@article {pmid42847312,
year = {2026},
author = {Leppänen, L and Lehtonen, A and Aaltonen, M and Aho, K and Kivisild, A and Ullgren, A and Rinnankoski, I and Soppela, H and Haapasalo, A and Portaankorva, AM and Hartikainen, P and Katisko, K and Solje, E and Krüger, J},
title = {Comorbidities and health-care use prior to early-onset Alzheimer's disease: A population-based case-control study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71831},
pmid = {42847312},
issn = {1552-5279},
support = {//The Finnish Medical Foundation/ ; //Finnish Alzheimer's Disease Research Society/ ; //Finnish Brain Foundation/ ; //The Swedish Dementia Foundation/ ; //The Foundation for Geriatric Diseases at Karolinska Institutet/ ; //Uulo Arhio Foundation/ ; 360445//The Research Council of Finland/ ; 360451//The Research Council of Finland/ ; //Wihuri Foundation/ ; //Jane and Aatos Erkko Foundation/ ; //The State Research Funding/ ; //The Finnish Cultural Foundation/ ; //Päivikki & Sakari Sohlberg Foundation/ ; //Sigrid Juselius Foundation/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/epidemiology/diagnosis ; Male ; Case-Control Studies ; Comorbidity ; Finland/epidemiology ; Aged ; Age of Onset ; Aged, 80 and over ; Prevalence ; Middle Aged ; },
abstract = {INTRODUCTION: We examined whether comorbidities and health-care use differ between individuals later diagnosed with early-onset Alzheimer's disease (EOAD) and matched controls during the 15 years preceding diagnosis.

METHODS: This population-based case-control study included 407 EOAD patients diagnosed at two Finnish university hospitals (2010-2021), and 4035 age- and sex-matched controls. Prior diagnoses and health-care visits were obtained from nationwide registers.

RESULTS: EOAD patients had higher prevalence of vertigo (5.9% vs. 2.1%, p < 0.001), depression (5.7% vs. 2.3%, p < 0.001), headache (4.9% vs. 1.6%, p < 0.001), delirium (1.5% vs. 0.1%, p < 0.001), brain injuries (2.9% vs. 0.9%, p = 0.002), thyroid disorders (2.5% vs. 0.8%, p = 0.008), alcohol-related disorders (3.4% vs. 1.4%, p = 0.009), epilepsy (2.2% vs. 0.7%, p = 0.009), strokes (4.4% vs. 2.0%, p = 0.008), and otorhinolaryngologic diseases (5.2% vs. 2.9%, p = 0.027) 1-5 years before diagnosis. Only otorhinolaryngologic diseases (4.7% vs. 2.1%, p = 0.036) differed 6 to 10 years prior, whereas no differences were seen 11 to 15 years before diagnosis. Hypertension and dyslipidemia showed no between-group differences. Health-care use increased markedly from year before EOAD diagnosis.

DISCUSSION: EOAD is preceded by recognizable patterns of morbidity and increased health-care use, which may support earlier detection.},
}

Humans
Female
*Alzheimer Disease/epidemiology/diagnosis
Male
Case-Control Studies
Comorbidity
Finland/epidemiology
Aged
Age of Onset
Aged, 80 and over
Prevalence
Middle Aged

@article {pmid42847328,
year = {2026},
author = {Tee, M and Gutierrez, J and Cui, J and Chiang, E and Venketasubramanian, N and Chen, C and Petr, J and Mutsaerts, HJMM and Hilal, S},
title = {Association of stenosis and arterial remodeling with cerebral hemodynamics and cognition.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494130},
doi = {10.1177/13872877261494130},
pmid = {42847328},
issn = {1875-8908},
abstract = {BackgroundAssociations between intracranial stenosis, arterial remodeling, cerebral hemodynamics, including cerebral blood flow (CBF) and arterial transit time (ATT), white matter hyperintensities (WMH), and cognition remain unclear.ObjectiveThis study investigates the relationships between MRA-derived vascular parameters, cerebral hemodynamics, WMH burden, and cognition. We hypothesized that greater stenosis or remodeling is associated with impaired hemodynamics, increased WMH burden, and poorer cognition.MethodsCross-sectional study of 452 memory clinic patients (median age 74 [IQR 68-78], 53% female) who underwent 3T MRI with time-of-flight MRA and pseudo-continuous ASL. Automated quantification derived global stenosis and brain arterial remodeling (BAR) scores. CBF and spatial coefficient of variation (sCoV) assessed hemodynamics; WMH volume from FLAIR; cognition from a validated neuropsychological battery. Structural equation modelling (SEM) evaluated associations, adjusting for demographics and cardiovascular risk factors.ResultsHigher sCoV was associated with higher BAR (β = 0.14, 95% CI:0.06-0.23). WMH was associated with stenosis (β = 0.20, CI:0.12-0.28) and BAR (β = 0.07, CI:0.001-0.140). Lower CBF (β = -0.26, CI:-0.36 to -0.15) and higher sCoV (β = 0.27, CI:0.17-0.36) were associated with greater WMH burden. Higher BAR was associated with better global cognition (β = 0.07, CI:0.00-0.14). SEM indicated indirect associations with cognition via WMH and CBF.ConclusionsVascular remodeling and stenosis are associated with cerebral hemodynamics, WMH, and cognition, with CBF and WMH as potential mediators, underscoring the importance of vascular health in Alzheimer's disease. These direct and indirect associations are not mutually exclusive: higher BAR was associated with better cognition directly, while also relating to poorer cognition indirectly through greater WMH burden and perfusion heterogeneity.},
}

@article {pmid42847329,
year = {2026},
author = {Hu, G and Liu, Y and Zhang, M},
title = {Multisystem aging discordance and cognitive decline in Chinese older adults: A longitudinal study from CHARLS.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494123},
doi = {10.1177/13872877261494123},
pmid = {42847329},
issn = {1875-8908},
abstract = {BackgroundMultisystem aging discordance may represent an early risk factor for cognitive decline, but prospective evidence in Chinese older adults is limited.ObjectiveWe constructed a blood-based Aging Discordance Index (ADI) and examined its 3-year association with cognitive function in a nationally representative Chinese cohort. ADI was derived from five routine biomarkers (creatinine, total cholesterol, C-reactive protein, mean corpuscular volume, and glycated hemoglobin).MethodsData were from the China Health and Retirement Longitudinal Study (CHARLS). ADI was calculated as the standard deviation of age-adjusted Z-scores. Cognitive function was assessed via orientation, calculation, drawing, and equated word recall in 2018 data. Survey-weighted linear regression adjusted for baseline cognition, sociodemographic, lifestyle, and clinical covariates.ResultsAmong 1688 participants aged ≥60 years, higher ADI was independently associated with worse 3-year cognitive performance (fully adjusted β = -0.336, 95% CI: -0.598 to -0.075, p = 0.011) and greater cognitive decline (β = -0.326, 95% CI: -0.575 to -0.077, p = 0.010). To address potential bias due to loss to follow-up, we further applied linear mixed models (LMM) with random intercepts in an expanded sample of 2912 participants, which utilizes all available repeated measures. The ADI × time interaction remained significant (β = -0.346, 95% CI: -0.580 to -0.112, p = 0.004), confirming the robustness of the primary findings against attrition bias.ConclusionsA simple blood-based index of multisystem aging discordance independently predicts cognitive decline in Chinese older adults. ADI may offer a practical, low-cost tool for early risk stratification in community settings.},
}

@article {pmid42847330,
year = {2026},
author = {Nolin, SA and Aghamoosa, S and Rieter, WJ and Jones, A and Nietert, PJ and Benitez, A},
title = {Greater amyloid burden in cognitive networks in preclinical Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493984},
doi = {10.1177/13872877261493984},
pmid = {42847330},
issn = {1875-8908},
abstract = {BackgroundIn preclinical Alzheimer's disease (pAD), regional patterns of amyloid-β (Aβ) deposition are well characterized but have not been systematically compared across functional networks.ObjectiveDetermine how Aβ accumulation in functional networks ("network-amyloid burden" [NAB]) varies by age, network type (cognitive versus non-cognitive), and Aβ status (Aβ+/Aβ-), and relates to cognition.Methods157 cognitively unimpaired adults (45-84 years; n = 28 Aβ+ per neuroradiological read) underwent brain MRI, amyloid PET ([18]F-florbetapir), and neuropsychological testing. NAB was calculated as the mean standard uptake value ratio within 7 networks categorized as cognitive (fronto-parietal, default mode, ventral and dorsal attention, limbic) or non-cognitive (somato-motor, visual). Linear mixed models tested how NAB varies across age, networks (by type and each separately), Aβ status, and their interactions, and relationships between NAB and cognition.ResultsNAB increased with age, most prominently in fronto-parietal and default mode networks. NAB was higher in cognitive than non-cognitive networks, and this difference was more pronounced in Aβ+ individuals. NAB was not significantly associated with cognition.ConclusionsCognitive brain networks are more vulnerable to amyloid accumulation with aging and in pAD than non-cognitive networks. Cognitive NAB may be useful for early detection and as a target for intervention in pAD.},
}

@article {pmid42847333,
year = {2026},
author = {Cheng, CH and Lu, H},
title = {A randomized pilot trial of non-flickering 40 Hz light stimulation: EEG activity and cognitive outcomes in cognitively normal older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494219},
doi = {10.1177/13872877261494219},
pmid = {42847333},
issn = {1875-8908},
abstract = {BackgroundGamma-frequency (40 Hz) sensory stimulation is a promising non-pharmacological approach for modulating neural activity and cognitive function in aging and Alzheimer's disease. However, conventional flickering stimulation is often poorly tolerated, and evidence for non-flickering approaches remains limited.ObjectiveTo evaluate the neurophysiological and cognitive effects of 4-week (28-session) non-flickering 40 Hz light stimulation in cognitively normal older adults.MethodsIn this randomized, double-blind, active-controlled pilot trial, 33 cognitively normal older adults were assigned to receive either non-flickering 40 Hz light stimulation (n = 17) or a 70 Hz active-controlled condition (n = 16) over four weeks. Per-protocol analyses were conducted in 29 participants who completed the intervention. Resting-state electroencephalography (EEG) was acquired at baseline, immediately after the first intervention session, and after completion of the 4-week intervention. Neuropsychological assessments were performed at baseline and after the intervention. Prespecified primary outcomes were resting-state gamma-band power spectral density (PSD) and functional connectivity (FC).ResultsNo significant between-group differences were observed in resting-state gamma-band PSD or FC following either one-session or 28-session intervention. Unadjusted secondary analyses suggested potential improvements in selected episodic memory measures in the 40 Hz group. Exploratory analyses further identified a positive association between improvements in visuospatial memory and increases in occipital-temporal FC. Both interventions were well tolerated.ConclusionsA 28-session non-flickering 40 Hz light stimulation was well tolerated and may improve selected episodic memory measures in cognitively normal older adults. Although no measurable group-level EEG effects were observed, the exploratory cognitive findings warrant further investigation in larger randomized trials.ClinicalTrial.gov (ID: NCT06715995) https://clinicaltrials.gov/expert-search?term=NCT06715995.},
}

@article {pmid42847459,
year = {2026},
author = {Balverde-Caballero, FB and Pérez-Tur, J and Cardona, F},
title = {A Hierarchical Framework for In Vitro Models of Alzheimer's Disease.},
journal = {WIREs mechanisms of disease},
volume = {18},
number = {5},
pages = {e70015},
pmid = {42847459},
issn = {2692-9368},
support = {CB06/05/1123//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas ISCIII. Ministerio de Ciencia, Innovación y Universidades/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism ; Humans ; Animals ; Induced Pluripotent Stem Cells/metabolism/pathology ; Neurons/pathology/metabolism ; *Models, Biological ; Organoids/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) remains a major global health challenge, with a high rate of clinical trial failures often attributed to the limited translational predictive value of traditional experimental models. In vitro systems, ranging from induced pluripotent stem cell (iPSC)-derived neurons to complex three-dimensional (3D) organoids, have emerged as promising alternatives to investigate disease mechanisms in a controlled experimental setting. However, their rapid expansion has generated fragmented nomenclature and heterogeneous classification schemes. In this systematic review, we propose a hierarchical framework that categorizes in vitro AD models according to their architectural complexity and the biological questions they are designed to address. We organize these platforms into four progressive tiers: genetically defined iPSC-derived cell-autonomous models, stimulus-based reductionist models, interaction-dependent neuron-glia co-cultures, and advanced multicellular 3D or neurovascular platforms. Our findings indicate that low complexity models (Tier 1 and Tier 2) are particularly suited to dissect cell-intrinsic genetic drivers and acute toxic signaling, but they often fail to capture the chronic multicellular feedback loops and vascular dysfunction characteristic of AD. In contrast, high-complexity systems (Tier 3 and Tier 4), including organ-on-chip platforms and vascularized organoids, provide the spatial and physiological context necessary to model neuroinflammation and network-level degeneration, although they present greater technical variability. Finally, we propose an integrative hierarchical strategy that aligns model selection with specific pathological questions. By linking cellular complexity with mechanistic objectives, this framework provides a structured roadmap to improve experimental rigor, facilitate cross-study comparability, and support the development of more predictive experimental models for AD.},
}

*Alzheimer Disease/pathology/metabolism
Humans
Animals
Induced Pluripotent Stem Cells/metabolism/pathology
Neurons/pathology/metabolism
*Models, Biological
Organoids/pathology/metabolism

@article {pmid42847522,
year = {2026},
author = {Donlin-Asp, PG and Clayton, EL},
title = {Synaptic Proteostasis in Health and Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {10},
pages = {e70565},
pmid = {42847522},
issn = {1471-4159},
support = {309570/Z/24/Z/WT_/Wellcome Trust/United Kingdom ; ARUK-SRF2022A-005//Alzheimer's Research UK/ ; //CureSynGAP/ ; 571/ALZS_/Alzheimer's Society/United Kingdom ; //Simons Initiative for the Developing Brain/ ; },
mesh = {Humans ; *Proteostasis/physiology ; *Synapses/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Autophagy/physiology ; *Neurons/metabolism/pathology ; Proteotoxic Stress ; },
abstract = {Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.},
}

Humans
*Proteostasis/physiology
*Synapses/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
Autophagy/physiology
*Neurons/metabolism/pathology
Proteotoxic Stress

@article {pmid42847555,
year = {2026},
author = {Lopez, FV and Erani, F and Bangen, KJ and Coughlin, DG and Galasko, D and Thomas, KR},
title = {Subjective Cognitive Concerns and Cognitive Trajectories in Parkinson's Disease: Biomarker Impact.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
pmid = {42847555},
issn = {2328-9503},
support = {//Michael J. Fox Foundation for Parkinson's Research/ ; AARG-22-723000/ALZ/Alzheimer's Association/United States ; K23 NS122038/NH/NIH HHS/United States ; P30 AG062429/NH/NIH HHS/United States ; RF1 AG082726/NH/NIH HHS/United States ; },
abstract = {OBJECTIVE: To examine the relationship of subjective cognitive concerns (SCC) with biomarkers of Alzheimer's disease (AD), neurodegeneration, and Parkinson's disease (PD) and domain-specific cognitive trajectories among cognitively unimpaired persons with de novo PD.

METHOD: Cognitively unimpaired participants with SCC (n = 294) and without SCC (n = 857) from the Parkinson's Progression Markers Initiative underwent neuropsychological testing, lumbar puncture, and dopamine transporter (DaT) single-photon emission computed tomography (SPECT). Multiple regression analyses examined SCC associations with biomarkers of AD (CSF phosphorylated-tau181/amyloid-beta42 [p-tau181/Aβ42]), neurodegeneration (CSF neurofilament light [NfL]), and PD (DaT-SPECT in contralateral putamen). Linear mixed effects models examined 5-year cognitive trajectories (working memory, category fluency, learning and memory, visuospatial functioning, processing speed) by SCC status and the extent to which biomarkers of AD, neurodegeneration, and PD moderated these associations.

RESULT: At baseline, the SCC group had higher p-tau181/Aβ42 (FDR-adjusted p = 0.004) than the No SCC group, while NfL and DaT-SPECT did not differ. Relative to the No SCC group, the SCC group exhibited faster decline in learning (FDR-adjusted p = 0.016), delayed recall (FDR-adjusted p = 0.016) and working memory (FDR-adjusted p = 0.016). AD and PD-related biomarkers moderated cognitive trajectories: SCC in combination with (1) higher CSF p-tau181/Aβ42 was related to steeper declines in working memory (FDR-adjusted p = 0.032); and (2) lower DaT-SPECT was related to steeper declines in delayed recall (FDR-adjusted p = 0.032).

INTERPRETATION: SCC is related to AD biomarkers and accelerated cognitive decline in the earliest stages of PD. SCC may serve as an early marker of cognitive risk, especially among persons with greater AD- or PD-related burden.},
}

@article {pmid42847638,
year = {2026},
author = {Schneider, RB and Skibinski, G and Fiske, B and Kopil, CM and Merchant, K and Simuni, T},
title = {Considerations for therapeutic targets for clinical trials in biomarker-characterized prodromal Parkinson's disease populations.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261493297},
doi = {10.1177/1877718X261493297},
pmid = {42847638},
issn = {1877-718X},
abstract = {Parkinson's disease (PD) is a growing public health problem and biologically targeted therapeutics (BTTs) that slow disease progression are urgently needed. However, the development of effective BTTs is challenging as PD is a clinically defined syndrome with pathobiological heterogeneity and the pathobiological process begins many years before the onset of clinically detectable motor symptoms. Testing BTTs in a biomarker-defined population at an earlier stage in the disease course, before a clinical PD diagnosis, may be the key to achieving this objective. The recent emergence of biological definitions of neuronal α-synuclein disease (NSD) and research frameworks for staging disease represent the first step towards testing BTTs in biomarker-defined prodromal populations. While biomarker-defined populations are essential for implementing precision therapeutic approaches, selecting and prioritizing BTTs for testing in early-stage populations is also critical, and requires consideration of biological relevance, safety, and operational feasibility. Here, in preparation for such studies, we review the landscape of publicly available PD BTTs organized by mechanistic pathways and targets, and summarize scientific, safety, and operational considerations relevant to early-stage, biomarker-defined trials targeting NSD participants prior to PD clinical diagnosis. Recognizing that there are shared biological mechanisms across neurodegenerative disorders, we complement this review of the PD therapeutic target landscape with a review of publicly available Alzheimer's dementia and amyotrophic lateral sclerosis BTTs and provide a comprehensive list of agents for reference.},
}

@article {pmid42847732,
year = {2026},
author = {O'shea, DM and Disla, S and Gosling, AE and Valdelamar, GA and Ioana Tolea, M and Galvin, JE},
title = {Limitations of current neuroprotective therapies in dementia with Lewy bodies.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2026.2742316},
pmid = {42847732},
issn = {1751-2441},
abstract = {INTRODUCTION: Dementia with Lewy bodies (DLB) is characterized by progressive cognitive, neuropsychiatric, motor, autonomic, and sleep impairment. Pharmacological interventions developed with disease-modifying intent have entered clinical testing, but their biological rationale and adequacy of evaluation remain uncertain.

AREAS COVERED: This structured narrative review appraises pharmacological interventions developed with disease-modifying intent in DLB, focusing on biological rationale, central nervous system (CNS) exposure and target engagement, and whether trials adequately tested neuroprotection or altered clinical progression. PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from January 2023 through 29 July 2026, with trial and registry reconciliation continuing through 30 July 2026. Twelve DLB trials evaluated interventions targeting endosomal signaling, kinase-related proteostasis, autophagy-lysosomal function, cellular bioenergetics, oligomer-associated synaptic injury, or neurotrophic signaling. No completed trial established neuroprotection or disease modification. Interpretation was limited by biological heterogeneity, Alzheimer disease co-pathology, incomplete CNS target-engagement evidence, short treatment duration, small samples, and endpoints unable to distinguish symptomatic effects from altered progression.

EXPERT OPINION: Future trials should prioritize biomarker-supported diagnosis, prospective co-pathology assessment, demonstrated CNS exposure and target engagement, and longer follow-up combining clinical and mechanism-linked outcomes.},
}

@article {pmid42847983,
year = {2026},
author = {Cattaldo, S and Scarpina, F and Prina, E and Piterà, P and Milesi, A and Sabattini, E and Bigoni, M and Azzaro, C and Pradotto, LG and Mauro, A and Priano, L},
title = {Cerebrospinal fluid surfactant protein-G in neurodegenerative dementia: A comparative study with idiopathic normal-pressure hydrocephalus.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487596},
doi = {10.1177/13872877261487596},
pmid = {42847983},
issn = {1875-8908},
abstract = {BackgroundSurfactant protein G (SP-G) is a recently characterized protein potentially involved in cerebrospinal fluid (CSF) dynamics. Its role in human neurodegenerative dementia remains unknown.ObjectiveTo investigate the potential clinical relevance of CSF SP-G levels in neurodegenerative dementia (ND; including Alzheimer's disease [AD] and frontotemporal dementia [FTD]), idiopathic normal-pressure hydrocephalus (iNPH), vascular dementia (VaD), and clinical controls (CTR).MethodsCSF SP-G levels were quantified in 94 individuals: 35 with ND (11 AD + 24 FTD), 19 with iNPH, 13 with VaD, and 27 CTR. Group differences were analyzed using ANOVA with post hoc tests. ANCOVA was performed to adjust for age.ResultsCSF SP-G levels differed significantly among groups in the primary analysis (ANOVA: F(3,90) = 3.862, p = 0.012), with higher levels in iNPH compared with ND (p = 0.012) and CTR (p = 0.026). No significant differences were observed between ND, VaD, and CTR groups. After adjustment for age, the group effect was no longer significant (F(3,89) = 2.253, p = 0.088).ConclusionsThis is the first study to investigate CSF SP-G levels in neurodegenerative dementia. Our findings suggest that SP-G is more closely related to altered CSF physiology in iNPH than to neurodegenerative pathology, although the influence of age indicates that these observations should be interpreted with caution. SP-G may represent a candidate marker of CSF homeostasis and fluid dynamics. Larger, age-matched studies integrating SP-G with established CSF biomarkers and neuroimaging are needed to clarify its diagnostic and pathophysiological significance.},
}

@article {pmid42847994,
year = {2026},
author = {Chen, Y and Emam, KAF and Yue, S and Tian, J and Wang, T and Park, A and Mishra, S and Deep, G and Wang, ZJ and Du, H and Guo, L},
title = {Disrupted synaptic vacuolar H+-ATPase renders synaptic vulnerability to Alzheimer's disease.},
journal = {JCI insight},
volume = {11},
number = {19},
pages = {},
doi = {10.1172/jci.insight.202983},
pmid = {42847994},
issn = {2379-3708},
mesh = {*Alzheimer Disease/pathology/metabolism/genetics/enzymology ; Animals ; *Vacuolar Proton-Translocating ATPases/metabolism/genetics ; Humans ; Mice ; Synaptic Transmission ; Female ; *Synapses/pathology/metabolism ; Brain/pathology/metabolism ; Male ; Disease Models, Animal ; *Synaptic Vesicles/metabolism ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Aged ; Mice, Transgenic ; },
abstract = {Defective synaptic transmission is a prominent pathology that underlies cognitive deficits in Alzheimer's disease (AD), highlighting the need to elucidate molecular mechanisms of synaptic failure. Vacuolar H+-ATPase (V-ATPase), a proton-pumping enzyme, is essential for synaptic vesicle acidification and neurotransmitter loading. However, whether SV-associated V-ATPase is vulnerable to AD remains unclear. Here, using SV-rich fractions from postmortem brain tissues, we identified SV-associated V-ATPase deficits, including decreased enzymatic activity, impaired complex assembly, and altered expression of its key subunits in AD. SV-associated V-ATPase dysfunction was further associated with pathological and clinical characteristics of AD. Genetic downregulation of the V-ATPase V1D subunit, a component reduced in AD brains, disrupted V-ATPase proton transport and impaired SV acidification. Further experiments using 5×FAD mice, which exhibited AD-like SV-associated V-ATPase deficits, demonstrated the deleterious impact of V-ATPase dysfunction on SV acidification and synaptic transmission including presynaptic neurotransmitter release. In addition, ex vivo studies identified amyloid β-induced oxidative stress as a driver of V1D loss and V-ATPase disassembly, linking AD pathology to SV-associated V-ATPase dysfunction. These findings indicate that SV-associated V-ATPase dysfunction contributes to synaptic failure and cognitive deficits in AD. Therapeutic avenues to mitigate V-ATPase dysfunction have the potential to attenuate synaptic failure for the management of AD.},
}

*Alzheimer Disease/pathology/metabolism/genetics/enzymology
Animals
*Vacuolar Proton-Translocating ATPases/metabolism/genetics
Humans
Mice
Synaptic Transmission
Female
*Synapses/pathology/metabolism
Brain/pathology/metabolism
Male
Disease Models, Animal
*Synaptic Vesicles/metabolism
Oxidative Stress
Amyloid beta-Peptides/metabolism
Aged
Mice, Transgenic

@article {pmid42848122,
year = {2026},
author = {Nimbalkar, J and Shinde, R},
title = {Plant-derived phytochemicals for Alzheimer's disease: mechanisms of action, experimental evidence, and therapeutic perspectives.},
journal = {Journal of natural medicines},
volume = {},
number = {},
pages = {},
pmid = {42848122},
issn = {1861-0293},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cholinergic deficits, amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction, which collectively contribute to cognitive decline and neuronal loss. Conventional pharmacotherapies provide symptomatic relief but largely target single pathological pathways, highlighting the need for multi-targeted approaches. Herbal therapeutics have emerged as promising complementary or alternative interventions, offering multifaceted mechanisms that simultaneously modulate key disease processes. Preclinical studies, including in vitro and animal models, indicate that extracts of medicinal plants, including Bacopa monnieri (aerial parts), Ginkgo biloba (leaves), Curcuma longa (rhizomes), and Withania somnifera (roots), may enhance cognitive function, exert neuroprotective effects, attenuate oxidative stress and inflammation, and modulate amyloid and tau pathology. However, clinical evidence remains limited, heterogeneous, and inconclusive, with existing studies reporting variable effects on memory, attention, executive function, and global cognition and generally providing only preliminary evidence of safety and efficacy. This translational gap is further influenced by poor bioavailability and brain delivery of several phytoconstituents, variability in herbal preparations, inadequate standardisation, differences in dosing and study design, and the scarcity of adequately powered, long-term clinical trials. Emerging approaches, including nanotechnology-based delivery systems, rational combinations with conventional therapeutics or complementary herbal agents, and personalised interventions based on genetic and metabolic characteristics, may improve therapeutic precision and clinical translation. Integrating mechanistic insights with experimental and clinical evidence may help identify the most promising herbal candidates while defining their translational limitations. This review synthesises current evidence and future directions, providing a framework for advancing herbal interventions in AD.},
}

@article {pmid42848243,
year = {2026},
author = {Song, H and Du, M and He, H and Zhang, R and Fan, F and Xie, S and Zhang, J and Li, T and Qu, C and Zhang, J},
title = {Maresin1 Improves Angiogenesis and Cognitive Function by Regulating Perivascular Macrophages in Rats with Chronic Cerebral Hypoperfusion.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42848243},
issn = {1573-6903},
support = {2025AFD143//the Enshi Innovation and Development Joint Fund Project/ ; 82071210//Innovative Research Group Project of the National Natural Science Foundation of China/ ; 2021YFC2500102//National Key Research and Development Program of China/ ; PTXM2020006//the Zhongnan Hospital of Wuhan University Medical Science and Technology Innovation Platform Support Project/ ; PTYX2024024//the Hubei Provincial Clinical Research Center for Dementia and Cognitive Impairment/ ; },
mesh = {Animals ; *Macrophages/drug effects/metabolism ; Male ; Rats, Sprague-Dawley ; *Docosahexaenoic Acids/pharmacology/therapeutic use ; Specialized Pro-Resolving Mediators ; *Cognition/drug effects/physiology ; Rats ; *Brain Ischemia/drug therapy ; *Angiogenesis/drug effects/physiology ; Cerebrovascular Circulation/drug effects/physiology ; Signal Transduction/drug effects ; },
abstract = {Population aging imposes a substantial dementia burden. Chronic cerebral hypoperfusion (CCH) serves as a crucial early pathological basis for Alzheimer's disease (AD) and Vascular Dementia (VaD). Our previous studies have demonstrated that macrophage-derived docosahexaenoic acid metabolite Maresin1 can ameliorate CCH-induced cognitive impairment, though the underlying angiogenesis-related mechanisms remain to be elucidated. We developed a rat model of chronic cerebral hypoperfusion using the bilateral common carotid artery occlusion surgical approach. Cognitive improvements and angiogenic mechanisms by Maresin1 were systematically evaluated using behavioral assessments, immunofluorescence techniques, Western blotting (WB), ELISA, and cerebral blood flow measurements via laser Doppler. Our findings revealed that Maresin1 administration significantly ameliorated CCH-induced cognitive deficits, promoted hippocampal angiogenesis and enhanced cerebral perfusion. Further analysis showed significant enhancement of IGF-1/p-Akt/VEGF/eNOS signaling pathway activation by Maresin1, and the increased VEGF expression was predominantly mediated by perivascular macrophage (pvMΦ) activation. Depletion of pvMΦ using clodronate liposomes suppressed the VEGF upregulation and cognitive improvement mediated by Maresin1. Our research demonstrates that IGF-1/p-Akt/VEGF pathway activation in pvMΦ plays a crucial role in Maresin1-mediated angiogenesis in CCH rats.},
}

Animals
*Macrophages/drug effects/metabolism
Male
Rats, Sprague-Dawley
*Docosahexaenoic Acids/pharmacology/therapeutic use
Specialized Pro-Resolving Mediators
*Cognition/drug effects/physiology
Rats
*Brain Ischemia/drug therapy
*Angiogenesis/drug effects/physiology
Cerebrovascular Circulation/drug effects/physiology
Signal Transduction/drug effects

@article {pmid42849086,
year = {2026},
author = {Ali, SK},
title = {Re-evaluating the neuroprotective landscape of Nigella sativa: Molecular mechanisms, nanomedicine, and clinical translation.},
journal = {Current opinion in pharmacology},
volume = {91},
number = {},
pages = {102676},
doi = {10.1016/j.coph.2026.102676},
pmid = {42849086},
issn = {1471-4973},
abstract = {Nigella Sativa (NS) L., commonly known as black seed, and its major bioactive compound, thymoquinone (TQ), have long been used in traditional medicine and have recently gained increasing attention as potential neuroprotective agents. TQ exerts pleiotropic effects within the central nervous system through several interconnected mechanisms, including activation of the Nrf2/HO-1 antioxidant pathway, inhibition of NF-κB-mediated neuroinflammation and NLRP3 inflammasome signaling, and regulation of the mitochondrial Bax/Bcl-2/caspase-3 apoptotic pathway. These effects have been reported in diverse preclinical models of neurodegeneration and neurotoxicity, including amyloid-β-, 6-hydroxydopamine-,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and rotenone-induced neuronal injury, global and focal cerebral ischemia-reperfusion, pentylenetetrazole- and status epilepticus-associated seizures, and toxicant- or trauma-related brain injury. However, the clinical translation of native TQ is limited by its poor aqueous solubility, rapid systemic metabolism, and restricted penetration of the blood-brain barrier. These challenges have stimulated the development of nanomedicine-based delivery systems, including solid lipid nanoparticles, PLGA/chitosan nanoparticles, and mesoporous silica nanocarriers, which are designed to improve TQ stability, brain availability, and therapeutic performance. A limited number of controlled human studies have reported potential benefits of NS seed or oil preparations on memory, attention, mood, and pediatric seizure frequency, with generally acceptable tolerability at conventional doses. Nevertheless, substantial variability in reported rodent oral median lethal dose (LD50) values, together with carrier-specific organ toxicity reported for some nanoformulations (renal and hepatic changes with silica-based carriers), underscores the need for formulation- and exposure-specific safety assessment. Overall, current evidence positions NS and thymoquinone as promising but predominantly preclinical neuroprotective candidates. Their potential applications in Alzheimer's disease, Parkinson's disease, ischemic stroke, and epilepsy remain hypothesis-generating and will require validation through pharmacokinetically optimized formulations and adequately powered clinical trials.},
}

@article {pmid42849148,
year = {2026},
author = {Freischmidt, A and Weishaupt, JH},
title = {Update on somatic mutations in major neurodegenerative diseases: mutational signatures in neurons and mosaicism.},
journal = {Current opinion in genetics & development},
volume = {101},
number = {},
pages = {102549},
doi = {10.1016/j.gde.2026.102549},
pmid = {42849148},
issn = {1879-0380},
abstract = {Somatic mutations in major neurodegenerative diseases are poorly understood, but research over the past 2 years provides valuable insights. Single-cell whole-genome sequencing of vulnerable neurons in Alzheimer's disease and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) revealed excess accumulation of single-nucleotide variant signatures and two-bp deletions independent of pathogenic protein aggregation. Increased oxidative DNA damage and possibly impaired DNA damage repair pathways may explain more pronounced signatures in patients. Ultra-deep sequencing of disease-associated genes in relevant tissues in ALS/FTD identified a subset of sporadic patients carrying mosaic variants that cause disease when present in the germline, but the pathogenicity of such mosaic variants at low allele frequencies is unclear. Research on somatic variants in Parkinson's disease remains underrepresented in the literature.},
}

@article {pmid42849166,
year = {2026},
author = {Sarwar, S and Mehmood, T and Abbasi, GR},
title = {Region-wise chemometric framework for identifying FTIR functional-group signatures associated with cholinesterase inhibition.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109474},
doi = {10.1016/j.compbiolchem.2026.109474},
pmid = {42849166},
issn = {1476-928X},
abstract = {Two key therapeutic targets in the treatment of Alzheimer's disease are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Understanding the molecular characteristics associated with cholinesterase inhibition is important for the development of new inhibitors. In this study, a chemometric framework integrating Fourier Transform Infrared (FTIR) spectroscopy, Principal Component Analysis (PCA), and region-wise Partial Least Squares Regression (PLSR) was applied to explore spectral-response relationships in newly synthesized flurbiprofen hydrazide and hydrazone derivatives. The dataset comprised 27 compounds with 1868 spectral variables covering the 4000-400 cm[-1] region and experimentally determined AChE and BuChE inhibition activities. Following SNV preprocessing, PCA was used to characterize spectral variability and define five major spectral domains: O-H/N-H, C-H, carbonyl/amide, C-O/C-N, and fingerprint regions. Region-wise PLSR models were evaluated using 5-fold cross-validation based on RMSECV and MAE-CV, with Y-randomization providing an additional assessment of the observed modeling performance. Among the investigated regions, the C-H stretching domain (3000-2800 cm[-1]) showed the most favorable relative cross-validated performance for both AChE (RMSECV = 5.49; MAE-CV = 4.02) and BuChE (RMSECV = 5.09; MAE-CV = 5.13). Y-randomization further supported the response-related performance of the C-H region, particularly for BuChE. Regression coefficient profiles provided additional spectral information for interpreting the response-related variation across the investigated regions. Overall, the FTIR-PCA-PLSR framework provides an interpretable approach for comparative assessment of spectral domains and for generating chemically testable hypotheses regarding cholinesterase inhibition in the investigated flurbiprofen derivative series.},
}

@article {pmid42849193,
year = {2026},
author = {Del Percio, C and Lizio, R and Noce, G and Carpi, M and Lopez, S and Carducci, F and De Bartolo, M and Afragola, AP and Soricelli, A and Salvatore, M and Giubilei, F and Güntekin, B and Yener, G and Massa, F and Arnaldi, D and Famà, F and Pardini, M and Ferri, R and Lanuzza, B and Stocchi, F and Vacca, L and Coletti, C and Infarinato, F and Marziali, S and Marizzoni, M and Taylor, JP and Hanoğlu, L and Yırıkoğulları, H and Frisoni, GB and Cuoco, S and Cappiello, A and Barone, P and Bonanni, L and Biundo, R and Cauzzo, S and Fiorenzato, E and Antonini, A and De Pandis, MF and D'Antonio, F and Bruno, G and Babiloni, C},
title = {Association among white matter lesions, rsEEG rhythms, amyloid tau markers, and cognitive status in mild cognitive impairment patients.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {193},
number = {},
pages = {2112432},
doi = {10.1016/j.clinph.2026.2112432},
pmid = {42849193},
issn = {1872-8952},
abstract = {OBJECTIVE: Abnormalities in posteriorly dominant resting-state eyes-closed electroencephalographic (rsEEG) alpha rhythms are associated with cerebrospinal fluid (CSF) tau neuropathology and Mini-Mental Status Examination (MMSE) score, reflecting global cognition, in patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD). The present study examined the relationships between white matter cerebrovascular lesions (WMLs) and CSF amyloid-tau markers, posterior rsEEG alpha rhythms, and cognitive status in patients with MCI-AD versus those with mild cognitive impairment not due to Alzheimer's disease (MCI-noAD).

METHODS: An international database provided clinical, demographic, CSF amyloid-tau, rsEEG, and magnetic resonance imaging (MRI) datasets for 68 MCI-AD and 44 MCI-noAD patients. The WMLs were segmented from T2-weighted and FLAIR MRI images. Cortical rsEEG sources at individual delta, theta, and alpha frequencies were estimated using eLORETA freeware.

RESULTS: In MCI-AD patients, greater WMLs were not associated with increased AD neuropathology, greater alterations in rsEEG alpha or other source activities, or worse MMSE scores. In contrast, higher WMLs were associated with lower MMSE scores in patients with MCI-noAD.

CONCLUSIONS: These results suggest that WMLs had a limited role in prodromal AD, while it affects global cognitive status in patients with MCI-noAD.

SIGNIFICANCE: These findings highlight the stage-dependent, region-specific, and pathology-specific nature of cerebrovascular-neurodegenerative interactions. The limited role of WMLs in MCI-AD may indicate that synergistic neurotoxic effects between vascular burden and AD pathology require more advanced disease stages or higher thresholds of vascular burden to manifest clinically.},
}

@article {pmid42849557,
year = {2026},
author = {Shrirame, D and Tatode, A and Dabhade, D and Taksande, J and Taksande, B and Kakade, O and Umekar, M},
title = {Intermittent Fasting as a Therapeutic Strategy in Alzheimer's Disease: Understanding of Brain-Derived Neurotrophic Factor Modulation.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115522},
doi = {10.1016/j.physbeh.2026.115522},
pmid = {42849557},
issn = {1873-507X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with amyloid-beta (Aβ) plaques, tau tangles, neuroinflammation, and oxidative stress, and it causes cognitive impairment and neuronal loss. The pharmacological treatment is of limited effectiveness, therefore the interest in novel approaches such as intermittent fasting (IF). IF, a nutritional regimen of periodic caloric restriction, has shown a potential to modulate neurodegenerative alterations by metabolic and molecular mechanisms. This review presents the implications of IF in the etiopathogenesis of AD, specifically in controlling brain-derived neurotrophic factor (BDNF). BDNF is a major neurotrophin that plays a key role in synaptic plasticity, neuronal survival, and cognition. Evidence indicates that BDNF is drastically decreased in AD, therefore enhancing disease progression. IF enhances BDNF expression via mechanisms such as improved mitochondrial function, increased ketone body production, and reduced systemic inflammation. Preclinical studies indicate that IF not only upregulates BDNF but also alleviates key AD pathologies, including Aβ deposition and tau hyperphosphorylation. Additionally, clinical data highlight the cognitive benefits of IF and its role in modulating metabolic health, although studies specifically linking IF, BDNF and AD in humans remain limited. This review underscores the need for further research to determine optimal IF protocols and clarify its long-term impact on AD progression. IF's ability to modulate BDNF and other neuroprotective pathways positions it as a promising non-pharmacological intervention for AD management. By bridging metabolic health and neuroprotection, IF offers potential therapeutic synergy for mitigating AD's complex etiopathogenesis.},
}

@article {pmid42849643,
year = {2026},
author = {Chen, R and Sun, X and Wu, T and Tao, L and Zhao, L and Zhong, X and Zhang, Q and Yan, Q and Lu, S and Song, Z and Song, D and Li, L and Niu, J and Yang, H and Teng, Y and Zou, J},
title = {CXCL16-driven neutrophil extracellular traps promote osteoporosis in APP/PS1 mice by disrupting bone remodeling.},
journal = {Bone},
volume = {},
number = {},
pages = {118126},
doi = {10.1016/j.bone.2026.118126},
pmid = {42849643},
issn = {1873-2763},
abstract = {Patients with Alzheimer's disease (AD) often exhibit abnormal bone loss alongside cognitive impairment. However, the mechanisms linking these two conditions remain insufficiently understood. We first employed amyloid precursor protein/presenilin 1 (APP/PS1) mice as the experimental model and demonstrated that they exhibit significant bone loss concurrent with cognitive impairment. Subsequently, we analyzed public datasets for AD and osteoporosis (OP) and identified CXC chemokine ligand 16 (CXCL16) as a shared hub gene between the two diseases. Transcriptomic sequencing further showed increased CXCL16 expression in the femoral tissue of APP/PS1 mice. Immunoblot analysis of brain and bone tissues, together with serum enzyme-linked immunosorbent assay (ELISA), verified the systemic elevation of CXCL16. These findings suggest that CXCL16 may link cognitive impairment with bone loss in APP/PS1 mice. In vitro experiments showed that CXCL16 did not directly affect the differentiation of bone marrow mesenchymal stem cells or bone marrow-derived macrophages. Instead, CXCL16 acted through neutrophils by promoting their migration and potentiating PMA-stimulated neutrophil extracellular trap (NET) formation. Conditioned medium from NET-producing neutrophils inhibited osteogenic differentiation and promoted osteoclastogenesis. In APP/PS1 mice, antagonism of CXCR6, the cognate receptor for CXCL16, with ML339 improved trabecular bone microarchitecture and osteogenic activity and alleviated cognitive impairment. Degradation of NETs with deoxyribonuclease I (DNase I) produced similar effects. Collectively, these results implicate CXCL16-associated enhancement of NET formation in AD-related skeletal deterioration and highlight the CXCL16-NETs pathway as a possible intervention target for maintaining bone homeostasis.},
}

@article {pmid42849896,
year = {2026},
author = {Tavakoli, M and Dadgostar, M and Green, JR and Salat, DH and Arnold, SE and Connaghan, KP and Richburg, B and Barnett, NV and Tkeshelashvili, M and Eshghi, M},
title = {Remote Identification of APOE-ε4 Carrier Status in Cognitively Normal Adults via Speech Acoustics: Cross-Sectional Observational Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e89830},
doi = {10.2196/89830},
pmid = {42849896},
issn = {2561-326X},
mesh = {Humans ; Cross-Sectional Studies ; *Apolipoprotein E4/genetics/analysis ; Aged ; Female ; Male ; Adult ; Middle Aged ; Aged, 80 and over ; *Heterozygote ; *Speech Acoustics ; *Cognition/physiology ; Speech/physiology ; },
abstract = {BACKGROUND: Apolipoprotein E ε4 (APOE-ε4), the strongest genetic risk factor for late-onset Alzheimer disease (AD), is associated with early neuromotor vulnerability that may precede measurable cognitive decline. Because speech integrates fine neuromotor processes, acoustic analysis could offer a sensitive, noninvasive marker of preclinical effects.

OBJECTIVE: This study aims to determine if speech acoustics distinguish cognitively normal APOE-ε4 carriers from noncarriers, and to assess which speech tasks provide optimal classification performance.

METHODS: In this cross-sectional observational study, 80 cognitively normal adults aged 41 to 89 years (22 APOE-ε4 carriers and 58 noncarriers) completed sustained phonation, oral diadochokinetic syllable repetition, passage reading, and spontaneous-speech tasks. Speech samples were collected remotely using participants' personal devices and processed to extract 88 acoustic features from the extended Geneva Minimalistic Acoustic Parameter Set. Task-specific random forest classifiers were developed to distinguish APOE-ε4 carriers from noncarriers. A genetic algorithm was used to select informative features, and model performance was evaluated using leave-one-participant-out cross-validation. Performance metrics included balanced accuracy, accuracy, precision, sensitivity, specificity, F1-score, and receiver operating characteristic area under the curve (ROC-AUC).

RESULTS: Spontaneous speech produced the strongest classification performance, with balanced accuracy of 0.84, accuracy of 0.89, sensitivity of 0.73, specificity of 0.95, F1-score of 0.78, and ROC-AUC of 0.75. Performance was lower for sustained phonation (F1-score=0.69), diadochokinetic syllable repetition (F1-score =0.70 for /ba/ and 0.64 for /pa/), and passage reading (F1-score=0.61). Combining recordings across tasks reduced performance (F1-score=0.53), indicating that task-specific acoustic patterns were more informative than pooled data.

CONCLUSIONS: Automated analysis of task-specific acoustic speech features, particularly spontaneous speech, internally distinguished cognitively normal APOE-ε4 carriers from noncarriers. These findings support further validation of speech acoustics as a low-burden digital biomarker of preclinical AD risk and suggest that spontaneous-speech tasks may be especially well suited for future remote and longitudinal assessment.},
}

Humans
Cross-Sectional Studies
*Apolipoprotein E4/genetics/analysis
Aged
Female
Male
Adult
Middle Aged
Aged, 80 and over
*Heterozygote
*Speech Acoustics
*Cognition/physiology
Speech/physiology

@article {pmid42850105,
year = {2026},
author = {Calafate, S and Mancuso, R},
title = {Sleep-dependent microglial functions in Alzheimer's disease.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.09.005},
pmid = {42850105},
issn = {1878-108X},
abstract = {Sleep is a fundamental regulator of brain homeostasis, yet how distinct brain cell types contribute to this process remains poorly understood. Microglia, the resident immune cells of the central nervous system, actively regulate neuroinflammatory tone, metabolic waste clearance, and synaptic remodeling, thereby contributing to neural circuit maintenance and proteostasis. Delineating the different functions played by microglia during specific brain states, such as sleep, represents an active area of research. In this article, we review a growing literature supporting the notion that sleep dynamically shapes microglial functional outputs. We further suggest that the failure of the sleep-microglia axis may represent an important component of the molecular framework of Alzheimer's disease (AD), contributing to disease progression. Finally, we discuss preclinical and clinical evidence suggesting that sleep-targeting interventions may modulate AD pathology, and highlight the possibility that restoring sleep physiology could recalibrate microglial homeostatic functions and slow disease progression.},
}

@article {pmid42850312,
year = {2026},
author = {Hou, Y and Li, Y and Zhang, P and Lorincz-Comi, N and Gohel, D and Fan, F and Qiu, Y and Yang, J and Chen, X and Song, W and Yang, X and Tan, Z and Liu, Z and Fang, X and Rivera Paz, I and Martin, W and Feng, Y and Zhou, Y and Xu, J and Dou, L and Border, J and Zhang, H and Mazique, JN and Hwang, SH and Roman, RJ and Babak, T and Bekris, L and Karavani, E and Danziger, M and Rosen-Zvi, M and Haines, JL and Yu, H and Hammock, BD and Leverenz, JB and Pieper, AA and Cummings, J and Cheng, F},
title = {Alzheimer's disease target and drug discovery by leveraging multiomics and electronic health data.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42850312},
issn = {1546-1726},
support = {U01AG073323//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R35AG71476, R25 AG083721-01//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG072959//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1NS133812//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {Despite prolific genomic data from individuals with Alzheimer's disease (AD), translation into treatments has lagged. Here we applied Mendelian randomization to multiple AD genome-wide association studies and functional multiomics datasets to nominate druggable targets, identifying 19 targets for individuals of European ancestry and 7 for African ancestry. This included epoxide hydrolase 2 (EPHX2), for which we identified a protective missense variant (p.Arg287Gln). Experiments in induced pluripotent stem cell-derived neurons and cerebral organoids from patients with AD validated the protective role of p.Arg287Gln via reduced levels of EPHX2 and phosphorylated tau (pTau-181). Pharmacological inhibition of EPHX2 improved cognitive performance in the 5xFAD mouse model of AD. Finally, by leveraging electronic health data from 111,680 patients with mild cognitive impairment, we identified 12 drugs associated with reduced AD incidence, including trazodone (targeting ADRA1A) and baclofen (targeting GABBR1). Thus, integrating multiomics data, functional validation and electronic health data identifies new approaches for treating AD.},
}

@article {pmid42850455,
year = {2026},
author = {Padovani, A and Altini, M and Bellelli, G and Bozzali, M and Brignoli, O and Cagnin, A and Cherubini, A and Iannacci, M and Lodi, R and Logroscino, G and Marra, C and Nicora, C and Parretti, S and Sacco, A and Spadin, P and Zappia, M},
title = {Organizing healthcare delivery in the era of disease-modifying therapies for Alzheimer's Disease: an Italian RAND/UCLA consensus.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {11},
pages = {},
pmid = {42850455},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; Italy ; *Delivery of Health Care/organization & administration ; Consensus ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) poses a growing clinical and organizational challenge, requiring coordinated, multidisciplinary care models. In Italy, significant regional variability in resources and access to diagnostic services persists, while the implementation of community-based care models, the expanding role of biomarkers, and the advent of disease-modifying therapies (DMTs) further highlight the need for a more coordinated and equitable dementia care network.

OBJECTIVE: Develop system-level recommendations to optimise the organisation of AD care delivery in Italy in anticipation of DMTs introduction.

METHODS: Using the RAND/UCLA Appropriateness Method, a multidisciplinary panel rated 55 statements across nine domains, evaluating appropriateness in two rounds and priority of implementation in a third round.

RESULTS: Consensus was achieved for all statements, with high appropriateness and priority ratings. The statements outline a regional, network-based model organised across territorial services, Spoke and Hub centres, with formal governance responsible for pathway definition and monitoring. Referral pathways from primary care are based on cognitive and frailty assessment, with non-frail patients referred to Spoke for clinical, neuropsychological and neuroradiological evaluation. Patients potentially eligible for DMTs are referred to Hub centres, where diagnostic confirmation is completed and multidisciplinary teams assess treatment eligibility. When authorised, Hub centres are responsible for DMTs prescription and administration. The statements emphasise the need for standardised neuropsychological and neuroradiological protocols for amyloid-related imaging abnormalities (ARIA) monitoring, alongside the progressive adoption of plasma biomarkers, telemedicine, and structured communication with patients and caregivers.

CONCLUSION: This consensus provides a pragmatic framework to support the reorganisation of AD care in Italy, ensuring that every patient is directed to the most appropriate level of care across a flexible regional network.},
}

Humans
*Alzheimer Disease/therapy/diagnosis
Italy
*Delivery of Health Care/organization & administration
Consensus

@article {pmid42851057,
year = {2026},
author = {Chen, S and He, M and Huo, Y and Xing, F and Gao, Y and Dai, Y and Gao, N and Yin, S},
title = {[Research progress on the correlation mechanism between innate immune imbalance and Alzheimer's disease based on Drosophila model].},
journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology},
volume = {42},
number = {10},
pages = {931-937},
pmid = {42851057},
issn = {1007-8738},
mesh = {Animals ; *Immunity, Innate ; *Alzheimer Disease/immunology ; Disease Models, Animal ; Humans ; *Drosophila melanogaster/immunology/genetics ; Signal Transduction ; },
abstract = {Innate immune dysregulation is a common pathological basis for the development and progression of both infectious diseases and various chronic diseases. Drosophila melanogaster, owing to its highly conserved immune system, well-established genetic manipulation tools, and intact in vivo physiological environment, has become an important model for studying human immune-related diseases. This article systematically reviews the latest research progress on the Drosophila model regarding the "infection-innate immune dysregulation-Alzheimer's disease (AD)" axis. Studies using Drosophila models have shown that Gram-positive bacteria and fungi activate the Toll pathway, while Gram-negative bacteria activate the immune deficiency (Imd) pathway, leading to innate immune dysregulation; all of the above pathogen infections are associated with the pathological progression of AD. Peripheral immune dysregulation can mediate cross-organ inflammatory transmission through the gut-brain axis and the oral-gut-brain axis, thereby contributing to the exacerbation of AD pathological damage. The Drosophila tumor necrosis factor α (TNF-α) homolog Eiger, via activation of the tumor necrosis factor-c-Jun N-terminal kinase (TNF-JNK) pathway, mediates peripheral-immune-driven remote central neuroinflammation. These findings suggest that precise regulation of the innate immune system is critical for maintaining organismal homeostasis, and its dysregulation serves as a link between infectious diseases and AD. The Drosophila model provides a unique perspective for dissecting the pathological progression of "infection-innate immune dysregulation-AD," laying a theoretical foundation for AD intervention strategies targeting immune pathways, the gut-brain axis, and the oral-gut-brain axis, and also offering a reference for translational research on innate immunity-related diseases. It should be noted that the above conclusions are mainly based on mechanistic studies in the Drosophila model, and their extrapolation to human AD still requires further validation.},
}

Animals
*Immunity, Innate
*Alzheimer Disease/immunology
Disease Models, Animal
Humans
*Drosophila melanogaster/immunology/genetics
Signal Transduction

@article {pmid42851103,
year = {2026},
author = {Zhang, L and Lin, P and Zhang, Y and Lin, Z},
title = {Clinical Value of Neuropsychiatric Scales in the Preliminary Identification of Frontotemporal Dementia from Alzheimer's Disease.},
journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP},
volume = {36},
number = {10},
pages = {1344-1349},
doi = {10.29271/jcpsp.2026.10.1344},
pmid = {42851103},
issn = {1681-7168},
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Frontotemporal Dementia/diagnosis/psychology ; Female ; Male ; Cross-Sectional Studies ; *Activities of Daily Living ; *Neuropsychological Tests ; Caregivers/psychology ; Middle Aged ; Aged ; Diagnosis, Differential ; *Psychiatric Status Rating Scales ; Sensitivity and Specificity ; China ; ROC Curve ; },
abstract = {OBJECTIVE: To provide a reference for the clinical differentiation of behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) by analysing differences in scores across various neuropsychiatric scales and their relationships with activities of daily living and caregiver burden.

STUDY DESIGN: A cross-sectional study. Place and Duration of the Study: Department of Neurology, the Affiliated Hospital of Putian University, Putian, China, from January 2024 to March 2025.

METHODOLOGY: Data from the Mild Behavioural Impairment Checklist (MBI-C), Neuropsychiatric Inventory (NPI), Frontal Behavioural Inventory (FBI), Activities of Daily Living (ADL) scale, and Zarit Caregiver Burden Interview (ZBI) were collected from patients with bvFTD and AD. t-test or chi-square test was used to analyse differences in the scores between the two groups. Pearson's correlation analysis was conducted to examine the relationship between ADL and ZBI scores and MBI-C, NPI, and FBI scores. ROC curve analysis was used to evaluate the sensitivity and specificity of the MBI-C, NPI, and FBI scales. The AUC values were calculated and compared.

RESULTS: The bvFTD group exhibited significantly higher MBI-C, NPI, and FBI scores than the AD group (p <0.05). Emotional problems, lack of motivation, disinhibition, speech disorders, impaired judgment, lack of self-awareness, inattention, stubbornness, and incontinence were all more pronounced in the bvFTD group. ADL and ZBI scores were positively correlated with MBI-C, NPI, and FBI scores in both groups. The FBI scale had an AUC value of 0.85, with sensitivity and specificity of 81.82% and 74.71%, respectively, when the score exceeded 20.5.

CONCLUSION: The MBI-C, NPI, and FBI scales can quickly and effectively distinguish bvFTD from AD, with the FBI scale having the highest diagnostic value. Neuropsychiatric disturbances in patients with bvFTD and AD reduce their daily living abilities and increase their caregiver burden.

KEY WORDS: Behavioural variant frontotemporal dementia, Alzheimer's disease, Mild behavioural impairment checklist, Neuropsychiatric inventory, Frontal behavioural inventory.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
*Frontotemporal Dementia/diagnosis/psychology
Female
Male
Cross-Sectional Studies
*Activities of Daily Living
*Neuropsychological Tests
Caregivers/psychology
Middle Aged
Aged
Diagnosis, Differential
*Psychiatric Status Rating Scales
Sensitivity and Specificity
China
ROC Curve

@article {pmid42851117,
year = {2026},
author = {Powell, WR and Melcher, EM and Otte, RC and Lim, S and Etter, L and Pfaff, A and DeWitt, A and Lee, ARS and Ketchum, FB and Salamat, MS and Bradfield, CA and Goutman, SA and Zuelsdorff, ML and Bakulski, KM and Rissman, RA},
title = {Association between early-life farming exposure and Alzheimer's disease neuropathological burden.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71904},
doi = {10.1002/alz.71904},
pmid = {42851117},
issn = {1552-5279},
support = {R21AG079277//National Institute on Aging Awards/ ; R01AG070883//National Institute on Aging Awards/ ; P30AG062715//National Institute on Aging Awards/ ; R01AG079303//National Institute on Aging Awards/ ; P30AG066530//National Institute on Aging Awards/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/epidemiology ; Female ; Male ; *Brain/pathology ; *Agriculture ; *Environmental Exposure/adverse effects ; Aged ; Adolescent ; Risk Factors ; Child, Preschool ; Infant ; Child ; Aged, 80 and over ; Middle Aged ; Infant, Newborn ; Neuropathology ; },
abstract = {BACKGROUND: Farming populations may face a disproportionate share of adverse exposures influencing Alzheimer's disease (AD), yet farming data are rarely connected to cohorts with characterized AD neuropathology. Whether early-life exposure is related to AD neuropathology is limited.

METHOD: Brain donors from two Alzheimer's Disease Research Centers (N = 1035; between 1986-2018) were included. US Census records were used to identify those with early-life farming exposure (birth to 17 years old) and examined alongside AD neuropathology assessments.

RESULT: Early-life farming exposure (≈ 17% of donors) was associated with 60% higher odds of AD neuropathological burden (odds ratio = 1.60, 95% confidence interval: 1.09-2.35) adjusting for age, sex, and year of death.

CONCLUSION: Findings suggest exposure to farming early in life is linked to increased levels of AD neuropathology. Deeper occupational and residential phenotyping is needed to identify the potential multiple, overlapping risk pathways, which may include cumulative and sensitive life stage exposure to chemical toxicants, hearing loss, and psychosocial hazards.},
}

Humans
*Alzheimer Disease/pathology/epidemiology
Female
Male
*Brain/pathology
*Agriculture
*Environmental Exposure/adverse effects
Aged
Adolescent
Risk Factors
Child, Preschool
Infant
Child
Aged, 80 and over
Middle Aged
Infant, Newborn
Neuropathology

@article {pmid42851120,
year = {2026},
author = {Han, X and Hu, R and Ping, X and Chen, J and Liu, J and Liu, Z and Jin, X and Gao, X and Lin, M and Zhao, Y and Wang, N},
title = {Diffusion MRI reveals amyloid plaque-associated cellular signatures through spatial transcriptomic integration.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71908},
doi = {10.1002/alz.71908},
pmid = {42851120},
issn = {1552-5279},
support = {RP210099//Cancer Prevention and Research Institute of Texas/ ; //The UT System Rising STARs (Science and Technology Acquisition and Retention) Award/ ; //Ralph W. and Grace M. Showalter Research Trust Fund/ ; R01 NS125020//Foundation for the National Institutes of Health/ ; },
mesh = {Animals ; *Diffusion Magnetic Resonance Imaging/methods ; *Plaque, Amyloid/diagnostic imaging/pathology/genetics ; Spatial Transcriptomics ; *Alzheimer Disease/diagnostic imaging/pathology/genetics ; *Brain/pathology/diagnostic imaging ; Mice ; Disease Models, Animal ; Microglia/pathology/metabolism ; Mice, Transgenic ; Oligodendroglia/metabolism/pathology ; Neurons/pathology/metabolism ; Neural Networks, Computer ; Transcriptome ; },
abstract = {INTRODUCTION: Amyloid plaque deposition is a defining feature of Alzheimer's disease (AD), yet how plaque-associated cellular alterations are reflected in noninvasive imaging remains unclear.

METHODS: We integrated high-resolution diffusion magnetic resonance imaging (dMRI) with spatial transcriptomics (ST) in an AD mouse model. Spatial correlations were assessed across the whole brain and in disease-control and plaque-non-plaque comparisons. Neural network models were trained to predict AD-associated cell types from dMRI metrics.

RESULTS: dMRI metrics showed moderate spatial correlations (r = -0.41 to 0.36) with oligodendrocyte- and neuron-related gene expression. Disease-control comparisons revealed region-specific MRI-derived microstructural alterations aligned with transcriptional changes in microglia, astrocytes, oligodendrocytes, and neurons. Plaque-rich regions exhibited distinct diffusion and susceptibility signatures associated with oligodendrocyte and microglial expression. Neural networks predicted spatial distributions of AD-associated cell types with 80%-86% accuracy.

DISCUSSION: dMRI captures plaque-associated cellular pathology and supports biologically informed interpretation of imaging contrasts in AD.},
}

Animals
*Diffusion Magnetic Resonance Imaging/methods
*Plaque, Amyloid/diagnostic imaging/pathology/genetics
Spatial Transcriptomics
*Alzheimer Disease/diagnostic imaging/pathology/genetics
*Brain/pathology/diagnostic imaging
Mice
Disease Models, Animal
Microglia/pathology/metabolism
Mice, Transgenic
Oligodendroglia/metabolism/pathology
Neurons/pathology/metabolism
Neural Networks, Computer
Transcriptome

@article {pmid42851142,
year = {2026},
author = {Aqeel, A and Bashir, F and Asad, M and Asad, A and Jafar, S and Yasir, M},
title = {Rational modification of olive derived 4-ethylguaiacol into a BBB-permeable acetylcholinesterase inhibitor via molecular docking, DFT, and molecular dynamics: a computational approach to alzheimer's drug discovery.},
journal = {SAR and QSAR in environmental research},
volume = {},
number = {},
pages = {1-37},
doi = {10.1080/1062936X.2026.2740626},
pmid = {42851142},
issn = {1029-046X},
abstract = {Alzheimer's disease (AD) affects more than 55 million people worldwide, yet no disease-modifying therapy has been approved. Here, 23 phytochemicals from Olea europaea (olive) were evaluated using a multi-filter pipeline comprising ADME/drug-likeness screening, BBB permeability assessment, molecular docking, DFT analysis, and MD simulations. This is the first computational study of olive phytochemicals targeting AChE to use BBB permeability as an explicit screening filter, addressing the CNS penetrance gap that limits translation of prior in silico hits. ADME screening (through SwissADME) identified three Lipinski-compliant, BBB-permeable candidates. Among these, 4-ethylguaiacol exhibited the strongest AChE binding (-7.0 kcal/mol) and a favorable HOMO-LUMO energy gap (6.09 eV), indicating moderate chemical reactivity and stability. Structure-guided optimization of 4-ethylguaiacol using RDKit led to the design of AM-11; 4-ethyl-5-(1-hydroxycyclopropyl)-2-methoxyphenol, whose C-5 hydroxycyclopropyl group forms direct hydrogen bond with catalytic residue, Ser203. AM-11 showed improved binding affinity (-7.9 kcal/mol), stable RMSD throughout a 100 ns MD simulation, and a predicted LD50 of 720 mg/kg (Class IV), a better acute toxicity profile than donepezil (505 mg/kg). These findings position AM-11 as a as a computational lead for a BBB-permeable AChE inhibitor scaffold requiring experimental validation, and the pipeline as a reproducible framework for phytochemical-based lead optimization in AD.},
}

@article {pmid42851145,
year = {2026},
author = {Han, SW and Park, YH and Pyun, JM and Bice, PJ and Bennett, DA and Oveisgharan, S and Saykin, AJ and Kim, S and Nho, K},
title = {Proteomic dysregulation associated with cerebral amyloid angiopathy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71901},
doi = {10.1002/alz.71901},
pmid = {42851145},
issn = {1552-5279},
support = {P30 AG010161/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; U01 AG072572/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; R01 AG075959/AG/NIA NIH HHS/United States ; R01 AG082348/AG/NIA NIH HHS/United States ; R01 AG081951/AG/NIA NIH HHS/United States ; R01 AG057739/AG/NIA NIH HHS/United States ; R01 AG070883/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 LM013463/LM/NLM NIH HHS/United States ; T32 AG071444/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; U01 AG072177/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; R01 AG068193/AG/NIA NIH HHS/United States ; R01 LM012535/LM/NLM NIH HHS/United States ; //National Research Foundation of Korea/ ; RS-2024-00461936//Ministry of Science and ICT, Republic of Korea/ ; RS-2025-25426019//Ministry of Science and ICT, Republic of Korea/ ; },
mesh = {*Cerebral Amyloid Angiopathy/pathology/metabolism/cerebrospinal fluid ; Humans ; *Proteomics ; *Brain/pathology/metabolism ; Alzheimer Disease/pathology ; Female ; Male ; Biomarkers/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA) is characterized by impaired vascular amyloid-β clearance, distinct from Alzheimer's disease (AD), underscoring the need to clarify its molecular basis for predicting therapy-related amyloid-related imaging abnormalities.

METHODS: We analyzed post-mortem brain proteomics from Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) and cerebrospinal fluid (CSF) proteomics from Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify CAA-associated proteins and network modules, delineate their biological processes and cellular origins, and determine their diagnostic performance.

RESULTS: Proteomics analysis identified 30 proteins as associated with CAA severity, enriched in pathways distinct from AD pathology, with 11 replicated in ADNI. Two CAA-associated modules were enriched for microglial vesicle transport and astrocytic potassium-ion homeostasis. Pseudotime analysis demonstrated a molecular trajectory aligned with increasing CAA severity. Three proteins (RCSD1, FRZB, AKAP6) improved CAA classification beyond demographics and APOE ε4.

DISCUSSION: This integrative proteomics analysis identifies distinct, reproducible molecular signatures of CAA, revealing glia-mediated pathways and promising biomarkers for CAA detection and therapy-related risk assessment.},
}

*Cerebral Amyloid Angiopathy/pathology/metabolism/cerebrospinal fluid
Humans
*Proteomics
*Brain/pathology/metabolism
Alzheimer Disease/pathology
Female
Male
Biomarkers/cerebrospinal fluid
Aged, 80 and over

@article {pmid42851166,
year = {2026},
author = {Hwang, J and Figueredo, LF and Valencia, DI and Tolbert, TM and Hamada, E and Zhou, L and Gills, JL and Ruiz, J and Martillo, KR and Chu, SS and Kumar, A and Blessing, EM and Bubu, OM and Parekh, A and Kam, K and Mullins, AE and Rapoport, DM and Ayappa, I and Osorio, RS and Varga, AW},
title = {Longitudinal associations of rapid eye movement (REM) sleep and slow-wave sleep with plasma Alzheimer's disease biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71910},
doi = {10.1002/alz.71910},
pmid = {42851166},
issn = {1552-5279},
support = {R01 AG066870/AG/NIA NIH HHS/United States ; R01 AG080609/AG/NIA NIH HHS/United States ; R01 AG056031/AG/NIA NIH HHS/United States ; R01AG056531//NIH/ ; T32 HL160511/HL/NHLBI NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //American Thoracic Society (ATS)/ ; ASPIRE Fellowship//American Thoracic Society/ ; AARFD-24-1306796/ALZ/Alzheimer's Association/United States ; T32 HL160511/HL/NHLBI NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Sleep, REM/physiology ; Aged ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/blood/physiopathology ; Biomarkers/blood ; Female ; Male ; *Sleep, Slow-Wave/physiology ; Polysomnography ; *Peptide Fragments/blood ; Longitudinal Studies ; Aged, 80 and over ; Middle Aged ; Disease Progression ; Cross-Sectional Studies ; },
abstract = {INTRODUCTION: Data on how sleep architecture relates to progression of plasma Alzheimer's disease biomarkers remains limited.

METHODS: Sixty-four cognitively unimpaired older adults (ages 55-90) underwent plasma collection twice 2.6 years apart and polysomnography proximate to the first plasma collection. Plasma amyloid beta (Aβ) 42 and 40 were measured via mass spectrometry.

RESULTS: Frontal slow-wave activity (SWA) was inversely associated with plasma Aβ42/40 at cross-section in bivariate analysis and in a covariate-adjusted model. In comparison, low rapid eye movement (REM) sleep percentage was associated with a large longitudinal decline in annualized blood-based Aβ42/40. In exploratory analyses, the association between low REM sleep percentage and faster decline in Aβ42/40 ratio was stronger in the amyloid-positive group.

DISCUSSION: In cognitively unimpaired older adults, non-REM SWA correlates with cross-sectional amyloid load, whereas REM sleep may predict accelerated amyloid accumulation in preclinical stage, suggesting both may serve as early biomarkers and modifiable interventional targets.},
}

Humans
*Sleep, REM/physiology
Aged
*Amyloid beta-Peptides/blood
*Alzheimer Disease/blood/physiopathology
Biomarkers/blood
Female
Male
*Sleep, Slow-Wave/physiology
Polysomnography
*Peptide Fragments/blood
Longitudinal Studies
Aged, 80 and over
Middle Aged
Disease Progression
Cross-Sectional Studies

@article {pmid42851167,
year = {2026},
author = {Chen, Y and Li, F and Zhang, J and Wei, M and Ni, J and Li, T and Yao, L and Tian, J and Shi, J},
title = {Spatiotemporal heterogeneity and dynamic evolution of microglial glucose metabolic reprogramming in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71909},
doi = {10.1002/alz.71909},
pmid = {42851167},
issn = {1552-5279},
support = {BZY-JMZY-2022-002//Beijing University of Chinese Medicine/ ; 82074362//National Natural Science Foundation of China/ ; 8240154297//National Natural Science Foundation of China/ ; //Clinical Research and Achievement Commercialization Capacity Improvement Pilot Project of Beijing University of Chinese Medicine/ ; DZMG-JBZX-25001//Dongzhimen Hospital/ ; },
mesh = {*Microglia/metabolism ; *Alzheimer Disease/metabolism/pathology ; Humans ; Metabolic Reprogramming ; *Glucose/metabolism ; Animals ; Oxidative Phosphorylation ; *Brain/metabolism/pathology ; Energy Metabolism ; Glycolysis ; },
abstract = {Alzheimer's disease (AD) is accompanied by persistent disturbances in brain energy metabolism, and microglial glucose metabolic reprogramming constitutes an important link among pathological protein deposition, neuroinflammation, and impaired clearance. This review examines these metabolic changes across disease stages, brain regions, and plaque-associated microenvironments and proposes a dynamic state-composition model. In this model, microglia in different metabolic states coexist, and their relative proportions and spatial distribution change as AD progresses. In early disease or during active phagocytosis, some microglia show enhanced glycolytic and oxidative phosphorylation (OXPHOS) programs. Under persistent pathological stress, increased glucose uptake may not translate into effective energy production and can coexist with inflammation and impaired lipid metabolism. In late disease, microglia with reduced metabolic capacity and impaired phagocytosis become more prevalent. However, higher expression of OXPHOS-related genes in some microglial states associated with tau pathology does not necessarily indicate improved mitochondrial respiration. These population-level patterns do not imply that individual microglia follow a fixed sequence of metabolic changes. Longitudinal cell tracking and microglia-specific metabolic flux measurements are needed to test this model and inform interventions tailored to disease stage and microglial state.},
}

*Microglia/metabolism
*Alzheimer Disease/metabolism/pathology
Humans
Metabolic Reprogramming
*Glucose/metabolism
Animals
Oxidative Phosphorylation
*Brain/metabolism/pathology
Energy Metabolism
Glycolysis

@article {pmid42851168,
year = {2026},
author = {Whitwell, JL and Bhaskaran, JG and Satoh, R and Graff-Radford, J and Machulda, MM and Lowe, VJ and Mielke, MM and Dickson, DW and Tzeng, SC and Bui, J and Verghese, PB and West, T and Venkatesh, V and Josephs, KA},
title = {Plasma eMTBR-tau243 as a disease biomarker across Alzheimer's disease clinical phenotypes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71898},
doi = {10.1002/alz.71898},
pmid = {42851168},
issn = {1552-5279},
support = {R01-AG50603/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/pathology ; *tau Proteins/blood ; Female ; Biomarkers/blood ; Positron-Emission Tomography ; Male ; Aged ; Phenotype ; Amyloid beta-Peptides/metabolism ; Phosphorylation ; Aged, 80 and over ; Brain/diagnostic imaging/metabolism ; },
abstract = {INTRODUCTION: The concentration of endogenous tau microtubule-binding region containing residue-243 in plasma (eMTBR-tau243) has been proposed to be a sensitive biomarker of tangle pathology in Alzheimer's disease (AD). We assessed eMTBR-tau243 and phosphorylated tau217 (p-tau217) with tau and Aβ-positron emission tomography (PET) across different AD clinical phenotypes.

METHODS: Plasma eMTBR-tau243, p-tau217, and the ratio of non-phosphorylated to phosphorylated tau217 (%p-tau217) were measured in 20 Aβ-PET positive AD patients representing four clinical phenotypes and 10 cognitively unimpaired controls. Plasma levels were correlated with PET, demographic and cognitive variables.

RESULTS: Plasma eMTBR-tau243, p-tau217, and %p-tau217 levels were greater in AD than controls, with greatest levels observed in motor-predominant AD. Plasma biomarker levels correlated with cortical flortaucipir-PET uptake; eMTBR-tau243 correlations were strongest. In AD, eMTBR-tau243 levels were undetectable in patients with mild/focal flortaucipir-PET uptake (45%). Only eMTBR-tau243 correlated with cognition.

DISCUSSION: Plasma eMTBR-tau243 may be an excellent biomarker for tau deposition and cognition in AD across different phenotypes.},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging/pathology
*tau Proteins/blood
Female
Biomarkers/blood
Positron-Emission Tomography
Male
Aged
Phenotype
Amyloid beta-Peptides/metabolism
Phosphorylation
Aged, 80 and over
Brain/diagnostic imaging/metabolism

@article {pmid42851206,
year = {2026},
author = {Fernandez, S and Dempsey, DA and Chaudhuri, S and Huang, YN and Park, T and Liu, S and Unverzagt, FW and Gao, S and , and Wilcock, DM and Yang, J and Rebholz, CM and Risacher, SL and Saykin, AJ and Nho, K},
title = {MIND diet-related plasma proteins are associated with Alzheimer's disease risk.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71884},
doi = {10.1002/alz.71884},
pmid = {42851206},
issn = {1552-5279},
support = {//National Institute on Aging (NIA)/ ; P30AG010133//National Institutes of Health (NIH):/ ; P30AG072976//National Institutes of Health (NIH):/ ; R01AG019771//National Institutes of Health (NIH):/ ; R01AG057739//National Institutes of Health (NIH):/ ; U19AG024904//National Institutes of Health (NIH):/ ; R01AG068193//National Institutes of Health (NIH):/ ; T32AG071444//National Institutes of Health (NIH):/ ; U01AG068057//National Institutes of Health (NIH):/ ; U01AG072177//National Institutes of Health (NIH):/ ; U19AG074879//National Institutes of Health (NIH):/ ; R01LM012535//National Institutes of Health (NIH):/ ; R01 LM013463//National Library of Medicine (NLM) NIH/ ; R01LM012535//National Library of Medicine (NLM) NIH/ ; R01 HL153178//National Heart, Lung, and Blood Institute (NHLBI), NIH/ ; 75N92022D00001//NHLBI, NIH, Department of Health and Human Services/ ; 75N92022D00002//NHLBI, NIH, Department of Health and Human Services/ ; 75N92022D0000375N92022D00004//NHLBI, NIH, Department of Health and Human Services/ ; 75N92022D00005//NHLBI, NIH, Department of Health and Human Services/ ; U01HL096812//NIH (NHLBI, NINDS, NIA and NIDCD)/ ; U01HL096814//NIH (NHLBI, NINDS, NIA and NIDCD)/ ; U01HL096899//NIH (NHLBI, NINDS, NIA and NIDCD)/ ; U01HL096902//NIH (NHLBI, NINDS, NIA and NIDCD)/ ; U01HL096917//NIH (NHLBI, NINDS, NIA and NIDCD)/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/prevention & control ; Female ; Male ; *Diet, Mediterranean ; *Blood Proteins/analysis ; Proteomics ; *Dietary Approaches To Stop Hypertension ; Aged ; Risk Factors ; },
abstract = {INTRODUCTION: Adherence to the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet is associated with reduced dementia risk, but underlying mechanisms remain unclear.

METHODS: Plasma proteomics (SomaScan 7k) from 206 Indiana Alzheimer's Disease Research Center participants were analyzed using network analysis to identify modules associated with MIND diet scores. Diet-related hub proteins were then investigated for associations with Alzheimer's disease (AD) phenotypes and as potential diet-AD outcome mediators. Validation analyses were conducted in the Atherosclerosis Risk in Communities study (n = 10,228) and Global Neurodegeneration Proteomics Consortium (n = 3,723) datasets.

RESULTS: Higher MIND diet scores were associated with lower AD odds (odds ratio = 0.75, p = 0.01) and lower plasma neurofilament light chain levels (β = -0.07, p = 0.02). Two proteins, MCTS1 and cytidylate kinase, were associated with MIND diet and AD risk, and may mediate their relationship (p[a × b < 0] ≥ 0.95). Validation analyses supported the MCTS1 finding.

DISCUSSION: Vascular-related biological mechanisms may underlie associations between diet and dementia risk.},
}

Humans
*Alzheimer Disease/blood/prevention & control
Female
Male
*Diet, Mediterranean
*Blood Proteins/analysis
Proteomics
*Dietary Approaches To Stop Hypertension
Aged
Risk Factors

@article {pmid42851222,
year = {2026},
author = {Sankar, G and R, I and Umasankar, H},
title = {Therapeutic role of deferasirox loaded niosomes against aluminium-maltolate induced Alzheimer disease: A study in Swiss albino mice.},
journal = {The Indian journal of medical research},
volume = {164},
number = {4},
pages = {550-558},
doi = {10.25259/IJMR_3060_2025},
pmid = {42851222},
issn = {0971-5916},
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/pathology ; *Deferasirox/administration & dosage ; Mice ; Oxidative Stress/drug effects ; Male ; Humans ; Liposomes/chemistry/administration & dosage ; Brain/drug effects/pathology ; Aluminum/toxicity ; Neuroprotective Agents ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Organometallic Compounds/toxicity ; Maze Learning/drug effects ; Aluminum Compounds/toxicity ; Pyrones ; },
abstract = {Background and objectives Aluminium, a common component in underarm deodorants, has been reported to increase oxidative stress when present in the bloodstream, and chronic exposure is considered a potential risk factor for Alzheimer disease. This study investigates the neuroprotective and chelating effects of deferasirox (DFX) and its niosome-based formulation (DFX-NS) against aluminium-maltolate (Almal)-induced neurotoxicity in mice. Methods Thirty male Swiss albino mice were randomly assigned into five groups: Control, Almal, Standard (STD), DFX, and DFX-NS. For 21 d, all groups except the control received Almal to induce neurotoxicity, followed by respective treatments for an additional 21 d. After the treatment period, cognitive function was assessed using behavioral tests such as the Morris Water Maze and Y Maze. An in vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed on SH-SY5Y cells to evaluate the neuroprotective potential of DFX. In vivo analyses-including elemental analysis (ICP-MS), histopathology, oxidative stress parameters [Reactive Oxygen Species (ROS), Malondialdehyde (MDA), Catalase (CAT)], urine analysis, and protein estimation (Bradford assay)-were performed on the brain, which was isolated after cervical dislocation. Results The results obtained shows that the Deferasirox has optimum capacity to chelate the aluminium ions in the brains of the Alzheimer-diseased swiss albino mice. Though, the evidence obtained were not fully conclusive, but still the results from the niosomes group shows effective treatment option for the Alzheimer disease caused by the aluminium exposure. Interpretation and conclusions The efficacy of DFX and DFX-NS in reducing aluminium-induced neurotoxicity and oxidative stress in the brain proves that DFX could be a possible candidate for treating Alzheimer's patients linked with metal toxicities.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/pathology
*Deferasirox/administration & dosage
Mice
Oxidative Stress/drug effects
Male
Humans
Liposomes/chemistry/administration & dosage
Brain/drug effects/pathology
Aluminum/toxicity
Neuroprotective Agents
Reactive Oxygen Species/metabolism
Disease Models, Animal
Organometallic Compounds/toxicity
Maze Learning/drug effects
Aluminum Compounds/toxicity
Pyrones

@article {pmid42851246,
year = {2026},
author = {Bianco, CR and Rabaneda-Lombarte, N and Fatima, H and Celedon, J and Oakley, DH and Arnold, SE and Kivisäkk, P and Serrano-Pozo, A},
title = {Associations between plasma biomarker levels and quantitative postmortem neuropathologic measures in Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71883},
doi = {10.1002/alz.71883},
pmid = {42851246},
issn = {1552-5279},
support = {P30 AG062421/AG/NIA NIH HHS/United States ; R21AG087072/AG/NIA NIH HHS/United States ; R01AG089349/AG/NIA NIH HHS/United States ; BEVP36A7461//Fundación Ramón Areces Research Fellowship/ ; AARG-24-1309896/ALZ/Alzheimer's Association/United States ; ABA-25-1373553/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology/blood ; *Biomarkers/blood ; Female ; *tau Proteins/blood ; Male ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; Aged ; *Brain/pathology ; Plaque, Amyloid/pathology ; Aged, 80 and over ; Amyloid beta-Peptides/blood ; Longitudinal Studies ; Autopsy ; Astrocytes/pathology ; *Dementia/pathology/blood ; Neurons/pathology ; },
abstract = {INTRODUCTION: Validation of Alzheimer's disease blood-based biomarkers (BBMs) has relied largely on amyloid beta (Aβ) and tau positron emission tomography (PET), with limited quantitative neuropathologic correlation studies. We examined associations between BBMs and quantitative postmortem neuropathology in 124 participants from the Massachusetts Alzheimer's Disease Research Center (MADRC) Longitudinal Cohort Study.

METHODS: Plasma phosphorylated tau 217 (p-tau217), p-tau181, total tau (t-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Meso Scale Discovery platform and correlated with postmortem quantitative measures of Aβ plaques, AT8[+] pTau neurons, cortical thickness, and GFAP[+] astrocytes across the temporal, frontal, and occipital lobes.

RESULTS: Plasma p-tau217 strongly associated with Aβ plaques (especially neuritic) and AT8[+] neurons. Associations were weaker for p-tau181 and t-tau. NfL associated only with lower cortical thickness. GFAP correlated with Aβ plaques, AT8[+] neurons, and cortical and white matter GFAP[+] astrocytes. Plasma p-tau217 and GFAP mediated the association between Aβ plaques and AT8[+] neurons.

DISCUSSION: These findings support BBM biological specificity and utility for in vivo characterization of distinct neuropathologic processes.},
}

Humans
*Alzheimer Disease/pathology/blood
*Biomarkers/blood
Female
*tau Proteins/blood
Male
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood
Aged
*Brain/pathology
Plaque, Amyloid/pathology
Aged, 80 and over
Amyloid beta-Peptides/blood
Longitudinal Studies
Autopsy
Astrocytes/pathology
*Dementia/pathology/blood
Neurons/pathology

@article {pmid42851352,
year = {2026},
author = {Tran, ML and Kim, K and Kim, JU and Choi, YY and Do, J and Lee, KH and Seok, JW},
title = {Low-density lipoprotein cholesterol modulates amyloid-related entorhinal vulnerability and episodic memory performance in older adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1933036},
pmid = {42851352},
issn = {1663-4365},
abstract = {INTRODUCTION: Cerebral amyloid-beta (Aβ) burden does not fully explain variation in Alzheimer's disease (AD)-related brain structure and episodic memory. We examined whether circulating low-density lipoprotein cholesterol (LDL-C) modifies the cross-sectional statistical association between Aβ burden, the entorhinal cortex (EC) thickness and episodic memory performance.

METHODS: Cross-sectional data from 1,253 individuals in the Gwangju Alzheimer's Disease and Related Dementias cohort (798 cognitively normal, 425 mild cognitive impairment, 30 AD dementia) were analyzed. Primary conditional-process models were adjusted for age, sex, education, body mass index, and HbA1c; clinical diagnosis was examined in sensitivity analyses. HC3 heteroskedasticity-consistent inference was used for the focal interaction, and indirect associations were estimated using 10,000 bootstrap resamples.

RESULTS: Greater Aβ burden was associated with lower EC thickness (β = -0.0863, p = 0.0012), and EC thickness was positively associated with episodic memory (β = 0.3809, p < 0.001). The unconditional indirect statistical association was supported (β = -0.0329, 95% bias-corrected bootstrap CI [-0.0647, -0.0072]). LDL-C modified the Aβ-EC association (β = -0.0937, HC3 SE = 0.0332, 95% CI [-0.1589, -0.0285], p = 0.0049), although the incremental explanatory magnitude was small (ΔR[2] = 0.0082). The conditional Aβ-EC association was unsupported at approximately 66 mg/dL LDL-C (β = 0.0263, p = 0.583), not statistically supported at approximately 100 mg/dL (β = -0.0639, p = 0.060), and negative at 138 mg/dL (β = -0.1648, p < 0.001). The index of moderated indirect association was supported (β = -0.0357, 95% bias-corrected bootstrap CI [-0.0637, -0.0119]); conditional indirect associations were most clearly supported at higher LDL-C levels. A similar interaction was observed for non-HDL cholesterol, suggesting that the pattern may reflect a broader atherogenic lipid context.

CONCLUSION: Circulating LDL-C was associated with modest heterogeneity in the cross-sectional Aβ-EC relationship, with more clearly negative conditional associations observed at higher LDL-C levels. Longitudinal studies are needed to determine the temporal and clinical relevance of these findings.},
}

@article {pmid42851448,
year = {2026},
author = {Mishra, P and D, S and Jain, PR and Sharma, A and J C, K},
title = {Alzheimer's detection using quanvolutional neural networks with federated training.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1904876},
pmid = {42851448},
issn = {1662-4548},
abstract = {Alzheimer's disease detection from MRI data is challenging because of subtle anatomical patterns, high-dimensional image data, and privacy constraints associated with centralized medical-data training. We propose a hybrid quantum-classical federated learning framework using a frozen four-qubit quanvolutional front-end. The 128 × 128 grayscale MRI images are divided into 2 × 2 patches, and quantum features are pre-extracted using a fixed circuit implemented in PennyLane. The resulting features are classified using trainable classical dense layers implemented in TensorFlow/Keras. Federated training is performed across five non-IID clients using FedAvg and FedNova over ten communication rounds, with dynamic local epochs of 5-30 and batch size 32. Expectation-Value Local Differential Privacy (EV-LDP) is also evaluated. The proposed FedNova-DQ framework achieved a final global accuracy of 0.923, compared with 0.921 using FedAvg. The centralized QCNN achieved 0.891 accuracy compared with 0.872 for the classical CNN baseline. Under EV-LDP with ϵ = 2.0, the model maintained 90.85% accuracy. At K = 200 clients, FedNova achieved 90.15% accuracy compared with 82.15% for FedAvg. The frozen quantum front-end eliminates quantum-parameter communication and decouples quantum feature extraction from federated communication rounds while maintaining strong classification performance under heterogeneous client distributions.},
}

@article {pmid42851539,
year = {2026},
author = {Lei, Q and Liu, Q},
title = {Global trends, research hotspots, and clinical evidence mapping of music therapy interventions for cognitive impairment: a bibliometric and visualization analysis from 2006 to 2026.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1917320},
pmid = {42851539},
issn = {1664-1078},
abstract = {BACKGROUND: Cognitive impairment is an important public health issue in ageing societies. Music therapy, as a safe and accessible non-pharmacological intervention, has been increasingly used in the management of cognitive impairment. However, the overall research pattern, evolution of research hotspots, and features of clinical evidence in this field have not been systematically reviewed. This study aimed to analyze the current status, major topics, and development trends of research on music therapy interventions for cognitive impairment from 2006 to 2026.

METHODS: A stratified multi-database search strategy was used. The Web of Science Core Collection (WoSCC) served as the main data source. Bibliometric and visualization analyses were performed using Bibliometrix, CiteSpace, and VOSviewer. The Scopus database was also used to cross-validate key findings. In addition, randomized controlled trials (RCTs) retrieved from PubMed were analyzed to further assess the clinical evidence base.

RESULTS: A total of 835 publications were included from WoSCC. From 2006 to 2025, the annual number of publications increased steadily, with an average annual growth rate of 13.35%. The publication output reached its peak in 2025, and the exponential model showed a good fit to the growth trend (R [2] = 0.913). The United States, China, the United Kingdom, and Australia were the leading contributing countries, while institutions such as the University of Melbourne made notable contributions. The main research topics focused on dementia, music therapy, Alzheimer's disease, quality of life, and cognitive dysfunction. Over time, research hotspots have extended toward cognitive improvement, long-term care, and neuroplasticity-related mechanisms. A total of 250 RCTs were identified from PubMed, indicating a growing body of clinical evidence.

CONCLUSION: Research on music therapy interventions for cognitive impairment has shown continuous growth. Core topics mainly involve cognitive function, behavioral symptoms, quality of life, and care support. Mechanistic studies, especially those related to neuroplasticity, have become an important research frontier. Future studies should place greater emphasis on high-quality clinical research, clarify the mechanisms of music therapy, and promote its precise application and clinical translation.},
}

@article {pmid42851564,
year = {2026},
author = {Brink, D and Theart, R and Loos, B},
title = {Differential autophagy cargo engagement in amyloid-β-induced neuronal toxicity.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1913175},
pmid = {42851564},
issn = {1662-4548},
abstract = {Neurodegenerative diseases are characterized by progressive neuronal loss and the accumulation of misfolded proteins. In Alzheimer's disease, several pathogenic protein species, including amyloid precursor protein, amyloid beta, tau, phosphorylated tau, and alpha-synuclein, are known substrates of macroautophagy. However, the extent to which macroautophagy selectively engages these proteins for degradation under conditions of proteotoxic stress remains poorly understood. Here, the contribution of specifically macroautophagy to the degradation of amyloid precursor protein, amyloid beta, tau, phosphorylated tau, and alpha-synuclein was investigated using an amyloid precursor protein overexpression model. Mouse neuroblastoma N2A cells stably expressing the human Swedish amyloid precursor protein mutation were treated with butyric acid for 24 and 48 h to produce increasing proteotoxicity and molecular pathology. Autophagic flux was assessed using bafilomycin A1 and protein abundance quantified by western blotting. Confocal microscopy and colocalization analysis was performed to examine intracellular protein localization and recruitment to the autophagy compartment. Amyloid precursor protein overexpression and autophagosome/lysosome fusion inhibition elicited distinct protein-specific responses, with phosphorylated tau showing highest accumulation and autophagic recruitment. In contrast, tau and amyloid precursor protein exhibited moderate increases, while alpha-synuclein and amyloid beta showed differential and limited responses upon macroautophagy inhibition. Collectively, these findings suggest that the autophagy molecular machinery does not engage uniformly with Alzheimer's disease-associated proteins but may be characterized by a highly differential cargo engagement under amyloid precursor protein-driven proteotoxic stress. Phosphorylated tau emerged as the earliest and most prominent protein to be target to the autophagy compartment, highlighting its potential importance in disease progression and therapeutic intervention.},
}

@article {pmid42851601,
year = {2026},
author = {An, X and Wei, C and Cao, M and Xu, J and Yu, W and Ren, Z},
title = {MAPK3 as a ferroptosis driver in excitatory neurons in Alzheimer's disease: from genetic causal inference to in vivo functional validation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1868908},
pmid = {42851601},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and ferroptosis-an iron-dependent form of regulated cell death-has been increasingly implicated in AD-related neuronal loss. However, the causal relationship between specific ferroptosis-related genes and AD, particularly within defined neuronal subtypes, remains incompletely understood.

METHODS: We integrated two-sample Mendelian Randomization (MR) with single-cell expression quantitative trait locus (eQTL) analysis, followed by in vivo validation using AAV9-c-fos-mediated MAPK3 knockdown in APP/PS1 transgenic mice and in vitro validation using siRNA-mediated MAPK3 silencing in Aβ-treated HT22 neurons.

RESULTS: MR analysis of large-scale genetic datasets identified seven ferroptosis-related genes with causal associations with AD. Single-cell eQTL MR prioritized MAPK3 as a significant risk factor specifically within excitatory neurons. AAV9-c-fos-mediated MAPK3 knockdown in APP/PS1 mice significantly ameliorated cognitive deficits in the Morris water maze. Mechanistically, MAPK3 knockdown inhibited aberrant CaMKII phosphorylation, activated the Nrf2-GPX4 antioxidant axis (upregulation of GPX4, HO-1, and FTH1; downregulation of ACSL4 and KEAP1), and reestablished the Bax/Bcl-2 equilibrium, thereby reducing both ferroptosis and apoptosis. These effects were reproduced in Aβ-treated HT22 neurons following siRNA-mediated MAPK3 silencing.

DISCUSSION: Our findings identify MAPK3 in excitatory neurons as a potential causal link between genetic risk and AD pathogenesis, bridging population-level genetic risk and cellular vulnerability. Targeting the MAPK3-CaMKII-Nrf2 axis may represent a promising, cell-type-specific therapeutic strategy for AD.},
}

@article {pmid42851615,
year = {2026},
author = {Ohara, M and Ishigaki, S and Watts, JK and Yamada, K and Ikezu, T and Ikezu, S},
title = {Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {41},
pmid = {42851615},
issn = {3059-4944},
abstract = {Neurodegenerative disorders have diverse etiologies from monogenic mechanisms such as toxic gain-of-function mutation in subsets of amyotrophic lateral sclerosis (ALS) to multifactorial cascades exemplified by Alzheimer's disease (AD), which feature proteostasis failure, neuroinflammation, mitochondrial dysfunction, or age-associated cellular stress. While small molecules can modulate downstream pathways, nucleic acid therapeutics (NATs) target defined RNA sequences to directly reduce pathogenic gene expression, correct or shift isoform usage via splice modulation, and tune disease-relevant networks, positioning them as promising therapeutic modalities for neurodegenerative disorders. Recent clinical applications of NATs in the central nervous system (CNS) have made significant progress by optimized chemistries, improved tolerability, and established intrathecal administration routes, supporting sustained target engagement in relevant neural and glial compartments. This review summarizes three major NAT platforms-antisense oligonucleotides, small interfering RNAs, and aptamers-by highlighting their mechanisms of action, design principles to enhance their biodistribution, durability, and safety, and emerging novel delivery strategies for CNS targeting. We further discuss emerging translational opportunities across ALS, AD, polyglutamine disorders, prion diseases, and synucleinopathies by integrating disease biology with therapeutic rationale, and by summarizing regulatory approvals, ongoing clinical trials, and next generation NATs in preclinical development.},
}

@article {pmid42851655,
year = {2026},
author = {Luo, Y and Dai, N and Qiao, Y and Zheng, T and Zhang, Y and Zhang, Y and Yu, H and Cao, H and Zhang, A and Li, M and Li, Y and Yang, N and Wang, T and Zhou, J and Li, X},
title = {A collaborative multi-view fusion framework with Deep Forest for multi-class diagnosis of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1888587},
pmid = {42851655},
issn = {1663-4365},
abstract = {OBJECTIVE: A key aspect of diagnosing Alzheimer's disease (AD) is identifying mild cognitive impairment (MCI), a sensitive transitional stage between normal cognition (NC) and AD. We divided AD disease progression into three stages: NC, MCI, and AD according to severity. We used CoopLearning to integrate multi-view medical data with a Deep Forest (DF) classifier to classify three stages of AD to aid diagnosis.

METHODS: We used data from the Alzheimer's Disease Neuroimaging Initiative database. The research variables were divided into five views: demographic information, biological sample information, relevant scale information, pixel identification, and magnetic resonance imaging regional information. We compared CoopLearning for feature selection and fusion, least absolute shrinkage and selection operator cross-validation (LassoCV) for single-view feature selection, and LassoCV for multi-view feature selection. The fused data were processed using Synthetic Minority Oversampling Technique (SMOTE), SMOTETomek, and SMOTE Edited Nearest Neighbors (ENN) methods to achieve class balance. The balanced data were then applied to multiple classifiers, such as DF, Random Forest, etc., for performance evaluation.

RESULTS: Multi-view feature selection and fusion using CoopLearning, multi-view feature selection, and single-view overall feature selection using LassoCV identified 20 features from five views. Applying these results to the classifier revealed that model performance was optimal when using SMOTEENN in conjunction with CoopLearning multi-view feature selection and the DF classifier (Accuracy = 0.9898, multi-class area under the receiver operating characteristic curve = 0.9997).

CONCLUSION: Collaborative multi-view fusion substantially improved direct multi-class classification across the AD continuum. Integrating clinical and neuroimaging data with Deep Forest may provide a robust and interpretable framework for early auxiliary diagnosis and disease-stage stratification in Alzheimer's disease.},
}

@article {pmid42851720,
year = {2026},
author = {Liu, K and Yang, X and Kong, L},
title = {Disproportionality analysis of adverse event signals associated with seven Alzheimer's drugs: insights from the FAERS database.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1955230},
pmid = {42851720},
issn = {1663-9812},
abstract = {OBJECTIVE: To compare adverse event reporting patterns for seven Alzheimer's disease (AD) drugs (aducanumab, donanemab, lecanemab, donepezil, galantamine, rivastigmine, and memantine) using the FDA Adverse Event Reporting System (FAERS), and to explore potential reporting signals.

METHODS: FAERS reports from the first quarter of 2004 to the second quarter of 2026 were retrospectively analyzed. Adverse events were coded using MedDRA version 28.1 preferred terms (PTs) and system organ classes (SOCs). Disproportionality signals were detected using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma-Poisson shrinker (MGPS). PT-level signals were additionally controlled using Benjamini-Hochberg false discovery rate correction. Drug-level comparisons, sex- and age-stratified analyses, time-to-onset (TTO) analysis, and Weibull distribution fitting were performed.

RESULTS: A total of 39,301 valid reports involving the seven AD drugs were included. Reports were more frequent among women (52.3%, n = 20,537) and patients aged ≥65 years. Anti-Aβ monoclonal antibodies showed concentrated reporting signals in nervous system disorders, with amyloid related imaging abnormalities (ARIA) related events as the core PT-level signal. Donanemab and lecanemab were also associated with prominent infusion-related reaction signals. Conventional symptomatic drugs demonstrated broader multi-system reporting patterns: donepezil and galantamine were mainly associated with cholinergic cardiovascular and fall-related signals; rivastigmine with administration-site reactions and fall-related events; and memantine with confusional state, agitation, dizziness, and somnolence. Several PT-level signals were not listed in the reviewed prescribing information and were annotated as potential reporting signals. Sex- and age-stratified analyses showed broadly consistent PT-level spectra. TTO analyses revealed heterogeneous onset patterns among different drug and adverse events.

CONCLUSION: This study utilized FAERS data to compare adverse event reporting signals for seven anti-AD drugs. Distinct reporting profiles were observed across drugs, and several potential ADE signals, including potential unlabeled reporting signals, were identified. These findings may support pharmacovigilance surveillance and hypothesis generation, but should be interpreted as reporting associations rather than evidence of causality.},
}

@article {pmid42851935,
year = {2026},
author = {Ghaderi, S and Pirozzi, MA and Sharbafshaaer, M and Trojsi, F and Mohammadi, S and Fereshtehnejad, SM},
title = {Thalamic quantitative susceptibility mapping and susceptibility source separation: a critical narrative review of evidence and interpretation.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1878540},
pmid = {42851935},
issn = {1664-2295},
mesh = {Humans ; *Thalamus/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Animals ; *Brain Mapping/methods ; },
abstract = {Quantitative susceptibility mapping (QSM) measures net tissue magnetic susceptibility, which can conceal coexisting contributions of opposite sign. This is relevant to the thalamus, where nuclei differ in cellular composition, myelinated fibers, and susceptibility contrast. This narrative review evaluates what QSM and magnetic susceptibility source separation, including χ-separation, currently establish about thalamic alterations in aging and neurological disease. The synthesis prioritizes human thalamic evidence and distinguishes it from methodological validation, findings outside the thalamus, and animal experiments. We use paramagnetic component susceptibility (PCS) and diamagnetic component susceptibility (DCS) as the principal notation, with PCS nonnegative and DCS nonpositive. These model-derived components describe magnetic behavior and do not independently identify iron, myelin, calcium, amyloid, or tau. Reduced thalamic bulk susceptibility is repeatedly reported in multiple sclerosis, whereas findings in Alzheimer's disease and Parkinson's disease are less consistent. Differences in acquisition, referencing, segmentation, cohort composition, and treatment of atrophy affect interpretation, although methodological variability does not explain every disagreement. Source separation can provide information concealed by net susceptibility, but depends on relaxation modeling, acquisition conditions, and reconstruction assumptions. Evidence for thalamic protein mapping, calcification of characterization, and treatment monitoring remains limited or indirect. PCS and DCS are research measurements with potential biological interpretability; standardized acquisition and processing, independent tissue validation, longitudinal replication, and clinically useful decision thresholds are required before they can be regarded as validated clinical biomarkers.},
}

Humans
*Thalamus/diagnostic imaging/pathology
*Magnetic Resonance Imaging/methods
Animals
*Brain Mapping/methods

@article {pmid42852011,
year = {2026},
author = {Byun, G and Delaney, SW and Mork, D and Kaur, M and Choi, Y and Zanobetti, A and Lee, JJ and Benmarhnia, T and James, P and Dominici, F and Gill, TM and Braun, D and Bell, ML},
title = {PM2.5 and 30-Day Readmission in Medicare Beneficiaries with Alzheimer's Disease and Related Dementias: Effect Modification by Neighborhood Green and Blue Space.},
journal = {Environmental health perspectives},
volume = {134},
number = {6},
pages = {707-714},
pmid = {42852011},
issn = {1552-9924},
mesh = {*Particulate Matter/analysis ; United States/epidemiology ; *Alzheimer Disease/epidemiology ; Humans ; *Patient Readmission/statistics & numerical data ; Medicare/statistics & numerical data ; Aged ; Female ; *Environmental Exposure/statistics & numerical data ; Male ; *Dementia/epidemiology ; Aged, 80 and over ; *Air Pollutants/analysis ; Neighborhood Characteristics ; },
abstract = {Hospital readmissions are a major concern among people living with Alzheimer's disease and related dementias (ADRD), contributing to substantial burden on patients, caregivers, and health care systems. We evaluated whether short-term exposure to fine particulate matter (PM2.5) was associated with 30-day all-cause readmission among older adults with ADRD and whether residential green and blue space modified this association. We conducted a nationwide time-stratified case-crossover study using Medicare fee-for-service inpatient claims from 2000 to 2016 in the contiguous United States. We identified 30-day all-cause readmissions following the first index admission with ADRD. Daily modeled PM2.5 concentrations were linked to residential ZIP Codes, and exposure windows up to lag 2 days were examined. Measures of green and blue space were derived from Landsat and Google Street View data. Conditional logistic regression was used to estimate associations between PM2.5 and readmission with interaction terms used to evaluate effect modification by levels of green and blue space. Among 6,098,836 beneficiaries with an index admission with ADRD, 759,128 (12.4%) experienced a 30-day all-cause readmission. An interquartile range (IQR; 7.2 μg/m[3]) increase in PM2.5 averaged over lag 0 to 2 days was associated with a higher risk of readmission (odds ratio: 1.010; 95% confidence interval: 1.006, 1.015). Associations were higher for beneficiaries with longer intervals to readmission (>7 days). Effect modification by green or blue space was not conclusive. These findings suggest that short-term PM2.5 exposure may increase the risk of 30-day all-cause hospital readmission among Medicare beneficiaries with ADRD. Reducing ambient PM2.5 exposure may help prevent avoidable readmissions and lessen burden on patients, caregivers, and health care systems.},
}

*Particulate Matter/analysis
United States/epidemiology
*Alzheimer Disease/epidemiology
Humans
*Patient Readmission/statistics & numerical data
Medicare/statistics & numerical data
Aged
Female
*Environmental Exposure/statistics & numerical data
Male
*Dementia/epidemiology
Aged, 80 and over
*Air Pollutants/analysis
Neighborhood Characteristics

@article {pmid42852058,
year = {2026},
author = {Hickman, R and Lin, JJ and McAlaine, KA and Punshon, T and Jackson, BP and Barr, MN and Bidlack, FB and Germine, L and Bartell, SM and Mangano, JJ and Farmer, J and Schwartz, JD and Mukherjee, R and Korrick, SA and Weisskopf, MG},
title = {The Impact of Childhood Cognitively Stimulating Activities on the Association between Prenatal and Early Postnatal Lead Exposure and Later Adulthood Cognitive Function.},
journal = {Environmental health perspectives},
volume = {134},
number = {6},
pages = {699-706},
pmid = {42852058},
issn = {1552-9924},
mesh = {Humans ; *Lead/toxicity ; Female ; *Cognition/drug effects ; Pregnancy ; *Prenatal Exposure Delayed Effects/epidemiology ; Child ; *Environmental Exposure/statistics & numerical data ; Male ; Adolescent ; *Environmental Pollutants ; Missouri ; },
abstract = {INTRODUCTION: Early lead exposure is linked to cognitive function in later adulthood. In animal studies, enriched environments appear to protect against adverse effects of lead exposure, but there has been limited exploration in humans. Our objective was to assess whether engagement in cognitively stimulating activities in childhood modifies the association between early lead exposure and later adult cognitive function.

METHODS: Participants come from the St. Louis Baby Tooth - Later Life Health Study (SLBT), a cohort study which recruited beginning in 2021. SLBT is composed of individuals primarily from the St. Louis, USA area who donated deciduous (baby) teeth to a prior study, the Baby Tooth Survey, in 1958-1972. Participants who completed a survey and cognitive testing were selected through stratified random sampling for tooth lead analysis. Prenatal and postnatal tooth dentin lead concentrations were measured in the donated teeth using laser ablation inductively coupled plasma mass spectrometry. A summary cognitive function score was derived from z-scored outcomes on six cognitive tests completed online through the TestMyBrain platform. Participation in cognitively stimulating activities at ages 6, 12, and 18 years was retrospectively assessed at the time of cognitive testing with the Rush Alzheimer's Disease Center Lifetime Cognitive Activities scale.

RESULTS: From 4236 participants who completed the survey and cognitive tests, 717 had tooth metals analyzed, from which 704 had non-outlying lead measures and sufficient survey information. Participants were on average 62 years (SD = 3.6) at the time of cognitive testing, and 376 (53%) were female. The level of cognitively stimulating activities averaged across childhood modified the effect of second-trimester lead exposure on later adulthood cognitive function. For those with less-frequent childhood cognitively stimulating activities, 1 ppm higher second-trimester lead was associated with 0.34 (95% CI: -0.52, -0.16) SD lower later adulthood cognitive function, while the association among those with high cognitively stimulating activities was null (-0.02 SD, 95% CI: -0.12, 0.07). Results were robust to adjustment for additional childhood socioeconomic characteristics and restriction to white non-Hispanic race.

CONCLUSIONS: Our work supports the hypothesis that engaging in cognitively stimulating activities in childhood, after earlier lead exposure, could buffer its deleterious effects on later adult cognitive function.},
}

Humans
*Lead/toxicity
Female
*Cognition/drug effects
Pregnancy
*Prenatal Exposure Delayed Effects/epidemiology
Child
*Environmental Exposure/statistics & numerical data
Male
Adolescent
*Environmental Pollutants
Missouri

@article {pmid42852093,
year = {2026},
author = {Fotouhi, M and Chui, HC and Choupan, J and Jahanshad, N and Cen, S and Varghese, BA and Ringman, JM and Schneider, LS and Sheikh-Bahaei, N},
title = {Diagnostic classifications based on cognitive, CSF, and PET biomarkers across ADNI cohorts: cross-sectional and longitudinal variability.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag312},
pmid = {42852093},
issn = {2632-1297},
abstract = {Alzheimer's disease and related neurodegenerative disorders exhibit marked clinicobiological heterogeneity, posing challenges for accurate diagnosis, prognosis and therapeutic development. Using data from multiple cohorts of the Alzheimer's Disease Neuroimaging Initiative (ADNI), we conducted comprehensive cross-sectional and longitudinal concordance analyses of dementia severity, CSF and PET amyloid and tau. We also examined the stability of biomarker positivity and cognitive status (stable, progressive, reversive and fluctuating) and their inter-relationships. The ability to separate methodological from biological sources of variability is relevant to understanding the robustness of the Amyloid/Tau/Neurodegeneration classification framework, which is particularly important in the era of disease-modifying therapies. Our data revealed both temporal and spatial discrepancies among variables used for classifying the level of cognitive impairment and between the methods used for classifying positive amyloid or tau status (CSF/PET). Methodological discrepancies in region-specific definitions, positivity thresholds and segmentation constraints contributed to PET inconsistencies. Additionally, biomarker status for CSF and PET positivity fluctuated over time, and there was no evidence of temporal precedence for either CSF or PET. There was pronounced spatiotemporal heterogeneity in tau-PET patterns, with implications for the clinical trajectory. Initial tau deposition in the entorhinal cortex, compared to non-limbic meta-temporal regions, was associated with more rapid cognitive decline and greater amyloid burden. Notably, a subset of mild cognitive impairment cases demonstrated diagnostic reversion to cognitively normal status and showed lower amyloid and tau burden and a higher prevalence of affective symptoms, possibly representing individuals without or at an early stage of Alzheimer's pathology. Results underscore the complexity and variability of Alzheimer's disease phenotypes and progression and provide a sanguine perspective on current diagnostic frameworks. Recognizing variability sources in biomarkers is particularly important when diagnosis relies on a single biomarker or cross-sectional data. More importantly, given the complex interplay of factors contributing to dementia and cognitive decline, deep learning and artificial intelligence-based algorithms are needed for precise and individualized diagnoses. Harmonized and standardized datasets with clearly defined variables, without excluding atypical cases, are needed for the effectiveness of such machine learning models. Therefore, investigating Alzheimer's disease biomarker heterogeneity is critical towards maximizing the potential of artificial intelligence in integrating multi-dimensional clinical and biomarker data beyond human-centred interpretation. In this comprehensive work, we provide insights into the observed heterogeneities and their potential contributing factors. We aim to use this insight and continue this effort by harmonizing the conflicting data, making them suitable for diagnostic algorithms and sharing the harmonized dataset in the near future.},
}

@article {pmid42852183,
year = {2026},
author = {Taylor, JL and Hernandez, B and Lazzeroni, LC and McNerney, MW and Heath, A and Ashford, JW and Cheng, JJ and Chao, S and Bhatt, P and Iv, M and Mojabi, FS and Yesavage, JA},
title = {Parietal and prefrontal transcranial magnetic stimulation (TMS) for mild cognitive impairment (MCI): A pilot randomized clinical trial.},
journal = {Brain disorders (Amsterdam, Netherlands)},
volume = {23},
number = {},
pages = {100322},
pmid = {42852183},
issn = {2666-4593},
abstract = {BACKGROUND: Even though studies of repetitive transcranial magnetic stimulation (rTMS) have demonstrated improvements in cognitive function, we know little about what site of stimulation would be ideal for improving memory.

METHODS: We investigated two sites: (1) the dorsolateral prefrontal cortex (DLPFC); and (2) the lateral parietal cortex (LPC), a more novel site. Forty amnestic MCI participants were randomized to one of three rTMS groups: (1) active DLPFC; (2) active LPC; and (3) sham. After completing 20 sessions of MRI-neuronavigated, bilateral rTMS, the participants were followed for 6 months. The primary outcome/endpoint was the California Verbal Learning Test-II (CVLT-II) list learning score assessed at 1-week post intervention.

RESULTS: Thirty-seven of 40 randomized participants provided primary endpoint data. Compared with the sham group, the active LPC group performed significantly higher on CVLT-II list learning (p = .048; standardized mean difference (SMD) = 0.86). No significant differences in CVLT-II list learning were detected between the active DLPFC and sham groups (p = .629; SMD = 0.20). Exploratory analyses revealed that the active LPC group performed better than sham on CVLT-II long-delay recall at the 1-week-post primary endpoint (p = .004; SMD = 1.30), and higher on CVLT-II semantic clustering at the 3-month follow-up (p = .015, SMD = 1.16).

CONCLUSION: The parietal cortex is a promising TMS target for improving memory function in MCI. More definitive trials are needed to compare the efficacy of parietal and DLPFC TMS for treatment of memory and cognitive impairment.},
}

@article {pmid42852212,
year = {2026},
author = {Geng, R and Zhang, Y and Liu, M and Deng, S and Ding, J and Zhong, H and Tu, Q},
title = {Correction: Elevated serum uric acid is associated with cognitive improvement in older American adults: a large, population-based-analysis of the NHANES database.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1972629},
doi = {10.3389/fnagi.2026.1972629},
pmid = {42852212},
issn = {1663-4365},
abstract = {[This corrects the article DOI: 10.3389/fnagi.2022.1024415.].},
}

@article {pmid42852552,
year = {2026},
author = {Choudhury, A and Prabha, S and Saeed, MU and Sulaimani, MN and Hassan, MI},
title = {Targeting protein misfolding and aggregation in neurodegenerative diseases: challenges for the identification and validation of targets for small molecules.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2747518},
pmid = {42852552},
issn = {1744-7631},
abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and related proteinopathies are characterized by the misfolding, aggregation, and accumulation of specific proteins that disrupt neuronal homeostasis, leading to neuronal death. Despite major advances in structural biology and molecular neuroscience, identifying and validating druggable targets in neurodegenerative diseases remains challenging. Many involved proteins are intrinsically disordered, exhibit conformational heterogeneity, and form highly dynamic toxic species.

AREAS COVERED: This review summarizes the mechanisms of protein folding, misfolding, aggregation, and prion-like propagation in major neurodegenerative proteinopathies, including amyloid-beta and tau in Alzheimer's disease, alpha-synuclein in synucleinopathies, TDP-43 and FUS in ALS/FTLD, polyglutamine-expanded proteins, prion proteins, and rare hereditary amyloidosis. We also discuss major barriers to target identification and validation, including conformational flexibility, oligomer toxicity, blood-brain barrier penetration, and target engagement complexity. Finally, we highlight emerging strategies integrating structural biology, computational methods, and improved experimental models to discover small-molecule inhibitors for neurodegenerative diseases.

EXPERT OPINION: Effective therapeutic discovery will require moving beyond single-target models toward ensemble-based validation strategies. Integrating structural biology, advanced imaging, biomarkers, and computational approaches may improve the identification of druggable targets and support precision-medicine-based interventions for neurodegenerative diseases.},
}

@article {pmid42852594,
year = {2026},
author = {Wang, Y and Ge, D and Jin, Z and Zhao, L and Wu, D and Lin, Z and , },
title = {The Effects of Cerebrovascular Reactivity on the Coupling Between CSF Dynamics and Global Neurovascular Fluctuations in the Alzheimer's Disease Continuum.},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.70584},
pmid = {42852594},
issn = {1522-2586},
support = {82302144//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Mounting evidence revealed that the weakened coupling between CSF flow and global brain activity (gBOLD-CSF coupling) is associated with Alzheimer's Disease (AD) pathology and cognitive impairments. However, the mechanisms underlying this weakened coupling remain unclear.

PURPOSE: To investigate the region-specific effects of cerebrovascular reactivity (CVR) on the gBOLD-CSF coupling.

STUDY TYPE: Retrospective.

POPULATION: One hundred ninety-eight cognitively normal controls (70.2 ± 8.7 years; 128 female, 70 male), 115 mild cognitive impairment patients (73.1 ± 7.1 years; 50 female, 65 male), and 24 dementia patients (75 ± 9.3 years; 14 female, 10 male) from ADNI.

FIELD STRENGTH/SEQUENCE: 3 T gradient-echo blood-oxygenation-level-dependent (BOLD).

ASSESSMENT: gBOLD-CSF coupling and CVR maps were respectively derived from resting-state fMRI. The former reflects the temporal coordination between CSF dynamics and global neurovascular fluctuations, while the latter quantifies the capacity of vessels to dilate or constrict. AD-related clinical scales including Aβ-PET, tau-PET, and cognitive assessments were also involved.

STATISTICAL TESTS: Linear regression models were employed to examine the association of gBOLD-CSF coupling with AD-related clinical scales and with CVR of major cerebral arteries. Mediation analyses were employed to investigate the potential pathways linking these metrics. p < 0.05 was considered significant.

RESULTS: gBOLD-CSF coupling was significantly associated with cognitive assessments (CDR Global: β = 0.366; ADAS-Cog: β = 10.613), accumulation of cortical summary Aβ (β = 37.937) and tau in Braak stage ROIs (Braak I-II: β = 0.444; Braak III-IV: β = 0.565; Braak V-VI: β = 0.474). Analysis also revealed the regional differences in the association of gBOLD-CSF coupling with CVR. CVR, especially in posterior cerebral arteries (PCA) region, was significantly associated with gBOLD-CSF coupling (β = -0.313). The gBOLD-CSF coupling, both directly and through its effect on the accumulation of Aβ and tau, mediated the association between CVR and cognition.

DATA CONCLUSION: Data revealed a significant CVR-coupling association in the PCA region and potential pathways linking CVR, gBOLD-CSF coupling, AD pathology, and cognition, providing deeper insights into weakened gBOLD-CSF coupling in AD.

EVIDENCE LEVEL: 3.

TECHNICAL EFFICACY: Stage 2.},
}

@article {pmid42852610,
year = {2026},
author = {Thomas, BP and Vyas, K},
title = {Editorial for "The Effects of Cerebrovascular Reactivity on the Coupling Between CSF Dynamics and Global Neurovascular Fluctuations in the Alzheimer's Disease Continuum".},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.70585},
pmid = {42852610},
issn = {1522-2586},
}

@article {pmid42852756,
year = {2026},
author = {Sivamaruthi, BS and Kesika, P and Alagarsamy, K and Sisubalan, N and Varman, DR and Vijay, N and Chaiyasut, C},
title = {Phytochemical Composition, Pharmacological Activities, and Clinical Evidence of Bacopa monnieri in Cognitive and Memory Enhancement.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128496771260919124515},
pmid = {42852756},
issn = {1873-4286},
abstract = {Bacopa monnieri (B. monnieri), a traditional Ayurvedic nootropic herb, has garnered growing scientific attention for its diverse pharmacological activities and potential therapeutic relevance across neurological, metabolic, inflammatory, and oncological disorders. This review consolidates current evidence on the phytochemical composition, bioactivity, molecular mechanisms, and clinical efficacy of B. monnieri and its major bioactive constituents, particularly bacosides, bacopasides, and bacopasaponins. Preclinical investigations have demonstrated that B. monnieri exhibits antioxidant, anti-inflammatory, anti-amyloidogenic, and neuroprotective properties, mediated by modulation of cholinergic, serotonergic, glutamatergic, and GABAergic systems and by enhancement of long-term potentiation, synaptic plasticity, and dendritic arborization. Emerging in silico and systems pharmacology approaches identify multi-target interactions and modulate pathways linked to neurodegeneration, glucose metabolism, and cancer progression. Clinical trials across healthy populations, mild cognitive impairment, Alzheimer's disease, and Parkinson's disease indicate that chronic supplementation improves memory consolidation, cognitive processing, emotional well-being, and sleep architecture. Additionally, accumulating evidence supports its role in metabolic regulation, including enhanced insulin sensitivity, β-cell protection, and attenuation of diabetes-associated neurodegeneration, supported by multi-omics and network pharmacology analyses. Anticancer studies reveal synergistic effects of bacopaside derivatives in reducing tumour cell proliferation, migration, and aquaporin-mediated invasion. Collectively, the evidence positions B. monnieri as a multi-target botanical with translational promise in cognitive enhancement and as a complementary therapeutic candidate across metabolic, neurodegenerative, inflammatory, and cancer models. Future research should prioritize the development of standardized extracts, long-term safety evaluation, mechanistic validation in humans, and precision medicine stratification to optimize clinical applications.},
}

@article {pmid42852773,
year = {2026},
author = {Qiu, X and Zhang, Q and Meng, Y and He, Y and Tang, Z and Chu, L and Tan, Y},
title = {N1-methylnicotinamide Mediates Multi-Target Cognitive Deficit Relief via AMPK-Lysosome Axis Regulation.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X482182260914104640},
pmid = {42852773},
issn = {1875-6190},
abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) progresses via interconnected Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and lysosomal failure, while current single-target drugs only relieve cognitive symptoms without halting pathogenesis. Gut microbiota-derived N1-methylnicotinamide (MNAM) is associated with lower AD risk, yet its comprehensive multilevel regulatory mechanism remains unclear. This study systematically elucidated MNAM's neuroprotective network using in vitro neuronal/microglial injury models and two AD-relevant mouse models.

METHODS: In silico prediction and LC-MS verified MNAM's BBB permeability. TMT proteomics, siRNA knockdown and pharmacological rescue validated the CAB39L-AMPK-lysosomal axis. Immunofluorescence, enzyme assays and molecular docking assessed MNAM's CTSB inhibitory capacity. 16S rRNA sequencing and metabolomics characterized gut microbiota and NAD+ metabolic remodeling.

RESULTS: In vitro, MNAM crossed the blood-brain barrier, improved neuronal viability, reduced ROS and pro-inflammatory cytokines (IL-1β, TNF-α). In AD-like mice, it alleviated cognitive deficits, tau hyperphosphorylation, Aβ deposition, microglial activation, and restored SOD activity. MNAM upregulated CAB39L to activate AMPK, stabilized lysosomes, and restrained CTSB leakage. It reshaped protective intestinal flora, suppressed hepatic NNMT, and restored NAD+ balance. In LPS-challenged mice, MNAM selectively alleviated microglial activation and IL-1β accumulation.

DISCUSSION: MNAM targets multiple AD pathological nodes (Aβ deposition, tau phosphorylation, neuroinflammation, lysosomal dysfunction, gut microbiota-metabolite interactions) via the CAB39L-AMPK-lysosomal axis and gut microbiota/NAD+ metabolism regulation, which is distinct from single-target drugs. Its ability to cross the BBB and regulate host-microbiota metabolic crosstalk provides a novel mechanistic basis for AD therapy, supporting a shift from single-target to multi-target intervention strategies.

CONCLUSION: MNAM targets the CAB39L-AMPK-lysosomal axis, inhibits CTSB, and remodels gut microbiota-NAD+ metabolism to concurrently suppress core AD pathologies. This metabolite serves as a promising multi-target disease-modifying candidate for AD, warranting further validation in transgenic AD models and human neurons.},
}

@article {pmid42852776,
year = {2026},
author = {Chandrasekar, P and Kumar, JAK and Vellapandian, C and Naduchamy, KP},
title = {Neuroprotective Effect of Imeglimin Hydrochloride on H2O2-Induced SH-SY5Y Cells.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249512928260918130405},
pmid = {42852776},
issn = {1875-6166},
abstract = {INTRODUCTION: Alzheimer's disease is characterized by cognitive decline accompanied by the degeneration of cholinergic neurons. Notably, ROS make neurons more vulnerable to oxidative stress-induced damage and functional impairment in the brain. Hence, this research aimed to explore the antioxidant and neuroprotective activities of Imeglimin HCl in the SH-SY5Y cell line.

METHODS: Initially, the cytotoxic effect of Imeglimin HCl at 6.25 and 12.5 μg/mL was determined using the MTT assay. Subsequently, the inhibitory effect of Imeglimin HCl on H2O2-induced Reactive Oxygen Species (ROS) in SH-SY5Y cells was carried out.

RESULTS: The study demonstrated that 70% of cells were viable up to 12.5 μg/mL. The ROS inhibition assay showed that Imeglimin HCl inhibited the H2O2-induced ROS production in SH-SY5Y cells. It was concluded from the study that Imeglimin HCl has a neuroprotective effect.

DISCUSSION: In SH-SY5Y cells, HⁿOⁿ exposure mimics AD-related oxidative damage by elevating ROS and impairing mitochondrial function. Excessive ROS generation induced by H2O2 compromises mitochondrial membrane stability, which in turn activates the intrinsic apoptotic pathway. In the present study, Imeglimin hydrochloride significantly attenuated HⁿOⁿ-induced ROS generation, indicating a protective effect against oxidative stress.

CONCLUSION: It was concluded from the study that Imeglimin hydrochloride acts on GABA-A and M2 Muscarinic acetylcholine receptors, which play a prominent role in AD, since it has a better binding affinity. In addition, Imeglimin HCl exhibited antioxidant properties in SH-SY5Y cell lines by reducing reactive oxygen species production.},
}

@article {pmid42852840,
year = {2026},
author = {Manica, I and Mendonça, MD},
title = {Beyond WEIRD populations: Interpreting the gap between subjective cognitive complaints and objective impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497234},
doi = {10.1177/13872877261497234},
pmid = {42852840},
issn = {1875-8908},
abstract = {Subjective cognitive complaints (SCC) are shifting from a quasi-diagnostic marker to a multidimensional clinical signal. Leniz et al. use the semi-rural Chilean MAUCO cohort to extend this debate beyond Western-dominated settings. They show a subjective-objective discrepancy: baseline objective performance did not predict incident SCC, whereas benzodiazepine use, and depressive symptoms did, highlighting affective and iatrogenic influences. Yet SCC predicted incident cognitive impairment. We argue that these findings are better interpreted by a model of SCC with at least two-components: affective/iatrogenic and degeneration-related components. In resource-limited contexts, SCC may aid risk-enrichment while prompting medication and mood review.},
}

@article {pmid42852844,
year = {2026},
author = {Devi, G},
title = {The Alzheimer's Association 2024 diagnostic criteria: Generalizability of supporting autopsy evidence.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261496550},
doi = {10.1177/13872877261496550},
pmid = {42852844},
issn = {1875-8908},
abstract = {The Alzheimer's Association 2024 (AA-2024) diagnostic criteria permit a biological diagnosis of Alzheimer's disease based on a positive amyloid biomarker alone. This commentary examines the three autopsy analyses underpinning that framework, focusing on their implications for generalizability. The supporting cohorts were enriched for Alzheimer's disease pathology and derived from selected brain-bank populations whose demographic and clinical characteristics differ from the community-dwelling older adults increasingly undergoing biomarker testing. Independent studies have also produced differing estimates of concurrent tau pathology among amyloid-positive asymptomatic individuals. These observations support further validation of biologic diagnostic criteria in representative aging cohorts before widespread application in routine clinical practice.},
}

@article {pmid42852863,
year = {2026},
author = {Melin, JM and Young, NA and Camardo, J},
title = {Beyond the cerebrospinal fluid: Preclinical and clinical evidence on central nervous system penetration and functional activity of oral rapamycin (sirolimus).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261495936},
doi = {10.1177/13872877261495936},
pmid = {42852863},
issn = {1875-8908},
abstract = {Rapamycin, a potent mTORC1 inhibitor, is a leading candidate for treating age-related neurodegenerative disease. Numerous studies demonstrate beneficial effects in a variety of diseases that affect the brain. Yet a persistent belief among researchers is that rapamycin cannot penetrate brain tissue, citing as evidence its absence of detection in cerebrospinal fluid (CSF). This narrative review synthesizes clinical and preclinical evidence challenging this "CSF misconception." In humans, direct tissue sampling in glioblastoma detects rapamycin in brain at mTORC1-inhibitory concentrations, while functional measures-tumor regression and seizure control in tuberous sclerosis complex, cerebral metabolic preservation on PET in Alzheimer's disease, increased cerebral blood flow in APOE4 carriers, and prolonged antidepressant response-demonstrate incontrovertible activity in the brain. In mice, LC-MS/MS confirms dose-dependent brain accumulation, and rapamycin modulates mTORC1 signaling, autophagy, and synaptic, epigenetic, and inflammatory pathways. Rapamycin cannot be reliably detected in CSF because of four pharmacological factors-high lipophilicity with parenchymal sequestration, extreme red-cell and protein binding, P-glycoprotein efflux at the blood-CSF barrier, and assay insensitivity-none of which supports the contention that rapamycin fails to enter brain tissue. We flag the field's central gap: direct measurement of parent drug in intact human brain parenchyma at therapeutic doses is lacking. CSF concentration is a flawed proxy for rapamycin's CNS penetration. Alzheimer's disease and related dementias (ADRD) trials should instead track surrogate markers of mTORC1 inhibition, functional neuroimaging, clinical outcomes, and ADRD fluid biomarkers. These pharmacodynamics measurements are essential to the rational design and interpretation of prevention trials for the aging brain.},
}

@article {pmid42852881,
year = {2026},
author = {Ri, K},
title = {Rethinking Behavioral and Psychological Symptoms of Dementia in Severe Alzheimer's Disease: From Intentional Explanation to an Ecological, Body-Environment Framework.},
journal = {International journal of aging & human development},
volume = {},
number = {},
pages = {914150261495486},
doi = {10.1177/00914150261495486},
pmid = {42852881},
issn = {1541-3535},
abstract = {In contemporary dementia care, behavioral and psychological symptoms of dementia (BPSD) are often understood as expressions of the person's intentions or needs. This paper examines the limits of understanding BPSD as "expressions of intention" in severe Alzheimer's disease. It argues that while desires may still be preserved, the formation and maintenance of beliefs-an essential constituent of intentions in the standard desire-belief model-are likely to be severely compromised. As a result, many behavioral and perceptual symptoms closely related to basic activities of daily living cannot be adequately explained within an intention-based framework. As a complementary framework to existing dementia care theories, this paper proposes a reconceptualization of BPSD as arising from the interaction between embodied procedural memory and environmental affordances. Many BPSD are better understood not as expressions of intention, but as the outcome of situational and non-selective reactivation of fragments of relatively preserved procedural memory in response to the structure of the immediate environment. This reconceptualization extends the focus of care practice beyond the interpretation of the presumed meanings or intentions underlying BPSD and highlights the importance of modifying care environments in ways that appropriately support or constrain the reactivation of procedural memory.},
}

@article {pmid42852934,
year = {2026},
author = {Bakker, ED and van der Veere, PJ and Heymans, MW and van Harten, AC and van der Flier, WM and van Maurik, IS},
title = {The impact of the COVID-19 pandemic on institutionalization and healthcare costs in memory clinic patients.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261486732},
doi = {10.1177/13872877261486732},
pmid = {42852934},
issn = {1875-8908},
abstract = {BackgroundThe COVID-19 pandemic disrupted healthcare services and daily routines, which may have particularly affected individuals with cognitive impairment or dementia who rely on continuity of care. However, the impact of these disruptions on institutionalization and healthcare costs remains largely unknown.ObjectiveWe investigated the impact of COVID-19-pandemic on institutionalization and healthcare costs in a mixed memory clinic population, compared to a well-balanced historical control group.MethodsWe included memory clinic patients from the Amsterdam Dementia Cohort: 1) n = 911 pandemic-patients (baseline: 2017-2018, follow-up: until 2021), and 2) n = 821 well-balanced historical controls (baseline: 2015-2016, follow-up: until 2019). Time to institutionalization was analyzed using restricted mean survival time (RMST), and healthcare costs using linear regression with spline knot at 2 years.ResultsWe found no difference for time until institutionalization between groups for all diagnoses together. Stratified for syndrome diagnosis, we found that pandemic-patients with dementia (RMST between group contrast (BGC)[95%-CI] = -0.241 year[-0.456 - -0.026], i.e., -2.9 months) and another diagnosis (RMST BGC[95%-CI] = -0.214 year[-0.407 - -0.021], i.e., -2.6 months) had shorter time to institutionalization. Total healthcare costs did not differ between groups (B [95%-CI] = 302.12 [-1229.17-1833.40], p = 0.699).ConclusionsIn conclusion, we found no indications of a significantly decreased or increased healthcare consumption as a result of COVID-19 pandemic.},
}

@article {pmid42852936,
year = {2026},
author = {Frommann, I and Vogel, S and Jansen, L and Meiberth, D and Schild, AK and Jessen, F and Zank, S and Schneider, A and McCormick, C and Wagner, M},
title = {Accelerated forgetting in memory clinic patients with subjective cognitive decline: Results from a 7-day follow-up long-term retrieval assessment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490478},
doi = {10.1177/13872877261490478},
pmid = {42852936},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) is recognized as an early indicator of preclinical Alzheimer's disease (AD). However, individuals with SCD do not exhibit cognitive impairment on standard neuropsychological tests. Accelerated forgetting (AF) has been reported in individuals with preclinical AD and is characterized by intact learning and early retention but impaired retrieval after several days. Currently, AF is not captured by standard neuropsychological testing.ObjectiveThe present study investigated recall performance in memory clinic patients with SCD, without impairment on standard cognitive tests, during a 7-day follow-up telephone assessment for detecting AF.MethodsOne week after completing the neuropsychological assessment, participants underwent a structured telephone-based follow-up interview. This included various measures of verbal and visual memory. AF was operationalized as the rate of forgetting between initial recall and 7-day delayed recall.ResultsData from 35 individuals with SCD, who showed no cognitive impairment on standard tests, and 54 healthy controls (HC) were analyzed. Although there were no significant differences between the groups in learning and short-delay memory performance, after seven days, the SCD group showed lower recall and a higher forgetting rate on the FCSRT-IR free and total recall measures compared to the HC group.ConclusionsAF can be detected using a brief, telephone-based assessment in cognitively unimpaired participants with SCD. It could bridge the gap between subjective and objective memory decline. Further research is necessary to improve potential follow-up assessments in neuropsychological testing and to investigate the link between AF and AD biomarkers and memory decline.},
}

@article {pmid42852947,
year = {2026},
author = {Rogers, JT and Maroof, AM and Sarang, SS and Hamanaka, G and Wang, C and Cho, H and Parikh, T and Cahill, CM},
title = {Role of subcortical iron in Parkinson's disease, prodromal-depression, and dementia: Comparative links to anemias and osteoporosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489296},
doi = {10.1177/13872877261489296},
pmid = {42852947},
issn = {1875-8908},
abstract = {Three reports employing Mendelian randomization and quantitative susceptibility mapping from 41,581-patients in the UK biobank provide evidence to support that excess subcortical iron accumulation causally accelerates Parkinson's disease (PD). While subcortical iron was not a significant driver of Alzheimer's disease (AD), neural shrinkage and ferroptosis in grey matter featured in vascular dementia. Subcortical iron was changed in depression, anemia and osteoporosis patients. Since iron chelators were not beneficial to either AD or PD patients in clinical trials, we propose that translational control of the iron-homeostatic protein α-synuclein (iron importer) could therapeutically normalize subcortical iron during PD progression.},
}

@article {pmid42852955,
year = {2026},
author = {Korczyn, AD},
title = {The problem with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491987},
doi = {10.1177/13872877261491987},
pmid = {42852955},
issn = {1875-8908},
abstract = {Despite decades of intensive research, progress in treating late-onset Alzheimer's disease remains limited. A central problem may be conceptual: Alzheimer's disease may not be a single disease, but a heterogeneous syndrome arising from differing combinations of aging, genetic susceptibility, vascular injury, metabolic stress, inflammation, and other pathologies. Research has focused largely on biomarkers rather than the pathways leading to them. The dominance of amyloid- and tau-centered models, together with limited animal models, may constrain therapeutic progress. A more productive strategy may require an integrated, personalized approach targeting the relevant contributing and modifiable factors in each individual.},
}

@article {pmid42853103,
year = {2026},
author = {Gómez-Oliva, R and Chamorro-Francisco, A and Atienza-Navarro, I and Carrascal, L and Freire-Aragón, MD and Hernández-Galán, R and Nunez-Abades, P and García-Alloza, M and Castro, C},
title = {Sex-Specific Neurogenic and Cognitive Responses in a Murine Model of Accelerated Aging.},
journal = {Aging cell},
volume = {25},
number = {10},
pages = {e70663},
doi = {10.1111/acel.70663},
pmid = {42853103},
issn = {1474-9726},
support = {PID2022-142418OB-C21//MICIU/AEI/10.13039/501100011033 ERDF/UE/ ; PID2022-142418OB-C22//MICIU/AEI/10.13039/501100011033 ERDF/UE/ ; FEDER-UCA-2024-A2-13//Andalusia 2021-2027 ERDF/UE Operational Program/ ; },
mesh = {Animals ; Male ; *Neurogenesis/drug effects ; *Aging ; Mice ; *Cognition/drug effects/physiology ; Female ; Disease Models, Animal ; Hippocampus/drug effects ; Sex Characteristics ; },
abstract = {Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer's disease-like neuropathology, and an initial increase in hippocampal neurogenesis that ultimately depletes the neural stem cell pool. Notably, most studies using murine models of aging or neurodegeneration have focused on males or mixed-sex cohorts, leaving sex-specific differences in neurogenesis and cognitive decline largely unexplored. Recent evidence indicates that diterpenoid treatment is associated with improved cognitive performance and enhanced neurogenesis in 6-month-old male SAMP8 mice. However, whether females exhibit similar responses remains unknown. In this study, we characterized sex differences in hippocampal neurogenesis in 6-month-old SAMP8 mice and examined potential sex-dependent effects of diterpenoid therapy. Our findings reveal sex-specific differences in physiological and pathological hippocampal neurogenesis and in responsiveness to ER272 treatment. Male SAMR1 mice displayed higher baseline neurogenesis than females, while male and female SAMP8 mice followed distinct neurogenic aging trajectories. ER272 was associated with improved cognitive performance and preservation of multiple neurogenic parameters in males but showed limited effects in females. These results suggest sex-specific mechanisms of brain aging and indicate that mixed-sex analyses may mask biologically relevant differences, highlighting the importance of considering sex in aging studies and therapeutic development.},
}

Animals
Male
*Neurogenesis/drug effects
*Aging
Mice
*Cognition/drug effects/physiology
Female
Disease Models, Animal
Hippocampus/drug effects
Sex Characteristics

@article {pmid42853231,
year = {2026},
author = {Liu, H and Yin, Z and Ye, Z and Chen, Y},
title = {Multi-Scale Integrative Transcriptomic Analysis of Alzheimer's Disease and Atopic Dermatitis Reveals Shared Immune and Cellular Networks.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261495656},
doi = {10.1177/15333175261495656},
pmid = {42853231},
issn = {1938-2731},
mesh = {*Dermatitis, Atopic/immunology/genetics ; *Alzheimer Disease/immunology/genetics ; Humans ; Gene Expression Profiling ; *Transcriptome ; Signal Transduction ; },
abstract = {BackgroundAlzheimer's disease and atopic dermatitis may converge on shared immunoinflammatory pathways, but their molecular relationship remains poorly defined.MethodsWe integrated differential expression, enrichment analysis, network prioritization, machine learning, external dataset assessment, and Mendelian randomization to identify shared molecular signatures and assess their causal relevance. Single-cell transcriptomics, cell-cell communication analysis, virtual knockout, and molecular simulation were further applied to define cell-type-specific signaling networks and evaluate drug-target interactions.ResultsIntegrative transcriptomic analyses identified MYD88 and FGR as hub genes linking immune activation with structural regulation. Convergent evidence highlighted the IgSF CAM signaling pathway, suggesting that impaired cell adhesion and intercellular communication represent a common pathological feature of both diseases. Single-cell analyses revealed distinct microenvironmental signaling landscapes, characterized by NRG-ERBB4 activity in Alzheimer's disease and MIF-centered immune networks in atopic dermatitis.ConclusionsThese findings suggest potential shared immune-structural regulatory features between Alzheimer's disease and atopic dermatitis.},
}

*Dermatitis, Atopic/immunology/genetics
*Alzheimer Disease/immunology/genetics
Humans
Gene Expression Profiling
*Transcriptome
Signal Transduction

@article {pmid42842105,
year = {2026},
author = {Tiwari, R and Balaji, M and Chivukula, N and Sil, P and Samal, A},
title = {An integrated resource for systems-level analysis of aging hallmarks and associated genes.},
journal = {Biogerontology},
volume = {27},
number = {5},
pages = {},
pmid = {42842105},
issn = {1573-6768},
support = {Advanced Research and Education in Mathematical Sciences at IMSc [O.M. No. 2103/1/2025-R&D-II-DAE/IMSc/4885 dated 23.4.2026]//Department of Atomic Energy, Government of India/ ; },
mesh = {*Aging/genetics ; Humans ; *Databases, Genetic ; Protein Interaction Maps ; Animals ; Gene Regulatory Networks ; },
abstract = {AgingHallmarksDB is an interactive web platform designed to facilitate systems-level aging research centered on 11 aging hallmarks. It comprises 3111 aging hallmark-associated genes integrated from seven established databases, including a high-confidence consensus set comprising 1089 genes. It further incorporates tissue, cell-type class, exosomes, protein-protein and regulatory interactions to facilitate deeper biological insights. AgingHallmarksDB enables over representation analysis (ORA) and gene set enrichment analysis (GSEA) to elucidate varying molecular mechanisms underlying aging. Gene overlaps and Jaccard similarity revealed interconnectedness among the hallmarks. Network analyses further showed these pairs are connected within the protein-protein interaction (PPI) network. The utility of this resource was demonstrated through multiple hallmark-associated analyses. PPI network topology analysis of common hallmark genes revealed several key age-associated genes that act as central hubs across multiple aging hallmarks. Hallmark enrichment analyses revealed extensive coverage across aging-related diseases compared to limited enrichment seen in non-aging-related diseases like developmental and congenital diseases. Further these analyses showed biologically meaningful disease-associated processes, like "Loss of proteostasis" in Alzheimer's disease and "Chronic inflammation" in atherosclerosis as highly significant hallmarks. These disease-hallmark associations were further supported by network proximity analyses. In addition, GSEA of the PM2.5 exposure-associated skin transcriptome identified significant enrichment of aging hallmarks, particularly "Epigenetic alterations", demonstrating the resource's utility in interpreting transcriptomic datasets within the context of aging biology. Overall, AgingHallmarksDB provides a robust framework for investigating hallmark-associated functionality, and potential therapeutic discovery in aging and longevity. AgingHallmarksDB is accessible at https://cb.imsc.res.in/aginghallmarksdb/ .},
}

*Aging/genetics
Humans
*Databases, Genetic
Protein Interaction Maps
Animals
Gene Regulatory Networks

@article {pmid42842141,
year = {2026},
author = {Liu, S and Lu, J and Liu, J and Liu, H and Liu, Z and Yang, D and Liang, X and Xu, J},
title = {Advances in Extracellular Vesicle-Based Innovative Drugs Targeting Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42842141},
issn = {1559-1182},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Extracellular Vesicles/metabolism ; Animals ; *Drug Delivery Systems/methods ; },
abstract = {The scarcity of effective therapies for Alzheimer's disease (AD) underscores the urgent need for innovative strategies. This review focuses on the targeted delivery of engineered small extracellular vesicles (sEVs, 30-150 nm). By capitalizing on their intrinsic properties as natural nanocarriers-including low immunogenicity and excellent biocompatibility-these EVs can be engineered to co-deliver therapeutic cargoes such as specific miRNAs, neurotrophic factors (e.g., BDNF), and nucleic acid modalities (e.g., siRNA/ASO targeting BACE1). While a single construct simultaneously delivering all these agents with proven in vivo synergy remains a conceptual framework rather than a validated reality, independent studies have demonstrated that EV-mediated delivery of each cargo type exerts beneficial effects on AD pathology, including Aβ clearance, Tau pathology alleviation, and neuroinflammation suppression. The intranasal administration offers a significant brain-targeting advantage by enabling direct nose-to-brain delivery, bypassing the blood-brain barrier and minimizing peripheral biodistribution. Recently, a phase I/II trial (Ruijin Hospital) demonstrated that intranasal MSC-EVs are safe and produce durable cognitive improvements (ADAS-Cog ↓ 2.33 points at week 12, sustained to - 3.98 points at week 36) in the medium-dose cohort, exceeding the minimal clinically important difference (MCID) of ≥ 2 points for AD. Based on these demonstrated clinical and preclinical evidence, we propose that rationally engineered EVs, following rigorous systematic pharmacology and safety assessments, hold transformative potential to pioneer a safe, efficacious, and non-invasive breakthrough therapy for AD, while acknowledging that critical challenges in GMP manufacturing, biodistribution, and regulatory approval remain to be resolved.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Extracellular Vesicles/metabolism
Animals
*Drug Delivery Systems/methods

@article {pmid42842169,
year = {2026},
author = {Singh, RK and Banerjee, C and Mehan, S},
title = {Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42842169},
issn = {1557-1904},
mesh = {Animals ; Humans ; *Clemastine/pharmacology/therapeutic use ; *Central Nervous System Diseases/drug therapy/immunology/metabolism ; *Myelin Sheath/drug effects ; *Neuroimmunomodulation/drug effects/physiology ; *Remyelination/drug effects/physiology ; Neuroinflammatory Diseases/drug therapy/immunology ; *Histamine H1 Antagonists/pharmacology/therapeutic use ; },
abstract = {Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.},
}

Animals
Humans
*Clemastine/pharmacology/therapeutic use
*Central Nervous System Diseases/drug therapy/immunology/metabolism
*Myelin Sheath/drug effects
*Neuroimmunomodulation/drug effects/physiology
*Remyelination/drug effects/physiology
Neuroinflammatory Diseases/drug therapy/immunology
*Histamine H1 Antagonists/pharmacology/therapeutic use

@article {pmid42842336,
year = {2026},
author = {Frontzkowski, L and Roemer-Cassiano, S and Gnörich, J and Janowitz, D and Eyob, H and Probst, K and Dhoqina, D and Dewenter, A and Steward, A and Zhu, Z and Klonowski, M and Hirsch, F and Biel, D and Paulus, M and Vöglein, J and Schönecker, S and Rauchmann, BS and Kurz, C and Koriath, C and Häckert, J and Stöcklein, S and Palleis, C and Perneczky, R and Levin, J and Buerger, K and Werner, RA and Höglinger, G and Brendel, M and Franzmeier, N},
title = {Network-dependent remote effects and local tau burden jointly shape neuronal dysfunction in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71914},
pmid = {42842336},
issn = {1552-5279},
support = {AARG-22-973496/ALZ/Alzheimer's Association/United States ; 390857198//Deutsche Forschungsgemeinschaft/ ; 01EK1605A//Bundesministerium für Bildung und Forschung/ ; HitTau//Bundesministerium für Bildung und Forschung/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology/physiopathology ; *tau Proteins/metabolism ; Positron-Emission Tomography ; *Brain/diagnostic imaging/metabolism/pathology ; Female ; Male ; Aged ; Neurons/pathology ; Aged, 80 and over ; },
abstract = {BACKGROUND: Tau pathology in Alzheimer's disease (AD) propagates along the brain's connectome, yet the mechanisms by which tau drives neuronal dysfunction remain unclear. We hypothesized that dysfunction primarily emerges in regions close to tau-harboring epicenters.

METHODS: One hundred thirty-one amyloid-positive individuals underwent dynamic [[18]F]PI-2620 tau positron emission tomography. Kinetic modeling yielded distribution volume ratios (DVRs) and perfusion (R1). Tau epicenters were defined as top 10% DVR regions. Connectivity-based distance to epicenters was derived from normative resting-state functional connectivity.

RESULTS: At the individual level, hypoperfusion was more closely related to distance from tau epicenters than to local tau deposition, particularly in early AD, consistent with diaschisis-like disconnection. With advancing biological disease severity, local tau deposition increasingly converged with hypoperfusion. Critically, hypoperfusion mediated the relationship between tau accumulation and cognitive decline.

DISCUSSION: Tau epicenters shape the brain-wide pattern of neuronal dysfunction, while local tau burden determines the degree of damage driving cognitive decline.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/pathology/physiopathology
*tau Proteins/metabolism
Positron-Emission Tomography
*Brain/diagnostic imaging/metabolism/pathology
Female
Male
Aged
Neurons/pathology
Aged, 80 and over

@article {pmid42842388,
year = {2026},
author = {Vashishath, Y and Beaver, SA and Saeed, F and Bozdag, S and , },
title = {HINN prioritizes multi-omics biomarkers associated with cognitive decline.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag741},
pmid = {42842388},
issn = {1367-4811},
abstract = {MOTIVATION: Integrating multi-omics data for disease prediction remains challenging due to the complexity of cross-layer biological interactions and the limited use of prior biological knowledge in many machine learning models. We present the Hierarchical Input Neural Network (HINN), a deep learning framework that incorporates biologically informed connections across genomic, epigenetic, and transcriptomic layers to model regulatory relationships in a structured and interpretable manner. HINN was applied to blood-derived multi-omics data to predict cognitive assessment scores, including MMSE, MoCA, ADAS11, and RAVLT.Immediate. A biologically guided feature construction pipeline was used to integrate GWAS-derived SNPs, promoter-region DNA methylation, and gene expression data through Gene Ontology Biological Process (GO-BP) and KEGG pathway mappings.

RESULTS: The model was evaluated using a rigorous training strategy that separates feature selection from testing and incorporates cross-validation as well as repeated runs to ensure robustness. Across all cognitive outcomes, HINN achieved the lowest mean normalized MSE among the evaluated models, with statistically significant improvements over most baseline methods. Ablation analyses showed that the contributions of individual omics modalities and biologically informed connectivity varied across cognitive outcomes, with the clearest benefits of structured connectivity observed for ADAS11 and MMSE. Feature attribution analysis identified a multi-omics cascade involving SNP (rs116557230), CpG site (cg24041822), and a SOCS4 gene expression probe, which showed consistent associations with multiple cognitive outcomes. These findings highlight the ability of HINN to uncover biologically meaningful cross-omics relationships relevant to cognitive decline. Together, this work demonstrates that integrating deep learning with biological knowledge enables biomarker discovery for complex diseases.

All code, sample data, and instructions are publicly available via GitHub (https://github.com/bozdaglab/HINN) and archived on Zenodo (https://doi.org/10.5281/zenodo.19197057) to ensure reproducibility and long-term accessibility.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}

@article {pmid42842469,
year = {2026},
author = {Mah, E and Gallagher, D and Kang, Y and Gao, F and Ramirez, J and Ismail, Z and Black, SE and Cao, X and Herrmann, N and Marzolini, S and Oh, P and Chen, JJ and Survilla, K and Swardfager, W and Vieira, D and Rapoport, MJ and Lanctôt, KL},
title = {White matter hyperintensities moderate neuropsychiatric response to N-acetylcysteine and exercise therapy in vascular mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490542},
doi = {10.1177/13872877261490542},
pmid = {42842469},
issn = {1875-8908},
abstract = {BackgroundVascular mild cognitive impairment (vaMCI) is frequently accompanied by neuropsychiatric symptoms (NPS), particularly apathy, which are associated with white matter hyperintensities (WMH). N-acetylcysteine (NAC) combined with exercise may provide neuroprotective benefits.ObjectiveWe hypothesized that baseline frontal and global WMH burden would moderate the neuropsychiatric response to NAC plus exercise. We further hypothesized that the strongest domain-specific effects would be observed for apathy and affective dysregulation.MethodsParticipants with vaMCI were randomized to NAC (2400 mg daily) or placebo plus exercise for 6 months. WMH volumes were quantified using structural MRI. NPS were assessed using the Mild Behavioral Impairment Checklist (MBI-C) at baseline, 3 months, and 6 months. Negative binomial generalized linear mixed models examined WMH × time × treatment interactions. False discovery rate (FDR) correction was applied.ResultsFifty-one participants were included. Lower baseline frontal (β = 0.229, SE = 0.070, FDR-adjusted p = 0.007) and global (β = 0.258, SE = 0.080, FDR-adjusted p = 0.007) WMH volume was associated with greater reductions in NPS over 6 months in the NAC plus exercise group. This effect was driven by improvements in apathy (frontal: β = 0.186, SE = 0.076, FDR-adjusted p = 0.048; global: β = 0.207, SE = 0.089, FDR-adjusted p = 0.049).ConclusionsBaseline WMH burden moderates neuropsychiatric treatment response in vaMCI. These findings support the importance of optimizing care for cerebrovascular risk factors in this vulnerable population.},
}

@article {pmid42842740,
year = {2026},
author = {Lanza, M and Basilotta, R and Scuderi, SA and Giovani, P and Caccamo, A and Casili, G and Oddo, S and Esposito, E},
title = {Alterations in diacylglycerol kinase θ define early pathological features of Alzheimer's disease in a mouse model.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490813},
doi = {10.1177/13872877261490813},
pmid = {42842740},
issn = {1875-8908},
abstract = {BackgroundDiacylglycerol kinase theta (DGKθ) is an enzyme involved in lipid signaling pathways and has been implicated in Alzheimer's disease (AD). DGKθ plays a crucial role in regulating diacylglycerol and phosphatidic acid levels, which are important for neuronal function and survival. Dysregulation of DGKθ leads to abnormal lipid signaling, contributing to neuroinflammation, synaptic dysfunction, and neurodegeneration-hallmarks of AD.ObjectiveThis study aimed to assess the involvement of DGKθ in AD by measuring DGKθ levels as a function of age in the brains of APP/PS1 mice and associating its changes with key AD neuropathological markers.MethodsTo investigate the role of DGK-θ in AD, brain tissues from young and aged APP/PS1 transgenic and wild-type mice were analyzed using western blot, immunohistochemistry, and Pearson correlation analyses to establish relationships between protein expression levels.ResultsWe found that DGKθ levels were higher in older, but not in younger, APP/PS1 mice compared to age-matched controls. Notably, there was a positive correlation between DGKθ levels, Aβ42 levels, and astrogliosis.ConclusionsThese results suggest that DGKθ may play an important role in AD and that its modulation could represent a potential therapeutic strategy for this insidious disorder.},
}

@article {pmid42842789,
year = {2026},
author = {Gebremichael, D and Bekena, S and Singh, RK and Walker, AIB and Millsap, M and Banks, CF and Bekele, B and Zhu, Y and Trani, JF and Babulal, GM},
title = {Multimorbidity, Polypharmacy, and Neighborhood Disadvantage as Determinants of Cognitive Performance in the ARCHES Cohort.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261491344},
pmid = {42842789},
issn = {1552-4523},
abstract = {BackgroundAfrican American adults experience a disproportionate burden of dementia, shaped by structural and clinical factors that remain unclear.ObjectiveTo quantify associations between multimorbidity, polypharmacy, and cognition in the context of neighborhood disadvantage.MethodsThis study is a cross-sectional analysis of 348 African American adults aged 45-92 years (mean 64.3 years; 73.6% female) from the Aging Research Characterizing Health Exposome via Social drivers (ARCHES) cohort. Comorbidity burden was assessed using a modified Charlson Comorbidity Index (CCI), polypharmacy as ≥5 medications, and neighborhood disadvantage using the Area Deprivation Index (ADI). Linear regression estimated associations with a Preclinical Alzheimer's Cognitive Composite (PACC). The polypharmacy model included modified CCI as a covariate, and effect modification by ADI was assessed using an interaction term between polypharmacy and ADI.ResultsHigher modified CCI was associated with lower cognitive performance (B = -0.071; 95% CI: -0.130, -0.012). Polypharmacy was not independently associated with cognition after modified CCI adjustment (B = -0.081; β = -0.057; p = 0.257). No significant ADI interaction was found (p = 0.064).},
}

@article {pmid42842820,
year = {2026},
author = {Eygasier, J and Piolino, P and Baudouin, A},
title = {[Early Onset and Independence of Prospective Memory Impairments in Alzheimer's Disease - A Challenge for Diagnosis].},
journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement},
volume = {24},
number = {3},
pages = {289-301},
doi = {10.1684/pnv.2026.1299},
pmid = {42842820},
issn = {2115-7863},
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis/complications ; *Memory, Episodic ; *Memory Disorders/diagnosis/psychology ; Neuropsychological Tests ; Aged ; Early Diagnosis ; Aged, 80 and over ; Executive Function ; },
abstract = {Prospective memory (PM) refers to the ability to remember to carry out an intended action at a specific point in the future. Despite its crucial role in autonomy and quality of life, this cognitive function remains understudied and is still rarely assessed in patients with Alzheimer's disease (AD). This review examines whether PM impairments emerge independently and at an early stage of AD. Some studies suggest that PM deficits appear earlier than, and independently of, retrospective memory (RM) deficits. They may therefore constitute a valuable complementary marker for the early identification of cognitive profiles consistent with Alzheimer's disease. However, other studies indicate that PM impairments may primarily reflect declines in RM or executive functioning. PM thus appears to lie at the interface between memory processes and cognitive control and may represent an early manifestation of cognitive decline. The heterogeneity of the findings, partly attributable to methodological differences, precludes a clear consensus. Nevertheless, assessing PM appears clinically relevant, both for refining the characterization of patients' cognitive profiles and for better capturing the functional impact of AD on everyday functioning.},
}

Humans
*Alzheimer Disease/psychology/diagnosis/complications
*Memory, Episodic
*Memory Disorders/diagnosis/psychology
Neuropsychological Tests
Aged
Early Diagnosis
Aged, 80 and over
Executive Function

@article {pmid42842986,
year = {2026},
author = {Tejada-Vera, B and Bastian, BA and Miniño, AM},
title = {Deaths: Leading Causes for 2024.},
journal = {National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System},
volume = {75},
number = {7},
pages = {},
pmid = {42842986},
issn = {1551-8930},
mesh = {Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Age Distribution ; *Cause of Death/trends ; Sex Distribution ; United States/epidemiology ; Adolescent ; Young Adult ; Adult ; },
abstract = {OBJECTIVES: This report presents final 2024 data on the 10 leading causes of death in the United States by age group, race and Hispanic origin, and sex. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements "Deaths: Final Data for 2024," the National Center for Health Statistics' annual report of final mortality statistics.

METHODS: Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2024. Causes of death classified by the International Classification of Diseases, 10th Revision are ranked according to the number of deaths. Cause-of-death statistics are based on the underlying cause of death.

RESULTS: In 2024, the ranked order of 9 of the 10 leading causes of death remained unchanged from 2023. The 10 leading causes of death in 2024 in ranked order were: Diseases of heart; Malignant neoplasms; Accidents (unintentional injuries); Cerebrovascular diseases; Chronic lower respiratory diseases; Alzheimer disease; Diabetes mellitus; Nephritis, nephrotic syndrome and nephrosis; Chronic liver disease and cirrhosis; and Intentional self-harm (suicide). These causes accounted for 70.9% of all deaths occurring in the United States. Rankings are presented by age, race, Hispanic origin, and sex. The 10 leading causes of infant death for 2024 in ranked order were: Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Sudden infant death syndrome; Accidents (unintentional injuries); Newborn affected by maternal complications of pregnancy; Bacterial sepsis of newborn; Newborn affected by complications of placenta, cord and membranes; Respiratory distress of newborn; Diseases of the circulatory system; and Intrauterine hypoxia and birth asphyxia.},
}

Aged
Aged, 80 and over
Child
Child, Preschool
Female
Humans
Infant
Infant, Newborn
Male
Middle Aged
Age Distribution
*Cause of Death/trends
Sex Distribution
United States/epidemiology
Adolescent
Young Adult
Adult

@article {pmid42843009,
year = {2026},
author = {Jack, K and Lui, E and van Dam, PH and Dennett, L and Kraut, RY},
title = {Regularly Scheduled Acetaminophen for Pain in Long-Term Care: Systematic Review and Meta-Analysis.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {11},
pages = {106432},
doi = {10.1016/j.jamda.2026.106432},
pmid = {42843009},
issn = {1538-9375},
abstract = {OBJECTIVE: Pain is common among long-term care (LTC) residents, and acetaminophen is often recommended as first-line therapy. We aimed to determine whether regularly scheduled acetaminophen, compared with any comparator, improves pain outcomes in LTC.

DESIGN: Systematic review and meta-analysis.

SETTING AND PARTICIPANTS: Residents in LTC METHODS: MEDLINE, EMBASE, CINAHL, and Scopus were searched from inception to June 9, 2026. Risk of bias (RoB) was assessed using the Cochrane RoB1 tool. The primary outcome was pain, with secondary outcomes including quality of life and adverse events. Pain outcomes were pooled using standardized mean differences with inverse-variance weighting and a random-effects model. The certainty of evidence was evaluated using GRADE (Grading of Recommendations, Assessment, development and evaluation).

RESULTS: Four randomized controlled trials conducted in the United States and Europe met inclusion criteria, enrolling 482 LTC residents with mild-to-moderate pain at baseline and moderate-to-severe dementia. Acetaminophen was administered 3 to 4 times daily at total daily doses of 2500 to 3000 mg, with follow-up ranging from 4 to 13 weeks. Comparators included placebo (n = 3) and usual care (n = 1). Pain was assessed using MOBID-2 (Mobilization-Observation-Behavior-Intensity-Dementia-2 Pain Scale) and DS-DAT (Discomfort Scale-Dementia of the Alzheimer's Type) scales. Overall RoB was low, with the main concerns related to incomplete reporting of study methods and outcomes. There was no statistically significant reduction in pain with regularly scheduled acetaminophen compared with placebo or usual care (standardized mean difference, -0.14; 95% CI, -0.39 to 0.11; I[2] = 6%; moderate-certainty evidence). One study evaluated quality of life and found no statistically significant differences between groups. Adverse event reporting was limited and inconsistent among studies.

CONCLUSIONS AND IMPLICATIONS: Regularly scheduled acetaminophen probably does not improve pain in LTC residents with moderate-to-severe dementia and mild-to-moderate pain. These findings suggest that regularly scheduled acetaminophen for pain management in LTC may need to be reconsidered.},
}

@article {pmid42843091,
year = {2026},
author = {Venkatesan, A and Sinha, P and Basak, J and Bahadur, RP},
title = {Gene regulatory co-expression networks decipher potential lncRNA-miRNA-mRNA interactions modulating transcription regulation in neurodegeneration.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109462},
doi = {10.1016/j.compbiolchem.2026.109462},
pmid = {42843091},
issn = {1476-928X},
abstract = {Neurodegenerative diseases are complex disorders characterised by progressive neuronal loss and widespread transcriptomic dysregulation. However, understanding the molecular interactions among coding and non-coding RNAs, especially lncRNAs and miRNAs, contributing to disease progression remains elusive. In this study, RNA-Seq datasets from disease-relevant neuronal populations and different brain tissues representing Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are analysed using an integrative network-based framework. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) are combined to identify disease-associated modules and prioritise highly connected hub genes. They are subsequently integrated with curated RNA interaction databases to construct candidate lncRNA-miRNA-mRNA regulatory networks. Functional enrichment and UTR variant analyses are further incorporated to connect the regulatory network framework with biological processes and potential sequence variations. The novelty of the present study lies in the systematic integration of transcriptomic co-expression, post-transcriptional regulation, functional and sequence-level analyses within a single framework. This framework enables the identification of disease-specific and shared regulatory features, and links the candidate regulatory interactions with potential UTR sequence alterations. Across eight tissue-specific samples, 163 hub genes and 4869 candidate lncRNA-miRNA-mRNA interactions are identified. Additionally, we also identify 414 UTR variants associated with the hub genes. Pathways associated with hub genes including axonogenesis, synaptic organization, intracellular transport and RNA regulatory mechanisms are commonly found to be enriched in AD, PD and ALS. These findings provide a quantitative resource for prioritising regulatory interactions between candidate hub genes and associated UTR variants for future experimental validation.},
}

@article {pmid42843100,
year = {2026},
author = {Zhu, Y and Jafari, Z and Kolb, BE and Mohajerani, MH},
title = {From pathogenesis to non-medical therapy: A review of exploring sensory and multi-sensory stimulation as a non-invasive treatment approach for Alzheimer's disease.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {107004},
doi = {10.1016/j.neubiorev.2026.107004},
pmid = {42843100},
issn = {1873-7528},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, marked by the accumulation of amyloid-beta plaques, tau pathology, and synaptic dysfunction, ultimately leading to memory loss, cognitive decline, neuropsychiatric symptoms and neuronal degeneration that impairs daily functioning. Despite the availability of pharmacological treatments developed to slow down symptom progression, their clinical efficacy remains uncertain, and they are frequently associated with adverse side effects, underscoring the urgent demand for safer and more effective therapeutic alternatives. Non-pharmacological approaches, therefore, have been investigated and are considered promising alternative therapeutic strategies for AD. This paper outlines the pathological features and neural network changes that occur across the progression of Alzheimer's disease (AD), reviews the effects of different sensory stimulation approaches on reducing these AD-associated changes, and discusses the potential mechanisms underlying various sensory and multisensory stimulation interventions in mitigating AD-related symptoms. These sensory stimulation interventions, including 40 Hz Gamma Entrainment Using Sensory Stimulation [GENUS], Photobiomodulation, Bright Light Therapy, Music Therapy, Aromatherapy, Tactile Stimulation, and Multisensory Stimulation, are found to slow down the progression of AD by ameliorating multiple AD pathologies, enhancing cognitive function, promoting neuroplasticity, regulating sleep patterns, and reducing behavioural or neuropsychiatric symptoms. Crucially, this present work integrates both human and animal studies, aligning clinical outcomes with mechanistic insights derived from animal studies, thereby bridging preclinical and clinical research to promote the translation of sensory interventions into effective treatments for patients with AD.},
}

@article {pmid42843155,
year = {2026},
author = {Guzman, S and Granholm, AC and Benson-Gallanis, M and Denney, A and Olofsson, HE and Raust, M and Phares, J and Aragon, S and Bretsch, C and Carlson, AM and Yu, X and Piquet, AL},
title = {Histopathological investigation in Glycine receptor antibody positive progressive encephalomyelitis with rigidity and myoclonus (PERM): A case report.},
journal = {Journal of neuroimmunology},
volume = {422},
number = {},
pages = {579107},
doi = {10.1016/j.jneuroim.2026.579107},
pmid = {42843155},
issn = {1872-8421},
abstract = {OBJECTIVE: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare autoimmune neurologic disorder associated with antibodies against the glycine receptor (GlyR). Neuropathologic descriptions are limited. We here report clinical and autopsy findings of a patient with GlyR antibody-associated PERM.

METHODS: Comprehensive postmortem neuropathologic examination was performed using routine histology, immunohistochemistry, and immunofluorescence across neocortical, subcortical, brainstem, cerebellar, and spinal cord regions. Antibodies included GAD65/67, GlyR, IBA1, CD163, GFAP, CD3, and CD20.

RESULTS: A 68-year-old man presented with rapidly progressive trismus, bulbar dysfunction, rigidity, myoclonus and ataxia. Symptoms eventually progressed resulting in respiratory failure and cardiac arrest. Work up was remarkable for positive CSF GlyR antibody confirming the diagnosis of GlyR antibody-associated PERM. Autopsy demonstrated preserved neuronal architecture despite severe clinical disease. The motor cortex demonstrated focal neuropil vacuolation, mild myelin pallor, and prominent microglial activation in the motor cortex, with abnormal foaming, vacuolated cytoplasm appearance. Microgliosis was identified within the thalamus, basal ganglia, amygdala, substantia nigra, dentate nucleus, and spinal cord. Despite the patient's cardiopulmonary arrest, eosinophilic ("red") neurons, diffuse neuronal dropout, and infarct-type tissue injury were not identified. Significant T-cell or B-cell infiltrates and concomitant Alzheimer's disease neuropathologic changes were absent.

CONCLUSIONS: This case expands the limited neuropathologic literature on GlyR antibody-associated PERM by demonstrating pathological changes involving cortical, subcortical, cerebellar, brainstem, and spinal cord regions with preserved neuronal architecture and widespread microglial activation. Additional autopsy studies are needed to define the spectrum and reproducibility of these findings.},
}

@article {pmid42843274,
year = {2026},
author = {Di Martino, E and De Vos, R and Koenig Gimeno, S and Ricciardi, F and Luchicchi, A and Orefice, NS},
title = {ER-Nε-lysine acetylation machinery in neurological disorders: A context-dependent regulator of proteostasis.},
journal = {Current opinion in chemical biology},
volume = {95},
number = {},
pages = {102786},
doi = {10.1016/j.cbpa.2026.102786},
pmid = {42843274},
issn = {1879-0402},
abstract = {Despite extensive characterization of cytosolic and nuclear acetylation, the functional relevance of luminal ER-Nε-lysine acetylation in the nervous system remains poorly understood. This modification is mediated by a coordinated metabolic-secretory axis involving acetyl-CoA availability and the ER-resident acetyltransferases ATase-1 (NAT8B) and ATase-2 (NAT8), which depend on acetyl-CoA import into the ER via the transporter SLC33A1 (AT-1). Upstream, the citrate transporters SLC25A1 and SLC13A5 contribute to shaping the cytosolic acetyl-CoA pool. Emerging evidence identifies this pathway as a key regulator of proteostasis within the early secretory pathway, linking cellular metabolism to protein processing, trafficking, and degradation. Recent studies in neurological disease models suggest that excessive activation of this machinery may exert pathogenic effects through distinct mechanisms. In experimental models of autism spectrum disorder (ASD), increased ER acetylation is associated with altered secretory pathway flux, impaired synaptic proteostasis, and abnormal neuronal connectivity, ultimately leading to ASD-like phenotypes. In Alzheimer's disease (AD) models, excessive ER-Nε-lysine acetylation appears to suppress reticulophagic clearance of aggregation-prone proteins within the secretory pathway, whereas genetic or pharmacological reduction of AT-1/ATase activity enhances proteostatic clearance and confers protective effects. In this opinion article, we discuss ER-Nε-lysine acetylation as a context-dependent regulator of proteostasis in neurodevelopmental and neurodegenerative disease models. We highlight key unresolved questions regarding acetylation substrates, relevance to human biology, and future therapeutic opportunities. We further consider its potential relevance to additional disorders, including multiple sclerosis, where its contribution remains largely unexplored.},
}

@article {pmid42843275,
year = {2026},
author = {Adrita, N and Claassen, I and Huerta, M and Black, SM and Estevez, AG and Roberts, BR and Beckman, JS and Franco, MC},
title = {Tyrosine nitration: An emerging mechanistic landscape in neurodegeneration and cardiopulmonary disease.},
journal = {Redox biology},
volume = {97},
number = {},
pages = {104423},
doi = {10.1016/j.redox.2026.104423},
pmid = {42843275},
issn = {2213-2317},
abstract = {Protein tyrosine nitration is a post-translational modification associated with conditions of oxidative and inflammatory stress, driven by the production of reactive oxygen and nitrogen species (ROS and RNS). Once considered primarily a footprint of oxidative damage, tyrosine nitration is increasingly recognized as a selective modification that, in specific biological contexts, can alter protein structure, stability, enzymatic activity, and interaction networks. Mechanistically, nitration occurs through peroxynitrite-dependent and heme-peroxidase-dependent pathways and preferentially targets specific tyrosine residues based on local protein structure, solvent accessibility, and microenvironmental chemistry. Accumulating evidence has identified disease-specific nitration signatures across multiple pathological contexts. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, nitration of proteins such as tau, α-synuclein, manganese superoxide dismutase, ATP synthase, glyceraldehyde-3-phosphate dehydrogenase, heat shock proteins, and cytoskeletal components contributes to mitochondrial dysfunction, protein aggregation, metabolic failure, and neuronal loss. Similarly, in cardiovascular and pulmonary diseases, protein tyrosine nitration disrupts vascular and epithelial homeostasis by impairing endothelial signaling, fibrinolysis, lipid metabolism, and barrier integrity through modification of key regulatory proteins. By influencing phosphorylation-dependent signaling, enzymatic function, and protein-protein interactions, tyrosine nitration contributes to the connection between redox imbalance and progressive cellular and tissue dysfunction. This review summarizes current mechanistic insights into site-specific protein tyrosine nitration, highlights the emerging disease-associated nitroproteome, and discusses how advances in analytical and structural approaches are redefining nitration as a functional regulatory modification. Understanding the molecular determinants and consequences of tyrosine nitration may enable the development of targeted diagnostics and therapeutic strategies across diverse human diseases.},
}

@article {pmid42843548,
year = {2026},
author = {Yeom, J and Park, H and Jang, H and Noh, Y and Koh, SB and Lee, JI and Kim, HH and Kim, SY and Kim, C and Cho, J},
title = {Differential associations of PM2.5 and particulate manganese with blood-based amyloid and tau biomarkers in cognitively unimpaired older adults.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {},
number = {},
pages = {129304},
doi = {10.1016/j.envpol.2026.129304},
pmid = {42843548},
issn = {1873-6424},
abstract = {There are mixed findings on the associations of particulate matter (PM) with amyloid beta (Aβ) and phosphorylated tau (pTau) proteins, key pathologies of Alzheimer's disease (AD). The associations of airborne manganese (Mn) with AD biomarkers remain underexplored. We investigated the associations of PM with diameters ≤10 μm (PM10) and ≤2.5 μm (PM2.5) and their Mn constituents (Mn10, Mn2.5) with AD biomarkers. We included 340 cognitively unimpaired adults. Air pollution exposure was assessed using PM sampling and spatial modeling. Plasma Aβ40, Aβ42, pTau-181, and their ratios were measured using highly sensitive assays. Associations between air pollution exposure and the AD biomarkers were evaluated using single- and two-pollutant linear regression models per interquartile-range increase, with stratified analyses assessing potential effect modification. PM2.5 was inversely associated with the Aβ42/Aβ40 ratio (β = -0.002, 95% CI = -0.004, -0.001, p = 0.001). Mn2.5 was positively associated with pTau-181 (β = 0.387, 95% CI = 0.084, 0.691, p = 0.013) and the pTau-181/Aβ42 ratio (β = 0.057, 95% CI = 0.005, 0.108, p = 0.032). In the two-pollutant model, PM2.5 remained inversely associated with the Aβ42/Aβ40 ratio (β = -0.002, 95% CI = -0.003, -0.001, p = 0.008), and Mn2.5 remained positively associated with pTau-181 (β = 0.400, 95% CI = 0.073, 0.727, p = 0.017). Neither PM10 nor Mn10 exposure showed significant associations with any biomarker. The positive association between PM2.5 and the pTau-181/Aβ42 ratio appeared stronger in APOE-ε4 carriers (β = 0.109, 95% CI = 0.016, 0.201, p = 0.022) than in non-carriers (β = 0.007, 95% CI = -0.046, 0.060, p = 0.804) (p for interaction = 0.054). PM2.5 exposure was associated with the amyloid biomarker, whereas Mn2.5 exposure was nominally associated with the tau biomarker. These findings suggest differential associations of PM2.5 and its Mn constituent with amyloid- and tau-related biomarkers.},
}

@article {pmid42843795,
year = {2026},
author = {Chakraborty, A and Desai, N and Kaxon-Rupp, A and Lamichhane Khadka, R and Mohaddes, G},
title = {Microbiota-Brain Interactions in Dementia: Role of Diet in Neuroinflammation.},
journal = {Annals of geriatric medicine and research},
volume = {},
number = {},
pages = {},
doi = {10.4235/agmr.26.0122},
pmid = {42843795},
issn = {2508-4909},
abstract = {Aging is one of the risk factors for dementia, a group of neurocognitive disorders characterized by a progressive decline in cognitive function. Alzheimer's disease (AD) is the most prevalent, followed by vascular dementia (VaD). Other subtypes, such as frontotemporal dementia (FTD) and Lewy body disease (LBD), are less common but exhibit distinctive symptoms related to motor deficits, behavioral changes, and neuropsychiatric disturbances. Each type of dementia is associated with specific pathological features, such as amyloid plaques in AD and tau tangles in FTD. Recent research highlights the significant role of gut microbiota in the pathogenesis of dementia. Gut dysbiosis, or an imbalance in the gut microbiota, has been linked to neuroinflammation, cognitive decline, and neurodegenerative diseases through the gut-brain axis (GBA). Key microbial species, such as Bacteroides and Firmicutes, produce metabolites that influence neuroinflammation, immune response, and the integrity of the blood-brain barrier (BBB). Short-chain fatty acids (SCFAs), such as butyrate, have anti-inflammatory effects, while tryptophan derivatives, such as indole-3-acetic acid (IAA), support intestinal barrier function and modulate neuroinflammatory pathways. Microbial-derived metabolites may serve as potential therapeutic targets to mitigate neurodegeneration, highlighting the intricate relationship between the gut microbiota and brain health. Dietary interventions, such as a balanced diet rich in fiber, antioxidants, and anti-inflammatory compounds, may help support gut health by promoting a balanced gut microbiota and reducing the risk of developing dementia. This review highlights the relationship between brain function, gut microbiota composition, and dementia, providing insights into potential dietary strategies for prevention and management.},
}

@article {pmid42843827,
year = {2026},
author = {Hall, J},
title = {Lessons from the history of antipsychotic discovery: part 3 - muscarinic mechanisms.},
journal = {BJPsych bulletin},
volume = {},
number = {},
pages = {1-4},
doi = {10.1192/bjb.2026.10267},
pmid = {42843827},
issn = {2056-4694},
abstract = {After more than seven decades in which antipsychotic drug development has been dominated by dopaminergic mechanisms, the recent emergence of a muscarinic receptor-based treatment represents a conceptual shift in the pharmacotherapy of psychosis. This article reviews the history and development of the first clinically effective non-dopaminergic antipsychotic, tracing its origins to unexpected behavioural effects observed during trials of muscarinic agonists developed for Alzheimer's disease. Early studies of the muscarinic agonist xanomeline demonstrated antipsychotic efficacy, but were limited by poor tolerability due to peripheral cholinergic adverse effects. Subsequent progress depended on the dissociation of central therapeutic effects from peripheral side-effects, through the combination of xanomeline with the peripherally restricted muscarinic antagonist trospium. The development of this treatment highlights several broader lessons for psychiatric drug discovery, including the value of revisiting previously abandoned compounds, the benefits of leveraging existing human safety data on the importance of early-phase translational research and the role of innovative companies.},
}

@article {pmid42843980,
year = {2026},
author = {Deng, D and Chen, C and Zhang, L and Chinchilli, VM and Wang, M},
title = {A data integration framework to improve the efficiency of survival analysis by leveraging multiple external studies with multifaceted heterogeneity.},
journal = {Biostatistics (Oxford, England)},
volume = {27},
number = {1},
pages = {},
pmid = {42843980},
issn = {1468-4357},
support = {1R01HL175410/NH/NIH HHS/United States ; },
mesh = {Humans ; Survival Analysis ; Alzheimer Disease ; *Models, Statistical ; Data Interpretation, Statistical ; Dementia ; },
abstract = {In survival analysis, integrating multiple data sources holds significant potential to increase event counts, improve statistical efficiency, and enhance scientific discovery. However, challenges arise when external datasets differ in data forms, distributions, and covariate availability. We propose a novel learning framework that strengthens statistical inference of internal Cox regression coefficients through efficient data integration. Our framework is robust integration and accommodates multifaceted data heterogeneity through transformation, working models, penalized approach, and weighting that adaptively selects homogeneous components. The resulting estimators are consistent, asymptotically normal, more efficient than internal-only estimators, and robust to working model misspecification and data heterogeneity. Simulation studies confirm our framework's favorable properties. We applied our method to study dementia risk among black individuals in the Religious Orders Study and the Rush Memory and Aging Project, integrating information from external cohorts, including the Alzheimer's Disease Neuroimaging Initiative and the National Alzheimer's Coordinating Center. The analysis identified key risk factors with improved efficiency and demonstrated clinical relevance.},
}

Humans
Survival Analysis
Alzheimer Disease
*Models, Statistical
Data Interpretation, Statistical
Dementia

@article {pmid42844026,
year = {2026},
author = {Gaete-Espina, M and Becerra-Quinteros, A and Hermosilla-Navea, C and Orellana-Rubilar, J and López-Véliz, X and Flores-Carrasco, S},
title = {Cognitive and linguistic impairments in adults with Down syndrome and Alzheimer's disease: a systematic review.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13607863.2026.2733920},
pmid = {42844026},
issn = {1364-6915},
abstract = {OBJECTIVES: To explore the cognitive and linguistic impairments associated with Alzheimer's disease (AD) in individuals with Down syndrome (DS), identify gaps in current research, and propose directions for future investigation.

METHODS: A systematic review following PRISMA guidelines was conducted using PubMed, Scopus, and Web of Science from database inception to May 2026. Studies examining cognitive and linguistic impairments in adults with DS and AD were included. Findings were synthesized across cognition and memory, language and communication, and functional and social impact domains.

RESULTS: Fourteen studies met the inclusion criteria. Significant impairments in episodic memory, executive functioning, and attention were consistently identified as early markers of AD-related decline in adults with DS. Linguistic deficits, particularly receptive language impairments, semantic verbal fluency decline, naming difficulties, and short-term memory alterations, were also frequently reported. Functional consequences included reduced independence in daily activities and increasing communicative limitations. Across studies, assessment tools primarily emphasized cognitive domains, while language impairments remained comparatively underexplored.

CONCLUSION: DS-associated AD requires integrated assessment approaches addressing cognitive, linguistic, communicative, and functional domains. Future research should prioritize longitudinal studies and population-sensitive assessment tools to improve early detection and individualized interventions.},
}

@article {pmid42844061,
year = {2026},
author = {Booker, SA},
title = {On the nature of GABAB receptors and their plasticity in the mammalian brain.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.09.004},
pmid = {42844061},
issn = {1878-108X},
abstract = {Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter of the mammalian CNS, essential for circuit function and behaviour. In the brain, GABA activates GABAA and GABAB receptors to modulate circuit activity on behaviourally relevant timescales. GABAB receptor signalling in pre- and postsynaptic domains of neurons is often overlooked, despite the strong inhibition it produces. Importantly, GABAB receptors are diversely phosphorylated and interact with various auxiliary subunits to modify function. This review compares the evidence for the expression and modulation of GABAB receptors, their effectors, and regulatory mechanisms between cell types, brain areas, and mammalian species, particularly focusing on the plasticity of these mechanisms and their relationship to neurological diseases such as epilepsy and dementia.},
}

@article {pmid42844308,
year = {2026},
author = {Gandhi, SM and Patel, S and Haswani, NG and Wahab, S and Sabah, ZU and Kapoor, DU},
title = {RVG29-functionalized nanocarriers for brain-targeted therapy of neurodegenerative diseases: mechanisms, therapeutic advances, and translational perspectives.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42844308},
issn = {1432-1912},
abstract = {Neurodegenerative diseases (NDs) affect more than 55 million people worldwide, with this number projected to exceed 139 million by 2050 due to population aging. Alzheimer's disease (AD) accounts for 60-70% of dementia cases, while Parkinson's disease (PD) affects over 10 million individuals globally, highlighting the growing clinical and socioeconomic burden of these progressive neurological disorders. Effective treatment of AD, PD, amyotrophic lateral sclerosis (ALS), and related central nervous system disorders remains hindered by the blood-brain barrier (BBB), poor brain accumulation, rapid systemic clearance, and off-target toxicity. RVG29, a 29-amino-acid peptide derived from rabies virus glycoprotein, has emerged as a promising brain-targeting ligand because of its high affinity for nicotinic acetylcholine receptors expressed on neuronal and brain endothelial cells. This review critically examines the mechanisms underlying RVG29-mediated receptor-dependent BBB transcytosis, intracellular trafficking, and neuronal uptake. Furthermore, it comprehensively evaluates RVG29-functionalized lipid nanoparticles, polymeric nanoparticles, exosomes, biomimetic nanocarriers, micelles, inorganic nanostructures, and hybrid systems with respect to their physicochemical characteristics, targeting efficiency, therapeutic efficacy, and safety. Collectively, these nanocarriers demonstrate enhanced BBB penetration, increased drug accumulation in diseased brain regions, and efficient delivery of small molecules, genes, mRNA, and siRNA. By modulating oxidative stress, neuroinflammation, protein aggregation, ferroptosis, and mitochondrial dysfunction, RVG29-engineered nanocarriers provide significant neuroprotection with favorable biocompatibility and minimal immunogenicity. Despite these advances, challenges related to large-scale manufacturing, peptide stability, regulatory approval, and long-term biosafety must be addressed to facilitate their clinical translation as precision neurotherapeutics.},
}

@article {pmid42844556,
year = {2026},
author = {Paź, M and Kamiński, M and Nowicka, A},
title = {Age-related differences in neural activity and functional connectivity during self- and other-referential processing: An EEG study.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42844556},
issn = {2509-2723},
abstract = {Research on brain aging has largely focused on neurological disorders such as Alzheimer's disease, mild cognitive impairment, and other forms of cognitive decline. However, relatively few studies have examined how age affects self-knowledge in healthy older adults. Thus, the present study aimed to investigate the impact of age on the neural correlates of self-referential and other-referential processing, as well as patterns of task-related connectivity. To this end, trait adjectives were presented to younger and older adults, who evaluated their suitability for describing the self, a close other, and a famous person while EEG data were recorded. EEG analyses focused on the early attention-related positivity (P1) and the late positive potential (LPP), reflecting enhanced processing of salient stimuli, as well as task-related functional connectivity assessed using the full-frequency directed transfer function. Compared to younger adults, older participants exhibited lower P1 amplitudes, indicating reduced attentional engagement. In the older group, LPP amplitudes associated with self-related personality traits were higher than in the younger group. This enhanced LPP may suggest stronger emotional responses to self-related traits and/or increased cognitive effort during self-evaluation. Overall, directed connectivity analyses revealed reduced information flow in older adults along both bottom-up and top-down pathways, including feed-forward signaling from perceptual regions to higher-order evaluative systems, as well as feedback signaling from internally oriented networks to sensory regions. Age-related differences were also evident in local connectivity patterns, with younger participants exhibiting stronger within-region connectivity than older participants in perceptual processing regions and regions supporting internally oriented cognitive processes.},
}

@article {pmid42844635,
year = {2026},
author = {Yang, M and Ouyang, X and Gautam, S and Singleton, M and Davydzenka, V and Zhang, J and Li, Y},
title = {Forced treadmill running and ladder climbing physical activity attenuates cognitive decline and protein aggregates in aged 3xTg-AD mice.},
journal = {Molecular brain},
volume = {19},
number = {1},
pages = {},
pmid = {42844635},
issn = {1756-6606},
support = {P30 AG050886/NH/NIH HHS/United States ; 5P20GM121310 , 2P20GM103432, R01NS129878/NH/NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/physiopathology/pathology/therapy/complications ; Mice, Transgenic ; *Aging/pathology ; *Cognitive Dysfunction/physiopathology/therapy/pathology ; *Protein Aggregates ; *Physical Conditioning, Animal ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Hippocampus/pathology/physiopathology ; *Running ; Gliosis/pathology/complications ; Social Behavior ; Male ; Maze Learning ; },
abstract = {Alzheimer's disease (AD) is characterized by a progressive cognitive decline and pathological cascade involving amyloid-β (Aβ) plaque, hyperphosphorylated tau (pTau), neuroinflammation, and neurodegeneration. Although anti-amyloid antibody therapies have recently been approved, their clinical benefits remain limited and often accompanied with significant adverse effects. Physical activity has emerged as a promising non-pharmacological intervention for AD, with both aerobic and resistance physical activity showing beneficial effects in preclinical studies. However, the effects of different types of physical activity remain insufficiently understood. In this study, we investigated the effects of a forced treadmill running and ladder climbing physical activity procedure on cognitive behaviors, gliosis, and protein aggregate pathology in aged 3xTg-AD mice. Thirteen to fourteen months old 3xTg-AD mice were subjected to a six-week forced treadmill running and ladder climbing physical activity protocol. Cognitive functions were evaluated using the novel object recognition, Y-maze, and social behavior tests. Hippocampal and cortical tissues were analyzed by immunostaining for Aβ, pTau, Glial Fibrillary Acidic Protein (GFAP), Ionized Calcium-Binding Adapter Molecule 1 (IBA1), and inhibitory neuron markers. Our study demonstrated that the six-week forced treadmill running and ladder climbing physical activity procedure reduced age-associated cognitive declines in spatial working memory, object recognition memory, and sociability in aged 3xTg-AD mice. Such physical activity procedure also reduced Thioflavin S (Thio S) labeled misfolded protein aggregates and reactive gliosis in the cortex and/or hippocampus. Notably, forced treadmill running and ladder climbing physical activity procedure decreased Thio S positive neuropathology within somatostatin-positive interneurons of the hippocampus and cortex, indicating a cell-specific neuroprotective effect. Our results demonstrated that forced treadmill running and ladder climbing physical activity procedure produced significant behavioral and neuropathological benefits in aged 3xTg-AD mice, supporting physical activity as a promising non-pharmacological intervention for modulating gliosis and protein aggregate pathology in aging and AD.},
}

Animals
*Alzheimer Disease/physiopathology/pathology/therapy/complications
Mice, Transgenic
*Aging/pathology
*Cognitive Dysfunction/physiopathology/therapy/pathology
*Protein Aggregates
*Physical Conditioning, Animal
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Hippocampus/pathology/physiopathology
*Running
Gliosis/pathology/complications
Social Behavior
Male
Maze Learning

@article {pmid42844735,
year = {2026},
author = {Yang, G and Meng, C and Zhu, D},
title = {Alzheimer's disease and olfactory dysfunction: A 20-year systematic bibliometric and genomic analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261486344},
doi = {10.1177/13872877261486344},
pmid = {42844735},
issn = {1875-8908},
abstract = {With the acceleration of global population aging, early diagnosis and intervention of Alzheimer's disease (AD) and other neurodegenerative disorders have become major public health challenges. Olfactory dysfunction (OD) is increasingly recognized as one of the earliest clinical manifestations of AD, highlighting the importance of understanding the relationship between AD and olfactory impairment. This study integrates bibliometric analysis and genomic approaches to systematically characterize global research trends and explore potential molecular mechanisms underlying AD and OD from 2006 to 2025. Publications related to AD and OD were retrieved from the Web of Science Core Collection, and bibliometric analyses were performed using CiteSpace and VOSviewer, with results further validated through the Scopus database. A total of 1412 publications were identified, demonstrating sustained growth over the past two decades and a rapid expansion phase after 2019. The United States and China were the leading contributors in publication output and international collaboration, although research development remained geographically uneven. Keyword analysis revealed a gradual transition from behavioral and pathological investigations toward early diagnosis, biomarker discovery, therapeutic exploration, and advanced technologies. Genomic analysis identified 1838 shared genes between AD and OD, with key hub genes including AKT1, INS, and ALB involved in common biological pathways associated with neuronal function, cognitive regulation, and olfactory system homeostasis. This study provides a comprehensive overview of the evolving research landscape of AD and OD, identifies emerging trends and potential molecular targets, and offers valuable insights for early screening, mechanistic investigation, and translational research in neurodegenerative diseases.},
}

@article {pmid42845276,
year = {2026},
author = {Rahimzadeh, N and Morabito, S and Khullar, S and Shi, Z and Cao, Z and Swarup, V},
title = {An Integrated Single-Nucleus Atlas Resolves Cell-Type-Specific Programs and Molecular Subtypes in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.03.747935},
pmid = {42845276},
issn = {2692-8205},
abstract = {Interindividual heterogeneity in Alzheimer's disease (AD) remains poorly understood, as disparate single-cell studies leave it unclear whether findings reflect shared architecture or dataset-specific idiosyncrasies. Here, we present panAD, a transcriptomic atlas of >3 million nuclei from 791 individuals across 13 studies, spanning AD, mild cognitive impairment, and cognitively normal aging. AD converges on a reproducible, cell-type-specific molecular architecture: co-expression modules track neuropathology and cognitive decline; GWAS risk genes act predominantly as downstream targets of transcription factor hubs such as microglial SPI1 ; intercellular communication is remodeled with disease stage; and sex differences concentrate in microglial immune-activation programs. To model patient-level transcriptomic heterogeneity, we developed the Multi-seed Optimization of Neural Embeddings for subTyping (MONET) framework, in which a masked variational autoencoder applied to covariate-adjusted, multi-cell-type profiles resolves four subtypes (Metal-Ion Stress, Neuroinflammatory, Synaptic Integrity, and Tissue Remodeling) that dissociate neuropathological burden from cognitive impairment and nominate predominantly non-overlapping candidate therapeutics. Finally, Stellar Atlas provides an AI-native conversational interface to the atlas.},
}

@article {pmid42845305,
year = {2026},
author = {Naderi, P and Matai, L and Adewale, Q and Castanho, I and Rodrigues, A and Mavrikaki, M and Vlachos, IS and Slack, FJ and Hide, W},
title = {MicroRNA correlates of resilience to Alzheimer's disease identify candidate therapeutic targets for neuroprotection.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.04.737285},
pmid = {42845305},
issn = {2692-8205},
abstract = {UNLABELLED: Many aged individuals accumulate advanced Alzheimer's disease (AD) neuropathology without cognitive decline, signifying potent endogenous resilience mechanisms. Mimicking resilience to AD may offer new therapeutic opportunities by emulating endogenous neuroprotection, but the molecular pathways that underpin resilience remain largely unknown. MicroRNAs (miRNAs)-small noncoding RNA molecules that post-transcriptionally regulate gene expression-influence neuronal and glial processes associated with development, aging, and AD neurodegeneration but their role in resilience has not been characterized. We investigated resilience-associated miRNAs and their targeted programs in the dorsolateral prefrontal cortex of post-mortem human brains. We analyzed matched miRNA and messenger RNA (mRNA) expression across resilient, AD, and control subjects from the Religious Order Study and Memory and Aging Project (ROSMAP) cohort. Nine miRNAs were differentially expressed in resilience compared with AD, including previously unreported miR-362-3p and miR-433-3p and new resilience-associated roles for known AD-related miRNAs, including neuronal miR-132-3p and miR-129-5p. By analyzing miRNA activity across AD progression, we found additional cognitive-associated miRNAs (e.g., miR-335-5p and miR-19b) and one plaque-restricted miRNA (miR-199a-5p). Sex-specific miRNA dysregulation was observed: miR-7-5p showed male-specific upregulation in AD versus resilience and suggested sex-specific differences in AD patients. Integrated co-expression and target-enrichment analyses linked resilience-associated miRNAs to pathways that were associated with cognitive decline, including transforming growth factor β, Rho guanosine triphosphatases, and neurotransmitter receptor regulation. We also report restricted co-activity in AD subjects for miR-362-3p with inflammatory pathways, including tumor necrosis factor and Toll-like receptor signaling. These results demonstrate systematic involvement of miRNAs across neuronal and glial programs of AD resilience, cognitive decline, and sex-specific regulation. Our study provides an important resource for discovery of actionable regulatory programs that could lead to new therapies, based on endogenous molecules, that emulate natural resilience to AD.

KEY POINTS: Nine distinct cortical microRNA (miRNA) signatures correlate with resilience to Alzheimer's disease (AD)-related cognitive decline, pointing to endogenous regulatory programs that may help preserve cognitive function.At the miRNA level, resilient brains show minimal or no detectable differences to healthy individuals, despite the profound pathological differences, supporting the idea that resilience reflects preserved molecular homeostasis rather than a separate disease state.Some miRNA signatures are specific to a certain pathology (e.g., one linked to amyloid-β plaques independently of tau pathology and cognitive decline), helping to disentangle the regulation of these processes.Sex-specific miRNA dysregulation in AD suggests that resilience-linked pathways may be regulated differently in males and females, reinforcing the value of sex-stratified analyses and the potential for differential therapeutic strategies.Integrative miRNA-pathway analysis highlights candidate regulatory networks involved in inflammation, matrisome, and cellular stress responses, providing a framework for resilience-linked therapeutic targets.},
}

@article {pmid42845383,
year = {2026},
author = {Moss, SE and Wolsh, CC and Brown, R and Brown, AR and Manchikalapudi, S and Beversdorf, DQ and Ma, L and Boychuk, JA},
title = {Distinct Motor Cortex Somatotopy in Experimental Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.08.743539},
pmid = {42845383},
issn = {2692-8205},
abstract = {Alzheimer's Disease (AD) and related dementias (AD/RDs) impact cortical motor and sensory biology whereas the precise changes to these systems, and their clinical relevance, remain under debate. We hypothesized that cortical representations of complex and simple movements are differently altered during disease progression in 5XFAD mice, a well-established model of AD. Motor cortex somatotopy was determined in 5XFAD and Wild-Type Control (WT Control) mice at 6 and 12 months (mos.) of age using long-duration intracortical microstimulation (LD-ICMS) to systematically identify cortical sites evoking complex and simple forelimb movements. At 6 mos. of age, 5XFAD mice exhibited a significant expansion of motor cortical sites representing simple movements, specifically Elbow Flexion (p=0.0004) and Wrist Flexion (p=0.024). The over-sized territory for Elbow Flexion significantly distinguished 5XFAD from WT mice (Receiver Operating Characteristic [ROC] area under the curve [AUC]= 0.94, p= 0.0009) whereas discriminative performance of Wrist Flexion was a non-significant trend (AUC=0.75, p=0.059). By 12 mos. of age, motor cortex organization was markedly reorganized in 5XFAD mice, with significantly fewer cortical sites evoking complex Advance movement (p<0.0001) as well as simple Shoulder (p=0.0001), Elbow Extension (p=0.024), and Wrist Extension (p=0.003) movements. The number of sites for simple Wrist Flexion was significantly increased (p=0.011) in 12 mo. old 5XFAD mice. At 12 mos., territory size of several of these movement zones highly distinguished 5XFAD from WT mice, including Advance (AUC= 0.96, p= 0.0005), Shoulder (AUC= 0.97, p= 0.0004), Elbow Extension (AUC=0.78, p=0.034), Wrist Extension (AUC=0.85, p= 0.0082), and Wrist Flexion (AUC=0.80, p= 0.023). These findings demonstrate progressive, age-dependent remodeling of motor cortex somatotopy in 5XFAD mice, characterized by early expansion of specific simple movement cortical sites followed by deterioration of both complex and simple motor cortical maps as disease advances. Motor cortex somatotopic remodeling may provide a sensitive biomarker of AD/RDs progression.},
}

@article {pmid42845384,
year = {2026},
author = {Huang, Z and McGrath, PM and Ferdinand, DC and McCormick, BA and Ward, DV and Bucci, V and Haran, JP},
title = {Gut community-level analysis reveals an altered balance between Phocaeicola vulgatus and Bacteroides fragilis in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.12.743985},
pmid = {42845384},
issn = {2692-8205},
abstract = {Gut microbiome differences in Alzheimer's disease (AD) are typically cataloged taxon by taxon, yet bacterial competition and cross-feeding make species' roles dependent on the entire community. We analyzed 274 stool metagenomes from 119 older adults (18 with AD) as communities, retaining 22 recurring across 1,000 runs. Using our AI framework, we identified 15 species differing in abundance in AD, particularly the commensal Phocaeicola vulgatus (Cohen's d -0.91, 95% CI [-1.23, -0.59]), a finding robust to repeated sampling. It correlated negatively with its sister species, Phocaeicola dorei (r -0.57), suggesting possible niche competition; this replicated in an independent cohort (r -0.43). P. vulgatus was depleted in AD and the opportunistic pathogen Bacteroides fragilis enriched, shifting their balance toward B. fragilis (d -0.70), a modestly reproduced AD-associated pattern (d -0.24). Our findings suggest that AD-associated gut microbiome variation extends beyond taxon-specific abundance to the balance between specific species within a community matrix.},
}

@article {pmid42845405,
year = {2026},
author = {Seerley Nolan, AL and McElroy, SD and Mace, AA and Grindeland Panter, AL},
title = {A New Frontier in CWD Detection: Antemortem Plasma Biomarkers and Behavioral Profiling in Transgenic Mouse Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.04.742870},
pmid = {42845405},
issn = {2692-8205},
abstract = {Chronic Wasting Disease (CWD) is a fatal transmissible spongiform encephalopathy (TSE) that is confined to cervids (deer, moose, elk, and reindeer) but shares key properties with human neurodegenerative conditions such as Alzheimer's, Parkinson's, Huntington's disease and frontal-temporal dementia. CWD and other TSEs are caused by the misfolded prion protein (PrP). Although the identification of diagnostic and prognostic biomarkers at all stages of disease progression is becoming exceedingly critical as CWD continues to increase in prevalence, accurate antemortem testing techniques are extremely limited. This study made use of cervidized transgenic mice (mice carrying the cervid PrP) that recapitulate CWD in various disease stages and investigated the utility of neurological biomarkers and neurobehavioral manifestations for CWD detection. Neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and total Tau (t-Tau) were assessed under the hypothesis that combined biomarker signatures might more reliably reflect CWD-related neurodegeneration and disease progression. Analyses at 90, 132, 174, and 230 days post-CWD inoculation show distinct biomarker elevation, with all three biomarkers significantly elevated in the CWD animals by 132 days post-inoculation. To our knowledge, this is the first demonstration that these three plasma biomarkers are useful not only for detecting CWD, but also for identifying it at early antemortem stages of disease. Novel phenotypes were also revealed by comprehensive phenotypic profiling, including rigid tail elevation, increased grip strength, and impaired coordination, to lend further support to plasma biomarker data indicating neurologic impairment associated with brain pathology. Ultimately, the goal is to improve antemortem, non-invasive CWD detection methods to enable earlier detection and assist with disease management.},
}

@article {pmid42845429,
year = {2026},
author = {Wang, N and Cardenas, C and Nieto-Caballero, VE and Turner, D and Feinberg, H and Yuan, D and Scott, N and DeBerardine, M and Dan, S and Caceres, L and Schembri, J and Yao, Z and Lee, C and Pillow, JW and Krienen, FM},
title = {PIANO: Probabilistic Inference Autoencoder Networks for multi-Omics enables robust generative modeling of gene expression and scales single-cell integration to 100 million cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.06.743394},
pmid = {42845429},
issn = {2692-8205},
abstract = {Single-cell RNA technologies enable the routine acquisition of transcriptomic atlases. However, these molecular profiles are influenced by overlapping sources of variation. Since these covariates confound comparisons, data integration is the first step in most analyses. Three challenges remain: correcting strong batch effects, scaling to millions of cells, and modeling how covariates influence gene expression. To address these challenges, we developed PIANO: Probabilistic Inference Autoencoder Networks for multi-Omics, a deep learning framework whose central feature is a generative model of gene expression data. Additionally, PIANO achieves robust integrations and trains 10x faster than previous methods. PIANO accurately integrates single-cell data across species and across single-cell and spatial transcriptomics modalities. As practical applications, PIANO models spatially-resolved gene expression during Alzheimer's disease progression in human brains and integrates over 100 million cancer cells to model drug perturbations. In summary, PIANO's integration and generative modeling capabilities will empower novel insights for countless future studies.},
}

@article {pmid42845447,
year = {2026},
author = {Dzigurski, S and Al-Abri, R and Li, X and Grasty, MR and Rodrigues, AC and Weed, MR and Elsworth, JD and Lawrence, MS and Heng, YJ and Bogsan, CS and Naderi Yeganeh, P and Hide, WA and Slack, FJ and Gursoy, G and Miranker, AD and Brown, BRP},
title = {African Green Monkey Cerebrospinal Fluid miRNome Captures Conserved miRNAs Relevant to Human Neurodegenerative Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.07.743104},
pmid = {42845447},
issn = {2692-8205},
abstract = {BACKGROUND: The African green monkey (AGM) is increasingly used as a model for early-stage Alzheimer's disease (AD), with cerebrospinal fluid (CSF) targeted for biomarker discovery and longitudinal disease monitoring of shifts in the central nervous system. MicroRNAs (miRNAs) are particularly informative indicators of early neuropathological change. Despite the complementary value of an early-stage disease model and a molecular marker capable of capturing early change, the miRNA composition (miRNome) of AGM remains undefined. We established the AGM CSF miRNome from antemortem samples using miRNA sequencing and a qRT-PCR-based array. We also developed a hierarchical annotation pipeline to classify miRNAs as either family-conserved or unclassified and to assess sequence alignment across humans and other species.

RESULTS: We used untargeted miRNA sequencing to characterize the AGM CSF miRNome and identified 205 miRNAs that could be classified into three family-conserved categories: canonical, noncanonical, and 3'-terminal variants. Of these, 150 were also detected using a human-targeted qRT-PCR array, providing independent support for the sequence-derived miRNome. Sequencing abundance and qRT-PCR array Ct values showed significant cross-platform concordance overall, although concordance was lower for 3'-terminal isomiRs than for canonical miRNAs. Comparison with human GTEx tissue-expression data indicated that several human homologs of AGM CSF miRNAs exhibited brain-preferential expression. Notably, predicted targets of many of these miRNAs were enriched for pathways implicated in neurodegenerative disease. Finally, we identified 20 unclassified candidates that could not be assigned to established miRNA families, two of which we propose as putatively novel miRNAs.

CONCLUSION: The AGM CSF miRNome is substantially conserved with the human miRNome but also contains 3'-terminal isomiRs and unclassified miRNA candidates. AGM CSF contains miRNAs homologous to human miRNAs associated with AD and other neuropathologies, highlighting the translational potential of this model. However, our study also reveals challenges related to species-specific sequence variation and reduced cross-platform concordance for isomiRs. Thus, comparative studies will be needed to validate the functional and biomarker relevance of these miRNAs across species. More generally, this initial miRNome provides a reference resource for future studies of miRNAs in AGM across disease-related, physiological, experimental, and evolutionary contexts.},
}

@article {pmid42845496,
year = {2026},
author = {Flores Romero, KR and Gutierrez, S and Zimmerman, SC and Pederson, AM and Thoma, M and Chen, R and Kotwal, A and Glymour, M and Casaletto, K and Torres, JM},
title = {Social isolation, loneliness, and blood-based AD/ADRD biomarkers in a nationally-representative study of middle-aged and older adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.06.26359882},
pmid = {42845496},
abstract = {IMPORTANCE: The biological mechanisms underlying the associations of social isolation and loneliness with dementia risk are not well understood.

OBJECTIVE: To evaluate the relationship of prospectively measured social isolation and loneliness with AD/ADRD blood-based biomarkers.

DESIGN: Observational study using the U.S. Health and Retirement Study (2010-2016). Venous blood draws were conducted in 2016 and AD/ADRD biomarkers were released in 2025. We estimated associations of social isolation and loneliness patterns between 2012 and 2014 with continuous biomarkers using linear regressions, accounting for socio-demographic and health covariates. We evaluated effect modification by sex and APOE ɛ4 carrier status.

SETTING: Population-based.

PARTICIPANTS: Community-dwelling HRS participants aged 50 years or older (n = 3862).

EXPOSURES: Primary exposures were four-category multi-wave variables of persistent, resolving, new-onset, or no social isolation/loneliness across the two exposure waves. Social isolation was classified as "severe" and "moderate-to-severe" based on a 5-item scale including marital status, household size, proximity to children, religious service attendance, and volunteering. Past-week loneliness was measured with a single-item question (yes/no).

MAIN OUTCOMES AND MEASURES: Neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and the ratio of amyloid beta 42 to amyloid beta 40 (Aβ42/40), measured in plasma via a Multiplex Simoa Assay and phosphorylated tau (p-tau181), measured in serum via a Simoa Assay.

RESULTS: At the analytic baseline, respondents were a mean age of 64 (9.5) years, 59% female, and 25% APOE ɛ4 carriers. Across the two exposure waves, 4% experienced persistent severe social isolation, 16% experienced persistent moderate-to-severe social isolation, and 8% reported persistent loneliness. Multiple patterns of social isolation (vs. no social isolation) were associated with higher NfL, including persistent severe social isolation (β : 0.31), new-onset moderate-to-severe social isolation (β : 0.14), and resolving moderate-to-severe social isolation (β : 0.20). Persistent severe social isolation was associated with lower GFAP (β : - 0.31) while persistent loneliness and, for men, new-onset loneliness were associated with higher GFAP (β persistent : 0.16; β new onset _ men : 0.25). New-onset severe social isolation was associated with a lower Aβ42/40 ratio (β : - 0.25) while resolving moderate-to-severe social isolation and, for men, persistent severe social isolation were each associated with higher p-tau181 (β resolving : 0.11; β persistent _ men : 0.41). There was some additional variation by APOE ɛ4 carriership, although selective survival is a concern.

CONCLUSIONS: Social isolation was associated with elevated blood-based biomarkers of neuronal injury, with variation by patterns of exposure over time. Associations between social isolation and loneliness with biomarkers related to astrocyte damage and Alzheimer's disease were less consistent, and varied in sign and magnitude by exposure and sex.},
}