel-arm, double-blind clinical trial evaluating the efficacy of personalized, home-based gamma-frequency tACS over the left angular gyrus, delivered 5 days a week for 4 weeks, in individuals with MCI. Safety and tolerability are monitored throughout the intervention. Forty participants aged ≥55 years with clinically diagnosed MCI will be recruited at the Geneva University Hospitals and randomized to active or sham stimulation. All participants undergo baseline and post-stimulation assessments, including cognitive testing, structural MRI, and high-density EEG (hdEEG). Individual MRI-based electric-field modeling personalizes stimulation montages targeting the left angular gyrus, a key node of the memory network.

OUTCOMES: The primary outcome is the change in global cognitive function measured by the Montreal Cognitive Assessment (MoCA) from baseline to post-intervention. Secondary outcomes include changes in gamma-band oscillatory power measured with hdEEG. Exploratory EEG analyses will examine spectral, temporal, and spatial brain dynamics. Cognitive assessments are repeated 3 months post-intervention to evaluate persistence of effects.

DISCUSSION: This trial investigates whether personalized gamma-frequency tACS can modulate hdEEG measures of resting-state brain activity and improve memory function in MCI. By integrating individualized stimulation targeting, electrophysiological biomarkers, and remotely supervised home-based delivery, the MemStim study aims to advance personalized neuromodulation as a scalable therapeutic strategy for early intervention in cognitive decline.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT05708001.},
}

@article {pmid42602177,
year = {2026},
author = {Azimzadeh, M and Ababzadeh, S and Kahaki, AG and Babaei, SMH and Seyedebrahimi, R and Farsani, ME},
title = {The Gut-Brain Axis in Neurodegeneration: Mechanistic Links Between Dysbiosis and Neuropathology.},
journal = {Iranian journal of pathology},
volume = {21},
number = {4},
pages = {507-522},
pmid = {42602177},
issn = {1735-5303},
abstract = {BACKGROUND & OBJECTIVE: The gut-brain axis is essentially a two-way communication system that physically connects the brain and the intestinal tract. The connection is mediated through a series of pathways, including neural, endocrine, and immune pathways. Gut dysbiosis, which is explained as an imbalance in the microbial community, has been linked to the causation of various neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the pathological mechanisms in the brain are only partially known. The present review outlines the process of gut dysbiosis and neurodegeneration, detailing the roles of protein aggregation, neuroinflammation, barrier disruption, and neuroglial dysfunction. Then, extending the comparison to a range of neurodegenerative diseases, we discuss the possibility of common pathway therapeutics and actual microbiome-based treatment options planning from the standpoint of microbiome-directed interventions.

CONTENT/FINDINGS: Gut dysbiosis triggers a definable cascade, starting with the disruption of the intestinal barrier and increased permeability (leaky gut), which allows bacterial products (lipopolysaccharides, bacterial amyloids) and pro-inflammatory cytokines to enter systemic circulation. Such peripheral changes weaken the blood-brain barrier and thus allow these factors to access the CNS, where they lead to neuroglial dysfunction (microglial priming, astrocytic reactivity, and oligodendrocyte injury) by disruption of glial homeostasis. CNS glial cell malfunction leads to the development of proteinopathies characteristic of each disease: amyloid and tau hyperphosphorylation in Alzheimer's disease through BACE1 upregulation and kinase activation; synuclein in Parkinson's disease via molecular mimicry, oxidative stress, and impaired clearance; and demyelination in multiple sclerosis through oligodendrocyte apoptosis. Oral bacteria such as Porphyromonas gingivalis aggravate this inflammatory loop through the direct invasion of the CNS and proteolytic cleavage of amyloid and tau. The vagus nerve is yet another pathway through which gut-derived inflammatory signals and pathological synuclein can be transmitted to the brain.

CONCLUSION: The gut microbiome is more than just a correlate of neurodegeneration; it actively promotes neurodegenerative diseases through pathways that can be mechanistically defined. Microbiome-targeted interventions such as dietary changes, precision probiotics, fecal microbiota transplantation, and anti-inflammatory agents offer a measure of hope for changing these pathological processes. Future studies need to be directed at determining the time sequence of cause and effect, finding dependable microbiota-based biomarkers, and formulating tailored strategies that can account for individual microbial composition variability, genetic susceptibility, and environmental exposures. A deeper understanding of the gut-brain axis from this mechanistic perspective could eventually lead to the prevention or postponement of neurodegeneration.},
}

@article {pmid42598783,
year = {2026},
author = {Liu, M and Gong, K and Chen, Y and Heo, G and Xu, Y and Timsina, J and Western, D and Budde, J and Morris, JC and Marco, G and Holtzman, DM and Hinson, J and Levin, S and Ashton, N and Denkinger, M and Schindler, SE and Das, K and Ali, M and Cruchaga, C},
title = {A plasma-based protein signature combining NPTXR, ACHE, and p-tau217 predicts progression to symptomatic Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71748},
pmid = {42598783},
issn = {1552-5279},
support = {R01-AG058501/NH/NIH HHS/United States ; //Cure Alzheimer's Fund/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; Disease Progression ; *tau Proteins/blood ; Biomarkers/blood ; Female ; Male ; *Acetylcholinesterase/blood ; *Nerve Tissue Proteins/blood ; Aged ; Longitudinal Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We recently identified a plasma-based seven-protein model with strong performance for Alzheimer's disease (AD) classification. Here, we evaluated whether these proteins, alone or combined with plasma phosphorylated tau 217 (p-tau217), predict progression from cognitively unimpaired to symptomatic AD.

METHODS: Using longitudinal data from Knight-ADRC (Alzheimer's Disease Research Center) with replication in Alzheimer's Disease Neuroimaging Initiative (ADNI), we modeled time to progression using Cox regression. Models included p-tau217, the seven-protein panel, and their combination.

RESULTS: The p-tau217 alone showed similar progression prediction (hazard ratio [HR] = 4.08) than the seven-protein model (HR = 4.85). Integrating the seven-protein model with ptau217 significantly improved risk, identifying a high-risk group (HR = 11.15) with two intermediate-risk groups. Simplified models retained prognostic value, with top-performing ratios, Complexin-2/Synaptic vesicle membrane protein VAT-1 homolog (CPLX2/VAT1) and Acetylcholinesterase/Neuronal pentraxin receptor (ACHE/NPTXR) also lead to a significantly better risk stratification than p-tau217 alone.

DISCUSSION: Integrating p-tau217 with targeted plasma proteins enables graded risk stratification and identifies individuals at highest risk of progression, supporting clinically scalable approaches for early risk assessment.},
}

Humans
*Alzheimer Disease/blood/diagnosis
Disease Progression
*tau Proteins/blood
Biomarkers/blood
Female
Male
*Acetylcholinesterase/blood
*Nerve Tissue Proteins/blood
Aged
Longitudinal Studies
Aged, 80 and over

@article {pmid42599498,
year = {2026},
author = {Zhang, P and Guo, X and Yang, M and Cai, Y and Wang, L and Gao, Y},
title = {Photo/Copper-Catalyzed Oxidative Direct Diphosphorothiolation of Indolin-2-ones with P(O)SH Compounds.},
journal = {The Journal of organic chemistry},
volume = {91},
number = {32},
pages = {11141-11147},
doi = {10.1021/acs.joc.6c01443},
pmid = {42599498},
issn = {1520-6904},
support = {22201242//National Natural Science Foundation of China/ ; 22271285//National Natural Science Foundation of China/ ; 2025J09053//Natural Science Foundation of Fujian Province/ ; XYBSKYZZ201926//Xinxiang Medical University/ ; 505527//Research Foundation for Distinguished Professor?s Team of Xinxiang Medical University/ ; },
abstract = {A visible-light-promoted cross-dehydrogenative coupling (CDC) of indolin-2-ones with S-hydrogen phosphorothioates via 4H elimination has been developed, providing 3,3-diphosphorothiolated oxindoles in good yields with broad functional group tolerance. The protocol was also extended to monophosphorothiolation and late-stage diversification of drug-derived substrates. Notably, the products displayed potent and selective butyrylcholinesterase (BuChE) inhibitory activity, suggesting potential as leads for Alzheimer's disease.},
}

@article {pmid42599532,
year = {2026},
author = {Raj, SN and Natnan, ME and Lou, WP and Mediani, A and Tencomnao, T and Baharum, SN},
title = {Unravelling the phytochemical complexity of neuroprotective plants: a metabolomics approach to Alzheimer's disease.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42599532},
issn = {1573-4978},
support = {GGP-2020-043//Universiti Kebangsaan Malaysia/ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy ; *Metabolomics/methods ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use/metabolism ; *Phytochemicals/metabolism/therapeutic use/pharmacology ; *Plants, Medicinal/metabolism/chemistry ; Animals ; Metabolome ; Drug Discovery/methods ; },
abstract = {Metabolomics is a comprehensive study of organisms at the metabolite level. The emergence of metabolomics as one of the 'omics' in systems biology perspectives has gained significance in relation to disease research. The use of metabolomics pipeline to unravel the potential of bioactive compounds in medicinal plants for benefiting mankind has become a powerful strategy for drug discovery. While traditional metabolite profiling has mainly classified medicinal plants according to broad biological activities, such as anti-inflammatory, anticancer, anti-diabetic and atherosclerosis effects, the non-targeted and targeted metabolomics offer a comprehensive approach for characterizing novel or previously unknown secondary metabolites providing a far more detailed approach. These advanced methodologies allow researchers to expand current research by providing deeper insight into how these compounds work and their underlying mechanisms at the molecular level. To investigate these metabolic shifts particularly in neurodegenerative diseases model, studies frequently use advanced analytical platform, such as nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS) to analyze metabolites in biofluids like blood, urine, and cerebrospinal fluid (CSF). This review will highlight recent metabolomics discoveries on unravelling the complex phytochemical composition of selected medicinal plants in producing neuroprotective bioactive compounds and therapeutic potential to combat neurodegenerative related disease especially Alzheimer's disease (AD).},
}

*Alzheimer Disease/metabolism/drug therapy
*Metabolomics/methods
Humans
*Neuroprotective Agents/pharmacology/therapeutic use/metabolism
*Phytochemicals/metabolism/therapeutic use/pharmacology
*Plants, Medicinal/metabolism/chemistry
Animals
Metabolome
Drug Discovery/methods

@article {pmid42599667,
year = {2026},
author = {Wang, Y and Gu, Z and Zhang, H and Bi, X and Chen, L and Lu, J},
title = {Multimodal MRI insights into hippocampal pathological changes across the Alzheimer's disease continuum: advances and challenges.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42599667},
issn = {1867-108X},
support = {82371495//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with early and progressive hippocampal pathology serving as a hallmark across the AD continuum, including subjective cognitive decline, mild cognitive impairment, and AD dementia. Single-modal MRI fails to fully capture multilevel hippocampal neuropathology, hindering accurate early diagnosis and prognostic prediction of AD. This narrative review summarizes recent advances in structural MRI, diffusion tensor imaging, magnetic resonance spectroscopy, quantitative susceptibility mapping, arterial spin labeling, and functional MRI for evaluating hippocampal and medial temporal lobe abnormalities in AD. These techniques provide a multifaceted characterization of AD-associated hippocampal alterations, including macroscopic atrophy, microstructural degeneration, metabolic dysregulation, aberrant iron deposition, hemodynamic dysfunction, and abnormal neuronal activity. Hippocampal damage in AD exhibits distinct subfield specificity, hemispheric asymmetry, and stage-dependent progression, modulated by Aβ/tau pathology, neuroinflammation, and apolipoprotein E ε4 genotype. Notably, multimodal imaging fusion integrated with machine learning outperforms single-modal biomarkers, significantly improving the accuracy of AD early screening, differential diagnosis, and prognostic prediction. Nevertheless, existing studies are hampered by inadequate pathological validation, limited sample sizes, unsatisfactory reproducibility, and multicenter technical heterogeneity. Multimodal MRI offers robust non-invasive evidence for exploring AD hippocampal pathophysiology. Future large-scale multicenter longitudinal studies combining artificial intelligence will advance precision diagnosis and targeted therapy for AD by clarifying the interplay among AD pathology, genetics, and heterogeneous hippocampal injury.},
}

@article {pmid42599691,
year = {2026},
author = {Wang, S and Zou, S and , },
title = {Cerebrospinal fluid glial cell line-derived neurotrophic factor levels interact with APOE ε4 genotype to influence cognitive decline in older adults without dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477047},
doi = {10.1177/13872877261477047},
pmid = {42599691},
issn = {1875-8908},
abstract = {BackgroundAlthough both apolipoprotein E (APOE) ε4 and glial cell line-derived neurotrophic factor (GDNF) are implicated in the pathogenesis of Alzheimer's disease (AD), it remains unclear whether they interact to affect cognitive decline among older adults without dementia.ObjectiveThis study aimed to examine the interactive effects of APOE ε4 and GDNF on longitudinal cognitive decline.MethodsA total of 543 individuals (mean age 73 [±7] years; 43% female) with cognitively unimpaired (CU) or mild cognitive impairment (MCI) were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Linear mixed-effects models were used to examine the contributions of cerebrospinal fluid (CSF) GDNF levels and APOE ε4 status to longitudinal changes in cognitive measures, including the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating - Sum of Boxes (CDR-SB), the 13-item Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog-13), and the Rey Auditory Verbal Learning Test (RAVLT) total score.ResultsWe found that the 3-way interaction (APOE ε4 × GDNF × time) was significant for MMSE, CDR-SB, and ADAS-Cog-13, and of marginal significance for RAVLT total score, after adjusting for age, sex, and education. Specifically, individuals who were APOE ε4 carriers with low CSF GDNF levels showed the fastest rate of cognitive decline among the four groups (Low/APOE4-, High/APOE4-, Low/APOE4+, and High/APOE4+).ConclusionsAPOE ε4 appears to interact with CSF GDNF levels to affect longitudinal cognitive decline among older adults without dementia.},
}

@article {pmid42599695,
year = {2026},
author = {Alavi, A and Gujral, J and Gandhi, OH and Amanullah, AA and Ayubcha, C and Patil, S and Werner, TJ and Høilund-Carlsen, PF},
title = {The case for FDG-PET and NaF-PET in risk stratification of mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477750},
doi = {10.1177/13872877261477750},
pmid = {42599695},
issn = {1875-8908},
abstract = {According to a recent study, integrating amyloid-PET, structural MRI, carotid Doppler ultrasound, cognitive testing, and APOE genotyping improves estimation of dementia progression in patients with mild cognitive impairment, with carotid plaque burden emerging as a dominant predictor in amyloid-β-negative cases. We agree that vascular pathology is crucial but suggest that future models consider supplementing amyloid-PET with FDG-PET, a well-validated functional marker of neuronal injury, and carotid Doppler with [18]F-sodium fluoride (NaF)-PET which can detect and quantify early, active microcalcification. This could further improve risk stratification while facilitating detection of potentially modifiable disease processes.},
}

@article {pmid42599799,
year = {2026},
author = {Liu, R and Zhang, Y and Lai, M and Davydzenka, V and Moffitt, C and England, N and Barbera, G and Chen, R and Lin, DT and Li, Y},
title = {Graph theory identifies altered prefrontal microcircuit organization in Shank3 mice, a mouse Model of autism.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117852},
doi = {10.1016/j.celrep.2026.117852},
pmid = {42599799},
issn = {2211-1247},
abstract = {Graph theory provides unique tools to assess complex networks. It has been previously used with functional magnetic resonance imaging (fMRI) datasets to quantify macroscopic-scale connections among different brain regions, readily capturing brain network changes in subjects with Alzheimer's disease. Here, we apply graph theory to miniscope calcium imaging data recorded from the prefrontal cortex of freely behaving wild-type (WT) and Shank3[fx] mice (a mouse model of autism) during social behavior tasks to compare microscopic-scale functional connections among individual neurons. We demonstrate that Shank3[fx] mice display reduced population-level neural activity and a less-integrated and rigid prefrontal microcircuit. Furthermore, we employ machine learning to predict genotypes and behavioral differences between WT and Shank3[fx] mice using graph-theoretic metrics extracted from prefrontal microcircuits. Our results indicate strong links between altered prefrontal microcircuits and social behavior deficits in the Shank3[fx] mice, highlighting prefrontal microcircuitry as a potential diagnostic and therapeutic target for autism.},
}

@article {pmid42599802,
year = {2026},
author = {Bhatta, S and Grzybowski, A and Ortiz, G and DiStasio, M},
title = {TTN[+] macrophages are enriched in the human choroid plexus in Alzheimer's disease.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117859},
doi = {10.1016/j.celrep.2026.117859},
pmid = {42599802},
issn = {2211-1247},
abstract = {The choroid plexus (ChP) regulates cerebrospinal fluid homeostasis and immune surveillance, but its cellular organization and response to Alzheimer's disease (AD) remain incompletely defined. Here, we integrate single-nucleus RNA sequencing with spatial transcriptomics to generate a high-resolution atlas of the adult human ChP. We identify all major epithelial, stromal, and immune populations and resolve heterogeneity within macrophages, including a distinct subset expressing the giant protein TTN. These TTN[+] macrophages exhibit coordinated cytoskeletal, stress-response, and phagocytic gene programs and localize to perivascular and stromal niches. In AD, we observe broad, cell type-specific transcriptional remodeling across epithelial, endothelial, mesenchymal, and immune compartments, with expansion of TTN[+] macrophages and increased senescence signatures. Spatial and ligand-receptor analyses reveal altered tissue organization and macrophage interaction patterns with neighboring cells. Combined with in situ validations, these findings provide evidence of TTN expression by macrophages, and reveal a broader AD-associated contextual shift in human ChP immune function in which TTN[+] macrophages are enriched.},
}

@article {pmid42599805,
year = {2026},
author = {Zou, ZM and Wang, D and Tang, WJ and Chen, XL and Li, HJ and Li, GL and Xiao, R and Xu, LH and Si, WK and Chen, ZY},
title = {GLUT4 plasma translocation in lateral septum GABAergic neurons supports neuronal activation and social familiarity.},
journal = {Cell reports},
volume = {45},
number = {8},
pages = {117854},
doi = {10.1016/j.celrep.2026.117854},
pmid = {42599805},
issn = {2211-1247},
abstract = {Social interaction regulates neuronal excitability and behavior, and the lateral septum (LS) plays an important role in social behavior. However, the molecular mechanisms that support LS-dependent social responses remain unclear. Here, we show that neuronal activity-driven glucose transporter 4 (GLUT4) plasma translocation in LS GABAergic neurons supports social familiarity. Neuronal activation triggers CaMKIIα-mediated phosphorylation of GLUT4 at Ser243 and Ser254, which enhances Rab10 binding, GLUT4 surface insertion, and glucose uptake. A cell-permeable TAT-GLUT4(2D) peptide disrupts GLUT4-Rab10 binding, blocks activity-dependent GLUT4 translocation, and impairs social familiarity. LS GLUT4 knockdown disrupts social novelty preference, and this deficit is rescued by wild-type GLUT4 but not trafficking- or transport-deficient mutants. In 5xFAD mice, GLUT4 plasma translocation is reduced during social novelty preference. Selective expression of plasma-localized GLUT4 in LS GABAergic neurons restores neuronal activation and social familiarity impairments, identifying GLUT4 trafficking as a potential target for Alzheimer's disease-related social impairments.},
}

@article {pmid42600000,
year = {2026},
author = {Chae, H and Park, Y and Kim, Y and Yoon, E and Kim, KW and Yoo, S},
title = {Wearable transparent OLED glasses for cognitive stimulation: Enhancing brain connectivity through gamma entrainment.},
journal = {Science advances},
volume = {12},
number = {33},
pages = {eaee5504},
pmid = {42600000},
issn = {2375-2548},
mesh = {Humans ; *Wearable Electronic Devices ; *Cognition/physiology ; *Brain/physiology ; *Gamma Rhythm/physiology ; Cognitive Enhancement ; },
abstract = {Gamma wave entrainment is a promising approach for improving cognitive function, particularly in the early stages of Alzheimer's disease. However, for everyday treatment, a light source system that maintains visibility while delivering effective stimulation is essential for patient comfort and practicality. To address this need, we developed organic light-emitting diode (OLED) glasses with optimized large-area transparent OLEDs for gamma wave entrainment. The optimization involved all layers of the device, including encapsulation, to achieve high luminous transmittance (75%), uniformity (over 90%), and electrical performance, ensuring suitability for wearable applications. Under real-world conditions (see-through visibility and ambient light present), the transparent OLED glasses successfully induced gamma rhythm entrainment, enhancing brain connectivity between the occipital and frontal regions. They also notably reduced visual discomfort and showed a trend of enhanced connectivity compared to nontransparent OLEDs. These results highlight the potential of this noninvasive wearable technology for early cognitive intervention, providing comfortable therapeutic light stimulation.},
}

Humans
*Wearable Electronic Devices
*Cognition/physiology
*Brain/physiology
*Gamma Rhythm/physiology
Cognitive Enhancement

@article {pmid42600372,
year = {2026},
author = {Rudroff, T},
title = {Sex composition as an unaddressed confound in FDG-PET predictive models of Alzheimer's disease conversion.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {10},
pages = {100955},
doi = {10.1016/j.jnha.2026.100955},
pmid = {42600372},
issn = {1760-4788},
}

@article {pmid42600466,
year = {2026},
author = {Kumar, N and Khan, I and Singh, J and Kumar, K and Kushwaha, VK and Ojha, S and Raman, SK and Shankar, G},
title = {Recent developments in donepezil-based hybrid molecules as multi-target therapeutics for Alzheimer's disease: A paradigm shift beyond symptomatic treatment.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110361},
doi = {10.1016/j.bioorg.2026.110361},
pmid = {42600466},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder characterized by the gradual loss of cholinergic neurons, leading to cognitive impairment, synaptic dysfunction, and irreversible neuronal degeneration. The multifactorial nature of AD, involving cholinergic deficits, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, and metal dyshomeostasis, has limited the clinical success of single-target therapeutic strategies. Although donepezil (DPZ), a clinically approved acetylcholinesterase (AChE) inhibitor, remains one of the most widely prescribed agents for symptomatic management, it does not alter the underlying neurodegenerative processes. Consequently, DPZ has emerged as an attractive medicinal chemistry scaffold for the development of multi-target-directed ligands (MTDLs) that simultaneously modulate multiple interconnected pathological pathways implicated in AD. This review provides a comprehensive and critically organized overview of recent advances in DPZ-based hybrid molecules, emphasizing rational design strategies, hybridization approaches, structure-activity relationships (SAR), molecular mechanisms, and pharmacological profiles. To facilitate a mechanistic understanding, the reported hybrids are systematically classified according to structural modifications of the indanone moiety, the benzylpiperidine moiety, or simultaneous modification of both pharmacophoric regions. Comparative analysis reveals how scaffold engineering, linker optimization, and strategic incorporation of complementary pharmacophores influence cholinesterase inhibition, anti-amyloid activity, antioxidant capacity, neuroprotection, metal chelation, monoamine oxidase inhibition, and blood-brain barrier permeability. Importantly, this review critically examines the current translational landscape, highlighting that despite encouraging in vitro and in vivo findings, no DPZ-based hybrid has yet advanced to clinical evaluation. Key challenges, including pharmacokinetic optimization, metabolic stability, safety, target engagement, and clinical translatability, are discussed together with future medicinal chemistry directions. Rather than presenting DPZ-based hybrids as established disease-modifying therapies, the available evidence supports their role as promising multifunctional lead compounds and valuable molecular platforms for the rational design of next-generation anti-Alzheimer agents. By integrating emerging SAR trends with critical translational perspectives, this review provides a contemporary framework to guide future development of clinically relevant multifunctional therapeutics for AD.},
}

@article {pmid42600613,
year = {2026},
author = {Brioschi, S and Belk, JA and Storck, SE and Wu, Y and Wang, Z and Feng, Z and van Olst, L and Emery, JL and Sudan, R and Wu, J and Du, S and Genua, M and La Terza, F and Edwards, AJ and Nguyen, KM and Sanford, J and Lee, DD and Bugatti, M and Federico, AJ and Chen, Y and Wang, Z and Penati, S and Rodrigues, PF and Antonova, AU and Loo, HQ and Smirnov, I and Gilfillan, S and Halabi, CM and Ponce, J and Yan, J and Chang, HY and Randolph, GJ and Vermi, W and Cella, M and Meers, M and Ostuni, R and Gate, D and Nguyen, AT and Cruchaga, C and Hu, S and Kipnis, J and Colonna, M},
title = {Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.07.043},
pmid = {42600613},
issn = {1097-4172},
abstract = {Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries, affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer's disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communication with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF, providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.},
}

@article {pmid42600734,
year = {2026},
author = {Sharma, T and Sharma, P and Bashir, B and Singh, SK and Vishwas, S},
title = {Small nucleolar RNAs: Emerging therapeutic and diagnostic frontiers in Alzheimer's disease.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104771},
doi = {10.1016/j.drudis.2026.104771},
pmid = {42600734},
issn = {1878-5832},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which effective therapeutic interventions remain scarce, highlighting the urgent need for new molecular approaches. Small nucleolar RNAs (snoRNAs), classically known for directing ribosomal modifications, have recently emerged as multifunctional regulators of gene expression, stress responses and neuronal homeostasis. Emerging evidence shows snoRNA dysregulation in the biofluids and brain tissue of patients with AD, positioning them as promising diagnostic biomarkers and therapeutic targets. This review outlines the structural, functional and translational potential of snoRNAs, with a particular focus on their ability to modulate AD pathology while also addressing key challenges in their clinical translation, including delivery barriers, biological stability and target specificity.},
}

@article {pmid42600807,
year = {2026},
author = {Fereidouni, A and Nematollahi, S and Mathew, KT and Favennec, V and Liceran, L and Aldenhoff-Kelly, C and Valdivieso, MA and Trent, S and Moradikor, N},
title = {Allosteric modulation of ionotropic and G protein-coupled receptors in Alzheimer's disease: A neuroprotective strategy and therapeutic implications.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154063},
doi = {10.1016/j.ijbiomac.2026.154063},
pmid = {42600807},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and still lacks an effective treatment that can slow or stop disease progression. In addition to amyloid-β and tau pathology, AD involves major disturbances in calcium balance, neurotransmission, and synaptic plasticity. Conventional orthosteric drugs provide limited symptomatic benefit and often interfere with physiological receptor function, underscoring the need for more selective therapeutic strategies. This review explores allosteric modulation of neurotransmitter receptors as a potential neuroprotective strategy in AD, with an emphasis on mechanisms that restore synaptic integrity, regulate calcium homeostasis, and engage disease-relevant intracellular signaling pathways. The review synthesizes preclinical and clinical evidence on allosteric modulators targeting key ionotropic receptors, including NMDA, AMPA, GABA-A, nicotinic acetylcholine, and P2X7 receptors, and G protein-coupled receptors (GPCRs) such as M1 muscarinic receptors, metabotropic glutamate receptors, and the calcium-sensing receptor. Particular attention is given to receptor selectivity, signaling bias, and translational relevance. Allosteric modulation of ionotropic receptors can influence excitability and synaptic plasticity and may preserve endogenous neurotransmission, with circuit-stabilizing effects reported mainly in preclinical studies. GPCR-directed allosteric modulators can affect AD-related processes, including amyloid- and tau-associated toxicity, excitotoxicity, and neuroinflammation, although evidence for these effects is largely preclinical and clinical translation remains challenging. Convergent pathways, such as Ca[2+]-dependent signaling, ERK/CREB, PI3K/Akt, and cAMP/PKA, may represent shared mediators of disease-relevant effects. Allosteric modulation may offer a more refined, receptor-specific framework for therapeutic investigation in AD. Ionotropic and GPCR-targeted agents may each produce symptomatic or preclinical disease-relevant effects, but their capacity to slow disease progression in patients remains unproven and will require current pharmacological and translational challenges to be addressed.},
}

@article {pmid42600874,
year = {2026},
author = {Xiao, J and Lan, Z and Zhang, R and Zhang, J and Hu, Z and Jia, B and Tang, H and Xu, T and Bao, X and Xu, Y and Yu, L and Ji, SL and Zhu, X},
title = {Novel natural inhibitor Rubimaillin targets NLRP3 R167/Y381 to ameliorate inflammatory and neurodegenerative diseases.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122293},
doi = {10.1016/j.jep.2026.122293},
pmid = {42600874},
issn = {1872-7573},
abstract = {Rubia cordifolia L. is traditionally used in Chinese medicine for treating arthritic and inflammatory conditions by cooling blood and activating circulation. Gouty arthritis, one of the disease models investigated in this study, falls within this traditional anti-arthritic application. This study investigates whether rubimaillin (Rub), a naphthoquinone from Rubia cordifolia, selectively inhibits NLRP3 inflammasome activation and exerts therapeutic effects in relevant disease models. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a key driver of various inflammatory, metabolic, and neurodegenerative disorders; yet, no clinically approved inhibitor is currently available. Rubia cordifolia L. is a traditional medicinal herb, and Rubimaillin (Rub), a naphthoquinone isolated from this herb, has potential anti-inflammatory properties, but its role and mechanism in regulating NLRP3 activation remain unclear.

AIM OF STUDY: This study aimed to determine whether Rubimaillin (Rub), a naphthoquinone isolated from Rubia cordifolia L., can selectively inhibit NLRP3 inflammasome activation and yield therapeutic effects in relevant NLRP3-driven disease models.

MATERIALS AND METHODS: Mouse primary microglia, bone marrow-derived macrophages (BMDMs), and the human macrophage cell line THP-1 were primed with lipopolysaccharide (LPS) for 3 h, then stimulated with Nigericin or ATP to induce NLRP3 inflammasome assembly and pyroptosis. Caspase-1 activation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, interleukin-1β (IL-1β) release, and lactate dehydrogenase (LDH) secretion were quantified. Mutagenesis studies were conducted to identify critical residues required for Rub's binding to NLRP3. The in vivo therapeutic potential of Rub was assessed in three murine models of NLRP3-driven inflammation: LPS-induced sepsis, monosodium urate crystal (MSU)-induced gouty arthritis, and the APP/PS1 double-transgenic Alzheimer's disease (AD) mouse model. Mice received intraperitoneal Rub or vehicle, and disease severity was evaluated by histopathology, cytokine profiling, and behavioral tests.

RESULTS: Rub significantly reduced pyroptosis and IL-1β release in mouse primary microglia, BMDMs, and THP-1 cells in a dose-dependent manner, without affecting Absent in melanoma 2(AIM2) or NLR family CARD domain containing 4 (NLRC4) pathways. Mechanistically, Rub directly bound to NLRP3, thereby blocking the oligomerization of both NLRP3 and ASC, as well as preventing caspase-1 activation and gasdermin D (GSDMD) cleavage. Furthermore, mutagenesis studies identified arginine 167 and tyrosine 381 as critical residues for Rub's binding to NLRP3. In vivo, Rub treatment significantly prolonged survival and attenuated lung injury in the sepsis model, reduced paw swelling and bone erosion in the gout model, and ameliorated cognitive deficits and neuroinflammation in the AD model, respectively.

CONCLUSION: Collectively, these findings demonstrate that Rub selectively targets the NLRP3 inflammasome and exerts therapeutic effects on NLRP3-driven diseases including sepsis, gout, and AD. This study provides a molecular basis for the traditional application of Rubia cordifolia L. and highlights Rub as a promising natural lead compound for the treatment of NLRP3-driven disorders.},
}

@article {pmid42600903,
year = {2026},
author = {Wu, X and Ye, Q and Zi, M and Jiang, H and Meng, S and Zheng, J and Zeng, S and Ma, C and Hu, X and Zhao, B and Li, H},
title = {Pyroptosis in Alzheimer's disease: Mechanisms and neuroinflammatory networks.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104113},
doi = {10.1016/j.mcn.2026.104113},
pmid = {42600903},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuronal loss, and sustained neuroinflammation. In recent years, pyroptosis, a gasdermin-mediated form of inflammatory programmed cell death, has been recognized as a potential mechanism linking innate immune activation to neurodegenerative injury. This review summarizes the major molecular pathways of pyroptosis, including the canonical inflammasome-caspase-1-GSDMD pathway, the noncanonical caspase-4/5/11-GSDMD pathway, and alternative pathways involving caspase-3/GSDME and caspase-8, with a focus on their roles in the initiation, amplification, and propagation of neuroinflammation in AD. Current evidence suggests that AD-related stimuli, including Aβ aggregation, tau pathology, mitochondrial dysfunction, oxidative stress, and lysosomal damage, can induce inflammasome activation, gasdermin cleavage, and inflammatory mediator release, thereby sustaining chronic neuroinflammation. Concurrently, microglia, neurons, astrocytes, and oligodendrocytes may exhibit varying degrees of pyroptosis-related responses, contributing to impaired Aβ clearance, neuronal injury, glial dysfunction, and myelin pathology, respectively. This review further summarizes potential therapeutic strategies targeting the NLRP3 inflammasome, caspases, gasdermins, natural bioactive compounds, and the gut-brain axis. Overall, pyroptosis provides a novel framework for understanding the interplay between neuroinflammation and neurodegeneration in AD; however, its cell-type-specific roles, stage-dependent effects, and translational potential remain to be fully elucidated.},
}

@article {pmid42601004,
year = {2026},
author = {Shanehbandpour-Tabari, F and Golchoobian, R and Pourabdolhossein, F},
title = {Hippocampal Klotho Expression Is Associated with the Neuroprotective Effects of Metformin Against ICV-STZ-Induced Cognitive Deficits.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179245},
doi = {10.1016/j.ejphar.2026.179245},
pmid = {42601004},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation, oxidative stress, and neuroinflammation. Increasing evidence links metabolic dysfunction to AD, suggesting that antidiabetic drugs such as metformin may exert neuroprotective effects. This study investigated the effects of long-term metformin pretreatment on cognitive function, hippocampal pathology, and neuroprotective gene expression in an intracerebroventricular streptozotocin (ICV-STZ) rat model of AD. Adult male Sprague-Dawley rats were assigned to Sham, STZ, Metformin, and STZ+Metformin groups. Metformin (2 g/L in drinking water) was administered for 12 weeks before ICV-STZ injection. Spatial learning and memory were assessed using the Morris water maze. Hippocampal pathology was evaluated by H&E, Nissl, and Congo red staining, and gene expression was analyzed by quantitative PCR. ICV-STZ induced cognitive impairment, hippocampal Aβ deposition, neuronal loss, and increased expression of pro-inflammatory and oxidative stress markers. Metformin pretreatment significantly improved spatial learning and memory, reduced amyloid burden, and preserved neuronal integrity in the CA1 and CA3 regions. Metformin increased hippocampal Klotho mRNA expression, enhanced antioxidant defenses (Nrf2 and HO-1), suppressed TNF-α, IL-1β, and iNOS expression, and increased IL-10 levels. Although BDNF mRNA expression showed an upward trend, the change was not statistically significant. No significant changes in blood glucose levels were observed. In conclusion, long-term metformin pretreatment attenuated STZ-induced AD-like pathology and cognitive deficits. Its neuroprotective effects were associated with increased hippocampal Klotho expression and reduced oxidative stress and neuroinflammation, supporting further investigation of metformin and the Klotho pathway as potential preventive strategies for AD.},
}

@article {pmid42601176,
year = {2026},
author = {Koh, H and Choi, S and Sung, JE},
title = {Verb-Semantic Feature Analysis for Alzheimer's Dementia in a verb-final language: evidence from Korean.},
journal = {Neuropsychological rehabilitation},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/09602011.2026.2715712},
pmid = {42601176},
issn = {1464-0694},
abstract = {This study examined the effects of Verb-Semantic Feature Analysis (Verb-SFA) on verb naming, noun retrieval, sentence comprehension, and discourse production in individuals with Dementia of the Alzheimer's Type (DAT). Given the lexical-semantic degradation characteristic of DAT and the central role of verbs in Korean, a verb-final language, this study evaluated whether Verb-SFA facilitates treatment, near-transfer, and far-transfer effects. Three male participants, aged 60 or older with 16 years of education, completed 17 sessions: pre-treatment (4 sessions), treatment (10 sessions), and post-treatment (3 sessions). Treatment effects were assessed using 45-item probe sets derived from the Korean Item Selection Naming Test. Results showed significant improvement in naming accuracy for treated verbs, with a robust interaction between treatment sessions and treated items. No significant near-transfer effects were found for untreated verbs in the probe set or on the Action Naming Test. However, significant near-transfer effects were observed for noun retrieval on the Korean-Boston Naming Test, although verbal fluency tasks showed no improvement. Far-transfer effects emerged in sentence comprehension, suggesting strengthened verb-semantic processing supports higher-level linguistic abilities. No measurable gains were observed in discourse production. Overall, Verb-SFA treatment enhanced verb naming and sentence comprehension in individuals with DAT.},
}

@article {pmid42601455,
year = {2026},
author = {Coulon, A and Rabiller, F and Takalo, M and Roy, A and Pelletier, A and Martiskainen, H and Siedlecki-Wullich, D and Lannette-Weimann, N and Majerníková, N and Grenon, A and Gao, V and Erhardt, A and Pernodet, A and Lemaire, M and Limoge, F and Walle, P and Mendes, T and Guyot, K and Lemeu, C and Carvalho, LI and Melo de Farias, AR and Hulsman, M and Najdek, C and Freire-Regatillo, A and Saha, O and Amouyel, P and Charbonnier, C and Deleuze, JF and Dols-Icardo, O and Jeskanen, H and Willman, RM and Kuulasmaa, T and Kurki, M and Hardy, J and Heikkinen, S and Holstege, H and Mäkinen, P and Nicolas, G and Mead, S and Wagner, M and Ramirez, A and Rauramaa, T and Palotie, A and Sims, R and Soininen, H and van Swieten, J and Williams, J and Bellenguez, C and Gelle, C and Lambert, E and Costa, MR and Tcw, J and Glaab, E and Ayral, AM and Demiautte, F and Grenier-Boley, B and Muntaner, M and Eberlé, D and Deforges, S and Haas, JT and Kilinc, D and Mulle, C and Chapuis, J and Hiltunen, M and Dumont, J and Lambert, JC},
title = {PLCG2 downregulation impairs synaptic function and increases Alzheimer's disease hallmarks in neuronal cultures.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {42601455},
issn = {1546-1718},
abstract = {We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and by increasing Aβ levels and Tau phosphorylation in neurons.},
}

@article {pmid42601488,
year = {2026},
author = {Abila, E and Buljan, I and Zheng, Y and Kleissl, L and Klotz, S and Veres, T and Weng, Z and Nackenhorst, M and Kamies, R and Michl, A and Kadri, S and Moustafa, S and Hulla, W and Perkonigg, M and Drach, M and Tschandl, P and Sterniczky, B and Heinig, M and De Sadeleer, LJ and Wuyts, W and Vanaudenaerde, B and Ceulemans, LJ and Buchanan, DD and Fennell, LJ and Stary, G and Tolkach, Y and Wöhrer, A and Schiller, HB and Rendeiro, AF},
title = {Histological aging signatures for monitoring tissue-specific aging and disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42601488},
issn = {1546-170X},
support = {101220825//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; 70116893//Deutsche Krebshilfe (German Cancer Aid)/ ; 70116893//Deutsche Krebshilfe (German Cancer Aid)/ ; 1316/1-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 18E2B24N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; PAT 8019123//Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)/ ; LF-OC-24-001518//LEO Pharma Research Foundation/ ; GNT1194896//Department of Health | National Health and Medical Research Council (NHMRC)/ ; Dame Kate Campbell Fellowship//University of Melbourne (Melbourne University)/ ; CCAF-2024 Fennell//Cure Cancer Australia Foundation (CCAF)/ ; },
abstract = {Aging is the primary risk factor for chronic disease and is characterized by profound structural and architectural remodeling of human tissues. Here, we present a comprehensive assessment of these changes using 25,712 whole-slide histopathological images from 40 tissue types across 983 individuals in the Genotype-Tissue Expression cohort. By leveraging deep learning, we quantified nuanced morphological alterations to develop 'tissue clocks', predictors of biological age that reflect tissue structural integrity and physiological fitness. These clocks correlate with established aging markers, such as telomere attrition, subclinical pathologies and comorbidities. Through a systematic evaluation of biological aging rates across organs, we identified associations of tissue-specific age acceleration with demographic, lifestyle and medical factors, highlighting potentially modifiable risk factors that affect tissue aging. Furthermore, by integrating paired histology and transcriptomic data, we developed a strategy to predict tissue-specific age gaps directly from blood samples. We validated this approach by identifying disease-relevant organ aging across independent cohorts for eight prevalent diseases, including Alzheimer's disease, stroke and Crohn's disease. This work positions tissue architecture as a critical integrator of molecular and cellular changes over the course of aging, demonstrates that histopathological imaging provides a robust framework for monitoring tissue-specific aging and offers a scalable foundation for understanding organ-level physiological decline in health and disease.},
}

@article {pmid42601641,
year = {2026},
author = {Almela, F and Belondrade, M and Caillierez, R and Leclercq, S and Bouillet, T and Bégard, S and Oosterlynck, M and Eddarkaoui, S and Boluda, S and Buée, L and Nicot, S and Colin, M and Bougard, D},
title = {Amplification of seeding-competent tau aggregates by PMCA in human and experimental tauopathies.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42601641},
issn = {2051-5960},
support = {ANR-21-CE18-0046//Agence Nationale de la Recherche/ ; AmpliTAU//Association France Alzheimer/ ; },
mesh = {Animals ; Humans ; *tau Proteins/metabolism/genetics ; *Tauopathies/metabolism/pathology ; Mice, Transgenic ; *Brain/metabolism/pathology ; Mice ; Disease Models, Animal ; Protein Folding ; Alzheimer Disease/metabolism/pathology ; Female ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; Male ; },
abstract = {Tau assemblies, associated with tauopathies, are believed to self-propagate through prion-like mechanisms in the central nervous system, driving neurodegeneration. Recently, protein seed amplification assays have emerged as highly sensitive methods for detecting trace amounts of misfolded protein assemblies across various neurodegenerative diseases. In this study, we utilized protein misfolding cyclic amplification (PMCA) to demonstrate that tau assemblies from the brains of transgenic mice or human patients with tauopathies can be efficiently amplified. Amplification was achieved using complex matrix substrates, such as brain homogenates or cell lysates expressing aggregation-prone mutant tau proteins, with heparin as a cofactor. This assay enabled the highly sensitive detection of tau assemblies, even at 1-million-fold dilutions of brain homogenate from aged and symptomatic THY-Tau30 transgenic mice (a model of tauopathy) and human cases of frontotemporal lobar degeneration (FTLD-P301L). Tau assemblies from Alzheimer's disease (AD) patients were also successfully amplified, albeit with lower sensitivity compared to other tauopathies. Critically, the PMCA-generated tau assemblies retained seeding competence, inducing further tau aggregation in reporter tau "biosensor" cells and in young THY-Tau30 mice following intracerebral injection. Together, our findings establish PMCA as an in vitro model for studying the seeded aggregation of tau assemblies, providing a powerful tool to advance research into tau aggregation mechanisms and the development of therapeutic interventions.},
}

Animals
Humans
*tau Proteins/metabolism/genetics
*Tauopathies/metabolism/pathology
Mice, Transgenic
*Brain/metabolism/pathology
Mice
Disease Models, Animal
Protein Folding
Alzheimer Disease/metabolism/pathology
Female
*Protein Aggregation, Pathological/metabolism
Protein Aggregates
Male

@article {pmid42601653,
year = {2026},
author = {Jiang, M and Lan, G and Zhu, J and Zhang, L and Li, A and He, Z and Zhu, Y and Zhou, X and Liang, L and Gao, N and Sun, P and Cai, Y and Fan, X and Chen, X and Shi, D and Liu, Z and Wang, Q and Cheng, G and Wang, L and , and Dong, M and Wang, YJ and Guo, T},
title = {Cross-Sectional and Longitudinal Diagnostic Performance of Plasma p-tau217 and p-tau217/Aβ42 in Alzheimer's Disease.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78322},
pmid = {42601653},
issn = {1531-8249},
abstract = {OBJECTIVE: Recent studies suggest that combining plasma phosphorylated tau (p-tau) with β-amyloid (Aβ) may improve diagnosis accuracy for Alzheimer's disease (AD). However, the cross-sectional and longitudinal concordance of these markers with Aβ positron emission tomography (PET) positivity remains incompletely understood. This study aimed to evaluate the diagnostic performance of plasma p-tau, alone and in combination with plasma Aβ, in AD.

METHODS: We included 326 participants from the Alzheimer's Disease Neuroimaging Initiative and 357 Chinese older adults from the Greater-Bay-Area Healthy Aging Brain Study who underwent Aβ-PET imaging. Longitudinal data were available for 285 Alzheimer's Disease Neuroimaging Initiative participants. Plasma p-tau181, p-tau217, Aβ42, and Aβ40 were measured on different analytical platforms. Diagnostic performance for Aβ-PET positivity was assessed using a two-cutoff approach.

RESULTS: Combining plasma p-tau with Aβ42 or the Aβ42/40 ratio reduced the intermediate zone. Notably, p-tau217/Aβ42 showed stronger agreement with Aβ-PET positivity than p-tau217 alone. Among individuals classified as p-tau217/Aβ42 positive but p-tau217 intermediate, 57.1 to 83.3% were Aβ-PET positive. Longitudinally, most Stable Positive (88.0-96.1%) and Stable Negative (89.4-90.9%) cases defined by p-tau217 or p-tau217/Aβ42 were Aβ-PET positive and Aβ-PET negative, respectively. Critically, 69.7 to 75.8% of Non-positive to Positive cases defined by p-tau217/Aβ42 were Aβ-PET positive.

INTERPRETATION: These findings provide novel insights into the cross-sectional and longitudinal diagnostic performance of plasma p-tau217/Aβ42 in AD. To be specific, plasma p-tau217/Aβ42 can reduce the intermediate zone and improve agreement with Aβ-PET positivity, and longitudinal p-tau217/Aβ42 monitoring is particularly informative for identifying Aβ-PET-positive patients who were p-tau217/Aβ42 negative or intermediate at baseline and were misclassified as low risk of AD. ANN NEUROL 2026.},
}

@article {pmid42601701,
year = {2026},
author = {Yang, G and Hou, W and Wu, J and Yang, X and Yang, Y and Chen, Q and Liu, Y},
title = {Association between habitual sleep duration and Alzheimer's disease: A cross-sectional study based on NHANES 2007-2018.},
journal = {Medicine},
volume = {105},
number = {33},
pages = {e50086},
doi = {10.1097/MD.0000000000050086},
pmid = {42601701},
issn = {1536-5964},
support = {KS2325//the Kunshan Key Research and Development Program (Social Development) Project Fund/ ; SYWD2024196//Suzhou City Applied Basic Research and Science and Technology Innovation Project/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/mortality ; *Sleep Duration ; Cross-Sectional Studies ; Female ; Nutrition Surveys ; United States/epidemiology ; Male ; Aged ; Middle Aged ; Risk Factors ; *Sleep Wake Disorders/epidemiology ; Prevalence ; },
abstract = {Given the potential importance of sleep disturbances in the pathophysiology of Alzheimer's disease (AD), as well as the fact that habitual sleep duration - an observable and modifiable lifestyle factor - has become a significant potential target for early risk warning of neurodegenerative diseases, this study utilizes data from the National Health and Nutrition Examination Survey to thoroughly examine the association between AD and habitual sleep patterns among adults in the United States. It aims to determine the correlations among sleep duration, Alzheimer's disease, and all-cause mortality, thereby providing population-based evidence for the early prevention and public health intervention of AD. Using a cross-sectional design, 29,692 participants were selected. A multiple logistic regression model was used to assess the association between sleep duration and Alzheimer's disease. Additionally, all-cause mortality status was derived from matched records obtained from the United States National Death Index. The Cox regression model was used to calculate the hazard ratios and 95% confidence intervals of all-cause mortality associated with the relationship between sleep duration and AD. Our analysis revealed a significant positive correlation between increased sleep time and AD prevalence, a relationship that persisted in the adjusted model. Subgroup analysis showed that this association remained consistent across different populations. This study clarifies the effectiveness of sleep time as a predictive tool for AD and underscores its importance in AD assessment. Based on the predictive value of sleep time, our study advocates incorporating body composition factors into AD risk assessment, thus expanding the scope of Alzheimer's disease prevention strategies.},
}

Humans
*Alzheimer Disease/epidemiology/mortality
*Sleep Duration
Cross-Sectional Studies
Female
Nutrition Surveys
United States/epidemiology
Male
Aged
Middle Aged
Risk Factors
*Sleep Wake Disorders/epidemiology
Prevalence

@article {pmid42601718,
year = {2026},
author = {Huang, KY and Wei, YY and Zhang, ST and He, LC and Zhou, J and Zhou, LS and Su, HB and Lu, GD},
title = {Gut microbiota alterations and their correlation with constipation in older adults with Alzheimer's disease or mild cognitive impairment: A cross-sectional study.},
journal = {Medicine},
volume = {105},
number = {33},
pages = {e50227},
doi = {10.1097/MD.0000000000050227},
pmid = {42601718},
issn = {1536-5964},
support = {2023GXNSFAA026155//Natural Science Foundation of Guangxi/ ; RTFY202502//Key Laboratory of Human Development and Disease Research (Guangxi Medical University), Education Department of Guangxi Zhuang Autonomous Region/ ; 32160160//Natural Science Foundation of China/ ; 202410598018//College Students’ Innovative Entrepreneurial Training Plan Program/ ; S202410598106//College Students’ Innovative Entrepreneurial Training Plan Program/ ; },
mesh = {Humans ; *Constipation/microbiology ; *Alzheimer Disease/microbiology/complications ; *Cognitive Dysfunction/microbiology/complications ; Aged ; *Gastrointestinal Microbiome/physiology ; Female ; Cross-Sectional Studies ; Male ; Feces/microbiology ; Aged, 80 and over ; },
abstract = {Previous studies have suggested a link between gut microbiota, constipation and Alzheimer's disease (AD) as well as mild cognitive impairment (MCI). In this study, we aimed to investigate the changes in the gut microbiota and their relationship with constipation in patients with AD and MCI. A total of 90 participants (30 with AD, 30 with MCI, and 30 normal controls) were recruited from the community-based Nanning Community Elderly Population cohort. We collected fresh fecal samples for analysis and compared the differences in the gut microbiota among the groups. We also categorized these 90 participants into a constipation group and a non-constipation (normal) group using the Rome IV diagnostic criteria, allowing for a comparison of gut microbiota between these 2 groups. There were significant differences in alpha and beta diversity of the gut microbiota among the AD, MCI, and control groups, as well as between the constipation and non-constipation groups. At the genus level, the relative abundance of Lachnospira was decreased in both the AD group and the constipation group, while the relative abundance of Paeniclostridium was increased in both the MCI group and the constipation group. Our findings suggest that changes in the gut microbiota in patients with AD or MCI are partially consistent with those observed in older adults with constipation and may be involved in the pathogenesis of AD.},
}

Humans
*Constipation/microbiology
*Alzheimer Disease/microbiology/complications
*Cognitive Dysfunction/microbiology/complications
Aged
*Gastrointestinal Microbiome/physiology
Female
Cross-Sectional Studies
Male
Feces/microbiology
Aged, 80 and over

@article {pmid42601743,
year = {2026},
author = {Chen, IW and Chang, LC and Lai, YC and Ho, CN and Wu, JY and Hung, KC},
title = {Vitamin D deficiency and dementia risk in patients with chronic kidney disease: A multi-institutional 10-year retrospective cohort study.},
journal = {Medicine},
volume = {105},
number = {33},
pages = {e50267},
doi = {10.1097/MD.0000000000050267},
pmid = {42601743},
issn = {1536-5964},
mesh = {Humans ; *Vitamin D Deficiency/complications/epidemiology ; *Renal Insufficiency, Chronic/complications/epidemiology ; Retrospective Studies ; Female ; Male ; *Dementia/epidemiology/etiology ; Aged ; Risk Factors ; Vitamin D/blood/analogs & derivatives ; Middle Aged ; Alzheimer Disease/epidemiology ; },
abstract = {Patients with chronic kidney disease (CKD) face elevated dementia risk, and vitamin D deficiency (VDD) has emerged as a potential contributor to cognitive decline. This study investigated the association between VDD and dementia development in patients with CKD using real-world data. We conducted a retrospective cohort study using the TriNetX database, analyzing patients with CKD aged ≥50 years from January 2010 to December 2022. Patients were stratified by serum 25-hydroxyvitamin D levels as follows: VDD group (<20 ng/mL) vs control group (≥30 ng/mL). The primary outcome was new-onset dementia occurring 1 to 10 years post-index, with the risk of Alzheimer's disease (AD) as a secondary outcome. During the 10-year follow-up, patients with VDD were associated with a significantly higher dementia risk (hazard ratios [HR] 1.45, 95% confidence intervals [CIs]: 1.37-1.54, P < .001). The association emerged early, with a 5-year HR of 1.52 (1.41-1.64, P < .001). The risk of AD was similarly elevated (10-year HR 1.37, 95% CI: 1.21-1.56, P < .001). Dose-response analysis revealed an increased risk even with mild insufficiency (20-30 ng/mL), while severe deficiency (<10 ng/mL) showed the highest risk. Subgroup analysis identified hypertension as a significant effect modifier, with VDD conferring an elevated risk in hypertensive patients (HR 1.43, 95% CI: 1.35-1.52) but not normotensive individuals. VDD was significantly associated with increased risks of dementia and AD in patients with CKD, following a clear dose-response pattern. The association is particularly pronounced among hypertensive patients, suggesting that VDD represents a potentially modifiable risk factor warranting clinical attention in CKD management.},
}

Humans
*Vitamin D Deficiency/complications/epidemiology
*Renal Insufficiency, Chronic/complications/epidemiology
Retrospective Studies
Female
Male
*Dementia/epidemiology/etiology
Aged
Risk Factors
Vitamin D/blood/analogs & derivatives
Middle Aged
Alzheimer Disease/epidemiology

@article {pmid42601919,
year = {2026},
author = {Wei, H and Zhang, T and Liang, Z and Li, M and Kong, M and Ba, M},
title = {Amyloid-β modulates APOE ε4 effects on cognition but not on targeted structural or functional connectivity measures over 2 years in pre-dementia adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1889743},
pmid = {42601919},
issn = {1663-4365},
abstract = {BACKGROUND: The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet emerging evidence suggests its cognitive effects may be age- and pathology-dependent. Whether and how amyloid-β (Aβ) pathology modifies the longitudinal cognitive trajectory associated with APOE ε4 in the pre-dementia stage remains unclear.

METHODS: We conducted a 2-year longitudinal study in 70 pre-dementia adults from the Alzheimer's disease Neuroimaging Initiative (ADNI), assessing APOE genotype, Aβ status via positron emission tomography (PET), multi-domain cognition, structural magnetic resonance imaging (MRI) volumes, and resting-state functional connectivity of a predefined hippocampus-auditory network. Linear mixed-effects models evaluated the three-way interaction of time, APOE ε4 carrier status, and Aβ status on longitudinal trajectories. Sensitivity and exploratory mediation analyses were performed.

RESULTS: A significant three-way interaction (Time × APOE ε4 × Aβ status) was observed for global cognitive decline (ADAS13: β = -4.54, p = 0.001, P_FDR = 0.003), indicating that Aβ pathology moderates the effect of APOE ε4 on cognitive trajectories. Post-hoc analyses revealed that among Aβ-positive individuals, APOE ε4 carriers exhibited a slower rate of cognitive decline compared to non-carriers, whereas no such difference was evident in Aβ-negative individuals. This moderating effect was robust to sensitivity analyses and was consistently observed across multiple cognitive domains (MMSE, CDRSB, FAQ, MoCA; all P_FDR < 0.01). However, no significant three-way interactions survived multiple comparison correction for regional brain volumes or hippocampus-auditory functional connectivity, though nominally significant trends were observed in middle temporal gyrus volume and specific temporal lobe connections. Longitudinal hippocampal atrophy did not mediate the observed association.

CONCLUSION: Aβ pathology modifies the longitudinal cognitive trajectory associated with APOE ε4 in pre-dementia adults over a 2-year period. While consistent with the antagonistic pleiotropy framework, this observation requires independent replication, and alternative explanations including cognitive reserve and survivor bias warrant careful consideration.},
}

@article {pmid42601937,
year = {2026},
author = {Guo, Y and Niu, X and Xia, Y and Yang, Y and Fu, X and Li, T and Zhang, Y and Ji, Y and Ni, H},
title = {Microstructural white matter alterations in dementia with lewy bodies and Alzheimer's disease: a diffusion tensor imaging and neurite orientation dispersion and density imaging study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1830477},
pmid = {42601937},
issn = {1663-4365},
abstract = {BACKGROUND: Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are common types of dementia, however, diagnosis is challenging. An innovative MR method called neurite orientation dispersion and density imaging (NODDI) is used to assess different microstructural alterations between the conditions.

OBJECTIVE: To assess microstructural white matter (WM) changes in DLB and AD using NODDI.

METHODS: Diffusion images were acquired from 26 DLB patients, 36 AD patients, and 37 normal controls (NCs). The diffusion tensor imaging (DTI) was used to generate fractional anisotropy (FA), mean diffusivity (MD), and NODDI was used to generate neurite density index (NDI), orientation dispersion index (ODI), and volume fraction of isotropic water molecules (Viso), these parameters were compared among groups applying Tract-based spatial statistics (TBSS). We also analyzed the correlations between altered parameters and cognitive scores and investigated the diagnostic efficacy of different parameters using k-nearest neighbor (KNN).

RESULTS: Compared with NC, FA, ODI, and NDI significantly decreased, while MD and Viso significantly increased in both DLB and AD. Compared with DLB, ODI and NDI significantly decreased in AD. The diffusion parameters of multiple fibers were strongly correlated with cognition. NDI exhibited a relatively larger AUC value in differentiating between groups.

CONCLUSION: Widespread disruption of white matter microstructure is evident in both DLB and AD, with differences in these alterations between the two conditions. NDI holds promise as a neuroimaging biomarker for distinguishing DLB from AD.},
}

@article {pmid42601984,
year = {2026},
author = {Lai, A and Issa, M and Ali, A and Pereira, A and Ali, AA and Chhablani, J and Yan, P},
title = {Aging-Related Choroidal Heterogeneity and Loss: An Investigative Global Human Choroidal Thickness Review (ARCHLIGHT Study).},
journal = {Journal of vitreoretinal diseases},
volume = {},
number = {},
pages = {24741264261457969},
pmid = {42601984},
issn = {2474-1272},
abstract = {PURPOSE: To synthesize current evidence on the pathophysiology, clinical relevance, and implications for age-related choroidal thinning.

METHODS: A systematic literature search of relevant publications was conducted across MEDLINE, Embase, and Cochrane Library, up to and including May 2024. Identified studies reported choroidal thickness changes with aging. Data on subfoveal choroidal thickness, choroidal vascularity index, and associated factors (ethnicity, systemic disease, axial length) were analyzed (PROSPERO ID: CRD420251041101).

RESULTS: Choroidal thickness declines with age, with ethnicity-specific rates ranging from -0.93 µm/year in Spanish cohorts to -4.00 µm/year in Chinese populations. Age-related choroidal thinning correlates with retinal and neurodegenerative pathologies, including glaucoma (nasal choroidal thinning >250 µm in older adult patients), myopic maculopathy (subfoveal choroidal thickness <100 µm in high myopia), and Alzheimer disease (subfoveal choroidal thickness 169 µm vs 253 µm in control patients). Enhanced depth imaging optical coherence tomography (OCT) and swept-source OCT reveal preferential vascular loss (choroidal vascularity index <30%) and stromal atrophy. Systemic risks, such as hypertension or smoking, accelerate choroidal thinning.

CONCLUSIONS: Age-related choroidal thinning exists on a continuum between physiologic aging and pathology, with implications for retinal and systemic health. Future prospective studies will help determine diagnostic thresholds (subfoveal choroidal thickness <200 µm in nonmyopic adults >60 years or rapid thinning beyond ethnic normative values), management recommendations for high-risk cohorts (glaucoma, age-related macular degeneration, high myopia), and therapeutic considerations for monitoring of choroidal thickness changes from moderate- to low-certainty evidence.},
}

@article {pmid42533617,
year = {2026},
author = {Rasmussen, LK and Gomes Moreira, D and Okarmus, J and Simonsen, A and Meyer, M},
title = {Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/15548627.2026.2711596},
pmid = {42533617},
issn = {1554-8635},
abstract = {Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of PRKN-independent mechanisms, including additional ubiquitin-dependent, receptor-mediated, and lipid-mediated pathways. We explore how these pathways intersect and compensate for one another, highlighting the complexity and adaptability of mitochondrial quality control networks. Furthermore, we discuss how dysregulated mitophagy contributes to the onset and progression of neurodegenerative diseases. By examining the interplay between mitophagy pathways and their regulation under physiological and pathological conditions, this review underscores the therapeutic potential of targeting mitophagy in neurodegeneration. Future studies should aim to decode the spatiotemporal dynamics of these pathways to uncover novel opportunities for clinical intervention.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMFR/GP78: autocrine motility factor receptor; AMPK: AMP-activated protein kinase; ARIH1: ariadne RBR E3 ubiquitin protein ligase 1; ATG: autophagy related; Aβ: amyloid beta; BCL2L13: BCL2 like 13; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CAMc: core autophagy machinery components; CSNK2/CK2: casein kinase 2; DUB: deubiquitinase; DNM1L/DRP1: dynamin 1 like; FKBP8: FKBP prolyl isomerase 8; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; GLP-1: glucagon-like peptide 1; HD: Huntington disease; HUWE1: HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1; IMM: inner mitochondrial membrane; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARCHF5: membrane associated ring-CH-type finger 5; MCL1: MCL1 apoptosis regulator, BCL2 family member; MDV: mitochondria-derived vesicle; MFN1: mitofusin 1; MFN2: mitofusin 2; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; OMM: outer mitochondrial membrane; OMMAD: outer mitochondrial membrane-associated degradation; OPA1: OPA1 mitochondrial dynamin like GTPase; OPTN: optineurin; OXPHOS: oxidative phosphorylation; PARL: presenilin associated rhomboid like; PD: Parkinson disease; PE: phosphatidylethanolamine; PG: phagophore; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PINK1: PTEN induced kinase 1; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PtdIns3K: phosphatidylinositol 3-kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RHOT1/Miro1: ras homolog family member T1; ROS: reactive oxygen species; SIAH1: siah E3 ubiquitin protein ligase 1; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TCA: tricarboxylic acid cycle; TFAM: transcription factor A, mitochondrial; TIMM: translocase of inner mitochondrial membrane; TOMM: translocase of outer mitochondrial membrane; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UPRmt: mitochondrial unfolded protein response; UPS: ubiquitin-proteasome system; USP30: ubiquitin specific peptidase 30; VCP: valosin containing protein; VDAC: voltage dependent anion channel; WIPI: WD repeat domain, phosphoinositide interacting.},
}

@article {pmid42594034,
year = {2026},
author = {Stancu, P and Goodheart, AE and Hentsch, L and Hertler, C and Allali, G and Assal, F},
title = {When Walking Outlasts Cognition: Rethinking the Late-Stage of Lewy Body Dementia.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ndd/aduag001},
pmid = {42594034},
issn = {1660-2862},
abstract = {BACKGROUND: Lewy body dementia (LBD) is characterized by pervasive cognitive, motor, and neuropsychiatric symptoms. Although cognitive decline has traditionally shaped staging and prognosis, accumulating evidence indicates that gait and postural disturbances follow partially independent trajectories and may remain preserved even as cognition deteriorates. These observations challenge conventional assumptions about late-stage decline and suggest that locomotor function may complement cognitive measures when assessing late-stage transition in LBD.

SUMMARY: This review synthesizes current evidence on gait disturbances across the LBD spectrum and their neural substrates, in comparison with Alzheimer's disease (AD) and Parkinson's disease (PD). Gait impairment in LBD arises from distributed network dysfunction involving dopaminergic and cholinergic pathways, fronto-striatal, parietal, and cerebellar contributions, resulting in greater gait variability, reduced automaticity, and heightened dual-task costs relative to AD and PD. Despite this vulnerability, preserved procedural memory, brainstem locomotor circuits, and cerebellar-cortical compensation may allow walking to persist longer than cognition in some individuals. In advanced disease, rapid gait deterioration has been described near the end of life, suggesting that gait trajectories may capture aspects of late-stage decline that cognitive measures, affected by fluctuations and attentional instability, may not reliably reflect.

KEY MESSAGES: -Gait and cognition do not decline in parallel in LBD; in some individuals, walking may outlast cognitive abilities.-Gait disturbances reflect distributed network dysfunction rather than isolated motor system degeneration.-In late stages, gait performance may offer a clinically useful indicator of disease transition when cognitive testing becomes less reliable. -Integrating gait assessment into clinical evaluation may enhance prognostication and support palliative care planning in LBD.},
}

@article {pmid42594145,
year = {2026},
author = {Zhang, H and Chen, W and Yuan, S and Ding, S and Bao, H and Cai, B and Sun, J and Lu, W and Zhu, H and Shi, G},
title = {Unraveling the molecular Nexus of Alzheimer's Disease and HIV encephalitis: The role of cellular senescence and transcriptional regulation.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0355548},
pmid = {42594145},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/diagnosis/pathology ; Forkhead Box Protein O3/genetics/metabolism ; *Cellular Senescence/genetics ; Biomarkers/metabolism ; Gene Expression Regulation ; Female ; Male ; Transcription, Genetic ; STAT3 Transcription Factor/metabolism/genetics ; Gene Expression Profiling ; },
abstract = {Alzheimer's disease (AD) and HIV-associated neurocognitive disorder (HAND) share progressive cognitive decline. Their common molecular mechanisms remain poorly understood. Current therapeutic approaches lack effective biomarkers for early diagnosis and intervention. We integrated transcriptomic profiles from multiple independent cohorts across brain tissues and blood. We systematically evaluated diagnostic performance using machine learning algorithms including Random Forest, Support Vector Machine, and XGBoost. Notably, FOXO3 emerged as the top cross-disease biomarker. FOXO3 achieved diagnostic accuracy in AD temporal cortex (area under the curve [AUC] = 0.922, 95% CI: 0.885-0.959). FOXO3 showed diagnostic performance in HAND frontal cortex (AUC = 0.771, 95% CI: 0.724-0.818). FOXO3 expression positively correlated with APP (R = 0.558). FOXO3 expression negatively correlated with MAPT (R = -0.690) and SORL1 (R = -0.856). ACE showed strong positive correlation with FOXO3 (R = 0.685), suggesting vascular involvement. STAT3 and ZNF341 were identified from 21 transcription factor candidates. STAT3 ranked first in HAND integrated cohort (n = 107, AUC = 0.759). STAT3 may function as an inflammatory mediator through JAK-STAT signaling. ZNF341 showed strongest transcriptional association with disease status (β = 5.09 in AD, β = 4.85 in HAND). The two-gene panel (FOXO3-ZNF341) achieved diagnostic accuracy in blood samples (AUC = 0.764, n = 329). This performance approaches clinical utility thresholds. Blood-based detection offers non-invasive diagnostic potential. Saturation analysis identified three molecules as optimal panel size. Marginal AUC gains declined below 0.02 beyond this threshold. FOXO3, STAT3, and ZNF341 showed stable selection frequency (97%, 65%, and 100%, respectively). PI3K-Akt and FoxO signaling pathways were enriched, which are known to regulate apoptosis and cell survival. Taken together, these computational findings indicate FOXO3 transcriptional regulatory activity in neurodegeneration. The three-molecule panel represents candidate blood-based diagnostic biomarkers. These candidate biomarkers warrant further investigation in independent clinical cohorts.},
}

Humans
*Alzheimer Disease/genetics/metabolism/diagnosis/pathology
Forkhead Box Protein O3/genetics/metabolism
*Cellular Senescence/genetics
Biomarkers/metabolism
Gene Expression Regulation
Female
Male
Transcription, Genetic
STAT3 Transcription Factor/metabolism/genetics
Gene Expression Profiling

@article {pmid42594195,
year = {2026},
author = {Piller, C and Smith, JE},
title = {Magic or realism?.},
journal = {Science (New York, N.Y.)},
volume = {393},
number = {6812},
pages = {652-659},
doi = {10.1126/science.ael4184},
pmid = {42594195},
issn = {1095-9203},
abstract = {Recently discovered genetic variants seem to protect against Alzheimer's disease, suggesting a path toward a cure. But are their powers believable?},
}

@article {pmid42594210,
year = {2026},
author = {Reardon, S},
title = {Tau can wreak havoc in brain cells' energy factories.},
journal = {Science (New York, N.Y.)},
volume = {393},
number = {6812},
pages = {651},
doi = {10.1126/science.ael4194},
pmid = {42594210},
issn = {1095-9203},
mesh = {*Mitochondria/metabolism ; Humans ; *tau Proteins/metabolism ; *Brain/metabolism/cytology ; *Alzheimer Disease/metabolism/drug therapy ; Animals ; *Energy Metabolism ; *Neurons/metabolism ; },
abstract = {Study of mitochondria suggests new treatment strategy for Alzheimer's and other diseases.},
}

*Mitochondria/metabolism
Humans
*tau Proteins/metabolism
*Brain/metabolism/cytology
*Alzheimer Disease/metabolism/drug therapy
Animals
*Energy Metabolism
*Neurons/metabolism

@article {pmid42594414,
year = {2026},
author = {Dinnerstein, E},
title = {The missing improvers: Tau pathology, neuroplasticity, and the case for tau-informed patient selection before amyloid immunotherapy.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100653},
doi = {10.1016/j.tjpad.2026.100653},
pmid = {42594414},
issn = {2426-0266},
abstract = {Amyloid immunotherapy with lecanemab and donanemab has been approved on the basis of statistically significant slowing of cognitive and functional decline in early Alzheimer's disease (1,2). Yet clinicians treating individual patients face the everyday challenge of estimating whether a given patient is declining at the rate that would be expected for them, and whether their trajectory reflects a response to treatment. I argue that this difficulty arises in large part because the field cannot yet routinely stratify patients by tau pathology before treatment, even though tau burden is among the strongest available predictors of both the rate of progression and the magnitude of response to amyloid-targeting therapy. Post-hoc and open-label analyses of the Clarity AD and TRAILBLAZER-ALZ 2 programmes suggest that patients with absent, low, or medium tau burden may constitute a biologically distinct group in whom amyloid clearance is most likely to permit clinical stabilization or measurable functional gain. These observations remain hypotheses, generated largely from subgroup, open-label, and biomarker data rather than from prospective trials designed to test them I propose that tau status should be given strong consideration in patient selection, that tau-guided selection should be evaluated prospectively, and that the access, reimbursement, and standardization barriers to tau positron emission tomography (PET) - together with the promise of scalable plasma tau biomarkers - be addressed deliberately as the field moves toward tau-informed treatment. One tau PET tracer is currently approved by the US Food and Drug Administration, and a regulatory decision on a second is anticipated in 2026.},
}

@article {pmid42594416,
year = {2026},
author = {Calm, B and Hinojosa-Calleja, A and García-Gutiérrez, F and Blazquez-Folch, J and Alegret, M and Fernández, MV and De Rojas, I and García-González, P and Olivé, C and Valenzuela-Seba, A and Bayón-Buján, P and Cano, A and Puerta, R and Capdevila-Bayo, M and Muñoz-Morales, Á and Miguel, A and Solivar, A and Montrreal, L and Sanz-Cartagena, P and Rosende-Roca, M and Cantero-Fortiz, Y and Gurruchaga, MJ and Tárraga, L and Boada, M and Marquié, M and Ruiz, A and Valero, S and , },
title = {Predictive value of the Alzheimer polygenic risk score on cognitive decline in patients with mild cognitive impairment and Alzheimer's disease dementia.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100658},
doi = {10.1016/j.tjpad.2026.100658},
pmid = {42594416},
issn = {2426-0266},
abstract = {BACKGROUND: Polygenic risk scores for Alzheimer's disease (AD-PRS) are widely used to estimate genetic susceptibility to AD, but their relationship with the rate of cognitive decline (CD) after clinical onset remains insufficiently characterized.

OBJECTIVES: To examine the association between AD-PRS and longitudinal CD across the AD spectrum and to evaluate the predictive contribution of individual AD-PRS variants.

DESIGN: Large longitudinal observational study in a single-center cohort, with an external cohort to assess generalizability.

SETTING: Memory clinic cohort from Ace Alzheimer Center Barcelona (Ace) with external cohort using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

PARTICIPANTS: The study included 7,233 patients from Ace and 863 from ADNI, with a mean follow-up of 5.4 years in Ace and 3.6 years in ADNI. A biomarker sub-cohort included 1075 participants from Ace and 569 from ADNI.

MEASUREMENTS: CD was quantified as the annual change in Mini-Mental State Examination (MMSE) scores estimated using linear mixed-effects models. Associations between AD-PRS and longitudinal MMSE trajectories were tested adjusting for clinical and sociodemographic (CSD) variables and APOE genotype. Machine learning models and SHapley Additive exPlanations (SHAP) were used to evaluate the predictive relevance of individual variants.

RESULTS: Higher AD-PRS was associated with faster CD in the full clinical cohort and in biomarker subset, independently of APOE genotype. AD-PRS was not associated with baseline MMSE. APOE ε4 was associated with lower baseline MMSE and faster CD only in the full clinical sample. Genetic predictors provided limited improvement beyond CSD variables, and model performance showed limited reproducibility across cohorts.

CONCLUSIONS: AD-PRS is associated with longitudinal CD across the AD spectrum. Although polygenic burden contributes to variability in cognitive trajectories, its added predictive value beyond routinely available clinical variables remains modest.},
}

@article {pmid42594417,
year = {2026},
author = {Zamboni, G and Tondelli, M and Vinceti, G and Gallingani, C and Bercini, Z and Barbieri, A and Carbone, C and Iacovino, N and Cossutti, S and Ballotta, D and Salemme, S and Chiari, A},
title = {From regulatory approval to clinical practice: real-world eligibility for anti-amyloid monoclonal antibodies in an Italian dementia-care network.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100655},
doi = {10.1016/j.tjpad.2026.100655},
pmid = {42594417},
issn = {2426-0266},
}

@article {pmid42594686,
year = {2026},
author = {Xu, Z and Yang, Y and Xiang, K and Zhuo, L and Fang, Z and Lin, X and Dai, C and Liu, J and Sun, J and Tong, Q},
title = {Integrative machine learning and single-nucleus transcriptomics reveal MAPK-centered neuronal responses underlying the potential Alzheimer's disease risk of GenX.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {5},
pages = {e01047},
doi = {10.1016/j.neurot.2026.e01047},
pmid = {42594686},
issn = {1878-7479},
abstract = {Hexafluoropropylene oxide-dimer acid (GenX or HFPO-DA) is a novel per- and polyfluoroalkyl substance developed as a replacement for legacy compounds, yet its potential neurotoxic effects remain poorly understood. In this study, we combined bibliometric profiling, in silico target prediction, in vivo behavioral assessments, single-nucleus RNA sequencing (snRNA-seq), network biology, machine learning, molecular docking, and in vitro validation to explore the potential relevance of GenX in Alzheimer's disease (AD). Bibliometric analysis revealed increasing research attention to GenX-associated health hazards, including emerging concerns regarding brain-related effects. Target prediction identified 301 putative GenX-related genes, which were significantly enriched in AD-related pathways. Behavioral analyses demonstrated that chronic GenX exposure impaired recognition memory and spatial learning in mice. Analysis of human prefrontal cortex snRNA-seq data revealed pronounced transcriptional alterations in AD neurons and identified 200 AD-related neuronal DEGs. Integration with GenX targets yielded 10 overlapping genes, which were further prioritized through protein-protein interaction (PPI) network analysis. Machine learning further identified an 8-gene signature with robust diagnostic performance across training and external validation cohorts. Molecular docking showed favorable binding affinities between GenX and core target proteins. Finally, GenX exposure reduced SH-SY5Y cell viability, activated the RAS-RAF-MEK-ERK cascade, and promoted apoptosis-related alterations, supporting a MAPK-centered neurotoxic mechanism potentially relevant to AD-associated neuronal vulnerability. Collectively, this integrative multi-level analysis provides mechanistic insights into the potential neurotoxic effects of GenX and underscores its possible relevance to neurodegeneration-associated molecular processes in AD.},
}

@article {pmid42594906,
year = {2026},
author = {Koychev, I and Holman, RR},
title = {Semaglutide treatment fails but might prevent Alzheimer's disease.},
journal = {Lancet (London, England)},
volume = {408},
number = {10555},
pages = {602-603},
doi = {10.1016/S0140-6736(26)01647-8},
pmid = {42594906},
issn = {1474-547X},
}

@article {pmid42594919,
year = {2026},
author = {Yang, X and Wang, C and Li, X and Duan, A and Zhou, J and Jiang, Z and Wang, J and 陈, 元},
title = {Bidirectional cross-modal attention with adaptive gating for multimodal alzheimer's disease classification.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae995e},
pmid = {42594919},
issn = {2057-1976},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder, and mild cognitive impairment (MCI) represents a transitional stage between AD and cognitively normal (CN) individuals. Early diagnosis is clinically important for delaying disease progression. To address the limitations of single-modal approaches and the insufficient modeling of complex cross-modal interactions in existing multimodal fusion methods, this paper proposes a multimodal deep learning classification framework integrating structural magnetic resonance imaging (sMRI) and clinical features. The framework employs a 3D ResNet-34 to extract imaging features and a multilayer perceptron (MLP) to encode clinical data. A bidirectional cross-modal attention mechanism enhances associations between imaging and clinical modalities, followed by an adaptive gated fusion module that dynamically integrates concatenated global multimodal features with cross-modal interaction features. To evaluate the robustness of the proposed framework, all experiments were repeated using five different random seeds, and the results are reported as mean ± standard deviation. Experimental results demonstrate competitive performance across multiple classification tasks, achieving accuracies of 95.67% ± 1.70% for three-class classification (CN vs. MCI vs. AD) and 93.64% ± 2.36% for four-class classification (CN vs. early MCI (EMCI) vs. late MCI (LMCI) vs. AD). For binary classification (AD vs. CN, AD vs. MCI, MCI vs. CN, and EMCI vs. LMCI), the method achieves accuracies of 96.83% ± 1.53%, 95.33% ± 1.00%, 95.83% ± 1.39%, and 93.61% ± 2.35%, respectively. The proposed framework provides an effective solution for multimodal deep learning-based computer-aided diagnosis of AD.},
}

@article {pmid42595023,
year = {2026},
author = {Guo, R and Li, D and Zhang, X and Liu, S and Wang, D and Du, Y and , },
title = {Alterations in dynamic connectivity in Alzheimer's disease: Network changes and improved multi-stage classification.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113285},
doi = {10.1016/j.exger.2026.113285},
pmid = {42595023},
issn = {1873-6815},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by large-scale network disruption. While static functional connectivity (sFC) has been extensively studied, dynamic functional connectivity (dFC) and its discriminative value across the AD spectrum remain insufficiently understood. In this study, resting-state functional magnetic resonance imaging (rs-fMRI) data from 174 participants in the Alzheimer's Disease Neuroimaging Initiative, including cognitively normal (CN, n = 44), subjective memory concern (SMC, n = 24), early mild cognitive impairment (EMCI, n = 46), late MCI (LMCI, n = 30), and AD (n = 30), were analyzed to assess group differences in sFC, dFC, and graph-theoretical metrics, as well as their associations with cognition. A BrainNetCNN model was further employed to evaluate the classification performance of sFC, dFC, and their combined features. The results revealed that sFC decreased across MCI stages but increased in AD, whereas dFC variability was predominantly reduced in the pre-dementia groups and increased in AD, particularly in frontal and temporal regions. Several static graph-theoretical metrics were significantly correlated with Mini-Mental State Examination (MMSE) scores, while dFC provided complementary information. In classification tasks, dFC showed higher accuracy than sFC in binary and five-class tasks, and their integration achieved the highest accuracy (CN vs. SMC: 89.6%; five-class: 82.7%). These findings suggest that dFC may provide complementary imaging information for characterizing stage-related network alterations and differentiating diagnostic groups across the AD spectrum.},
}

@article {pmid42595185,
year = {2026},
author = {Liu, WZ and Piao, ZJ and Zhu, TL and Lim, V and Ooi, JP and Niu, QQ},
title = {Peroxynitrite: A Potential Therapeutic Target for Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103299},
doi = {10.1016/j.arr.2026.103299},
pmid = {42595185},
issn = {1872-9649},
abstract = {The pathogenesis of Alzheimer's disease (AD) involves multiple pathological processes, including β-amyloid (Aβ) deposition, aberrant tau modification, oxidative stress, and neuroinflammation. The molecular interaction mechanism among them remains to be further clarified. Peroxynitrite (ONOO[-]) is a potent oxidizing and nitrating reactive nitrogen species formed from the rapid reaction between nitric oxide and superoxide. It mediates protein nitration, lipid peroxidation, and mitochondrial damage, thereby contributing to multiple pathological events in AD. This review outlines the physicochemical properties and biological behavior of ONOO[-], and summarizes recent advances in detection techniques such as fluorescent probes and electrochemical sensors. It focuses on the role of ONOO[-] within the AD pathological network and its interconnections with Aβ deposition, tau pathology, neuroinflammation, and blood-brain barrier disruption. Additionally, this review discusses the therapeutic potential of ONOO[-]-targeted strategies, aiming to provide novel insights into the crosstalk among multiple pathological pathways in Alzheimer's disease.},
}

@article {pmid42595198,
year = {2026},
author = {Seo, J and Kim, K and Park, M},
title = {Distinct Roles of AMPA Receptor Subunits as Potential Therapeutic Targets in Alzheimer's Disease.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108394},
doi = {10.1016/j.phrs.2026.108394},
pmid = {42595198},
issn = {1096-1186},
abstract = {AMPA receptors (AMPARs) mediate fast excitatory neurotransmission and play central roles in synaptic plasticity, learning, and memory. They are heterotetrameric complexes organized as two dimers, with subunits from GluA1 to GluA4. Dysregulation of AMPAR trafficking, localization, and function has been increasingly implicated in amyloid beta (Aβ)- and tau-associated synaptic deficits, which are the pathological hallmarks for Alzheimer's disease (AD). Accumulating evidence suggests that AMPARs play distinct, subunit-specific roles in synaptic plasticity and learning and memory in physiological and pathological contexts. This review synthesizes current understanding of subunit-specific AMPAR-mediated pathological mechanisms in AD and discusses emerging pharmacological strategies targeting AMPARs as potential therapeutic approaches to delay or attenuate disease progression.},
}

@article {pmid42595220,
year = {2026},
author = {Liu, CW and Liu, YM and Li, WJ and Qu, QW and Shan, ZX and Dong, FX and Hou, XQ},
title = {Osthol Ameliorates Alzheimer's Disease-Associated Cognitive Impairment by Targeting the Estrogen-Cholinergic Axis in Age-Stratified Female 3×Tg-AD Mice.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106241},
doi = {10.1016/j.neuint.2026.106241},
pmid = {42595220},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) represents a devastating neurodegenerative disorder globally. It is clinically characterized by cognitive dysfunction, predominantly learning and memory impairments, and is closely associated with cholinergic system damage. Osthol (OST), a bioactive compound with well-documented neuroprotective properties, has been shown to enhance learning and memory functions. However, the precise molecular mechanisms underlying its therapeutic effects on AD-related cognitive impairment remain unclear. This study elucidates the critical interplay between estrogen-cholinergic system imbalance and AD progression across distinct temporal windows in female AD models. By focusing on this sex-specific regulatory axis, we aimed to address a key gap in understanding AD pathogenesis and OST's targeted efficacy. We employed age-stratified 3×Tg-AD mice as an experimental model and utilized comprehensive behavioral paradigms to assess learning and memory functions. An age-dependent gradient of cognitive impairment, accompanied by varying degrees of neuropathological damage, was observed in 3×Tg AD mice across different age groups. OST significantly improved learning and memory performance in 3×Tg AD mice of all age groups. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment effectively alleviated damage to the estrogen-cholinergic-NGF axis through multiple synergistic mechanisms: upregulation of Acetylcholine (ACh), Choline acetyltransferase (ChAT), Tyrosine kinase-A (TrkA), and Nerve growth factor (NGF) expression; downregulation of Acetylcholinesterase (AChE) activity; and increased expression of Estradiol (E2), Estrogen receptor-α (ERα), and Estrogen receptor-β (ERβ). In addition, OST improved synaptic plasticity (Postsynaptic density protein-95 (PSD95), Synuclein (SYN), and Brain-derived neurotrophic factor (BDNF)), inhibited neuronal apoptosis (B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX)), and enhanced neurotransmitter signaling cascades (γ-aminobutyric acid (GABA), Glutamic acid (Glu), Epinephrine (E), and ACh). These findings provide new insights into the mechanisms of AD and support OST as a promising candidate for targeted AD therapy.},
}

@article {pmid42595239,
year = {2026},
author = {Zhang, Z and Zhang, W and Jin, L and Wei, C and Chen, H and Cheng, X and Wei, J},
title = {Decoding TREM2: A microglial receptor governing the fate of myelin.},
journal = {Cellular signalling},
volume = {148},
number = {},
pages = {112815},
doi = {10.1016/j.cellsig.2026.112815},
pmid = {42595239},
issn = {1873-3913},
abstract = {Impaired myelin integrity and defective myelin regeneration represent core pathological features shared by central nervous system (CNS) diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), ischemic cerebral white matter lesions and spinal cord injury (SCI). Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is highly enriched in central resident microglia; it is also expressed by border-associated macrophages and lesion-infiltrating monocyte-derived macrophages, rather than being restricted to parenchymal microglia, acting as a key membrane receptor regulating microglial immune balance, lipid transport, lysosomal degradation and cell polarization. Existing studies demonstrate that TREM2 binds various ligands including myelin lipid debris, apolipoprotein E (APOE) and apoptotic cell components, then activates multiple DNAX-activating protein of 12 kDa (DAP12)-dependent signaling cascades: spleen tyrosine kinase (SYK)-phosphatidylinositol 3-kinase (PI3K), phospholipase C gamma 2 (PLCγ2), beta-catenin and transcription factor EB (TFEB). These pathways jointly clear myelin debris, remodel cholesterol circulation, restrain pro-inflammatory microenvironment and promote oligodendrocyte precursor cell (OPCs) differentiation, exerting bidirectional functions in physiological myelin homeostasis, acute injury response and chronic repair. This narrative review summarizes TREM2's gene and protein structure, ligand recognition modes and full signal transduction network. It illustrates the molecular mechanisms of TREM2 in myelin maintenance, debris clearance and regeneration, compares its distinct pathological roles in various demyelinating diseases, and concludes translational strategies including TREM2 agonism, downstream pathway intervention and biomarker exploitation. Furthermore, this narrative review analyzes unsolved core scientific issues and puts forward research routes for mechanistic research and clinical transformation, offering systematic theoretical basis for targeted drug development against demyelinating encephalopathies.},
}

@article {pmid42595331,
year = {2026},
author = {Amorim Molina, AR and Ansai, JH and Bueno Neto, D and Tsen, C and Gerassi, RC and Silva, MJGD and Gomes, GAO and de Andrade, LP},
title = {Physical Activity, Stress, Burden, and Quality of Life of Caregivers of Older Adults With Dementia: A Cross-Sectional Study During the COVID-19 Pandemic.},
journal = {Journal of aging and physical activity},
volume = {},
number = {},
pages = {1-10},
doi = {10.1123/japa.2024-0304},
pmid = {42595331},
issn = {1543-267X},
abstract = {BACKGROUND/OBJECTIVES: Providing care for older adults with dementia generates stress and challenges, impacting quality of life (QoL). Physical activity offers benefits, and the link between physical activity levels (PAL) and these factors during the pandemic can be further explored. This study aimed to examine associations between PAL, stress, burden, and QoL among dementia caregivers during COVID-19.

METHODS: Eighty-nine caregivers of older adults with mild to moderate dementia participated in the study. The online assessment included a medical history questionnaire, the short version of the International Physical Activity Questionnaire, Zarit Burden Scale, Perceived Stress Scale, and the Alzheimer's Disease Quality of Life Scale-Caregiver Version. Spearman's rho was used to examine correlations between PAL and stress, burden, and QoL. A generalized linear model (gamma distribution) analyzed associations between metabolic equivalents per week and stress, burden, and QoL.

RESULTS: A negative correlation between metabolic equivalents per week and burden (ρ = -.26, p = .014) indicated that higher PAL was correlated to lower burden. A positive correlation between metabolic equivalents per week and QoL (ρ = .34, p = .001) showed that higher PAL was associated with better QoL. No correlation was found between PAL and stress. However, significant associations were observed between PAL and both burden, χ2(1) = 5.065, p = .024, and QoL, χ2(1) = 6.983, p = .008.

CONCLUSIONS: Higher PAL in dementia caregivers is associated with lower burden and better QoL. Significance/Implications: Promoting physical activity may improve caregivers' QoL and reduce burden, guiding future research.},
}

@article {pmid42595466,
year = {2026},
author = {Dowling, T and Zhu, S and Ford, J and Ganem Chagui, O and Omid-Fard, N and Martinez Imbett, RE and Wleklinski, M and Yu, E and Romero, J and Rohatgi, S},
title = {Baseline Amyloid PET Centiloid Score and Risk of Amyloid-Related Imaging Abnormalities in Patients Treated With Lecanemab.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9590},
pmid = {42595466},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Amyloid-related imaging abnormalities (ARIA) are a known complication of anti-amyloid monoclonal antibody therapy for Alzheimer's disease. Centiloid score, derived from amyloid PET/CT, provides a quantitative assessment of baseline amyloid burden; however, its relationship with ARIA risk remains uncertain. This study evaluated whether baseline Centiloid score was associated with ARIA in patients treated with lecanemab and included a secondary exploratory analysis of regional amyloid uptake.

MATERIALS AND METHODS: We retrospectively identified patients treated with lecanemab within a single academic health system who underwent pretreatment florbetaben amyloid PET/CT. Centiloid scores were generated using a standardized processing pipeline. Multivariable logistic regression evaluated the association between baseline Centiloid and ARIA, adjusting for age, sex, APOE ε4 carrier status, and baseline cerebral microbleed presence. ARIA-H and ARIA-E subgroups were evaluated separately using Firth penalized logistic regression. A secondary Cox proportional hazards analysis accounted for unequal follow up durations. Exploratory regional analysis compared baseline amyloid uptake in regions that subsequently developed ARIA-E with that in mirrored contralateral regions.

RESULTS: The primary analysis included 41 patients with ARIA and 72 controls who completed at least 14 lecanemab infusions without ARIA. Baseline Centiloid was not independently associated with ARIA (adjusted OR per 10-Centiloid increase, 1.01 [95% CI, 0.89-1.15]; P = .90), ARIA-H (OR, 1.01 [95% CI, 0.89-1.14]; P = .91), or ARIA-E (OR, 1.02 [95% CI, 0.87-1.21]; P = .78). In the Cox analysis of 41 patients with ARIA and 100 patients without ARIA, baseline Centiloid was not associated with time to ARIA (adjusted HR, 1.01 [95% CI, 0.91-1.11]; P = .91). Among 19 patients with ARIA-E included in the regional analysis, baseline uptake was modestly greater in regions that subsequently developed ARIA-E than in mirrored contralateral regions for SUVmax (3.44 ± 0.78 versus 3.25 ± 0.77; P = .02) and SUVmean (2.60 ± 0.56 versus 2.45 ± 0.64; P = .01).

CONCLUSIONS: Baseline global Centiloid was not independently associated with ARIA in patients treated with lecanemab. Exploratory regional analysis demonstrated modest differences in baseline amyloid uptake in regions that subsequently developed ARIA-E, warranting confirmation in larger prospective studies.},
}

@article {pmid42595483,
year = {2026},
author = {Zhou, L and Keil, S and Wang, XH and Hojjati, SH and Castellanos, CB and Wartchow, KM and Dartora, WJ and Mclntire, LB and Chiang, GC and Li, Y and Butler, TA},
title = {Contribution of Myelin Content to the PET-Measured Amyloid Burden.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.126.272591},
pmid = {42595483},
issn = {1535-5667},
abstract = {Off-target binding to white matter myelin is well established in amyloid-β (Aβ) PET. Whether tracer binding to intracortical myelin influences cortical PET quantification remains unknown. We tested whether accounting for myelin water fraction (MWF), an MRI measure of myelin, improves the correlation between Aβ PET and the Alzheimer disease (AD) plasma biomarker phosphorylated tau 217 (p-tau217). Methods: This study included 114 participants with and without AD who underwent Aβ PET with [11]C-Pittsburgh compound B (n = 60) or [18]F-florbetaben (n = 54), multiecho fast T2 MRI to quantify MWF, and semiquantitative in vitro diagnostic immunoassay to measure plasma p-tau217 levels. Cortical Aβ burden was quantified using SUV ratio and Centiloids. Nested regression models predicted PET signal using age and p-tau217 level, with and without cortical MWF. Results: MWF independently predicted PET-measured Aβ signal and improved model fit by approximately 6% in both the combined and tracer-specific cohorts. Conclusion: Intracortical myelin contributes to Aβ PET signal. Incorporating MWF may improve Aβ PET quantification, with implications for AD diagnosis, patient selection, and monitoring response to anti-Aβ therapies.},
}

@article {pmid42595486,
year = {2026},
author = {Mathoux, G and Boccalini, C and Peretti, DE and Scheffler, M and Margot, H and Ashton, NJ and Zetterberg, H and Frisoni, GB and Garibotto, V},
title = {Clinical and Biologic Characterization of a 3-Level Centiloid-Based Classification of Amyloid PET.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.126.272655},
pmid = {42595486},
issn = {1535-5667},
abstract = {Amyloid PET is commonly interpreted using binary visual classification. However, quantitative assessment on the Centiloid scale identifies an intermediate range of amyloid burden not always captured by dichotomous interpretation. The biologic and clinical relevance of this intermediate category remain unclear, despite its implications for biomarker interpretation, prognostic stratification, and eligibility for amyloid-targeting therapies. Our aim was to characterize individuals within this intermediate range using multimodal biomarker profiles and longitudinal cognitive outcomes, as well as deriving Centiloid thresholds for early tau PET positivity, advanced tau PET positivity, and cognitive decline. Methods: We retrospectively analyzed participants who underwent amyloid PET between 2016 and 2024 at the Geneva Memory Center, including cognitively unimpaired individuals and patients with mild cognitive impairment or dementia. Global amyloid burden was quantified in Centiloids, and participants were categorized into low (<12), intermediate (12-37), or high (>37) groups. Group comparisons, receiver-operating-characteristic curve analyses, and linear mixed-effects models were used to assess fluid biomarker differences, define Centiloid thresholds for tau positivity and cognitive decline, and evaluate longitudinal change in Mini-Mental State Examination scores. Results: Among the 512 participants, 202 (39%) had low, 63 (12%) had intermediate, and 247 (48%) had high Centiloid values. The intermediate-Centiloid group showed biomarker profiles, including cerebrospinal fluid and plasma markers of amyloid, tau pathology, and neurodegeneration, between those of the low and high groups. Both the intermediate- and high-Centiloid groups exhibited faster cognitive decline than did individuals in the low-Centiloid group, with a moderate rate in the intermediate-Centiloid group. Thresholds of 13 and 14 Centiloids best identified individuals with cognitive decline and tau accumulation in the mesial temporal lobe, respectively, whereas 51 Centiloids best discriminated advanced neocortical tau involvement. Conclusion: Centiloid-based classification delineates biologically and clinically distinct stages along the amyloid continuum. Individuals with intermediate Centiloid values already show tau involvement and increased risk of cognitive decline, whereas higher amyloid levels are associated with advanced tau pathology. These findings support a 3-level interpretation of amyloid PET beyond binary classification and highlight the clinical relevance of the intermediate zone.},
}

@article {pmid42595893,
year = {2026},
author = {Konrad-Vicario, KD and Paradise, V and Demir, LY and Nguyen, C and Makinson, CD and Ming, Z and Ramachandran, KV},
title = {Dendritic translation and neuroproteasome-mediated degradation of endogenous tau revealed by STARFISH.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42595893},
issn = {1546-1726},
support = {7DP5OD028133//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; AARFD-23-1151195/ALZ/Alzheimer's Association/United States ; },
abstract = {In Alzheimer's disease, the protein tau is thought to redistribute from axons to the somatodendritic compartment and form fibrillar aggregates. Although tau aggregation is a hallmark of Alzheimer's disease, the dynamics of its synthesis and degradation are not well characterized. Given that nascent polypeptides are particularly susceptible to misfolding, local control of tau synthesis and degradation may be essential to prevent aggregation. Here we develop STARFISH, a method for visualizing the subcellular site of endogenous mRNA translation in primary neurons and in vivo with single-molecule sensitivity and near-codon resolution, without modifying the nascent polypeptide. Using STARFISH, we show that despite the broad distribution of Mapt mRNA, tau is translated exclusively in neuronal dendrites. About one-third of newly synthesized tau is co-translationally or peri-translationally degraded in dendrites by a neuronal-specific plasma-membrane-associated proteasome, the neuroproteasome. Failure of neuroproteasome-mediated degradation leads to the protein synthesis-dependent accumulation of somatodendritically mislocalized endogenous tau aggregates. These findings define a proteostasis mechanism that counterbalances the constitutive physiological overproduction of tau. We speculate that failure of this proteostasis system contributes to tau aggregation in dendrites in Alzheimer's disease.},
}

@article {pmid42596024,
year = {2026},
author = {Reeves, MM and Aviles Carpintero, S and Zanovello, M and Jansen-West, K and Yue, M and Calliari, A and Song, Y and Dunmore, J and Maroto Cidfuentes, C and Ball, S and Kachergus, JM and Killeen, HE and Rawlinson, B and Engelberg-Cook, E and DeTure, M and Day, GS and Graff-Radford, NR and Boeve, BF and Knopman, DS and Petersen, RC and Murray, M and Thompson, AE and Dickson, DW and Fratta, P and Petrucelli, L and Josephs, KA and Prudencio, M},
title = {The UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42596024},
issn = {1758-9193},
support = {P30AG062677/AG/NIA NIH HHS/United States ; U01AG006786/AG/NIA NIH HHS/United States ; U54NS123743, R35NS097273//NIH/ ; R01NS120992, R01AG037491//NIH/ ; R01NS120992, U54NS123743//NIH/ ; MR/M008606/1 and MR/S006508/1//Lady Edith Wolfson Fellowship/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/complications ; Polymorphism, Single Nucleotide/genetics ; Male ; Female ; DNA-Binding Proteins/metabolism ; *Exons/genetics ; *Nerve Tissue Proteins/genetics ; Aged ; Brain/pathology/metabolism ; Aged, 80 and over ; Cohort Studies ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: TAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer's disease (AD), where it co-occurs with amyloid β plaques and tau neurofibrillary tangles, and associates with accelerated cognitive decline and brain atrophy. TDP-43's function of repressing the inclusion of cryptic exons (CEs) during RNA splicing is compromised in AD. A single-nucleotide polymorphism (SNP) located within the CE in the UNC13A gene [rs12973192 (C > G)] is associated with higher disease risk and reduced survival in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) by weakening TDP-43 binding promoting CE inclusion.

OBJECTIVE: To investigate the influence of the rs12973192 UNC13A CE SNP and UNC13A cryptic splicing on TDP-43 pathology, survival and cognitive impairment in AD.

METHODS: We evaluated the UNC13A CE SNP in a cohort of 1,672 AD, including 643 AD brains with available cognitive measurements and 73 AD cases for which we measured cryptic RNA levels in the amygdala. We also evaluated a cohort of 466,517 from the UK Biobank to determine associations between the UNC13A CE SNP and dementia diagnosis.

RESULTS: In AD, the UNC13A CE SNP associated significantly with cognitive decline, but not with TDP-43 pathology or with survival. UNC13A cryptic RNA levels in the amygdala were a better predictor of cognitive decline than the UNC13A CE SNP itself, while STMN2-another well-known CE target-exhibited no such association.

CONCLUSIONS: These findings point to UNC13A cryptic splicing as a specific driver of cognitive decline in AD, outperforming both genetic risk and other cryptic targets.},
}

Humans
*Alzheimer Disease/genetics/pathology/complications
Polymorphism, Single Nucleotide/genetics
Male
Female
DNA-Binding Proteins/metabolism
*Exons/genetics
*Nerve Tissue Proteins/genetics
Aged
Brain/pathology/metabolism
Aged, 80 and over
Cohort Studies
Genetic Predisposition to Disease

@article {pmid42596083,
year = {2026},
author = {Gupta, R and Charankevich, H and Drabo, EF and Brown, T and Gross, AL and Polsky, D and Segal, JB and Ornstein, KA},
title = {Comparison of Claims-Based Algorithms for Dementia Identification: A Cross-Sectional Analysis of the National Health and Aging Trends Study (NHATS).},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70650},
pmid = {42596083},
issn = {1532-5415},
support = {P30AG066587//Hopkins' Economics of Alzheimer's Disease and Services (HEADS) Center of the National Institute on Aging/ ; R01AG060967/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Accurate identification of Alzheimer's disease and related dementias (ADRD) in administrative data is increasingly important for research, care delivery innovation, and policy applications such as risk adjustment. Despite the widespread use of existing claims-based algorithms to identify ADRD, few studies have compared their use to ongoing longitudinal aging studies.

METHODS: In this cross-sectional study, we included 2204 NHATS respondents aged 65 years or older classified as having dementia and enrolled in fee-for-service Medicare in 2019. We determined the performance characteristics of 3-claims-based dementia algorithms using NHATS as a reference standard.

RESULTS: Among NHATS respondents classified as having "probable" dementia, sensitivity was generally low (48.8%-70.5%), while specificity was high (91.5%-97.8%) across all 3 algorithms. The Chronic Conditions Warehouse (CCW) algorithm had the highest sensitivity (70.5, 95% CI: 64.3-76.6), followed by Bynum-Standard 3-year (65.8, 95% CI: 59.6-71.9). Bynum-Standard 1-year had the highest PPV (65.6, 95% CI: 56.9-74.4). The Youden Index and F1 score were generally low and clustered closely across the three algorithms. Odds of ADRD misclassification differed across patient characteristics.

CONCLUSION: Commonly used claims-based algorithms to identify ADRD had reasonable validity, though each presented important context-dependent tradeoffs and none was uniformly superior. These findings highlight the importance of accurately diagnosing ADRD in clinical settings and of understanding each algorithm's strengths and limitations based on the use case. Limitations include that NHATS is not a "gold standard" for comparison of claims-based algorithms and we only analyzed NHATS respondents in a single year.},
}

@article {pmid42596580,
year = {2026},
author = {Desai, P and Howard, M and Tangney, CC and Stone, KL and Redline, S and Holland, TM and Halloway, S and Ba, KK and Santana, JA and Whitmer, RA and Espeland, MA and Hayden, KM and Baker, LD},
title = {Napping, Sleep Apnea, and Cognitive Function: Cross-sectional Results from the U.S. POINTER-zzz Sleep Ancillary Study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag198},
pmid = {42596580},
issn = {1758-535X},
abstract = {BACKGROUND: The relationship between the duration of napping and cognitive function is unclear. We examine this association by analyzing baseline data from the US POINTER-zzz Sleep Ancillary Study.

METHODS: This study evaluates sleep assessments obtained via home apnea-screening device, wrist actigraphy, and sleep diaries among 686 older adult participants. Naps were defined as sleep periods with at least 30 continuous minutes outside of the primary period of sleep or the longest sleep duration. We conducted linear regression analyses to test the association between napping minutes and baseline global cognitive function and its domains, including executive function, episodic memory, and processing speed. We also examined whether the association between duration of napping and cognitive function outcomes differed by the presence (n = 223) or absence of sleep apnea (n = 463).

RESULTS: For the total sample, greater minutes of napping were associated with decreased processing speed (β= - 0.0973 (95% CI= - 0.1664, -0.0282)). The interaction analyses between sleep apnea and napping did not reach statistical significance, providing no evidence that sleep apnea modifies the association between napping and cognition in the total sample. Greater minutes of napping were associated with poor executive function in participants with sleep apnea and who were in an under-represented ethno-racial group (β=-0.2493 (95% CI=-0.4943, -0.0042)).

CONCLUSIONS: Study findings are exploratory and suggest that it may be important to detect and treat sleep apnea for possible cognitive benefits, especially in certain subgroups of older adults.},
}

@article {pmid42596624,
year = {2026},
author = {Zhang, Z and Tan, H and Shi, F and Dai, J and Ding, W and Li, J and Wang, Y and Yang, R and Xu, X and Chen, C and Xiao, F and Huang, LA and Liu, X and Liao, R and Yan, L},
title = {A Novel Nogo-A Receptor Antagonist Peptide Impedes Alzheimer's Disease Pathology by Nogo-A/NgR/ROCK Signaling Pathway.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {8},
pages = {e71052},
doi = {10.1002/cns.71052},
pmid = {42596624},
issn = {1755-5949},
support = {82102690//National Natural Science Foundation of China/ ; 2026A1515011575//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 20211128182437730//Guangdong Provincial Medical Science and Technology Research Fund/ ; 2024A03J0902//2024 Joint between City, University (College) and Enterprise/ ; 21626406//Fundamental Research Funds for the Central Universities/ ; 2025-WJHX-31//Horizontal Research from the Guangdong Provincial Health Economics Association/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism/genetics ; *Signal Transduction/drug effects/physiology ; *rho-Associated Kinases/metabolism ; Mice, Transgenic ; *Nogo Proteins/metabolism/antagonists & inhibitors ; Mice ; Amyloid beta-Peptides/metabolism ; *Nogo Receptor 1/antagonists & inhibitors/metabolism ; Humans ; Peptide Fragments/metabolism ; Amyloid beta-Protein Precursor/genetics ; Male ; Disease Models, Animal ; tau Proteins/metabolism ; Presenilin-1/genetics ; *Peptides/therapeutic use/pharmacology ; },
abstract = {AIMS: To evaluate the therapeutic effects of NAP2, a novel NgR1 antagonist peptide, on Alzheimer's disease (AD) pathology and to determine whether inhibition of the Nogo-A/NgR1/ROCK signaling axis can ameliorate neurodegenerative alterations in APP/PS1 mice.

METHODS: APP/PS1 transgenic mice received a three-month NAP2 intervention. Cognitive performance was assessed using standard learning and memory tests. Amyloid-β plaque burden, dendritic spine density, tau phosphorylation, and Aβ42 levels were examined by histological and biochemical analyses. Mitochondrial function and downstream ROCK signaling activity were also evaluated.

RESULTS: NAP2 treatment significantly improved cognitive performance in APP/PS1 mice. NAP2 reduced amyloid-β plaque deposition, decreased Aβ42 expression, and increased hippocampal dendritic spine density. Tau hyperphosphorylation was notably attenuated. In addition, NAP2 alleviated Aβ42-induced mitochondrial dysfunction. Mechanistic studies revealed that NAP2 interfered with ROCK signaling downstream of Nogo-A.

CONCLUSION: NAP2 ameliorates multiple AD-related pathological features, an effect accompanied by the inhibition of the Nogo-A/NgR1/ROCK pathway. These findings highlight the therapeutic potential of NAP2 to enhance resilience against Alzheimer's disease pathology.},
}

Animals
*Alzheimer Disease/pathology/drug therapy/metabolism/genetics
*Signal Transduction/drug effects/physiology
*rho-Associated Kinases/metabolism
Mice, Transgenic
*Nogo Proteins/metabolism/antagonists & inhibitors
Mice
Amyloid beta-Peptides/metabolism
*Nogo Receptor 1/antagonists & inhibitors/metabolism
Humans
Peptide Fragments/metabolism
Amyloid beta-Protein Precursor/genetics
Male
Disease Models, Animal
tau Proteins/metabolism
Presenilin-1/genetics
*Peptides/therapeutic use/pharmacology

@article {pmid42596762,
year = {2026},
author = {Mokdad, AH and Dwyer-Lindgren, L and Murray, CJL},
title = {Chronic Disease and Disability in the United States: Trends, Inequities, and Imperatives for Policy Reform.},
journal = {The Milbank quarterly},
volume = {},
number = {},
pages = {},
doi = {10.1111/1468-0009.70109},
pmid = {42596762},
issn = {1468-0009},
abstract = {UNLABELLED: Policy Points Position Universal, High-Quality Education as a Foundational Public Health Strategy. Long-term health and life expectancy in the United States are shaped more by educational attainment than by any other single factor. Disparities in access to early childhood, K-12, and higher education perpetuate cycles of chronic disease, economic hardship, and shortened lifespan, particularly in marginalized communities. Policymakers must recognize education as a critical public health intervention and commit to providing universal access to high-quality education at every stage of life. This transformation requires shifting the focus from mere per-pupil spending toward the national scaling of high-impact instructional models, such as intensive, high-dosage tutoring and adaptive learning. Leveraging generative AI to provide personalized, real-time instruction tailored to individual student needs is essential to bridge the achievement gap at scale. Furthermore, achieving true educational equity requires decoupling school quality from local property taxes, integrating health literacy and nutrition into curricula, and ensuring higher education remains affordable and accessible for all. Transform the Food and Built Environment to Advance National Metabolic Resilience. The structure of America's food system and built environment directly fuels the escalating burden of obesity, diabetes, and related chronic diseases. Federal and state policies must fundamentally shift agricultural subsidies away from calorie-dense, nutrient-poor commodities toward specialty crops and fresh produce. To ensure these healthy choices are the default for every household, the federal government must finalize and enforce mandatory, interpretive front-of-package warning labels for ultra-processed foods. This shift, designed to move beyond the passive Nutrition Facts panel, will provide at-a-glance transparency and incentivize industrywide reformulation. Furthermore, metabolic health must be integrated into the K-12 experience through mandatory daily high-intensity physical activity to improve cardiorespiratory fitness and cognitive performance and minimally processed school meals. Finally, investments in active transportation infrastructure, including pedestrian greenways and safe routes to school, are essential to encourage movement as a default, closing the "convenience gap" that disproportionately burdens low-income and rural Americans. Normalize Chronic Obesity Management. Acknowledging that no nation has successfully reversed the obesity epidemic through behavioral advice alone, the United States must treat obesity as a chronic biological condition rather than a temporary lifestyle lapse. It is imperative that public and private payers guarantee universal, affordable access to evidence-based treatments, including next-generation pharmacotherapies (such as GLP-1 receptor agonists). These clinical strategies must be coupled with a modernized, real-time health data infrastructure to monitor outcomes and ensure equitable access at the neighborhood level.

CONTEXT: Over the past three decades, mortality from leading causes such as cardiovascular disease and cancer has declined in the United States, but the burden of chronic, disabling conditions, including musculoskeletal disorders, mental and substance use disorders, and obesity, has grown or stagnated, widening the gap between total years lived and years lived in good health. These shifts are accompanied by persistent and widening inequities in longevity by geography, race/ethnicity, and socioeconomic status.

METHODS: This analysis draws on the 2023 Global Burden of Disease Study, which estimates mortality, disability, and risk factor burden for 375 diseases and 88 risk factors nationally and at the state level, combined with findings from the US Health Disparities project. The latter uses small-area estimation to evaluate county-level life expectancy and mortality across five racial/ethnic groups and four educational strata, and the "Ten Americas" framework, which stratifies the population by race/ethnicity, geography, and socioeconomic context.

FINDINGS: In 2023, US life expectancy reached 78.5 years and healthy life expectancy 64.5 years, both still below prepandemic 2019 levels, with a persistent 13-14-year gap between life expectancy and healthy life expectancy. Ischemic heart disease remained the leading cause of death, but drug use disorders rose from the 26th to the leading cause of disability, a 562% increase since 1990, while Alzheimer disease and musculoskeletal disorders also climbed in rank. High systolic blood pressure remained the top mortality risk factor despite a large decline, while high body mass index and high fasting plasma glucose burdens grew substantially. State-level disparities widened, with West Virginia and Mississippi trailing Hawaii by wide and increasing margins. Life expectancy gaps by race/ethnicity, education, and place were large and growing, reaching 20.4 years across the "Ten Americas" by 2021, with county-level life expectancy spanning more than 27 years nationally.

CONCLUSIONS: US health trends reflect a shift from fatal to disabling disease, driven substantially by the obesity/metabolic and substance use epidemics, layered onto deep and widening structural inequities by race/ethnicity, place, and education. Reversing these trends requires a multidimensional policy agenda spanning universal, high-quality education; reform of the food and built environment; normalized clinical management of obesity; expanded, integrated substance use and mental health treatment; and modernized, real-time public health data infrastructure.},
}

@article {pmid42597032,
year = {2025},
author = {Bazan, M and Hsieh, TYJ and Wei, JC and Collier, AY},
title = {Association of preeclampsia with long-term risk of neurodegenerative disorders.},
journal = {Pregnancy (Hoboken, N.J.)},
volume = {1},
number = {4},
pages = {e70041},
pmid = {42597032},
issn = {2997-9684},
abstract = {OBJECTIVE: Preeclampsia (PE) is a common complication of pregnancy linked to increased lifetime risk of multiple comorbidities. However, the link between PE and development of adverse neurologic conditions is still poorly understood. Our objective was to investigate the risk of neurodegenerative disorders for women with PE compared to those without PE.

STUDY DESIGN: We utilized the TriNetX database including electronic health records from 66 healthcare organizations and identified women 18+ years old with their last delivery between January 2000 and December 2023. PE was defined using ICD-10 codes that occurred before delivery up until December 2020. The comparator group included pregnant women in the same period without PE diagnosis. After 1:1 propensity score matching on age at index pregnancy, demographics, health utilization, comorbidities, depression, reproductive factors, and body mass index, hazard ratios (HR), and 95% confidence intervals (CIs) for cognitive disorders were estimated between the PE and comparator group using a Cox proportional hazard regression model. Cognitive outcomes were identified by ICD-10 codes and censored until one of the following conditions was met: (1) development of an outcome, (2) July 26, 2024, or (3) loss to follow-up in the system.

RESULTS: The PE group had a 9% increased risk of symptomatic cognitive impairment (HR 1.09; 95% CI 1.03, 1.16) and a 9% increased risk of composite cognitive impairment outcomes, including clinical, symptomatic, mild cognitive impairment, dementia, or related medication use (HR 1.09; 95% CI 1.03, 1.15) compared to the non-PE group. Similar trends were observed in the term birth subgroup for symptomatic cognitive impairment (HR 1.06; 95% CI 1.00, 1.12) and composite outcomes(HR 1.06; 95% CI 1.01, 1.13). No significant associations were found in the preterm subgroup due to limited events. Risk of Parkinson's disease, parkinsonism, or related outcomes was not statistically different in the main model but was higher in sensitivity analyses with natural language processing (NLP) and accounting for death as competing risk. Cognitive impairment, dementia/Alzheimer's, and vascular dementia showed no differences in the main or NLP sensitivity analyses but were elevated in the competing risk sensitivity analysis.

CONCLUSION: Our findings demonstrate an increased risk of cognitive impairment among individuals with a history of PE, with additional associations for Parkinson's disease and parkinsonism identified in sensitivity analyses. These results highlight the importance of obstetrical health as a predictor of lifelong neurocognitive health, underscoring the need for targeted surveillance and early intervention strategies for neurodegenerative diseases in this population.},
}

@article {pmid42597288,
year = {2026},
author = {Miao, X and Zhang, Y and Gao, C and Meng, W and Yan, J and Zeng, T and Tang, G},
title = {The changing epidemiology of infection-associated mortality in Alzheimer's disease in the United States, 1999-2024.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1885030},
pmid = {42597288},
issn = {1663-4365},
abstract = {BACKGROUND: Infections are major immediate causes of death in patients with Alzheimer's disease, trends across infection subtypes remain poorly characterized. We examined temporal trends, demographic geographic disparities, COVID-19-era patterns, projected infection-associated mortality in United States, 1999-2024.

METHODS: Using CDC Multiple Cause of Death database, infection-associated AD deaths were classified into six subtypes. AAMRs and temporal trends were estimated using joinpoint regression. Kitagawa decomposition assessed demographic age-specific contributions to sex disparities, Bayesian Structural Time Series models projected burden through 2034.

RESULTS: Among 2,342,153 AD-related deaths, 308,045 (13.2%) were infection-associated. Overall infection-associated AAMR declined by 57.6% (AAPC -3.72% per year), diverging from rising AD mortality. Respiratory infections showed the steepest decline (AAMR -68.3%) with improvements across all regions and urbanization strata. By contrast, genitourinary infections were the only subtype with rising burden-absolute deaths increased 75.1%, rural AAMR rose 73.1% over 1999-2020, and central trend-continuation projections suggest a possible further increase, particularly over the near-term horizon, although uncertainty becomes substantial in the longer term. Kitagawa decomposition showed that the female excess in genitourinary mortality was attributable to higher age-specific female rates rather than to population age structure-uniquely among the subtypes examined (cumulative risk effect +11,337; 47.4% of the female excess; cumulative female deaths exceeding male by 170%); the increase in this risk component over time was directionally consistent but of model-dependent statistical significance. Mortality was overwhelmingly concentrated in the oldest age stratum (≥ 85-year rate 2,516-fold that of < 65 years). During the COVID-19 era, overall infection-associated AD mortality fell below pre-pandemic projections, with genitourinary infections showing the smallest cumulative deficit of any subtype. Hispanic individuals had the highest AAMR by 2024, while Non-Hispanic Black individuals maintained elevated septicemia mortality throughout.

CONCLUSION: Although infection-associated AD mortality declined substantially, a growing genitourinary infection burden widened across sex, rural, and racial strata, with trend-continuation projections suggesting a possible further increase, particularly over the near-term horizon. These findings, combined with external clinical evidence on infection prevention, suggest that targeted measures-including CAUTI prevention, sex-specific bladder health programs, and rural infection prevention investment-merit priority attention as baby boomers enter peak AD risk.},
}

@article {pmid42597411,
year = {2026},
author = {Zhang, J and Burkett, BJ and Schwarz, CG and Dizdar, N and Johnson, MP and Bilgin, C and Kemp, BJ and Durski, JM and Lowe, V and Johnson, DR},
title = {Inter-software variability of Centiloid quantification in amyloid PET: A head-to-head comparison of five software platforms.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70443},
pmid = {42597411},
issn = {2352-8729},
abstract = {INTRODUCTION: Centiloid (CL) scaling standardizes amyloid positron emission tomography (PET) quantification across tracers and platforms; however, variability across software implementations may affect diagnostic classification. This study evaluated inter-software variability and diagnostic performance across five platforms using identical [1] [8]F-florbetapir datasets.

METHODS: Retrospectively, 192 patients undergoing [1] [8]F-florbetapir PET/computed tomography (CT) and magnetic resonance imaging (MRI) were analyzed. CL values were generated using four US Food and Drug Administration (FDA) -cleared platforms and an in-house Centiloid standard pipeline. Agreement was assessed using intraclass correlation coefficient, with bias and limits of agreement evaluated by linear modeling and Bland-Altman analysis. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis and classification against visual interpretation.

RESULTS: Agreement was excellent (intraclass correlation coefficient [ICC] 0.969; 95%CI 0.961-0.975). Some platforms produced systematically higher CL values versus others slightly lower. LoA reached ± 30 CL. Diagnostic accuracy was high (area under the curve [AUC]: 0.949-0.975), with sensitivity 0.923-0.968 and specificity 0.667-0.806.

DISCUSSION: Despite excellent agreement, systematic differences persist and may affect classification near thresholds, supporting consistent use of a single processing pipeline.},
}

@article {pmid42597430,
year = {2026},
author = {Powell, WJB and Schindler, SE and Jiménez-Mausbach, M and Oh, IY and Hofmann, A and Snider, BJ and Paczynski, M and Ghoshal, N and Payne, PRO and Lai, AM and Hofford, MR and Gupta, A},
title = {Medical comorbidities of patients receiving amyloid-targeting treatments in a memory clinic.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70445},
pmid = {42597430},
issn = {2352-8729},
abstract = {INTRODUCTION: Trials of amyloid-targeting treatments (ATTs) for early symptomatic Alzheimer's disease (AD) enrolled selected patients with minimal medical comorbidities. We investigated whether real-world memory clinic patients who received ATTs also had fewer comorbidities than the broader clinic population.

METHODS: We extracted data on demographics, comorbidities, and medications from patients who were seen at the Washington University Memory Diagnostic Center from July 1, 2023, through July 1, 2025. We compared the characteristics of patients by biomarker testing status and ATT treatment status.

RESULTS: Of 9938 unique patients, 1948 underwent AD biomarker testing and 335 received ATT infusions (304 lecanemab, 31 donanemab). The patients who underwent biomarker testing or received ATTs were more likely to be White individuals and to have fewer comorbidities than patients who did not undergo testing or receive ATTs.

DISCUSSION: Real-world ATT patients were healthier than the general clinic population and more similar to clinical trial participants.},
}

@article {pmid42597443,
year = {2026},
author = {Tolosa-Tort, P and Okorie, M and Chatterjee, A and Boeriu, AI and Sharma, RU and Andrews, SJ},
title = {Toward personalized medicine in AD/ADRD through genetic-exposome dementia risk assessments.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {70},
pmid = {42597443},
issn = {3005-1940},
abstract = {Genetic-Exposome Dementia Risk Assessments (GEDRA) integrate genomic and environmental risk factors into actionable, patient-centered tools for Alzheimer's disease and related dementias (AD/ADRD). By enabling midlife risk stratification before biomarker or cognitive changes, GEDRA supports personalized medicine through targeted screening, tailored interventions, treatment guidance, and proactive planning. Strategic investment in GEDRA will advance responsible risk communication and translate precision prevention strategies into equitable, clinically meaningful practice.},
}

@article {pmid42597683,
year = {2026},
author = {Ding, S and Guo, Z and Ji, H and He, J},
title = {Metabolic cell death networks in Alzheimer's disease: mechanistic links and therapeutic perspectives of ferroptosis, cuproptosis, and disulfidptosis.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1879368},
pmid = {42597683},
issn = {2296-634X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized primarily by progressive cognitive impairment, whose pathogenesis involves multiple pathological processes including protein deposition, metal homeostasis dysregulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation. In recent years, metabolism-related cell death modalities such as ferroptosis, cuproptosis, and disulfidptosis have gradually been recognized as potentially involved in neuronal damage in Alzheimer's disease. This review summarizes the fundamental mechanisms of ferroptosis, cuproptosis, and disulfidptosis, along with their research evidence in AD. Ferroptosis is primarily driven by iron imbalance, lipid peroxidation buildup, and impaired GPX4 defense. This process exhibits a bidirectional amplification loop with Aβ and tau pathologies. Cuproptosis contributes to neuronal damage through abnormal copper accumulation, FDX1-related mitochondrial protein lipoylation dysfunction, loss of iron-sulfur cluster proteins, and proteotoxic stress. Disulfidptosis links glucose metabolism disorders, insufficient reducing power, and actin cytoskeleton vulnerability, providing novel insights into metabolic stress and structural damage in AD. Furthermore, the three modes of cell death can undergo cross-regulation through the SLC7A11-NADPH-GSH/GPX4 axis, the FDX1-DLAT/DLST-iron-sulfur cluster axis, as well as upstream factors such as p53, NRF2, and AMPK. Metabolic cell death may constitute a critical pathological network in AD. Targeting these death pathways and their shared hubs is expected to provide new directions for disease stratification, biomarker development, and disease-modifying therapies.},
}

@article {pmid42597738,
year = {2026},
author = {Wang, W and Xu, H and Wu, T and Zhang, Y and Tao, M and Zhao, X and Lu, J and Tang, X and Zhang, S and Zhang, Y and Nan, H},
title = {Differential detectability of pericyte and blood-brain barrier readouts across the Alzheimer's disease clinical continuum: a systematic review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1870764},
pmid = {42597738},
issn = {1663-4365},
abstract = {BACKGROUND: In Alzheimer's disease (AD), neurovascular unit and blood-brain barrier (BBB) abnormalities are assessed using biologically distinct readouts, often across separate cohorts, complicating interpretation across clinical stages and biomarker domains.

METHODS: We searched major databases (inception to February 7, 2026) for human observational studies quantifying cerebrospinal fluid (CSF) soluble platelet-derived growth factor receptor-β (sPDGFRβ), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) K [trans], or the CSF/serum albumin quotient (QAlb) in cognitively normal (CN), mild cognitive impairment (MCI), and AD dementia groups. Primary contrasts were MCI versus CN, AD dementia versus CN, and AD dementia versus MCI. Outcomes were analyzed separately using standardized mean differences (SMDs) in random-effects models with restricted maximum-likelihood estimation and Hartung-Knapp adjustment. Sensitivity analyses incorporated amyloid/AT (N)-informed biologic anchoring and evidence-tier restrictions where possible.

RESULTS: We included 24 cross-sectional studies (3,644 participants). Compared to CN, MCI showed higher CSF sPDGFRβ (SMD 0.38, 95% CI 0.03-0.73) and DCE-MRI K [trans] (SMD 0.91, 95% CI 0.09-1.73; highly heterogeneous and based on five studies), whereas the difference for QAlb was smaller (SMD 0.19, 95% CI 0.01-0.37). Stricter etiologic restriction weakened the robustness of MCI-stage estimates, particularly for early AD-specific inferences in cohorts without consistent biomarker confirmation. Tier 1-only pooling was not feasible because biomarker-confirmed MCI-stage evidence was sparse. AD dementia versus CN comparisons showed higher values across all readouts: CSF sPDGFRβ (SMD 0.43, 95% CI 0.12-0.73), K [trans] (SMD 0.90, 95% CI 0.56-1.25; based on four studies), and QAlb (SMD 0.28, 95% CI 0.10-0.45). AD dementia versus MCI comparisons showed no significant pooled differences for CSF sPDGFRβ or QAlb; K [trans] pooling was precluded by insufficient data.

CONCLUSION: Pericyte- and BBB-related readouts showed readout-specific, cross-sectional detectability patterns across the AD clinical continuum. K [trans] findings should be considered preliminary because of the small evidence base, and MCI-stage estimates remain limited by etiologic uncertainty. Overall, CSF sPDGFRβ, DCE-MRI K [trans], and QAlb appear related but non-interchangeable, and the present cross-sectional evidence should not be interpreted as demonstrating temporal priority, within-person progression, or head-to-head biomarker superiority.

PROSPERO, CRD420251142518.},
}

@article {pmid42597739,
year = {2026},
author = {Skourti, K and Katsaitis, F and Pavlidi, P and Anesti, M and Balla, J and Emvalomatis, A and Kokras, N and Dalla, C and Sotiropoulos, I},
title = {Mental health and gut-brain crosstalk: implications for depression and Alzheimer's disease.},
journal = {Neuroscience applied},
volume = {5},
number = {},
pages = {107023},
pmid = {42597739},
issn = {2772-4085},
abstract = {Brain health and mental health disorders are increasingly becoming an essential priority for modern societies as they affect different parameters of life, such as brain health, quality of life, and productivity with a heavy societal and economic burden. Among mental health disorders, depression and Alzheimer disease (AD) have the higher impact on mental health globally as they are highly prevalent, cause long-term cognitive and mood deficits while they are deeply interconnected, with chronic stress raising as a risk factor and potential link between both disorders. This review focuses on the gut-brain axis, a bidirectional communication network that links the gut microbiome with the central nervous system, and its role in brain malfunction and pathology related to stress, depression and AD. This intricate gut-brain crosstalk is orchestrated through top-down and bottom-up mechanisms implicating the HPA axis, the enteric nervous system as well as gut microbiota-derived metabolites, neurotransmitters, epigenetic processes and extracellular vesicles/exosomes that can contribute to depression and AD. The current work provides a comprehensive summary of evidence linking gut microbial alterations to these brain pathologies, with particular focus on lifestyle and nutrition (e.g. food, water) as critical regulators. Lastly, we explore the therapeutic potential of microbiome-targeted interventions including pro/pre/post-biotics, and trace elements (e.g. lithium and silicon). Overall, this review highlights the potential of microbiome-centered strategies as novel interventions to support mental health and wellbeing.},
}

@article {pmid42597745,
year = {2026},
author = {Martínez-Molina, N and Orte, S and Migliorelli, C and Ribas, V},
title = {Toward precision neuroscience in Alzheimer's disease: the role of multimodal AI.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1903637},
pmid = {42597745},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly understood as a biologically defined and heterogeneous continuum, requiring models that move beyond symptom-based diagnosis toward individualized risk prediction, stratification, and intervention.

OBJECTIVE: This mini-review outlines how precision neuroscience frameworks may support the characterization of AD by integrating multimodal biomarkers, systems biology, systems neurophysiology, digital health markers, and artificial intelligence (AI).

METHODS: We synthesize recent developments across multi-omics profiling, neuroimaging and electrophysiological biomarkers, AI-based speech analysis, and multimodal machine learning approaches, with emphasis on their potential contribution to biologically informed disease staging and personalized clinical decision-making.

RESULTS: Omics and systems biology approaches are expanding the characterization of molecular pathways involved in AD susceptibility, progression, and treatment response. Systems neurophysiology, including multimodal neuroimaging, electrophysiology, and whole-brain modeling, provides complementary markers of large-scale network disruption across the AD continuum. Digital health technologies, particularly AI-based speech analysis, offer scalable and ecologically valid tools for early risk enrichment and longitudinal monitoring. Multimodal AI models further enable the integration of heterogeneous clinical, molecular, imaging, genetic, and behavioral data into probabilistic representations of disease burden and progression. However, clinical translation remains constrained by interpretability, harmonization, validation, fairness, and accessibility challenges.

CONCLUSION: Precision neuroscience offers a promising framework for reconceptualizing AD as a dynamically modeled and biologically stratified disorder. Future progress will depend on robust multimodal datasets, transparent AI methods, longitudinal validation, and equitable implementation strategies capable of supporting early detection, trial enrichment, and personalized prevention or treatment.},
}

@article {pmid42597859,
year = {2026},
author = {Kang, H and Kang, J and Zeki, M and Seo, JH},
title = {Clustered pattern projection for EEG dementia classification: evaluating the reliability of disorder patterns.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1871265},
pmid = {42597859},
issn = {1662-4548},
abstract = {INTRODUCTION: Electroencephalography (EEG)-based classification of Alzheimer's disease (AD) and frontotemporal dementia (FTD) relative to cognitively normal (CN) controls is commonly interpreted through stable disease-related patterns. However, classification-relevant EEG responses in computational models may also appear fragmented or weakly preserved, making subject-level reliability difficult to assess. This study investigated whether recurrent disorder-like EEG patterns can provide exploratory evidence of subject-wise discriminative organization in dementia classification.

METHODS: We analyzed a publicly available resting-state EEG dataset including AD, FTD, and CN subjects. Clustered Pattern Projection (CPP) was applied to Dynamic Mode Decomposition (DMD)-based epoch descriptors to construct prototype-based EEG representations. Classification was performed using a linear support vector machine under a nested leave-one-subject-out cross-validation (LOSO-CV) framework. Subject-level reliability was further examined using margin-based analysis.

RESULTS: CPP showed competitive subject-level performance, particularly in the FTD vs. CN classification task, a setting in which resting-state discriminative patterns are often less consistently preserved than in AD. In addition, task-dependent subject-level margin patterns were observed under strict subject-wise validation, suggesting that margin analysis may provide a useful exploratory tool for evaluating the reliability of learned EEG representations.

DISCUSSION: These findings suggest that EEG generalization in dementia classification should not be interpreted only through preserved canonical biomarkers. Instead, recurrent disorder-like patterns may contribute to computationally detectable decision structure, and CPP provides a framework for examining such patterns under strict subject-wise validation.},
}

@article {pmid42598237,
year = {2026},
author = {Zhang, M and Zhang, Y and Zhang, Z and Jia, X and Lei, S and Bu, N and Wang, Y and Bai, Y and Wang, S},
title = {Effects of mindfulness-based exercise on Parkinson's disease and Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860499},
pmid = {42598237},
issn = {1664-2295},
mesh = {Humans ; *Parkinson Disease/therapy/psychology ; *Alzheimer Disease/therapy/psychology ; *Mindfulness/methods ; *Exercise Therapy/methods ; Yoga ; Qigong ; Tai Ji ; },
abstract = {OBJECTIVE: Currently, there is a lack of robust evidence demonstrating the efficacy of mindfulness-based exercise (MBE) on motor and cognitive outcomes in individuals with Parkinson's disease (PD) and Alzheimer's disease (AD), resulting in the absence of standardized and effective MBE treatment protocols. This systematic review and meta-analysis summarizes the available evidence to evaluate the therapeutic effects of MBE on motor and cognitive function in PD and AD.

METHODS: For two common neurodegenerative diseases, PD and AD, we searched PubMed, Embase, Cochrane Library, and Web of Science to identify studies published from inception to January 30, 2026. Search terms included neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, mindfulness, Tai Chi, yoga, and Qigong. Two independent reviewers assessed the risk of bias of included studies, performed data extraction, and evaluated the evidence. Treatment effects were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS-III), Timed Up and Go Test (TUG), Berg Balance Scale (BBS), Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Beck Depression Inventory (BDI), Parkinson's Disease Sleep Scale (PDSS), Activities of Daily Living (ADL), and Parkinson's Disease Questionnaire-39 (PDQ-39). Data analysis was performed using Review Manager 5.4 software to evaluate effect sizes and 95% confidence intervals (CIs). Heterogeneity tests were conducted to assess differences in treatment effects among Tai Chi, yoga, and Qigong.

RESULTS: We screened 4,576 articles and identified 28 studies that met the inclusion criteria. Of the included studies, 23 focused on PD and 5 on AD. Only 7 reported adequate allocation concealment, and 2 implemented participant blinding. GRADE assessment indicated moderate certainty of evidence for UPDRS-III, TUG, BBS, MoCA, and MMSE. BDI, PDSS, ADL, and PDQ-39 were rated as low-quality evidence. The pooled results showed significant effects: UPDRS-III (MD: -4.74, 95% CI [-6.78, -2.70], p < 0.00001); TUG(MD: -1.63, 95% CI [-2.41, -0.85], p < 0.0001); BBS(MD:2.80, 95% CI [1.54, 4.06], p < 0.0001); MoCA (MD: 1.93, 95% CI [1.12, 2.74], p < 0.00001); MMSE (MD: 2.80, 95% CI [0.32, 5.29], p = 0.03); BDI (SMD: -0.18, 95% CI [-0.47, 0.12], p = 0.24); PDSS (SMD: -0.31, 95% CI [-0.91, 0.28], p = 0.30); ADL (MD: -0.59, 95% CI [-3.49, 2.31], p = 0.69); and PDQ-39 (MD: -2.85, 95% CI [-6.36, 0.67], p = 0.11).

CONCLUSION: MBE demonstrated statistically significant improvements in motor function and certain cognitive domains in PD patients, suggesting its potential as a beneficial adjunctive non-pharmacological intervention for ameliorating motor symptoms and delaying cognitive decline, whereas evidence for non-motor symptom improvement remains insufficient. Subgroup analysis further indicated a favorable signal of MBE on cognitive function in AD patients; however, the current evidence is preliminary and warrants validation through additional high-quality studies. Given the inherent challenges in implementing double-blinding due to the nature of MBE interventions, coupled with inadequate allocation concealment, the present findings should be interpreted with caution owing to the substantial risks of performance and selection bias.},
}

Humans
*Parkinson Disease/therapy/psychology
*Alzheimer Disease/therapy/psychology
*Mindfulness/methods
*Exercise Therapy/methods
Yoga
Qigong
Tai Ji

@article {pmid42598344,
year = {2026},
author = {Wang, J and Caiola, C and Teng, CH and Cho, Y and Xu, Z and Finik, J and Siamdoust, S and Chan, YN and Ko, E and Seidenfeld, J and Bankole, AO and Bailey, DE and Mott, C and Wu, B and Plassman, BL and Anderson, RA},
title = {Behavior change techniques in a care partner-assisted oral health intervention for people with mild dementia: a secondary mixed-methods analysis.},
journal = {Innovation in aging},
volume = {10},
number = {9},
pages = {igag069},
pmid = {42598344},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: Oral hygiene declines early in mild dementia (MD), yet few interventions specify which behavior change techniques (BCTs) drive improvement. We examined the use of BCTs in relation to oral health outcomes in a care-partner-assisted intervention for persons living with MD.

RESEARCH DESIGN AND METHODS: Using a secondary convergent mixed-methods design, we analyzed the coaching arm of a three-arm randomized trial. Seventeen dyads (persons living with MD-care partners) completed four coaching sessions (68 coaching session transcripts). Seventeen BCTs were specified for use in the coaching manual. Transcripts were double-coded to denote frequency of BCTs used. Changes in the Gingival Index (GI) of persons living with MD between pre- and post-intervention were categorized as Stable/Worsened, Improved, or Meaningfully Improved. BCT frequencies were compared across these categories and integrated with qualitative data using joint displays.

RESULTS: The most frequently used BCTs were reviewing behavior goals, problem-solving, behavioral instruction, and prompts/cues. Two unspecified BCTs (action planning and emotional/relational support) were also commonly used. Meaningfully Improved dyads showed coordinated routines, greater autonomy for persons living with MD, and flexible BCT adaptation; Improved dyads used iterative action planning; Stable/Worsened dyads relied more on coach-led BCTs with limited adaptation. Care partners most often delivered prompts/cues and problem-solving, whereas persons living with MD engaged in goal setting and skill acquisition.

DISCUSSION AND IMPLICATIONS: While planned instructional BCTs established a necessary foundation, adaptive elements (e.g., action planning and relational support) proved essential for integrating oral care into daily life and achieving meaningful health improvement.},
}

@article {pmid42598552,
year = {2026},
author = {Bhatt, Y},
title = {Mechanistic convergence of Astragalus-derived phytochemicals in Alzheimer's disease: A systematic review.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {450-463},
pmid = {42598552},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β aggregation, tau pathology, oxidative stress, and neuroinflammation. Despite extensive research, effective disease-modifying therapies remain limited, underscoring the need for multi-target therapeutic strategies. Species of the genus Astragalus, widely used in traditional medicine, have gained attention for their neuroprotective potential due to diverse bioactive constituents, including saponins, flavonoids, and polysaccharides. This systematic review synthesizes current preclinical and emerging clinical evidence on the neuroprotective mechanisms of Astragalus species in AD. Literature was systematically analyzed in accordance with PRISMA guidelines. The findings indicate that Astragalus-derived compounds exert multi-target effects through modulation of key signaling pathways, including PI3K/Akt, Nrf2/ARE, MAPK, and NF-κB. These interactions collectively reduce oxidative stress, attenuate neuroinflammation, inhibit neuronal apoptosis, and improve synaptic function. Several studies further suggest roles in mitigating amyloid-β toxicity and tau hyperphosphorylation. Collectively, the evidence supports a systems-level pharmacological model in which Astragalus species mediate convergent neuroprotective effects across interconnected molecular pathways. However, translation to clinical application remains limited by insufficient human studies, variability in species-specific phytochemical profiles, and lack of standardized formulations. Future research should prioritize well-designed clinical trials, comparative species-level analyses, and mechanistic validation to establish the therapeutic potential of Astragalus in AD.},
}

@article {pmid42598558,
year = {2026},
author = {Abbasi, H and Hawn, SE and Javanbakht, A and Seedat, S and Bourassa, K and Sinnott, SM and Seligowski, AV and Hemmings, S and Kimbrel, NA and Wolf, E and Smith, AK and Brick, L and Mehta, D},
title = {From molecules to minds: Integrative multi-omics in psychiatry.},
journal = {Journal of mood and anxiety disorders},
volume = {15},
number = {},
pages = {100194},
pmid = {42598558},
issn = {2950-0044},
abstract = {Psychiatric disorders are biologically complex conditions arising from interactions across genomic, epigenomic, transcriptomic, proteomic, metabolomic, and metagenomic layers. Single-omics approaches rarely capture more than a fraction of the variance in complex conditions, underscoring the importance of integrative multi-omics frameworks. This mini-review summarizes key methodologies and their application in psychiatric research, with a focus on systems-level integration of genomic risk scores, transcriptomic networks, and neuroimaging data to advance biological understanding of disorders such as depression, schizophrenia, and Alzheimer's disease. We also outline the infrastructural requirements for effective multi-omics research, including standardized biobanking, Laboratory Information Management Systems, adherence to FAIR data principles, and federated learning approaches for privacy-preserving analysis. Importantly, we highlight the need for greater global inclusivity in psychiatric genomics. Current datasets are heavily biased toward relatively high-resourced and predominantly White, non-Hispanic populations, limiting generalizability. Initiatives such as the Psychiatric Genomics Consortium-Africa and H3ABioNet demonstrate how locally led efforts can strengthen capacity, promote data sovereignty, and support equitable research practices. Advancing multi-omics psychiatry will require coordinated investment in infrastructure, training, and inclusive international collaboration. This mini-review serves primarily as a conceptual roadmap, highlighting what integrative approaches have demonstrated so far and future directions for the field.},
}

@article {pmid42598675,
year = {2026},
author = {van de Zande, NA and Ruiter, CCC and Polman, MA and Brama, SCM and Roos, RAC and Kremer, PHC and de Bot, ST},
title = {Tracing neuroinflammation in neurodegeneration: insights from a scoping review on biofluid biomarkers.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag289},
pmid = {42598675},
issn = {2632-1297},
abstract = {Neuroinflammation is increasingly recognized as a key pathological process in neurodegenerative disease and can be monitored using biofluid biomarkers. Objective biomarkers may aid diagnosis, prognosis and progression. We conducted a scoping review of neuroinflammation biomarkers across major neurodegenerative diseases covering the past 23 years, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, Lewy body dementia, multiple system atrophy and progressive supranuclear palsy. PubMed and Web of Science were systematically searched for observational studies from 2003 to 2025 reporting neuroinflammation biomarkers in adult human subjects. Included markers encompassed blood, cerebrospinal fluid, saliva and urine, providing possible complementary information. Original studies on non-neuroinflammatory mechanisms, cellular or post-mortem biomarkers, animal models, genetics and comparisons between diseases were excluded. Two reviewers independently screened articles; biomarkers reported in ≥3 independent cohorts per disease were analysed. A total of 388 studies were included, predominantly in Alzheimer's disease/mild cognitive impairment (n = 214) and Parkinson's disease (n = 92). Eight biomarkers were most frequently reported: IL-6, TNF-α, IL-1β, CRP/hs-CRP, IL-10, MCP-1, YKL-40 and neutrophil-to-lymphocyte ratio (NLR), measured in blood or cerebrospinal fluid (CSF) as indicators of inflammatory processes associated with neurodegeneration. Across biomarkers, the strength and scope of evidence varied. Most studies demonstrated higher biomarker levels in disease, with more advanced stages, greater clinical severity and faster progression. NLR showed the most consistent pattern across staging, severity and progression, but is currently under-represented across diseases. CSF YKL-40 generally increased with disease presence and advancement; IL-6 showed consistent increases in advanced stages and with severity, although significant results were limited; MCP-1, CRP and TNF-α were mostly linked to severity and progression; IL-1β and IL-10 remained largely inconsistent. Other markers, including GFAP, showed associations in Alzheimer's disease but remain underexplored in other neurodegenerative diseases. Variability across studies, including differences in biofluid source, assay sensitivity, population characteristics and statistical approaches, limits interpretability and comparability. Although neuroinflammation is elevated in neurodegenerative diseases and generally intensifies as these diseases progress, potentially contributing to downstream pathology, the precise timing, role and predictive value of these biomarkers remain uncertain. A subset of markers, including NLR, YKL-40 and GFAP, shows relatively consistent associations and may warrant further investigation across diseases. In clinical practice, neuroinflammation biomarkers could serve as complementary tools to capture inflammatory processes related to disease heterogeneity and progression. Future longitudinal studies tracking pre-symptomatic and early-stage individuals, with standardized approaches, are needed to define temporal dynamics and explore their utility for monitoring disease progression and therapeutic response.},
}

@article {pmid42598748,
year = {2026},
author = {Tonietto, M and Silvestri, E and Belder, CRS and Barkhof, F and Fox, NC and Smith, J and Klein, G},
title = {Volume change with gantenerumab: Impact of amyloid-related imaging abnormalities and amyloid removal.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71749},
doi = {10.1002/alz.71749},
pmid = {42598748},
issn = {1552-5279},
support = {//F. Hoffmann-La Roche/ ; },
mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging/pathology ; *Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/pathology/drug effects ; Female ; Male ; Magnetic Resonance Imaging ; *Amyloid/metabolism ; White Matter/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: Amyloid-lowering antibodies are associated with neuroanatomical volume changes. This study aims to disentangle the contributions of amyloid-related imaging abnormalities (ARIA) and amyloid clearance to these changes.

METHODS: Data from the GRADUATE I and II trials of gantenerumab in early Alzheimer's disease were analyzed. Participants were grouped as placebo, gantenerumab-treated without ARIA, or gantenerumab-treated with ARIA.

RESULTS: Gantenerumab treatment was associated with greater parenchymal volume reduction than placebo, with no difference between ARIA and non-ARIA groups. The ARIA group exhibited greater ventricular enlargement which was offset by reduced external cerebrospinal fluid space expansion. Greater amyloid removal correlated with greater volume reduction, although volume changes also occurred in white matter, where amyloid is minimal. Furthermore, the ARIA group showed a flatter relationship between ventricular expansion and clinical decline.

DISCUSSION: ARIA are not associated with long-term parenchymal reduction; rather, they are linked to a fluid shift from the external space to the ventricles. Amyloid removal correlates with parenchymal changes, but white matter changes suggest additional mechanisms beyond local clearance. Neither phenomenon was associated with worse clinical outcomes.

TRIAL REGISTRATION NUMBER: NCT03444870 and NCT03443973.},
}

Humans
*Antibodies, Monoclonal, Humanized/therapeutic use
*Alzheimer Disease/drug therapy/diagnostic imaging/pathology
*Amyloid beta-Peptides/metabolism
*Brain/diagnostic imaging/pathology/drug effects
Female
Male
Magnetic Resonance Imaging
*Amyloid/metabolism
White Matter/pathology/diagnostic imaging

@article {pmid42598755,
year = {2026},
author = {Alexopoulos, H and Louka, XP and De Natale, ER and Koutroubi, K and Cashmore, L and Panayotacopoulou, MT and Trougakos, IP and Wilson, H and Politis, M},
title = {Regional astrocyte dysregulation and altered glymphatic-related markers in Alzheimer's disease frontal cortex.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71745},
doi = {10.1002/alz.71745},
pmid = {42598755},
issn = {1552-5279},
support = {//City Electrical Factors Ltd/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *Astrocytes/metabolism/pathology ; *Frontal Lobe/pathology/metabolism ; *Aquaporin 4/metabolism ; *Glial Fibrillary Acidic Protein/metabolism ; Female ; Male ; Aged ; Aged, 80 and over ; *Glymphatic System/metabolism/pathology ; White Matter/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Gray Matter/metabolism/pathology ; tau Proteins/metabolism ; },
abstract = {INTRODUCTION: Astrocyte dysfunction is central to Alzheimer's disease (AD), yet expression patterns of astrocytic markers remain poorly defined. We measured Aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) in post-mortem frontal cortex of AD patients and controls across BrainNet Europe (BNE) stages.

METHODS: We assessed marker expression across gray and white matter with immunohistochemistry and immunofluorescence.

RESULTS: In AD, gray-matter AQP4 area-fraction did not differ significantly overall by immunohistochemistry, while a stage-dependent increase emerged by BNE VI in both gray and white matter. AQP4/amyloid-β (Aβ) and AQP4/tau ratios were significantly reduced, consistent with reduced AQP4 retention relative to local proteinopathy burden. GFAP intensity was significantly decreased in both gray and white matter of AD patients, with disorganized peri-plaque morphology in gray matter.

DISCUSSION: These findings reveal compartment- and stage-specific astrocytic dysregulation in AD frontal cortex and identify local loss of AQP4 around proteinopathy. They support investigation of astrocyte/glymphatic-related pathways as biomarkers and therapeutic targets.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*Astrocytes/metabolism/pathology
*Frontal Lobe/pathology/metabolism
*Aquaporin 4/metabolism
*Glial Fibrillary Acidic Protein/metabolism
Female
Male
Aged
Aged, 80 and over
*Glymphatic System/metabolism/pathology
White Matter/metabolism/pathology
Amyloid beta-Peptides/metabolism
Biomarkers/metabolism
Gray Matter/metabolism/pathology
tau Proteins/metabolism

@article {pmid42585316,
year = {2026},
author = {Gallego-Rudolf, J and Wiesman, AI and Yakoub, Y and Zetterberg, H and Blennow, K and Baillet, S and Villeneuve, S and , },
title = {Prediction of mild cognitive impairment progression using time-sensitive multimodal biomarkers.},
journal = {Science advances},
volume = {12},
number = {33},
pages = {eaee2305},
pmid = {42585316},
issn = {2375-2548},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/blood/diagnostic imaging/metabolism ; *Biomarkers/blood ; Disease Progression ; Female ; Aged ; Male ; Alzheimer Disease/diagnosis ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; Magnetoencephalography ; },
abstract = {Alzheimer's disease (AD) develops silently for years before symptoms emerge, making early identification of at-risk individuals essential for prevention trials and early intervention. We tested whether combining neurophysiological, imaging, and blood biomarkers improves prediction of progression to mild cognitive impairment (MCI) in cognitively unimpaired older adults with a family history of AD (n = 102; 31 progressors; mean follow-up of 5.9 years). Magnetoencephalography, magnetic resonance imaging, plasma biomarkers, and amyloid and tau positron emission tomography each captured complementary aspects of disease biology. Multimodal models predicted progression more accurately than demographic and genetic factors alone. Higher MEG alpha power was associated with increased near-term risk, whereas higher gamma activity predicted lower near-term risk; both effects weakened over time. Higher neocortical amyloid burden predicted increasing risk over follow-up, whereas plasma biomarkers and entorhinal tau predicted higher risk without significant time-varying effects. These findings support a time-sensitive multimodal framework for identifying cognitively unimpaired individuals at risk of MCI due to AD.},
}

Humans
*Cognitive Dysfunction/diagnosis/blood/diagnostic imaging/metabolism
*Biomarkers/blood
Disease Progression
Female
Aged
Male
Alzheimer Disease/diagnosis
Positron-Emission Tomography
Magnetic Resonance Imaging
tau Proteins/metabolism
Magnetoencephalography

@article {pmid42585344,
year = {2026},
author = {Yuan, R and Liao, G and Su, S and Shan, J and Tang, S},
title = {Identification of B-cell senescence-related key genes and mechanisms in Alzheimer's disease through transcriptomic sequencing combined with Mendelian randomization analysis and experimental verification.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477008},
doi = {10.1177/13872877261477008},
pmid = {42585344},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Currently, no treatment method can treat AD completely successfully.ObjectiveThis work seeks to uncover new genetic signatures linking B-cell senescence to AD, elucidate the immune-related pathological mechanisms of AD.MethodsThe GSE85426 and GSE168813 for AD were obtained from public databases. Differential analysis of expression matrix in GSE85426 was conducted to screen differentially expressed genes (DEGs), WGCNA was explored to obtain B cell and cell senescence related hub genes. Then the key genes for AD were screened by intersection, Mendelian randomization (MR), receiver operating characteristic (ROC) curve, and Wilcoxon test. Additionally, enrichment analysis, immune infiltration analysis, and molecular docking were performed to investigate the molecular mechanism of key genes and drug targets related to key genes, respectively.ResultsIn this study, CCDC86 and PARP9 were identified as key genes, genetic association analysis suggested CCDC86 correlates with higher AD susceptibility while PARP9 tends to correlate with lowered AD risk. We also found that these two key genes were highly correlated with B cells, and the abundance of B cells in AD increased significantly. Finally, our calculation revealed that the binding free energy between PARP9 and bisphenol A was -7.6 kcal/mol, implying a favorable simulated binding tendency between the two molecules.ConclusionsThese findings suggest that PARP9 may serve as a promising and reliable drug target for clinical therapy, which may represent a tentative candidate worthy of further experimental validation for subsequent biomarker and therapeutic target research in AD.},
}

@article {pmid42585347,
year = {2026},
author = {Ferreira, LK and Westman, E and Wahlund, LO and Mohanty, R and , },
title = {Progression from mild cognitive impairment to dementia in Alzheimer's disease: Whole cortex voxelwise functional connectivity analysis with multivariate distance matrix regression.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477016},
doi = {10.1177/13872877261477016},
pmid = {42585347},
issn = {1875-8908},
abstract = {BackgroundDifferentiating individuals with mild cognitive impairment who convert to dementia due to Alzheimer's disease (MCI-C) from those who do not convert (MCI-NC) is increasingly important. Functional connectivity (FC) derived from resting state functional MRI (rs-fMRI) has been investigated as a potential biomarker. However, improved data analysis strategies are needed. One underexplored approach is pairwise voxel-to-voxel analysis.ObjectiveTo describe differences in FC between amyloid positive MCI-C and MCI-NC using a whole-cortex voxel-to-voxel pairwise approach.MethodsBaseline rs-fMRI from the Alzheimer's Disease Neuroimaging Initiative was retrieved for amyloid positive MCI participants. Voxel-to-voxel, pairwise, cortical FC was computed. Multivariate distance matrix regression was used to identify voxels presenting FC patterns that were significantly different between MCI-C and MCI-NC.Results21 MCI-C and 28 MCI-NC were included. The primary analysis with voxel-level threshold at p < 0.001 combined with cluster-level p < 0.05 yielded no significant results. At voxel-level p < 0.01 and the same cluster-level threshold, three significant clusters on the right visual cortex were found. These clusters, however, were not robust to head motion, fMRI protocol and additionally clinical or biological severity.ConclusionsProgression from Alzheimer-related MCI to dementia was not significantly associated with FC in the primary analysis. However, a less stringent threshold yielded FC differences in the occipital lobe in alignment with previous studies but were not robust to methodological and biological covariates between groups. Our findings highlight the need for larger samples and careful control of covariates to identify robust FC alterations related to dementia conversion.},
}

@article {pmid42585348,
year = {2026},
author = {Petrović, V and Reas, ET and Reimer, RA and Barha, CK},
title = {Role of previous parity in the relationship between lifetime physical activity and later life cognition: The Rancho Bernardo study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261477010},
doi = {10.1177/13872877261477010},
pmid = {42585348},
issn = {1875-8908},
abstract = {BackgroundParity history influences dementia risk and cognitive aging, and recent evidence suggests it may also influence the association between physical activity and cognition in later life.ObjectiveTo examine associations between total lifetime and life-stage-specific physical activity and later life cognition in postmenopausal females with differing parity histories.MethodsThis cross-sectional analysis using data from the Rancho Bernardo Study included 867 postmenopausal females with complete data, categorized into three parity groups (number of pregnancies >6-months): nulliparous, 1-2 pregnancies, and grand-multiparous (≥3 pregnancies). Cognitive outcomes included executive functions and memory. Physical activity was assessed using a self-report questionnaire capturing retrospective activity during adolescence, age 30, age 50, and current activity in later life. Covariates included age, education, health composite score, body mass index, and hysterectomy status. Linear models examined associations between physical activity and domain-specific later life cognitive outcomes stratified by parity.ResultsGreater total lifetime physical activity was associated with higher executive functions in nulliparous and grand-multiparous females. Moderate activity in nulliparous females and high activity in grand-multiparous females during adolescence and at age 30 were associated with higher executive functions. High physical activity at age 50 and currently was associated with higher executive functions in nulliparous females.ConclusionsThe findings suggest the relationship between self-reported physical activity and cognition was strongest in the two groups at greater risk for cognitive decline and Alzheimer's disease, the nulliparous and grand-multiparous groups. Further research is needed to understand the mechanisms driving parity differences.},
}

@article {pmid42585351,
year = {2026},
author = {Bubu, OM and Mbah, AK and Bernard, MA and Briggs, A and Faustin, A and Gurin, L and Rao, JA and Tall, SO and Osorio, RS and Masurkar, AV},
title = {Risk factors and cognitive domain markers of progression in subjective cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470393},
doi = {10.1177/13872877261470393},
pmid = {42585351},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) is increasingly recognized in some cases as an early clinical stage in the Alzheimer's disease continuum, yet the factors that predict which individuals will progress to objective impairment remain poorly understood.ObjectiveWe evaluated risk factor differences and cognitive domain markers associated with progression in participants with subjective cognitive decline (SCD) at baseline from the NYU Alzheimer's Disease Research Center.MethodsWe included SCD non-decliners (n = 27), who remained stable, and decliners (n = 24), who progressed to mild cognitive impairment or worse, between the second to sixth yearly follow-up visits. Adjusted mixed-effects models examined group differences and associations between demographic, APOE status, psychometric test performance and comorbidities with longitudinal-decline.ResultsOverall, mean (SD) age was 67.4 (9.2) and total follow-up time was 5.1 (1.8) years. Lower education (14.9 (3.2) versus 17.3 (2.1)), Hispanic ethnicity (50.0% versus 11.0%), and hypercholesterolemia (adjusted odds ratio: 6.67) were risk factors for progression in SCD, p ≤ 0.05, whereas APOE status was not. Notably, SCD decliners were at increased risk for both amnestic and non-amnestic cognitive-decline with psychometric changes in memory, executive, and language domains (p < 0.001 for all).ConclusionsThese findings inform further work on SCD outcomes and related biomarkers, as well as preventive studies that target modifiable risk factors for SCD progression.},
}

@article {pmid42585605,
year = {2026},
author = {Hazan, J and Salemme, S and Liu, KY and Howard, R},
title = {Blood-Based Biomarkers for Alzheimer Disease in Primary Care: The Gap Between Biology and Clinical Utility.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218403},
doi = {10.1212/WNL.0000000000218403},
pmid = {42585605},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; Primary Health Care ; },
abstract = {Blood-based biomarkers (BBMs) for Alzheimer disease (AD) have accelerated the prospect of earlier and more accessible detection of AD pathology, potentially beyond specialist settings. However, their introduction in primary care raises important questions about clinical sequencing, interpretability, pathway consequences, and real-world utility. In this Personal View, we argue that the main barrier to responsible implementation is not analytical performance alone, but the absence of a sufficiently defined diagnostic infrastructure in which a test result has a clear and actionable role. In low-prevalence and clinically heterogeneous primary care populations, inadequate clinical anchoring and unstable pretest probability may undermine interpretability and promote category drift from diagnostic testing towards case-finding or quasiscreening. Moreover, the value of a rule-out strategy depends on whether a negative result meaningfully changes management. Until stronger evidence, clearer guidance, and appropriate service conditions are in place, primary care use of AD BBMs should remain selective, clinically anchored, and pathway-dependent.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
Primary Health Care

@article {pmid42585606,
year = {2026},
author = {Bruno, J and Shaw, JS and Hosseini, SMH and , },
title = {Association Between Menopausal Hormone Therapy and Alzheimer Disease Neuropathology.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218413},
doi = {10.1212/WNL.0000000000218413},
pmid = {42585606},
issn = {1526-632X},
mesh = {Humans ; Female ; *Alzheimer Disease/pathology/diagnostic imaging ; *Estrogen Replacement Therapy/adverse effects ; Aged, 80 and over ; Aged ; Cohort Studies ; *Brain/pathology/diagnostic imaging/drug effects ; Middle Aged ; *Menopause/drug effects ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; },
abstract = {BACKGROUND AND OBJECTIVES: Although evidence suggests that the neurophysiologic impact of estrogen decline during menopause may contribute to increased risk of Alzheimer disease (AD) in women, the effect of menopausal hormonal therapy (MHT) on AD risk requires further study. We sought to examine the associations between MHT use and neuropathologic, clinical, and imaging/fluid biomarker outcomes.

METHODS: In this cohort study, we tested the association between estrogen-only MHT use and dementia outcomes in female participants using 2 independent, large-scale data sets: National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants included women 50 years and older with self-reported use of estrogen-only MHT or no self-reported use of MHT. Clinical, imaging/fluid biomarker, and neuropathologic outcomes were examined. Research was performed at academic medical centers.

RESULTS: Neuropathologic data were collected from NACC for 258 MHT users (mean age of death = 81.9, SD = 19.5) and 2,701 non-MHT users (mean age of death = 82.2, SD = 11.0). The ADNI cohort included 110 MHT users (mean age = 76.5, SD = 7.5) and 1,948 non-MHT users (mean age = 73.2, SD = 8.9). The odds of increased AD pathology on autopsy (primary outcome) were significantly decreased in MHT users relative to nonusers (odds ratio [OR] 0.65, 95% CI 0.48-0.88, p = 0.005). MHT use was associated with secondary outcomes including significantly decreased amyloid pathologic load assessed through plasma (β = 0.44, 95% CI 0.16-0.73, p = 0.0025) and CSF (β = 0.07, 95% CI 0.002-0.13, p = 0.030). MHT use was associated with significantly lower odds of clinical dementia diagnoses (OR 0.61, 95% CI 0.55-0.67, p < 0.0001) and lower odds of symptoms of memory/functional decline (OR 0.67, 95% CI 0.61-0.74, p < 0.0001).

DISCUSSION: Our findings demonstrate small but significant associations between MHT use during later life and a range of AD-related neuropathologic and clinical outcomes in 2 large cohorts of female participants. Although our results do not address causality and have limited generalizability due to the retrospective nature of the study, they suggest a protective effect of MHT use in the dementia course.},
}

Humans
Female
*Alzheimer Disease/pathology/diagnostic imaging
*Estrogen Replacement Therapy/adverse effects
Aged, 80 and over
Aged
Cohort Studies
*Brain/pathology/diagnostic imaging/drug effects
Middle Aged
*Menopause/drug effects
Biomarkers/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid

@article {pmid42585609,
year = {2026},
author = {Salemme, S},
title = {Menopausal Hormone Therapy and Alzheimer Disease: When, Which, and for Whom?.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218503},
doi = {10.1212/WNL.0000000000218503},
pmid = {42585609},
issn = {1526-632X},
}

@article {pmid42585730,
year = {2026},
author = {Shu, K and Li, J and Zhang, R and Cheng, N and Yang, P and Song, X and Lei, B},
title = {From voxel discovery to regional interaction: A multi-level interpretable framework for Alzheimer's disease diagnosis.},
journal = {Medical image analysis},
volume = {114},
number = {},
pages = {104243},
doi = {10.1016/j.media.2026.104243},
pmid = {42585730},
issn = {1361-8423},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder where early diagnosis serves as the only viable window for effective intervention. While Structural MRI (sMRI) is a primary clinical tool for this purpose, manual diagnosis is heavily constrained by clinician expertise and the difficulty of visually quantifying subtle, diffuse anatomical changes. Deep learning has emerged as a powerful solution to capture these complex patterns. However, the inherent black-box opacity of current models creates a trust deficit that severely impedes their clinical adoption. Furthermore, existing interpretability methods predominantly rely on post-hoc visualizations, which frequently suffer from significant background leakage and lack anatomical coherence. To overcome these barriers, we propose a novel multi-level interpretable framework that inherently integrates diagnostic reasoning into the model architecture. The framework operates through a progressive three-stage trajectory to bridge the gap between pixel-level signals and global pathology. First, to eliminate the ambiguity caused by background leakage, we introduce a voxel discovery module implemented via Hierarchical Evidential Masking (HiEM). By leveraging this iterative optimization strategy, the model actively filters out irrelevant background signals to autonomously discover AD-relevant voxel sets. Subsequently, to bridge the semantic gap between discrete voxels and clinical anatomy, these discovered signals are dynamically aggregated into coherent semantic regions. Finally, recognizing that AD pathology propagates through brain networks, we explicitly model the regional interaction among these defined areas using Graph Attention Network (GAT). This voxel-region-network progression allows the model to transparently zoom out from local cues to global interactions. Validated on the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Australian Imaging, Biomarkers and Lifestyle Study (AIBL) datasets, our method achieves performance comparable to state-of-the-art black-box models while autonomously reconstructing established neuropathological trajectories. Crucially, by extracting high-fidelity pathological signals, it offers a trustworthy tool for precise disease diagnosis and potentially serves as a digital biomarker discovery instrument for localizing subtle prodromal lesions. The source code is publicly available at: https://github.com/k-Jayus/HiEM.},
}

@article {pmid42585761,
year = {2026},
author = {Juanlu, C and Chen, LH},
title = {Pharmacological targeting of neuroimmune-synaptic interactions in Alzheimer's disease: Integrating NETosis, microglia, and synaptic vulnerability.},
journal = {Current opinion in pharmacology},
volume = {90},
number = {},
pages = {102650},
doi = {10.1016/j.coph.2026.102650},
pmid = {42585761},
issn = {1471-4973},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder involving interacting neuroimmune, glial, vascular, and synaptic processes that are not fully captured by single-pathway therapeutic models. Although anti-amyloid monoclonal antibodies slow clinical progression in selected early amyloid-positive patients, their benefit remains stage-dependent, monitoring-intensive, and incomplete with respect to downstream neural dysfunction. Clinically, vulnerable older adults may show abrupt cognitive decline after pneumonia-related hospitalization or other severe infections. This observation raises a pharmacological question: whether infection-triggered peripheral immune events activate modifiable risk processes before they become sustained neuroimmune and synaptic dysfunction. NETosis is one candidate mechanism linking peripheral inflammatory stress to endothelial injury, blood-brain barrier vulnerability, myeloid priming, and microglial dysregulation. Acute infection may represent a high-intensity peripheral NETosis-related trigger, whereas periodontitis provides a chronic, low-grade, neutrophil-rich, microbially driven, clinically measurable, and modifiable peripheral inflammatory model. We propose a node-based pharmacological framework organized around NETosis-associated immune amplification, microglial state dysregulation, and synaptic vulnerability. Selected phytochemicals are examined as node-aligned pharmacological probes rather than validated AD therapeutics: baicalin and hesperidin for NETosis-associated immune amplification, berberine for microglial state modulation, and catalpol as a synapse-proximal candidate.},
}

@article {pmid42585804,
year = {2026},
author = {Sun, J and Yu, M and Li, H and Ma, L},
title = {Edaravone dexborneol alleviates neuronal senescence injury by mitigating the innate immune response.},
journal = {Tissue & cell},
volume = {104},
number = {Pt 1},
pages = {103821},
doi = {10.1016/j.tice.2026.103821},
pmid = {42585804},
issn = {1532-3072},
abstract = {Aging is a key risk factor for neurodegenerative diseases, contributing to progressive neuronal damage and closely linked to the onset and progression of conditions like Alzheimer's and Parkinson's diseases. However, the effect of edaravone dexborneol (EDB) on neuronal senescence remains unclear, which is an urgent scientific question to be addressed. In this study, we established models of neuronal senescence induced by oxidative stress and OGD/R. EDB treatment partially restored the proliferation inhibition of senescent cells. EDB treatment significantly decreased senescence markers, as indicated by reduced senescence-associated β-galactosidase staining and lower p16 and p21 protein expression. Subsequent research demonstrated that EDB improved mitochondrial membrane potential and replenished intracellular ATP levels. In the OGD/R-induced neuronal injury model, EDB treatment notably decreased the expression of senescence markers (p16/p21/p53). Mechanistic studies revealed that EDB not only alleviated oxidative stress but also inhibited the cGAS-STING-mediated innate immune signaling pathway. This study is the first to demonstrate that EDB mitigates mitochondrial damage to exert anti-neuronal senescence effects, offering a novel intervention strategy for aging-related neurodegenerative diseases.},
}

@article {pmid42585890,
year = {2026},
author = {Şenol, H and Demir, Y and Tokalı, P and Şenol, AM and Akyıldırım, O and Tokalı, FS},
title = {Development of novel diaryl ether-phenolic Mannich Base derivatives with potent cholinesterase inhibition and low neuronal toxicity.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110354},
doi = {10.1016/j.bioorg.2026.110354},
pmid = {42585890},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cholinergic dysfunction, making acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) attractive therapeutic targets. In the present study, twelve novel phenolic Mannich base-derived hydrazones incorporating a diaryl ether scaffold were rationally designed, synthesized, and evaluated as cholinesterase inhibitors. All synthesized compounds exhibited potent nanomolar inhibition against both cholinesterases, with Ki values ranging from 24.27 to 98.56 nM for AChE and 28.68-148.41 nM for BChE. Compound 5 was identified as the most potent AChE inhibitor (Ki = 24.27 nM), whereas compound 6 showed the highest BChE inhibitory activity (Ki = 28.68 nM). Both compounds were considerably more potent than the reference inhibitors tacrine and donepezil. Enzyme kinetic studies revealed that all compounds acted as competitive inhibitors. Cytotoxicity evaluation against SH-SY5Y neuronal cells demonstrated low toxicity, with IC50 values ranging from 33.41 to 46.79 μM, indicating that effective cholinesterase inhibition occurred at concentrations far below those affecting neuronal cell viability. Molecular docking and MD simulations demonstrated stable binding of the most active compounds within the catalytic gorge of both enzymes through persistent hydrogen bonds, cation-π, and π-π interactions with key active-site residues. MM-GBSA and energy decomposition analyses further supported their favorable binding affinities. In addition, the synthesized compounds exhibited acceptable predicted pharmacokinetic properties, including favorable parameters related to blood-brain barrier permeability and oral absorption. These results identify phenolic Mannich base-derived hydrazones as promising lead compounds for the development of new cholinesterase inhibitors for the treatment of Alzheimer's disease.},
}

@article {pmid42586144,
year = {2026},
author = {Liu, X and Zhang, M and Wang, R and Sun, L and Hou, S},
title = {MDEEG-IMPA: Integrating multidimensional EEG features with an improved MPA for high-precision diagnosis neurodegenerative disease.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae98ba},
pmid = {42586144},
issn = {1741-2552},
abstract = {OBJECTIVE: Current clinical differentiation of Alzheimer's disease (AD) and frontotemporal dementia (FTD) suffers from a misdiagnosis rate exceeding 40% due to overlapping symptomatology, and existing Electroencephalography (EEG)-based tools inadequately integrate multidimensional features or lack adaptive optimization. We aimed to develop a framework combining periodic and aperiodic EEG features with adaptive optimization for high-precision differential diagnosis.

APPROACH: We proposed a dual-branch neural network integrating multi-dimensional electroencephalogram (MDEEG) features with an improved Marine Predator Algorithm (IMPA). The MDEEG-IMPA model combines Convolutional Neural Network (CNN)-based power spectral density (PSD) feature extraction with a fully connected branch for aperiodic parameters (1/f offset and exponent), enhanced by IMPA for adaptive feature weighting. The model was evaluated on resting-state EEG from 88 subjects (36 AD, 23 FTD, 29 healthy controls (HC)).

MAIN RESULTS: MDEEG-IMPA achieved 99.20% accuracy in discriminating AD from FTD (Recall = 98.82%, F1-score = 99.02%), substantially outperforming comparative methods including STEADYNnet (84.59%) and SVM (93.5%). The MDEEG-IMPA model demonstrated robust performance in discriminating between AD and HC (Accuracy = 98.11%) and between FTD and HC (Accuracy = 98.95%). Ablation studies confirmed that 96.3% of the improvement in performance originated from the synergy between features and algorithms.

SIGNIFICANCE: The MDEEG-IMPA framework provides a reliable, high-precision computer-assisted diagnostic solution for neurodegenerative diseases with overlapping clinical presentations. By integrating periodic and aperiodic EEG features within an optimized multi-branch architecture, this work demonstrates that multidimensional electrophysiological characterization combined with adaptive optimization can substantially improve differential diagnostic accuracy, offering significant potential for clinical translation in early and accurate identification of AD and FTD.},
}

@article {pmid42586245,
year = {2026},
author = {Rathore, S and Gupta, A and Shah, K and Chauhan, NS and Gupta, SK},
title = {Targeting the Hallmarks of Ageing: Pharmacological Challenges and Breakthroughs in CRISPR Delivery Systems and Future Prospects.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103301},
doi = {10.1016/j.arr.2026.103301},
pmid = {42586245},
issn = {1872-9649},
abstract = {CRISPR has emerged as a next-generation gene-editing tool with the potential to target the molecular pathways associated with ageing and related disorders. It functions through RNA-guided Cas nucleases, directing DNA cleavage and utilizing the native DNA repair machinery for genetic manipulations. Advances in CRISPR technology have significantly enhanced the precision and flexibility of techniques for genome editing. The enzyme Cas9's ability to cut DNA at exact site has revolutionized genome editing by enabling accurate modifications within living eukaryotic cells. This review critically examines recent developments in CRISPR-based technologies, including Cas9, Cas12, base editing, prime editing, and CRISPR-mediated gene regulation. It highlights their rising applications in ageing research, with more emphasis on neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The review also discusses the major pharmacological and translational challenges that currently limit clinical applications, including inefficient tissue-specific delivery, off-target genome editing, immunogenicity, manufacturing complexity, and long-term safety concerns. Also, recent progress in both, viral and non-viral delivery methods are critically evaluated, including adeno-associated viruses, lentivirus vectors, lipid nanoparticles, gold nanoparticles, exosomes, electroporation, and microinjection, is thoroughly discussed to highlight their therapeutic potential and translational limitations. Current studies indicate that CRISPR-based approaches have preclinical potential for targeting important hallmarks of ageing, particularly genomic instability, telomere attrition, and mitochondrial dysfunction. Other hallmarks of ageing, such as stem cell exhaustion, epigenetic modifications, and microbiome changes, are at earlier stages of development. Overall, this review describes future strategies for developing safe, precise, and clinically translatable CRISPR-based treatments to promote healthy ageing.},
}

@article {pmid42586290,
year = {2026},
author = {Zhang, C and Cheng, C and Wang, L and Zhang, H and Yu, Y and Zhang, J and Zhang, J},
title = {Bibliometric analysis in the field of photobiomodulation in the last two decades: research trends and evolution of hot topics.},
journal = {Photodiagnosis and photodynamic therapy},
volume = {},
number = {},
pages = {105610},
doi = {10.1016/j.pdpdt.2026.105610},
pmid = {42586290},
issn = {1873-1597},
abstract = {BACKGROUND: Photobiomodulation (PBM) has evolved into a vibrant interdisciplinary field. Despite rapid research expansion, a comprehensive quantitative mapping of its knowledge structure, key contributors, and emerging trends remains lacking.

METHODS: We conducted a bibliometric analysis of PBM publications from the Web of Science Core Collection (2006-2025). Knowledge mapping utilized CiteSpace, VOSviewer, and the bibliometrix R package. Additionally, PubMed clinical trial data were extracted to cross-validate bibliometric trends with actual clinical practice.

RESULTS: We identified 4,907 publications, exhibiting a compound annual growth rate of 14.67%. Michael R. Hamblin was the most prolific author (n=100, h-index=54), and Lasers in Medical Science was the core journal (n=1,180). Brazil dominated global output (32.2%, n=1,579), led by the University of São Paulo (n=821). Thematic analysis highlighted "photobiomodulation" and "low-level laser therapy" as fundamental themes, while "Alzheimer's disease" emerged as a specialized, rapidly growing niche.

CONCLUSIONS: Over two decades, PBM has matured into a promising mainstream therapeutic modality. Future research must prioritize the standardization of treatment parameters, alongside deeper exploration of biological mechanisms and long-term clinical validation. This 20-year mapping provides a strategic roadmap to guide evidence-based PBM practice.},
}

@article {pmid42586342,
year = {2026},
author = {Kim, HJ and Kim, DH and Han, CW and Jeong, MS and Jang, SB},
title = {Structural basis of α-synuclein and DJ-1 complex.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154021},
doi = {10.1016/j.ijbiomac.2026.154021},
pmid = {42586342},
issn = {1879-0003},
abstract = {The structure of α-synuclein is predominantly α-helical when bound to cellular membranes. However, under pathological or destabilizing conditions, this α-helical structure transitions into β-sheet-rich conformations, promoting protein aggregation and formation of Lewy bodies (LBs) in neurodegenerative disorders such as Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and Alzheimer's disease (AD). DJ-1 is a multifunctional brain protein acting as a chaperone or protease under oxidative stress and associating with abnormal protein aggregates. Although previous studies suggested DJ-1 inhibits α-synuclein aggregation, the structural basis remained elusive. Here, we elucidate the direct interaction between α-synuclein and DJ-1 using size-exclusion chromatography (SEC), fluorescence spectroscopy, and multi-angle light scattering (MALS), and determined their crystal structure by X-ray diffraction. The interaction interface was mapped to residues Q24, E28, A29, and N65 of α-synuclein and K148, N173, and Q180 of DJ-1, with Q180 forming strong hydrogen bonds (2.60-2.97 Å) with α-synuclein. Transmission electron microscopy (TEM) demonstrated DJ-1 suppresses α-synuclein fibril formation. Based on the structure, we designed a DJ-1-derived peptide (173-180) that significantly inhibited α-synuclein aggregation in TEM and ELISA assays, suggesting its potential as a therapeutic candidate for α-synucleinopathies.},
}

@article {pmid42586403,
year = {2026},
author = {Faieta, JM and Devos, H and Philippou, E and Negm, A and Vaduvathiriyan, P and Erickson, KI and Hirsch, MA and van Wegen, EEH and Fakorede, S and Dagne, MB and Wong, KLY and Krishnan, S and Kahya, M and Sood, P and Heyn, PC},
title = {Exercise Interventions for Older Adults with Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Archives of physical medicine and rehabilitation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.apmr.2026.08.001},
pmid = {42586403},
issn = {1532-821X},
abstract = {OBJECTIVE: Increased Alzheimer's disease (AD) prevalence paired with improved ability to diagnose the disease at earlier stages now, more than ever, necessitates interventions that will support the AD population for extended periods of time. Even with the substantial body of literature available, the effectiveness of physical exercise (PE) on various cognitive domains and the optimal dosage of PE are yet to be confirmed. Therefore, our objectives were to determine 1) the effectiveness of PE on cognitive function in older adults with AD, and 2) the optimal PE dosage for targeted outcomes.

DATA SOURCES: The search was carried out across Embase, PsycInfo, and Ovid Medline databases.

STUDY SELECTION: Of an initial return of 1,001 articles, 142 remained after title and abstract review, and 21 after full text review.

DATA EXTRACTION: Primary outcomes extracted from included articles spanned four cognitive domain outcomes (global cognition, memory, language, attention, and executive function). Data on secondary outcomes included activities of daily living, emotional well-being, quality of life, and caregiver burden.

DATA SYNTHESIS: The 21 included studies were published between 1991 and 2020 and sample sizes ranged from 12 to 494. Results confirm significant improvement in 4 of 5 cognitive domains favoring PE versus control conditions. Similarly, results favored exercise over control conditions for activities of daily living, emotional well-being, and quality of life outcomes, but not caregiver burden. The optimal PE dose was determined to be less than 60 minutes at least 3 times per week as compared to fewer more intense bouts.

CONCLUSIONS: The results of this systematic review and meta-analysis provide important insight into the effectiveness of exercise on cognitive outcomes and guidance on the most effective PE parameters for optimizing cognitive function in AD.},
}

@article {pmid42586624,
year = {2026},
author = {},
title = {Expression of Concern: "Pharmacological activation of the Nrf2 pathway by 3H-1, 2-dithiole-3-thione is neuroprotective in a mouse model of Alzheimer disease'' [BBR, 336 (2018) pp 219-226].},
journal = {Behavioural brain research},
volume = {514},
number = {},
pages = {116388},
doi = {10.1016/j.bbr.2026.116388},
pmid = {42586624},
issn = {1872-7549},
}

@article {pmid42586939,
year = {2026},
author = {Sheng, S},
title = {Gait Disturbances and Alzheimer's Disease Pathology: Unresolved Causal-Temporal Ambiguities and Methodological Considerations for the Proposed Mechanistic Framework.},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {8},
pages = {e70799},
doi = {10.1111/ggi.70799},
pmid = {42586939},
issn = {1447-0594},
}

@article {pmid42587009,
year = {2026},
author = {Barnett, EJ and Hess, JL and Hou, J and Escott-Price, V and Fennema-Notestine, C and Kremen, W and Lin, SJ and Zhang, C and Demontis, D and Børglum, AD and Gaiteri, C and Elman, J and Holmans, P and Faraone, SV and Glatt, SJ},
title = {A novel method to disentangle tightly linked risk and resilience genes for brain disorders: application to Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42587009},
issn = {1476-5578},
abstract = {Genetic risk factors for neuropsychiatric disorders are well documented. However, some individuals with high genetic risk remain unaffected, and the mechanisms underlying such resilience remain poorly understood. The presence of protective resilience factors that mitigate risk could help explain the disconnect between predicted risk and reality, particularly when genetic contributions are substantial but incompletely understood. Identifying and studying resilience factors could improve our understanding of pathology, enhance risk prediction, and inform preventive measures or treatment strategies. However, such efforts are complicated by the difficulty of identifying resilience that is separable from low risk. We developed a novel adversarial multi-task neural network model to detect genetic resilience markers. The model learns to separate high-risk unaffected individuals from affected individuals at similar risk while "unlearning" patterns found in low-risk groups using adversarial learning. In simulated and existing Alzheimer's disease (AD) datasets, we identified markers of resilience with a feature-importance-based approach that prioritized specificity, generated resilience scores, and analyzed associations with polygenic risk scores (PRS). In simulations, our model had high specificity and sensitivity in identifying resilience markers, significantly outperforming traditional approaches. Applied to AD data, the model generated genetic resilience scores protective against AD and independent of PRS. We identified five resilience-associated SNPs, including known AD-associated variants, underscoring their potential involvement in resilience. Our findings support the utility of resilience scores in modifying risk predictions, particularly for high-risk groups. Expanding this method could aid in understanding resilience mechanisms, potentially improving diagnosis, prevention, and treatment strategies for AD and other brain disorders.},
}

@article {pmid42587122,
year = {2026},
author = {Dolgin, E},
title = {A controversial Alzheimer's surgery is said to reverse symptoms - here's what scientists know.},
journal = {Nature},
volume = {656},
number = {8127},
pages = {286-289},
pmid = {42587122},
issn = {1476-4687},
}

@article {pmid42587138,
year = {2026},
author = {Feng, X and Jiang, BW and Zhai, SN and Liu, CX and Wu, H and Zhu, BQ and Wei, MY and Wei, J and Yang, L and Chen, LL},
title = {Author Correction: Circular RNA aptamers targeting neuroinflammation ameliorate Alzheimer disease phenotypes in mouse models.},
journal = {Nature biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41587-026-03281-3},
pmid = {42587138},
issn = {1546-1696},
}

@article {pmid42587229,
year = {2026},
author = {Sahu, S and Chidamabaram, H and Ananthanarayanan, V and Qureshi, T and Desale, S and Chandrashekar, M and Santhoshkumar, R and Mishra, M and Chinnathambi, S},
title = {Oral Administration of Different Forms of Exogenous Tau Protein Induces Multi-Organ Defects Across Developmental Stages in Drosophila melanogaster.},
journal = {Neurotoxicity research},
volume = {44},
number = {4},
pages = {},
pmid = {42587229},
issn = {1476-3524},
mesh = {Animals ; *tau Proteins/administration & dosage/toxicity ; Drosophila melanogaster ; Larva/drug effects ; Administration, Oral ; *Drosophila Proteins/administration & dosage ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Pupa/drug effects ; },
abstract = {Tau is a crucial protein involved in many neurodegenerative diseases, including Alzheimer's disease. Natively, Tau is an unfolded protein found predominantly in axons that play a vital role in maintaining and stabilizing microtubules. Under pathological circumstances, Tau disengages from microtubules and forms insoluble intracellular filaments on its own, building neurofibrillary tangles in the brains of Alzheimer's patients. Although Tau exists in aggregates found in the brain and gut of Alzheimer's patients, the function of Tau in the brain is well studied, while the role of Tau in the gut needs further investigation. We have investigated the effects of Tau monomer, oligomer, and aggregates at 10 µM concentration via feeding them to the third instar larvae. To evaluate the genotoxicity, we did 4', 6-diamidino-2-phenylindole staining, while dichloro-dihydro-fluorescein diacetate staining was performed to assess cytotoxicity. Furthermore, we performed a TUNEL assay to detect apoptotic cells. Additionally, we carry out an NBT assay for biochemical estimation of reactive oxygen species by extracting hemolymph. Phenotypes were examined in different stages, i.e., larvae, pupae, and adult flies. Histological studies were performed on eye, gut tissue and reproductive organs of D. melanogaster to check the cytoskeletal alterations. The current study finds that the administration of monomer, oligomer, and aggregate forms causes genotoxicity, cytotoxicity, and cytoskeletal defects in D. melanogaster.},
}

Animals
*tau Proteins/administration & dosage/toxicity
Drosophila melanogaster
Larva/drug effects
Administration, Oral
*Drosophila Proteins/administration & dosage
Apoptosis/drug effects
Reactive Oxygen Species/metabolism
Pupa/drug effects

@article {pmid42587260,
year = {2026},
author = {Musaeus, CS and Hasselbalch, SG and Waldemar, G and Sellebjerg, F and Budtz-Jørgensen, E and Simonsen, AH},
title = {Cerebrospinal fluid/plasma albumin quotient in dementia: a systematic review of biomarker potential and clinical associations.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42587260},
issn = {2509-2723},
abstract = {The blood-cerebrospinal fluid barrier (BCB) maintains central nervous system homeostasis. Its dysfunction, reflected by an increased cerebrospinal fluid/plasma albumin ratio (Q-Alb), has been reported in several neurodegenerative diseases. However, the diagnostic utility of Q-Alb in dementia remains uncertain. This review aimed to systematically evaluate Q-Alb as a biomarker in dementia by examining inter-group differences, diagnostic performance, and associations with other biomarkers. To address this questions, PubMed was searched for observational and longitudinal studies reporting Q-Alb in patients with dementia and healthy controls (HC). Data on Q-Alb levels, diagnostic accuracy, and biomarker associations were extracted. Meta-analyses were performed for Alzheimer's disease (AD) and vascular dementia (VaD). The search identified forty-three studies, spanning AD, VaD, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Q-Alb was significantly higher in VaD compared with HC (pooled standardized mean difference 0.69, 95% CI: 0.53-0.86) and moderately increased in AD compared with HC (0.25, 95% CI: 0.14-0.36). Only two studies directly investigated the diagnostic accuracy. Q-Alb correlated positively with IgG index, neurofilament light chain, and vascular and inflammatory markers. Taken together, these findings suggest that Q-Alb is not a reliable standalone diagnostic biomarker, particularly for AD, but is consistently elevated in VaD and disorders with subcortical or vascular pathology. Findings support its role as a supportive marker of blood-cerebrospinal fluid barrier dysfunction. Further large, multimodal studies integrating vascular imaging are warranted to clarify its diagnostic and prognostic utility.},
}

@article {pmid42587262,
year = {2026},
author = {Martínez-Flores, R and Zapata, LP and Del Campo Milan, M and Blasco-Forniés, H and Jiménez-Moyano, E and Torres-Torronteras, J and Suárez-Calvet, M and Ibáñez, A and Martín-Sobrino, I and Falgàs, N and Grau-Rivera, O and Cristi-Montero, C and Perone, C and Supèr, H},
title = {Attentionally directed oculomotor training produces disease-stage-dependent effects on plasma tau, cognition, and oculomotor signatures in patients with mild cognitive impairment.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42587262},
issn = {2509-2723},
support = {PID2022-139968OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; },
abstract = {Attentionally directed oculomotor training may engage circuits implicated in gamma-band modulation and early Alzheimer's disease (AD) pathophysiology, yet its effects across mild cognitive impairment (MCI) risk strata remain unclear. We aimed to determine whether this training, delivered through a gamified eye-tracking task, is associated with differential effects on plasma neurodegeneration biomarkers, cognitive performance, and oculomotor signatures in individuals with MCI at differential risk of conversion to Alzheimer's dementia. Twenty-nine participants with MCI were stratified into MCI-HR (n = 17) and MCI-LR (n = 12) based on validated MoCA and MoCA-MIS cut-off scores and completed 8 weeks of daily oculomotor training. Outcomes were assessed pre/post using permutation tests, bootstrapped Hedges' g, and linear mixed-effects models. Cognitive performance improved in both groups (MoCA: g = 1.27-2.17; MoCA-MIS: g = 1.02-1.68), with no between-group difference. Plasma tau diverged by stratum: MCI-LR showed reductions in pTau-181 (g = -0.64, 95% CI [-1.07, -0.15]) and pTau-217 (g = -0.72, 95% CI [-1.08, -0.36]), whereas MCI-HR showed an increase in pTau-181 (g = 0.82, 95% CI [0.53, 1.16]; between-group g = 1.31, 95% CI [0.89, 1.78], p = 0.001). Amyloid, GFAP, and NfL remained stable. MCI-HR showed reduced accuracy and increased reaction times (+196.4 ms, p < 0.001); MCI-LR maintained stable performance. Oculomotor signatures diverged between strata post-training (group × time × stimulus interactions, p = 0.013-0.045). In MCI-LR, oculomotor changes correlated with reductions in pTau-181 (ρ = -0.60, 95% CI [-0.96, -0.20]) and pTau-217 (ρ = -0.69, 95% CI [-0.95, -0.20]). Oculomotor training produced stratum-dependent responses: biomarker reductions and oculomotor-molecular coupling in MCI-LR, and dissociated physiological and behavioral outcomes in MCI-HR, suggesting disease-stage-specific neuroplasticity capacity linked to tau-related processes.},
}

@article {pmid42587389,
year = {2026},
author = {Grant, RA and Doser, RL and LaRocca, TJ},
title = {Distinct Transposable Element Transcript Patterns in Microglia Across Aging and Alzheimer's Disease.},
journal = {Aging cell},
volume = {25},
number = {8},
pages = {e70653},
doi = {10.1111/acel.70653},
pmid = {42587389},
issn = {1474-9726},
support = {AG078859/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/genetics/pathology/metabolism ; *Microglia/metabolism/pathology ; Humans ; Animals ; *Aging/genetics ; Mice ; *DNA Transposable Elements/genetics ; Aged, 80 and over ; Mice, Transgenic ; Female ; },
abstract = {Microglia, the brain's resident immune cells, are transcriptionally diverse and highly dynamic, but during aging and disease they lose their transcriptomic flexibility and adopt a chronically activated state that is associated with neuroinflammation and pathology. An emerging transcriptomic process that is also increasingly implicated in brain aging, neuroinflammation, and disease is the dysregulation of transposable elements (TEs), repetitive genomic sequences with the potential to cause cellular stress/dysfunction. However, there are limited data on microglial TE transcript patterns in these contexts. Here, we analyzed multiple RNA-seq datasets from isolated human and mouse microglia across aging, Alzheimer's disease (AD), and AD-associated pathology. In contrast to previous observations based on whole-brain tissue and other brain cell types, we found that microglial TE transcript levels remained relatively consistent throughout most of the human lifespan before increasing in late life. We also found that TE transcript levels in microglia from AD patients showed minimal changes compared to age-matched controls, and in RNA-seq analyses of transgenic AD mouse models we observed pathology-associated TE transcript decreases. Subsequent analyses identified inverse associations between TE transcript levels and autophagy/lysosome-related gene expression, and in vitro studies suggested that aging- and AD-relevant stimuli, as well as pharmacological autophagy inhibition, modulate TE transcript expression in cultured human microglia. Together, these data provide novel insight into TE transcript dynamics in microglia, highlighting TE transcript patterns that differ from those observed in whole-brain samples and other cell types in aging and AD.},
}

*Alzheimer Disease/genetics/pathology/metabolism
*Microglia/metabolism/pathology
Humans
Animals
*Aging/genetics
Mice
*DNA Transposable Elements/genetics
Aged, 80 and over
Mice, Transgenic
Female