@article {pmid42627514,
year = {2026},
author = {Cao, Q and Shen, M and Liu, Y and Li, C and Liu, L and Zhou, J and Yue, R and Niu, D and Ren, Y and Pan, L and Yao, J and Zhang, G},
title = {The role of microglia glucose metabolism reprogramming in Alzheimer's disease treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478594},
doi = {10.1177/13872877261478594},
pmid = {42627514},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment, and there remains a lack of effective treatments capable of reversing or significantly slowing disease progression. Accumulating evidence indicates that the immune function of microglia, the resident immune cells of the central nervous system, is a critical factor in regulating AD pathogenesis. Emerging research in immunometabolism further reveals that glucose metabolic reprogramming serves as a central driver of microglial phenotypic and functional differentiation. This review systematically outlines the fundamental characteristics of microglial glucose metabolism and focuses on how the dynamic metabolic reprogramming it undergoes during AD progression regulates microglial immune behavior and inflammatory responses. Building on this, we further summarize key regulatory targets within the "metabolism-immune axis" and corresponding pharmacological intervention strategies. Finally, this article discusses current challenges and future research directions in the field of microglial immunometabolism. This review aims to provide a theoretical foundation for AD intervention strategies targeting the "metabolism-immune axis" and to offer insights for the development of novel disease-modifying therapeutics.},
}

@article {pmid42627571,
year = {2026},
author = {Wang, Q and Wei, Y and Shen, C and Kang, W and Wang, L},
title = {CT1812 Attenuates Surgery-Induced Cognitive Impairment and Modulates TMEM97- and PGRMC1-Associated Hippocampal Stress Responses in Aged Mice.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42627571},
issn = {1573-6903},
support = {82201549//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Membrane Proteins/metabolism ; *Hippocampus/drug effects/metabolism ; Male ; Mice, Inbred C57BL ; Mice ; *Aging/drug effects/metabolism ; *Cognitive Dysfunction/metabolism/drug therapy/etiology ; *Postoperative Cognitive Complications/metabolism/drug therapy ; Receptors, Progesterone ; },
abstract = {Postoperative neurocognitive disorders (PND) are common complications in older surgical patients, but druggable mechanisms linking surgical trauma to hippocampal synaptic and cognitive vulnerability remain poorly defined. The σ-2 receptor (σ-2R), encoded by transmembrane protein 97 (TMEM97), and progesterone receptor membrane component 1 (PGRMC1) intersect membrane lipid biology and synaptic stress signaling; CT1812, a pharmacological σ-2R complex modulator, has shown target engagement in early Alzheimer's disease trials, but whether this pathway participates in postoperative hippocampal injury is unknown. This study examined whether surgery-induced hippocampal stress in aged mice is associated with TMEM97 and PGRMC1 signaling and whether early CT1812 treatment can attenuate this response. Young adult (2-3 months) and aged (18-20 months) male C57BL/6J mice underwent sham operation or laparotomy; aged mice were further treated with vehicle or CT1812 (3 mg/kg, intravenous injection, days 0-3). Hippocampal molecular changes were assessed by western blotting and immunofluorescence on day 3, and behavior was evaluated by open field test (OFT) and Morris water maze (MWM) on days 6-10. Laparotomy increased hippocampal TMEM97 and PGRMC1 expression and induced anxiety-like and spatial-memory deficits preferentially in aged mice, without evidence that locomotor impairment explained the behavioral phenotype. TMEM97 and PGRMC1 were detected in neuronal nuclei (NeuN)-positive neurons, ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia, and glial fibrillary acidic protein (GFAP)-positive astrocytes in hippocampal cornu ammonis 1 (CA1), supporting multicellular pathway involvement. In aged surgical mice, CT1812 significantly reduced upregulation of TMEM97 and PGRMC1, improved OFT center-zone occupancy and MWM performance, and restored the synaptic markers postsynaptic density protein 95 (PSD95) and synaptophysin. CT1812 also normalized lipid-handling proteins, including apolipoprotein E (ApoE), ATP-binding cassette transporter A1 (ABCA1), cholesterol 24-hydroxylase (CYP46A1), and low-density lipoprotein receptor (LDLR), and reduced perilipin 2 (PLIN2) accumulation in neurons and microglia. In parallel, CT1812 attenuated a selective endoplasmic reticulum (ER) stress response involving binding immunoglobulin protein (BIP) and protein kinase R-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) signaling in hippocampal neurons, and suppressed microglial nuclear factor κB (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammatory activation, whereas C/EBP homologous protein (CHOP) was not significantly changed. These findings support a model in which postoperative injury in the aged hippocampus engages a lipid-proteostatic and inflammatory stress program associated with TMEM97 and PGRMC1, and suggest that CT1812 attenuates cognitive vulnerability by restraining this coupled response.},
}

Animals
*Membrane Proteins/metabolism
*Hippocampus/drug effects/metabolism
Male
Mice, Inbred C57BL
Mice
*Aging/drug effects/metabolism
*Cognitive Dysfunction/metabolism/drug therapy/etiology
*Postoperative Cognitive Complications/metabolism/drug therapy
Receptors, Progesterone

@article {pmid42627617,
year = {2026},
author = {Fawzy, MN},
title = {The neuroimmune network in Alzheimer's and Parkinson's diseases: from mechanistic insights to biomarker-guided immunotherapies and clinical translation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42627617},
issn = {1568-5608},
abstract = {Neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) have traditionally been examined from the perspectives of neurons or microglia, resulting in constrained therapeutic achievements. Recent findings endorse a cohesive neuroimmune framework in which central nervous system (CNS)-resident microglia, border-associated macrophages, clonally proliferated CD8[+] T cells, and peripheral signaling centers (IL-20 family, gut-brain axis) perpetuate chronic maladaptive inflammation via feed-forward mechanisms. This review critically examines investigational immunotherapies aimed at this network: the CNS‑penetrant NLRP3 inhibitor NT-0796 (Phase 1b/2a) demonstrated preliminary biomarker reductions in axonal damage and T-cell activation in PD but remains unapproved and necessitates further confirmatory trials; the anti‑SIGLEC10 antibody ONC-841 improved microglial phagocytosis of Aβ and tau in preclinical studies but has yet to commence human trials; and CAR‑based platforms (CAR-T/NK) remain in the nascent preclinical phase, facing significant delivery and toxicity challenges. A three-part biomarker framework, encompassing target engagement (CSF IL-1β, caspase-1), pharmacodynamic responses (neurofilament light chain, ASC specks), and predictive endotyping (T-cell clonality, complement profiles), is proposed to facilitate patient stratification by neuroimmune endotype. None of these agents have received regulatory approval for neurodegenerative conditions; all findings are preliminary. Effective immunotherapy may ultimately necessitate multi-node, network-aware combinations (e.g., inflammasome inhibition coupled with Treg augmentation) rather than single-target suppression. Embracing this complexity offers a roadmap for future disease-modifying therapies, though rigorous clinical validation remains essential.},
}

@article {pmid42627656,
year = {2026},
author = {Meiselbach, MK and Xu, J and Brown, T and Polsky, D},
title = {Medicare Advantage Beneficiary Enrollment Decisions Following New Complex Conditions.},
journal = {JAMA health forum},
volume = {7},
number = {8},
pages = {e262843},
doi = {10.1001/jamahealthforum.2026.2843},
pmid = {42627656},
issn = {2689-0186},
mesh = {Humans ; *Medicare Part C/statistics & numerical data ; United States ; Female ; Male ; Aged ; Chronic Disease/epidemiology ; Aged, 80 and over ; Cohort Studies ; Insurance, Medigap/statistics & numerical data ; },
abstract = {IMPORTANCE: Prior research has demonstrated higher rates of disenrollment from Medicare Advantage (MA) among people with greater health care needs. Yet, less is known about how disenrollment responds to changes in medical complexity, whether disenrollment varies by the degree of complexity, and how these patterns differ by state Medigap protections and MA plan characteristics.

OBJECTIVE: To examine changes in MA plan disenrollment following the development of new complex medical conditions and assess heterogeneity by number of conditions, state Medigap policy, and plan characteristics.

This cohort study used Medicare enrollment and claims data from 2016 to 2021. The study population included beneficiaries continuously enrolled in MA in 2016 without complex medical conditions from 2016 through 2018. A treatment group developed a new complex condition in 2019; a comparison group did not develop a complex condition through 2021. Data were analyzed from December 1, 2025, to March 1, 2026.

EXPOSURE: Development of 1 or more new complex medical conditions in 2019, including acute myocardial infarction, Alzheimer disease and related dementia, atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease, depression, congestive heart failure, or stroke.

MAIN OUTCOMES AND MEASURES: Annual disenrollment from the prior year MA plan, which included disenrollment to traditional Medicare (TM) or switching to another plan within MA. Difference-in-differences models with beneficiary and year fixed effects were estimated and converted to differences in percentage points.

RESULTS: The analytic sample included 1 054 926 beneficiaries, including 219 942 (mean [SD] age, 75.3 [6.3] years; 54.6% female) who developed new complex conditions in 2019 and 834 984 (mean [SD] age, 73.8 [5.6] years; 56.7% female) who did not develop a new complex condition in 2019. Developing any new complex condition was associated with an increase of 3.3 (95% CI, 3.1-3.5) percentage points (pp) in MA disenrollment, including an increase of 2.8 (95% CI, 2.7-2.9) pp in disenrollment to TM. The number of new complex conditions was associated with increased disenrollment, from 1.4 (95% CI, 1.3-1.6) pp for 1 condition to 12.8 (95% CI, 11.6-13.9) pp for 4 or more conditions. Disenrollment to TM was 1.5 (95% CI, 0.9-2.1) pp higher among beneficiaries residing in states with Medigap guaranteed issue and community rating protections.

CONCLUSIONS AND RELEVANCE: In this study, development of new complex medical conditions was associated with higher MA disenrollment, particularly to TM and in states with Medigap protections, and the magnitude increased with medical complexity. These findings highlight how changes in health status and state policy may shape Medicare coverage decisions.},
}

Humans
*Medicare Part C/statistics & numerical data
United States
Female
Male
Aged
Chronic Disease/epidemiology
Aged, 80 and over
Cohort Studies
Insurance, Medigap/statistics & numerical data

@article {pmid42627738,
year = {2026},
author = {Chang, Y and Kim, HJ and Kim, Y and Park, A and Nam, S and Banerjee, DR and Hasenour, CM and Young, JD and Brooks, GA and Wolfe, RR and Kim, IY},
title = {Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.},
journal = {American journal of physiology. Cell physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpcell.00268.2026},
pmid = {42627738},
issn = {1522-1563},
support = {2021R1A2C3005801//National Research Foundation of Korea (NRF)/ ; GCU-202106260001//Gachon University/ ; //Myocare Inc/ ; },
abstract = {A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As the glucose utilization declines in AD patients, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (A(?)) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under A(?)-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of AD patients. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by A(?) aggregates. Using a [13]C stable isotope tracer, we verified cellular lactate uptake and its incorporation into TCA cycle in neurons under the neurotoxic condition. [13]C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.},
}

@article {pmid42627850,
year = {2026},
author = {Noor, AI and Suha, HN and Hossain, I and Almatarneh, MH and Al-Msiedeen, AM and Bari, MAU and Poirier, RA and Uddin, KM},
title = {Computational insights into the anti-Alzheimer potential of alkynyl-3-carboxamide derivatives.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cp00485g},
pmid = {42627850},
issn = {1463-9084},
abstract = {Alzheimer's disease (AD) remains a major global health challenge due to its complex pathological mechanisms and the limited availability of effective disease-modifying therapies. In this study, a dataset of fifty novel alkynyl-3-carboxamide derivatives (1-50) was systematically evaluated as potential inhibitors of asparagine endopeptidase (legumain), a key enzyme implicated in AD-associated neurodegeneration. An integrated computational approach involving molecular docking, molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy analysis, density functional theory (DFT) calculations, and ADMET profiling was employed to investigate ligand-protein interactions, structural stability, electronic properties, and drug-likeness. Molecular docking analysis across ten disease-relevant protein targets identified ligand 4 as the most promising candidate, showing the highest binding affinity toward legumain (PDB ID: 5LUA) with a docking score of -8.1 kcal mol[-1]. Temperature-dependent MD simulations performed at 300, 305, 310, and 320 K confirmed the stability of the 5LUA-ligand 4 complex, as indicated by consistently low root-mean-square deviation (RMSD) fluctuations and stable binding interactions. MM/PBSA calculations further demonstrated favorable binding thermodynamics for ligand 4, with a total Gibbs free energy of binding (ΔG_bind) of -37.05 kcal mol[-1]. Furthermore, physicochemical and pharmacokinetic assessments revealed favorable drug-like characteristics, including compliance with Lipinski's and Veber's criteria, suitable lipophilicity (c log P = 2.03), topological polar surface area (TPSA = 131.4 Å[2]), and an acceptable predicted hERG inhibition profile (pIC50 = 0.9881) with no significant toxicity alerts. Overall, these computational findings, supported by previously reported in vitro evidence, suggest that ligand 4 represents a promising alkynyl-3-carboxamide-based lead scaffold for further development as a potential legumain-targeted therapeutic candidate for AD. Additional experimental validation through advanced biological assays and in vivo studies is required to confirm its efficacy and safety profile.},
}

@article {pmid42628375,
year = {2026},
author = {Erukulla, R and Reid, G and Yotter, C and Dounavi, ME and Low, A and O'Brien, JT and Ritchie, C and Lawlor, B and Naci, L and Malhotra, P and Koychev, I},
title = {Insulin resistance and brain health in midlife: a potential dementia prevention target.},
journal = {EBioMedicine},
volume = {131},
number = {},
pages = {106448},
doi = {10.1016/j.ebiom.2026.106448},
pmid = {42628375},
issn = {2352-3964},
abstract = {BACKGROUND: Insulin resistance is recognised as a midlife risk factor for cognitive decline, yet the pathways linking metabolic dysfunction to early brain changes remain unclear.

METHODS: We cross-sectionally analysed 355 cognitively normal adults from the PREVENT cohort to test associations between insulin sensitivity (Homoeostatic Model Assessment for Insulin Resistance; HOMA-IR), frontal white matter hyperintensities (WMH), cerebral blood flow (CBF), hippocampal volume, and cognition.

FINDINGS: Multivariable regression showed higher log-transformed HOMA-IR was associated with greater frontal WMH burden (β = 0.118, p = 0.026) and lower global cognitive performance (β = -0.132, p = 0.012). Decreased insulin sensitivity was not associated with global CBF (β = -0.019, p = 0.74). Adjusting for WMH burden, hippocampal volume, and CBF, lower insulin sensitivity remained associated with lower global cognition (β = -0.123, p = 0.021). Structural equation modelling (n = 328) demonstrated a direct negative association between higher HOMA-IR and cognition (β = -0.055, p = 0.042) and trended toward higher vascular burden (p = 0.06). The indirect pathway through vascular burden was non-significant (p = 0.23), as vascular burden, hippocampal volume, and CBF did not associate with cognition.

INTERPRETATION: Decreased insulin sensitivity was linked to early small vessel disease and measurable cognitive differences, suggesting the cognitive association was largely direct rather than explained by vascular injury, hippocampal atrophy, or global perfusion. These findings point toward partially parallel metabolic and vascular pathways rather than a sequential process. These cross-sectional associations suggest that insulin sensitivity warrants investigation as a modifiable midlife factor for cognitive health; interventional studies are needed to determine whether targeting it preserves cognition before neurodegenerative markers emerge.

FUNDING: MRC Dementias Platform UK, NIHR, Alzheimer's Society, Alzheimer's Association, Race Against Dementia, and HRB.},
}

@article {pmid42628381,
year = {2026},
author = {Quan, YS and Liu, JY and Liu, H and Sun, YX and Wang, YL and Liu, Z and Quan, ZS and Shen, QK},
title = {Design synthesis and evaluation of usnic acid derivatives as multi-target drugs for Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110398},
doi = {10.1016/j.bioorg.2026.110398},
pmid = {42628381},
issn = {1090-2120},
abstract = {The pathogenesis of AD is complex, and existing clinical drugs only alleviate symptoms and are difficult to block the course of the disease. Although UA has neuroprotective activities such as antioxidant and anti-inflammatory properties, its anti-AD activity is severely restricted by drug defects such as a single target and insufficient blood-brain barrier permeability. Therefore, this study takes UA as the lead compound, designs and synthesizes 38 UA derivatives, systematically evaluates their anti-AD biological activity, and aims to screen for multifunctional anti AD lead compounds. Among them, the lead compound S12 exhibited exceptional activity, with an EC50 value of 1.24 μM representing a 17.9-fold improvement in potency relative to the parent compound. Furthermore, WB assays were conducted to elucidate the underlying mechanism of action of this compound. The results revealed that compound S12 exerts anti-AD activity through the synergistic modulation of multiple signaling pathways: it inhibits activation of the MAPK and NF-κB pathways, as well as aberrant phosphorylation of tau protein; concurrently, it downregulates BACE1 expression to reduce Aβ production, and suppresses activation of the Bax/Bcl-2 pathway thereby inhibiting caspase-1 activation and ultimately confers neuroprotective, anti-AD effects. The apparent permeability coefficient of compound S12 across an in vitro (BBB) model was determined to be 7.66 × 10[-6] cm/s, confirming its ability to effectively cross the BBB. Further pharmacological evaluation demonstrated that S12 exerted a potent ameliorative effect on learning and memory deficits in an AD mouse model. In vivo toxicity assessment, no gross or histopathological abnormalities were observed in the major organs, including the heart, liver, spleen, and kidneys. Moreover, S12 significantly attenuated neuronal pathological injury in the hippocampus of Aβ-induced AD model mice, underscoring its robust neuroprotective activity. In conclusion, compound S12 demonstrates robust efficacy in ameliorating learning and memory deficits, enhancing blood-brain barrier permeability, and exerting anti-AD activity. Accordingly, it represents a highly promising multifunctional therapeutic candidate for the treatment of AD.},
}

@article {pmid42628699,
year = {2026},
author = {Bergamo, G and Fernandes, M and Maio, S and Albanesi, G and Antonucci, M and Barbaro, I and Cirillo, F and Fernando, L and Amicucci, G and Centonze, D and Liguori, C},
title = {Instrumental, Neurophysiological, cognitive and Sleep InvestiGations into the High risk of neurodegeneraTion in Late Onset Epilepsy of Unknown aetiology: the INSIGHT-LOEU study.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {112237},
doi = {10.1016/j.mad.2026.112237},
pmid = {42628699},
issn = {1872-6216},
abstract = {Late-onset epilepsy (LOE) remains of unknown aetiology (LOEU) in around 20% of cases. Longitudinal studies have demonstrated the presence of early cognitive impairment at seizure onset, progressive memory decline and a substantially elevated risk of dementia within a decade of diagnosis, with an increased risk of subsequent neurodegenerative disorders, particularly Alzheimer's disease (AD). LOEU is associated with cognitive network alterations and epileptiform activity, although links remain unclear. Further emerging data suggest that neurodegenerative processes related to β-amyloid and tau pathology may precede the onset of epilepsy. Although epilepsy is highly prevalent among older adults, its impact on quality of life remains unclear, with affective symptoms and sleep disturbances as key determinants of subjective well-being. These findings suggest that LOEU should be reconceptualised as a multidimensional neurological condition. This protocol advocates an integrated approach, combining neuropsychological assessment, advanced biomarkers, neurophysiological measures and systematic sleep evaluation to identify high-risk phenotypes and define optimal windows for neuroprotective interventions in LOEU. This strategy could improve the early detection of cognitive decline, guide personalised management, and ultimately enhance quality of life, while contributing to the long-term sustainability of healthcare systems in an ageing population, focusing on LOEU as a model for dementia prevention.},
}

@article {pmid42628701,
year = {2026},
author = {Wyatt-Johnson, SK and Joshi, S and Blair, M and Desai, JM and Haeryfar, SMM and Lasagna-Reeves, CA and Brutkiewicz, RR},
title = {The MR1/MAIT cell axis has limited effects on the start of tau pathology in a mouse model of tauopathy.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106969},
doi = {10.1016/j.bbi.2026.106969},
pmid = {42628701},
issn = {1090-2139},
abstract = {Immunity impacts all aspects of Alzheimer's disease (AD) pathology. Previously, we found improved pathology and cognition in the amyloid-focused 5XFAD mouse model deficient in the innate immune cell axis consisting of the innate-like mucosal-associated invariant T (MAIT) cells and the MHC class I-like antigen-presenting molecule they recognize, MR1. However, little is known about how a lack of the MR1/MAIT cell axis impacts cognition and whether an increased abundance of MAIT cells impacts pathology and cognition in the tau-focused PS19 mouse model. We crossed PS19 mice onto an MR1 KO background, resulting in a lack of both MR1 and MAIT cells, and alternatively, onto MAIT[CAST] mice, that have ∼7× more MAIT cells. Using immunofluorescent microscopy, flow cytometry, and cognitive tests including Barnes maze and Novel Object Recognition, we analyzed the impact of MAIT cell numbers on tau pathology. Although an elevation in MAIT cell frequency was found that expressed higher levels of CD69 in PS19 mice on the MAIT[CAST] vs. wildtype background, overall MAIT cell numbers in the brain did not differ between these groups. Interestingly, increased MR1 expression was detected on microglia only in PS19 mice, whereas MR1 was higher in PS19 and PS19/MAIT[CAST] mouse astrocytes. Increased MAIT cell numbers did not alter tau accumulation or cognitive performance, whereas the lack of the MR1/MAIT cell axis did not affect tau burden, but was associated with reduced neuronal density and impaired recognition memory. Together, these findings suggest that the MR1/MAIT cell axis does not substantially influence the early development of tau pathology.},
}

@article {pmid42628773,
year = {2026},
author = {Tani, H},
title = {A replicated astrocyte long non-coding RNA signature of Alzheimer's disease is inverted in amyotrophic lateral sclerosis.},
journal = {Brain research},
volume = {1891},
number = {},
pages = {150513},
doi = {10.1016/j.brainres.2026.150513},
pmid = {42628773},
issn = {1872-6240},
abstract = {Reactive astrocyte transitions are central to neurological disease, yet their long non-coding RNA (lncRNA) regulators remain poorly defined, and single-nucleus studies frequently treat nuclei rather than donors as replicates. This study analyses publicly available human single-nucleus RNA sequencing from four disorders using donors as the unit of inference throughout: Alzheimer's disease (AD; middle temporal gyrus, 88 donors), C9orf72-associated amyotrophic lateral sclerosis and ALS/frontotemporal dementia (ALS; frontal cortex), multiple sclerosis (MS; cortex and white matter), and major depressive disorder (MDD; amygdala). The public MDD release pools nuclei by condition, so that arm cannot support donor-level inference and is exploratory only. Covariate-adjusted pseudobulk analysis of 70,009 CE astrocytes, controlling for sex, age at death and assay chemistry, identified 1,019 down-regulated autosomal lncRNAs after sex-chromosome transcripts were removed. This signature was not attributable to astrocyte subtype composition, which did not differ between groups, and 99.9% of members remained down-regulated within the dominant homeostatic subtype alone. The signature replicated in an independent AD cohort (32 of 41 testable members concordant; resampling P < 0.0001). Testing it outside AD gave a directional result: it was concordant in the MS discovery cohort (P < 0.0001) but inconclusive in an independent MS cohort in which the transcripts lay near the detection floor, and it was reproducibly inverted in ALS, in the C9orf72 discovery cohort and in an independent motor-cortex cohort not restricted to C9orf72 carriers. The inversion survived negative controls for global normalisation and expression level. These astrocyte lncRNA changes are therefore disorder-specific rather than pan-neuroinflammatory.},
}

@article {pmid42628775,
year = {2026},
author = {Marakhovskaya, YA and Churov, AV and Arbatsky, MS and Sergeeva, SP},
title = {Ferroptosis and Alzheimer's disease: Neuroimmune crosstalk and pharmacological opportunities.},
journal = {Brain research},
volume = {},
number = {},
pages = {150514},
doi = {10.1016/j.brainres.2026.150514},
pmid = {42628775},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) develops through interacting proteinopathic, metabolic, oxidative, and neuroimmune processes. Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation and failure of antioxidant defense systems. This review examines the bidirectional interface between ferroptosis and neuroinflammation in AD and distinguishes direct AD-related evidence from findings derived from experimental models and broader ferroptosis or inflammatory studies. Iron dyshomeostasis, impaired ferroportin-dependent iron export, lipid peroxidation, and reduced glutathione/GPX4-dependent protection may increase neuronal susceptibility to ferroptotic injury. In turn, oxidized lipids and danger-associated molecular patterns released from damaged neurons may activate microglia and astrocytes, engage inflammasome and complement signaling, and amplify inflammatory responses. Conversely, cytokine signaling, altered iron handling, and immune-cell redox and lipid remodeling may further increase ferroptotic vulnerability. We also compare ferroptosis-related markers and pathways in neurons, microglia, and astrocytes and discuss potential therapeutic approaches targeting iron metabolism, lipid peroxidation, GPX4 activity, system xc - function, NRF2-related antioxidant defense, neuroimmune signaling, and multitarget compounds. Although available evidence supports an association between ferroptosis-related processes and AD pathobiology, no single marker is sufficient to establish ferroptosis in human AD tissue. This limitation currently restricts the diagnostic and therapeutic interpretation of ferroptosis in AD.},
}

@article {pmid42628844,
year = {2026},
author = {Huang, JW and Wang, YF and Zheng, WH and Cui, QQ and Gao, SQ and Guo, Y},
title = {Viral infection and dementia risk: A systematic bidirectional Mendelian randomization analysis.},
journal = {Virus research},
volume = {},
number = {},
pages = {199794},
doi = {10.1016/j.virusres.2026.199794},
pmid = {42628844},
issn = {1872-7492},
abstract = {BACKGROUND: Viral infections have attracted increasing interest as potentially alterable risk factors for dementia; nonetheless, the results from observational research are variable and prone to confounding bias and reverse causation. This work seeks to systematically explore the potential causal associations between several viral infections and various forms of dementia by a Mendelian randomization methodology utilizing summary statistics and extensive genomic data from the Finnish FinnGen R12 database.

METHODS: This study initially included 14 viral infections, including anogenital herpes, infectious mononucleosis, acute hepatitis B, herpesviral infections, acute poliomyelitis, rubella, varicella, viral warts, herpes zoster, COVID-19, measles, mumps, acute hepatitis A, and HIV infection. The outcome measurements included 15 forms of dementia, including Alzheimer's dementia, vascular dementia and its subtypes, and frontotemporal dementia. The principal analysis utilized the inverse variance weighted (IVW) methodology. This report provides the number of SNPs in each analysis, the mean F statistic, the causal effect estimates, and their 95% confidence ranges. All the MR-Egger regression, weighted median, simple mode, and weighted mode approaches were used in the sensitivity analyses.

RESULTS: The final analysis omitted acute hepatitis A, HIV infection, and measles because of inadequate instrumental variables (only 1-2 SNPs). The IVW primary analysis revealed 6 associations with uncorrected P < 0.05 among the remaining 11 viral infections. Rubella infection was associated with a decreased risk of vascular dementia (subcortical type) (OR = 0.8304; 95% CI: 0.7154-0.9638; P = 0.0145; SNPs = 7; mean F statistic = 25.56) and showed a negative association with the outcome of the composite dementia, including that of Alzheimer's disease (OR = 0.9553; 95% CI: 0.9128-0.9998; P = 0.0488). Viral wart infection was associated with a reduced risk of Alzheimer's dementia (OR = 0.9095; 95% CI: 0.8332-0.9928; P = 0.0338; SNPs = 11; mean F-statistic = 56.01), any dementia (strict exclusion criteria) (OR = 0.9278; 95% CI: 0.8668-0.9932; P = 0.0310), and Parkinson's-related dementia (OR = 0.8182; 95% CI: 0.6796-0.9852; P = 0.0342). There was a suggestive link between mumps infection and a higher risk of vascular dementia (mixed type) (OR = 1.5579; 95% CI: 1.2219-1.9864; P = 0.0003; SNPs = 5; mean F-statistic = 22.63). This link was equally strong in the weighted median analysis (OR = 1.4131, P = 0.0277). In fact, statistically significant connections were not found between any types of viral infections and dementias (after multiple testing correction). Furthermore, for the other viral infections, no associations were observed even at the uncorrected P < 0.05 level. All findings with uncorrected P < 0.05 were successfully tested for heterogeneity and pleiotropy, and sensitivity analyses revealed consistent effect directions.

CONCLUSION: This study offers suggestive genetic evidence for potential associations between certain viral infections and specific forms of dementia. Infections with rubella and viral warts may correlate with a diminished risk of dementia; however, mumps infection may increase the risk of vascular dementia (mixed type). It was not possible to reliably evaluate acute hepatitis A and HIV infection since there were not enough instrumental variables. These results provide preliminary insights into the influence of infectious agents on neurodegenerative disorders, serving as a hypothesis-generating framework for future epidemiological and mechanistic research.},
}

@article {pmid42629112,
year = {2026},
author = {Chen, X and Zhang, X and Chen, C and She, J and Liu, Y and Zhang, C and Cai, J and Tang, L and Zhou, X},
title = {"Marine Rule": discovery of marine natural small molecule drug leads in China in the past decade.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {9},
pages = {1025-1049},
doi = {10.1016/S1875-5364(26)61202-2},
pmid = {42629112},
issn = {1875-5364},
mesh = {*Drug Discovery ; China ; *Biological Products/chemistry/pharmacology ; *Aquatic Organisms/chemistry ; Humans ; Animals ; Structure-Activity Relationship ; },
abstract = {This review systematically analyzes 186 valid data points derived from 157 distinct marine natural small-molecule drug leads discovered in China in the past decade (2015-2024). These compounds have all undergone phenotypic and target studies, and certain "structure-activity-target" relationships have been established, revealing the recent progress in the basic research of marine drug discovery in China. Therapeutically, antitumor agents dominated (50.0%), while emerging candidates for Alzheimer's disease (3.8%) and osteoporosis (5.4%) demonstrated the multi-target potential of marine chemistry. Ecologically, marine fungi (45.2%) and mangrove symbionts (11.8%) have emerged as prolific sources. Strikingly, 38.2% of the compounds exceeded Lipinski's 500 Da threshold, with higher-molecular-weight agents leveraging macrocyclic architectures (e.g., polyketide-alkaloid hybrids) to enhance bioactivity. These findings challenge traditional drug-likeness criteria and propose a "Marine Rule" framework that prioritizes conformational rigidity, ecosystem-driven scaffold optimization, and the repurposing of defense molecules. This review provides critical insights into China's evolving leadership in marine natural product research and offers strategic guidance for future innovations in the discovery of small molecule leads.},
}

*Drug Discovery
China
*Biological Products/chemistry/pharmacology
*Aquatic Organisms/chemistry
Humans
Animals
Structure-Activity Relationship

@article {pmid42629121,
year = {2026},
author = {Chinnathambi, S and Suresh, S and Velmurugan, G and Mishra, A},
title = {Alzheimer's disease: Extracellular Tau internalization in neuro-glial axis and its propagation mechanisms.},
journal = {Advances in immunology},
volume = {171},
number = {},
pages = {1-31},
doi = {10.1016/bs.ai.2025.11.004},
pmid = {42629121},
issn = {1557-8445},
mesh = {Humans ; *tau Proteins/metabolism ; Animals ; *Alzheimer Disease/metabolism/pathology/immunology ; *Astrocytes/metabolism/pathology ; *Microglia/metabolism/pathology/immunology ; *Neuroglia/metabolism ; *Neurons/metabolism/pathology ; Inflammasomes/metabolism ; Oxidative Stress ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; },
abstract = {Tau is a protein associated with microtubules that is essential to the central nervous system's extracellular and intracellular functions. Aberrant post-translational changes cause Tau to dissociate from microtubules in pathological circumstances like Tauopathies and also in AD (AD). The free Tau can diffuse into the extracellular space, contributing to neurofibrillary tangles formation and paired helical filaments. Moreover, pathogenic Tau can spread in a prion-like manner from diseased neurons to healthy ones exacerbating Tau pathology. By stimulating the NLRP3 inflammasome and other pathways, extracellular Tau has an impact on microglia. This, in turn, triggers inflammatory responses and leads to neuroinflammation. Astrocytes, the predominant brain cells, absorb extracellular Tau and undergo morphological and functional changes that result in the production of neurotoxic compounds, which ultimately cause neurodegeneration. The uptake of Tau by astrocytes results in a proinflammatory phenotype and cellular senescence, which intensify neuroinflammatory processes and oxidative stress and accelerate the advancement of neurodegenerative illnesses.},
}

Humans
*tau Proteins/metabolism
Animals
*Alzheimer Disease/metabolism/pathology/immunology
*Astrocytes/metabolism/pathology
*Microglia/metabolism/pathology/immunology
*Neuroglia/metabolism
*Neurons/metabolism/pathology
Inflammasomes/metabolism
Oxidative Stress
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism

@article {pmid42629123,
year = {2026},
author = {Chidamabram, H and Ananathanarayana, V and Chinnathambi, S},
title = {G-Protein coupled receptor-mediated internalization and endosomal sorting of Tau-GPCR complex in microglia.},
journal = {Advances in immunology},
volume = {171},
number = {},
pages = {147-173},
doi = {10.1016/bs.ai.2025.11.003},
pmid = {42629123},
issn = {1557-8445},
mesh = {Humans ; *Microglia/metabolism/immunology ; *tau Proteins/metabolism ; Animals ; *Alzheimer Disease/metabolism/immunology/pathology ; *Receptors, G-Protein-Coupled/metabolism ; *Endosomes/metabolism ; *Receptors, Purinergic P2Y12/metabolism ; Endocytosis ; Protein Transport ; },
abstract = {Microglia are the resident immune cells of the central nervous system (CNS), which are in constant surveillance of the brain microenvironment to maintain tissue homeostasis. Microglia play significant role both in the physiological and pathological conditions of the brain. Alzheimer's Disease (AD) is a neurodegenerative disease that includes progressive dementia and cognitive deficits. The two main culprits of AD are extracellular amyloid-β plaques and neurofibrillary tangles formed by Tau protein. In AD brain, intrinsically disordered Tau undergoes rapid oligomerization and self-aggregates to form filamentous species. Clearance of these toxic species is mainly performed by microglia, which can sense through various receptors such as Toll-like receptors (TLRs), G-Protein coupled receptor (GPCRs), purinergic receptors, etc. One such receptor is P2Y12R, a purinergic receptor whose expression is restricted to microglia in CNS. In this review, we envisioned providing an insight into the involvement of P2Y12R, a purinergic cell surface receptor that facilitates the internalization of Tau along with the other mechanisms of Tau clearance in microglia. Exploring these receptors and elucidating the mechanisms underlying Tau transmission could pave the way for the development of innovative therapeutic approaches aimed at impeding the spread of Tau pathology in neurodegenerative diseases.},
}

Humans
*Microglia/metabolism/immunology
*tau Proteins/metabolism
Animals
*Alzheimer Disease/metabolism/immunology/pathology
*Receptors, G-Protein-Coupled/metabolism
*Endosomes/metabolism
*Receptors, Purinergic P2Y12/metabolism
Endocytosis
Protein Transport

@article {pmid42629124,
year = {2026},
author = {Chinnathambi, S and Adityan, A and Chandrashekar, M and Velmurugan, G},
title = {iPSC-derived neurospheres: A cellular platform for Tau and Alzheimer's disease immunotherapy.},
journal = {Advances in immunology},
volume = {171},
number = {},
pages = {175-203},
doi = {10.1016/bs.ai.2025.11.001},
pmid = {42629124},
issn = {1557-8445},
mesh = {Humans ; *Alzheimer Disease/therapy/immunology/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *tau Proteins/metabolism/immunology ; Animals ; *Neurons/metabolism ; Amyloid beta-Peptides/metabolism ; Microglia/metabolism ; *Immunotherapy/methods ; Astrocytes/metabolism ; },
abstract = {Alzheimer's disease is the most prevalent type of dementia, which is characterized by a progressive loss of memory and cognitive impairment. The internalization of extracellular Tau and Amyloid-β-induced pluripotent stem cells plays a crucial role in understanding the AD pathology. iPSC-derived neuron, microglia, and astrocyte are used as models to study the spreading of pathological proteins and their contribution in the disease progression. iPSC-derived neurons serve as an essential model for studying AD, particularly in relation to Tau aggregation, prion-like propagation, and the toxic effects of oligomeric amyloid beta. Extracellular Tau, along with oligomeric amyloid beta, enters neurons via endocytosis and macropinocytosis, leading to cellular abnormalities, oxidative stress, and dysfunction in neurons. Additionally, iPSC-derived microglia provide insights into neuroinflammatory responses and neurotoxic effects of Tau aggregation and Amyloid-β, highlighting their combined role in Alzheimer's pathology. Extracellular Tau internalization by microglia involves phagocytosis and exhibits activation response to Tau aggregates, releasing cytokines and undergoing calcium homeostasis. iPSC-derived astrocytes demonstrated a reactive state and disruption in calcium homeostasis upon the exposure of the pathological proteins, contributing to neurodegeneration. Further, the mechanisms of Tau and Amyloid-β internalization in iPSC-derived cells provide insights into disease progression and highlights potential therapeutic targets for neurodegenerative disease.},
}

Humans
*Alzheimer Disease/therapy/immunology/metabolism/pathology
*Induced Pluripotent Stem Cells/metabolism
*tau Proteins/metabolism/immunology
Animals
*Neurons/metabolism
Amyloid beta-Peptides/metabolism
Microglia/metabolism
*Immunotherapy/methods
Astrocytes/metabolism

@article {pmid42629128,
year = {2026},
author = {Saini, V and Mukherjee, S and Vora, C and Jindal, H and Jha, HC},
title = {Microglia in Alzheimer's disease: Insights into disease progression and therapy.},
journal = {Advances in immunology},
volume = {171},
number = {},
pages = {283-306},
doi = {10.1016/bs.ai.2026.06.004},
pmid = {42629128},
issn = {1557-8445},
mesh = {*Microglia/immunology/metabolism/pathology ; Humans ; *Alzheimer Disease/therapy/metabolism/pathology/immunology ; Animals ; Disease Progression ; Receptors, Immunologic/metabolism ; Membrane Glycoproteins/metabolism ; Metabolic Reprogramming ; Cellular Senescence ; },
abstract = {The role of microglia, once seen as bystanders, has recently shifted to that of central regulators in disease pathology. The shift has been observed in M1/M2-polarized microglia to multiple configurations, including disease-associated microglia (DAM), lipid-droplet-accumulating microglia (LDAM), senescent microglia, and interferon-responsive microglia. This chapter provides a comprehensive synthesis of microglial biology across multiple interfaces, including transcriptomic, lipid-associated metabolic, cell senescence, and metabolic reprogramming. Metabolic disharmony in microglia occurs when lipid dysregulation and inflammasome activation occurs, leading to chronic inflammation beyond the basic phagocytic repair function of microglia. The TREM2-associated therapeutic trajectory also shows a translational gap with mechanistic and clinical benefits. We also identify the need for critical disease-associated microglial biomarkers and intervention strategies. Moreover, advanced iPSC-derived microglia and chimeric models often yield specialized organoid co-cultures, accelerating microglia-mediated therapeutic studies. Collectively, this chapter entails microglia as a central player in AD. This positions microglia biology as a metabolically plastic, spatially organized immune-regulated microenvironment that can efficiently aid in reprogramming and AD therapeutics.},
}

*Microglia/immunology/metabolism/pathology
Humans
*Alzheimer Disease/therapy/metabolism/pathology/immunology
Animals
Disease Progression
Receptors, Immunologic/metabolism
Membrane Glycoproteins/metabolism
Metabolic Reprogramming
Cellular Senescence

@article {pmid42629129,
year = {2026},
author = {Sha, L and Jha, S},
title = {Microglia extracellular traps (MiETs) in Neurodegeneration: Mechanisms, Evidence Gaps, and Untapped Therapeutic Promise.},
journal = {Advances in immunology},
volume = {171},
number = {},
pages = {307-341},
doi = {10.1016/bs.ai.2026.04.008},
pmid = {42629129},
issn = {1557-8445},
mesh = {Humans ; *Extracellular Traps/immunology/metabolism ; *Microglia/immunology/metabolism ; Animals ; *Neurodegenerative Diseases/immunology/therapy/metabolism/pathology ; Histones/metabolism ; Signal Transduction ; Neuroinflammatory Diseases/immunology ; },
abstract = {Microglia are the resident myeloid cells of the central nervous system, they play essential roles in neural tissue homeostasis, including synaptic pruning, clearance of debris and protein aggregates, and regulation of neuroinflammatory processes. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, microglial activation and chronic glial-driven inflammation contribute substantially to neuronal dysfunction and loss. Beyond these well-characterised functions, recent evidence indicates that microglia can release chromatin-based extracellular traps (microglia extracellular traps, or MiETs), similar to the neutrophil extracellular traps (NETs) observed in peripheral immunity. Microglia ETs are induced by stimuli such as dopamine and microbial infection, dependent or independent of NADPH oxidase/ROS pathways and histone citrullination. This chapter provides a detailed examination of MiET formation, triggers, intracellular signalling, and structural components, as well as contribution to neurodegenerative pathology. Potential mechanisms include amplification of neuroinflammation via extracellular histones and proteases, disruption of the blood-brain barrier and extracellular matrix, synaptic damage, and possible facilitation of spread of misfolded protein aggregates. We situate MiET formation within the broader microglial functional repertoire (phagocytosis, cytokine production, synaptic stripping) and focus on how ET-dominant responses may compromise homeostatic or neuroprotective roles. The chapter reviews evidence from disease models, highlights key gaps and discusses translational implications. Targeting MiET formation or promoting the clearance of MiETs represents promising, yet unexplored, therapeutic avenues in neurodegenerative disease. By focusing on MiETs, this work expands the conceptual framework for microglial pathogenicity and invites future mechanistic and translational research.},
}

Humans
*Extracellular Traps/immunology/metabolism
*Microglia/immunology/metabolism
Animals
*Neurodegenerative Diseases/immunology/therapy/metabolism/pathology
Histones/metabolism
Signal Transduction
Neuroinflammatory Diseases/immunology

@article {pmid42629135,
year = {2026},
author = {Ananathanarayana, V and Upadhyay, R and Illanad, GH and Krishnan, D and Bochageri, NP and Sevanan, M and Bagewadi, Z and Sivasamy, R and Chinnathambi, S},
title = {Chemokine receptor CX3CR1 modulates microglial activity through Tau and amyloid-β interactions in Alzheimer's disease.},
journal = {Advances in immunology},
volume = {171},
number = {},
pages = {83-108},
doi = {10.1016/bs.ai.2025.11.002},
pmid = {42629135},
issn = {1557-8445},
mesh = {Humans ; *Alzheimer Disease/metabolism/immunology/pathology ; *Microglia/metabolism/immunology ; *CX3C Chemokine Receptor 1/metabolism ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Animals ; Signal Transduction ; Chemokine CX3CL1/metabolism ; Neurons/metabolism ; },
abstract = {Alzheimer's disease is one of the most prevalent forms of dementia characterized by neurocognitive decline. Key proteins involved in the progression of disease is amyloid-β and Tau. Abnormal accumulation of amyloid-β senile plaques and Tau neurofibrillary tangles are characteristic features of AD which drives synaptic dysfunction and leads to cognitive decline. Recent studies emphasizes the importance of G-protein coupled receptors in regulating microglial cells and has diverse functions in modulating AD, particularly in the clearance of these pathological proteins. Among these GPCRs, the chemokine receptor CX3CR1 has a critical role at the intersection of pathological proteins and microglial signalling. CX3CR1 receptor mediated signalling influences interaction between microglia and neuron mediating microglial uptake and processing of Aβ and Tau. Aging is also one of the risk factors of AD which alters CX3CR1 signalling, thereby exacerbating disease progression. This review highlights the multifaceted role of CX3CR1 in Tau and Aβ pathology and outlines its signalling mechanisms. Importantly, this review emphasizes the therapeutic potential of targeting the CX3CL1-CX3CR1 axis and involved in protein clearance and reduces neuroinflammation preserving synaptic function, offering a promising way to prevent AD.},
}

Humans
*Alzheimer Disease/metabolism/immunology/pathology
*Microglia/metabolism/immunology
*CX3C Chemokine Receptor 1/metabolism
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Animals
Signal Transduction
Chemokine CX3CL1/metabolism
Neurons/metabolism

@article {pmid42629343,
year = {2026},
author = {Moon, HE and Lee, YS and Roh, S and Allick, C and Sites, KW and Rote, S and Stone, ST},
title = {Cultural Contexts of Caregiving: Exploring Alzheimer's Disease Experiences and Service Needs Among American Indian Communities.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag201},
pmid = {42629343},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: American Indian and Alaska Native (AIAN) experience disproportionately high rates of Alzheimer's disease and related dementias (ADRD), yet little research examines caregiving experiences and service needs within these communities. Guided by the Sociocultural Stress and Coping Model, this study explored dementia caregiving experiences, cultural contexts, and service needs among American Indian community members, tribal health professionals, and leaders in a Northern Plains tribal community using a community-based participatory research approach.

RESEARCH DESIGN AND METHODS: In 2024, seven focus groups were conducted with 60 American Indian adults (48 community members, 12 health professionals/tribal leaders) living in the Northern Plains. Semi-structured focus groups explored caregiving experiences, cultural beliefs, and service needs. A participant background survey captured demographics and care characteristics. Qualitative data were analyzed using conceptual content analysis with iterative team-based coding.

RESULTS: Three themes emerged across positive, negative, and service need domains. Community members emphasized cultural duty, love/reciprocity, and humor as coping mechanisms. Negative experiences included emotional and intergenerational trauma from childhood dementia exposure, and safety/supervision challenges. Critical service needs included medical guidance, community-based education, and respite services. Health professionals and tribal leaders navigated dual clinician-caregiver identities while advocating for system-level reforms. Both groups identified geographic barriers and resource scarcity.

DISCUSSION AND IMPLICATIONS: Findings reveal cultural strengths sustaining caregiving amid substantial systemic barriers. Effective interventions must be family-centered, community-based, and strength-focused. Healthcare systems require fundamental realignment to accommodate Indigenous epistemologies.},
}

@article {pmid42629457,
year = {2026},
author = {Nonino, F and Vignatelli, L and Richard, E},
title = {Reply to "Pooling Alzheimer's disease: when methodological rigor risks obscuring biological complexity".},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {9},
pages = {},
pmid = {42629457},
issn = {1590-3478},
}

@article {pmid42629610,
year = {2026},
author = {Bundschuh, BF and Kley, F and Wang, Y and Strodel, B},
title = {Membrane Complexity and Phase Behavior Dictate the Stability of Membrane-Inserted Aβ42 Hexamers.},
journal = {Chemphyschem : a European journal of chemical physics and physical chemistry},
volume = {27},
number = {16},
pages = {e70538},
doi = {10.1002/cphc.70538},
pmid = {42629610},
issn = {1439-7641},
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Molecular Dynamics Simulation ; *Lipid Bilayers/chemistry/metabolism ; *Peptide Fragments/chemistry/metabolism ; Phosphatidylcholines/chemistry ; Protein Stability ; *Cell Membrane/chemistry/metabolism ; },
abstract = {Protein-membrane interactions are vital to Alzheimer's pathogenesis, as lipid environments modulate both the aggregation and toxicity of amyloid-β (Aβ) peptides. Using atomistic molecular dynamics simulations, this study investigates the stability of an NMR-derived hexameric Aβ42 β-barrel in aqueous solution, a fluid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer, and a complex neuronal membrane. While the hexamer is unstable and conformationally heterogeneous in water, lipid environments provide essential structural reinforcement. Notably, the multicomponent neuronal membrane offers superior stabilization compared to POPC, supporting the β-barrel in a stable transmembrane conformation. This superior stability is driven by the rigid scaffolding of the liquid-ordered phase alongside specific electrostatic anchoring between the ethanolamine headgroups of the POPE component and the acidic Aβ42 residues E22/D23. We characterize a reciprocal relationship where the membrane stabilizes the β-barrel architecture, while the peptide induces localized lipid disorder and flip-flop translocation. Our findings demonstrate how membrane complexity and phase behavior dictate the stability of toxic Aβ42 oligomers, offering key insights into the membrane-mediated mechanisms of neurotoxicity.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Molecular Dynamics Simulation
*Lipid Bilayers/chemistry/metabolism
*Peptide Fragments/chemistry/metabolism
Phosphatidylcholines/chemistry
Protein Stability
*Cell Membrane/chemistry/metabolism

@article {pmid42630070,
year = {2026},
author = {Alsharayri, S and Knox, S and Cutty, M and Mollalo, A},
title = {Dual eligibility and neuropsychiatric symptoms and treatment disparities among Medicare Part D beneficiaries with Alzheimer's disease and related dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478140},
doi = {10.1177/13872877261478140},
pmid = {42630070},
issn = {1875-8908},
abstract = {BackgroundNeuropsychiatric symptoms (NPS) are common and clinically consequential in Alzheimer's disease and related dementias (ADRD), yet their recognition and treatment may vary across socioeconomic groups. Dual-eligible Medicare-Medicaid beneficiaries represent a vulnerable population, but differences in NPS documentation and management remain unclear.ObjectiveTo examine whether dual eligibility is associated with differences in (1) documented NPS and (2) prescription fills among Medicare beneficiaries with ADRD who received home health (HH) care.MethodsWe conducted a cross-sectional study of 167,484 Medicare Part D beneficiaries with ADRD who received HH care and were identified using the Chronic Conditions Warehouse flag. Dual eligibility was the primary exposure. NPS were identified using diagnosis codes from medical claims. Prescription fills for NPS-related medications were identified using Medicare Part D prescription drug event data (≥2 prescription fills for anxiety-related medications and antidepressants). Logistic regression models estimated associations of dual eligibility with NPS documentation and prescription fills, adjusting for demographic characteristics, original Medicare entitlement, and comorbidity burden.ResultsDual-eligible beneficiaries comprised 30.7% of the cohort. Documented confusion and anxiety were the most prevalent symptoms. Dual-eligible beneficiaries had a higher prevalence of confusion (83.5% versus 82.0%) and anxiety (57.0% versus 53.2%) compared with Medicare-only beneficiaries. After adjustment, dual eligibility was associated with higher odds of documented confusion (aOR 1.18, 95% CI 1.14-1.22) and anxiety (aOR 1.19, 95% CI 1.15-1.22). Dual eligibility was also associated with slightly higher odds of anxiety-related prescription fills (aOR 1.21, 95% CI 1.17-1.26), whereas antidepressant prescription fills did not differ (aOR 1.00, 95% CI 0.95-1.05).ConclusionsDual eligibility was associated with modest differences in NPS documentation and prescription fills, suggesting differences in recognition and management of NPS among beneficiaries with ADRD.},
}

@article {pmid42630074,
year = {2026},
author = {Tu, T and Zhang, QL and Sun, ZP and Kang, C and Li, D and Huo, XH and Zhang, XJ and Zhang, Y and Cui, M and Pan, A and Wang, J and Yan, XX},
title = {Aberrant ɑSMA expression reveals broad mossy fiber reorganization integrating with tangle and plaque formation and mitoenergetic alteration in the human hippocampus.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71778},
doi = {10.1002/alz.71778},
pmid = {42630074},
issn = {1552-5279},
support = {#2021ZD0201103//Ministry of Science and Technology of China/ ; #2021ZD02018//Ministry of Science and Technology of China/ ; #82201595//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Plaque, Amyloid/pathology/metabolism ; Female ; *Hippocampus/pathology/metabolism ; *Actins/metabolism ; *Alzheimer Disease/pathology/metabolism ; Aged ; Male ; *Mossy Fibers, Hippocampal/pathology/metabolism ; Aged, 80 and over ; *Neurofibrillary Tangles/pathology/metabolism ; Electron Transport Complex IV/metabolism ; },
abstract = {INTRODUCTION: Neural network and bioenergetic abnormalities occur with Alzheimer's disease (AD) pathogenesis.

METHODS: We explored mossy fiber (MF) and mitoenergetic alteration using ɑ-smooth muscle actin (ɑSMA) and cytochrome c oxidase (COX) immunolabeling in human hippocampus relative to tangle and plaque formation by referring to Braak (0-VI) and Thal (0-5) staging scores.

RESULTS: In the brain group with Braak/Thal 0/0 scores (control), ɑSMA labeling occurred in CA3 and dentate gyrus. In groups with 1a to IV/0 and II to VI/1 to 5 scores, ɑSMA labeling appeared in CA2 to subiculum, with increased density in these and the dentate subregions. ɑSMA-labeled MF terminals infiltrated into ghost tangles co-expressing amyloidogenic markers and coexisted among β-secreatse-1 labeled neurites and amyloid beta plaques. COX immunolabeling was increased in CA2 to subiculum in the groups with 1a to IV/0 to 1 compared to 0/0.

DISCUSSION: MF reorganization/dystrophy develops and integrates with tangle and plaque formation and mitoenergetic alteration in the human hippocampus.},
}

Humans
*Plaque, Amyloid/pathology/metabolism
Female
*Hippocampus/pathology/metabolism
*Actins/metabolism
*Alzheimer Disease/pathology/metabolism
Aged
Male
*Mossy Fibers, Hippocampal/pathology/metabolism
Aged, 80 and over
*Neurofibrillary Tangles/pathology/metabolism
Electron Transport Complex IV/metabolism

@article {pmid42630075,
year = {2026},
author = {Stenberg, E and Cao, Y and Eliasson, B and Näslund, E},
title = {The effects of bariatric surgery on dementia in patients with diabetes and obesity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71802},
doi = {10.1002/alz.71802},
pmid = {42630075},
issn = {1552-5279},
support = {//Region Örebro County, Åke Wiberg Foundation, and Region Stockholm/ ; },
mesh = {Humans ; *Bariatric Surgery ; *Obesity/surgery/epidemiology/complications ; *Dementia/epidemiology/prevention & control ; *Diabetes Mellitus, Type 2/epidemiology/complications/surgery ; Female ; Male ; Middle Aged ; Aged ; Incidence ; Risk Factors ; Registries ; Propensity Score ; },
abstract = {INTRODUCTION: Type 2 diabetes (T2D) and obesity are among the most important risk factors for dementia. Although weight loss is an important preventive strategy, the impact of metabolic and bariatric surgery (MBS) on dementia risk remains contradictory.

METHODS: We conducted a propensity score matched study using nationwide, high-quality clinical registries to compare the outcomes in patients with obesity and T2D who underwent MBS with matched controls who did not undergo surgery.

RESULTS: Over a mean follow-up of 9 years, MBS was associated with a reduced risk of dementia (15-year cumulative incidence 1.8% vs. 2.7%, subdistribution hazard ratio [SHR] 0.60, 95% CI 0.47-0.76). The incidence was lower for Alzheimer's disease (1.2% vs. 1.9%, SHR 0.56, 95% CI 0.41-0.76) and vascular dementia (0.4% vs. 0.7%, SHR 0.49, 95% CI 0.29-0.85), but increased for alcohol-related dementia (0.2% vs. 0.04%, SHR 3.67, 95%CI 1.33-10.14).

DISCUSSION: These findings suggest that the collected long-term effects of MBS may reduce the risk of developing dementia in individuals with obesity and T2D.},
}

Humans
*Bariatric Surgery
*Obesity/surgery/epidemiology/complications
*Dementia/epidemiology/prevention & control
*Diabetes Mellitus, Type 2/epidemiology/complications/surgery
Female
Male
Middle Aged
Aged
Incidence
Risk Factors
Registries
Propensity Score

@article {pmid42630093,
year = {2026},
author = {Lep, M and Plesingrova, K and Sedmik, J and Cesnarikova, S and Feole, M and Bernatik, O and Pozo Devoto, VM and Hribkova, H and Amruz Cerna, K and Fojtik, P and Vaskovicova, N and Bartova, S and Pospisilova, V and Vanova, T and Andersen, OM and Bohaciakova, D and Raska, J},
title = {SORL1 variant links endosomal amyloid precursor protein mis-sorting to axonal transport defects and neuronal dysfunction.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71782},
doi = {10.1002/alz.71782},
pmid = {42630093},
issn = {1552-5279},
support = {NU22J-08-00075//Agentura Pro Zdravotnický Výzkum České Republiky/ ; GA24-12028S//Grantová Agentura České Republiky/ ; LX22NPO5107//NextGenerationEU/ ; 101087124//HORIZON EUROPE Framework Programme/ ; 857560//Horizon 2020/ ; ADPriOMICS2023-087//EU Joint Programme - Neurodegenerative Disease Research/ ; MUNI/A/1738/2024//Lékařská fakulta, Masarykova univerzita/ ; },
mesh = {Humans ; *Amyloid beta-Protein Precursor/metabolism ; *Axonal Transport/genetics/physiology ; *Endosomes/metabolism ; *Neurons/metabolism/pathology ; *LDL-Receptor Related Proteins/genetics/metabolism ; *Membrane Transport Proteins/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Alzheimer Disease/genetics ; Protein Transport ; },
abstract = {INTRODUCTION: SORL1 encodes the sorting receptor SORLA, a major genetic contributor to Alzheimer's disease (AD). Although SORL1 loss disrupts endosomal trafficking and promotes amyloidogenic amyloid precursor protein (APP) processing, the functional consequences of specific missense variants in human neurons remain unclear.

METHODS: We used isogenic induced pluripotent stem cell (iPSC)-derived NGN2 neurons and 3D cerebral organoids carrying wild-type, SORL1 p.Y1816C knock-in, or SORL1 knockout alleles. We analyzed SORLA maturation and shedding, APP localization, amyloid-β (Aβ) secretion, endosomal morphology, axonal transport of Rab5+ endosomes and APP, and network activity.

RESULTS: The p.Y1816C variant impaired SORLA maturation and shedding and, together with knockout, caused enlarged early endosomes, APP retention, elevated Aβ secretion, amyloid deposition in organoids, axonal swellings, disrupted axonal transport, and neuronal hyperexcitability.

CONCLUSIONS: The SORL1 p.Y1816C variant is pathogenic in human neurons, and we reveal novel roles for SORLA in axonal transport and neuronal excitability. These findings highlight endosomal trafficking disruption as a central mechanism in AD pathogenesis.},
}

Humans
*Amyloid beta-Protein Precursor/metabolism
*Axonal Transport/genetics/physiology
*Endosomes/metabolism
*Neurons/metabolism/pathology
*LDL-Receptor Related Proteins/genetics/metabolism
*Membrane Transport Proteins/genetics/metabolism
Induced Pluripotent Stem Cells/metabolism
Alzheimer Disease/genetics
Protein Transport

@article {pmid42630134,
year = {2026},
author = {Kumar, A and Sharma, M and Su, Y and Singh, S and Tanley, JE and Casanova, R and Hsu, FC and Craft, S and Mielke, MM and Hughes, TM and Deep, G},
title = {Dissecting Alzheimer's proteomic landscape through NULISA profiling of brain cell-specific extracellular vesicles.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71717},
doi = {10.1002/alz.71717},
pmid = {42630134},
issn = {1552-5279},
support = {75N92020D00001/NH/NIH HHS/United States ; HHSN268201500003I/NH/NIH HHS/United States ; N01-HC-95159/NH/NIH HHS/United States ; 75N92020D00005/NH/NIH HHS/United States ; N01-HC-95160/NH/NIH HHS/United States ; 75N92020D00002/NH/NIH HHS/United States ; N01-HC-95161/NH/NIH HHS/United States ; 75N92020D00003/NH/NIH HHS/United States ; N01-HC-95162/NH/NIH HHS/United States ; 75N92020D00006/NH/NIH HHS/United States ; N01-HC-95163/NH/NIH HHS/United States ; 75N92020D00004/NH/NIH HHS/United States ; N01-HC-95164/NH/NIH HHS/United States ; 75N92020D00007/NH/NIH HHS/United States ; N01-HC-95165/NH/NIH HHS/United States ; N01-HC-95166/NH/NIH HHS/United States ; N01-HC-95167/NH/NIH HHS/United States ; N01-HC-95168/NH/NIH HHS/United States ; N01-HC-95169/NH/NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; R01AG054069/TR/NCATS NIH HHS/United States ; R01AG058969/TR/NCATS NIH HHS/United States ; P30AG072947/TR/NCATS NIH HHS/United States ; 1R01AG084696/TR/NCATS NIH HHS/United States ; 1RF1AG068629/TR/NCATS NIH HHS/United States ; /AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Extracellular Vesicles/metabolism ; *Proteomics/methods ; *Brain/metabolism/pathology ; Biomarkers/blood/metabolism ; Cognitive Dysfunction/metabolism ; Neurons/metabolism ; Microglia/metabolism ; Astrocytes/metabolism ; *Proteome ; Endothelial Cells/metabolism ; Oligodendroglia/metabolism ; },
abstract = {INTRODUCTION: Blood-based biomarkers are essential for early detection, monitoring, and therapeutic development in Alzheimer's disease (AD) and related dementia (ADRD), but current assays lack brain cell specificity and sensitivity to low-abundant proteins.

METHOD: We isolated the following brain cell-derived small extracellular vesicles (sEV) from the plasma of individuals with normal cognition (CN), mild cognitive impairment (MCI), or ADRD: neurons (NDE), astrocytes (ADE), microglia (MDE), oligodendrocytes (ODE), pericytes (PDE), and endothelial cells (EDE). Using NULISAseq, we profiled 122 proteins, spanning AD pathology, neurodegeneration, and neuroinflammation.

RESULTS: sEV proteomes showed distinct brain cell-type-specific signatures. MCI exhibited early dysregulation of neuroprotective, inflammatory, and vascular markers in NDE, MDE, and ODE. ADRD displayed broader alteration tau, amyloid, neuroinflammation, vascular dysfunction, and synaptic loss across multiple sEV populations.

DISCUSSION: Combining NULISAseq with brain cell-derived plasma sEV enables the detection of multicellular molecular changes in ADRD, supporting their use as a minimally invasive platform for biomarker discovery.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Extracellular Vesicles/metabolism
*Proteomics/methods
*Brain/metabolism/pathology
Biomarkers/blood/metabolism
Cognitive Dysfunction/metabolism
Neurons/metabolism
Microglia/metabolism
Astrocytes/metabolism
*Proteome
Endothelial Cells/metabolism
Oligodendroglia/metabolism

@article {pmid42630226,
year = {2026},
author = {Kim, H and Parker, C and Severance, JJ and Wiechmann, A},
title = {When mild impairment is not safe: mini-mental state examination scores of ≤21 are associated with emergency response failure.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1916712},
doi = {10.3389/fnagi.2026.1916712},
pmid = {42630226},
issn = {1663-4365},
abstract = {INTRODUCTION: Unrecognized emergency-response deficits contribute to preventable harm and loss of independence in older adults with cognitive decline. Although the Mini-Mental State Examination (MMSE) is widely used to assess global cognition, clinicians often use MMSE scores to inform judgments about everyday functioning. However, the relationship between MMSE performance and emergency-response ability remains unclear. The Test of Executive Functioning in an Emergency (TEFE) is a brief, performance-based assessment that evaluates a patient's ability to relay critical information and contact emergency services. This study examined whether an MMSE threshold was associated with failure on TEFE 911 tasks.

METHODS: A retrospective analysis included 905 patients from a university-affiliated memory clinic with Alzheimer's disease, vascular dementia, mixed dementia, mild cognitive impairment, or normal cognition. Associations between MMSE scores and TEFE 911 knowledge and behavioral task failure were examined using correlation, adjacent-score comparisons, receiver operating characteristic (ROC) analyses, Youden's J, and multivariable logistic regression adjusted for demographic and diagnostic covariates.

RESULTS: MMSE and TEFE scores were moderately correlated (r = 0.596, p < 0.0001). Failure rates were higher at MMSE scores of 21 than 22. ROC analyses demonstrated good discrimination for 911 task failure (AUC = 0.860-0.867). An MMSE cutoff of ≤21 yielded 61.9% sensitivity and 88.9% specificity for failure on 911 tasks and remained independently associated with failure after adjustment (adjusted OR = 3.71, 95% CI: 1.82-7.56).

DISCUSSION: Patients with MMSE scores ≤21 may warrant further performance-based assessment of emergency-response ability. Prospective studies should determine whether this threshold predicts real-world safety outcomes.},
}

@article {pmid42630294,
year = {2026},
author = {Shafi, S and Ansari, GA},
title = {Developing artificial intelligence-based techniques for brain MRI image segmentation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1894751},
doi = {10.3389/fnins.2026.1894751},
pmid = {42630294},
issn = {1662-4548},
abstract = {INTRODUCTION: Brain MRI image segmentation is essential for the accurate diagnosis and treatment of neurological disorders, including brain tumors, Alzheimer's disease, and multiple sclerosis. Artificial intelligence (AI), particularly deep learning, has emerged as an effective approach for improving the precision and efficiency of medical image segmentation while reducing manual effort.

METHODS: This study utilized a publicly available Kaggle brain MRI dataset containing labeled images for supervised learning. A Convolutional Neural Network (CNN)-based framework was developed for automatic brain MRI segmentation. The methodology incorporated preprocessing techniques, including noise removal, normalization, and data augmentation, to improve image quality and model performance. The proposed model was evaluated using Accuracy, Dice Score, and Intersection over Union (IoU).

RESULTS: Experimental results demonstrated that the proposed AI-based segmentation framework achieved high segmentation accuracy and effectively distinguished normal brain tissue from abnormal regions. The model outperformed conventional image-processing methods by providing improved segmentation precision, reducing manual intervention, and enhancing the reliability of medical image analysis.

DISCUSSION: The findings demonstrate the potential of AI-based deep learning techniques for automated brain MRI segmentation in clinical applications. The proposed framework can support clinicians by improving diagnostic accuracy and reducing processing time. Future work will focus on implementing more advanced deep learning architectures and expanding the dataset to further improve segmentation performance and clinical applicability.},
}

@article {pmid42630395,
year = {2026},
author = {Fan, R and Wu, X},
title = {From fragmented neurotechnologies to closed-loop brain health systems: integrating artificial intelligence, digital health, digital twins, and advanced materials for brain disorders.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {14},
number = {},
pages = {1904561},
doi = {10.3389/fbioe.2026.1904561},
pmid = {42630395},
issn = {2296-4185},
abstract = {Brain disorders have traditionally been managed through fragmented clinical pathways in which diagnosis, monitoring, intervention, and long-term follow-up are treated as separate processes. This paradigm is increasingly insufficient for conditions such as Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, glioma, epilepsy, and neuropsychiatric disorders, whose trajectories are dynamic, heterogeneous, and strongly shaped by biological, behavioral, environmental, and health-system factors. Recent advances in artificial intelligence, digital health, digital twin modeling, and advanced biomaterials provide an opportunity to move beyond isolated technological applications toward integrated brain health systems. In this Perspective, we argue that the major translational opportunity is not simply to apply artificial intelligence to neuroimaging, use wearable devices for neurological monitoring, or develop biomaterials for brain repair in parallel. Rather, the field should aim to build closed-loop systems in which computational models identify disease states, digital platforms continuously update patient trajectories, and advanced materials deliver adaptive therapeutic or regenerative interventions. We propose that future progress depends on three related shifts: moving from episodic diagnosis to longitudinal brain-state modeling; redefining advanced materials as programmable therapeutic interfaces rather than passive carriers; and evaluating success at the level of health-system integration rather than single-device performance. This framework may help reorient brain disease innovation from fragmented neurotechnologies toward clinically deployable, patient-specific, and dynamically adaptive brain health systems.},
}

@article {pmid42630537,
year = {2026},
author = {},
title = {Correction to "Translational Medicine in Alzheimer's Disease: The Journey of Donanemab From Discovery to Clinical Application".},
journal = {Chronic diseases and translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/cdt3.70063},
pmid = {42630537},
issn = {2589-0514},
abstract = {[This corrects the article DOI: 10.1002/cdt3.155.].},
}

@article {pmid42630799,
year = {2026},
author = {Peng, L and Wu, Z and Yuan, X and Zhou, C and Fu, H},
title = {The potential connection between inflammatory bowel disease and Alzheimer's disease: mechanistic insights and therapeutic implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1910604},
doi = {10.3389/fimmu.2026.1910604},
pmid = {42630799},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism/epidemiology/drug therapy ; *Inflammatory Bowel Diseases/immunology/metabolism/drug therapy/epidemiology ; Animals ; Gastrointestinal Microbiome/immunology ; Dysbiosis ; Glymphatic System/metabolism/immunology ; },
abstract = {Inflammatory bowel disease (IBD) and Alzheimer's disease (AD) are two chronic conditions previously considered pathologically unrelated. However, accumulating epidemiological evidence suggests that patients with IBD may have an elevated risk. This review systematically analyzes the mechanistic links between IBD and AD, emphasizing the roles of gut microbiota dysbiosis, systemic and neuroinflammation, and glymphatic dysfunction. We propose a putative conceptual framework incorporating the 'gut-glymphatic axis' as a potential conduit through which IBD-associated microbial and immune perturbations may influence AD pathology. Key pathways include short-chain fatty acids, tryptophan metabolites, trimethylamine N-oxide, and bile acids, all of which modulate neuroinflammation and amyloid-β clearance. Additionally, circadian disruption and impaired aquaporin-4 polarity in the glymphatic system may represent novel links between intestinal inflammation and neurodegenerative changes. Preclinical animal models suggest that colitis exacerbates AD-like pathology via NLRP3 inflammasome activation, neutrophil infiltration, and microglial dysfunction. Natural bioactive compounds-such as ginsenosides, curcumin, baicalin, berberine, and magnolol-show dual therapeutic potential in both IBD and AD by targeting shared inflammatory and microbiota pathways. However, validated comorbidity models and clinical trials are lacking. This review provides a scientifically grounded basis for future mechanistic studies and integrated interventions for IBD-AD comorbidity.},
}

Humans
*Alzheimer Disease/immunology/metabolism/epidemiology/drug therapy
*Inflammatory Bowel Diseases/immunology/metabolism/drug therapy/epidemiology
Animals
Gastrointestinal Microbiome/immunology
Dysbiosis
Glymphatic System/metabolism/immunology

@article {pmid42630903,
year = {2026},
author = {Hung, KC and Weng, HL and Lai, YC and Chen, IW},
title = {U-shaped pattern in the association between serum magnesium levels and long-term dementia risk after traumatic brain injury: a retrospective cohort study.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1870929},
doi = {10.3389/fnut.2026.1870929},
pmid = {42630903},
issn = {2296-861X},
abstract = {BACKGROUND: In the general population, abnormal serum magnesium levels are associated with an increased risk of cognitive decline and dementia. However, whether this association extends to patients with traumatic brain injury (TBI), a population with distinct neurobiological vulnerabilities, remains unknown.

METHODS: Using the TriNetX Global Collaborative Network, we identified adults aged ≥50 years with a history of intracranial injury (ICD-10-CM: S06). Patients with repeatedly low serum magnesium levels (< 1.7 mg/dL, two measurements within 1 year) were compared with those with normal levels (1.70-2.20 mg/dL) using 1:1 propensity score matching. A 1-year landmark period was applied to reduce the reverse causation. The primary outcome was incident dementia over 10 years of follow-up. The secondary outcomes included dementia subtypes, cognitive dysfunction, and all-cause mortality. To explore a potential U-shaped relationship, a parallel analysis was conducted comparing patients with repeatedly high magnesium levels (>2.20 mg/dL) with the same reference cohort. Sensitivity analyses, subgroup analyses by sex and TBI severity, and multivariable Cox regression were performed.

RESULTS: After matching, 11,716 patients were retained in each cohort. Low magnesium levels were associated with a higher 10-year risk of incident dementia [2.53% vs. 1.78%; hazard ratio (HR) 1.62, 95% confidence interval (CI), 1.36-1.94; p < 0.001]. Among the secondary outcomes, associations were observed for vascular dementia (HR 1.97, p = 0.001), other dementia types (HR 1.63, p < 0.001), cognitive dysfunction (HR 1.43, p = 0.009), and all-cause mortality (HR 1.29, p < 0.001), whereas Alzheimer's disease did not reach significance (HR 1.43, p = 0.075). High magnesium levels were similarly associated with an increased risk of dementia (HR 1.57, p < 0.001). The findings were consistent across sensitivity and subgroup analyses and after multivariable adjustment (adjusted HR 1.50, p < 0.001).

CONCLUSION: In adults with prior TBI, both low and high serum magnesium levels were associated with a greater long-term risk of dementia, suggesting a U-shaped relationship. Prospective studies are needed to determine whether monitoring or modifying magnesium status can alter the post-traumatic dementia trajectory.},
}

@article {pmid42630973,
year = {2026},
author = {Kaur, B and Nada, H and Zhang, L and Gabr, M},
title = {Structure-Guided Optimization of CHI3L1 Modulators Reveals G721-0377 as a Lead Compound for Restoring Astrocyte Function in Alzheimer's Disease.},
journal = {ACS bio & med chem Au},
volume = {6},
number = {4},
pages = {329-341},
doi = {10.1021/acsbiomedchemau.5c00279},
pmid = {42630973},
issn = {2694-2437},
abstract = {Alzheimer's disease (AD) involves astrocytic dysfunction characterized by impaired lysosomal activity, defective amyloid clearance, and neuroinflammation, processes strongly regulated by the inflammatory effector CHI3L1. G721-0282, a reported CHI3L1-binding small molecule with demonstrated modulation of downstream signaling pathways including MAPK and STAT3, provides a validated chemical starting point for targeting CHI3L1-driven astrocytic pathology in AD, but it exhibits suboptimal potency and drug-like properties that limit its translational potential. We therefore performed a virtual screening of commercially available analogues of G721-0282 to enable structure-guided optimization, generating a detailed structure-activity map, and prioritizing 24 derivatives. Biophysical analyses identified compound G721-0377 as the most promising candidate, with optimized substitutions resulting in enhanced CHI3L1-binding affinity (K d = 45 μM), representing a ∼3-5-fold improvement over related analogs (K d = 65-236 μM). Compound G721-0377 also exhibited favorable physicochemical and pharmacokinetic properties, including improved solubility, balanced permeability, reduced microsomal clearance, and an enhanced cardiac safety margin. Given their micromolar potency, all functional studies were conducted in vitro. Functionally, G721-0377 uniquely reversed CHI3L1-induced astrocytic dysfunction, restoring amyloid uptake, lysosomal proteolysis and acidification, suppressing CHI3L1 and IL-6 secretion, and inhibiting NF-κB activation to levels comparable to a neutralizing anti-CHI3L1 antibody. Collectively, these findings establish G721-0377 as a promising early stage lead compound with improved affinity, safety, and robust functional efficacy, supporting its further development as a disease-modifying therapeutic for AD.},
}

@article {pmid42631058,
year = {2026},
author = {Medrano, M and Pacheco-Herrero, M and Borges, Z and Laureano, JR and Dominguez-Garcia, J and Gil-Ventura, R and Castro-Tejada, G},
title = {Characterization of the intestinal microbial profile in mild cognitive impairment and Alzheimer's disease.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250440},
doi = {10.1590/1980-5764-DN-2025-0440},
pmid = {42631058},
issn = {1980-5764},
abstract = {UNLABELLED: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are major contributors to dementia, with growing prevalence in Latin America. Evidence suggests that gut microbiota alterations may influence neurodegeneration, but data on Hispanic population are lacking.

OBJECTIVE: Characterize gut microbiota in individuals with AD, MCI, and controls in the Dominican Republic, exploring clinical, demographic, and dietary associations.

METHODS: Prospective-translational study including 88 participants aged ≥60 years. Performed clinical, cognitive, and functional assessments. Stool samples analyzed using 16S rRNA gene sequencing. Bioinformatic processing using Quantitative Insights into Microbial Ecology Version 2 (QIIME2) and R. Alpha and beta diversity, taxonomy, and differential abundance were evaluated. Dietary influences were assessed using PERMANOVA.

RESULTS: No significant differences in alpha diversity (Shannon index 4-5, Simpson index 0.94-0.99, p>0.05) or beta diversity (p>0.05) were observed between groups. Firmicutes (51.9%) and Bacteroidota (34.1%) dominated the microbiota. Higher Desulfobacterota abundance in MCI and AD (0.54 and 0.61%, respectively, vs. 0.34% in controls; p<0.05). The Firmicutes/Bacteroidota ratio was lower in men with MCI (1.09) compared to controls and AD (1.70). MCI and AD were associated with increased levels of the genera Bilophila, Odoribacter, and Parabacteroides (p<0.05) and reduced levels of Mitsuokella and Eubacterium ruminantium. Dietary interactions, e.g., mango, lettuce, and carrot, influenced specific taxa (p<0.05).

CONCLUSION: This study pioneers gut microbiota characterization in AD and MCI in the Dominican Republic, identifying microbial alterations in cognitive impairment and highlighting regional dietary and ethnic factors. Longitudinal and multi-omics studies are warranted to clarify causality and therapeutic potential.},
}

@article {pmid42631064,
year = {2026},
author = {Tao, X and Nassuna, T and Zhai, RG},
title = {Polyamine Metabolism in Brain Health and Disease.},
journal = {Neuropharmacology and therapy},
volume = {3},
number = {},
pages = {49-62},
doi = {10.15212/npt-2025-0028},
pmid = {42631064},
issn = {2990-8779},
abstract = {Polyamines, primarily spermidine and spermine, are small polycationic molecules essential for cell growth, signaling, and survival. Through electrostatic interactions with nucleic acids, lipids, and proteins, they regulate gene expression, organelle function, and adaptive responses to environmental cues. Polyamine metabolism also intersects with a myriad of other cellular pathways, including methionine, acetyl-CoA, and oxidative stress pathways, and is therefore involved in epigenetic control, cellular metabolism, and stress-response regulation. In the brain, beyond these general cellular functions, polyamines act as dynamic modulators of neurodevelopment, neural maintenance, and synaptic plasticity by influencing local proteostasis, transmitter release, and ion channel activity in both neurons and glia. Emerging evidence indicates that disruption of polyamine homeostasis contributes to neurological disorders as diverse as rare inborn errors of metabolism and common neurodegenerative diseases. Mutations in polyamine metabolic or transport genes lead to syndromes characterized by intellectual disability, hypotonia, movement disorders, and neurodegeneration; therefore, polyamine balance is critical for brain development and maintenance. In conditions such as Alzheimer's and Parkinson's diseases, dysregulated polyamine synthesis, catabolism, or lysosomal transport perturbs autophagic flux and proteostasis, thereby promoting Tau and α-synuclein aggregation, oxidative stress, and neuronal loss. Multi-omics analyses have further revealed that polyamine metabolism shapes glial inflammatory responses. Therapeutically, modulation of polyamine metabolism offers multiple intervention points. Spermidine supplementation or administration of polyamine analogues has been found to enhance autophagy and improve cognitive performance in models of aging and Alzheimer's disease. Additional strategies to reestablish metabolic equilibrium and support neuronal resilience include targeted manipulation of key enzymes, such as ornithine decarboxylase 1 (ODC1), spermidine/spermine acetyltransferase 1 (SAT1), spermine oxidase (SMOX), and spermine synthase (SMS), or restoration of lysosomal polyamine export via ATP13A2. This review synthesizes current understanding of polyamine metabolism in brain health and disease, by integrating molecular, cellular, and systems-level perspectives, and further highlights emerging therapeutic directions aimed at harnessing this pathway to mitigate neurological pathology.},
}

@article {pmid42631141,
year = {2026},
author = {O'Neill, HM and Kumar, K and Rathore, VS},
title = {From plate to brain: role of mediators and moderators on the impact of diet on Alzheimer's disease.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1898935},
doi = {10.3389/fnut.2026.1898935},
pmid = {42631141},
issn = {2296-861X},
abstract = {Diet represents one of the most clinically accessible modifiable risk factors for Alzheimer's disease (AD), with potential to influence disease onset and progression through multiple biological pathways. Emerging evidence from observational studies suggests that adherence to specific dietary patterns, including the Mediterranean (MedDiet) and Mediterranean-DASH intervention for neurodegenerative delay (MIND) diets, is associated with reduced AD risk and slower cognitive decline. However, the mechanistic pathways underpinning these associations remain incompletely understood, and evidence from randomized controlled trials has been less consistent. A critical but frequently overlooked distinction lies between mediators, defined as the biological mechanisms linking diet to AD outcomes, and moderators, which are individual or contextual factors that influence the magnitude and direction of these associations. Integrating mediators and moderators within a unified analytical framework is increasingly recognized as essential for advancing precision nutrition approaches to AD prevention (with multiple recent publications explicitly calling for this approach and providing empirical examples of its implementation). This mini-review, developed as the conceptual foundation for a planned meta-analysis, synthesizes current evidence on key mediating pathways, including neuroinflammation, brain insulin resistance, oxidative stress, blood-brain barrier dysfunction, hyperhomocysteinaemia, and gut-brain axis dysregulation. We further examine major moderating factors such as apolipoprotein E (APOE) ε4 genotype, biological sex, age, disease stage, and socioeconomic context that may determine who benefits from dietary interventions and under what conditions.},
}

@article {pmid42622814,
year = {2026},
author = {Elliott, L and Post, E and McClendon, A and Singer, J},
title = {The impact of psychosocial factors on neurocognitive functioning in family caregivers of persons with Alzheimer's disease and related dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261476965},
doi = {10.1177/13872877261476965},
pmid = {42622814},
issn = {1875-8908},
abstract = {BackgroundLimited research has examined neurocognitive decline in family caregivers of persons with Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD), despite most caregivers being over 65 and more susceptible to age-related declines due to increased stressors. The lack of insight into how psychosocial factors interact with caregivers' neurocognitive functioning limits our ability to identify targets for reducing neurocognitive risk.ObjectiveInvestigate the effects of psychosocial factors on neurocognitive functioning of AD/ADRD caregivers.MethodsThe caregiver sample (n = 42) consisted predominantly of older adults (Mage = 69.40, SDage = 11.58) who were caring for a spouse (64.3%). On average, caregivers provided 99 h of care per week for several years (M = 3.42, SD = 2.39). Multiple linear regressions were conducted to examine the effects of psychological (i.e., depression, anxiety, pre-death grief, perceived stress) and social (i.e., social support, social network) factors on caregivers' neurocognitive functioning (i.e., visuospatial memory, verbal memory, processing speed, intelligence, executive functioning).ResultsSocial support significantly predicted visuospatial memory and processing speed. As social support increased, delayed visuospatial memory and processing speed improved when controlling for social network size.ConclusionsCaregivers may face additional stressors and have limited time or opportunities for social engagement. Social support may be especially important for spousal caregivers losing a primary support source (i.e., spouse). Findings suggest social support is a potential intervention target for reducing caregivers' risk of neurocognitive decline.},
}

@article {pmid42622822,
year = {2026},
author = {Zhang, H and Lai, J and Wang, T and Li, T and Liu, S and Sun, DL and Chen, W and Kuang, W and Li, X and Zhang, M and Liao, Z and Xiang, X and Tuerxun, M and Zhang, X and Zhang, N and Xiao, S and Jessen, F and Yu, E and Yu, X and Wang, H},
title = {Adaptation and feasibility of the International Registry for Alzheimer's Disease and Other Dementias real-world datasets in old-age mental healthcare practice in China.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478137},
doi = {10.1177/13872877261478137},
pmid = {42622822},
issn = {1875-8908},
abstract = {BackgroundAnti-amyloid disease-modifying therapies (DMTs) for early Alzheimer's disease (AD) are entering routine care, increasing the need for harmonized, registry-ready real-world data. The International Registry for Alzheimer's Disease and Other Dementias (InRAD) proposed a minimum dataset (MDS) and extended dataset (EDS), but their applicability to psychiatry-led old age mental healthcare practices in China is uncertain.ObjectiveTo adapt the InRAD dataset for real-world AD DMT practice across multiple psychiatry institutions in China and assess the feasibility of routine data capture for the proposed MDS/EDS.MethodsWe conducted a modified Delphi consensus study and a multicenter feasibility survey. Forty-nine experts classified domains/items into the MDS or EDS using predefined agreement thresholds. Thirty-five DMT-initiating mental healthcare teams reported the routine availability of the proposed data elements.ResultsHighly consistent with InRAD, ten domains were included in the China-adapted MDS/EDS, covering patient profiles and lifestyle, diagnostic work-up and biomarkers, treatment, outcomes, safety, treatment-monitoring examinations, and registry discontinuation. However, item prioritization reflected local practice, emphasizing diagnostic traceability, functional and neuropsychiatric outcomes, caregiver burden, and structured safety capture. Feasibility results revealed that many MDS elements were collected, but the consensus-defined MDS exceeded what is currently captured in a standardized, analysis-ready format; most EDS items were moderately feasible, while WHO-5 (patient version) and DAT-scan were least feasible.ConclusionsAn InRAD-aligned dataset is broadly acceptable for psychiatry-led AD DMT practices in China, but implementation gaps remain. A phased registry approach with standardized definitions and workflow-supported capture may improve the completeness and comparability of real-world DMT evidence.},
}

@article {pmid42622974,
year = {2026},
author = {Talebi, A and Nabili, S and Alaei, M and Koohsarian, P and Doostmohammadi, A and Dadashpour, M},
title = {Exosome-derived biomarkers as non-invasive tools in stroke, Parkinson's disease, and Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42622974},
issn = {1573-7365},
mesh = {Humans ; *Exosomes/metabolism ; Biomarkers/metabolism ; *Alzheimer Disease/metabolism/diagnosis ; *Parkinson Disease/metabolism/diagnosis ; *Stroke/metabolism/diagnosis ; Animals ; MicroRNAs/metabolism ; },
abstract = {Neurological disorders, including stroke, Parkinson's disease (PD), and Alzheimer's disease (AD), are among the most prevalent and debilitating neuropathological conditions, affecting over 50 million people globally. Effective prevention and treatment strategies require a comprehensive understanding of reliable and disease-specific biomarkers. Such insights can enhance diagnostic precision, enable early detection, and support the development of targeted therapeutic approaches. In this review, we focus on exosome-derived proteins and small non-coding RNAs as promising non-invasive biomarkers for stroke, PD, and AD, given the accessibility and stability of exosomes in biological fluids. Furthermore, we examine their potential diagnostic and therapeutic relevance, emphasizing their functional roles, specificity, and sensitivity. Finally, we discuss current limitations, emerging challenges, and future research directions to guide the advancement of exosome-based biomarker discovery and clinical translation in neurological disorders. However, we emphasize that the comparative effectiveness of exosomal microRNAs (miRNAs) versus protein biomarkers requires direct validation in future head‑to‑head cohort studies.},
}

Humans
*Exosomes/metabolism
Biomarkers/metabolism
*Alzheimer Disease/metabolism/diagnosis
*Parkinson Disease/metabolism/diagnosis
*Stroke/metabolism/diagnosis
Animals
MicroRNAs/metabolism

@article {pmid42623026,
year = {2026},
author = {Yılmaz, F and Menteşe, E and Eyüpoğlu, OE and Kahveci, B and Emirik, M},
title = {Design, Synthesis, and Biological Evaluation of Benzimidazol-2-One Hybrids as Potential Anti-Alzheimer's Disease Agents.},
journal = {Drug development research},
volume = {87},
number = {6},
pages = {e70369},
pmid = {42623026},
issn = {1098-2299},
support = {FDK-2018-951//Recep Tayyip Erdogan Üniversitesi/ ; },
mesh = {*Alzheimer Disease/drug therapy ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Benzimidazoles/chemistry/pharmacology/chemical synthesis ; Drug Design ; *Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis ; Butyrylcholinesterase/metabolism ; Humans ; Antioxidants/pharmacology/chemistry/chemical synthesis ; Acetylcholinesterase/metabolism ; Monoamine Oxidase/metabolism ; Structure-Activity Relationship ; Animals ; Molecular Docking Simulation ; Coumarins/chemistry ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which single-target therapies often provide insufficient benefit, motivating the development of multi-target-directed ligands (MTDLs). In this study, a novel series of benzimidazolone-based hybrids incorporating piperazine, coumarin, and triazole moieties was designed, synthesized, and evaluated for inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase-B (MAO-B), as well as antioxidant potential via on-line HPLC-based assays. Structures were confirmed by [1]H-NMR, [13]C-NMR (APT), and elemental analysis. Several compounds showed notable, micromolar-range inhibitory activity, though less potent than the reference drugs. Kinetic analysis showed that the leading compounds inhibited their respective enzymes via a mixed-type mechanism. Compound 1 showed the strongest AChE inhibition (IC50 = 0.777 ± 0.014 µM), compound 9b the highest BChE inhibition (IC50 = 0.659 ± 0.005 µM), and compound 9c the most potent MAO-B inhibition (IC50 = 2.431 ± 0.003 µM). Compound 8a showed the highest CUPRAC copper-reducing capacity, while 7c displayed the strongest DPPH radical-scavenging activity. Liposomal formulations of 4c, 7c, and 8a exhibited enhanced antioxidant responses relative to their free forms. In silico ADME predictions (SwissADME) indicated favorable drug-likeness and blood-brain barrier permeation for the compact scaffold (compound 1) and the piperazine-based hybrids, whereas the larger bis-conjugated derivatives were limited by high polarity and molecular weight. Overall, these benzimidazolone-based hybrids represent promising multi-target candidates for AD drug development.},
}

*Alzheimer Disease/drug therapy
*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
*Benzimidazoles/chemistry/pharmacology/chemical synthesis
Drug Design
*Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis
Butyrylcholinesterase/metabolism
Humans
Antioxidants/pharmacology/chemistry/chemical synthesis
Acetylcholinesterase/metabolism
Monoamine Oxidase/metabolism
Structure-Activity Relationship
Animals
Molecular Docking Simulation
Coumarins/chemistry

@article {pmid42623143,
year = {2026},
author = {Chen, Y and Ge, L and Lazarovici, P and Zheng, W},
title = {Artemisinin Attenuates Aβ1-42 Aggregation via the CaMK IV/PKA-CREB-Ace-H4 Cascade in Neuronal Cultures and 3xTg-AD Models.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-23},
doi = {10.1142/S0192415X26500667},
pmid = {42623143},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disease with a rising global prevalence, is characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, inflammation, oxidative damage, and neuronal apoptosis. Studies have increasingly recognized epigenetic modifications as key regulators in the development of AD. Epigenetic modifications, particularly histone acetylation, are increasingly recognized as critical regulators of cell survival and AD pathogenesis. Although artemisinin (ART) exhibits potent anti-oxidative, anti-inflammatory, and neuroprotective properties, its impact on histone acetylation in AD remains uncharacterized. This study investigated whether ART regulates histone acetylation to confer neuroprotection and rescue behavioral deficits in Alzheimer's disease models. Using SH-SY5Y cells, primary neurons, and 3xTg-AD mice, we found that ART restores histone acetylation homeostasis by enhancing histone H4 acetylation. Mechanistically, this effect is driven by the activation of the CaMK IV/PKA-CREB signaling cascade. Treatment with ART reduced ROS, improved mitochondrial function, decreased Aβ1-42 deposition, and suppressed neuronal apoptosis. However, these beneficial effects were abolished by PKA or CaMK IV inhibitors. Consequently, ART treatment significantly reduced reactive oxygen species (ROS) generation, restored mitochondrial function, decreased Aβ1-42 deposition, suppressed neuronal apoptosis, and alleviated AD-like neuropathology and cognitive deficits. Crucially, the neuroprotective and epigenetic benefits of ART were entirely abolished by pharmacological inhibitors of PKA or CaMK IV. This study is the first to demonstrate that artemisinin ameliorates AD pathology and behavioral impairments via the CaMK IV/PKA-CREB-Ace-H4 axis, establishing ART as a promising therapeutic candidate for epigenetic intervention in AD.},
}

@article {pmid42623159,
year = {2026},
author = {Tewolde, S and Rosenberg, SB and Jimenez, MP and Rubenstein, E},
title = {Brief Report: Alzheimer's Disease and Related Dementia in People With Intellectually Disability in the United States.},
journal = {American journal on intellectual and developmental disabilities},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/19447515.2026.2712358},
pmid = {42623159},
issn = {1944-7558},
abstract = {People with intellectual disability (ID) are living longer lives than in generations past, and experience aging-related health issues, like Alzheimer's disease and related dementia (ADRD). Our objective was to document prevalence and age of diagnosis of ADRD in the population with ID (excluding Down syndrome) ≥30 years old in the United States from 2011 to 2022 enrolled in Medicaid and/or Medicare. We measured ADRD and ID using International Classification of Disease-9/10 claims algorithms and examined demographics and trends in ADRD. We examined age at incident ADRD diagnosis. Among 1,046,621 adults with ID ≥30 years old enrolled in Medicaid and/or Medicare between 2011 and 2022, 184,206 (17.6%) had claims for ADRD, corresponding to an 11-year prevalence of one case per 5.7 people. Yearly prevalence was lowest in 2011 (11.3%) and highest in 2019 (16.7%). There were few differences in prevalence for each age group between sexes, races, and ethnic group. Mean age at onset was 62.6 years (13.1 = SD). ADRD is common in people with ID and individuals, clinicians, and families should be prepared as individuals and populations age. As a heterogenous and often idiopathic group of conditions, further research is warranted to understand biologic and social risk factors for ADRD in this population.},
}

@article {pmid42623762,
year = {2026},
author = {Wang, X and Liu, Y and Liu, J and Wang, R and Zheng, J and Deng, Z and Song, K and Zhang, D and Wang, C and Zhu, K and Zhang, J and Wu, C and Hou, G and de Vries, EFJ and Wang, Y},
title = {Translational imaging evidence for rapid reversal of amyloid and myelin pathology following deep cervical lymphatic-venous anastomosis in Alzheimer's disease.},
journal = {Nuclear medicine and biology},
volume = {160-161},
number = {},
pages = {109675},
doi = {10.1016/j.nucmedbio.2026.109675},
pmid = {42623762},
issn = {1872-9614},
abstract = {BACKGROUND: Recently, microsurgical restoration of extracranial lymphatic outflow through lymphatic-venous anastomosis (LVA) has been explored as a potential, albeit controversial, therapeutic strategy to enhance glymphatic clearance in Alzheimer's disease (AD); however, its impact on AD-related neuropathology has not yet been quantitatively or longitudinally evaluated. In this study, we performed translational PET imaging to determine whether restoring extracranial lymphatic outflow can rapidly and reversibly modulate cerebral glucose metabolism, myelin integrity, and amyloid burden in relation to cognitive improvement.

METHODS: A cervical lymphatic obstruction model was established in rats, followed by longitudinal [[18]F]FDG-PET and [[11]C]MeDAS-PET to assess cerebral glucose metabolism and myelin integrity before and after LVA, with imaging findings further validated by immunohistochemistry. A cohort of eight AD patients underwent LVA and received [[11]C]PIB and [[11]C]MeDAS PET imaging at baseline and follow-up. The imaging results were correlated with cognitive performance.

RESULTS: In Sprague-Dawley rats, cervical lymphatic obstruction led to significantly elevated cerebral glucose metabolism and reduced myelin integrity, both of which were largely restored to near-normal levels following LVA treatment, as further validated by immunohistochemical analyses. Similarly, in AD patients, LVA produced a 36.0 ± 2.1% decrease in cortical amyloid burden on [[11]C]PIB-PET (p < 0.001) and a 59.8 ± 29.0% increase in [[11]C]MeDAS uptake (p = 0.005). Subsequent correlation with MMSE scores demonstrated that short-term cognitive improvement was associated with greater myelin restoration and greater amyloid reduction.

CONCLUSION: These preliminary findings provide initial evidence that restoration of extracranial lymphatic outflow may modulate core neuropathological processes in AD, justifying further investigation in larger cohorts with appropriate control groups and randomized controlled designs to validate and extend these observations.

TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial website on April 21, 2025 (Registration No. ChiCTR2500101149).},
}

@article {pmid42624084,
year = {2026},
author = {Pieper, AA and Miller, E and Khalimonchuk, O and Paul, BD},
title = {STINGing the brain: S-nitrosylation drives neuroinflammation in Alzheimer's disease.},
journal = {Cell chemical biology},
volume = {33},
number = {8},
pages = {1065-1067},
doi = {10.1016/j.chembiol.2026.07.003},
pmid = {42624084},
issn = {2451-9448},
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Brain/metabolism/pathology ; *Membrane Proteins/metabolism ; Animals ; cGAS-STING Signaling Pathway ; *Neuroinflammatory Diseases/metabolism/pathology ; STING Protein ; },
abstract = {Neuroinflammation is a major secondary driver of Alzheimer's disease (AD). In this issue of Cell Chemical Biology, Carnevale et al.[1] demonstrate that S-nitrosylation of the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway sustains pathological neuroinflammation in AD, identifying a promising therapeutic target for this devastating disease.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Brain/metabolism/pathology
*Membrane Proteins/metabolism
Animals
cGAS-STING Signaling Pathway
*Neuroinflammatory Diseases/metabolism/pathology
STING Protein

@article {pmid42624102,
year = {2026},
author = {Guruacharya, A and Hartung, T and Souza Dos Reis, R and Moreira, NCDS and Attisano, L and Bolognin, S and Iqbal, K and Rajbanshi, B},
title = {Brain organoids in Alzheimer disease and related tauopathies: Challenges and opportunities for translational readiness.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {103051},
doi = {10.1016/j.stemcr.2026.103051},
pmid = {42624102},
issn = {2213-6711},
abstract = {A major hurdle in Alzheimer disease research is the failure of mouse models to capture complexities of the human brain that contributes to repeated clinical trial failure. Although the recent US Food and Drug Administration (FDA) Modernization Act 2.0 has enabled non-animal preclinical pathways, brain organoid models of tauopathies remain nascent compared with other disease areas. Here, we identify three challenges for their translational readiness, maturity, disease-relevant cellular complexity, and pathological accuracy, and examine current achievements and emerging solutions. We propose a ten-metric benchmarking framework and discuss the opportunities and remaining challenges for translational readiness in tauopathy modeling.},
}

@article {pmid42624157,
year = {2026},
author = {Banerjee, G and Edgren, G and Zhao, J and Ferguson, NM and Harvala, H and Hope, J and Jackson, GS and Lowry, PJ and Mead, S and Purro, SA and Schott, JM and Turner, ML and Werring, DJ and Zetterberg, H and Collinge, J},
title = {Risk of transmission of amyloid β pathology via transfused blood products.},
journal = {Lancet (London, England)},
volume = {408},
number = {10556},
pages = {753-760},
doi = {10.1016/S0140-6736(26)00767-1},
pmid = {42624157},
issn = {1474-547X},
mesh = {Humans ; *Amyloid beta-Peptides/metabolism ; Creutzfeldt-Jakob Syndrome/transmission ; *Transfusion Reaction ; *Blood Transfusion ; *Cerebral Amyloid Angiopathy/etiology ; Prions/metabolism ; Prion Diseases/transmission ; },
abstract = {Seeded protein misfolding and aggregation are relevant to many neurodegenerative diseases. The archetype are prions: protein-only infectious agents that cause fatal neurodegenerative diseases including Creutzfeldt-Jakob disease (CJD). The recent recognition of iatrogenic amyloid β cerebral amyloid angiopathy (CAA) and Alzheimer's disease, caused by inadvertent seeding of amyloid β pathology following historical medical procedures, raises concerns that these conditions might also be transmitted via blood components and products, as was the case in rare instances for variant CJD. Recent epidemiological data showing the apparent transmission of haemorrhage risk between blood donors and recipients raise the possibility of blood-based CAA transmission. In this Viewpoint, we review the evidence for amyloid β transmission, provide an overview of relevant prion biology, and consider the circumstances under which bloodborne prion transmission has previously occurred. We discuss the implications for blood transfusion services, particularly in light of the UK Infected Blood Inquiry, and the key questions that need to be addressed to better quantify transfusion-related risk.},
}

Humans
*Amyloid beta-Peptides/metabolism
Creutzfeldt-Jakob Syndrome/transmission
*Transfusion Reaction
*Blood Transfusion
*Cerebral Amyloid Angiopathy/etiology
Prions/metabolism
Prion Diseases/transmission

@article {pmid42624381,
year = {2026},
author = {Chen, X and Wang, X and Li, C and Shan, K and Wang, L and Hashimoto, K and Shao, K and Wei, P and Yang, JJ},
title = {PD-1/PD-L1 signaling in neurological and psychiatric disorders: neuroimmune mechanisms and therapeutic potential.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106965},
doi = {10.1016/j.bbi.2026.106965},
pmid = {42624381},
issn = {1090-2139},
abstract = {Programmed cell death protein-1 (PD-1) and its ligand PD-L1 constitute a central immune checkpoint pathway that maintains immune tolerance and limits excessive inflammation. Beyond oncology, emerging evidence indicates that PD-1/PD-L1 signaling plays fundamental roles in central and peripheral nervous system (CNS and PNS) homeostasis. In the brain, PD-1/PD- L1 restrains neuroinflammation, regulates microglial and astrocytic activation, and influences synaptic function and neurodevelopment, thereby contributing to the pathophysiology of autoimmune demyelinating disease, stroke, Alzheimer's disease, Parkinson's disease, and psychiatric disorders. Outside the brain, PD-1/PD-L1 signaling modulates nociceptive processing in sensory ganglia and the spinal cord, as well as the trafficking and function of circulating monocytes, revealing a multi-layered neuroimmune regulatory network. However, the functional impacts of PD-1/PD-L1 are highly dependent on factors like disease context, cell type, disease stage, and sex. Accordingly, we critically evaluate the therapeutic opportunities and limitations of both PD-1/PD-L1 blockade and agonism across these diverse neurological and psychiatric conditions. Due to major translational hurdles, including limited CNS drug penetration, immune-related adverse events, and the opposing outcomes of pathway modulation in different compartments or phases of disease, future strategies will likely require spatiotemporally controlled and cell-specific modulation of PD-1/PD-L1 signaling, improved central nervous system drug delivery, and biomarker-guided patient stratification. Collectively, this review integrates CNS, PNS, and systemic immune interactions to position PD-1/PD-L1 as a potential target for next-generation neuro-immunotherapies across neurological and psychiatric disorders.},
}

@article {pmid42624382,
year = {2026},
author = {Yenkoyan, K and Davtyan, T and Torosyan, H and Galstian, S and Chavushyan, V},
title = {Bone marrow remodeling and brain-bone marrow crosstalk in Alzheimer's disease-like neurodegeneration.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106968},
doi = {10.1016/j.bbi.2026.106968},
pmid = {42624382},
issn = {1090-2139},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a systemic disorder involving not only central neurodegeneration but also alterations in peripheral immune regulation and systemic homeostasis. Among these, the bone marrow represents a critical yet underexplored interface between the brain and systemic homeostasis. In the present study, we investigated whether AD-like neurodegeneration induces functional and structural remodeling of the bone marrow and whether these changes can be modulated through central neural stimulation and treatment with embryonic proteoglycans (PEG). An AD-like model was induced in adult male rats by intracerebroventricular administration of aggregated amyloid-β (Aβ1-42). Bone marrow alterations were assessed using ELISA for insulin-like growth factor-1 (IGF-1) and nerve growth factor (NGF), Western blot analysis of c-Fos and NF-κB, high-performance liquid chromatography for GABA determination, flow cytometry of hematopoietic and niche-associated cell populations, and morphological evaluation using hematoxylin and eosin and Giemsa staining. Additional modulation was performed by sequential electrostimulation of the hypothalamic supraoptic and paraventricular nuclei and by administration of embryonic proteins. Amyloid exposure significantly increased bone marrow IGF-1 levels, c-Fos expression, and NF-κB activation, accompanied by marked remodeling of marrow architecture characterized by reduced adiposity, increased hematopoietic cellularity, megakaryocytic abnormalities, and altered expression of progenitor-, neuronal-, and apoptosis-associated markers. Flow cytometry revealed shifts in specific CD3[+]CD3[+] T-cell subpopulations and increased apoptotic signaling, indicating dynamic reorganization of the hematopoietic niche. Hypothalamic stimulation and PEG treatment partially normalized these alterations, reducing inflammatory activation and restoring trophic and cellular balance. These findings demonstrate that AD-like neurodegeneration is associated with coordinated bone marrow remodeling and support the existence of a functional brain-bone marrow axis. The reversibility of these changes suggests that the bone marrow represents a biologically active and therapeutically accessible component of systemic responses to neurodegeneration, with potential relevance for future Alzheimer's disease interventions.},
}

@article {pmid42624418,
year = {2026},
author = {Wolf, OT and Akan, O and Axmacher, N},
title = {Stress, Path Integration, and the Entorhinal Cortex.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106921},
doi = {10.1016/j.neubiorev.2026.106921},
pmid = {42624418},
issn = {1873-7528},
abstract = {The stress induced release of glucocorticoids influences neural excitability and plasticity in the hippocampus. Surprisingly the entorhinal cortex (EC), an adjacent region, has received little attention in stress research, even though it is also rich in glucocorticoid receptors. Grid cells in the medial EC play a decisive role in path integration (PI). Interestingly, the EC is a brain region damaged very early in Alzheimer's disease (AD). Three recent studies investigated the associations between stress, cortisol and PI. In the first study chronic stress was associated with poorer PI. Acute stress induction impaired PI in the second study. In the third study cortisol administration impaired PI and reduced grid like representations in the EC as measured via fMRI. These findings have important implications. Future research on stress and spatial navigation should take the EC into account. Moreover, chronic stress is associated with an increased risk for AD. The findings suggest that the direct effect of cortisol on the EC may partially underly these clinical findings. Directions for future research are discussed.},
}

@article {pmid42624449,
year = {2026},
author = {Zhou, C and Zhu, C and Wang, X and Yang, Y and Wei, J},
title = {Therapeutic targeting of G protein-coupled receptors in central nervous system disorders: from novel mechanisms to precision pharmacology.},
journal = {European journal of pharmacology},
volume = {1033},
number = {},
pages = {179275},
doi = {10.1016/j.ejphar.2026.179275},
pmid = {42624449},
issn = {1879-0712},
abstract = {G protein-coupled receptors (GPCRs) are major therapeutic targets for central nervous system disorders, with more than 500 approved drugs targeting this receptor family worldwide. This review comprehensively examines the pathophysiological roles and therapeutic potential of GPCRs in major neurological and psychiatric disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and depression. We highlight how dysregulated signaling through specific GPCRs, including dopamine and adenosine A2A receptors in PD, the mGlu5 receptor and muscarinic acetylcholine receptors in AD, S1P and GPR17 receptors in MS, and 5-HT1A and GPR39 receptors in depression, contributes to disease pathogenesis. Beyond canonical monomeric activation, this review emphasizes emerging concepts in GPCR heterodimerization (e.g., the 5-HT1A/orexin 1 receptor complex activating Gαs pathways), biased signaling, and allosteric modulation, which provide opportunities to develop therapeutics with greater specificity and fewer adverse effects. We also evaluate the therapeutic potential of targeting these mechanisms using specific pharmacological agents, including synthetic compounds and structurally defined natural product-derived molecules. The chemical structures of key natural products-including paeoniflorin, rosmarinic acid, and ergothioneine-are presented, with their GPCR interactions and critical pharmacophores highlighted. Finally, we discuss future directions involving advanced technologies, including cryo-electron microscopy, induced pluripotent stem cell-derived brain organoids, structural biology, and artificial intelligence, to improve understanding of complex GPCR signaling. The development of biased ligands, stage-specific interventions, and GPCR-based biomarkers represents a critical step toward personalized and more effective treatments for neurological disorders.},
}

@article {pmid42624451,
year = {2026},
author = {Coccurello, R},
title = {Hierarchical Inference Dysfunction in Autism and Alzheimer's Disease: A Conceptual Predictive-Coding Framework From Hyper-Precision to Predictive Collapse.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179276},
doi = {10.1016/j.ejphar.2026.179276},
pmid = {42624451},
issn = {1879-0712},
abstract = {Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are characterized by profound alterations in cortical circuit function, synaptic plasticity, and neuromodulatory regulation, leading to disrupted hierarchical integration of feedforward and feedback signaling. This review synthesizes evidence that these disorders represent opposing patterns of dysfunction within hierarchical cortical systems governing sensory integration and contextual modulation. Within a predictive coding framework, these alterations can be understood as disturbances in precision weighting, a process critically implemented by neuromodulatory systems. In ASD, neurodevelopmental alterations in excitatory-inhibitory balance, parvalbumin-positive interneuron function, laminar microcircuit organization, and neuromodulatory tuning bias cortical networks toward excessive bottom-up signaling and heightened synaptic gain, associated with increased gamma-band activity, local hyperconnectivity, and impaired contextual integration. In contrast, AD is marked by progressive degeneration of deep-layer pyramidal neurons, entorhinal-hippocampal circuits, and long-range feedback projections, together with cholinergic and dopaminergic depletion, disrupting beta- and alpha-mediated top-down coordination, impairing synaptic plasticity, and destabilizing large-scale networks such as the default mode system. Across the lifespan, these processes produce opposite distortions in hierarchical signal flow, namely hyper-reactive sensory processing in ASD and degraded generative control in AD. By integrating findings from laminar anatomy, interneuron vulnerability, oscillatory dynamics, and neuromodulatory systems, this review proposes a mechanistic framework linking microcircuit pathology to network dysfunction and clinical phenotypes. Dopaminergic, cholinergic, and noradrenergic systems emerge as key modulators of precision-related processes, positioning neuromodulation as a plausible pharmacological entry point for probing and potentially recalibrating hierarchical inference.},
}

@article {pmid42624557,
year = {2026},
author = {Halder, D and Prajapati, D and Banerjee, T and Biswas, S and Ghosh, B},
title = {Epigenetic modulators as therapeutics for neurodegenerative disorders/Alzheimer's disease.},
journal = {Methods in enzymology},
volume = {733},
number = {},
pages = {163-222},
doi = {10.1016/bs.mie.2026.06.010},
pmid = {42624557},
issn = {1557-7988},
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Epigenesis, Genetic/drug effects ; Animals ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; DNA Methylation/drug effects ; *Neurodegenerative Diseases/drug therapy/genetics ; Histone Deacetylases/metabolism ; },
abstract = {Epigenetic dysregulation is recognized as a primary contributor to the pathogenesis of neurodegenerative disorders, especially Alzheimer`s disease (AD). Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA regulation, govern gene expression without altering the DNA sequence, which plays a crucial role in neuronal development, synaptic plasticity, and memory formation. In AD, abnormal epigenetic alterations disrupt neuronal homeostasis, promote Aβ aggregation, tau hyperphosphorylation, and neuroinflammation, which leads to cognitive impairment. This chapter explores the assays performed and their processes using epigenetic modulators, along with their therapeutic potential in neurodegenerative diseases, especially AD. HDAC inhibitors, DNMT inhibitors, and emerging approaches, such as PROTACs for selective degradation of epigenetic enzymes, were discussed in the context of neurocognitive disorders. Preclinical and clinical evidence suggest that targeting specific HDAC isoforms (HDAC3, HDAC6, etc) can restore synaptic plasticity and improve cognitive function. This chapter further discusses recent advances, challenges in drug specificity, BBB permeability, and off-target epigenetic effects, which remain barriers to clinical translation. Case studies highlighting successful epigenetic interventions in AD models were presented to demonstrate therapeutic feasibility. Overall, epigenetic modulators present a promising therapeutic approach for neurodegeneration, and continued research integrating various assays like DNA methylation analysis, histone modification analysis, non-coding RNA analysis, neuroinflammation analysis, and functional and behavioral assays in AD models is significant in harnessing the full potential for AD treatment.},
}

Humans
*Alzheimer Disease/drug therapy/genetics/metabolism
*Epigenesis, Genetic/drug effects
Animals
*Histone Deacetylase Inhibitors/pharmacology/therapeutic use
DNA Methylation/drug effects
*Neurodegenerative Diseases/drug therapy/genetics
Histone Deacetylases/metabolism

@article {pmid42624562,
year = {2026},
author = {K C, B and D K, H and Priyadarshini, P},
title = {Synergetic inhibition of deubiquitinases and acetyltransferases to regulate tau acetylation and aggregation in SH-SY5Y cell line model of Alzheimer's disease.},
journal = {Methods in enzymology},
volume = {733},
number = {},
pages = {297-319},
doi = {10.1016/bs.mie.2026.05.034},
pmid = {42624562},
issn = {1557-7988},
mesh = {Humans ; *tau Proteins/metabolism ; Acetylation/drug effects ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Ubiquitination/drug effects ; *Acetyltransferases/antagonists & inhibitors/metabolism ; Cell Line, Tumor ; *Deubiquitinating Enzymes/antagonists & inhibitors/metabolism ; Protein Processing, Post-Translational/drug effects ; Aminopyridines ; Thiocyanates ; },
abstract = {Tau protein homeostasis depends on a balance between ubiquitination and acetylation, two key post-translational modifications (PTMs) which simultaneously compete for lysine residues that govern tau stability. Importantly, ubiquitination signals of proteins for degradation through the 26S proteasome, whereas acetylation prevents ubiquitin attachment, leading to tau stabilization and an increased risk of aggregation. In Alzheimer's disease (AD), this balance is disrupted by upregulation of acetyltransferase activity, such as p300/CBP, and increased deubiquitinase (DUBs) activity, which together hinder proteasomal clearance and accumulation of pathological tau. Since these pathways are interconnected, targeting only one may be insufficient to address tau-mediated neurotoxicity. In this book chapter, we highlight the importance of a dual approach aimed at inhibiting both aberrant acetylation and deubiquitinases activity, thereby restoring ubiquitination and promoting tau degradation. In addition, the development of standardized cell culture models in the SH-SY5Y neuronal system will be crucial to evaluating the therapeutic potential of this synergetic inhibition strategy.},
}

Humans
*tau Proteins/metabolism
Acetylation/drug effects
*Alzheimer Disease/metabolism/drug therapy/pathology
Ubiquitination/drug effects
*Acetyltransferases/antagonists & inhibitors/metabolism
Cell Line, Tumor
*Deubiquitinating Enzymes/antagonists & inhibitors/metabolism
Protein Processing, Post-Translational/drug effects
Aminopyridines
Thiocyanates

@article {pmid42624563,
year = {2026},
author = {Mehta, B and Nambiar, S and Shirke, O and Pandita, S and Markandeya, YS},
title = {Histone deacetylases in neurodegeneration and neuronal plasticity.},
journal = {Methods in enzymology},
volume = {733},
number = {},
pages = {321-366},
doi = {10.1016/bs.mie.2026.06.025},
pmid = {42624563},
issn = {1557-7988},
mesh = {Humans ; *Histone Deacetylases/metabolism/genetics ; Animals ; *Neuronal Plasticity ; *Neurodegenerative Diseases/enzymology/metabolism/pathology/drug therapy/genetics ; Cell Nucleus/metabolism ; Neurons/metabolism/pathology ; Histone Deacetylase 6/metabolism ; Brain/metabolism/pathology ; Protein Transport ; },
abstract = {This chapter pulls together current research on how HDAC shuttling between the nucleus and cytoplasm affects neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and epilepsy. It takes a close look at why these shifts in HDAC localization matter so much in brain disease and its implications for new treatments. Histone deacetylases (HDACs) are a big deal when it comes to gene regulation in the brain. They play key roles in both neurodegeneration and the brain's ability to adapt, working inside the nucleus and out in the cytoplasm. This chapter unpacks the molecular mechanisms behind HDAC trafficking-how they move around-highlights the different roles of HDAC isoforms, and compares localization-specific effects. It digs into how HDACs impact protein aggregation and synaptopathies. Some findings stand out: HDAC4 and HDAC1 are tightly controlled by phosphorylation signals, which change their cellular localization and influence neuronal mortality. For example, HDAC6 is majorly involved in cellular trafficking and clearing protein aggregates, whereas HDAC4 aggregation in the nucleus is responsible for driving neuronal toxicity. If HDAC1 undergoes nuclear export, it interacts with motor proteins to impact mitochondrial transport. Drugs that block HDAC6 look promising in preclinical models-they help restore neuronal transport systems and clear protein aggregation. Moving HDAC4 out of the nucleus seems to support better synaptic function and motor skills. As a general rule, HDAC accumulation in the nucleus shuts down genes that keep neurons alive, but keeping them in the cytoplasm helps preserve connections between neurons. You'll also find thorough, practical advice on how to study HDACs in brain research-covering everything from enzyme assays and cell experiments to live animal models, plasticity tracking, drug testing, and data analysis. A major innovation featured here is using CRISPR-based tricks to control exactly where HDACs go inside cells: forced targeting using dCas9 fusions, editing natural localization signals, and even using optogenetics for precise on-demand control. In short, the chapter is a hands-on guide for anyone trying to unravel HDAC mechanisms in diseases like Alzheimer's, Parkinson's, Huntington's, or in studies of brain plasticity. Some standout methods include tracking HDAC localization in the cells, measuring how phosphorylation affects their shuttling, and using HDAC2 inhibitors for cognitive boosts. It also covers isoform-specific approaches in Huntington's models, manipulating HDAC location with CRISPR for deeper insights, and combining live-cell imaging with biochemical and chromatin studies for robust validation. This chapter sheds light on the latest advances, with a strong focus on precision, quantitative results, and translating these findings into real-world applications.},
}

Humans
*Histone Deacetylases/metabolism/genetics
Animals
*Neuronal Plasticity
*Neurodegenerative Diseases/enzymology/metabolism/pathology/drug therapy/genetics
Cell Nucleus/metabolism
Neurons/metabolism/pathology
Histone Deacetylase 6/metabolism
Brain/metabolism/pathology
Protein Transport

@article {pmid42624566,
year = {2026},
author = {Chinnathambi, S and Desale, SE},
title = {Histone Decatylase 6 and Tau-induced microglial chemotaxis by trans-well migration and wound-scratch assay.},
journal = {Methods in enzymology},
volume = {733},
number = {},
pages = {385-406},
doi = {10.1016/bs.mie.2026.05.033},
pmid = {42624566},
issn = {1557-7988},
mesh = {*Microglia/cytology/metabolism ; *tau Proteins/metabolism ; *Histone Deacetylase 6/metabolism ; Animals ; *Chemotaxis ; Humans ; Cell Movement ; },
abstract = {Development of Alzheimer's is promoted through the accumulation of Tau and Amyloid Beta (Aβ) proteins at various neuronal as well as glial junctions. Tau, a microtubule-associated protein, is localized at the axonal region of neurons under physiological conditions. The main function of Tau protein is to stabilize microtubules, mediated by the electrostatic interaction of their surface with the repeat domains of Tau. The post-translational modifications (PTMs) are necessary for the physiological functioning of protein, but upon abnormal phosphorylation of Tau, Neuro-fibrillary Tangles of protein are generated disrupting normal brain functionality. Cell migration is a physiological functioning of the cell necessary for various signalling from development, cellular communication, immune function etc. cellular microenvironment affect the behaviour of the cell, which can be detected by its migration propensity. The in vitro assays assist in understanding the adhesion, migration and invasion strategies of migratory cells in response to extracellular stimuli. The migration property can be linked to phenotypic changes of microglia as anti-inflammatory phenotype of microglia display increase migration and invasion, hence understanding migration propensity over Tau and HDAC6 exposure is necessary.},
}

*Microglia/cytology/metabolism
*tau Proteins/metabolism
*Histone Deacetylase 6/metabolism
Animals
*Chemotaxis
Humans
Cell Movement

@article {pmid42624569,
year = {2026},
author = {Balmik, AA and Chinnathambi, S},
title = {Zinc-finger ubiquitin-binding domain of histone deacetylase 6 modulates Tau structure and function.},
journal = {Methods in enzymology},
volume = {733},
number = {},
pages = {81-110},
doi = {10.1016/bs.mie.2026.05.036},
pmid = {42624569},
issn = {1557-7988},
mesh = {*Histone Deacetylase 6/metabolism/chemistry/genetics ; *tau Proteins/metabolism/chemistry ; Zinc Fingers ; Humans ; Protein Binding ; Protein Domains ; Ubiquitin/metabolism ; Protein Conformation ; },
abstract = {Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic deacetylase, has emerged as a critical regulator of protein homeostasis, and plays an important role in neurodegenerative disorders characterized by Tau pathology. We investigated the role of zinc-finger ubiquitin-binding domain (ZnF UBP) of HDAC6 in modulating tau structure and function. HDAC6 is well known for its deacetylase activity and involvement in aggresome formation but the functional contribution of its ZnF UBP domain in tau biology remains not well explored. Using a combination of biochemical, biophysical, and molecular approaches, we demonstrate that the ZnF UBP domain of HDAC6 directly interacts with tau, influencing its conformational dynamics and aggregation propensity. Our findings reveal that this interaction is independent of HDAC6's catalytic deacetylase activity, highlighting a non-canonical mechanism through which HDAC6 regulates tau. Structural analyses indicate that binding of ZnF UBP induces conformational rearrangements in tau, potentially altering its microtubule-binding capacity and aggregation behavior. Furthermore, we show that the HDAC6-tau interaction modulates tau aggregation, suggesting a protective or regulatory role in preventing aberrant tau aggregation. Functional assays support the notion that ZnF UBP-mediated modulation of tau contributes to maintaining cytoskeletal integrity and cellular proteostasis. These observations suggests that HDAC6 functions not only as a deacetylase but also performs regulatory functions through ZnF UBP domain that can influence the function and properties of intrinsically disordered proteins (IDPs) like tau. Overall, this chapter provides mechanistic insights into the non-enzymatic functions of HDAC6, specifically through its ZnF UBP domain, in regulating tau structure and function. Understanding this interaction expands the current perspective on HDAC6 biology and underscores its potential as a therapeutic target in tauopathies, including Alzheimer's disease and targeting domain-specific interactions of HDAC6 may offer a novel therapeutic strategy to modulate tau pathology.},
}

*Histone Deacetylase 6/metabolism/chemistry/genetics
*tau Proteins/metabolism/chemistry
Zinc Fingers
Humans
Protein Binding
Protein Domains
Ubiquitin/metabolism
Protein Conformation

@article {pmid42624961,
year = {2026},
author = {Yarahmadian, S and Alzahrani, Y and Ojha, VP},
title = {Metal-Ion-Mediated Amyloid- β Aggregation in Alzheimer's Disease: A Mathematical Model of Chelation and Inhibitory Therapies.},
journal = {Bulletin of mathematical biology},
volume = {88},
number = {9},
pages = {},
pmid = {42624961},
issn = {1522-9602},
mesh = {*Alzheimer Disease/metabolism/drug therapy/therapy ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors/chemistry ; Chelating Agents/therapeutic use/pharmacology ; Humans ; *Models, Biological ; Mathematical Concepts ; Protein Aggregation, Pathological/metabolism/drug therapy ; Computer Simulation ; Copper/metabolism ; Chelation Therapy/statistics & numerical data ; Kinetics ; Metals/metabolism ; Zinc/metabolism ; Iron/metabolism ; Protein Aggregates/drug effects ; },
abstract = {We develop a novel, comprehensive, and rigorously validated mathematical framework to investigate the kinetics of amyloid- β (A β) aggregation in the presence of biologically relevant metal ions, chelating agents, and inhibitor drugs. Building upon and extending existing aggregation models, our approach integrates metal-assisted aggregation, A β self-assembly, and therapeutic interventions within a unified and mechanistically consistent formulation. The model captures the microscopic reaction pathways governing A β dynamics and explicitly incorporates the catalytic roles of copper, zinc, and iron ions-key contributors to neurotoxic plaque formation in Alzheimer's disease. Distinctively, the framework combines dual therapeutic strategies: (i) metal chelation therapy, which sequesters free metal ions, and (ii) direct inhibition of A β aggregation. Numerical simulations across multiple kinetic regimes reveal how these interventions modulate aggregation pathways, both independently and synergistically. To further validate the model, we perform a quantitative comparison with experimental data by reconstructing aggregate morphology distributions and benchmarking them against reported AFM measurements. The model successfully captures key experimental features, including peak structure and metal-dependent heterogeneity, thereby demonstrating its predictive capability. Overall, this work provides an extended and unified modeling platform that advances the quantitative understanding of metal-mediated amyloid aggregation and offers a predictive tool for evaluating and optimizing therapeutic strategies for Alzheimer's disease.},
}

*Alzheimer Disease/metabolism/drug therapy/therapy
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors/chemistry
Chelating Agents/therapeutic use/pharmacology
Humans
*Models, Biological
Mathematical Concepts
Protein Aggregation, Pathological/metabolism/drug therapy
Computer Simulation
Copper/metabolism
Chelation Therapy/statistics & numerical data
Kinetics
Metals/metabolism
Zinc/metabolism
Iron/metabolism
Protein Aggregates/drug effects

@article {pmid42624989,
year = {2026},
author = {Vosbein, P and Mao, H and Lou, C},
title = {Targeting soluble misfolded oligomers in anti-amyloid research.},
journal = {Nature reviews. Chemistry},
volume = {},
number = {},
pages = {},
pmid = {42624989},
issn = {2397-3358},
abstract = {Protein misfolding drives a range of non-curable diseases, such as Alzheimer disease, Parkinson disease, type 2 diabetes and Huntington disease, that devastate tens of millions of patients each year. The pathological proteins are misfolded into soluble oligomers, which eventually evolve into insoluble amyloid plaques. Increasing evidence suggests that soluble oligomers are the primary cytotoxic species leading to amyloidoses. However, the transient, heterogeneous and low-abundance nature of soluble oligomers makes it extremely challenging to study these species using conventional methods. This Review surveys emerging chemical tools developed for in vitro detection, separation and analysis of soluble amyloid oligomers. We exemplify how the present arsenal can be extended to construct individual amyloid oligomers as potential drug targets. Finally, we summarize their technical limits and discuss possibilities of adapting these chemical tools to target specific soluble oligomers in the fight against amyloidoses.},
}

@article {pmid42625098,
year = {2026},
author = {Ai, M and Turnbull, A and Zhao, K and Liu, Y and Zhang, Y and Vankee-Lin, F},
title = {BRAIN-DISC: a novel analytical approach integrating data-driven brain pattern discovery with cohort studies for evaluating findings in brain modulation interventions.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42625098},
issn = {2509-2723},
support = {NR015452/NR/NINR NIH HHS/United States ; MH120734//National Institute of Mental Health and Neurosciences/ ; MH129694//National Institute of Mental Health and Neurosciences/ ; AG080425/AG/NIA NIH HHS/United States ; AARG-22-972541/ALZ/Alzheimer's Association/United States ; },
abstract = {Brain modulation interventions (BMIs) targeting cognitive and neuropsychiatric symptoms have shown substantial heterogeneity in response, limiting their clinical utility. Resting-state functional connectivity (rsFC) may capture BMI-induced neuroplasticity and support patient stratification. However, examining these biomarkers within small, heterogeneous intervention samples remains challenging. The objective of this study is to present BRAIN-DISC, an analytic framework that links large-scale cohort-derived rsFC patterns with evaluation in targeted BMI trials. Three demonstrations were conducted. In the CogTE trial (n = 74), the Alzheimer's-resilient connectome (ARC), derived from cohort contrasts of Superagers and Alzheimer's disease, was evaluated as a response biomarker for cognitive training in mild cognitive impairment (MCI). In the BEEM trial (n = 26), a brain-derived neuropsychiatric phenotyping (BNP) subtype was used to stratify response to transcranial direct current stimulation combined with training. In a third demonstration, we conducted an end-to-end implementation by discovering rsFC biotypes jointly informed by autonomic nervous system (ANS) and cognitive function (rsFC-AC) in the MIDUS cohort (n = 208), and evaluating it as a predictive biomarker in BREATHE trial (n = 56). In CogTE, greater shifts toward the ARC pattern were associated with improvements in executive function and episodic memory. In BEEM, individuals with the affective dysregulation subtype showed greater improvement in corresponding neuropsychiatric domains. In the third demo, three rsFC-AC biotypes were discovered in MIDUS cohort; the high-ANS subtype showed greater improvement in episodic memory in BREATHE trial. BRAIN-DISC provides a scalable framework for translating cohort-derived rsFC signatures into intervention settings to support both response monitoring and patient stratification.},
}

@article {pmid42625110,
year = {2026},
author = {Südhof, TC},
title = {Challenges in Studying Synapses in Alzheimer's Disease.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78331},
pmid = {42625110},
issn = {1531-8249},
support = {R01AG070919//National Institutes of Health (NIH)/ ; RF1AG048131//National Institutes of Health (NIH)/ ; SPO327570//Greater Houston Community Foundation/ ; },
abstract = {Developing therapies for Alzheimer's disease (AD) is a pressing need. A key feature of AD is synapse loss. ApoE4, amyloid-β (Aβ)-peptides, phospho-tau, and neuroinflammation are thought to induce AD pathogenesis, but their molecular mechanisms are incompletely understood. Free Aβ-peptides whose levels decrease in AD are synaptogenic, whereas aggregating Aβ-peptides that accumulate in AD are synaptotoxic. It is unclear whether AD is driven primarily by the loss of free Aβ, the increase of aggregated Aβ, or both, nor do we know how ApoE4 affects synapses. Therefore, understanding the molecular pathways mediating synapse loss in AD is a priority in developing new therapies. ANN NEUROL 2026.},
}

@article {pmid42625117,
year = {2026},
author = {Reuben, DB},
title = {Mild Cognitive Impairment: In or Out of the Closet?.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70673},
pmid = {42625117},
issn = {1532-5415},
}

@article {pmid42625178,
year = {2026},
author = {Rossi, SL and Bovenkamp, DE},
title = {Advancing a systems-level understanding of neurodegeneration: the BrightFocus Alzheimer's disease research portfolio.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42625178},
issn = {1750-1326},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; Animals ; Proteostasis/physiology ; *Neurodegenerative Diseases ; *Biomedical Research ; },
abstract = {Alzheimer's disease research is entering a period of rapid acceleration. After decades focused on identifying individual disease-associated proteins and pathways, the field is moving toward a deeper understanding of how these mechanisms interact to influence cellular function, biological systems, and ultimately behavior and cognition. The emphasis is moving from isolated molecular targets to coordinated biological systems. Underlying pathological mechanisms point toward the breakdown of core cellular maintenance systems, including proteostasis, metabolism, and immune regulation. This dysfunction propagates from organelles to cells, from cells to neural circuits, and, ultimately, to cognition and behavior. Moving beyond single-target approaches will depend on understanding these upstream drivers, how they interact, and how sex, genetic background, and accumulated stressors shape when and how these systems fail. Underlying pathological mechanisms point toward the breakdown of core cellular maintenance systems, including proteostasis, metabolism, and immune regulation. This dysfunction propagates from organelles to cells, from cells to neural circuits, and ultimately to cognition and behavior. The BrightFocus Alzheimer's Disease Research (ADR) program [1] has long operated within this broad framework. Rather than focusing narrowly on single disease targets, the portfolio takes a 360° approach and prioritizes innovative research that reveals how fundamental cellular processes interact across cell types and biological systems to drive neurodegeneration and resilience. This includes supporting early-career investigators and researchers entering the field from other disciplines to advance current hypotheses and define where the field is going next.},
}

Humans
*Alzheimer Disease/metabolism/pathology
Animals
Proteostasis/physiology
*Neurodegenerative Diseases
*Biomedical Research

@article {pmid42625315,
year = {2026},
author = {Guzman-Castillo, M and Korhonen, K and Murphy, M and Martikainen, P},
title = {Future trends in dementia incidence and mortality: projecting the burden of dementia on long-term care in Finland by 2040.},
journal = {Scandinavian journal of public health},
volume = {},
number = {},
pages = {14034948261471053},
doi = {10.1177/14034948261471053},
pmid = {42625315},
issn = {1651-1905},
abstract = {AIMS: We projected the future number of individuals with dementia and long-term care (LTC) residents in Finland by education level through 2040. We also examined the impact of different future scenarios regarding declining dementia and LTC trends, as well as the effect of past educational expansion on the future prevalence of dementia and LTC.

METHODS: A multistate model tracks the population aged 65 years and over through states characterised by the presence of dementia, LTC residence, or death. We calculated age, gender, education and year-specific transition probabilities from Finnish registry data under various scenarios.

RESULTS: Assuming constant transition probabilities, the number of individuals with dementia is projected to rise by 74% (from 123,800 to 215,900) between 2018 and 2040. The number of LTC residents is expected to increase by 58% (from 73,900 to 116,800). Driven mainly by shifts in population education distribution, the number of people with dementia is projected to decrease by 29% among those with basic education, while increasing by 215% and 260% among those with secondary and tertiary education, respectively. If both dementia incidence and mortality decrease as projected for overall mortality, the number of people with dementia and LTC residents would rise by 67% and 73%, respectively. If the declining trend in LTC use observed prior to 2018 persists, the number of LTC residents could decrease by 10% by 2040.

CONCLUSIONS: Even under optimistic assumptions of declining dementia incidence and mortality, the burden of dementia on health and social care systems is projected to persist.},
}

@article {pmid42625393,
year = {2026},
author = {Okafor, NI and Abdelgader, A and Abobaker, M and Choonara, YE},
title = {A Review of the Therapeutic Potential of Stem Cell-Derived Nanocarriers to Treat Neurological Disorders.},
journal = {ChemistryOpen},
volume = {15},
number = {9},
pages = {e202500425},
doi = {10.1002/open.202500425},
pmid = {42625393},
issn = {2191-1363},
support = {//National Research Foundation (NRF) of South Africa/ ; },
mesh = {Humans ; *Nervous System Diseases/therapy/drug therapy ; Animals ; *Stem Cells/cytology/metabolism ; *Nanoparticles/chemistry ; Blood-Brain Barrier/metabolism ; *Drug Carriers/chemistry ; Stem Cell Transplantation ; },
abstract = {Neurological disorders (NDs) are characterized by substantial loss of specific neurons, with Alzheimer's and Parkinson's diseases being the most frequent NDs and nearly 99% of all "foreign substances" are prohibited from entering the brain by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (CFB). These barriers, while crucial for brain protection, pose significant challenges for drug delivery, as they restrict the entry of many therapeutic agents into the brain, and this represents the primary manifestation of the absence of pathogenesis-targeting therapeutics. With significant success across multiple cell transplantation research efforts, stem cell therapy has been utilized for decades to treat neurological disorders. They work by replacing injured or lost cells directly, releasing proliferation and neurotrophic factors through autocrine and paracrine actions, suppressing neurological inflammation, and activation of endogenous brain progenitor cells. Nanocarriers derived from stem cells represent an innovative and promising therapeutic strategy for combating neurological diseases, combining faculties of regeneration of stem cells with the precision of nanotechnology. These nanocarriers possess natural biocompatibility and can efficiently cross the BBB to transport the therapeutic agents directly to affected neural tissues, thereby promoting enhanced treatment efficacy while reducing off-target effects. However, key challenges remain in large-scale production, standardization, and long-term safety. Thus, this review has examined the potential applications of stem cell extracellular vesicle (EV)-nanocarriers, mainly exosomes and recent development in the treatment of neurological diseases.},
}

Humans
*Nervous System Diseases/therapy/drug therapy
Animals
*Stem Cells/cytology/metabolism
*Nanoparticles/chemistry
Blood-Brain Barrier/metabolism
*Drug Carriers/chemistry
Stem Cell Transplantation

@article {pmid42625495,
year = {2026},
author = {Bernath, MM and Brosch, J and Saykin, AJ and Wilcock, D and Summanwar, D and Willis, DR},
title = {Beyond the Cochrane review: Re-evaluating anti-amyloid therapy in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71769},
doi = {10.1002/alz.71769},
pmid = {42625495},
issn = {1552-5279},
support = {P30 AG072976/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/drug therapy ; },
abstract = {The global burden of Alzheimer's disease (AD) is accelerating, with U.S. prevalence projected to reach nearly 13 million by 2060. Although the "amyloid cascade hypothesis" has long-guided drug development, a 2026 Cochrane review challenged amyloid beta (Aβ) targets for therapy by citing insufficient clinical benefit and safety concerns. We highlight several methodological limitations in this study. The primary concern is a "dilution effect" caused by analyzing monomer-selective antibodies alongside newer treatments that directly target toxic Aβ plaques. This statistical noise, compounded by a decade of failed studies, obscures the significant cognitive preservation achieved by U.S. Food and Drug Administration (FDA)-approved therapies, like lecanemab and donanemab. We contend that these cognitive outcomes are clinically meaningful, as dismissing them ignores the vital impact on preserved independence and reduced caregiver burden. We emphasize current stratified safety frameworks for amyloid-related imaging abnormalities (ARIA) management. The path forward lies in an integrated framework combining Aβ clearance with novel, multi-pathway therapies.},
}

Humans
*Alzheimer Disease/drug therapy
*Amyloid beta-Peptides/metabolism
Plaque, Amyloid/drug therapy

@article {pmid42625502,
year = {2026},
author = {Goll, J and Martinaityte, I and Kirsebom, BE and Halvorsen, DS and Gonzalez-Ortiz, F and Zetterberg, H and Fladby, T and Gundersen, MD},
title = {Interpreting p-tau217 on the ward: frailty and plasma biomarkers in acutely admitted older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71768},
doi = {10.1002/alz.71768},
pmid = {42625502},
issn = {1552-5279},
support = {2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; HNF1713-24//Northern Norway Regional Health Authority/ ; //University Hospital of North Norway/ ; },
mesh = {Humans ; Biomarkers/blood ; *tau Proteins/blood ; Female ; Male ; Aged ; *Frailty/blood ; Aged, 80 and over ; Glomerular Filtration Rate/physiology ; Norway ; Phosphorylation ; Neurofilament Proteins/blood ; Hospitalization ; Glial Fibrillary Acidic Protein/blood ; Frail Elderly ; Alzheimer Disease/blood ; },
abstract = {INTRODUCTION: Older adults living with frailty are prone to adverse events upon acute hospitalization. Frailty biomarkers aiding early identification are lacking. This study explores frailty and Alzheimer's disease (AD)-related biomarkers.

METHODS: Participants were recruited from the Norfrail study (n = 178) and from the Norwegian Dementia Disease Initiative (n = 105). Linear regression was used to analyze associations between frailty and the plasma biomarkers phosphorylated tau-217 (p-tau217), neurofilament light chain (NfL), brain-derived tau, ubiquitin carboxyl-terminal hydrolase L1, and glial fibrillary acidic protein in older adults admitted acutely to hospital.

RESULTS: No significant association was found between p-tau217 and frailty. Estimated glomerular filtration rate (eGFR) explained 27% of the variance of plasma p-tau217 (p < 0.001). NfL was the only biomarker significantly associated with frailty (p < 0.01).

DISCUSSION: Except for NfL, plasma biomarkers were independent of frailty. Substantial p-tau217 variability was explained by eGFR. Clinicians need to consider renal function when interpreting p-tau217 in unselected populations.},
}

Humans
Biomarkers/blood
*tau Proteins/blood
Female
Male
Aged
*Frailty/blood
Aged, 80 and over
Glomerular Filtration Rate/physiology
Norway
Phosphorylation
Neurofilament Proteins/blood
Hospitalization
Glial Fibrillary Acidic Protein/blood
Frail Elderly
Alzheimer Disease/blood

@article {pmid42625899,
year = {2026},
author = {Sekita, A and Sprügel, MI and Balk, S and Haupenthal, D and Engelhorn, T and Schmidt, MA and Doerfler, A and Oberstein, TJ and Maler, JM and Kornhuber, J and Lewczuk, P and Rothhammer, V and Schwab, S and Kuramatsu, JB and Sembill, JA},
title = {Cerebrospinal fluid biomarkers for cerebral amyloid angiopathy with non-hemorrhagic imaging marker.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70431},
pmid = {42625899},
issn = {2352-8729},
abstract = {INTRODUCTION: Reduced cerebrospinal fluid (CSF) amyloid beta (Aβ) 40 has been reported in cerebral amyloid angiopathy (CAA) diagnosed by hemorrhagic magnetic resonance imaging (MRI) markers. Whether similar alterations occur when fulfilling Boston Criteria 2.0 solely through non-hemorrhagic markers remains unclear.

METHODS: We analyzed 358 memory clinic patients undergoing MRI and CSF assessment. CAA was categorized by hemorrhagic markers (CAA 1.5 H) or exclusively non-hemorrhagic markers (CAA 2.0 NH) per Boston Criteria 1.5 and 2.0, respectively. Primary comparison of CSF-Aβ40 between CAA groups was complemented by secondary (Aβ42, phosphorylated tau [p-tau181], total tau [t-tau]) and exploratory analyses including Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy controls, adjusted for age, sex, MRI characteristics, and assay type.

RESULTS: Sixty-five patients were reclassified as CAA 2.0 NH. Aβ40 was higher in CAA 2.0 NH than CAA 1.5 H (15,808 vs. 13,792 pg/ml, p = 0.033) and did not differ from AD, MCI, or controls. p-tau181 reached significance after adjustment (p = 0.010), likely reflecting AD co-pathology. However, within CAA-2.0-NH, patients with AD CSF profile showed Aβ40 comparable to hemorrhagic CAA.

DISCUSSION: Non-hemorrhagic imaging markers alone were not associated with characteristic CAA-related CSF alterations, suggesting biological heterogeneity, limited specificity, or lesion type-dependent variability.},
}

@article {pmid42626026,
year = {2026},
author = {Mehta, V and Singh, D and Kelman, J and Nimma, S and Lutz, H and Schnee, A and Weisman, D and Rosenbloom, MH},
title = {Real-world determinants of time to initiation of anti-amyloid treatments: comparative data from private and academic practice settings.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70436},
pmid = {42626026},
issn = {2352-8729},
abstract = {INTRODUCTION: Earlier anti-amyloid therapy (AAT) initiation results in improved clinical outcomes in Alzheimer's disease (AD). We sought to identify demographic, clinical, and disease-related factors impacting door-to-treatment times (DTTs).

METHODS: A retrospective review of AAT data was conducted at private and academic neurological practices.

RESULTS: A total of 329 patients (53.2% from private versus 46.8% academic practices), mean age 73.5 ± 7.2 (55.3% female), with most being non-Hispanic White were treated with lecanemab (81.2%) or donanemab (18.2%). DTTs were significantly reduced (p < 0.05) in both practices when diagnosis was confirmed with blood-based biomarkers (BBBs) as well as with greater clinic experience dosing AATs. DTT increased in patients with non-Medicare insurance and was not impacted by diagnosis, referral source, apolipoprotein E genotype status, or clinic distance.

DISCUSSION: Patients with private insurance may experience greater delay in DTT, whereas BBBs may reduce DTT relative to traditional confirmatory biomarkers. DTT improves with clinic experience.},
}

@article {pmid42626038,
year = {2026},
author = {Oi, Y and Shen, Q and Solders, SK and Rivera, CS and Williams, ME and Reas, ET},
title = {APOE ε4-related blood-brain barrier disruption and APOE ε4-independent microstructural abnormalities in white matter hyperintensities.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70459},
pmid = {42626038},
issn = {2352-8729},
abstract = {INTRODUCTION: While the apolipoprotein E (APOE) ε4 allele promotes blood-brain barrier (BBB) permeability and microstructural disruption, its specific contribution to white matter hyperintensity (WMH) pathological heterogeneity remains unknown.

METHODS: We measured BBB permeability (K trans) in 31 and microstructure in 59 cognitively normal older adults with WMHs and normal-appearing white matter (NAWM) using dynamic contrast-enhanced magnetic resonance imaging and restriction spectrum imaging (RSI). Linear mixed-effects models (LMMs) examined differences between WMHs and NAWM by APOE ε4 status.

RESULTS: In APOE ε4 carriers, K trans was elevated and restricted isotropic diffusion (RI) was reduced within WMHs compared to NAWM. This effect was absent in non-carriers. In contrast, reduced restricted directional diffusion and elevated isotropic free water within WMHs was observed in both genotypes. K trans did not correlate with brain microstructure.

DISCUSSION: Our data suggest that WMHs comprise both APOE ε4-related and APOE ε4-independent pathological components. These findings implicate neurovascular and non-vascular mechanisms through which APOE ε4 may contribute to WMH pathological heterogeneity.},
}

@article {pmid42626185,
year = {2026},
author = {Alvarez-Ginarte, Y and López, R and García de la Vega, JM and De Ema, I and Alpízar-Pedraza, D},
title = {Integrated Virtual Screening and Molecular Electrostatic Surface Potential Descriptors for Predicting BACE1 Inhibitor Interactions in Alzheimer's Disease.},
journal = {ACS omega},
volume = {11},
number = {32},
pages = {47739-47753},
pmid = {42626185},
issn = {2470-1343},
abstract = {Developing brain-penetrant BACE1 inhibitors remains a major challenge in Alzheimer's disease. Unlike conventional studies focusing solely on binding affinity, this work presents an integrated computational pipeline that prioritizes both potency and pharmacokinetic developability from the outset. A robust quantitative structure-activity relationship (QSAR) model was built for 41 N-(pyridin-3-yl)-picolinamide derivatives using Molecular Electrostatic Surface Potential (MESP) descriptors. Principal component analysis identified three key electrostatic features - mean MESP, variance of negative MESP, and number of local MESP maxima/minima as drivers of BACE1 inhibitory activity. A key novelty is the early integration of Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) filtering, using ADMETlab 3.0, to ensure blood-brain barrier (BBB) permeability and low P-glycoprotein efflux properties whose absence contributed to the failure of several clinical BACE1 inhibitors. Only compound N-[3-[(1S,5S,6S)-3-amino-1-(difluoromethyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-hept-3-en-5-yl]-4-fluorophenyl]-5-chloropyrazine-2-carboxamide (5) simultaneously satisfied the criteria for high predicted potency, favorable BBB penetration, low PgP efflux, and good synthetic accessibility. Molecular docking revealed that compound 5 binds strategically to the S1 and S3 substrate-recognition pockets through hydrogen bonds with THR280, GLN121, LYS155, as well as a halogen interaction with ARG283, while avoiding direct interaction with the catalytic dyad. This binding mode balances affinity and permeability, distinguishing compound 5 from clinically unsuccessful inhibitors. The practical implication is a rational framework that rapidly prioritizes candidates with high potency and favorable Central Nervous System (CNS) drug-like properties, thereby reducing the risk of late-stage attrition. All predictions are computational and require experimental validation (enzymatic, cellular, and in vivo) before any translational claims can be made. Thus, combining QSAR, ADMET, and molecular docking with an early emphasis on BBB penetration offers a time-efficient strategy for CNS drug discovery against Alzheimer's disease.},
}

@article {pmid42626279,
year = {2026},
author = {Diling, C and Tianqiao, Y and Jian, Y and Chaoqun, Z and Ou, S and Yizhen, X},
title = {Correction: Docking studies and biological evaluation of a potential β-secretase inhibitor of 3-Hydroxyhericenone F from Hericium erinaceus.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1943698},
doi = {10.3389/fphar.2026.1943698},
pmid = {42626279},
issn = {1663-9812},
abstract = {[This corrects the article DOI: 10.3389/fphar.2017.00219.].},
}

@article {pmid42626436,
year = {2026},
author = {Schuessler, M and Mundorf, A},
title = {Hemispheric asymmetries in rodent models of neurological diseases: a systematic review.},
journal = {Frontiers in integrative neuroscience},
volume = {20},
number = {},
pages = {1843068},
pmid = {42626436},
issn = {1662-5145},
abstract = {INTRODUCTION: Hemispheric asymmetries are a core organizational principle of the vertebrate brain, but they are still not fully integrated into the study of preclinical models of neurological disease. Although many rodent models naturally include lateralization through unilateral interventions, hemispheric differences are not consistently examined or systematically reported.

METHODS: A systematic review was conducted following PRISMA guidelines, combining evidence from 48 studies on hemispheric asymmetries in rodent models of neurological conditions, including mild traumatic brain injury, epilepsy, stroke, Alzheimer's, and Parkinson's disease.

RESULTS: Across these models, disease processes cause strong lateralized effects on behavior, neurochemistry, and regional metabolism. In epilepsy models specifically, hemispheric asymmetries depend on the model: early seizure spread and network excitability can be lateralized, while other paradigms show more symmetric responses, emphasizing the role of baseline circuit asymmetries and genetic background. Similar lateralized effects are seen in stroke and Parkinson's models, reflecting clinical phenomena such as lesion-side-dependent outcomes and unilateral symptom onset.

DISCUSSION: Models focusing on intrinsic hemispheric asymmetry or interhemispheric/bilateral response highlight existing differential sensitivity to experimental manipulations that may predispose the system to asymmetric outcomes. Nonetheless, variability and dynamic shifts in hemispheric organization are rarely taken into account. Incorporating hemispheric analysis systematically into experimental design and data interpretation could enhance the sensitivity, clarity, and clinical relevance of rodent models of neurological disease.},
}

@article {pmid42626456,
year = {2026},
author = {Pollard, C and Miller, R and Stirland, I and Keni, M and Jenkins, A and Saito, E and Hill, JT and Jenkins, T},
title = {Circulating neuron-derived cfDNA for blood-based detection of Alzheimer's and other neurodegenerative conditions.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1822479},
pmid = {42626456},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; DNA Methylation ; *Neurons/metabolism ; *Cell-Free Nucleic Acids/blood ; Biomarkers/blood ; *Neurodegenerative Diseases/blood/diagnosis ; Female ; Male ; Amyotrophic Lateral Sclerosis/blood/diagnosis ; },
abstract = {Blood-based biomarkers for neurodegenerative diseases are improving early detection and staging, but current assays primarily reflect aggregate neuropathology or generalized neuronal injury and do not resolve the specific neuronal populations affected. Circulating cell-free DNA (cfDNA) retains stable DNA methylation patterns reflective of tissue and cellular origin, making it a promising substrate for cell-of-origin analysis. However, conventional methylation approaches are limited by bisulfite-associated DNA damage and amplification-related bias, hindering the detection of neuron-derived cfDNA, a small fraction of total circulating cfDNA. Here, we present proof-of-concept evidence that native nanopore sequencing can support both brain methylation atlas generation and downstream cfDNA cell-of-origin classifier development in neurodegenerative disease. By directly profiling endogenous DNA methylation without bisulfite conversion or PCR amplification, nanopore sequencing preserves native molecules, reduces processing-related bias, and enables flexible, genome-wide methylation profiling that can be iteratively expanded as additional reference cell types are incorporated. Using whole-genome native nanopore sequencing, we generated a methylation reference atlas from six primary human neural cell populations-cortical neurons, dopaminergic neurons, spinal motor neurons, astrocytes, Schwann cells, and microglia-and developed cell-type-informed cfDNA classifiers. Classifier performance was assessed in silico using dilution series designed to model physiologic admixture. The framework was then applied to 137 blood plasma samples from individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and healthy controls. Elevated circulating cfDNA fragments exhibited methylation patterns similar to reference profiles from selectively vulnerable neuronal populations, including cortical neuron-like signatures in AD and progressive MCI, dopaminergic neuron-like signatures in PD, and spinal motor neuron-like signatures in ALS. Multivariate integration of neuronal signatures improved the separation of diagnostic groups within this cohort (AUC > 0.85). Although the reported atlas is limited and additional validation in larger and independent cohorts will be required, these results support the feasibility of native cfDNA nanopore methylation sequencing as a flexible platform for brain-derived cfDNA analysis and more cell-type-informed investigation of neurodegeneration from peripheral blood.},
}

Humans
*Alzheimer Disease/blood/diagnosis
DNA Methylation
*Neurons/metabolism
*Cell-Free Nucleic Acids/blood
Biomarkers/blood
*Neurodegenerative Diseases/blood/diagnosis
Female
Male
Amyotrophic Lateral Sclerosis/blood/diagnosis

@article {pmid42626563,
year = {2026},
author = {Lin, X and Zhao, W and Zhou, J and Qiu, J},
title = {Association between fasting serum uric acid levels and Alzheimer's disease in nursing home residents: a cross-sectional study.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1878852},
pmid = {42626563},
issn = {2296-861X},
abstract = {INTRODUCTION: Evidence regarding the association between fasting serum uric acid (FSUA) and Alzheimer's disease (AD) is limited and inconsistent. This study investigated the association between FSUA levels and AD.

METHODS: In this cross-sectional study, 852 participants from a hospital specializing in geriatric care were enrolled. Multivariable logistic regression analysis, restricted cubic spline curves, and subgroup analyses were employed to analyze the association between FSUA and AD.

RESULTS: The average age of eligible participants was 81.0 ± 8.8 years; 23% were patients with AD and 33.7% were male. Multivariate logistic regression analysis revealed an inverse relationship between FSUA levels and AD. Specifically, a 10 μmol/L increase in FSUA was associated with a 5% decrease in AD odds (OR, 0.95; 95% confidence interval [CI], 0.93-0.97). When FSUA levels were divided into quartiles, the higher quartiles showed progressively lower odds of developing AD than those in the lowest quartiles (p for trend < 0.001). No interactions were observed between FSUA and AD. Restricted cubic spline regression model demonstrated a linear inverse association between the odds of AD and FSUA levels.

CONCLUSION: We observed a negative association between FSUA levels and AD. Further prospective studies are required to confirm this causal relationship.},
}

@article {pmid42626599,
year = {2026},
author = {, },
title = {Retraction: AD-Diff: enhancing Alzheimer's disease prediction accuracy through multimodal fusion.},
journal = {Frontiers in computational neuroscience},
volume = {20},
number = {},
pages = {1957950},
doi = {10.3389/fncom.2026.1957950},
pmid = {42626599},
issn = {1662-5188},
abstract = {[This retracts the article DOI: 10.3389/fncom.2025.1484540.].},
}

@article {pmid42626968,
year = {2026},
author = {Lautrup, S and Cao, SQ and Long, X and Liu, BHM and Escobar-Doncel, B and Ferrante, A and Frank, J and Schmauck-Medina, T and Leung, GHD and Liang, KX and Lu, N and Veverova, K and Vyhnalek, M and Pun, FW and Zhavoronkov, A and Fang, EF},
title = {A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD[+]-mitophagy axis on aging and neurodegeneration.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71680},
doi = {10.1002/alz.71680},
pmid = {42626968},
issn = {1552-5279},
support = {#282952//Cure Alzheimer's Fund/ ; #284930//Cure Alzheimer's Fund/ ; #2020001//The South-Eastern Norway Regional Health Authority (Helse Sør-øst RHF)/ ; #2021021//The South-Eastern Norway Regional Health Authority (Helse Sør-øst RHF)/ ; #2023093//The South-Eastern Norway Regional Health Authority (Helse Sør-øst RHF)/ ; #262175//Research Council of Norway/ ; #334361//Research Council of Norway/ ; #119986//NordForsk Foundation/ ; #81971327//National Natural Science Foundation of China/ ; #269901//Akershus University Hospital/ ; #261973//Akershus University Hospital/ ; #262960//Akershus University Hospital/ ; #281931//Civitan Norges Forskningsfond/ ; #TO01000215//Czech Republic-Norway KAPPA programme/ ; #207819//the Rosa sløyfe/Norwegian Cancer Society and Norwegian Breast Cancer Society/ ; #101073251//HORIZON-TMA-MSCA-DN/ ; #104617//Ellcome Leap's Dynamic Resilience Program (jointly funded by Temasek Trust)/ ; PTC-Gene-25-1439553/ALZ/Alzheimer's Association/United States ; #281956//Norwegian Health Association/ ; #43622//Norwegian Health Association/ ; #NW26-04-00501//Czech Ministry of Health project/ ; },
mesh = {Humans ; Animals ; *Aging/metabolism ; Caenorhabditis elegans ; *NAD/metabolism ; *Neurodegenerative Diseases/metabolism/genetics ; *Mitophagy/physiology ; *Brain/metabolism/pathology ; *Artificial Intelligence ; Neurons/metabolism ; Alzheimer Disease/metabolism/genetics ; Induced Pluripotent Stem Cells ; },
abstract = {INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD[+]) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD[+]-mitophagy axis contributes to brain aging and neurodegeneration.

METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD[+]-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.

RESULTS: The NAD[+]-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.

DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD[+]-mitophagy axis as a central player in brain aging and AD.},
}

Humans
Animals
*Aging/metabolism
Caenorhabditis elegans
*NAD/metabolism
*Neurodegenerative Diseases/metabolism/genetics
*Mitophagy/physiology
*Brain/metabolism/pathology
*Artificial Intelligence
Neurons/metabolism
Alzheimer Disease/metabolism/genetics
Induced Pluripotent Stem Cells

@article {pmid42627127,
year = {2026},
author = {Copsey, A and Oakley, SS and Maina, MB and Parker, R and Marshall, KE and Harrington, CR and Storey, JMD and Wischik, CM and Serpell, LC},
title = {A proteomic analysis of the PHF-forming tau fragment (tau297-391) following uptake into differentiated human neuronal SHSY5Y cells.},
journal = {Bioscience reports},
volume = {},
number = {},
pages = {},
doi = {10.1042/BSR20260349},
pmid = {42627127},
issn = {1573-4935},
abstract = {Tau self-assembly and intracellular deposition is associated with a group of neurodegenerative diseases called tauopathies, which include Alzheimer's disease (AD) and Pick's disease. Here, we measured the proteome response in human neuronal cells (differentiated SH-SY5Y) following addition of a spontaneously amyloidogenic region of tau known as dGAE (tau297-391) which forms AD-like paired helical filaments in vitro and proteomic analysis showed increased endogenous tau expression. Further interactome analysis uncovered increased association between tau and proteins associated with nuclear chromatin, the nucleolus, and the spliceosome as well as the thiol-peroxidase, PRDX6 alongside an increase in reactive oxygen species (ROS). This work highlights a method to identify proteome pathways that may play an important role in the development of tau pathology and reveals an oxidative stress response to dGAE.},
}

@article {pmid42627134,
year = {2026},
author = {Mahjoubin-Tehran, M and Sahebkar, A},
title = {RNA interference (RNA)-based therapeutics for treating neurodegenerative diseases.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/17582024.2026.2722300},
pmid = {42627134},
issn = {1758-2032},
}

@article {pmid42627473,
year = {2026},
author = {Liu, JC and Liu, WJ and Yu, LQ and Li, J and Sun, YY and Li, S and Ma, QH},
title = {Distinct Transcriptional States of TDP-43 Pathology in an Alzheimer's Disease Mouse Model.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42627473},
issn = {1995-8218},
abstract = {Alzheimer's disease (AD) is frequently accompanied by cytoplasmic TDP-43 inclusions, although its pathogenic role remains unclear. Using Immuno-LCM-RNAseq in hippocampal excitatory neurons from APP/PS1 mice, we characterized two distinct TDP-43 states: diffuse cytoplasmic mislocalization (Cyto[+]) and punctate aggregates (Aggre[+]). Cyto[+] neurons exhibited a compensatory "pre-aggregation" signature characterized by enhanced synaptic organization and long-term potentiation pathways, along with altered nucleocytoplasmic transport, phosphorylation/proteolysis regulation, and lipid dysregulation. Aggre[+] neurons showed pronounced transcriptional changes associated with neuronal hyperexcitability, including increased calcium signaling and exocytosis, together with protein polymerization and autophosphorylation, mitochondrial dysfunction, and impaired regenerative pathways. Shared features included persistent lipid dysregulation, altered ApoE signaling, and transcriptional repression. Comparison of these states revealed potential upstream therapeutic targets, including ERK1/2, PI3K, small GTPases, and mRNA splicing pathways. These findings provide a transcriptional framework linking early TDP-43 stress responses to pathological aggregation in AD.},
}

@article {pmid42627505,
year = {2026},
author = {Wang, YX and Qin, SH and Liu, Q and Zhou, XW and Zhang, CY and Ma, ZY},
title = {Design, synthesis, biological activity and computational simulation evaluation of pyrimidine-2-aminoacetamide derivatives as cholinesterase inhibitors.},
journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
volume = {},
number = {},
pages = {},
pmid = {42627505},
issn = {1554-8120},
support = {H2024201041//Hebei Natural Science Foundation/ ; },
abstract = {To search for novel anti-Alzheimer's disease candidate molecules, a series of pyrimidine-2-aminoacetamide derivatives were designed and synthesized, and their cholinesterase (ChE) inhibitory activities were systematically evaluated. The results showed that all target compounds exhibited varying degrees of inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, compound 17v had the most excellent activity, with IC50 values of 0.96 and 7.12 μM for AChE and BuChE, respectively, which were superior to the positive control galantamine (AChE: IC50 = 5.10 μM, BuChE: IC50 = 14.76 μM). In terms of antioxidant activity, the results indicated that the overall activity of all compounds was relatively weak, with the most active compound 17d having an IC50 value of 115.77 μM, which was inferior to ascorbic acid (IC50 = 41.17 μM). Molecular docking revealed that 17v binds to both catalytic and peripheral anionic sites of AChE, supporting a mixed-type inhibition mechanism confirmed by enzyme kinetics. A 100 ns molecular dynamics simulation confirmed stable binding of 17v within AChE and BuChE pockets. Target prediction and toxicity assessment suggested that compound 17v may possess multi-target neuroprotective potential and a favorable preliminary safety profile, supporting its further investigation as a potential therapeutic candidate for Alzheimer's disease. SwissADMET prediction indicated favorable physicochemical properties and drug-likeness profiles. In conclusion, compound 17v represents a promising lead compound for anti-Alzheimer's therapy.},
}

@article {pmid42615950,
year = {2026},
author = {Hu, CJ and Huang, YH and Cho, S and Wang, BCM and Shen, SP and Newson, RS and Tang, CH},
title = {Epidemiology, Patient Characteristics, Treatment Patterns, and Costs of Mild Cognitive Impairment and Alzheimer's Disease in Taiwan.},
journal = {Value in health regional issues},
volume = {},
number = {},
pages = {101687},
doi = {10.1016/j.vhri.2026.101687},
pmid = {42615950},
issn = {2212-1102},
abstract = {OBJECTIVES: Alzheimer's disease (AD) with mild cognitive impairment (MCI) and AD are stages along the cognitive decline continuum and represent growing public health concerns. This study aimed to assess the diagnosed prevalence, claims-identified incidence, treatment patterns, healthcare costs, comorbidities, and observed mortality outcomes of individuals with AD with MCI, and AD with dementia in Taiwan claims data over a 10-year period.

METHODS: We conducted a retrospective cohort study using Taiwan's National Health Insurance Research Database. Individuals diagnosed with AD with MCI, or AD, between 2013 and 2022 were identified via ICD-9-CM and ICD-10-CM codes. Cross-sectional and longitudinal analyses examined epidemiology, treatment trends, costs, comorbidities, and mortality using descriptive statistics, survival analysis, and cost evaluations.

RESULTS: The estimated prevalence of AD with MCI, and AD from the claims database, increased from 109 379 cases in 2018 to 131 053 in 2022. Among pharmaceutical interventions, donepezil usage was predominant and increased over time, whereas nonpharmacologic therapies remained minimal. Healthcare costs rose with disease severity, with nonpharmacological inpatient care being the highest expense. Cardiovascular and metabolic comorbidities were prevalent and increased with severity. Observed cumulative mortality proportions increased with advancing disease severity; patients with AD with severe dementia had the highest mortality burden (41.98% at year 3).

CONCLUSION: AD with MCI and AD with dementia prevalence estimation is rising, demonstrating increasing costs and high comorbidity burdens. Disease severity is linked to higher mortality, reinforcing the need for integrated care and early cost-effective interventions to optimize outcomes in AD with MCI and AD with patients with dementia.},
}

@article {pmid42615981,
year = {2026},
author = {Suksatan, W},
title = {Socioeconomic and geographic inequalities in hospital-level ADRD burden: implications for hospital-to-home transitions and dementia care coordination.},
journal = {Home health care services quarterly},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/01621424.2026.2717528},
pmid = {42615981},
issn = {1545-0856},
abstract = {Alzheimer's disease and related dementias (ADRD) create challenges for hospital-to-home transitions, caregiver preparation, and home health care coordination. This cross-sectional study examined socioeconomic and geographic inequalities in hospital-level ADRD burden among 3,027 U.S. hospitals serving Medicare fee-for-service beneficiaries. Multivariable quasibinomial regression assessed associations between ADRD prevalence and hospital characteristics, rurality, census region, and patient composition. An age-adjusted sensitivity analysis was conducted among 3,003 hospitals with complete age-composition data. Mean hospital-level ADRD prevalence was 22.00% among patients and 24.00% among events. In the primary model, ADRD prevalence was higher in hospitals in the South and among hospitals serving higher proportions of dual-eligible, female, and White patients. In the age-adjusted sensitivity model, dual eligibility remained strongly associated with ADRD prevalence, while the female-composition association was attenuated. These hospital-level patterns may help identify settings where enhanced discharge planning and home health care coordination should be considered.},
}

@article {pmid42616215,
year = {2026},
author = {Thakur, A and Sharma, R and Kumari, S and Prakash, D and Devi, A},
title = {Neuroinflammatory and molecular pathways in Alzheimer's disease: mechanistic crosstalk and emerging therapeutic opportunities.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42616215},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative condition characterized by the interaction of various molecular, cellular and systemic mechanisms that culminate in synaptic dysfunction, neuronal loss and memory decline. Therapeutic success remains limited despite decades of research, and accumulating evidence suggests that an exclusive focus on single-pathology mechanisms may have contributed to the limited efficacy of many therapeutic strategies. The interplay of pathogenic mechanisms seems to contribute to the disorder in a dynamic and continuous manner, much like the growing evidence supporting a network-based model. This review engages with 30 major pathogenic pathways contributing to AD, including amyloid-β and tau pathology, neuroinflammation, oxidative stress and mitochondrial dysfunction, synaptic and neurotransmitter dysfunction, metabolic and vascular dysfunction, calcium signaling, proteostasis ,gut-brain axis and hormone-related pathways. The study also presents emerging mechanisms such as metal ion dishonesties, prion-like propagation and Wnt/β-catenin Signaling. Particular emphasis is placed on neuroinflammatory and immunometabolism pathways, which mediate the clearance of amyloid, propagation of tau, maintenance of synaptic integrity, and regulation of neurovascular function. In addition, the review examines therapeutic strategies targeting these pathways, including monoclonal antibodies, inflammasome inhibitors, metabolic modulators, and emerging gene- and RNA-based therapies. Multi-target and precision medicine approaches represent promising strategies for potential disease modification, although their clinical efficacy remains under investigation.Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.},
}

@article {pmid42616216,
year = {2026},
author = {Kumawat, A and Sharma, MM and Nathani, S},
title = {Bacopa monnieri and Alzheimer's disease: mechanistic convergence, cognitive outcomes and translational perspectives.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42616216},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD), the leading cause of age-related cognitive decline and dementia, represents a growing neurological and socioeconomic burden, while currently approved therapies offer limited symptomatic benefit and minimal disease modification. Bacopa monnieri (L.) Wettst. (BM), a traditional Ayurvedic nootropic herb, has emerged as a promising phytotherapeutic candidate owing to its bioactive bacosides, which target multiple molecular pathways implicated in AD pathogenesis. This review, conducted following PRISMA 2020 principles, critically synthesizes evidence on the therapeutic relevance of BM in AD and cognitive decline. Literature from PubMed, Scopus, Web of Science and Cochrane Library was evaluated to examine phytochemistry, pharmacological mechanisms, preclinical and clinical evidence, cognitive outcomes, pharmacokinetics, safety, formulation strategies, comparative medicinal plant mechanisms and pharmacoeconomic positioning. Mechanistically, bacosides exert neuroprotective effects through cholinergic modulation, attenuation of amyloid-β accumulation, suppression of tau hyperphosphorylation via GSK-3β regulation, enhancement of brain-derived neurotrophic factor (BDNF)-mediated neuroplasticity and mitigation of oxidative stress and neuroinflammation through NF-κB signaling modulation. Preclinical findings consistently demonstrate improvements in cognition, synaptic plasticity and neuronal survival, whereas clinical studies using standardized extracts report favorable effects on memory, attention and processing speed with acceptable tolerability. Comparative analysis positions BM among promising neuroprotective medicinal plants for cognitive enhancement and supports its relevance to SDGs 3, 12 and 15. Nevertheless, variability in extract standardization, limited long-term clinical evidence and absent Alzheimer-specific pharmacoeconomic evaluations warrant biomarker-driven, large-scale randomized trials to clarify its therapeutic utility in AD.},
}

@article {pmid42616318,
year = {2026},
author = {Chen, Y and Song, E and Yu, S and Wan, S and Zheng, W},
title = {SCRIB is a Shared Transcriptomic Biomarker Candidate Linking Cardioembolic Stroke and Alzheimer's Disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42616318},
issn = {1559-1166},
support = {2022R52038//Special Support Program for High Level Talents of Zhejiang Province/ ; 2025C02151//Zhejiang Province's Vanguard Geese Leading Plan Project/ ; CXTD202501002//Zhejiang Clinovation Pride/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism ; Humans ; *Embolic Stroke/genetics/metabolism ; *Transcriptome ; Biomarkers/metabolism ; },
abstract = {Acute ischemic stroke is a major cause of death and disability, and post-stroke cognitive impairment remains a major clinical challenge. Cardioembolic stroke (CES), often associated with atrial fibrillation, is closely linked to cognitive decline. Increasing evidence suggests that vascular dysfunction contributes to both vascular cognitive impairment and Alzheimer's disease (AD), but the shared molecular basis remains unclear. This study aimed to identify shared molecular signatures and candidate biomarkers linking CES and AD. Gene expression datasets were obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using limma, and disease-related gene modules were constructed using weighted gene co-expression network analysis. Functional enrichment analyses were performed to explore shared pathways. Three machine learning algorithms-LASSO, SVM-RFE, and random forest-were used to prioritize candidate genes. Receiver operating characteristic analysis, nomogram modeling, single-gene gene set enrichment analysis, and external validation were performed to evaluate the potential relevance of the identified gene. Seven overlapping genes were identified between CES and AD. Among them, SCRIB was consistently selected by the integrated feature-selection workflow and showed moderate diagnostic performance in both internal datasets. Supportive validation was observed in an independent AD dataset and in an atrial fibrillation-related surrogate validation cohort. SCRIB may represent a shared transcriptomic biomarker candidate linking CES and AD. These findings provide preliminary transcriptomic evidence for a potential molecular link between cerebrovascular pathology and neurodegeneration, but further mechanistic and clinical validation is required.},
}

*Alzheimer Disease/genetics/metabolism
Humans
*Embolic Stroke/genetics/metabolism
*Transcriptome
Biomarkers/metabolism

@article {pmid42616473,
year = {2026},
author = {Facchetti, T and Joyce, JL and Rizer, S and Tom, SE and Marder, K and Chapman, S and Rosser, ML and Cosentino, S},
title = {Age at menopause and subjective cognitive symptoms predict digital cognitive outcomes at the gynecological Well-Woman visit.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/13803395.2026.2707992},
pmid = {42616473},
issn = {1744-411X},
abstract = {INTRODUCTION: Women are at increased risk for Alzheimer's Disease (AD). Growing evidence suggests that the menopausal transition may represent a vulnerable window for development of AD-related pathology. Yet, women are diagnosed with AD later than men. Conducting routine cognitive screenings and integrating information about both cognitive symptoms and age at menopause may help address sex-based disparities in detection and prevention. This study investigated whether subjective cognitive symptoms, in combination with age at menopause, were associated with performance on a digital cognitive task in postmenopausal women.

METHODS: 183 postmenopausal women (mean age = 63.8, range = 45-85) were recruited after their Well-Woman visit. Participants completed the Screener for Cognitive Problems in Everyday Life (SCoPE) to assess subjective cognitive symptoms, followed by a sensitive measure of objective cognition: the Linus Health Digital Clock and Recall (DCR™). Information was also collected on age at menopause. We examined associations of subjective cognitive symptoms and age at menopause with digital cognitive performance, adjusting for age, education and depression. Model fit was evaluated using adjusted R[2], AIC, and BIC.

RESULTS: 48.1% of women reported one or more cognitive symptoms on the SCoPE. On objective testing, 73.2% scored in the normal range, 20.8% in the borderline range, and 6.0% in the impaired range. SCoPE total score was negatively associated with objective cognitive performance in adjusted models (B = -.12, p = .03). Age at menopause showed a significant quadratic association with cognitive performance (B = -0.006, p<.001). SCoPE total was not associated with DCR subtests, while age at menopause predicted both Delayed Recall and Clock Drawing.

CONCLUSION: Subjective cognitive symptoms and age at menopause were associated with lower performance on a sensitive, objective cognitive test. Findings support routine cognitive screening and suggest that subjective cognitive symptoms as well as age at menopause are associated with cognitive function.},
}

@article {pmid42616564,
year = {2026},
author = {Salunkhe, J and Ugale, V},
title = {Ferroptosis and NMDA Receptor Activity in Alzheimer's Disease: Implications for Amyloid Pathology and P-Glycoprotein Regulation.},
journal = {Drug development research},
volume = {87},
number = {6},
pages = {e70367},
doi = {10.1002/ddr.70367},
pmid = {42616564},
issn = {1098-2299},
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Receptors, N-Methyl-D-Aspartate/metabolism ; *Ferroptosis/physiology ; Amyloid beta-Peptides/metabolism ; Animals ; *ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation, oxidative stress, and excitotoxicity. Ferroptosis and N-methyl-D-aspartate (NMDA) receptor activity,may be interconnected in the pathogenesis of Aβ accumulation and associated neurodegeneration in AD. However, the interplay between these pathways remains poorly understood and underexplored for therapeutic intervention against the AD. The review aims to explore the shared molecular triggers of ferroptosis and NMDA receptor overactivation, including the roles of iron, glutamate overload, calcium dysregulation, and reactive oxygen species (ROS) accumulation. We further highlighted the convergent consequences of these processes on mitochondrial dysfunction, lipid peroxidation, and their impact on Aβ pathology. Particular attention is given to P-glycoprotein (P-gp), an efflux transporter involved in the Aβ clearance at the blood-brain barrier, whose expression and function may be modulated by oxidative stress, iron homeostasis, and NMDA receptor signaling. Emerging evidence indicated that ferroptosis and NMDA receptor activity may disrupt P-gp function, thereby impairing Aβ clearance and promoting its accumulation in the AD. Overall, the review elucidates the molecular mechanisms linking ferroptosis and NMDA receptor overactivation and their impact on P-gp-mediated Aβ transport in the AD, providing integrated mechanisms and harnessing their potential for AD therapeutics.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Receptors, N-Methyl-D-Aspartate/metabolism
*Ferroptosis/physiology
Amyloid beta-Peptides/metabolism
Animals
*ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
Oxidative Stress
Reactive Oxygen Species/metabolism
Iron/metabolism

@article {pmid42616623,
year = {2026},
author = {Dolci, G and Saglia, S and Brusini, L and Calhoun, VD and Galazzo, IB and Menegaz, G},
title = {Algebraic Connectivity Reveals Modulated High-Order Functional Networks in Alzheimer's Disease.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3725845},
pmid = {42616623},
issn = {2168-2208},
abstract = {Functional MRI is a neuroimaging technique that analyzes the functional activity of the brain by measuring blood-oxygen-level-dependent signals throughout the brain. The derived functional features can be used for investigating brain alterations in neurological and psychiatric disorders. In this work, we employed a hypergraph to model high-order functional relations across brain regions, introducing algebraic connectivity ($a(\mathcal {G})
$) for estimating the hyperedge weights. The hypergraph structure was derived from healthy controls to build a common topology across individuals. The considered cohort for subsequent analyses included subjects covering the Alzheimer's disease (AD) continuum, encompassing both mild cognitive impairment and AD patients. Statistical analysis and three classification tasks: HC vs AD, MCI vs AD, and HC vs MCI, were performed to assess differences across the three groups and the potential of the hyperedge weights as functional features. Furthermore, a mediation analysis was performed to evaluate the reliability of the $a(\mathcal {G})
$ values, representing functional information as the mediator between tau-PET levels, a key biomarker of AD, and cognitive scores. The proposed approach identified a larger number of hyperedges statistically different across groups compared to state-of-the-art methods. The $a(\mathcal {G})
$ hyperedge weights also achieved higher performance in two classification tasks, while similar performance in the third. Finally, two hyperedges belonging to salience/ventral attention and somatomotor networks showed a partial mediation effect between the tau biomarker and cognitive decline. These results suggested that $a(\mathcal {G})
$ can be an effective approach for extracting the hyperedge weights, including important functional information that resides in the brain areas forming the hyperedges.},
}

@article {pmid42617348,
year = {2026},
author = {Li, J and Kaneko, F and Saita, K and Okamura, H},
title = {Disordered eating behaviors in patients with severe Alzheimer's disease: A preliminary study.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {73},
number = {},
pages = {104267},
doi = {10.1016/j.gerinurse.2026.104267},
pmid = {42617348},
issn = {1528-3984},
abstract = {PURPOSE: This study aimed to identify the errors and error monitoring ability in the eating behavior of patients with severe Alzheimer's disease (AD) and evaluate the association between disordered eating behaviors and cognitive dysfunction.

METHODS: After recording the eating behavior of 20 patients with severe AD, the video was viewed multiple times. The behaviors that did not reflect the achievement of a meal task were identified as errors. The error rate (number of errors/total number of actions) was calculated, and the error-monitoring ability (ability to detect and correct errors) was also evaluated based on the presence or absence of error correction (recognizing and correcting errors). We also examined the associations among the error rate, error-monitoring ability, and cognitive function.

RESULTS: The error rate was approximately 41%. Unless corrected by the caregiver, the participant's errors persisted and similar errors occurred frequently; that is, participants' error-monitoring ability declined. There were no significant associations between the error rate, decreased error-monitoring ability, and cognitive dysfunction.

CONCLUSIONS: Disordered eating behaviors were associated with numerous errors in severe AD. Further, patients do not perceive these actions as errors when they occur, and thus fail to recognize the need for correction. This study's results can be useful in devising caregiving strategies that address disordered eating behaviors in patients with severe AD.},
}

@article {pmid42617419,
year = {2026},
author = {Jácome, D and Pérez-Palau, M and Martínez-Soria, I and Lidón, L and Vergara, C and Carbajo, D and Pulido, X and Sánchez-Navarro, M and Giralt, E and Albericio, F and Royo, M and Gavín, R and Del Río, JA},
title = {cis-γ-Amino-L-proline peptides as chemical probes of amyloidogenic processing in neurons and APP/PS1 mice.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110386},
doi = {10.1016/j.bioorg.2026.110386},
pmid = {42617419},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides, which are a key factor in its pathogenesis. In this study, we present the design and evaluation of cis-γ-amino-L-proline peptides as metabolically stable, cell-penetrating molecules that can modulate amyloidogenic processing. We screened a library of γ-peptides in primary neuronal cultures to determine their effects on endogenous Aβ1-42 production, cytotoxicity, and β-secretase (BACE1)-associated activity. Comparative analysis of structurally related analogues enabled the identification of molecular features associated with Aβ-lowering activity, establishing a qualitative structure-activity relationship. Peptide 33 (P33) emerged as a lead candidate, selectively reducing BACE1-associated activity without significantly inhibiting the associated activity of the homologous enzyme, BACE2. In vitro blood-brain barrier (BBB) assays revealed that P33 exhibits favorable transendothelial permeability. Intraperitoneal administration of P33 in APP/PS1 mice decreased Aβ levels, reduced amyloid plaque burden, and improved performance in a behavioral recognition task without inducing cytotoxicity, and with no overt histopathological or selected neuroinflammatory changes. These results define cis-γ-amino-L-proline peptides as a bioorganically distinct and modular scaffold for the development of intracellular modulators of Aβ production.},
}

@article {pmid42617572,
year = {2026},
author = {Tang, WX and Yang, C and Zhang, M and Kushida, CA and de Lecea, L and Li, SB},
title = {Sleep-wake control with age and neurodegenerative diseases.},
journal = {Sleep medicine reviews},
volume = {90},
number = {},
pages = {102352},
doi = {10.1016/j.smrv.2026.102352},
pmid = {42617572},
issn = {1532-2955},
abstract = {Aging causes dramatic alterations in bodily functions. Among them, sleep quality declines with age, particularly in individuals with neurodegenerative diseases. In this review, we first describe alterations in sleep-wake architecture and discuss potential mechanisms underlying sleep disorders that arise with age. We discuss evidence linking sleep disorders with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) syndrome. Even though the causes of AD, PD, PSP, and HD are diverse, several shared symptoms including difficulty falling asleep, fragmented sleep, and disrupted circadian rhythm collectively suggest their pathologies disrupt sleep-wake control. Hyperexcitability of implicated neurons is commonly observed prior to neurodegeneration. Upregulated neuronal excitability in the early phase of these diseases appears as a potential shared mechanism among neurodegenerative diseases. Abnormal protein accumulation and aggregation in these diseases exacerbate neuronal circuit hyperactivity by increasing neurons' intrinsic excitability or dampening inhibitory inputs to neurons controlling sleep-wake cycles. A better understanding of the mechanisms underlying sleep disorders that emerge with age may greatly benefit the development of novel preventative and therapeutic strategies for neurodegenerative diseases, and therefore improve the life quality of older adults.},
}

@article {pmid42617666,
year = {2026},
author = {Fide, E and Yerlikaya, D and Ada, E and Yener, G},
title = {Regionally heterogeneous gamma alterations and their diagnostic value in early-onset Alzheimer's disease.},
journal = {International journal of psychophysiology : official journal of the International Organization of Psychophysiology},
volume = {},
number = {},
pages = {113454},
doi = {10.1016/j.ijpsycho.2026.113454},
pmid = {42617666},
issn = {1872-7697},
abstract = {Growing evidence links amyloid accumulation to altered gamma activity, positioning gamma oscillations as a promising biomarker for Alzheimer's pathology. We examined resting state gamma activity in early-onset Alzheimer's disease (EOAD) patients confirmed by CSF biomarkers. We aim to provide a holistic view of gamma activity patterns in EOAD by integrating structural and functional neuroimaging. In this cross-sectional study, we compared gamma power and coherence-total gamma (30-48 Hz), and sub-bands (gamma-1: 30-35 Hz; gamma-2: 35-40 Hz; gamma-3: 40-48 Hz)- alongside gray matter volumes in EOAD patients (N = 24) and matched healthy controls (N = 24). We further assessed gamma-related changes in relation to CSF biomarkers, cognitive performance, and structural brain alterations. Finally, discriminant analysis evaluated classification performance of these measures. EOAD patients showed increased gamma power, with region-specific increases and decreases in coherence. Frontal gray matter volume negatively correlated with coherence, whereas posterior volumes showed positive correlations. A combined model of parietal gamma power and coherence achieved 83.3% classification accuracy, with a cross-validated accuracy of 77.1% (ROC-AUC = 0.844). Overall, we showed that the gamma activity does not follow a strict pattern in EOAD pathology. Gamma power is elevated, whereas connectivity patterns vary by brain region, closely mirroring structural brain alterations. These findings underscore the relevance of gamma activity in Alzheimer's research and open new avenues for future investigation. CLINICAL TRIAL REGISTRATION NUMBER: NCT05989087. NAME OF THE TRIAL REGISTRY: The Resting-state EEG Gamma Oscillations in Alzheimer's Disease.},
}

@article {pmid42617705,
year = {2026},
author = {Ling, Z and Xu, X and Cheng, Y and Liu, X and Ding, W and Zhu, Z and Wu, L and Chen, Y and Hu, P and Xia, L},
title = {Integrated multi-omics profiling identifies a convergent gut-metabolic-immune signature in Alzheimer's disease.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.08.023},
pmid = {42617705},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with rising global prevalence, yet the peripheral mechanisms linking gut dysbiosis, systemic redox imbalance, and immune activation remain poorly understood. Here, we performed integrated multi-omics profiling of fecal microbiome, serum metabolome, and circulating cytokines in 40 patients with AD and 40 cognitively matched controls, with a specific focus on oxidative stress and antioxidant signatures. Compared with controls, AD patients exhibited marked gut microbial dysbiosis characterized by butyrate-producing genera (including Faecalibacterium and Roseburia) and enrichment of pro-inflammatory taxa (including Escherichia/Shigella). Serum metabolomics identified a distinct oxidative stress phenotype: AD samples showed significantly elevated levels of xanthosine, (±)-3-hydroxynonanoic acid, and several acyl-carnitines, alongside a marked reduction in the antioxidant carotenoid capsorubin (AUC = 0.98) and other protective compounds. Lipid peroxidation products, including 15,16-epoxy-9,12-octadecadienoic acid and (Z)-5,8,11-trihydroxyoctadec-9-enoic acid, inversely correlated with cognitive scores (MMSE, Barthel Index, WAIS-IV). Concurrently, circulating pro-inflammatory cytokines (IL-8, MCP-1, IP-10, TNF-α) were elevated and correlated positively with both AD-enriched bacteria and oxidative metabolites, while showing negative correlations with antioxidant-related compounds. Integrated network analysis linked loss of butyrate-producing microbes to accumulation of oxidative stress biomarkers and heightened chemokine signaling, which together associated with worse cognitive performance. Selected microbial and redox-related metabolic features achieved excellent diagnostic accuracy (AUC > 0.95). Collectively, these findings define a convergent gut-metabolic-immune axis in AD where systemic oxidative stress serves as a central hub, providing specific, measurable redox biomarkers and mechanistic insights for noninvasive screening and therapeutic targeting.},
}

@article {pmid42617975,
year = {2026},
author = {Razi, P and Rashtiani, S and Rostampour, M and Rohampour, K and Jafari, A},
title = {Pharmacological evidence suggesting the involvement of autophagy-related signaling in the cognitive effects of neuropeptide Y in an amyloid-β-induced model of Alzheimer's disease.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116443},
doi = {10.1016/j.bbr.2026.116443},
pmid = {42617975},
issn = {1872-7549},
abstract = {INTRODUCTION: Neuropeptide Y (NPY) exerts neuroprotective effects; however, its functional relationship with autophagy-related signaling pathways in AD-associated cognitive dysfunction remains insufficiently understood. Using an Aβ-induced rat model of AD, the present study evaluated the effects of NPY on learning and memory. Specifically, we examined whether pharmacological manipulation with 3-methyladenine and MHY1485 modifies the cognitive effects of NPY, providing an indirect behavioral-pharmacological assessment of processes potentially related to autophagy and mTOR signaling.

METHODS: This experimental study was conducted on 88 male Wistar rats (200-250g) randomly divided to 11 groups (n = 8 per group). An intracerebroventricular (ICV) injection of Aβ (2µg/µl per rat) was used to induce the AD model. NPY (10ng /µl), MHY1485 (an mTOR activator; 2µM), and 3-methyladenine (3-MA; an autophagy inhibitor; 300 nmol, 30 nmol, and 3 µmol) were administered via ICV injection. Cognitive performance was assessed using the passive avoidance and Y-maze tasks.

RESULTS: NPY administration significantly decreased time spent in the dark compartment (TDC), increased step-through latency (STL) in the passive avoidance task, and enhanced spontaneous alternation behavior in the Y-maze (P < 0.05). Importantly, administration of MHY1485 and 3-MA (300nM), either alone or in combination, significantly attenuated the cognitive-enhancing effects of NPY (P < 0.05) CONCLUSION: NPY improved cognitive performance in an Aβ-induced rat model of Alzheimer's disease. Our behavioral-pharmacological findings suggest that autophagy-related signaling contributes to the memory-enhancing effects of NPY. Pharmacological modulation with 3-MA and MHY1485 provides functional evidence consistent with the potential involvement of Beclin-1- and mTOR-related signaling, although direct molecular confirmation warrants further investigation.},
}

@article {pmid42617977,
year = {2026},
author = {Liu, K and Zhang, XY and Wang, YT and Wang, SY and Jin, RH},
title = {Somatostatin expression is associated with mitochondrial-related gene expression in a brain region-specific manner: Evidence from human transcriptomic analysis.},
journal = {Behavioural brain research},
volume = {515},
number = {},
pages = {116444},
doi = {10.1016/j.bbr.2026.116444},
pmid = {42617977},
issn = {1872-7549},
abstract = {BACKGROUND: Somatostatin (SST) is a critical neuropeptide whose deficiency is implicated in schizophrenia, major depressive disorder, and Alzheimer's disease. Mitochondrial dysfunction is a convergent pathological mechanism in these conditions. However, whether SST expression is associated with mitochondrial-related gene expression in the human brain remains unexplored.

METHODS: We analyzed the GSE53987 dataset (n = 205 postmortem human brain samples across three regions: hippocampus, pre-frontal cortex, and associative striatum; four diagnostic groups: schizophrenia, bipolar disorder, major depressive disorder, and controls). SST expression was modeled as a continuous variable in linear regression models simultaneously adjusting for brain region, diagnosis, age, and sex. Analyses were performed both across all samples and within each brain region separately. Findings were examined for replication in GSE5281 (n = 161 non-demented control brain samples from six regions profiled by laser-capture microdissection).

RESULTS: After covariate adjustment, SST expression was significantly associated with BCL2 (adj.P = 6.49 × 10⁻⁴), MFN2 (adj.P = 1.76 × 10⁻³), and SOD2 (adj.P = 2.68 × 10⁻³). Brain region-stratified analyses revealed distinct patterns: hippocampus showed associations with SOD2, BCL2, and MFN2; pre-frontal cortex with BCL2, TFAM, ATP5A1, and PPARGC1A; associative striatum showed no significant associations. Analysis of GSE5281 showed similar region-specific SST-mitochondrial gene association patterns, with Superior Frontal Gyrus showing the strongest concordance (8/11 genes significant).

CONCLUSIONS: SST expression is associated with specific mitochondrial-related genes in a brain region-dependent manner. These hypothesis-generating findings warrant future experimental investigation of the SST-mitochondria relationship in neural tissue.},
}

@article {pmid42617979,
year = {2026},
author = {Pei, J and Perumal, NC and Meng, P and Long, Q and Palanisamy, CP},
title = {AI-assisted FTIR spectroscopic profiling of exosomes: Emerging frontiers in early detection of Alzheimer's disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103311},
doi = {10.1016/j.arr.2026.103311},
pmid = {42617979},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) remains one of the most challenging neurodegenerative disorders, primarily due to the lack of reliable tools for its early and non-invasive diagnosis. Exosomes, nanosized extracellular vesicles secreted by neural and peripheral cells, have emerged as promising biomarkers reflecting the molecular alterations associated with AD pathogenesis. Fourier Transform Infrared (FTIR) spectroscopy, with its capacity to capture unique biochemical fingerprints of biomolecules, provides a rapid, label-free, and cost-effective approach for exosome characterization. The recent integration of Artificial Intelligence (AI), particularly machine learning and deep learning algorithms, has significantly advanced the interpretation of complex FTIR spectra, enabling the identification of subtle spectral variations linked to disease progression. This review highlights the synergistic potential of AI-assisted FTIR spectroscopy for exosomal profiling in AD, discussing advances in spectral data analytics, biomarker discovery, and diagnostic modeling. Furthermore, it explores current challenges, technological gaps, and future perspectives toward establishing intelligent, exosome-based diagnostic frameworks for the early detection and personalized management of Alzheimer's disease.},
}

@article {pmid42618102,
year = {2026},
author = {Chen, J and Liang, Y and Xu, P and Kong, C and Zhang, Y and Zhou, R and Wu, O and Jiang, Z and Zhao, H and Song, M and Jiang, T and Pan, Y},
title = {A dual-enhanced magnetically separable SERS strategy enabled by Fe3O4@Au nanovilli and UiO-66-NH2 for ultrasensitive detection of p-tau217.},
journal = {Analytica chimica acta},
volume = {1419},
number = {},
pages = {345893},
doi = {10.1016/j.aca.2026.345893},
pmid = {42618102},
issn = {1873-4324},
mesh = {Spectrum Analysis, Raman/methods ; *tau Proteins/analysis/blood ; *Gold/chemistry ; Humans ; *Phthalic Acids/chemistry ; Limit of Detection ; *Metal-Organic Frameworks/chemistry ; Immunoassay/methods ; },
abstract = {BACKGROUND: The accurate detection of highly specific biomarkers like phosphorylated tau217 (p-tau217) is a prerequisite for realizing the early diagnosis of Alzheimer' s disease. However, the reliable monitoring of p-tau217 is still prohibited by its extremely low abundance in complex biological fluids with significant interference.

RESULTS: Herein, we propose a magnetically separable SERS-active sandwich immunosensor for the ultrasensitive detection of p-tau217. This design utilizes Fe3O4 submicrospheres enveloped by dense Au nanovilli (NVs) as capture substrates, and UiO-66-NH2 nanopolyhedron as SERS probes. Besides robust magnetic responsiveness, the Fe3O4@Au NVs architecture prepared by a seed-mediated growth strategy provides tremendous electromagnetic enhancement driven by abundant sharp protrusions, achieving an enhancement factor of 2.95 × 10[8]. Combined with this electromagnetic enhancement, the optimal UiO-66-NH2 probe offers an expansive mesoporous surface area for physical enrichment and immobilization of Raman reporters to effectively prevent its desorption, while further amplifies signals through chemical enhancement via photo-induced charge transfer. Benefiting from the synergistic enhancement effect, this platform based on a typical sandwich immunosensor achieves a remarkable enhancement factor of 7.39 × 10[8], enabling the trace detection of p-tau217 with an exceptional limit of detection down to 3.80 × 10[-9] mg/mL in cerebrospinal fluid.

SIGNIFICANCE: This work establishes an ultrasensitive and magnetically separable SERS platform for the trace detection of p-tau217, which highlights the broad potential of synergizing hierarchical magnetic substrates with mesoporous metal-organic framework probes in clinical diagnostics.},
}

Spectrum Analysis, Raman/methods
*tau Proteins/analysis/blood
*Gold/chemistry
Humans
*Phthalic Acids/chemistry
Limit of Detection
*Metal-Organic Frameworks/chemistry
Immunoassay/methods

@article {pmid42618108,
year = {2026},
author = {Deng, Z and Wang, Y and Liu, L and Guo, X and Zhu, H and Dong, M and Ge, Y and Yu, Y and Ye, M},
title = {A robust HPLC-HILIC enrichment system for O-glycoproteomics profiling of plasma and cerebrospinal fluid across Alzheimer's disease progression.},
journal = {Analytica chimica acta},
volume = {1419},
number = {},
pages = {345899},
doi = {10.1016/j.aca.2026.345899},
pmid = {42618108},
issn = {1873-4324},
mesh = {Humans ; *Alzheimer Disease/blood/cerebrospinal fluid ; Chromatography, High Pressure Liquid/methods ; *Proteomics/methods ; Glycosylation ; *Glycoproteins/blood/cerebrospinal fluid ; Disease Progression ; Hydrophobic and Hydrophilic Interactions ; *Glycopeptides/blood/cerebrospinal fluid ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) pathogenesis involves widespread molecular alterations in both brain tissue and peripheral biofluids, yet the role of protein O-linked glycosylation in disease progression remains poorly characterized due to technical limitations in comprehensive O-glycoproteome profiling.

RESULTS: To address this gap, we developed a robust high-performance liquid chromatography-hydrophilic interaction chromatography (HPLC-HILIC) system optimized for efficient enrichment of intact O-glycopeptides from protein digests of complex biological matrices. This system was applied to characterize the O-glycoproteomes of plasma samples across different stages of AD progression, as well as those of cerebrospinal fluid (CSF) from AD patients. Notably, in plasma, it was found that fucosylated glycopeptides were down-regulated and sialylated glycopeptides were up-regulated as the disease progressed. In contrast, CSF samples exhibited an increased number of O-glycopeptides, accompanied by higher levels of sialylation. Furthermore, analysis of O-glycosylation patterns in AD CSF and plasma following blood-brain barrier disruption revealed increased O-glycosylation of ITIH4 (Q14624) and SERPINA5 (P05154) in plasma, and enhanced sialylated O-glycosylation of APOE (P02649) in CSF. These observations suggest that sialylated O- glycosylation may play a crucial role in the pathology of AD.

SIGNIFICANCE: Collectively, a robust O-glycoproteomic workflow was presented to investigate O-glycosylation patterns between CSF and plasma in AD. The results provide valuable insights into the involvement of O-glycosylation in AD progression and highlight the potential of this analytical platform for studying O-glycosylation dynamics in AD and other neurodegenerative disorders.},
}

Humans
*Alzheimer Disease/blood/cerebrospinal fluid
Chromatography, High Pressure Liquid/methods
*Proteomics/methods
Glycosylation
*Glycoproteins/blood/cerebrospinal fluid
Disease Progression
Hydrophobic and Hydrophilic Interactions
*Glycopeptides/blood/cerebrospinal fluid