@article {pmid42097504,
year = {2026},
author = {Agüero, P and Gómez Tortosa, E},
title = {ADAM10 and its role in Alzheimer disease.},
journal = {Neurologia},
volume = {},
number = {},
pages = {502083},
doi = {10.1016/j.nrleng.2026.502083},
pmid = {42097504},
issn = {2173-5808},
abstract = {BACKGROUND: The amyloidogenic pathway of amyloid precursor protein (APP) processing is well known in the pathogenesis and therapeutics of Alzheimer disease (AD), whereas the non-amyloidogenic pathway has been less studied. ADAM10 is the main α-secretase responsible for this pathway in the human brain.

CONTENT: ADAM10 belongs to a family of transmembrane proteins with catalytic activity. It acts as an α-secretase on APP and many other substrates, some of which are particularly relevant in the central nervous system. The ADAM10 gene has been identified in genome-wide association studies of patients with AD; mutations have been reported in families with strong functional support but incomplete segregation; and haploinsufficiency has been reported in a family carrying a nonsense mutation. However, genetic studies of AD cohorts have not identified causal variants. ADAM10 levels in biological fluids show conflicting results, except in platelets, where patients with AD consistently exhibit reduced levels. Stimulation of ADAM10 as a therapeutic target offers new opportunities through various components and such measures as physical exercise. However, only one (positive) clinical trial has been published to date, using the retinoid acitretin.

CONCLUSIONS: ADAM10 plays a fundamental role in brain function, and sufficient studies support its involvement in AD pathogenesis. There are only isolated examples of ADAM10 mutations as a genetic cause, but these encourage continued screening in familial AD. ADAM10 levels in platelets could be considered as a biomarker. The enhancement of ADAM10 expression in AD remains a therapeutic target that requires further research.},
}

@article {pmid42097853,
year = {2026},
author = {Rohatgi, S and Omid-Fard, N and Zhu, S and Martinez Imbett, RE and Ford, JN and Dowling, TP and Kirsch, JE and Romero, JM},
title = {Relationship of Inferior Frontal Sulcal Hyperintensities with Amyloid-Related Imaging Abnormalities.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9395},
pmid = {42097853},
issn = {1936-959X},
abstract = {OBJECTIVE: Anti-amyloid immunotherapies used to treat Alzheimer's disease (AD) are often associated with amyloid-related imaging abnormalities (ARIA). We aim to indirectly assess glymphatic function by using inferior frontal sulcal hyperintensity (IFSH) as a biomarker in patients receiving anti-amyloid therapy, both with and without ARIA, as well as in healthy controls. We hypothesize that patients who develop ARIA will have higher IFSH scores than non-ARIA patients and healthy controls.

METHODS: Eligible AD patients who received anti-amyloid treatment were included in our retrospectively collected dataset. Only scans performed at 3T were used. Inter-rater reliability was evaluated and statistical analyses of IFSH scores and demographic data were performed to compare between groups. Additionally, within-subject analysis was used to compare the baseline and ARIA scans. Significance set at P < 0.05.

RESULTS: A total of 104 patients were selected based on the study criteria, of whom 60 had a clinical diagnosis of dementia. 36 patients developed ARIA, while 24 did not develop ARIA. 23 were age-matched healthy controls, and 21 were young healthy controls. Inter-rater reliability between the two readers was concordant when using quadratic weights appropriate for ordinal data (κ (w) = 0. 91, 95% CI 0.86-0.95). IFSH was significantly higher in the older age cohorts compared to young healthy controls (median 3.5 [IQR 2.5-5] versus 0 [0-1], P<0.001), with no significant difference between the dementia and healthy elderly groups (3.25 [3-4.875] versus 3.5 [2.5-5]). Among dementia patients on anti-amyloid therapy, significantly higher IFSH was observed in ARIA patients (at time of ARIA scan) compared to their non-ARIA counterparts (3.75 [3-5] versus 3 [2-4], P= 0.04). There was no significant difference in IFSH score between baseline and ARIA scans (P = 0.16).

CONCLUSION: IFSH was higher among dementia patients on anti-amyloid therapy with ARIA than among their non-ARIA counterparts. This supports its role as a potential biomarker of glymphatic dysfunction, although its utility on an individual basis is limited. Future prospective studies could benefit from incorporating IFSH as a variable, particularly if glymphatic therapies become a reality.},
}

@article {pmid42097981,
year = {2026},
author = {Tammaro, P and Hashitani, H},
title = {Calcium-activated chloride channels in pericytes and their role in regulating organ blood flow.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP287607},
pmid = {42097981},
issn = {1469-7793},
support = {MR/X010511/1/MRC_/Medical Research Council/United Kingdom ; 23K08767//Japan Society for Promotion of Sciences/ ; },
abstract = {Pericytes are mural cells of the microvasculature, characterised by a distinctive 'bump-on-a-log' morphology and elongated processes extending along the abluminal surface of capillary and pre- and post-capillary segments. They are widely distributed across organs and exhibit functional heterogeneity. Contractile pericytes directly regulate local blood flow, whereas non-contractile pericytes contribute to electrical signalling by generating depolarising or hyperpolarising events that propagate to upstream vessels and coordinate tissue perfusion. These functions are closely linked to intracellular ion homeostasis. Recent evidence highlights a role for Ca[2+]-activated Cl[-] channels (CaCCs), particularly TMEM16A (ANO1), in coupling intracellular Ca[2] [+] signals to membrane depolarisation and pericyte activity. In contractile pericytes, TMEM16A-mediated currents promote depolarisation to activate L-type voltage-gated Ca[2] [+] channels, facilitating Ca[2+] entry to support contraction. In non-contractile capillary pericytes, periodically generated TMEM16A-dependent depolarisations contribute to the initiation and propagation of spontaneous electrical activity, supporting intercellular synchrony within microvascular networks. Alternatively, asynchronous TMEM16A-dependent depolarisations could sum with each other to maintain resting membrane potentials and basal vascular tone. In this review, we summarise current understanding of CaCC channel function in pericytes across organs, and discuss emerging directions for future research and therapeutic targeting.},
}

@article {pmid42098313,
year = {2026},
author = {Shinagawa, S and Onuki, K and Shimizu, K},
title = {Physicians' perceptions and treatment practices for agitation associated with Alzheimer's dementia vary by specialty in Japan.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-51118-5},
pmid = {42098313},
issn = {2045-2322},
support = {NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; },
abstract = {Agitation, a behavioural and psychological symptom of dementia, is under-recognized in Japan. To describe the physician's perceptions and treatment practice for agitation in Alzheimer's dementia (AAD) in Japan, we conducted a cross-sectional web-based survey in October 2024. The survey included physicians in neurology, neurosurgery, psychiatry, or general internal medicine who were registered with the survey panel; consented to participation; affiliated with hospitals or clinics; treating ≥ 10 people with Alzheimer's dementia (AD)/month. Responses from 529 physicians showed that they treated an average of 35.0 people with AD per month, of whom 8.4 (24%) had AAD. When asked what "agitation" brought to mind, physicians most commonly selected the Japanese term for "excitability", corresponding to the "agitation/aggression" item in the Neuropsychiatric Inventory (58.6%). In general internal medicine, 24.2% were unaware of agitation. Anti-dementia drugs (91.7%) were most frequently selected as new medications for AD, whereas in psychiatry, antipsychotics were most frequently selected (95.8%), and side effects were cited more often as a key consideration than in other specialties. These results suggest that perceptions and treatment practices vary by specialty, particularly reflected in common antipsychotic prescriptions with higher safety awareness among psychiatrists and limited recognition of AAD in others, especially in general internal medicine.},
}

@article {pmid42098470,
year = {2026},
author = {Elghanam, Y and Kim, E},
title = {Evaluating the clinical effects of GLP-1 receptor agonists for Alzheimer's and Parkinson's diseases using minimal clinically important difference: systematic review and meta-analysis.},
journal = {Archives of pharmacal research},
volume = {},
number = {},
pages = {},
pmid = {42098470},
issn = {1976-3786},
support = {NRF-2021R1F1A1062044//Ministry of Science and ICT/ ; NRF-2021R1A6A1A03044296//Ministry of Education/ ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are promising candidates for Alzheimer's disease (AD) and Parkinson's disease (PD). However, their effects in non-diabetic populations, independent of metabolic confounding, remain unclear. We evaluated the effects of GLP-1RAs on cognition, clinical outcomes, biomarkers, and safety in non-diabetic individuals with PD, AD, and mild cognitive impairment. We assessed the clinical meaningfulness of these effects using minimal clinically important difference thresholds. Relevant studies were retrieved from PubMed, Embase, and Web of Science from inception to November 2025. A random-effects meta-analysis was applied to calculate standardized mean differences (SMDs), mean differences (MDs), and risk ratios with 95% confidence intervals (CIs). The protocol was registered in PROSPERO (CRD420261277032). Fourteen randomized controlled trials enrolling 1260 participants were included. GLP-1RAs showed a small statistically significant improvement in global cognition (SMD 0.14, 95% CI 0.01 to 0.27; I[2] = 7%), supported by high-certainty evidence. Despite statistical significance, findings suggest only a trivial probability (1%) of a clinically important benefit. Conversely, GLP-1RAs were associated with poorer verbal fluency (SMD - 0.43, 95% CI - 0.79 to - 0.08; I[2] = 0%), supported by high-certainty evidence. For clinical severity, function, depression, and PD-related outcomes, pooled estimates generally favored GLP-1RAs, but none reached statistical significance. A significant between-disease subgroup difference was observed for function. In the PD subgroup, GLP-1RAs significantly improved depression symptoms relative to control (MD - 2.09, 95% CI - 3.99 to - 0.20; I[2] = 0%). Nevertheless, this magnitude of improvement remained below the threshold for clinically important benefit. Biomarker findings were inconsistent across trials. GLP-1RAs significantly reduced weight and were associated with poorer tolerability and increased gastrointestinal adverse events. Current evidence provides no convincing support for a clinically meaningful or disease-modifying effect of GLP-1RAs, and adverse effects may limit their clinical utility. Large-scale trials are needed to definitively weigh potential benefits against associated risks.},
}

@article {pmid42098564,
year = {2026},
author = {Oriquat, G and Hamed Ahmed, M and Al-Hasnaawei, S and Malathi, H and Mishra, S and Nanda, A and Arora, V and Chauhan, AS},
title = {Bridging neuroinflammation, oxidative stress, and neurogenesis: aromatic turmerone as a multifunctional modulator via NF-κB and Nrf2 pathways.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42098564},
issn = {1568-5608},
abstract = {Neuroinflammation and oxidative stress are central mechanisms driving neurodegenerative diseases, while impaired neurogenesis limits regeneration. Aromatic-turmerone (ar-turmerone), a bioactive sesquiterpenoid from Curcuma longa, has emerged as a multifunctional neuroprotective agent capable of modulating inflammatory and regenerative processes simultaneously. Evidence from in vitro and in vivo models demonstrates that ar-turmerone suppresses Toll-like receptor 4 (TLR4)-dependent NF-κB and MAPK signaling, thereby reducing microglial activation, nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines (TNF-α, IL-1β, IL-6). Concurrently, it activates the Nrf2/HO-1 antioxidant pathway and enhances cAMP/PKA-CREB signaling, restoring redox homeostasis and promoting neuronal survival. Importantly, ar-turmerone drives microglial polarization toward the M2 anti-inflammatory phenotype and stimulates neural stem cell (NSC) proliferation and neuronal differentiation in the subventricular zone and hippocampus. These dual anti-inflammatory and neurogenic actions position ar-turmerone as a unique bridge between neuroinflammation suppression and neuroregeneration enhancement. Recent structure-activity relationship studies further reveal that N-substituted amide and naphthyl derivatives exhibit superior inhibition of NO and TNF-α release and improved neuroprotective potency in Alzheimer's and Parkinson's disease models. Collectively, ar-turmerone represents a promising multi-target natural scaffold for developing therapeutics that counteract neurodegeneration by simultaneously modulating microglial activation, oxidative stress, and endogenous neurogenesis.},
}

@article {pmid42098640,
year = {2026},
author = {Mao, X and Zhang, D and Ying, D and Yu, J and Ge, Y and Jia, Z},
title = {Integration of glymphatic system function and hippocampal radiomics for diagnosis and conversion prediction of Alzheimer's disease.},
journal = {BMC medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12880-026-02390-4},
pmid = {42098640},
issn = {1471-2342},
support = {SJCX24_2048//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; YJXYY202204-YSB73//Jiangsu Provincial Research Hospital/ ; BJ23030//Jiangsu Provincial Health Commission/ ; },
abstract = {BACKGROUND: Glymphatic system (GS) function and hippocampal microstructural changes are promising imaging markers of Alzheimer's disease (AD). This study aims to investigate the effectiveness of combining diffusion tensor image analysis along the perivascular space (DTI-ALPS) with hippocampal radiomics for diagnosing AD, and to develop an innovative multivariable model integrating hippocampal radiomics and clinical biomarkers for predicting mild cognitive impairment (MCI) progression.

METHODS: We included three cohorts from two databases retrospectively, using an internal (n = 210) and an external dataset (n = 430) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The ALPS index was employed to measure GS function, and 3D-T1WI hippocampal radiomics features were extracted to construct machine learning models for classifying and diagnosing AD. Conversion of MCI to AD was assessed through integrating the hippocampal radiomics features, ALPS index, and AD-related clinical biomarkers.

RESULTS: The ALPS index was lower in patients with AD than in healthy controls (HCs) in both the internal and external cohorts (p < 0.001). The combined hippocampal radiomics features and ALPS index model demonstrated good performance in AD classification. The multivariable prediction model of MCI progression to AD achieved an area under the curve of 0.97 and 0.92 for the training and testing cohorts, respectively.

CONCLUSIONS: Integrated ALPS index and hippocampal-based radiomics features can improve diagnostic performance in patients with AD, showing predictive capability for identifying the MCI conversion.},
}

@article {pmid42098663,
year = {2026},
author = {Tian, S and Lin, G and Zeng, Y and Wang, Q and Lin, Y and Yao, K and Wang, Z and Xiao, Z and Chen, J and Zheng, Y and Tan, H and Wu, Z and Yang, M and Xu, D and Li, X and Lao, J and Liang, S and Chen, Y and Liu, Q and Li, J and Gan, Y and Zeng, M and Chen, B and Ning, Y and Zhong, X},
title = {A multifeature machine learning and resting-state EEG study reveals differences in beta oscillation in late-life depression with or without mild cognitive impairment.},
journal = {BMC psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12888-026-08126-6},
pmid = {42098663},
issn = {1471-244X},
support = {2023B0303010003//Guangdong Province Key Areas Research and Development Programs-Brain Science and Brain-Inspired Intelligence Technology/ ; 2023HT022//Industry-University-Research Innovation Fund for Chinese Universities/ ; 2023B03J1296//Guangzhou Key Research and Development Program/ ; 20232A010014//Guangzhou Traditional Chinese Medicine and Integrated Traditional Chinese and Western Medicine Science and Technology Project/ ; 202201010491//Basic and Applied Basic Research Project of Guangzhou Basic Research Program/ ; Comprehensive Department of the National Administration of Traditional Chinese Medicine [2024] No. 3//National Traditional Chinese and Western Medicine Collaborative Project for Major and Complex Diseases/ ; Comprehensive Department of the National Administration of Traditional Chinese Medicine [2024] No. 221//National Integrated Traditional Chinese and Western Medicine "Flagship" Department Construction Project/ ; },
abstract = {BACKGROUND: Late-life depression (LLD) often co-occurs with mild cognitive impairment (MCI), and patients with LLD and MCI (LLD-MCI) have an increased risk of progression to Alzheimer's disease (AD). However, differences in resting-state neural oscillation and cognitive impairment in LLD patients remain unclear. In this cross-sectional study, electroencephalography (EEG) was used to analyse, local rhythm activity and large-scale network communication to differentiate LLD patients with and without MCI.

METHODS: We enrolled 113 participants: 74 with LLD (50 with LLD-MCI and 24 with LLD-non-MCI) and 39 healthy older adults (HOAs). All participants underwent comprehensive neuropsychological assessments. Spectral power and source-level functional connectivity (Phase-Locking Value, PLV) were analysed across multiple frequency bands. A machine learning framework using nested stratified cross-validation was implemented to evaluate the potential of EEG features in classifying LLD clinical subtypes.

RESULTS: LLD-MCI patients exhibited a distinct dissociation in the beta band: significantly reduced spectral power in the left frontal cortex contrasted with extensive hyperconnectivity primarily centred on the right lateral orbitofrontal cortex (rLOFC). Complementary analyses also revealed widespread hyperconnectivity in the theta band in the LLD-MCI group. The Linear Discriminant Analysis (LDA) model achieved superior performance in distinguishing LLD-MCI patients from LLD-non-MCI patients, with an area under the curve (AUC) of 0.82 and an accuracy of 78.38%. Feature importance analysis revealed rLOFC-mediated beta synchronisation as the most discriminative biomarker.

CONCLUSION: Our findings suggest that beta-band oscillatory disruption-characterised by local power deficits and network hyperconnectivity-may represent a potential neurobiological signature of cognitive vulnerability in LLD patients. Whether this hyperconnectivity reflects a compensatory or pathological process remains a hypothesis for further validation. EEG metrics provide significant diagnostic value for the precise clinical subtyping and early identification of cognitive decline in the LLD population.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid42098771,
year = {2026},
author = {Badot, C and Bini, A and Duplan, E and Checler, F and Lauritzen, I},
title = {Functional relationships linking C99/APP-βCTF dimerization, proteostasis disruption, and organelle dysfunction.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02928-7},
pmid = {42098771},
issn = {1478-811X},
abstract = {BACKGROUND: The amyloid β (Aβ) precursor C99 (or APP-βCTF) accumulates in Alzheimer's disease and has been proposed to display Aβ-independent toxicity, notably by affecting the endosomal-lysosomal-autophagic (ELA) network. Our previous findings suggested that some ELA-associated C99 could correspond to dimeric and oligomeric species, but the intracellular sites of C99 dimerization, as well as the toxicity linked to it, remains unknown.

METHODS: We here developed a bimolecular fluorescence complementation (BiFC) probe to visualize de novo C99 dimerization and dimer trafficking, as well as to identify possible cellular responses specifically linked to C99 dimerization. Moreover, to confirm dimer localizations and toxicities, the localization and cellular effects of the dimerization mutant C99[G29L/G33L] was compared to that of wildtype C99. The C99 constructs were transfected into HeLa cells and dimer localizations, expression levels and intracellular toxicities were evaluated by Western blot and immunocytochemistry.

RESULTS: BiFC-C99 dimers were first detected within the TGN, in which monomers initially accumulate. The proteasomal inhibitor MG-132 led to increased dimer formation, indicating that the proteasomal activity status is a key determinant of C99 dimerization. Conversely, TGN-associated C99 dimerization had a negative impact on both the ubiquitin-proteasome system (UPS) and the TGN, as highlighted by the appearance of p62/SQSTM1-positive aggresomes and fragmented Golgi, then suggesting a two-way relationship between UPS function and C99 dimerization. Dimerization also led to lysosome repositioning and to the accumulation of LC3B-positive autophagy vesicles, agreeing with the well-known interplay between autophagy and proteasome in protein turnover. P62/SQSTM1 and LC3B accumulation could similarly be observed in cells expressing C99[G29L/G33L], a mutant favoring dimerization, while this was not the case in wildtype C99 expressing cells, confirming the dimerization-specific effect. While proteasomal inhibition caused TGN-associated dimer formation, repression of γ-secretase-mediated C99 proteolysis instead led to a redistribution of monomers to EEA1-positive endosomes, whereas already existing C99 dimers remained unaffected by this treatment. These new endosome-associated monomers were found also to dimerize, resulting in dimers destined for either secretion via small extracellular vesicles or autophagy-lysosomal degradation.

CONCLUSIONS: Taken together, our findings indicate that the cellular status of UPS, autophagy and γ-secretase activities are all determinant for C99 expression levels, and are thus crucial for both the level of C99 dimerization and for the fate of the dimers. Moreover, our data show that C99 dimerization itself negatively affects these activities thereby indicating a two-way relationship between C99 dimerization, proteostasis disruption and organelle dysfunction.},
}

@article {pmid42098772,
year = {2026},
author = {Laing, KK and Fialova, N and Wardlaw, J and Montagne, A},
title = {Impact of Apolipoprotein E4 on blood-brain barrier integrity in target replacement murine models: a systematic review and meta-analysis.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02018-3},
pmid = {42098772},
issn = {1758-9193},
abstract = {BACKGROUND: The E4 variant of Apolipoprotein E (APOE) is a primary genetic susceptibility risk factor for late-onset Alzheimer's disease and has been implicated in cerebrovascular dysfunction. Preclinical mouse models are widely used to study APOE4, but cohesive understanding of APOE's role is still inconsistent and lacking. The aim of this study was to systematically review and synthesise evidence from preclinical mouse studies assessing APOE4 related effects on blood-brain barrier (BBB) integrity, vascular morphology and cerebral blood flow (CBF). MAIN: A systematic search of MEDLINE, Embase, Scopus, and Web of Science was conducted (March-April 2025). Eligible studies included transgenic APOE-targeted replacement or knock-in mice reporting vascular outcomes (cerebral blood flow, blood brain barrier permeability, vascular measures). Risk of bias was assessed using SYRCLE and reporting quality with CAMARADES. Random-effects meta-analyses were conducted (where sufficient data was available), otherwise findings were narratively synthesised. Eighteen studies met inclusion. Outcome measures varied widely, including diverse approaches to CBF measurement (e.g. arterial spin labelling, autoradiography, DSC-MRI), immunohistochemical measures (e.g. collagen-IV, laminin, CD31), and diverse approaches to measurement of BBB leakage (e.g. fibronectin, fibrinogen, gadolinium-based ktrans). Seven studies contributed to meta-analysis: APOE4 mice showed a consistent reduction in CBF associated with APOE4 genotype (SMD = -2.87, 95% CI: -5.14 to -0.604, df = 2.66), and a negative non-significant trend towards reduced vascular morphology expression. Narrative synthesis identified three key mechanistic pathways linking APOE4 to vascular dysfunction: (i) insulin resistance and PI3K/AKT-mTOR signalling, (ii) Cyclophilin A-NFκB-MMP9 activation, and (iii) occludin/ECM remodelling. Risk of bias assessment revealed frequent shortcomings in randomisation, blinding, and sample size justification.

CONCLUSIONS: Preclinical evidence demonstrates that APOE4 drives alterations in vascular functioning primarily through involvement with pathways related to vascular metabolism, ECM remodelling and BBB leakage. However, heterogeneity in the model (e.g. age, sex, techniques), restricts direct comparability across studies. As such, standardisation or clarification of methodological approaches are necessary for rigorous assessment in the future.},
}

@article {pmid42098850,
year = {2026},
author = {Tarawneh, R and Moulder, KL and Topouza, DG and Kar, A and Qian, HT and Pankratz, VS and Timsina, J and Franklin, EE and Schindler, SE and Perrin, RJ and Ances, BM and Benzinger, TLS and Hassenstab, J and Morris, JC and Holtzman, DM and Cruchaga, C},
title = {Early syndecan-4 upregulation predicts cognitive and pathological trajectories in Alzheimer disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02043-2},
pmid = {42098850},
issn = {1758-9193},
support = {RF1AG083744/NH/NIH HHS/United States ; NCI P30CA118100-16/NH/NIH HHS/United States ; P30NS048056/NH/NIH HHS/United States ; P01AG03991/NH/NIH HHS/United States ; P01AG03991/NH/NIH HHS/United States ; R01AG044546/NH/NIH HHS/United States ; (P19-00559) for the Washington University-Centene ARCH Personalized Medicine Initiative//Centene Corporation/ ; },
abstract = {BACKGROUND: Brain endothelial dysfunction is an early pathological feature of Alzheimer disease (AD). We here investigate associations of the brain endothelial glycocalyx protein, syndecan-4 (SDC4), with amyloid and tau pathologies and cognitive impairment in a large longitudinal cohort of AD and controls.

METHODS: The study included n = 1,041 (n = 802 cognitively unimpaired and n = 239 cognitively impaired) participants who underwent biological classification using the NIA-AA "ATN" framework. Cognitive assessments included the Clinical Dementia Rating[®]-sum of boxes and the Knight- Preclinical Alzheimer's Cognitive Composite. Cerebrospinal fluid (CSF) measures of SDC4 and emerging AD biomarkers were obtained using Olink Proteomics. Amyloid-PET (n = 719) and tau-PET (n = 302) scans were performed in subsets of participants. Partial correlations and linear mixed models, respectively, examined cross-sectional and longitudinal associations of CSF SDC4 levels with amyloid-PET and tau-PET burden and cognition. Pseudo-time models estimated CSF biomarker trajectories across the course of AD progression.

RESULTS: CSF SDC4 levels were elevated in even the earliest preclinical stages of AD compared to controls and were closely associated with other CSF and imaging biomarkers of AD. Higher CSF SDC4 levels correlated with higher global and regional amyloid-PET and tau-PET burden and worse baseline cognition. Higher baseline CSF SDC4 levels predicted more rapid progression of brain amyloid and tau, and faster decline in global cognition, episodic memory, language, and executive functions over follow-up (mean, 8 years). CSF SDC4 associations with cognition were mainly mediated by global tau-PET burden. Importantly, our pseudo-time models estimate that SDC4 upregulation begins very early in AD pathogenesis near the point of amyloid-positivity and increases more robustly following the point of tau-positivity. SDC4 was among the top 10 most important proteins in predicting the pseudo-time models of AD progression and predicted these models to a potentially better extent than other emerging AD biomarkers.

CONCLUSION: Findings from this large longitudinal study suggest that CSF SDC4 levels are increased in the earliest preclinical stages of AD and are closely associated with the progression of amyloid and tau pathologies and future rates of cognitive decline. We propose that SDC4 upregulation is an important early event in AD pathogenesis which predicts cognitive and pathological disease trajectories.},
}

@article {pmid42099051,
year = {2026},
author = {Pereira da Silva, AM and Haddad Santos, D},
title = {Methodological considerations on the network meta-analysis of brexpiprazole dosing for agitation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449394},
doi = {10.1177/13872877261449394},
pmid = {42099051},
issn = {1875-8908},
}

@article {pmid42099104,
year = {2026},
author = {Oriquat, G and Jasim, IK and Gajjar, TB and Hanumanthayya, M and Abdulhameed Ahmad, I and Singh, G and Maharana, L and Bainsal, N},
title = {SUMOylation in Neural Health and Disease: From Cellular Homeostasis to Neurodegeneration.},
journal = {DNA and cell biology},
volume = {},
number = {},
pages = {10445498261444640},
doi = {10.1177/10445498261444640},
pmid = {42099104},
issn = {1557-7430},
abstract = {Neurodegenerative diseases (NDDs) represent a growing global health burden, particularly in aging populations. These disorders primarily affect neurons and are characterized by progressive neuronal dysfunction and loss within specific regions of the central nervous system. Major NDDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and stroke. Although each disorder exhibits distinct genetic backgrounds and pathological protein aggregates, they share common pathogenic mechanisms, including chronic neuroinflammation, impaired autophagy and mitophagy, disrupted proteostasis, telomere instability, and epigenetic alterations. A hallmark feature across NDDs is the accumulation of misfolded proteins, leading to synaptic dysfunction and neuronal degeneration. Small ubiquitin-like modifiers (SUMOs) are a family of ∼100 amino acid proteins, including SUMO1 and the closely related SUMO2/3 isoforms. SUMOylation is a dynamic posttranslational modification that regulates protein function through the covalent attachment or removal of SUMO moieties. This reversible process is mediated by SUMO-specific E1 activating, E2 conjugating, and E3 ligating enzymes and is counterbalanced by SUMO/Sentrin-specific proteases. The SUMOylation status of target proteins depends on the tightly controlled balance between conjugation and deconjugation systems. Acting as a molecular switch, SUMOylation modulates diverse cellular processes such as DNA damage repair, RNA metabolism, transcriptional regulation, and protein quality control, all of which are essential for maintaining cellular homeostasis. Accumulating evidence links dysregulated SUMOylation to the pathogenesis of multiple neurological disorders, including polyglutamine and synucleinopathies. SUMOylation influences neuroinflammation, oxidative stress, protein aggregation, neuroangiogenesis, ischemic injury, and demyelination. This review highlights recent advances in understanding the role of SUMOylation in NDDs and explores its potential as a promising therapeutic target.},
}

@article {pmid42099124,
year = {2026},
author = {Cheng, B and Wei, W and Cheng, S and Yang, X and Pan, C and He, D and Feng, J and Zhang, F},
title = {Dynamic comorbidity trajectories spanning the diagnosis of depression: nationwide cohort study.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-8},
doi = {10.1192/bjp.2026.10638},
pmid = {42099124},
issn = {1472-1465},
abstract = {BACKGROUND: Depression is often accompanied by multisystem comorbidities, but the time trajectories of these comorbidities remain unclear.

AIMS: We aimed to define the temporal sequence of comorbidity accrual relative to depression diagnosis, and examine how this trajectory differs in recurrent depression.

METHOD: A total of 32 953 individuals with depression were identified in the UK Biobank cohort, including 2402 with recurrent depression. The time between diagnosis of depression or recurrent depression and ten common comorbidities was established to determine the temporal order and rate of comorbidity diagnosis in relation to depression, based on the sequence of recorded diagnostic events. We further stratified the cohort by polygenic risk score, gender, age and history of antidepressant or antihypertensive medication use.

RESULTS: The study included 32 953 participants (mean age at diagnosis 52.6 years; 63.1% female). Hypertension and dorsopathies preceded depression diagnosis by a median of 2.6 years (interquartile range (IQR) -7.0 to 0.0) and 1.0 year (IQR -5.0 to 2.0), respectively. Alzheimer's disease and obesity emerged after diagnosis at medians of 2.5 years (IQR 0.0-5.0) and 0.8 years (IQR -2.0 to 3.0). High genetic risk was associated with an earlier onset of pre-depression cardiometabolic conditions, with hypertension occurring 2.8 years before diagnosis in individuals with a high polygenic risk score compared with 2.3 years in individuals with a low polygenic risk score. Crucially, individuals with recurrent depression exhibited a profoundly different trajectory, with most comorbidities manifesting many years after the index diagnosis. Stratification by medication history indicated that antihypertensive drug use was associated with an earlier recorded diagnosis of cardiometabolic conditions, whereas antidepressant use was linked to a later diagnosis of neurodegenerative diseases.

CONCLUSIONS: These findings identify three critical windows for intervention and reveal a distinct, delayed comorbidity trajectory in recurrent depression. This underscores the need for long-term, integrated surveillance strategies tailored to depression subtype and treatment history.},
}

@article {pmid42099162,
year = {2026},
author = {Kurmi, S and Shirodkar, S and Parab, SB and Doshi, G},
title = {A Multimodal Framework for Alzheimer's Prevention: Diet, Exercise, Fasting, Sleep, and Gut Microbiota.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050467997260323164241},
pmid = {42099162},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) and related dementias arise from a multifactorial interplay of genetic susceptibility, metabolic dysfunction, neuroinflammation, and lifestyle determinants. With limited disease-modifying pharmacotherapies, lifestyle interventions have emerged as compelling, evidence-based avenues for prevention and early management. This review integrates mechanistic, translational, and clinical insights on major modifiable behaviours, physical activity, diet, intermittent fasting, sleep regulation, and gut-microbiome-based approaches that collectively shape cognitive ageing. Aerobic, anaerobic, and resistance exercises exert neuroprotective effects by activating BDNF-TrkB signalling, enhancing hippocampal neurogenesis, improving synaptic plasticity, and stimulating peripheral myokines (CTSB, IGF-1, GPLD1) that cross the blood-brain barrier to support neuronal resilience. Dietary interventions such as the Mediterranean, Mediterranean- DASH Intervention for Neurodegenerative Delay (MIND), and ketogenic diets mitigate AD pathology by reducing oxidative stress, inhibiting Aβ deposition, improving mitochondrial efficiency, and modulating APOE4-linked metabolic vulnerability. Intermittent fasting induces a metabolic shift toward ketone utilisation, activates autophagy pathways (AMPK, SIRT3, Nrf2), remodels the gut microbiome, and promotes angiogenesis through GDF11 signalling. The gut-brain axis contributes to cognitive health through microbial metabolites, such as Short-Chain Fatty Acids (SCFAs), tryptophan derivatives, modulation of neuroinflammation, and enhanced neuronal survival. Meanwhile, sleep quality, particularly slow-wave sleep, optimises glymphatic clearance and prevents the pathological accumulation of Aβ and tau. Collectively, the evidence suggests that multidomain lifestyle approaches offer synergistic benefits that exceed those of individual interventions, representing promising strategies for delaying cognitive decline. However, gaps remain regarding dose-response relationships, personalised protocols for APOE4 carriers, and long-term validation in diverse populations. Strengthening these research directions is crucial for integrating lifestyle medicine into preventive neurology and public health frameworks.},
}

@article {pmid42099163,
year = {2026},
author = {Li, Y and Li, L and Yang, Q and Xiong, J},
title = {Comparative Efficacy and Safety of Cholinesterase Inhibitors and NMDA Receptor Antagonists in Alzheimer's Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050437623260417063631},
pmid = {42099163},
issn = {1875-5828},
abstract = {INTRODUCTION: The study aims to evaluate and rank cholinesterase inhibitors, the NMDA antagonist memantine, anti-amyloid monoclonal antibodies, and non-drug modalities with respect to cognitive outcomes, functional status, neuropsychiatric symptoms, and tolerability.

METHODOLOGY: We registered a protocol in PROSPERO and searched PubMed/MEDLINE, Embase, CENTRAL, Web of Science, trial registries, and gray literature through June 2025. Eligible randomized phase II/III trials in adults with clinically diagnosed AD were screened in duplicate. Data on interventions, comparators, outcomes (e.g., MMSE, ADAS-Cog, CDR-SB), and adverse events were extracted. Risk of bias was assessed using Cochrane RoB 2. A Bayesian random-effects NMA synthesized 125 trials (n > 30,000), estimating standardized Mean Differences (SMDs) with 95% Credible Intervals (CrIs). Heterogeneity (I²) and inconsistency (design-by-treatment, node-splitting) were evaluated.

RESULTS: The network was well connected, with low-to-moderate heterogeneity (global I² = 38.5%) and no significant inconsistency (p = 0.48). Cognitive training (SMD = 0.45; 95% CrI 0.30-0.60; SUCRA 92%), aerobic exercise (SMD = 0.55; 95% CrI 0.35-0.75; SUCRA 87%), and galantamine (SMD = 0.40; 95% CrI 0.22-0.58; SUCRA 84%) ranked highest versus placebo. Donepezil (SMD = 0.21; 95% CrI 0.11-0.30; SUCRA 78%) and memantine (SMD = 0.24; 95% CrI 0.13-0.35; SUCRA 72%) showed modest benefits.

DISCUSSION: Risk-of-bias ratings were low in 37% of trials, some concerns in 48%, and high in 15%. Subgroup analyses confirmed greater cholinesterase inhibitor efficacy in mild AD and superior memantine effects in moderate-to-severe disease.

CONCLUSION: Non-pharmacological interventions demonstrated short-term cognitive benefits primarily in mild Alzheimer's disease populations and should be interpreted as adjunctive symptomatic strategies rather than direct substitutes for pharmacological therapy.},
}

@article {pmid42099164,
year = {2026},
author = {Nayak, RK and Mohapatra, SR and Sahoo, SK and Sahu, SK and Chowdhury, B and Banu, Z and Das, NR},
title = {Gut Microbiota Dysbiosis in Alzheimer's Disease and Possible Therapeutic Options.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050448298260303052535},
pmid = {42099164},
issn = {1875-5828},
abstract = {Human microbiota consists of trillions of microbial cells dominated by bacteria, which live in the human body, while the term microbiome refers to the collective genetic material of microorganisms. Among them, the gut microbiota has emerged as pivotal, producing its own metabolites, neurotransmitter precursors, and immune mediators that affect brain development and function. These signals function via the complex, bidirectional Gut-Brain Axis (GBA). This is a communication network that connects the gastrointestinal tract to the central nervous system. This axis plays an important role in the regulation of gastrointestinal homeostasis, neurodevelopment, emotional regulation, and cognitive processes. Increasing evidence suggests that microbial dysbiosis within the gastrointestinal tract is involved in the pathogenesis and progression of several neurological and neurodegenerative disorders, including mood disorders, schizophrenia, autism spectrum disorder, Alzheimer's Disease (AD), Parkinson's Disease (PD), and Huntington's Disease. These insights have opened new therapeutic possibilities, and multiple microbiota-targeted interventions, such as dietary modification, prebiotics, probiotics, postbiotics, psychobiotics, antibiotics, and Fecal Microbiota Transplantation (FMT), are now being explored for their therapeutic value, especially in Alzheimer's disease.},
}

@article {pmid42099165,
year = {2026},
author = {Yang, Y and Huang, X and Liu, H and Yu, C},
title = {The Role of Ectopic Fat in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050461650260406064722},
pmid = {42099165},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder increasingly recognized to be associated with metabolic dysfunction. Accumulating evidence suggests that ectopic fat (abnormal fat deposition in non-adipose tissue) is a key factor. This review summarizes the crucial role that ectopic fat plays in the onset and progression of AD, as well as the interrelated pathways through which ectopic fat deposition promotes the pathological process of AD. Adipocytes have been reported to produce and secrete amyloid-β (Aβ), a hallmark pathological feature of AD. Accordingly, ectopic fat may aggravate cerebral Aβ accumulation by impairing peripheral Aβ clearance. In addition, ectopic fat can also cause Insulin Resistance (IR), adipokine dysregulation, inflammatory responses, and oxidative stress. Therefore, ectopic fat is closely associated with the progression of AD and may play a contributory role in its pathogenesis. The effects of ectopic fat on the occurrence and development of Alzheimer's Disease (AD) pathology were reviewed through mechanisms such as metabolic disorders, inflammatory pathways, and Aβ deposition, and potential intervention strategies for this harmful cycle were highlighted. As current therapies for AD remain limited, new opportunities for its prevention and treatment may be provided through a better understanding of these associations.},
}

@article {pmid42099166,
year = {2026},
author = {Chaudhari, DB and Barve, K},
title = {Targeting Shared Mechanisms in Atherosclerosis and Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050447493260327074829},
pmid = {42099166},
issn = {1875-5828},
abstract = {Atherosclerosis and Alzheimer's Disease are two significant health concerns characterised by overlapping pathophysiological mechanisms, including chronic inflammation, oxidative stress, and lipid metabolism dysregulation. Impaired vascular integrity in atherosclerosis enhances the accumulation of Aβ plaque in the brain by reducing cerebral perfusion and compromising the clearance of Aβ. This review examines the shared pathways linking these conditions, emphasizing the role of the NLRP3 inflammasome, Receptor for Advanced Glycation End Products, and the apolipoprotein E4 allele in exacerbating vascular dysfunction that promotes neurodegeneration. The interplay between these factors underscores the potential of targeting these common pathways as a therapeutic strategy for both diseases. In preclinical studies, emerging treatments, NLRP3 inflammasome inhibitors like MCC950 and CY-09, show promise in mitigating both arterial plaque formation and neuronal amyloid deposition, while innovative microRNA-based therapies targeting miR-146a and miR-155 offer novel approaches to reduce inflammatory responses. Additionally, modulation of lipid metabolism through liver X receptor agonists like T0901317 and cholesteryl ester transfer protein inhibitors, including Anacetrapib, offers potential dual benefits for cardiovascular and neurological health. However, challenges such as restricted BBB permeability, genetic and sex variability, and limited long-term clinical evidence continue to constrain the effectiveness of dual-targeted therapeutic approaches. Future perspectives suggest integrating multi-- modal therapies that combine anti-inflammatory, lipid-regulatory, and antioxidant strategies to effectively address these interrelated diseases. Advancements in molecular biology and imaging techniques may facilitate the development of personalised medicine approaches, ultimately improving outcomes for patients suffering from both atherosclerosis and Alzheimer's Disease.},
}

@article {pmid42099527,
year = {2026},
author = {Gong, T and Jiang, W and Han, Y and Liu, Y and Zhuo, W and Li, S and Hu, Z and Zeng, Z and Yue, R and Yang, M},
title = {Investigating the research trajectory and future trends in type 2 diabetes mellitus and aging: a bibliometric analysis from 2009 to 2025 based on big data.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1779773},
pmid = {42099527},
issn = {2673-6217},
abstract = {BACKGROUND: The relationship between type 2 diabetes mellitus (T2DM) and aging has attracted growing scientific attention. Growing evidence suggests that T2DM is not only a metabolic disorder but also a condition associated with accelerated biological aging. This study aimed to systematically map the global research landscape, intellectual structure, and emerging trends at the intersection of T2DM and aging using bibliometric approaches.

METHODS: Publications indexed in the Web of Science Core Collection from 1 January 2009 to 31 December 2025 were retrieved, yielding 3,048 records. Bibliometric analyses were conducted using VOSviewer, CiteSpace, and R to construct collaboration networks, co-citation structures, and keyword evolution patterns.

RESULTS: After a moderate growth phase from 2011 to 2015, publication output increased markedly from 2016 onward and reached a peak in 2025, accompanied by the progressive formation of an international collaboration network dominated by the United States and China. Mechanistic studies constituted the primary research focus, particularly those related to cellular senescence, oxidative stress, and inflammation. Cellular senescence emerged as a structurally central node within the knowledge network. Thematic evolution analysis further revealed increasing attention to aging-related comorbidities, including cardiovascular disease, Alzheimer's disease, erectile dysfunction, and cognitive impairment. Recent research fronts have increasingly focused on molecular pathways, including the senescence-associated secretory phenotype, the NLRP3 inflammasome, and epigenetic regulation.

CONCLUSION: This bibliometric analysis provides a comprehensive overview of the evolving research landscape linking T2DM and aging. The prominence of senescence-related pathways highlights a growing convergence between diabetes research and aging biology. Emerging strategies targeting fundamental aging mechanisms-including senolytic therapies and glucose-lowering drugs with potential geroprotective effects such as metformin and empagliflozin-represent promising directions for future research.},
}

@article {pmid42099528,
year = {2026},
author = {Patterson, SE and Caywood, K and Stinson, F},
title = {The sociological stakes of attitudes toward the families and care of older adults with dementia.},
journal = {Sociological forum (Randolph, N.J.)},
volume = {},
number = {},
pages = {},
pmid = {42099528},
issn = {0884-8971},
abstract = {This forum essay calls for greater sociological attention to the theoretical and empirical study of attitudes about the families and care of older adults living with Alzheimer's disease and related dementias (ADRD; dementia). Investigating these attitudes can help expand our understanding not only of the social experience of older adults with dementia, but also of family members and caregivers, as dementia is often highly stigmatized, memory loss changes relationships, and relationship dynamics influence care provision and inequalities. Attitudes and norms function at multiple levels - individual, family, and societal - and have large-scale consequences for social systems and inequality in an aging and increasingly diverse United States, where a growing number of older adults have dementia and family caregiving is normative. We briefly highlight demographic trends and interdisciplinary developments that underscore the urgency of and advantages to addressing these attitudes in sociology specifically. We conclude with a call to action and recommendations for scholars seeking to pursue related research within four relevant subfields within sociology: families, aging in the life course, stratification (race, gender, class), and medical sociology.},
}

@article {pmid42099715,
year = {2026},
author = {Dubois, JR and Kim, E and Pando-Bravo, J and Martin, LE and Yi, R},
title = {Scoping review of episodic future thinking and delay discounting observed in Alzheimer's disease, depression, and PTSD.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1764387},
pmid = {42099715},
issn = {1664-1078},
abstract = {Delay discounting (DD), the decrease in the subjective value of a reward as its receipt is delayed, is associated with a variety of risky health behaviors. Episodic Future Thinking (EFT), the capacity to imagine events that might occur in the future, is understood as a reliable intervention in reducing DD. While populations known to exhibit heightened DD rates may benefit from EFT-based interventions, impaired capacity for EFT may reduce their effectiveness. This scoping review examines the available evidence regarding the co-occurrence of steep DD rates and impoverished EFT across Alzheimer's disease (AD), post-traumatic stress disorder (PTSD), and depression to inform the transdiagnostic potential of EFT-based interventions. Searching and screening of articles were conducted on PsycINFO, PubMed, and Medline in February of 2025 following PRISMA guidelines. Across all disorders, clinical populations exhibited steeper DD rates, as well as impaired EFT characterized by marked reductions in specificity, detail, and novelty of the imagery. Cross-disorder comparisons highlighted reduced memory specificity impacting future simulation and physiological abnormalities in the hippocampus and vmPFC as potentially shared mechanisms in DD and EFT deficits. Despite a consistent pattern of steep DD and impoverished EFT occurring in each population and potentially influenced by similar mechanisms, the lack of studies examining DD and EFT in the same sample limits our conclusion and highlights where further research is warranted.},
}

@article {pmid42099804,
year = {2026},
author = {Rodrigues, KS and Yamashita, R and Katada, S},
title = {The choroid plexus- cerebrospinal fluid axis as a lifespan regulator of neural stem cells and circuit plasticity.},
journal = {Frontiers in neural circuits},
volume = {20},
number = {},
pages = {1818927},
pmid = {42099804},
issn = {1662-5110},
mesh = {*Choroid Plexus/physiology/metabolism ; Animals ; *Neural Stem Cells/physiology ; Humans ; *Neuronal Plasticity/physiology ; *Cerebrospinal Fluid/physiology/metabolism ; Neurogenesis/physiology ; },
abstract = {The choroid plexus-cerebrospinal fluid axis (ChP-CSF) functions as a dynamic signaling system that coordinates neural stem cell (NSC) behavior and neural circuit plasticity across the lifespan. Beyond its classical roles in cushioning the brain, CSF serves as a regulated conduit for growth factors, ions, extracellular vesicles, and other bioactive molecules. Emerging evidence suggests that the ChP contributes to shaping CSF composition through energy-dependent transport and state-responsive secretion. Ventricular-contacting NSCs sense CSF cues via apical endfeet and primary cilia, integrating signals to regulate their behavior. Lifespan-dependent remodeling of CSF composition and niche architecture reshapes NSC function from embryonic expansion to adult homeostasis and age-associated decline. Beyond the ventricular niche, ChP-derived factors influence circuit maturation and vulnerability to neurodegeneration. Orthodenticle homeobox 2 regulates critical period timing and neuroblast integration, whereas apolipoprotein E couples lipid metabolisms and amyloid-β homeostasis to neurogenesis with Alzheimer's disease risk. Additional ChP-secreted proteins, including transthyretin and clusterin, further shape the extracellular proteostatic and lipid environment. Together, these findings support the view of the ChP-CSF axis as an adaptive regulator across the lifespan that integrates stem cell dynamics, circuit plasticity, and neurodegenerative susceptibility.},
}

*Choroid Plexus/physiology/metabolism
Animals
*Neural Stem Cells/physiology
Humans
*Neuronal Plasticity/physiology
*Cerebrospinal Fluid/physiology/metabolism
Neurogenesis/physiology

@article {pmid42099973,
year = {2026},
author = {Chen, Y and Du, T and Lian, T and Jiang, Y and Yuan, T and Li, J and Meng, F and Yang, A and Zhang, W and Zhang, J},
title = {Clinical outcomes and anti-inflammatory mechanisms of nucleus basalis of Meynert deep brain stimulation in Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1773910},
pmid = {42099973},
issn = {1664-2295},
abstract = {AIM: Deep brain stimulation of the nucleus basalis of Meynert (NBM-DBS) represents an emerging therapeutic strategy for Alzheimer's disease (AD), yet clinical outcomes have been inconsistent and its mechanistic underpinnings are not fully elucidated. This study aimed to assess the cognitive and psychobehavioral effects of NBM-DBS and to explore its potential impact on systemic inflammatory markers.

METHODS: In this open-label trial, nine individuals with moderate-to-severe AD underwent bilateral NBM-DBS. Six participants (four with moderate and two with severe AD) completed the full 12-month protocol, which included serial neuropsychiatric assessments and serum cytokine profiling.

RESULTS: Stratification by baseline disease severity revealed divergent cognitive trajectories. Patients with moderate AD (CDR = 2) maintained their preoperative performance on the Montreal Cognitive Assessment (MoCA) and Boston Naming Test (BNT) over the 12-month follow-up. In contrast, patients with severe AD (CDR = 3) experienced significant decline on these measures. Serum analyses demonstrated a significant immunomodulatory effect, characterized by elevated levels of the anti-inflammatory cytokines IL-10 and IL-27, and reduced levels of the pro-inflammatory chemokines CXCL10 and RANTES at the 12-month timepoint.

CONCLUSION: Our findings indicate that NBM-DBS may be associated with stabilization of cognitive function in patients with moderate AD, potentially through the modulation of inflammation. The therapeutic benefit appears to be more pronounced in the moderate stage of the disease.},
}

@article {pmid42100106,
year = {2026},
author = {Bonnan, D and Kröger, E and Maheu, A and Morin, M and Bélanger, L and Vedel, I and Wilchesky, M and Sirois, C and Dallaire, C and Durand, É and Couturier, Y and Sourial, N and Guénette, L},
title = {Implementation of pharmacists' services into the care trajectory of older adults with neurocognitive disorder in multidisciplinary primary care clinics: A mixed-methods study.},
journal = {Exploratory research in clinical and social pharmacy},
volume = {23},
number = {},
pages = {100786},
pmid = {42100106},
issn = {2667-2766},
abstract = {INTRODUCTION: In Quebec, Canada, the "Alzheimer plan" encourages pharmacist participation in the care of older adults with neurocognitive disorders (NCDs) within multidisciplinary primary care clinics, known as Family Medicine Groups (FMGs). This study examined how these services were implemented from the perspective of physicians, nurses, and pharmacists.

METHODS: We conducted a convergent mixed-methods study combining cross-sectional questionnaires with semi-structured interviews across eight FMGs participating in a quasi-experimental project about the impact of pharmacists' activities on older adults' medication and well-being. Data collection and analysis were guided by the Normalization Process Theory and the Consolidated Framework for Implementation Research. A deductive thematic content analysis was carried out, using the five CFIR constructs as themes. Data from questionnaires were analyzed alongside interview data to gain a broader perspective on the implementation process.

RESULTS: Eighteen professionals (nine pharmacists, four physicians, five nurses) participated. From a quantitative perspective, pharmacists' integration was perceived positively: high agreement was reported regarding the intervention's potential value (90% pharmacists, 100% other professionals) and its adaptability (100% pharmacists, 80% other professionals). Also, 100% of physicians and nurses intended to continue to use pharmacists' services in the future. Qualitatively, facilitators included an easy-to-implement innovation (innovation characteristics), legislative changes (outer setting), the pharmacist's physical presence, strong interprofessional trust (inner setting), and proactive pharmacists' leadership (individuals) with regular team reminders (implementation process). Conversely, insufficient government funding (outer setting) and workload pressures were identified as primary barriers.

CONCLUSIONS: Implementing pharmacist services for older adults with NCDs in FMGs is feasible and beneficial, improving workflow and team efficiency beyond NCD care. Strong interprofessional collaboration, effective communication, and clear role definition were key facilitators, while insufficient funding and workload pressures remain major challenges to implementation. Co-construction between primary care teams and decision-makers is essential to achieve successful scale-up.},
}

@article {pmid42100263,
year = {2026},
author = {Wang, X and Yang, Z and Tang, T and Huang, H and Shi, J and He, J and Zhang, H},
title = {From neuroinflammation to neuroprotection: a bibliometric analysis of anesthesia-associated postoperative cognitive dysfunction to guide clinical research (2000-2024).},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1822901},
pmid = {42100263},
issn = {2296-858X},
abstract = {INTRODUCTION: Postoperative cognitive dysfunction is a common complication following anesthesia and surgery, particularly in elderly patients, yet its pathophysiology and optimal prevention strategies remain incompletely understood. This study employs bibliometric methods to analyze research trends in anesthesia-associated POCD from 2000 to 2024.

METHODS: A systematic review of 923 publications from the Web of Science Core Collection, cross-validated with the PubMed database, was conducted. Bibliometric analyses were performed using the R package "bibliometrix," VOSviewer, and CiteSpace to evaluate publication trends, key contributors, collaborative networks, co-citation patterns, and keyword evolution.

RESULTS: Research output has grown steadily since 2000, with notable acceleration after 2018. The United States leads in productivity and influence, followed by China and Germany. Duke University is the most prolific institution. The British Journal of Anaesthesia and Anesthesiology are the core journals in this field. Keyword analysis reveals an evolution from early focus on surgical types and cognitive assessment toward neuroinflammation as the central pathological mechanism, with increasing attention to the delirium-POCD continuum, anesthetic optimization, and multimodal prevention. Emerging frontiers include the intersection of POCD with Alzheimer's disease pathology, the role of the gut-brain axis, and the translation of mechanistic insights into targeted neuroprotective strategies.

CONCLUSION: This bibliometric analysis delineates the evolution of POCD research from descriptive epidemiology to mechanistic and translational inquiry. Neuroinflammation has emerged as the unifying pathological hub. Key challenges include heterogeneity in diagnostic criteria, difficulty isolating anesthesia effects from surgical trauma, and the gap between preclinical findings and clinical efficacy. Future research priorities should focus on harmonizing diagnostic standards, validating biomarkers, and conducting large-scale multi-center trials to translate mechanistic discoveries into perioperative brain health strategies.},
}

@article {pmid42100327,
year = {2026},
author = {Li, B and Cui, Z and Xu, Y and Xu, M},
title = {Modulation of programmed cell death by botanical drugs in Alzheimer's disease: a review from a traditional Chinese medicine perspective.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1811185},
pmid = {42100327},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) involves dysregulation of programmed cell death (PCD) pathways, such as apoptosis, ferroptosis, autophagy, and pyroptosis. Current therapeutic options are limited, prompting interest in multi-target regulators such as metabolites derived from traditional Chinese medicine (TCM) botanical drugs. This systematic review critically evaluates recent studies on TCM-derived metabolites that modulate PCD in AD models. We identify key limitations: many metabolites are pan-assay interference metabolites (PAINS) with questionable pharmacological relevance; preclinical models inadequately recapitulate sporadic AD; and translational challenges persist in bioavailability and brain targeting. Future research requires orthogonal validation, improved delivery systems, and stage-specific strategies. This review provides a critical foundation for the development of TCM-inspired therapies for AD.},
}

@article {pmid42100472,
year = {2026},
author = {Johnson, CN and Lysaker, CR and Cao, X and Csikos, V and Boakye, F and Kueck, PJ and Franczak, E and Geiger, PC and Morris, JK and Thyfault, JP and Wilkins, HM},
title = {APOE4 Drives Sex- and Diet-Dependent Effects on AD-Like Pathology, Cognition, and Mitochondrial Function.},
journal = {FASEB bioAdvances},
volume = {8},
number = {},
pages = {e70113},
pmid = {42100472},
issn = {2573-9832},
abstract = {Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), yet it's unclear how this allele promotes disease. While factors like diet and sex may modify AD susceptibility in APOE4 carriers, the interaction between these factors is poorly understood. Here, we sought to determine if APOE4, sex, and diet interact to influence AD related outcomes in mice. Male and female APOE3 and APOE4 targeted replacement (TR) mice were fed a low-fat diet or high-fat diet from 4 to 8 months old. Serum neurodegenerative disease biomarkers, brain amyloid beta (Aβ), APOE, and tau, learning and memory, hippocampal mitochondrial function and proteomics data were collected. Serum GFAP and NfL were unaffected by APOE4, while HFD was associated with greater serum NfL and GFAP. Whole brain Aβ was significantly altered by sex, diet, and genotype. There was a main effect of genotype on levels of brain APOE with levels being lower in APOE4 mice. APOE4 TR mice also exhibited impaired learning before diet. Proteomic analysis revealed that APOE4 exerts diet- and sex-dependent effects on mitochondrial pathways. This included downregulation of pyruvate metabolism in HFD males and oxidative phosphorylation in HFD females. Basal respiration was lower in APOE4 versus APOE3 TR females. We provide novel evidence that APOE4 may drive early sex- and diet-dependent reductions in pathways that support brain mitochondrial energy metabolism.},
}

@article {pmid42100481,
year = {2026},
author = {Khan, FF and Kim, JH and Kim, JI and Kwon, GR},
title = {APOE ε4 as a predictor of cognitive decline and its interaction with hippocampal volume in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1730265},
pmid = {42100481},
issn = {1663-4365},
abstract = {BACKGROUND/INTRODUCTION: The apolipoprotein E (APOE) ε4 allele is the strongest known genetic risk factor for late-onset Alzheimer's disease, and hippocampal atrophy is among the most reliable structural biomarkers of neurodegeneration. While both are independently associated with cognitive decline, whether APOE ε4 dose modulates the hippocampal volume-cognition relationship longitudinally in sporadic Alzheimer's disease remains underexplored at adequate statistical power.

METHODS: This study analyzed data from 2,417 Alzheimer's Disease Neuroimaging Initiative participants with complete APOE genotypes, intracranial volume-adjusted hippocampal volumes, and longitudinal cognitive assessments spanning a mean follow-up of 4.2 years and up to 19.3 years with an average of 4.9 visits per participant. Linear mixed-effects models with random intercepts and slopes per subject estimated cognitive trajectories across the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale Cognitive Subscale 13 (ADAS-Cog13) as a function of time, APOE ε4 dose, and ICV-adjusted hippocampal volume, including their three-way interaction and adjusting for age, sex, education, baseline diagnosis, and depression. Cox proportional hazards models were used to assess conversion risk.

RESULTS: A clear APOE ε4 dose-response gradient was observed at baseline across all cognitive and hippocampal measures (all p < 0.001). Linear mixed-effects models revealed a significant three-way interaction of time × APOE ε4 dose × hippocampal volume on MMSE (β = -0.79, 95% CI [-1.51, -0.08], p = 0.030) and CDR-SB (β = +0.47, 95% CI [+0.03, +0.91], p = 0.037) trajectories, both significant under Bonferroni correction (α = 0.017), indicating that APOE ε4 amplifies the association between smaller hippocampal volume and faster cognitive deterioration over time. The time × hippocampal volume interaction was confirmed as highly significant by likelihood ratio test (LR = 3712.99, p < 0.001). Cox proportional hazards analyses of 845 conversion events showed that each additional ε4 allele conferred a 48% increase in conversion risk (HR = 1.48, 95% CI [1.29, 1.71], p < 0.001). Sensitivity analyses across diagnostic strata, after outlier exclusion, and in multi-visit subsamples confirmed the robustness of hippocampal volume effects.

DISCUSSION/CONCLUSION: These findings demonstrate that APOE ε4 genotype significantly modulates the longitudinal relationship between hippocampal volume and cognitive decline, supporting the integration of APOE genotype and structural hippocampal imaging for refined individual risk stratification in Alzheimer's disease.},
}

@article {pmid42100482,
year = {2026},
author = {Zhao, H and Wang, H and Li, W and Su, R and Li, J and Liu, Y and Wang, L},
title = {Integrated transcriptomic profiling combined with in vitro validation reveals the involvement of TMEM140 in the link between periodontitis and brain aging.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1761218},
pmid = {42100482},
issn = {1663-4365},
abstract = {OBJECTIVE: Periodontitis (PD) is a prevalent chronic inflammatory disorder in adults, and moderate-to-severe PD (Stage II-III/IV) may accelerate brain aging and neurodegenerative changes via the peripheral-central immune-neural axis, although the molecular connections and mechanisms of interaction have yet to be fully elucidated. This study sought to identify senescence-associated molecules potentially shared by PD and Alzheimer's disease (AD) using integrated transcriptomic analysis, machine learning, and in vitro RNA interference assays, and to further assess the role of TMEM140 in linking PD to brain aging.

METHODS: Transcriptomic datasets related to PD and AD were retrieved from the GEO database, and differential gene expression analysis was performed following batch effect correction; shared aging-associated genes were subsequently identified by combining weighted gene co-expression network analysis (WGCNA) with aging gene databases (HAGR and aging Atlas). Four machine learning algorithms, namely random forest (RF), support vector machine (SVM), generalized linear model (GLM), and extreme gradient boosting (XGB), were further applied to identify key genes, and their diagnostic value was assessed using receiver operating characteristic (ROC) analysis and nomogram models. DSigDB was used to predict candidate small-molecule compounds. In the in vitro experiments, a Porphyromonas gingivalis lipopolysaccharide (PG-LPS)-induced inflammatory model in human gingival fibroblasts (HGFs) and an Aβ1-42 and D-galactose-induced senescence model in SH-SY5Y neuron-like cells were established; TMEM140 in SH-SY5Y cells was then silenced using small interfering RNA (siRNA), and the neuron-like cells were treated with the same batch of standardized conditioned medium (CM; prepared from the supernatant of PG-LPS-treated HGFs) to observe changes in cellular responses to inflammatory stimulation after TMEM140 downregulation.

RESULTS: Seven aging-related genes common to PD and AD were identified, and comprehensive analysis using multiple algorithms selected TMEM140, TIMP1, and ALDH2 as key genes. Notably, TMEM140 was upregulated in PD and downregulated in AD, showed significant correlations with plasma cell and γδ T-cell infiltration, and single-cell analysis further revealed its cell type-specific expression in distinct brain cell subsets. In vitro experiments demonstrated that PG-LPS treatment markedly increased TMEM140 expression in HGFs, whereas treatment with Aβ1-42 and D-galactose reduced TMEM140 expression in neuron-like cells. When exposed to the same batch of conditioned medium, neuron-like cells with TMEM140 knockdown displayed more evident injury and senescence-related phenotypes, including reduced cell viability, increased reactive oxygen species (ROS) production, a higher percentage of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and marked upregulation of IL-1β, IL-6, TNF-α, p16, p21, RELA, NFKBIA, and TP53, indicating that reduced TMEM140 expression may contribute to enhanced susceptibility of neuron-like cells to inflammatory stress.

CONCLUSION: Through integrated transcriptomic analysis together with in vitro experimental validation, this study indicates that TMEM140 may be a candidate bridge molecule connecting PD and AD comorbidity. TMEM140 may participate in shaping the peripheral-central immunosenescence network and contribute to the cross-system transmission of inflammatory signaling.},
}

@article {pmid42100483,
year = {2026},
author = {Patel, A and Guiler, W and Pepper, S and Kemna, RE and Kueck, PJ and Weidling, IW and Mayfield, HD and John, CS and Mudaranthakam, DP and Wilkins, HM and Swerdlow, RH and Burns, JM and Morris, JK and Honea, RA},
title = {Limbic-predominant neuroimaging correlates of plasma p-Tau217 in preclinical and clinical Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1748524},
pmid = {42100483},
issn = {1663-4365},
abstract = {BACKGROUND: Plasma phosphorylated tau at threonine 217 (p-Tau217) has emerged as a highly sensitive and specific blood-based biomarker for Alzheimer's Disease (AD). However, its regional brain correlates with multimodal neuroimaging, beyond tau-PET, remain underexplored, particularly in early disease phases where limbic involvement may predominate. This study aimed to map the associations of plasma p-Tau217 with amyloid-PET burden, FDG-PET metabolism, and structural brain morphometry in a well-characterized cohort spanning cognitively unimpaired (CU) and cognitively impaired (CI) individuals across AD dementia stages, hypothesizing increased AD neuroimaging biomarkers in individuals with elevated p-Tau217.

METHODS: We analyzed data from 259 participants from the University of Kansas Alzheimer's Disease Research Center (KU ADRC) Clinical Cohort. Imaging outcomes included amyloid-PET, FDG-PET, gray matter volumetric regions of interest as well as whole brain voxel-based morphometry (VBM), and surface-based morphometry (SBM) for cortical thickness (CT), sulcal depth (SD), gyrification index (GI), fractal dimension (FD). Analyses were stratified by diagnostic and pTau-217 positivity (CU pTau + , CU pTau -, CI pTau + and CI pTau-). Spearman's correlations and voxel/surface-wise regressions evaluated p-Tau217 associations with imaging metrics, accounting for age and sex.

RESULTS: Plasma p-Tau217 was elevated in CI versus CU. Individuals with elevated plasma p-Tau217 had increased amyloid-PET deposition across the cortex, as well as significantly higher centiloids, both in CU and CI individuals. In CI individuals, elevated p-Tau217 was associated with reduced voxel-wise gray matter volume and cortical thickness in limbic, temporal, parietal, and frontal regions, plus increased cingulate FD. In both CU and CI pTau + individuals, p-Tau217 correlated with AD Signature gray matter decreases.

CONCLUSION: These findings show that CU and CI individuals with elevated plasma p-Tau217 have both increased amyloid-PET burden but also temporolimbic gray matter atrophy and hypometabolism. This supports p-Tau217 as a minimally invasive, scalable biomarker for early AD detection, risk stratification, and prognostic monitoring in preclinical stages, potentially guiding trial enrichment and personalized interventions.},
}

@article {pmid42100484,
year = {2026},
author = {Bellaali, Y and Sulcova, D and Salatino, A and Dricot, L and Hanseeuw, BJ and Woodard, JL and Ivanoiu, A},
title = {Modulating the default mode network with deep TMS: a proof-of-concept framework with potential relevance to circuits implicated in lack of awareness of cognitive decline.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1742759},
pmid = {42100484},
issn = {1663-4365},
}

@article {pmid42100486,
year = {2026},
author = {Park, EJ and Mun, BR and Kim, SY and Elangovan, M and Kim, SB and Choi, WS and Park, WJ},
title = {Secretory form of viral protease NIa ameliorates amyloid-β pathology and cognitive deficits in a mouse model of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1720518},
pmid = {42100486},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by extracellular amyloid-β (Aβ) accumulation. Immunotherapies targeting Aβ clearance show promise, highlighting the therapeutic value of enhancing Aβ removal. We previously identified that nuclear inclusion a (NIa), a plant viral protease, fortuitously cleaves Aβ with strict sequence specificity. Here, we engineered a secretory form, SecNIa, to degrade extracellular Aβ. SecNIa was efficiently secreted from transfected cells while retaining potent Aβ-cleaving activity. Adeno-associated virus (AAV)-mediated delivery of SecNIa into 5xFAD mice resulted in robust hippocampal expression and cerebrospinal fluid secretion. SecNIa expression significantly reduced soluble and insoluble Aβ, decreased hippocampal plaques, and improved cognition, fully normalizing recognition memory and enhancing spatial learning. These findings establish SecNIa as a promising therapeutic strategy to directly target pathogenic extracellular Aβ in AD.},
}

@article {pmid42100568,
year = {2026},
author = {Genguelou, M and Platel, H and Bourgeois, C and Gambonnet, M and Bayard, S},
title = {Social engagement, pleasure, and memory in musical reminiscence workshops for individuals with Alzheimer's disease.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1803210},
pmid = {42100568},
issn = {1662-5161},
abstract = {INTRODUCTION: Social bonding is essential in Alzheimer's Disease (AD), as social withdrawal reduces quality of life and can worsen Behavioral and Psychological Symptoms in Dementia. Music therapy offer a promising approach. This study examines the effects on social engagement in AD and explores links between verbal interaction, memory, and emotion.

METHODS: Nineteen voluntary residents with moderate to severe AD from four nursing homes participated. Nine musical reminiscence workshops were conducted. A single-group intervention study was conducted, with assessments at baseline, three points during the intervention, post-intervention, and one-month follow-up. Emotions were assessed using the Observed Emotion Rating Scale. Social engagement was measured via the social interaction domain of the Alzheimer's Disease-Related Quality of Life scale. Episodic memory was evaluated with the simplified Tempau Test and an observational grid. Reminiscences and verbal interactions during workshops were counted.

RESULTS: Verbal interactions and memory episodicity increased across workshops. Pleasure correlated positively with interaction frequency. Daily social engagement also improved after the intervention.

DISCUSSION: Musical reminiscence workshops enhance autobiographical memory and foster social engagement. Pleasure appears to be associated with social interactions. Music interventions can improve the social quality of life in people living with Alzheimer's disease.},
}

@article {pmid42100599,
year = {2026},
author = {Siette, J and Kim, JW and Zammit, JL and Butt, A and Sonego, S and Ginige, JA and Georgiou, A and Low, LF},
title = {The characteristics and performance of health data domains in supporting dementia identification: A systematic review.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70313},
pmid = {42100599},
issn = {2352-8729},
abstract = {Electronic health records (EHRs) offer growing potential for dementia identification, yet a synthesis of how specific data domains contribute to accurate detection is lacking. This systematic review assessed the role and performance of EHR-derived data in identifying dementia. Six databases were searched up to April 2025. Fifty studies met inclusion criteria, examining routinely collected health data across care settings. Ten key domains supported dementia identification, including demographics, diagnoses, medications, symptoms, and structured assessments. Most data were sourced from primary care EHRs (48%), with studies primarily conducted in the United Kingdom and United States. Case-control and retrospective cohort designs were commonly applied, often using logistic regression. Cognitive and behavioral domains contributed most to specificity (57.5%-99.9%). Alzheimer's-specific models had higher accuracy than general dementia models (mean accuracy: 74.6 vs. 67.1). Integrating diverse EHR data, especially cognitive and symptomatic variables, can improve dementia detection. Future research should focus on model validation, standardization, and clinical implementation.},
}

@article {pmid42100633,
year = {2026},
author = {Sahoo, SS and Sahu, PK and Sa, N and Behera, A},
title = {Neuroprotective cellular and molecular mechanisms of physical exercise on neurodegenerative diseases.},
journal = {ADMET & DMPK},
volume = {14},
number = {},
pages = {3058},
pmid = {42100633},
issn = {1848-7718},
abstract = {BACKGROUND: Neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease are characterized by a progressive loss of neuronal function and loss of synaptic capacity. Physical exercise (PE) is one of the non-clinical techniques for the management of brain health and neurodegeneration.

MECHANISMS: PE enhances the body's metabolic functions through cellular and molecular changes. It trades off metabolic functions, energy expenditure, and signalling processes to ensure physiological homeostasis and defence against disease. Exercise produces cascades, at the molecular level, including neurotrophic signalling, similar to those generated by drugs. It increases the levels of the brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). These elements favour the growth of new neurons, vascular enlargement, and synaptic plasticity. PE also induces microglial cells to attain a neuroprotective, anti-inflammatory phenotype, reduces detrimental cytokines, promotes cellular clearance through autophagy, restores neurotransmitter homogenisation, and induces hippocampal cell formation. Collectively, it acts as a powerful modulator of health and brain activity.

IMPLICATIONS: The aggregate processes enhance neuronal vulnerability to harm, aid cognitive functioning, and ensure the stability of neural networks.

CONCLUSION: PE is an exciting additive therapy for preventing and treating various neurodegenerative disorders by orchestrating a diverse array of cellular and molecular responses.},
}

@article {pmid42100721,
year = {2026},
author = {Emanuele, E and Santos-Lozano, A and López-Ortiz, S and Khoramipour, K and García-Chico, C and Lista, S and Minoretti, P},
title = {Magnetic fields as biophysical activators of autophagy: A preclinical systematic review.},
journal = {Biochemistry and biophysics reports},
volume = {46},
number = {},
pages = {102613},
pmid = {42100721},
issn = {2405-5808},
abstract = {While pharmacological inducers of autophagy have been extensively studied, their systemic adverse effects may limit clinical use. Increasing preclinical evidence suggests that magnetic fields (MFs) can represent a non-invasive alternative for autophagy modulation. In this systematic review, we sought to evaluate preclinical evidence on MF-mediated autophagy activation, including intervention parameters, mechanistic pathways, and therapeutic outcomes, to guide future translational research. Following PRISMA guidelines, we searched (January 2010-August 2025) four structured electronic databases (PubMed, Scopus, Embase, and IEEE Xplore) for studies investigating MF effects on autophagy in preclinical models. Eligible reports included in vitro and animal investigations with clearly defined MF parameters and validated autophagy markers. Nine studies met inclusion criteria, covering diverse MF modalities such as repetitive transcranial magnetic stimulation, rotating fields, pulsed and power-frequency fields, and radiofrequency exposures. Across a wide range of frequencies (1-50 Hz) and intensities (20 mT-1.5 T), most studies reported autophagy activation, as evidenced by LC3-II accumulation, Beclin-1 upregulation, p62 degradation, and autophagic flux confirmation in select experimental models. Mechanistic analyses converged on PI3K/AKT/mTOR inhibition. Functionally, MF-induced autophagy conferred neuronal protection and drove behavioral recovery in models of Alzheimer's disease, vascular dementia, and stress, whereas it triggered autophagic cell death in cancer. Some studies reported incomplete flux or autophagosome accumulation. Risk of bias was generally unclear due to methodological heterogeneity. In summary, preclinical evidence indicates that MFs can act as versatile, non-pharmacological activators of autophagy. Defining optimal stimulation parameters, clarifying mechanistic pathways, and advancing translational studies will be essential for clinical application.},
}

@article {pmid42100730,
year = {2026},
author = {Copeland, EN and Marais, AAT and Mohammad, A and Marcella, BM and Baranowski, RW and Beaudette, SM and MacPherson, REK and Fajardo, VA},
title = {Tideglusib improves novel object recognition memory in the preclinical DBA/2J mdx mouse model of Duchenne muscular dystrophy.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1812975},
pmid = {42100730},
issn = {1662-4548},
abstract = {INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder characterized by progressive muscle wasting. Approximately 1 in 3 DMD patients experience cognitive dysfunction, with research suggesting an Alzheimer's disease (AD)-like pathology. We have previously shown that treatment with the glycogen synthase kinase 3β (GSK3) inhibitor, tideglusib, improves muscle quality, function, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. In this brief follow-up study, we report the effects of tideglusib treatment on cognitive function.

METHODS: Male D2 WT and mdx mice were purchased from Jackson Laboratories. Mice were separated into the following groups: (1) WT, (2) mdx-vehicle, and (3) mdx-tideglusib (10 mg/kg/day via oral gavage for 4 weeks). A novel object recognition test was performed to assess recognition memory. Hippocampus and serum samples were collected for BACE1 activity assays, amyloid beta (Aβ) ELISAs, and western blotting.

RESULTS: Compared to vehicle-treated mdx mice, tideglusib-treated mdx mice demonstrated improved recognition memory. These changes to recognition memory were accompanied by greater expression of beta-catenin, an indirect downstream marker of GSK3 inhibition. While there were no changes in BACE1 activity, tideglusib-treated mdx mice had higher concentrations of Aβ in the serum and lower protein levels of receptor of advanced glycation end products.

DISCUSSION: The results from this brief follow-up study offer preliminary support for tideglusib as a treatment for both muscle and brain impairments in mdx mice, potentially improving cognitive function through enhanced vascular Aβ clearance.},
}

@article {pmid42100765,
year = {2026},
author = {Zhu, Y and Ru, Y and Xie, J and Zuo, T and Hong, X and Wang, D},
title = {Development and application of an intelligent management and home care system for geriatric diseases under the 'Internet Plus' model: big data-based risk prediction and personalized intervention.},
journal = {Health information science and systems},
volume = {14},
number = {1},
pages = {63},
pmid = {42100765},
issn = {2047-2501},
abstract = {Under the "Internet Plus" model, this study aims to develop a proof‑of‑concept intelligent decision‑support system for elderly disease risk assessment, with a specific focus on Alzheimer's Disease (AD). The primary objective is to evaluate whether blood‑based transcriptomic biomarkers can be translated into an interpretable and scalable risk stratification framework suitable for home‑care and community health settings. Whole‑blood transcriptomic and associated clinical data were obtained from a publicly available microarray dataset comprising 329 individuals (144 AD, 104 MCI, and 81 cognitively normal controls). Transcriptomic features were used exclusively for model training, while clinical variables-including cognitive scores, frailty index, depression scores, and medication adherence-were used post hoc for risk annotation and alert simulation. Rigorous preprocessing and quality control were applied, followed by differential gene expression analysis using the limma framework and biologically informed biomarker selection. A Random Forest classifier trained on selected transcriptomic biomarkers achieved an accuracy of 91.2%, with sensitivity of 88.5% and specificity of 93.6% under stratified five‑fold cross‑validation. Model interpretability was supported through permutation‑based feature importance and SHAP analysis, enabling identification of key genes contributing to risk prediction. Based on probabilistic outputs, subjects were categorized into simplified alert states such as "Alzheimer's Risk Flagged" and "Monitoring Recommended." Although real‑time home monitoring data were not collected, the proposed system simulates how omics‑driven risk scores could be integrated into EMR‑compatible and IoT‑enabled care platforms. This study demonstrates a scalable and interpretable computational framework that bridges transcriptomic research and practical decision support, highlighting the potential of non‑invasive, individualized, and deployable risk assessment tools for elderly care, particularly in resource‑limited or home‑based environments.},
}

@article {pmid42100782,
year = {2026},
author = {Zhang, R and Sun, H and Di, Y and Cao, H and Zhang, C and Yao, H and Yan, H and Ding, D and He, Q and Wu, T},
title = {Sleep quality metrics combined with virtual reality motion parameters enhance early detection of mild cognitive impairment.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1727576},
pmid = {42100782},
issn = {1664-0640},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive and motor deficits. With its global prevalence increasing rapidly and no effective treatment available, early identification of high-risk individuals is critical. This study investigated the relationship between motor parameters extracted from virtual reality (VR) tasks, combined with sleep-related measures, and cognitive impairment in patients with mild cognitive impairment (MCI). Our goal was to determine whether integrating VR-derived digital markers with sleep quality metrics could provide an objective and clinically applicable tool for early detection.

METHODS: 66 participants were recruited, including 28 healthy controls (HC) and 38 patients with MCI. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). All participants performed two scenario-based VR tasks, during which task completion time, accuracy, and overall performance scores were recorded. Group differences were evaluated using independent-samples t-tests, and these behavioral features and sleep quality metrics were further incorporated into ROC analyze to assess predictive performance for distinguishing MCI from HC.

RESULTS: Compared with HC, patients with MCI reported significantly poorer sleep quality based on the Pittsburgh Sleep Quality Index (PSQI) and subdomains such as sleep latency and habitual sleep efficiency. In the VR tasks, MCI patients required more time and achieved lower accuracy than HC, consistent with MoCA and MMSE scores. Correlation analysis confirmed strong associations between VR performance metrics and cognitive test scores. Importantly, integrating VR-derived digital markers with sleep parameters yielded superior predictive accuracy for MCI (AUC = 0.863; sensitivity = 86.84%; specificity = 71.43%; p < 0.001) compared with single-modality models.

CONCLUSION: VR-based cognitive and sensorimotor tasks, when combined with sleep quality assessments, offer a robust and noninvasive approach for the early identification of prodromal AD. This multimodal strategy holds promise for enhancing clinical decision-making and enabling timely interventions.},
}

@article {pmid42100836,
year = {2026},
author = {Kaczmarek-Kryszak, KA and Dobrzyńska, M and Banaszak, M and Drzymała-Czyż, S},
title = {A comprehensive systematic review of human trials investigating herbal treatments for Alzheimer's disease and dementia.},
journal = {Acta neuropsychiatrica},
volume = {},
number = {},
pages = {1-55},
doi = {10.1017/neu.2026.10085},
pmid = {42100836},
issn = {1601-5215},
abstract = {OBJECTIVE: Dementia is a group of symptoms, characterized by a loss of cognition that interferes with everyday tasks, difficulty focusing, planning, problem solving, and behavioral changes, such as apathy, anxiety, or depression. The leading cause of dementia is Alzheimer's disease, but vascular dementia or mild cognitive impairment are also frequently occurring. There are six drugs legislated in Europe for use in the treatment of dementia. There are unmet clinical needs to find more effective, better tolerated or complementary therapeutic options. The aim of this study is to comprehensively analyze the results of clinical trials and other human studies regarding the efficacy and safety of herbal interventions used in patients with dementia.

METHODS: We enrolled a total of 48 studies for this systematic review, of which 27 were included into the statistical analysis of effect size (Cohen's d).

RESULTS: We found significant improvements mainly after administration of Ginkgo biloba, Crocus sativus, Salvia officinalis, and Melissa officinalis.It should be emphasized that some herbs and herbal formulations demonstrated efficacy comparable to that of donepezil, a widely used and approved medication, suggesting potential for phytopharmaceutical therapies as complementary approaches. In some studies, the observed effects were similar to those reported for conventional treatments, indicating promising directions for further research in Alzheimer's disease and dementia.

CONCLUSION: In light of the evidence, phytopharmaceuticals have a promising role as a co-therapeutic option or alternative for patients with dementia who do not tolerate or have contraindications to standard medications. However, further research is necessary to translate these initial promising results into clinical practice.

SUMMATIONS: Phytopharmaceuticals have a promising role as a complementary or alternative option for dementia patients who cannot tolerate or respond to standard medications. Certain phytopharmaceuticals demonstrated comparable short-term symptomatic effects to standard treatments in small trials; however, evidence is insufficient to support equivalence or superiority.

CONSIDERATIONS: Many of the studies reviewed are limited by very small sample sizes, which is associated with a high risk of bias when interpreting large effect sizes (Cohen's d). The short duration of interventions (often only 3 to 6 months) is insufficient to assess whether phytotherapeutics can constitute disease-modifying treatments (DMTs).},
}

@article {pmid42101083,
year = {2026},
author = {Cheng, J and Aung, CTZ and Suslavich, SF and Sahingur, SE and Hernandez-Kapila, YL},
title = {From senescence and inflammaging to systemic comorbidities: Drivers of aging-associated periodontitis.},
journal = {Periodontology 2000},
volume = {},
number = {},
pages = {},
doi = {10.1111/prd.70049},
pmid = {42101083},
issn = {1600-0757},
abstract = {BACKGROUND: Aging is accompanied by a chronic low-grade inflammatory process, known as inflammaging, as well as immunosenescence, an age-related decline and dysregulation of immune function, and cellular senescence, a process in which cells enter a state of irreversible growth arrest while actively releasing pro-inflammatory factors. These processes alter the host immune regulation and tissue homeostasis. Aging-associated mechanisms are being explored for their role in periodontal and peri-implant diseases because of their promotion of dysregulated inflammation, impaired healing, and heightened susceptibility to tissue destruction. Rather than viewing periodontitis as a condition driven solely by microbial burden, it should be understood as a multifactorial disease shaped by complex host-microbe interactions, in which host-driven processes, particularly senescence and inflammaging, play a central role in amplifying bidirectional oral-systemic interactions.

AIM: This scoping review aims to (i) highlight the current understanding of the role of aging and its alterations in host inflammatory responses on immune function, tissue homeostasis, and cellular stress responses; (ii) explore the potential impact of "inflammaging" on the periodontium and interactions with systemic health; and (iii) explore possible therapeutic targets for senotherapy.

MATERIALS AND METHODS: A literature search of the PubMed database was conducted using Boolean search strategies to identify publications related to the potential connections between aging and inflammation in the context of the oral cavity.

RESULTS: Of the total 283 articles that were screened, 87 met the eligibility criteria and were included in this scoping review. An additional 51 articles were obtained via manual search. The evidence demonstrates a link between inflammaging, age-related cellular senescence, and periodontal vulnerability to periodontal pathogens and periodontal destruction. Both experimental and clinical studies have shown increased senescence markers, dysregulated immune responses, and enhanced osteoclastic activity that lead to greater tissue destruction and alveolar bone loss. Systemic conditions such as Alzheimer's disease, diabetes, and cardiovascular disease can also amplify the inflammatory burden through shared pathways. Overall, our findings support the idea that older adults undergo immune dysregulation when challenged with microbes that ultimately cause a chronic periodontal inflammatory state.},
}

@article {pmid42101470,
year = {2026},
author = {Panchal, D and Solanki, D and Solanki, R and Yadav, AK and Bhatia, D and Yadav, P},
title = {Biomaterials and Nanoparticle-Based Therapeutics in Neurodegenerative Diseases: Bridging the Gap Between Innovation and Translation.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00245},
pmid = {42101470},
issn = {1948-7193},
abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and multiple sclerosis, represent a growing global health crisis characterized by irreversible neuronal loss, protein aggregation, chronic neuroinflammation, and mitochondrial dysfunction. Central to their therapeutic intractability is the blood-brain barrier (BBB), a highly selective neurovascular interface that excludes nearly 98% of conventional pharmacological agents from the central nervous system (CNS). Nanoparticle- and biomaterial-based delivery platforms have emerged as promising strategies to overcome these barriers, encompassing liposomes, polymeric nanoparticles, engineered exosomes, inorganic nanoparticles, and hydrogel scaffolds capable of enabling targeted CNS drug delivery. This Review systematically evaluates the landscape of nanomaterial-based neurotherapeutics across disease-specific pathological contexts, critically analyzing translational failure mechanisms including limited parenchymal brain exposure, receptor saturation during transcytosis, protein corona-mediated immune clearance, and nanoscale toxicity in postmitotic neural tissue. Preclinical-to-clinical translational gaps arising from interspecies BBB transporter heterogeneity and pharmacokinetic divergence are examined alongside manufacturing and regulatory barriers impeding Good Manufacturing Practice (GMP)-scale production. Emerging convergence strategies─including AI-integrated design, hybrid physiologically based pharmacokinetic modeling, theranostic nanoplatforms, and wearable bioresponsive delivery systems─are evaluated for their capacity to address these limitations. The review concludes by proposing a framework for developing clinically viable, disease-modifying CNS nanomedicines.},
}

@article {pmid42101516,
year = {2026},
author = {Zhou, B and Wu, X and Wang, J and Li, L and Xu, H and Shao, W},
title = {Compatibility of Acorus tatarinowii Schott and Polygala tenuifolia Willd. alleviate Alzheimer's disease through regulating Nos2-mediated calcium signaling pathway.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42101516},
issn = {1573-6903},
support = {ZY2023M027//the General Project of the Administration of Traditional Chinese Medicine of Hubei Province/ ; },
mesh = {PC12 Cells ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; Amyloid beta-Peptides/metabolism ; *Polygala/chemistry ; *Calcium Signaling/drug effects/physiology ; *Nitric Oxide Synthase Type II/metabolism ; *Acorus/chemistry ; *Plant Extracts/pharmacology/therapeutic use ; Cell Survival/drug effects ; Peptide Fragments/metabolism ; },
abstract = {Herb pair of Acorus tatarinowii Schott (ATS) and Polygala tenuifolia Willd. (PTW) is a classic drug pair in the treatment of Alzheimer's disease (AD), However, the mechanism by which the drug pair acts on AD is currently unknown. To address this, we constructed a PC12 cellular AD model using amyloid-beta peptide (Aβ) (25-35), follow by treating with different concentrations of ATS and PTW alone or their combination (1:1). The cell viability and Aβ-40, Aβ-42 and AQP4 expression were detected. In addition, RNA-sequencing combined with network pharmacology was performed to investigate the action mechanism of ATS and PTW, and the results were validated using in vitro experiments. The results showed that at drug-acting concentrations less than 100 mg/L, both single-agent and combined treatments of ATS and PTW increased the protective effects on PC12 cell, and the herb pair was superior to single-agent. In addition, both single-agent and combined treatments of ATS and PTW (at concentration of 100 mg/L) decreased Aβ-40, Aβ-42 and AQP4 expression compared with AD model. Further RNA-sequencing combined with network pharmacology analysis suggested that the underline action mechanism might be associated with Nos2-mediated calcium signaling pathway regulated. In vitro validation experiments showed that Nos2 overexpression increase the levels of Aβ-40, Aβ-42, AQP4, p-Tau, CaM, and p-CaMKII, which were reversed by the combination treatment of ATS and PTW. In conclusion, this work indicates that ATS and PTW combination might alleviate an Aβ-induced cellular model through regulating Nos2 - mediated calcium signaling pathway.},
}

PC12 Cells
Animals
*Alzheimer Disease/drug therapy/metabolism
Rats
Amyloid beta-Peptides/metabolism
*Polygala/chemistry
*Calcium Signaling/drug effects/physiology
*Nitric Oxide Synthase Type II/metabolism
*Acorus/chemistry
*Plant Extracts/pharmacology/therapeutic use
Cell Survival/drug effects
Peptide Fragments/metabolism

@article {pmid42101517,
year = {2026},
author = {Poli, M and Bonomi, CG and Di Donna, MG and Barberis, I and Ginevra, EL and Nuccetelli, M and Bernardini, S and Centonze, D and Martorana, A and Motta, C},
title = {Streamlining Alzheimer's disease diagnosis: real-world validation of two-cut-off diagnostic models based on plasma p-tau/Aβ42 ratios.},
journal = {Journal of neurology},
volume = {273},
number = {6},
pages = {},
pmid = {42101517},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood/cerebrospinal fluid ; *tau Proteins/blood/cerebrospinal fluid ; *Amyloid beta-Peptides/blood/cerebrospinal fluid ; Female ; Male ; Aged ; *Peptide Fragments/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; Sensitivity and Specificity ; },
abstract = {INTRODUCTION: Anti-amyloid monoclonal antibodies have increased the need for scalable, minimally invasive biomarkers for Alzheimer's disease (AD). In this single-center cohort study, we evaluated plasma biomarkers performance in detecting biologically defined AD, assessing diagnostic accuracy and generalizability outside dedicated laboratory settings and exploring suitability for clinical implementation.

METHODS: We enrolled 204 outpatients referred to the memory clinic of Policlinico "Rome Tor Vergata" who underwent standard work-up, lumbar puncture for cerebrospinal fluid (CSF) biomarkers and paired blood sampling. Among plasma biomarkers, phosphorylated tau (p-tau) 181, p-tau217, and their ratios adjusted for Aβ42 were measured on the Lumipulse platform. AD pathology was defined by CSF p-tau181/Aβ42 ≥ 0.069. ROC analyses estimated AUCs, and a two-cut-off approach targeting 90% sensitivity and specificity classified individuals as low, intermediate, or high AD risk. Subgroup analyses examined the impact of sex, age (< 75, ≥ 75 years), chronic kidney disease, and cognitive impairment (MMSE ≥ 26/30, < 26/30) on plasma biomarker levels.

RESULTS: Among single analytes, plasma p-tau217 showed the highest discriminative capacity (AUC 0.883). Combined ratios improved overall performance (p-tau181/Aβ42, AUC 0.928; p-tau217/Aβ42, AUC 0.894) and reduced intermediate-risk classifications to < 15%, with slightly better performance in women, patients < 75 and cognitively unimpaired. The two-cut-off model improved accuracy and rule-in ability.

DISCUSSION: Plasma p-tau/Aβ42 ratios show high and robust accuracy for detecting CSF-defined AD pathology. A two-step approach based on p-tau181/Aβ42 or p-tau217/Aβ42 could streamline diagnostic workflows in memory clinics, reserving second-line assessments to indeterminate cases and supporting selection of candidates for disease-modifying anti-amyloid therapies.},
}

Humans
*Alzheimer Disease/diagnosis/blood/cerebrospinal fluid
*tau Proteins/blood/cerebrospinal fluid
*Amyloid beta-Peptides/blood/cerebrospinal fluid
Female
Male
Aged
*Peptide Fragments/blood/cerebrospinal fluid
Biomarkers/blood/cerebrospinal fluid
Aged, 80 and over
Middle Aged
Cohort Studies
Sensitivity and Specificity

@article {pmid42101744,
year = {2026},
author = {Barrett-Young, A and Cawston, EE and Ryan, B and Abraham, WC and Ambler, A and Anderson, T and Cheyne, K and Goodin, E and Hogan, S and Houts, RM and Ireland, D and Knodt, AR and Kokaua, J and Melzer, TR and Ramrakha, S and Sugden, K and Williams, B and Wilson, P and Caspi, A and Hariri, AR and Moffitt, TE and Poulton, R and Theodore, R},
title = {Plasma pTau181 is associated with subjective cognitive concerns but not objective cognitive decline or structural brain integrity measures in midlife.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42101744},
issn = {2509-2723},
support = {2208-PRG//Neurological Foundation of New Zealand/ ; 16/604//Health Research Council of New Zealand/ ; 23/133//Health Research Council of New Zealand/ ; 24/690//Health Research Council of New Zealand/ ; R01AG069939/AG/NIA NIH HHS/United States ; R01AG032282/AG/NIA NIH HHS/United States ; R01AG049789/AG/NIA NIH HHS/United States ; MR/X021149/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Although plasma pTau181 has been shown to accurately discriminate patients with Alzheimer's disease from healthy older adults, there are few studies of plasma biomarkers among middle-aged populations. Given the potential utility of plasma AD biomarkers such as pTau181 in screening for disease risk, examining pTau181 in a middle-aged cohort without AD is important for future implementation. The objectives of this study were to characterise plasma pTau181 in a middle-aged birth cohort aged 45 years and to investigate associations with early indicators of dementia risk. Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972-1973. Plasma pTau181, self-reported cognitive concerns, MRI-based brain structure, and DunedinPACE (an epigenetic biomarker of biological ageing) were measured at age 45; cognition was measured in childhood and age 45. Plasma pTau181 concentrations at age 45 (n = 854, 49% female) were associated with self-reported cognitive concerns (β = 0.09, p = .008); however, no significant associations were observed with objective cognitive decline, worse structural brain integrity, or biological ageing. Higher plasma pTau181 was associated with self-reported cognitive concerns at age 45, but not objective AD-related measures. The association of plasma pTau181 and self-reported cognitive concerns in this cohort suggests that AD pathology may begin to accumulate by age 45 and may be associated with subtle changes in cognition that are not at objectively measurable levels.},
}

@article {pmid42101765,
year = {2026},
author = {Wong, WJ and Yang, SL and Subramaniam Kalianan, R and Teoh, CCO and Hwong, WY},
title = {Place of Death for People with Life-Limiting Illnesses in Malaysia: Trends (2005-2019) and Projections to 2030.},
journal = {Journal of epidemiology and global health},
volume = {},
number = {},
pages = {},
doi = {10.1007/s44197-026-00572-5},
pmid = {42101765},
issn = {2210-6014},
abstract = {BACKGROUND: Place of death (PoD) is an important component of end-of-life care as studies showed that home deaths are preferred among patients and caregivers. Studying trends in PoD is therefore essential to examine shifts in the distribution of PoD over time and inform decisions on future end-of-life care provision and policies. This study aimed to examine the past trends and future projections of PoD of patients with life-limiting illnesses in Malaysia.

METHODS: We analysed decedents aged 15 years and above who died from life-limiting illnesses between 2005 and 2019 using national mortality registry. PoD was categorized as home, hospital, care home and other. Future PoD trends were projected to 2030 using simple linear modelling, accounting for projected changes in the age and sex distribution of deaths. Multinomial logistic regression model was used to assess factors associated with PoD.

RESULTS: Between 2005 and 2019, 1,423,942 deaths were due to life-limiting illnesses; the most frequent cause was Alzheimer's disease, dementia and senility (37.0%, reflecting inclusion of non-medically certified senility deaths), followed by heart disease (22.9%) and malignant neoplasm (15.4%). The percentage of home deaths declined from 59.9% in 2005 to 49.2% in 2019. Contrastingly, percentages of hospital and care home deaths increased (35.1-45.2% and 0.6-1.1%). Based on current trend continuing, the proportion of home deaths is projected to decline further to 44.3% by 2030. Projection intervals were not calculated given the linear model assumptions; results should be interpreted as indicative trend extrapolations. Hospital deaths are projected to become the most common PoD and the largest proportion of deaths (48.3%). Decedents with Alzheimer's disease, dementia or senility had higher odds of dying at home than in hospital (AOR 31.66; 95% CI 31.14-32.19), while care home deaths were lower among females (AOR 0.85; 95% CI 0.82-0.89).

CONCLUSIONS: This study demonstrated an increasing trend in hospital deaths, a reduction in home deaths over time; hospitals are projected to become the most common PoD by 2030. The projected increase in hospital deaths raises considerations regarding the future sustainability of inpatient end-of-life care. These findings suggest potential needs to strengthen community palliative care services to meet future end-of-life care needs.},
}

@article {pmid42101771,
year = {2026},
author = {Seydi, KA and Kaya, D and Yavuz, I and Mahser, AC and Mutlay, F and Dost, FS and Isik, AT},
title = {Utility of the 4-meter backward walking speed test in older adults with neurodegenerative diseases.},
journal = {Irish journal of medical science},
volume = {},
number = {},
pages = {},
pmid = {42101771},
issn = {1863-4362},
abstract = {BACKGROUND AND AIM: Less is known about backward walking speed (BWS) in older adults. This study aims to establish a cutoff value for BWS to distinguish cognitively impaired individuals from healthy controls and to assess the association between backward walking slowing and risk of neurodegenerative diseases.

METHODS: 389 older patients, grouped into cognitively healthy (CH), amnestic mild cognitive impairment (aMCI), Alzheimer's disease (AD), Parkinson's disease (PD), and non-AD groups. BWS was measured using a standardized 4-meter protocol. Cognitive and functional status were evaluated via the comprehensive geriatric assessment. ROC analysis was used to determine the diagnostic threshold for BWS, and multinomial logistic regression was used to assess the associations.

RESULTS: A BWS cutoff of 0.395 m/s effectively distinguished CH individuals from those with neurodegenerative diseases (AUC=0.723). After adjusting for age, each 0.1 m/s decrease in BWS was associated with 22% increased odds of having aMCI, 37% increased odds of AD, 28% increased odds of PD, and 59% increased odds of having non-AD dementia. BWS showed a positive association with global cognitive scores in patients with CH and aMCI (p< 0.05) and with semantic verbal fluency scores in those with AD and aMCI (p< 0.05).

CONCLUSION: BWS is associated with an increased risk of neurodegenerative diseases, which can cause cognitive impairment, and may help indicate individuals at risk of cognitive decline.},
}

@article {pmid42101927,
year = {2026},
author = {Njume, CM and Petracci, I and Bellini, S and Goljanek-Whysall, K and Quinlan, LR and Fiszer, A and Borroni, B and Ghidoni, R and Kumbasar, A and Cakmak, A},
title = {When complexity does not pay: benchmarking deep learning and ensemble methods for biomarker discovery.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {3},
pages = {},
doi = {10.1093/bib/bbag211},
pmid = {42101927},
issn = {1477-4054},
support = {//Scientific and Technological Research Council of Turkey/ ; 124N069//EU Joint Programme-Neurodegenerative Disease Research/ ; TGA-2025-46998//Scientific Research Projects Unit of Istanbul Technical University/ ; 1009742021//National Center for High-Performance Computing/ ; //Italian Ministry of Health-EU Joint Programme-Neurodegenerative Disease Research/ ; 2023/05/Y/NZ3/00160//Polish National Science Centre/ ; JPND-2023-1/HRBI_/Health Research Board/Ireland ; },
mesh = {Humans ; *Deep Learning ; *Benchmarking ; *Biomarkers ; Alzheimer Disease/metabolism/genetics ; Breast Neoplasms/metabolism/genetics ; *Computational Biology/methods ; Female ; Support Vector Machine ; },
abstract = {The integration of multi-omics data holds great promise for identifying robust and clinically relevant biomarkers, yet the increasing complexity of computational methods raises questions about their practical utility. In this study, we present a comprehensive benchmarking framework that evaluates 27 feature selection strategies and 11 predictive models across three real-world disease cohorts: Alzheimer's disease, progressive supranuclear palsy, and breast cancer. We compare traditional machine learning, ensemble-based methods, and state-of-the-art deep learning models in terms of predictive performance, stability, and biological interpretability. Our results reveal that ensemble feature selection consistently improves robustness and accuracy, particularly for compact biomarker panels. Surprisingly, deep learning models did not outperform simpler classifiers such as logistic regression (L.Regression), support vector machines, or multilayer perceptrons, which often achieved comparable or superior results with lower computational cost and greater interpretability. Triple-omics yielded the highest validation, followed by dual-omics and then single-omics (Triple > Dual > Single). Biological validation against five independent databases confirmed the clinical relevance of the identified biomarkers, including both well-established and novel candidates. To support reproducibility and community adoption, we provide a web-based tool for applying our benchmarking pipeline. Our findings advocate for a pragmatic approach to biomarker discovery-prioritizing methodological transparency, reproducibility, and biological insight over algorithmic complexity.},
}

Humans
*Deep Learning
*Benchmarking
*Biomarkers
Alzheimer Disease/metabolism/genetics
Breast Neoplasms/metabolism/genetics
*Computational Biology/methods
Female
Support Vector Machine

@article {pmid42102034,
year = {2026},
author = {El-Nashar, HAS and Elhawary, EA and Nilofar, N and El Hassab, MA and Majrashi, TA and Eldehna, W and Zengin, G and Eldahshan, OA},
title = {Comparative metabolic profiling, enzyme inhibitory activities, and in-silico analysis of the hexane extract and the hydrodistilled oil of Boswellia serrata.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0348178},
doi = {10.1371/journal.pone.0348178},
pmid = {42102034},
issn = {1932-6203},
mesh = {*Boswellia/chemistry ; *Hexanes/chemistry ; *Plant Extracts/chemistry/pharmacology ; *Oils, Volatile/chemistry/pharmacology ; Gas Chromatography-Mass Spectrometry ; Antioxidants/pharmacology/chemistry ; *Enzyme Inhibitors/pharmacology/chemistry ; Computer Simulation ; Metabolomics ; *Metabolome ; alpha-Amylases/antagonists & inhibitors ; },
abstract = {Frankincense (Boswellia spp.) oleogum resin is a valuable natural source of bioactive phytoconstituents with diverse therapeutic potential. In this study, the hydrodistilled essential oil (EO) and n-hexane extract (HE) of Boswellia serrata gums were analyzed through gas chromatography-mass spectrometry (GC-MS) to determine their phytochemical composition. The GC-MS results in the identification of 62 and 71 components in the EO and HE, respectively. Acetic acid octyl ester (41.09%) and nerolidol (13.64%), were the major components of the EO. Meanwhile, incensole (28.56%), (1S,2E,4S,5R,7E,11E)-cembra-2,7,11-trien-4,5-diol (13.54%), and 24-norursa-3,12-diene (9.25%) in the HE. Regarding the antioxidant effects, the EO exhibited significantly higher antioxidant capacity compared to the HE (DPPH: 9.24 and 6.50 mg TE/g; ABTS: 25.71 and 4.94 mg TE/g), respectively. Moreover, the EO was more potent in the CUPRAC test (61.12 mg TE/g for the essential oil and 50.62 mg TE/g for HE), while the n-hexane extract (72.68 mg TE/g) showed stronger ability than the EO (13.22 mg TE/g) in the FRAP assay. The EO had a higher ability in phosphomolybdenum and metal chelation tests in comparison with the HE extracts. Further, the oil showed more potent inhibitory activity against cholinesterase, α-glucosidase, and tyrosinase than the HE extract. The HE extract was only more active on α-amylase compared to the oil. These findings suggest that olibanum EO possesses potent bioactive compounds that may contribute to the management of oxidative stress and age-related conditions, including Alzheimer's disease, diabetes mellitus, and skin hyperpigmentation.},
}

*Boswellia/chemistry
*Hexanes/chemistry
*Plant Extracts/chemistry/pharmacology
*Oils, Volatile/chemistry/pharmacology
Gas Chromatography-Mass Spectrometry
Antioxidants/pharmacology/chemistry
*Enzyme Inhibitors/pharmacology/chemistry
Computer Simulation
Metabolomics
*Metabolome
alpha-Amylases/antagonists & inhibitors

@article {pmid42102503,
year = {2026},
author = {Rafii, MS},
title = {Beyond amyloid positivity: Biological heterogeneity in the real-world use of lecanemab.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100584},
doi = {10.1016/j.tjpad.2026.100584},
pmid = {42102503},
issn = {2426-0266},
}

@article {pmid42102517,
year = {2026},
author = {Rajbanshi, B and Brentari, I and Denti, MA and Cummings, JL and Guruacharya, A},
title = {RNA-based therapeutics for Alzheimer's disease and related tauopathies: challenges and opportunities.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100585},
doi = {10.1016/j.tjpad.2026.100585},
pmid = {42102517},
issn = {2426-0266},
abstract = {Tauopathies are neurodegenerative diseases characterized by pathological tau protein accumulation. Though therapies involving monoclonal antibodies and small-molecule inhibitors have progressed, they have so far failed in multiple clinical trials, underscoring the need for innovative molecular approaches. RNA-based therapies offer an alternative disease-modifying approach by being able to target tau at its molecular origin. Diverse modalities, such as mRNA, ASO, RNAi, and SSO, offer distinct promises. Though their challenges are equally diverse, they also share common problems. This review examines the nascent field of RNA therapeutics for tauopathies, outlining emerging modalities, translational barriers, molecular targets, clinical trials, and patent trends.},
}

@article {pmid42102518,
year = {2026},
author = {Exalto, LG and Syaziyah, SS and Fang, XT and Prins, ND and Sikkes, SAM and van der Flier, WM and Vijverberg, EGB and Lim, YMF},
title = {Top five Alzheimer Disease trial eligibility criteria favor men compared to women in a clinic-based cohort.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100580},
doi = {10.1016/j.tjpad.2026.100580},
pmid = {42102518},
issn = {2426-0266},
abstract = {BACKGROUND: Less women participate in Alzheimer Disease (AD) trials compared to their estimated representation in the global dementia population.

OBJECTIVES: We aimed to apply five most commonly used eligibility criteria to a real-world memory clinic population to compare male and female eligibility according to these criteria.

DESIGN: Observational.

SETTING: Memory clinic setting.

PARTICIPANTS: Consecutive patients (2000-2024) from Amsterdam Dementia Cohort with a diagnosis of mild cognitive impairment (MCI) or AD (n = 3835).

MEASUREMENTS: Free-text eligibility criteria of n = 608 phase II and III AD drug trials were downloaded from ClinicalTrials.gov (March 28, 2025). A machine-learning model was trained and validated to extract all eligibility criteria. Next the criteria were applied on observational real world data from on memory clinic diagnostic work-up.

RESULTS: Top 5 most common AD clinical trial eligibility criteria were 1) no other central nervous system disorder related to cognitive impairment (84%), 2) participation of a caregiver (72%), 3) MMSE (66%, range 20-30), 4) no comorbidities, specifically vascular and mental health (62%), 5) no contra-indications for study procedures such as lumbar puncture, MRI and PET (59%). Applying the abovementioned criteria results in 33% of men and 23% of women remaining eligible (p<.001). Main reason for non-eligibility is caretaker absence (applicable for 20% of men and 38% of women) and low MMSE (32% of man and 54% of women).

CONCLUSION: Based on five commonly used eligibility criteria of AD clinical trials, women in our clinic-based cohort are less eligible for participation in AD drug trials than men. This discrepancy was mainly attributed to lack of caregiver presence and lower MMSE at presentation. These results provide clues for trial design to facilitate more equal inclusion of women.},
}

@article {pmid42102541,
year = {2026},
author = {Ota, S and Kakinuma, K and Katsuse, K and Kawakami, N and Morita, A and Kawamura, A and Ogawa, N and Iseki, C and Kanno, S and Matsuda, M and Suzuki, K},
title = {Anomic primary progressive aphasia with kanji-predominant dyslexia and dysgraphia.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {200},
number = {},
pages = {116-123},
doi = {10.1016/j.cortex.2026.04.013},
pmid = {42102541},
issn = {1973-8102},
abstract = {Reading and writing impairments in primary progressive aphasia (PPA) have received relatively limited attention both globally and in the Japanese context. Although several Japanese patients with anomic aphasia and kanji-predominant dysgraphia have been reported, kanji-predominant dyslexia at a relatively early stage has not been described. We report a case of anomic PPA presenting with kanji-predominant dyslexia and dysgraphia. A 69-year-old right-handed woman first noted word-finding difficulty at age 67 and subsequently developed reading difficulty. Examination revealed anomic aphasia with kanji-predominant dyslexia and dysgraphia. Reading errors occurred mainly with kanji irregular words. Kana word reading and writing were preserved, with reduced performance only in kana non-word reading. Reading sentences consisting of mixed kanji and kana revealed deficits in oral reading and comprehension. Visuospatial function remained intact. Cerebrospinal fluid biomarkers were compatible with Alzheimer's disease pathology. [123]I-iodoamphetamine single-photon emission computed tomography demonstrated hypoperfusion in the left inferior temporal region, most prominently in the middle to posterior fusiform gyrus. In contrast, five control patients with anomia and kanji dysgraphia, but without dyslexia, showed hypoperfusion confined to the left lateral temporal cortex, sparing the fusiform gyrus. These findings indicate that dysfunction of the left fusiform gyrus may contribute to the kanji-predominant dyslexia. Further studies are needed to better characterize script-specific deficits across languages and related brain regions in neurodegenerative language disorders.},
}

@article {pmid42102578,
year = {2026},
author = {Faraci, G and Goodfriend, B and Bishop, J and Vu, M and Avelar-Barragan, J and Dunham, SJB and Rothman, JA and Whiteson, KL and Cheema, AK and Milinkeviciute, G and Tenner, AJ and LaFerla, FM and MacGregor, GR and Green, KN and Mapstone, M},
title = {The TREM2 R47H variant is associated with liver-plasma-brain axis dyshomeostasis in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {165},
number = {},
pages = {24-37},
doi = {10.1016/j.neurobiolaging.2026.04.007},
pmid = {42102578},
issn = {1558-1497},
abstract = {The human Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene is expressed predominantly by microglia in the brain and the R47H coding variant of TREM2 is associated with increased risk for late-onset Alzheimer's disease (LOAD). We performed lipidomic and metabolomic analysis of liver, plasma, and brain in 4- and 12-month-old Trem2[R47H] homozygous (n = 27), 5xFAD hemizygous (n = 63), 5xFAD hemizygous, Trem2[R47H] homozygous (n = 25), and wild type (n = 65) mice. Lipid and metabolite abundances differed significantly across tissue types with the most differences seen in the liver and plasma of Trem2[R47H] mice at the 4-month timepoint. Cross-tissue correlation analyses revealed increased metabolic crosstalk along the liver-plasma-brain axis in Trem2[R47H] mice. Plasma triacylglyceride levels were significantly lower in females compared to males regardless of genotype, and 5-methyltetrahydrofolic acid levels were elevated in the brains of animals homozygous for the Trem2[R47H] variant. Together, these findings demonstrate early dyshomeostasis of the liver-plasma-brain axis of Trem2[R47H] mice which impacts several key metabolic pathways involving lipids, cellular energy metabolism, and brain folate metabolism.},
}

@article {pmid42102723,
year = {2026},
author = {Lee, SI and Luo, W and Gan, L},
title = {CAR-A astrocytes for Alzheimer's: Promise and challenge.},
journal = {Cell stem cell},
volume = {33},
number = {5},
pages = {720-721},
doi = {10.1016/j.stem.2026.04.008},
pmid = {42102723},
issn = {1875-9777},
mesh = {*Astrocytes/metabolism/immunology ; *Alzheimer Disease/therapy/pathology/immunology ; Humans ; *Receptors, Chimeric Antigen/metabolism/immunology ; Animals ; Amyloid beta-Peptides/metabolism/immunology ; },
abstract = {In a recent study in Science, Chen et al. engineer astrocytes with anti-amyloid chimeric antigen receptors (CARs) to enable sustained, antigen-directed clearance of amyloid-β (Aβ) in vivo, revealing how CAR design can shape both pathology and glial responses.},
}

*Astrocytes/metabolism/immunology
*Alzheimer Disease/therapy/pathology/immunology
Humans
*Receptors, Chimeric Antigen/metabolism/immunology
Animals
Amyloid beta-Peptides/metabolism/immunology

@article {pmid42102760,
year = {2026},
author = {Wu, X and Chen, Y and Liu, H and Sun, Z and Sun, P and Liu, Y and Shuai, P and Yang, H and Yang, L and Wan, Z},
title = {Association of dietary copper intake with Alzheimer's disease, brain structure and cognitive function.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {7},
pages = {100868},
doi = {10.1016/j.jnha.2026.100868},
pmid = {42102760},
issn = {1760-4788},
abstract = {OBJECTIVES: This study aimed to investigate the relationships between dietary copper intake and the risk of Alzheimer's disease (AD), cognitive function, and brain structural measures.

DESIGN: A combined prospective cohort and cross-sectional analysis.

SETTING: The UK Biobank.

PARTICIPANTS: This analysis included 126,660 participants (56,053 males and 70,607 females) from the UK Biobank who were free of baseline dementia and had complete dietary data. The mean age at baseline was 56.14 ± 7.83 years, and the median dietary copper intake was 1.33 mg/day (IQR: 1.10-1.61).

MEASUREMENTS: Dietary copper intake was assessed via 24-h dietary recalls. AD diagnosis was obtained from health records. Cognitive function and brain structural measures were derived from neuropsychological assessments and MRI scans, respectively. Cox proportional hazards models with restricted cubic splines were used to examine associations.

RESULTS: Over a median follow-up of 13.34 years, 619 participants developed AD. A nonlinear U-shaped association was observed between copper intake and AD risk (P for nonlinearity <0.001), with the lowest risk at an intake of 1.57 mg/day. Compared to the reference intake (1-2 mg/day), both lower and higher intakes were associated with increased AD risk, with the highest risk at intakes ≥3 mg/day (HR = 2.73, 95% CI: 1.53-4.87). This pattern remained consistent across subgroups stratified by genetic risk. Copper intake also showed significant nonlinear associations with cognitive function and brain structure, with optimal ranges consistently observed between approximately 1.3 and 2.0 mg/day.

CONCLUSION: Dietary copper intake exhibits a U-shaped association with AD risk, and maintaining intake within an appropriate range (approximately 1.3-2.0 mg/day) may help reduce AD risk and benefit cognitive function and brain health.},
}

@article {pmid42102977,
year = {2026},
author = {Zhang, J and Wang, C and Li, Y and Xiao, Z and Cai, Z and Qian, Y and Shi, L and Zhang, Q},
title = {Lipid Dysregulation as a Central Contributor of Neurodegenerative Diseases: Emerging Therapeutic Targets and Strategies.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103159},
doi = {10.1016/j.arr.2026.103159},
pmid = {42102977},
issn = {1872-9649},
abstract = {Lipid homeostasis is essential for preserving the structural integrity and functional capacity of the brain. A diverse array of lipids, including cholesterol, phospholipids, and sphingolipids, has been identified as playing pivotal roles. Dysregulation of lipid metabolism is increasingly recognized as a central pathological mechanism in neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Cerebrotendinous Xanthomatosis, though much of the existing evidence comes from associative studies, and causal relationships still need to be further validated through interventional studies. Here we systematically review the metabolic pathways and regulatory networks of major brain lipids, with a focus on delineating disease-specific alterations and summarizing emerging therapeutic strategies targeting lipid metabolism. These strategies encompass the modulation of cholesterol homeostasis, sphingolipid metabolism, phospholipid signaling, and fatty acid oxidation, alongside approaches that enhance lipid clearance and neural repair. Preclinical advances and ongoing clinical trials underscore the translational potential of lipid-targeted interventions. In conclusion, we emphasize the potential of lipid metabolism as a promising avenue for developing novel treatments, offering insights to guide future research and therapeutic innovation in neurodegeneration.},
}

@article {pmid42103033,
year = {2026},
author = {He, Z and Mao, Y and Chi, L and Sun, J},
title = {Astrocyte-mediated angiogenesis in CNS diseases: mechanisms and therapeutic implications.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111914},
doi = {10.1016/j.brainresbull.2026.111914},
pmid = {42103033},
issn = {1873-2747},
abstract = {Astrocytes are central, yet often underappreciated, regulators of angiogenesis in the central nervous system (CNS), exhibiting a profound context-dependent duality. They can foster restorative vascular repair after ischemic injury while simultaneously driving pathological vessel formation in tumors and other neurological disorders. This review synthesizes current knowledge on astrocyte-mediated angiogenesis across major CNS diseases, critically examining how disease-specific cues-such as hypoxia, tumor-derived factors, or Aβ plaques-are integrated to produce distinct vascular outcomes. We move beyond the binary A1/A2 paradigm to introduce a framework of "disease-associated astrocyte subsets" (e.g., ischemia-associated, glioma-associated, and Alzheimer's disease-associated astrocytes), as revealed by emerging single-cell studies. Key mechanisms are dissected, including the tightly regulated VEGF/Ang axis, HMGB1 signaling, the Sonic Hedgehog pathway, and the growing role of exosomal miRNA transfer. A central challenge highlighted is the temporal dichotomy of VEGF action, which transitions from acutely detrimental to beneficial during recovery. We explore therapeutic implications, from promoting reparative angiogenesis in ischemia to inhibiting pathological angiogenesis in glioblastoma. By identifying critical knowledge gaps, we propose future directions-such as astrocyte-specific gene editing and engineered exosomes-that aim to translate these insights into effective, context-specific CNS therapies.},
}

@article {pmid42090936,
year = {2026},
author = {Kose, MR and Ahirwal, MK and Atulkar, M},
title = {Causal ordinal connections based characterization of weighted effective brain network for schizophrenia detection.},
journal = {Psychiatry research. Neuroimaging},
volume = {361},
number = {},
pages = {112225},
doi = {10.1016/j.pscychresns.2026.112225},
pmid = {42090936},
issn = {1872-7506},
abstract = {The human brain is responsible for a wide range of a person's behavioral and cognitive capabilities. The functionality of the brain is affected by various disorders like schizophrenia, epilepsy, and Alzheimer. This study presents a novel framework for the automated detection of schizophrenia using EEG-based Weighted Effective Brain Connectivity Networks (WEBCNs). The proposed method introduces a new network descriptor called Weighted Directed Ordinal Connection (WDOC) that integrates causal directionality, connection strength, and ordinal relation between edges to capture complex brain dynamics. EEG signals from schizophrenia patients and healthy controls are preprocessed and transformed into WEBCNs using four causal connectivity estimators: Directed Transfer Function (DTF), Granger Causality (GC), Partial Directed Coherence (PDC), and Transfer Entropy (TE). WDOC-based features are extracted and classified using multiple machine learning algorithms, including KNN, SVM (linear, polynomial, RBF), and Random Forest. Among all models, the SVM with RBF kernel achieved the best performance, yielding 94.44% accuracy, 95% precision, 94% recall, and 89% kappa score for PDC-based networks. Structural and statistical analyses confirm distinct topological alterations in the causal flow between frontal and parietal regions in schizophrenia. The results demonstrate that WDOC-based characterization enhances discriminative power and interpretability in effective brain network analysis.},
}

@article {pmid42090937,
year = {2026},
author = {Rudraraju, A and Lakshmi, SV},
title = {Alzheimer's disease with progression analysis using a novel dilated convolutional attention based long short term memory model.},
journal = {Psychiatry research. Neuroimaging},
volume = {361},
number = {},
pages = {112232},
doi = {10.1016/j.pscychresns.2026.112232},
pmid = {42090937},
issn = {1872-7506},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative syndrome that affects memory, cognitive abilities and behaviour. Detecting AD in the early stage is crucial to improve the quality of life. However, traditional diagnostic approaches and manual analysis of neuroimaging data are slow, subjective and lead to human mistakes. Existing machine learning techniques often have difficulty in identifying complex patterns in high-dimensional biomedical data. These drawbacks emphasize the necessity for a more efficient and automated diagnostic system. This study introduced a new deep learning based hybrid framework for classifying and predict progression of AD. The method comprises three main steps: data acquisition, feature extraction and classification. Initially, EEG signals are collected from the CAU-EEG dataset. Then, features such as time domain features, frequency domain features and time frequency domain features are extracted. Finally, classification is performed by dilated convolutions attention based long short term memory (DC-ALSTM). Investigational results show that the proposed model outperforms existing baseline methods. DC-ALSTM achieved a classification 99.26% accuracy, 99.21% precision, recall at 99.23% and 99.22% F1-score, which indicates outstanding diagnostic capability.},
}

@article {pmid42091035,
year = {2026},
author = {Chandio, BQ and Olivetti, E and Romero-Bascones, D and Thomopoulos, SI and Villalon-Reina, JE and Nir, TM and Harezlak, J and Thompson, PM and Garyfallidis, E},
title = {BundleWarp: Enhancing white matter tractometry and morphometry with precise neuronal mapping using streamline-based nonlinear registration.},
journal = {Medical image analysis},
volume = {112},
number = {},
pages = {104114},
doi = {10.1016/j.media.2026.104114},
pmid = {42091035},
issn = {1361-8423},
abstract = {Tractometry analysis represents a significant advancement in neuroimaging, offering a detailed examination of the brain's white matter at a micro level. Unlike traditional ROI or voxel-based methods, tractometry precisely reconstructs and characterizes white matter tracts. Using advanced diffusion MRI and tractography algorithms, it maps the trajectory, shape, and connectivity patterns of individual white matter bundles. Accurate alignment of these tracts across different groups is crucial for reliable and reproducible results. Nonlinear registration techniques are essential for achieving this alignment, harmonizing bundle shapes, and improving sensitivity to disease-related changes. However, nonlinear registration is complex, especially with tractography data, which digitally represents the brain's white matter anatomy. Potential structural changes in the bundle's shape during registration can lead to artifacts that obscure critical anatomical details needed for disease identification. We introduce BundleWarp, a streamline-based nonlinear deformable registration method designed specifically for white matter tracts. BundleWarp employs a sophisticated approach to align two white matter bundles while preserving their topological and anatomical features. It is formulated as a probability density estimation problem with motion coherence penalties, ensuring coherent movement of points along streamlines and maintaining the anatomical integrity of tracts through displacement field regularization. Additionally, we introduce a tract morphometry framework utilizing the displacement field generated by BundleWarp to analyze white matter tract shape differences. Our results show that BundleWarp effectively quantifies bundle shape differences and enhances structural harmonization in tractometry analysis for diverse subjects, including those with Alzheimer's and Parkinson's disease. Test-retest experiments further demonstrate that BundleWarp substantially improves subject fingerprinting by increasing within-subject reproducibility of both bundle shape and microstructural profiles (FA, MD, RD, AD). It precisely maps the brain's neuronal pathways, offering a robust tractometry framework with enhanced sensitivity for detecting disease-related structural and microstructural changes in white matter tracts associated with Mild Cognitive Impairment (MCI), dementia, and early-stage Alzheimer's biomarkers, including amyloid-beta plaques and tau neurofibrillary tangles.},
}

@article {pmid42091041,
year = {2026},
author = {Plaza-Florido, A and Carrera-Bastos, P and Lucia, A},
title = {Exerkine GPLD1 bridges liver and brain.},
journal = {Cell metabolism},
volume = {38},
number = {5},
pages = {841-843},
doi = {10.1016/j.cmet.2026.04.002},
pmid = {42091041},
issn = {1932-7420},
mesh = {Humans ; *Brain/metabolism ; *Liver/metabolism ; *Phospholipase D/metabolism ; Animals ; *Exercise/physiology ; },
abstract = {A recent study by Bieri et al. shows that exercise elevates hepatic glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1), which cleaves endothelial tissue-nonspecific alkaline phosphatase (TNAP) to rejuvenate cerebrovascular signaling, enhance cognition in aging, and attenuate Alzheimer's-related pathology. This liver-to-brain enzymatic axis positions hepatokines as potent mediators of exercise-induced neuroprotection, which redefines systemic metabolism as a driver of brain resilience.},
}

Humans
*Brain/metabolism
*Liver/metabolism
*Phospholipase D/metabolism
Animals
*Exercise/physiology

@article {pmid42091384,
year = {2026},
author = {Guan, L and Mao, Z and Yang, S and Wu, G and Chen, Y and Yin, L and Qi, Y and Han, L and Xu, L},
title = {Corrigendum to "Dioscin alleviates Alzheimer's disease through regulating RAGE/NOX4 mediated oxidative stress and inflammation" [Biomed. Pharmacother. 152 (2022) 113248].},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {},
number = {},
pages = {119454},
doi = {10.1016/j.biopha.2026.119454},
pmid = {42091384},
issn = {1950-6007},
}

@article {pmid42091757,
year = {2026},
author = {Puthusseri, SP and Ravivarma, S and Johny, M and Vengellur, A},
title = {Hypoxia-inducible factor-1α: Dual roles in maintaining neuronal homeostasis and neuronal degeneration via regulation of oxidative stress, mitochondrial dynamics, and bioenergetics.},
journal = {Journal of physiology and biochemistry},
volume = {82},
number = {1},
pages = {},
pmid = {42091757},
issn = {1877-8755},
mesh = {*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics ; Humans ; *Oxidative Stress ; Energy Metabolism ; Animals ; *Neurons/metabolism/pathology ; *Mitochondrial Dynamics ; *Mitochondria/metabolism/pathology ; Homeostasis ; *Nerve Degeneration/metabolism/pathology ; },
abstract = {Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor with an inherently paradoxical biology: under mild-to-moderate hypoxic stress, it functions as a pro-survival regulator, yet under severe or prolonged hypoxia, the same signalling axis promotes apoptotic and autophagic cell death. This duality carries particular significance in neurons, where HIF-1α serves as a critical nexus among neuronal survival, metabolic adaptation, and mitochondrial integrity, and where the consequences of its dysregulation are most profound given their exceptional metabolic demands and limited regenerative capacity. This review examines the molecular determinants governing this protective-to-detrimental switch, integrating key interconnected dimensions: the context-dependent regulation of oxidative stress, the control of mitochondrial bioenergetics, dynamics, mitophagy, and axonal transport; the dual role of HIF-1α in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and cerebral ischemia; and the therapeutic implications of precision-targeted HIF-1α modulation. Across all these contexts, a consistent pattern emerges: early or acute HIF-1α activation is broadly neuroprotective, while chronic or severe hypoxic stress converts the same pathway into a driver of neurodegeneration. Understanding the determinants of this switch, including hypoxia duration, severity, and cell-type specificity, provides a framework for designing temporally precise therapeutic interventions for hypoxia-related neurological disorders.},
}

*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics
Humans
*Oxidative Stress
Energy Metabolism
Animals
*Neurons/metabolism/pathology
*Mitochondrial Dynamics
*Mitochondria/metabolism/pathology
Homeostasis
*Nerve Degeneration/metabolism/pathology

@article {pmid42091766,
year = {2026},
author = {Kumar, V and Kakoty, V and Wadhwa, P},
title = {Advancements in Gene Delivery using Nucleic Acid Loaded Nanoparticles for Region Specific Delivery in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42091766},
issn = {1559-1182},
mesh = {*Alzheimer Disease/therapy/genetics ; *Nanoparticles/chemistry/administration & dosage ; Humans ; *Gene Transfer Techniques ; Animals ; *Nucleic Acids/administration & dosage ; *Genetic Therapy/methods ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive and the most common neurodegenerative condition, having a deleterious effect on memory, eventually leading to death. In the recent past, gene therapy has emerged as a promising and revolutionary treatment for AD. This study demonstrated that nucleic acid-loaded nanoparticles which deliver small interfering RNA through lipid nanoparticles successfully reduced Alzheimer's disease-related symptoms in preclinical models by decreasing amyloid-β levels and enhancing cognitive abilities. However, every rose has its thorn, as the output of gene therapy is considerably hampered by the physiological barriers of the brain, which include the blood-brain barrier and the brain's extracellular matrix (ECM). For this reason, many researchers have modified the gene delivery technique by developing 'brain penetrating' NPs coated with components that can prevent sticking to the ECM. Moreover, to overcome the challenge of low transgene expression and reduced accumulation in the brain, even when delivered at high doses, scientists have proposed that injection/delivery of gene vectors directly into a specific area in the brain can achieve maximum therapeutic efficacy. Hence, this review focuses on the advancements and advantages of region-specific delivery of nucleic acid-loaded NPs for the effective therapeutic management of AD.},
}

*Alzheimer Disease/therapy/genetics
*Nanoparticles/chemistry/administration & dosage
Humans
*Gene Transfer Techniques
Animals
*Nucleic Acids/administration & dosage
*Genetic Therapy/methods
Brain/metabolism

@article {pmid42091792,
year = {2026},
author = {Otaegui, L and Lehoux, J and Begu, S and Moujellil-Legagneur, T and Zussy, C and Vitalis, M and Mathias, M and Beau, A and Durand, T and Givalois, L and Bernoud-Hubac, N and Crauste, C and Desrumaux, C},
title = {Intranasal lipid nanocapsule administration of the new lipophenol quercetin-3-O-DHA-7-O-iPr reduces carbonyl stress and improves behavior in a mouse model of Alzheimer's disease.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {42091792},
issn = {2190-3948},
support = {CBS2 PhD grant//Université Montpellier/ ; MUSE-AAP20REC-FRS09-GAiA//Université Montpellier/ ; PhD grant//Association France Alzheimer/ ; ANR-AAP2022-R22102FF-EpiNeurAge//Agence Nationale de la Recherche/ ; ANR-18-CE18-0017//Agence Nationale de la Recherche/ ; ANR-11-LABEX-0021-LipSTIC//Agence Nationale de la Recherche/ ; MND202003011477-OPA//Fondation pour la Recherche Médicale/ ; },
abstract = {Oxidative and carbonyl stresses (COS), which damage brain cells through the accumulation of toxic reactive carbonyl species (RCS), are key players in the etiology of Alzheimer's disease (AD). Our group developed lipophenols, i.e. COS-targeting hybrid molecules combining polyunsaturated fatty acids (PUFAs) and alkyl-(poly)phenols. Among them, quercetin-3-O-docosahexaenoate-7-O-isopropyl (Quercetin-3-O-DHA-7-O-iPr or "Q-iP-DHA") afforded neuroprotection against acrolein-induced toxicity, reduced carbonyl stress, and lowered amyloid-beta secretion in neuroblastoma cells. To evaluate Q-iP-DHA in vivo, it was formulated into lipid nanocapsules (to allow solubilization) then administered intranasally to J20 transgenic mice, a model of AD. This approach was chosen to optimize blood-brain barrier (BBB) penetration. This delivery led to improvements in well-being, organizational skills and spatial memory. In addition, Q-iP-DHA treatment reduced hippocampal amyloid plaque numbers, normalized expression of the Receptor for Advanced Glycation End-products (RAGE), and decreased microglial activation, indicating anti-inflammatory effects. Overall, our preclinical findings suggest that intranasal administration of nanoformulated Q-iP-DHA may represent a promising multitarget therapeutic approach against AD.},
}

@article {pmid42091863,
year = {2026},
author = {Corbett, A and Sander-Long, M and Ashton, NJ and Huber, H and Vavra, J and Braun-Wohlfahrt, LS and Zetterberg, H and Montoliu-Gaya, L and Cummings, J and Bateman, F and Davis, C and Ballard, C},
title = {Alzheimer's Disease blood biomarkers measured through remote capillary sampling correlate with cognition in older adults.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42091863},
issn = {2041-1723},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; Aged ; Male ; Female ; tau Proteins/blood ; *Cognition/physiology ; *Cognitive Dysfunction/blood/diagnosis ; Aged, 80 and over ; *Blood Specimen Collection/methods ; Middle Aged ; Capillaries ; },
abstract = {Blood biomarkers are rapidly becoming established for Alzheimer's Disease (AD) diagnosis. However, there is a need for more scalable tools to reach the 99% of individuals with early cognitive impairment who are not seen in specialist healthcare services. A recent study validated a capillary blood sampling technique to detect the p-tau217 and GFAP biomarkers. Here we used our PROTECT research study to show that these biomarkers, when collected using self-administered fingerprick tests, correlate well with venous blood biomarkers and with cognition and function in 174 people who were cognitively normal or who had mild cognitive impairment or AD. They can be used in combination with computerised cognitive testing to identify people with the highest risk of AD. The GFAP biomarker appears to be associated with vascular risk, unlike p-tau217. Patient feedback indicates high acceptability and usability of the capillary test method, giving confidence in the feasibility of this technology. The work suggests that capillary blood biomarkers could be used to enable triage of people with varying levels of risk of AD in clinical practice and for clinical trials, and could be used outside of clinical settings.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
Aged
Male
Female
tau Proteins/blood
*Cognition/physiology
*Cognitive Dysfunction/blood/diagnosis
Aged, 80 and over
*Blood Specimen Collection/methods
Middle Aged
Capillaries

@article {pmid42092056,
year = {2026},
author = {Teunissen, CE and van Harten, AC},
title = {Plasma biomarkers for Alzheimer disease: the road from laboratory results to clinical practice.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42092056},
issn = {1759-4766},
}

@article {pmid42092241,
year = {2026},
author = {Jiao, J and Wu, T and Li, F and Yang, S and Yu, C and Lv, S and Tian, S and Zhang, Z and Ge, Z and Jiang, J and Bi, Y},
title = {Associations of Visceral Obesity Indices and Risk of Mild Cognitive Impairment in Patients With Diabetes: A Retrospective Cohort Study.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.70832},
pmid = {42092241},
issn = {1463-1326},
support = {14380546//The Fundamental Research Funds for the Central Universities/ ; 2024ZD0523200//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; BK20240116//The Natural Science Foundation of Jiangsu Province of China/ ; BK20241721//The Natural Science Foundation of Jiangsu Province of China/ ; 82470866//National Natural Science Foundation of China Grant Awards/ ; 2024-92//National Chinese-Western Medicine Clinical Collaboration Project for Major Difficult Diseases/ ; BE2022666//The Key Research and Development Program of Jiangsu Province of China/ ; BE2023774//The Key Research and Development Program of Jiangsu Province of China/ ; 2022-LCYJ-ZD-03 and 2022-LCYJ-PY-02//Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University/ ; },
abstract = {AIMS: This study aimed to investigate the associations between visceral obesity indices and the risk of mild cognitive impairment (MCI) in patients with diabetes and to identify the most valuable visceral obesity index to develop a risk assessment nomogram.

MATERIALS AND METHODS: We explored the relationship between visceral obesity indices and MCI risk in patients with diabetes and developed a nomogram utilising a cohort of 1080 patients from Nanjing Drum Tower Hospital. MCI was diagnosed according to the criteria recommended by the National Institute on Aging-Alzheimer's Association Workgroup. Logistic regression models were used to identify factors independently associated with MCI in the cohort. Furthermore, the nomogram was externally validated by a multicenter retrospective cohort (Cohort 2) and a prospective cohort with a follow-up period of up to 10 years (Cohort 3).

RESULTS: We identified a positive but non-linear dose-response relationship between visceral obesity indices and the risk of MCI in patients with diabetes. Compared with a body shape index (ABSI), visceral adiposity index (VAI), lipid accumulation product (LAP) and Chinese visceral adiposity index (CVAI), body roundness index (BRI) exhibited superior discriminative ability (AUC: 0.734, 95% CI: 0.703-0.764). The nomogram constructed from BRI, age, education and haemoglobin A1c (HbA1c) achieved an optimal AUC of 0.804 (95% CI: 0.777-0.830) in the internal validation cohort. The model exhibited consistent performance across external validations, yielding a discriminative AUC of 0.756 (95% CI: 0.722-0.790) in Cohort 2 and a 10-year predictive AUC of 0.762 (95% CI: 0.727-0.797) in Cohort 3.

CONCLUSIONS: Higher visceral obesity indices were associated with an increased risk of MCI in patients with diabetes. Assessment of visceral obesity may help identify patients with diabetes who are at a high risk of MCI.},
}

@article {pmid42092335,
year = {2026},
author = {Shrestha, S and Zhu, X and Windham, BG and Sullivan, KJ and Palta, P and Gottesman, RF and Tracy, RP and Jack, CR and Cogswell, PM and Vemuri, P and Seshadri, S and Mosley, TH and Griswold, ME and Fornage, M},
title = {Associations of blood biomarkers of glial cell dysfunction and neuronal injury with future cognitive decline and incident dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71422},
doi = {10.1002/alz.71422},
pmid = {42092335},
issn = {1552-5279},
support = {75N92022D00001/HL/NHLBI NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; U01HL096812/NH/NIH HHS/United States ; U01HL096814/NH/NIH HHS/United States ; U01HL096899/NH/NIH HHS/United States ; U01HL096902/NH/NIH HHS/United States ; U01HL096917/NH/NIH HHS/United States ; U19NS120384/NH/NIH HHS/United States ; UH3NS100605/NH/NIH HHS/United States ; andUF1NS125513/NH/NIH HHS/United States ; R00AG052830/AG/NIA NIH HHS/United States ; Intramural Research Program/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/blood ; Female ; Male ; *Dementia/blood/epidemiology ; *Cognitive Dysfunction/blood ; Aged ; Chitinase-3-Like Protein 1/blood ; Glial Fibrillary Acidic Protein/blood ; *Neuroglia/pathology/metabolism ; tau Proteins/blood ; Middle Aged ; Prospective Studies ; Neurofilament Proteins/blood ; Ubiquitin Thiolesterase/blood ; *Neurons/pathology ; Incidence ; },
abstract = {INTRODUCTION: Prospective studies of blood-based biomarkers reflecting pathogenic processes, other than Alzheimer-specific pathologies, that contribute to dementia in diverse cohorts are lacking.

METHODS: We jointly fitted linear mixed-effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble cluster of differentiation-14 (sCD14), neurofilament light chain (NfL), total tau (t-tau), and ubiquitin C-terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community-based Atherosclerosis Risk in Communities Study. sCD14 and YKL-40 were measured in 3082 participants and the other four biomarkers in 1766 participants.

RESULTS: Higher serum GFAP, YKL-40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log-base2 YKL-40 was associated with -0.11SD faster 25-year cognitive decline (95% confidence interval [CI]: -0.15,-0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t-tau and UCHL1 were also associated with faster cognitive decline.

DISCUSSION: Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.},
}

Humans
*Biomarkers/blood
Female
Male
*Dementia/blood/epidemiology
*Cognitive Dysfunction/blood
Aged
Chitinase-3-Like Protein 1/blood
Glial Fibrillary Acidic Protein/blood
*Neuroglia/pathology/metabolism
tau Proteins/blood
Middle Aged
Prospective Studies
Neurofilament Proteins/blood
Ubiquitin Thiolesterase/blood
*Neurons/pathology
Incidence

@article {pmid42092343,
year = {2026},
author = {Burkett, BJ and Wiste, HJ and Johnson, DR and Boeve, BF and Kantarci, K and Petersen, RC and Knopman, DS and Vemuri, P and Graff-Radford, J and Lowe, V and Cogswell, PM and Pillai, J and Schwarz, CG and Nguyen, AT and Murray, ME and Dickson, DW and Jack, CR},
title = {Abnormal amyloid PET usually represents intermediate/high Alzheimer's disease neuropathologic change.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71449},
doi = {10.1002/alz.71449},
pmid = {42092343},
issn = {1552-5279},
support = {//Alexander Family Professorship of Alzheimer's Disease Research/ ; //GHR Foundation/ ; P30 AG062677//Foundation for the National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *Positron-Emission Tomography ; Male ; Female ; Autopsy ; Aged ; *Brain/pathology/diagnostic imaging/metabolism ; Aged, 80 and over ; *Amyloid/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET.

METHODS: Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years).

RESULTS: Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death (n = 39) not/low ADNC occurred in 3/39 (8%).

DISCUSSION: Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
*Positron-Emission Tomography
Male
Female
Autopsy
Aged
*Brain/pathology/diagnostic imaging/metabolism
Aged, 80 and over
*Amyloid/metabolism

@article {pmid42092345,
year = {2026},
author = {Butler, CA and Gee, MS and O'Gara, K and Milinkeviciute, G and Da Cunha, C and Kawauchi, S and Lu, YH and Kwang, N and Tsourmas, KI and Prekopa, C and Shi, Z and Liang, HY and Collins, SD and Pashkutz, ZA and Sanchez, JA and Shi, KX and Walker, AD and Wang, S and Wong, MLA and Genaro, K and Neumann, J and Gomez-Arboledas, A and Duong, DM and Seyfried, NT and Tenner, AJ and LaFerla, FM and Mortazavi, A and Swarup, V and MacGregor, GR and Green, KN},
title = {Abi3[S212F] Alzheimer's disease variant alters plaque structure and disrupts microglia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71452},
doi = {10.1002/alz.71452},
pmid = {42092345},
issn = {1552-5279},
support = {U54 AG054349/AG/NIA NIH HHS/United States ; P30CA62203//Chao Family Comprehensive Cancer Center/ ; },
mesh = {*Microglia/pathology/metabolism ; *Alzheimer Disease/genetics/pathology ; Animals ; *Plaque, Amyloid/pathology/genetics ; Mice ; Humans ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Cytoskeletal Proteins/genetics ; Brain/pathology ; },
abstract = {BACKGROUND: Genetic variants affecting microglial function can influence Alzheimer's disease (AD) risk, yet the underlying mechanisms remain unclear. The AD-associated ABI3[S209F] (Abi3[S212F] in mouse) variant regulates cytoskeletal dynamics, but its in vivo impact on pathology is unknown.

METHODS: An Abi3[S212F] mouse was developed and crossed with two humanized amyloid beta (Aβ) models. Amyloid pathology, microglial survival, and remodeling were analyzed using confocal imaging, biochemical assays, spatial transcriptomics, and single-cell analyses across the lifespan.

RESULTS: Abi3[S212F] produced a dysfunctional microglial state that reduced dense-core plaque compaction, selectively lowering dense-core burden without affecting diffuse or total Aβ. The variant also caused microglial loss via apoptosis and pyroptosis, requiring aging and human Aβ but occurring even without plaques, indicating plaque-independent vulnerability. Spatial transcriptomics revealed an age-dependent shift toward an Abi3-high state that predisposes microglia to degeneration.

DISCUSSION: Abi3[S212F] produces microglial dysfunction and vulnerability, highlighting cytoskeletal and cell death pathways as therapeutic targets.},
}

*Microglia/pathology/metabolism
*Alzheimer Disease/genetics/pathology
Animals
*Plaque, Amyloid/pathology/genetics
Mice
Humans
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Cytoskeletal Proteins/genetics
Brain/pathology

@article {pmid42092516,
year = {2026},
author = {Jaiswal, A and Sinnarkar, V and Sharma, DB},
title = {Comment on "Effect of extra virgin olive oil on mild cognitive impairment and dementia in older adults: a systematic review and meta-analysis of clinical trials".},
journal = {Clinical nutrition ESPEN},
volume = {},
number = {},
pages = {103313},
doi = {10.1016/j.clnesp.2026.103313},
pmid = {42092516},
issn = {2405-4577},
}

@article {pmid42092578,
year = {2026},
author = {Mohammady, RW and Samir, RK and Sayed, RM and Malak, MH and Magdy, MK and Mohamed, RG and Tawfiq, AH and Kamel, RA and Kamel, NM},
title = {Targeting eukaryotic elongation factor 2 (eEF2)/eEF2 kinase in neurological and neuropsychiatric Disorders: Mechanisms, therapeutic Implications, and translational challenges.},
journal = {Brain research},
volume = {1886},
number = {},
pages = {150368},
doi = {10.1016/j.brainres.2026.150368},
pmid = {42092578},
issn = {1872-6240},
abstract = {Eukaryotic elongation factor 2 kinase (eEF2K) phosphorylates eukaryotic elongation factor 2 (eEF2) and slows translation elongation. In the nervous system, this pathway links neuronal activity, calcium signaling, energy status, and stress responses to selective protein synthesis programs that shape synaptic plasticity, circuit excitability, and cell survival. Dysregulated eEF2K/eEF2 signaling has been implicated in epilepsy, Alzheimer's disease, Parkinson's disease, major depressive disorder, Down syndrome, and other brain conditions. However, the literature remains fragmented, largely preclinical, and often interpreted in an overly therapeutic manner. This review synthesizes the field using a mechanistic framework. Across disorders, altered eEF2 phosphorylation converges on five major axes: synaptic plasticity and excitatory/inhibitory balance, oxidative and mitochondrial stress responses, neuroinflammation/neuroimmune regulation, and aging-related neurogenesis and cognitive resilience. In chronic neurodegenerative and neurodevelopmental settings, excessive eEF2K activity is frequently associated with impaired de novo protein synthesis, synaptic dysfunction, and cognitive decline, whereas genetic or pharmacological suppression can improve selected behavioral and electrophysiological outcomes. By contrast, in acute metabolic stress or certain immune-cell contexts, eEF2K activity may serve adaptive and anti-inflammatory functions. These findings indicate that eEF2K has context-dependent, rather than uniformly pathogenic, roles. We also highlight major translational barriers, including dependence on rodent models, limited causal human data, incomplete cell-type resolution, and the off-target liabilities of commonly used inhibitors such as NH125 and A-484954. Overall, the eEF2K/eEF2 axis represents a biologically important but therapeutically complex target that will require selective, cell-aware, and stage-specific modulation. Future progress depends on better biomarkers, human models, and more selective brain-penetrant inhibitors.},
}

@article {pmid42092705,
year = {2026},
author = {Sun, M and Zhao, X and Gao, K and Ding, G and Yu, J},
title = {Hypothalamic microstructure and function are associated with mild cognitive impairment in aging.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111921},
doi = {10.1016/j.brainresbull.2026.111921},
pmid = {42092705},
issn = {1873-2747},
abstract = {BACKGROUND: The hypothalamus serves as a critical neuroendocrine center, yet its specific topographical and microarchitectural vulnerabilities during the preclinical stages of Alzheimer's disease remain poorly elucidated. This study aimed to comprehensively investigate the macroscopic volumetric and microstructural alterations within hypothalamic subregions in patients with mild cognitive impairment (MCI) and their associations with cognitive and functional decline.

METHODS: In this cross-sectional study, a total of 92 participants, comprising 47 MCI patients and 45 healthy controls (HC), underwent 3T multimodal magnetic resonance imaging. The hypothalamus was automatically segmented into five bilateral subregions. Macroscopic volumetry (adjusted for estimated total intracranial volume) and diffusion tensor imaging (DTI) metrics-including fractional anisotropy (FA) and mean diffusivity (MD)-were extracted. Multiple regression models and sex-stratified correlation analyses were utilized to map structural trajectories against age, education, and clinical assessments.

RESULTS: Hypothalamic alterations in MCI showed marked spatial heterogeneity and sexual dimorphism. Age-related volume loss was observed in HCs, whereas MCI patients exhibited sex-specific atrophic trajectories. MCI patients showed significantly reduced FA in the left anterior-inferior subregion compared with HCs. Microstructural disruption in the left tubular-superior subregion was significantly associated with lower MMSE scores and higher ADL scores. Higher educational attainment was independently associated with preserved microstructure in the posterior hypothalamus, supporting the cognitive reserve hypothesis.

CONCLUSION: Hypothalamic degeneration in MCI is a spatially heterogeneous and sex-specific process. Localized microstructural disruption, especially in the left tubular-superior subregion, represents a sensitive imaging biomarker for early cognitive and functional impairment.},
}

@article {pmid42092970,
year = {2026},
author = {Liu, H and Hu, C and Liu, H and Gong, Z and Jiang, S and Xie, J and Li, Y and Liu, C and Wang, Y and Zou, C and Yang, G},
title = {Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03815-1},
pmid = {42092970},
issn = {1742-2094},
support = {2023JJ40952//the Natural Science Foundation of Hunan Province/ ; 2024JJ6618//the Natural Science Foundation of Hunan Province/ ; 82204733//Foundation for Innovative Research Groups of the National Natural Science Foundation of China/ ; 20254677//Health Research Project of Hunan Provincial Health/ ; 82474009//the National Natural Science Foundation of China/ ; },
abstract = {The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing module that links DNA damage and mitochondrial dysfunction to innate immune activation. Here, we focus on canonical cGAS-STING signaling in the central nervous system (CNS) and discuss non-canonical branches only when directly relevant to neurodegeneration. We summarize structural and activation-termination mechanisms and synthesize cell-type-biased outputs across microglia, astrocytes, neurons, and oligodendroglial lineage cells. We then integrate Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease by mapping shared DNA-stress triggers to multicellular amplification loops and by grading causal evidence from genetic perturbation, pharmacological pathway interference, and correlative human datasets. Finally, we classify inhibitor modalities and emerging enabling technologies while emphasizing translational constraints, including blood-brain barrier (BBB) delivery, long-term safety, human STING-allele diversity, and pharmacodynamic biomarkers. Collectively, we propose an evidence-calibrated framework for judging when cGAS-STING is most plausibly positioned as a causal node, a permissive amplifier, or a secondary correlate in neurodegenerative disease, and where therapeutic translation should proceed cautiously.},
}

@article {pmid42093338,
year = {2026},
author = {Silva, MG and Vasconcelos, MB and Silva, RG and Feitosa, MÁL},
title = {Oral Health in Alzheimer's Disease: A Life-Course Perspective on Clinical Management and Caregiver Support.},
journal = {Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry},
volume = {46},
number = {3},
pages = {e70179},
doi = {10.1111/scd.70179},
pmid = {42093338},
issn = {1754-4505},
support = {Finance Code 001//the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
mesh = {Humans ; *Alzheimer Disease/complications ; *Caregivers/psychology ; *Oral Health ; },
abstract = {AIM: To synthesize current evidence on oral health conditions in individuals with AD and to discuss stage-specific dental management strategies, including caregiver involvement, from a life-course perspective.

METHODS: A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, Scielo, and Web of Science using MeSH and free-text terms related to Alzheimer's disease, oral health, and caregivers, with no language or time restrictions.

RESULTS: Individuals with AD commonly present with periodontal disease, root caries, xerostomia, traumatic mucosal lesions, and prosthesis-related complications. The available evidence does not strongly support a bidirectional causal relationship; instead, poor oral health and AD appear to be cumulative conditions influenced by shared antecedent factors, such as biological aging and chronic inflammation. Functional dependence and behavioral symptoms further contribute to oral deterioration over time. Effective dental care therefore requires stage-adapted approaches, ranging from preventive and restorative interventions in early stages to palliative strategies focused on infection control and comfort in advanced disease.

CONCLUSION: Oral health care for individuals with AD should be grounded in a life-course and biopsychosocial framework, prioritizing realistic, stage-specific clinical management and structured caregiver support within interdisciplinary geriatric care.},
}

Humans
*Alzheimer Disease/complications
*Caregivers/psychology
*Oral Health

@article {pmid42093362,
year = {2026},
author = {Liu, Q and Wang, Y and Wang, B and Wang, J and Zhang, M and Liu, Y and Min, X},
title = {Ziziphus jujuba Mill. Suspension Ameliorates Scopolamine-Induced Cognitive Impairment via PTGS2-Centered Neuroinflammatory Signaling.},
journal = {Mediators of inflammation},
volume = {2026},
number = {1},
pages = {e8871660},
doi = {10.1155/mi/8871660},
pmid = {42093362},
issn = {1466-1861},
support = {2022-JYJ-153//Luzhou Science and Technology Bureau/ ; 2022QN114//Natural Science Foundation of Southwest Medical University/ ; },
mesh = {Animals ; *Ziziphus/chemistry ; Mice ; *Scopolamine/toxicity ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; *Cyclooxygenase 2/metabolism ; Male ; Signal Transduction/drug effects ; Molecular Docking Simulation ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Mice, Inbred C57BL ; Inflammation/metabolism/drug therapy ; },
abstract = {BACKGROUND: Cognitive impairment is a common feature of neurodegenerative diseases, in which sustained neuroinflammation critically contributes to neuronal dysfunction and memory decline. As a representative condition, Alzheimer's disease (AD) provides key insights into inflammation-associated cognitive impairment. However, current anti-inflammatory interventions exhibit limited efficacy and potential adverse effects, highlighting the need for safer strategies targeting neuroinflammation-related cognitive dysfunction.

OBJECTIVE: Guided by the concept of food-medicine homology, this study aimed to elucidate the molecular mechanisms by which Ziziphus jujuba alleviates cognitive impairment associated with neuroinflammation.

METHODS: AD-relevant targets associated with cognitive dysfunction were obtained from Gene Expression Omnibus (GEO) and GeneCards, and active compounds of Z. jujuba were retrieved from traditional Chinese medicine systems pharmacology (TCMSP). Shared targets were prioritized using least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machine (SVM) algorithms. The diagnostic value of the core target was evaluated by receiver operating characteristic (ROC) analysis and a nomogram model with calibration and decision curve analysis (DCA). Functional enrichment, localization analyses, and molecular docking were performed. Experimental validation was conducted in a scopolamine-induced cognitive impairment mouse model using the Morris water maze (MWM), histopathology, and western blotting.

RESULTS: PTGS2 was identified as a key inflammatory target associated with neuroinflammation-related cognitive impairment and was enriched in the NOD-like receptor (NLR) signaling pathway. ROC and nomogram analyses indicated good diagnostic and predictive performance (area under the curve [AUC] > 0.7). PTGS2 was localized on chromosome 1 and showed relatively high expression in the cerebral cortex. Z. jujuba compounds exhibited strong binding to PTGS2 (ΔG ≤ -8.0 kcal/mol). In vivo, Z. jujuba improved cognitive performance, alleviated hippocampal injury, and downregulated PTGS2 and related inflammatory signaling pathways, including NLRP3/NF-κB/MAPK and interleukin (IL)-1β.

CONCLUSION: This study demonstrates that Z. jujuba ameliorates neuroinflammation-related cognitive dysfunction primarily by suppressing PTGS2-centered inflammatory signaling. Integrating computational analyses and in vivo validation in scopolamine-induced mice, our findings support Z. jujuba as a safe multitarget intervention for inflammation-associated cognitive impairment and highlight the potential of food-medicine homology in neuroinflammatory cognitive disorders.},
}

Animals
*Ziziphus/chemistry
Mice
*Scopolamine/toxicity
*Cognitive Dysfunction/drug therapy/chemically induced/metabolism
*Cyclooxygenase 2/metabolism
Male
Signal Transduction/drug effects
Molecular Docking Simulation
*Neuroinflammatory Diseases/drug therapy/metabolism
Mice, Inbred C57BL
Inflammation/metabolism/drug therapy

@article {pmid42093397,
year = {2026},
author = {Patir, S and Baruah, A},
title = {Computational investigation of BMS-984923 against Alzheimer's amyloid-beta (Aβ) structures: insights into their molecular interactions and inhibition of aggregation.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5cp04916d},
pmid = {42093397},
issn = {1463-9084},
abstract = {Normal brain function involves soluble Aβ peptides that support synaptic activity. However, Aβ peptides are prone to aggregation under abnormal or pathogenic conditions, forming clumps known as oligomers and protofibrils, which subsequently lead to the formation of mature, stable β-sheet rich fibrils. The accumulation of such misfolded amyloid aggregates in the brain is the hallmark of Alzheimer's disease (AD). Recent experimental studies suggested that BMS-984923 successfully blocks the action of Aβ induced toxicity while preserving glutamate signaling via the metabotropic glutamate receptor 5 (mGluR5), which is a key excitatory neurotransmitter in the brain. However, the molecular mechanism by which BMS-984923 interacts with Aβ peptide remains unclear. In this work, we investigated the inhibitory mechanism of BMS-984923 against the Aβ monomeric structures with the help of molecular docking and molecular dynamics (MD) simulations. To elucidate the atomic level interactions, we employed DSSP for performing secondary structure analysis, MM-PBSA, per-residue decomposition and free energy landscape (FEL) analyses. The two representative structures from the apo simulation are further subjected to MD simulation, followed by similar analyses. MD simulation analyses revealed the distinct modes of ligand interaction across the different monomeric forms, accompanied by extensive contacts with residues in the binding region. Therefore, our study, which provides insights for evaluating the efficacy of BMS-984923 to facilitate subsequent binding with the target protein, will offer a framework for the rational design of potential inhibitors against the pathogenic Aβ peptide.},
}

@article {pmid42093461,
year = {2026},
author = {Andreão, FF and da Silva, RO and Negreli, MFLA and Aguiar-Barros, ABP and Santos, DH},
title = {Baseline epidemiological differences between donanemab and lecanemab users in real-world settings: a retrospective cohort study.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/17582024.2026.2667432},
pmid = {42093461},
issn = {1758-2032},
abstract = {AIMS: Donanemab and Lecanemab are anti-amyloid monoclonal antibodies recently approved for the treatment of Alzheimer's disease. Although their efficacy and safety have been investigated in randomized trials, real-world epidemiological data on treated populations remain limited. This study aimed to compare baseline clinical and laboratory characteristics of patients treated with donanemab versus lecanemab in routine practice.

PATIENTS AND METHODS: We conducted a retrospective analysis using the TriNetX US Collaborative Network, including patients with Alzheimer's disease treated with donanemab or lecanemab between January 2024 and September 2025. Demographics, laboratory values, comorbidities, and concomitant medications were compared using standardized mean differences (SMD) and p-values. Variables with SMD ≥0.1 or p < 0.05 were considered meaningfully different.

RESULTS: A total of 1,799 patients were included (donanemab n = 360; lecanemab n = 1,439). Demographic characteristics were well balanced (mean age 73.1 vs 72.5 years; SMD 0.028). Lecanemab users were more likely to be prescribed antidepressants (52% vs 41%; p < 0.0001; SMD = 0.23) and donepezil (61% vs 52%; p = 0.0145; SMD = 0.14). Donanemab users had higher prothrombin time (12.2 ± 2.17 vs 11.8 ± 1.66 s; p = 0.0158; SMD = 0.20) and INR (1.06 ± 0.19 vs 1.03 ± 0.13; p = 0.0369; SMD = 0.17), and a higher prevalence of vascular dementia (81% vs 76%; p = 0.0272; SMD = 0.12).

CONCLUSION: While demographic variables were similar. These findings likely reflect real-world clinical selection patterns and should be accounted for in comparative effectiveness and safety analyses of anti-amyloid therapies.},
}

@article {pmid42093645,
year = {2026},
author = {Dolai, S and Alam, A},
title = {Lipid transport mechanisms in human ABCA family transporters: a structural perspective.},
journal = {Biochemical Society transactions},
volume = {54},
number = {5},
pages = {477-488},
doi = {10.1042/BST20250138},
pmid = {42093645},
issn = {1470-8752},
support = {5R01GM146906//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R21AG069180//HHS | NIH | National Institute on Aging (NIA)/ ; },
mesh = {Humans ; *ATP-Binding Cassette Transporters/metabolism/chemistry ; Biological Transport ; *Lipid Metabolism ; Lipid Bilayers/metabolism/chemistry ; Protein Conformation ; Models, Molecular ; },
abstract = {ATP-binding cassette (ABC) transporters are essential membrane proteins that couple ATP hydrolysis to move diverse substrates across lipid bilayers through large-scale conformational changes. In humans, 48 ABC transporters span seven subfamilies (A-G); within these, the ABCA subfamily mediates cellular lipid handling in contexts ranging from neural function to pulmonary surfactant production, and its dysfunction contributes to human disease from cardiovascular disorders to Alzheimer's. These diverse physiological roles all depend on precise lipid translocation within or across membrane systems, a shared principle that is often underemphasized in broad "lipid-transporter" classifications. This review summarizes the structural landscape of the ABCA family and re-examines the mechanistic insights that have emerged. We compare and contrast transport models derived from detergent-solubilized and lipid-embedded structures, with particular emphasis on lipid-embedded ABCA7, which supports a membrane-integrated mechanism in which the bilayer itself contributes to the transport pathway. We highlight shared rigid-body transitions, outline open questions surrounding transport directionality and protein-lipid coupling, and suggest that future models should treat the membrane not merely as a passive scaffold but as an integral component of the transport mechanism, while recognizing that membrane-integrated behavior is currently established structurally only for ABCA7 and remains a working hypothesis for other family members.},
}

Humans
*ATP-Binding Cassette Transporters/metabolism/chemistry
Biological Transport
*Lipid Metabolism
Lipid Bilayers/metabolism/chemistry
Protein Conformation
Models, Molecular

@article {pmid42093680,
year = {2026},
author = {Wu, J and Li, X and Liu, W and Ma, Y and Zhao, Q and Xiao, M and Wang, J},
title = {The Feasibility and Preliminary Effects of a Stress Process Model-Based Program in Dementia Caregiving (DeCare-SPM) for Family Caregivers: A Mixed-Methods Pilot Study.},
journal = {Journal of multidisciplinary healthcare},
volume = {19},
number = {},
pages = {585820},
pmid = {42093680},
issn = {1178-2390},
abstract = {BACKGROUND: Dementia caregiving causes significant stress, making psychosocial interventions crucial. However, its success depends on effective implementation. This study aimed to evaluate the feasibility, acceptability, and preliminary effects of DeCare-SPM, a theory-driven program designed to enhance positive aspects of caregiving and reduce burden.

METHODS: A single-group pre-post study without a control group, using an embedded mixed-methods design, was conducted from June to July 2023. The 1-month intervention included three face-to-face sessions and four weekly telephone-based consultations. The feasibility was evaluated through recruitment rate, adherence, and satisfaction. Focus group interviews with implementers and caregivers provided qualitative insights. Preliminary effects on positive aspects of caregiving (PAC), caregiver burden, sense of competence, social network, anxiety and depression, quality of life for caregivers, and neuropsychiatric symptoms and quality of life for individuals with dementia were measured at the end of the 1-month intervention period.

RESULTS: 32 caregivers were recruited; no dropouts. 81.3% (26/32) attended all sessions, and 87.5% (28/32) completed telephonic interventions. Overall satisfaction a showed a median score of 4 (P25-P75: 3.25-5), with the highest ratings for the intervention team (median 4, P25-P75: 4-4). Participation demonstrated a median score of 4 (P25-P75: 3.25-4), with particularly high engagement in reading the provided materials (median 4.5, P25-P75: 4-5). The most frequently applied strategy was seeking support from family and friends (median 4, P25-P75: 4-4). (2) Qualitative findings revealed four themes: Perceived Benefit, Peer Support, Suggestions for Improvement, and Reasons for Low Application. Post-intervention improvements were seen in PAC (t=3.553, P=0.001, d=0.63), sense of competence (t=4.673, P<0.001), social network (t=3.645, P=0.001), and EQ-5D index (t=2.785, P=0.009). Burden (t=-3.083, P=0.004, d=0.55) and anxiety (t=-3.544, P=0.001) decreased significantly.

CONCLUSION: The DeCare-SPM was feasible and acceptable for family caregivers and showed preliminary effects on family caregivers.},
}

@article {pmid42093988,
year = {2026},
author = {Wang, H and Li, F and Wang, H and Tian, Z and Fan, H and Shi, Z},
title = {Resveratrol and the neuroinflammation axis in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cerebral ischemia.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1758356},
pmid = {42093988},
issn = {1664-3224},
mesh = {Humans ; *Resveratrol/therapeutic use/pharmacology ; Animals ; *Multiple Sclerosis/drug therapy/metabolism/immunology ; *Alzheimer Disease/drug therapy/metabolism ; *Parkinson Disease/drug therapy/metabolism/immunology ; *Brain Ischemia/drug therapy/metabolism/immunology ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {Resveratrol (RES), a naturally occurring polyphenolic compound found in grapes, berries, and peanuts, has attracted considerable interest because of its antioxidant, anti-inflammatory, and neuroprotective properties. This narrative review examines the current evidence regarding the potential effects of RES on memory-related processes and neuroinflammatory biomarkers in major neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia. Relevant literature was identified through searches of major scientific databases, and studies addressing the molecular mechanisms, experimental outcomes, and therapeutic implications of RES in these conditions were evaluated. The available evidence indicates that RES can modulate several biological pathways associated with neurodegeneration, including oxidative stress, inflammatory signaling, mitochondrial dysfunction, and neuronal survival. Experimental studies suggest that RES may influence key molecular mediators such as pro-inflammatory cytokines, nitric oxide (NO) signaling, and matrix metalloproteinases, which are implicated in neuronal damage and blood-brain barrier disruption. In preclinical models of AD and PD, RES has been associated with improvements in cognitive performance, reduction of neuroinflammatory markers, and attenuation of neuronal loss. Similarly, studies in MS and cerebral ischemia models indicate that RES may modulate immune responses, reduce oxidative damage, and limit ischemia-related neuronal injury. However, most of the current evidence derives from in vitro and animal studies, and clinical data remain limited. Moreover, the low bioavailability of RES and variability in dosing regimens represent important challenges for clinical translation. Therefore, although experimental findings support the potential neuroprotective role of RES, further well-designed clinical studies are required to determine its therapeutic relevance and safety in human neurological disorders. This narrative review was developed through a structured search of PubMed, Scopus, and Web of Science for articles published between 2000 and 2024, focusing on mechanistic, preclinical, and clinical investigations of RES in neurological disorders. This review synthesizes current evidence on the molecular and cellular mechanisms underlying the neuroprotective effects of RES, with particular emphasis on its antioxidant, anti-inflammatory, and immunomodulatory activities. By integrating findings from experimental and clinical research, the review highlights the potential of RES to modulate key pathways involved in neurodegeneration and neuroinflammation. Although further well-designed clinical studies are required to clarify its therapeutic efficacy and translational relevance, the available evidence supports continued investigation of RES as a promising candidate for neuroprotective strategies in neurological disorders.},
}

Humans
*Resveratrol/therapeutic use/pharmacology
Animals
*Multiple Sclerosis/drug therapy/metabolism/immunology
*Alzheimer Disease/drug therapy/metabolism
*Parkinson Disease/drug therapy/metabolism/immunology
*Brain Ischemia/drug therapy/metabolism/immunology
*Neuroinflammatory Diseases/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Oxidative Stress/drug effects

@article {pmid42094052,
year = {2026},
author = {Tug, T and Liang, D and Teschke, S and Tan, Y and Gearing, M and Levey, AI and Lah, JJ and Wingo, AP and Wingo, TS and Lau, M and Ickstadt, K and Hüls, A},
title = {Development and Application of Brain Tissue Based Multi-omics Profile Scores for Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9438710/v1},
pmid = {42094052},
issn = {2693-5015},
abstract = {BACKGROUND Advances in omics technologies, such as epigenomics and metabolomics, provide novel insights into the biological mechanisms underlying Alzheimer's disease (AD). However, little is known how different omics layers interact and jointly relate to AD neuropathology. METHODS We performed a comprehensive single- and multi-omics analysis integrating genome-wide DNA methylation and high-resolution metabolomics data from 157 frontal cortex samples. We developed novel single and multi-omics profile scores (PS) for AD pathology, using a combination of machine learning, regression, and pathway analysis. RESULTS For the ABC score (Amyloid, Braak, CERAD) the PS of DNAm outperformed metabolomics-based PS (median R[2]: 0.11 vs. 0.04). Combining both omics layers with the best-performing multi-omics PS yielded a partial R[2] of 0.15 for the ABC score independent of age, sex, race and socioeconomic factors. DNAm-specific pathways highlighted redox balance, immune activation, synaptic signaling, and lipid biosynthesis, whereas metabolomics-specific pathways emphasized inflammatory, hormonal, lipid, and energy metabolism. Notably, both omics layers converged on lipid metabolism and signal transduction as shared biological systems implicated in AD neuropathology. CONCLUSIONS Despite limited gains in predictive accuracy, integrative pathway and network analyses of DNAm and metabolomics PS converged on lipid metabolism and signal transduction, underscoring shared biological mechanisms and the value of multi-omics approaches for biological insight rather than prediction alone.},
}

@article {pmid42094058,
year = {2026},
author = {Goate, A and Podlesny-Drabiniok, A and Kim, J and Bezemer, L and Patel, T and Cheng, H and Sewell, M and Montecillo, M and Church, N and Walley, A and Garretti, F and Marcora, E},
title = {MEF2C controls lysosomal and lipid clearance programs linked to Alzheimer's disease risk in macrophages.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9164252/v1},
pmid = {42094058},
issn = {2693-5015},
abstract = {Risk alleles for late-onset Alzheimer's disease (AD) are enriched in myeloid cis-regulatory elements, implicating myeloid gene-regulatory networks in disease susceptibility. A conserved lipid-associated transcriptional signature-spanning disease-associated microglia and peripheral lipid-associated macrophages (DLAM)-emerges across neurodegenerative and metabolic diseases characterized by lipid overload, yet the transcriptional regulators of this gene expression program remain incompletely defined. Here, we show that MEF2C-a candidate AD risk gene-is a master DLAM regulator. Using MEF2C knockout and knockdown in human iPSC-derived microglia and macrophages, we found that total or partial MEF2C loss is sufficient to induce DLAM-associated transcriptional, epigenomic, and functional remodeling, including enhanced lysosomal activity and cholesterol efflux. Integration of chromatin accessibility and regulatory epigenetic profiles with functionally informed fine-mapping linked candidate causal variants in AD risk loci to MEF2C-regulated cis-regulatory elements that target candidate AD risk genes at these loci. In a triculture model of AD, microglial MEF2C loss is associated with an increased DLAM population and a reduced Aβ42/40 ratio, supporting context-dependent reprogramming of microglia as a potential biological mechanism to modulate AD-relevant pathology.},
}

@article {pmid42094065,
year = {2026},
author = {Tamer, Y and Noon, A and Yang, Z and Yu, K and Shah, A and Karam, A and Hajjar, I},
title = {The Brain Vulnerability Index: Development and Validation of a Machine Learning-Derived, Community-Informed Geospatial Risk Score for Cognitive Impairment.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9381770/v1},
pmid = {42094065},
issn = {2693-5015},
abstract = {Background Social determinants of health (SDOH) are increasingly recognized as important contributors to cognitive impairment, including Alzheimer's disease and related dementias. Existing indices are heavily weighted toward financial indicators and are not validated against cognitive outcomes. We aimed to develop and validate a novel brain-specific SDOH index that identifies high-risk communities for cognitive impairment. Methods The Brain Vulnerability Index (BVI) integrates patient-level electronic health record data with neighborhood-level SDOH from the Community Vulnerability Compass, a population health analytics framework. In the model development phase, electronic health record data were obtained from patients seen at Parkland Health (Dallas, TX). Cases were defined as individuals with at least one ICD-10 diagnosis suggestive of cognitive impairment from 2015 to 2023 and controls were age-matched with no ICD-10 diagnosis. External validation against serial cognitive performance measured by the Montreal Cognitive Assessment (MoCA) and clinically adjudicated consensus diagnosis of cognitive impairment of any etiology was performed in community-based (Dallas Heart Study) and clinically based (Alzheimer's Disease Research Center) cohorts. Results The model development sample included 39,570 cases and 192,060 controls. Derived BVI at the block group level achieved detection of electronic health documentation suggestive of cognitive impairment at a balanced accuracy of 54.6%. In external validation (n = 1,395), higher BVI values were associated with lower MoCA scores (β = -0.35; p = 0.009) and with faster cognitive decline (- 1.04 vs - 0.42 MoCA points/year in high- vs low-risk groups; p < 0.0001). BVI was also associated with adjudicated cognitive impairment in the community-based cohort only (p = 0.04). Across analyses, BVI correlated with but outperformed existing neighborhood indices. Conclusions BVI, a novel multidimensional brain-specific SDOH index, is clinically anchored and is externally validated. It may assist in earlier identification of at-risk communities with accelerated cognitive decline and aid in resource allocation for targeted prevention strategies.},
}

@article {pmid42094067,
year = {2026},
author = {Fabian-Fine, R and Roman, AG and Winters, MJ and Lathram, KJ and Bennett, CH and Kipingi, LK and Brännare-Gran, SM and Whitley, AE and Paul, CM and Altman, LM and Carrillo, IC and Joyce, FM and Kragh, LA and McKnight, TJ and Reding, CJ and Reiderer, LJD and Rivera, LJ and Steen, HA and Weaver, AL},
title = {Uncovering the invisible giant: Amyloid beta plaques and their proposed association with waste removal in Alzheimer-affected human hippocampus.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9337412/v1},
pmid = {42094067},
issn = {2693-5015},
abstract = {According to the prevalent 'Amyloid Hypothesis,' the underlying cause for neurodegeneration in Alzheimer Disease (AD) is attributed to the accumulation of misfolded Amyloid ß and tau protein in the form of extracellular sticky plaques and neurofibrillary tangles, respectively. These protein accumulations are thought to be caused by impaired waste removal. In an alternative hypothesis, we have proposed the existence of an extensive glial canal system that is likely formed by myelinated aquaporin-4 (AQP4)-expressing tanycytes and removes cellular waste from the hippocampal formation. Here, we demonstrate that tanycyte-derived waste-internalizing receptacles are immunoreactive for Aß and emanate from specialized nucleus-like organelles in the following referred to as 'tanysomes.' Utilizing RNA-scope in situ hybridization, we demonstrate that these receptacle-forming tanysomes express RNA for AQP4 and the Aß-related genes, amyloid precursor protein, and presenilin-1. These findings suggest that Aß is likely synthesized where receptacle formation is observed and that Aß may play an important structural role in receptacle formation. In AD-affected hippocampus, excessive amounts of Aß-immunoreactive waste receptacles emerge from tanysomes and have the appearance of plaques in Aß-immunolabeled hippocampus. Moreover, we demonstrate that the same receptacle-forming organelles exhibit strong immunolabeling for hyperphosphorylated tau protein in AD-affected tissue. We postulate that both proteins may play important structural roles in waste uptake and that hypertrophic swelling of impaired tanycytes in AD-affected brain may be due to obstructions of this extensive interconnected glial canal system.},
}

@article {pmid42094071,
year = {2026},
author = {Area-Gomez, E and Cardona-Gómez, G and Salomon-Cruz, I and Galvis-Garrido, N and Lozano-Trujillo, L and Barbosa-Carvajal, J and Agudelo-Castrillon, S and Yun, T and Montesinos, J and Henao, E and Quiroz, Y and Kosik, K and Schon, E and Larrea, D and Aguillon, D and Villegas-Lanau, A and Aguirre-Acevedo, D and Arias-Londoño, J},
title = {Circulating lipids uncover early membrane disruption as a primary event preceding Alzheimer's disease onset.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9357482/v1},
pmid = {42094071},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) is not a single entity but a biologically heterogeneous disorder, with substantial inter-individual variability in clinical presentation, molecular drivers, and disease trajectories. This heterogeneity limits current diagnostic and therapeutic strategies, which largely rely on late-stage protein biomarkers that, while sensitive to prodromal impairment, remain insufficient for primary prevention and patient stratification. Lipids are fundamental to brain structure and function, yet their role in the earliest stages of AD remains poorly defined. Here, we identify a robust, early-life lipid signature in serum from asymptomatic carriers of the PSEN1-E280A mutation, detectable from childhood. Using latent profile analysis, we resolve distinct lipid states associated with risk and resilience to dementia, modulated by genetic status, sex, and APOE genotype, and supported by concordant changes in circulating protein biomarkers. Mechanistically, these lipid alterations point to early and sustained disruptions in cholesterol and sphingolipid metabolism, suggesting that impaired lipid turnover is a primary event in AD pathogenesis rather than a downstream consequence. Our findings position circulating lipids as dynamic reporters of disease-relevant cellular pathways and reveal a previously unrecognized metabolic dimension of the presymptomatic phase of AD. Together, this work reframes AD as a disorder of early metabolic dysregulation and highlights lipidomic profiling as a powerful approach for early detection, risk stratification, and mechanistic insight.},
}

@article {pmid42094127,
year = {2026},
author = {Zambrano-Astorga, MF and Moreno-Ulloa, A and , },
title = {Reproducibility-driven discovery and systematic benchmarking reveal a robust cerebrospinal fluid proteomic signature in Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.26.26351766},
pmid = {42094127},
abstract = {UNLABELLED: Numerous cerebrospinal fluid (CSF) proteomic signatures for Alzheimer's disease (AD) diagnosis and prognosis have been proposed. However, cross-cohort reproducibility and head-to-head comparison among signatures remain uncertain. We implemented a reproducibility-driven framework integrating systematic review, multi-cohort validation, and systematic benchmarking to prioritized robust biomarkers. Across eight discovery studies (n=759) we identified eleven consistently dysregulated proteins (termed PPAV11). In three independent validation cohorts (n=1,198), PPAV11 demonstrated high diagnostic accuracy (AUC>0.94) and significant prognostic capacity (CU to A[+]T[+] MCI HR>4.96, p =0.004; A[+]T[+] MCI to A[+]T[+] dementia HR>3.23, p =3.13×10[-7]). Comparative benchmarking against thirteen published signatures revealed superior cross-context stability across diagnostic definitions, disease stages, and proteomic platforms. Biologically, PPAV11 captures synaptic, metabolic, immune, and vascular processes and correlates with cognitive decline and neurodegeneration. Together, these findings establish reproducibility as an important criterion for proteomic biomarker prioritization and define a stable molecular signature for integrated AD diagnosis and prognosis.

HIGHLIGHTS: A reproducibility framework identifies stable CSF proteomic signature for AD.PPAV11 shows strong diagnostic accuracy across cohorts, platforms, and stratifications.PPAV11 levels correlate with cognitive decline and predict AD progression.PPAV11 unites synaptic, metabolic, immune, and vascular pathways in AD dynamics.},
}

@article {pmid42094129,
year = {2026},
author = {Guen, YL and Park, J and Peña-Tauber, A and Greicius, MD},
title = {Proteomic Signatures of Protected APOE -ε4 Carriers Reveal Causal Pathways Associated with Delayed Alzheimer's Disease Onset.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.26352191},
pmid = {42094129},
abstract = {INTRODUCTION: APOE -ε4 is the strongest common genetic risk factor for Alzheimer's disease (AD), yet many carriers remain cognitively unimpaired into late life. We tested whether a protected-ε4-first proteomic approach could identify plasma proteins associated with delayed clinical onset among ε4 carriers.

METHODS: We analyzed harmonized plasma proteomics from the Global Neurodegeneration Proteomics Consortium. Protected ε4 carriers (ε3/ε4 aged ≥75 years; ε4/ε4 aged ≥65 years; CDR=0; n=456) were compared with ε4 carriers with AD (n=1,096). Protein-wise linear models adjusted for age, sex, ε4 dosage, and plasma proteomic principal components. Top signals were integrated with high-confidence loss-of-function burden testing and plasma/CSF Mendelian randomization.

RESULTS: ε4 protected was associated with 721 protein levels. Integrated analyses prioritized proteins linked to ε4-modified disease biology, including LILRA5, DBI, BPNT1, PTEN, EPHA1, and PCDH10, and proteins aligned with broader AD-related change, including OMG, SELENOW, VAT1, and TPPP3. TREM2 and ACE were also identified, providing internal biological validation of the approach.

DISCUSSION: A protected-ε4-first plasma proteomic strategy highlights immune, synaptic, metabolic-stress, and myelin/axonal pathways that may delay AD onset and helps prioritize candidate ε4-specific modifiers for prevention-focused therapeutics.},
}

@article {pmid42094138,
year = {2026},
author = {Arrotta, K and Williams, M and Thompson, NR and Bangen, KJ and Reyes, A and Zawar, I and Punia, V and Wang, I and Shih, JJ and Bekris, LM and Ferguson, L and Almane, DN and Jones, JE and Hermann, BP and Busch, RM and McDonald, CR},
title = {AT(N) Framework in Older Adults with Epilepsy: Plasma Biomarkers and Associations with Demographic, Clinical, and Cognitive Features.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.24.26351489},
pmid = {42094138},
abstract = {BACKGROUND AND OBJECTIVES: Older adults with epilepsy have a 2- to 4-fold increased risk of dementia, including Alzheimer's disease (AD), yet underlying mechanisms remain poorly defined. The NIA-AA classifies AD using amyloid (A), tau (T), and neurodegeneration [(N)] biomarkers. We applied this framework to characterize AT(N) profiles and clinical correlates in epilepsy.

METHODS: Eighty-four older adults with focal epilepsy (mean age=66.3 years) from the Brain Aging and Cognition in Epilepsy (BrACE) study were classified as A+, T+, and/or (N)+ using plasma β-amyloid (Aβ) 42/40 ratio, phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL) levels, and grouped into normal, AD-continuum, and non-AD pathologic change. Demographic, clinical, and cognitive characteristics were compared. Cognition was assessed using the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) and the Montreal Cognitive Assessment (MoCA). Memory was examined using IC-CoDE memory domain classification, with word-list delayed recall analyzed separately. Associations with cognition were modeled using logistic and linear regression. Secondary analyses examined biomarkers continuously, including p-tau217, and substituted hippocampal volume for NfL.

RESULTS: Only 32% of participants had normal biomarkers, while 37% were on the AD-continuum and 31% showed non-AD pathologic change. Participants with normal biomarkers were younger with shorter epilepsy duration, whereas APOE -ε4 carriers were enriched in the AD-continuum group. Early-onset compared to late-onset epilepsy (cutoff:≥55 years) showed higher odds of biomarker abnormality (aOR=8.84, 95% CI [2.35, 41.89], P =0.003), driven by elevated p-tau217, NfL, and greater amyloid burden. While categorical AT(N) profiles were not associated with cognition, higher p-tau181 levels were independently associated with lower word-list delayed recall (95% CI [-10.31, -0.86], P =0.021). Substituting hippocampal volume for NfL shifted more participants to normal profiles (48% vs. 32%) and fewer to non-AD pathologic change (15% vs. 31%).

DISCUSSION: AT(N) biomarker profiles showed substantial heterogeneity, with higher abnormality rates than in aging populations, particularly among those with early-onset epilepsy. Continuous p-tau181 was associated with memory performance while categorical AT(N) profiles were not, and NfL and hippocampal volume showed discordant classifications, highlighting divergence across neurodegeneration markers. These findings underscore the complexity of applying AD-centric frameworks to epilepsy and support multimodal, epilepsy-adapted biomarker approaches to characterize neurodegenerative risk.},
}

@article {pmid42094273,
year = {2026},
author = {Wen, Z and Biros, G},
title = {LNODE: latent dynamics reveal the shared spatiotemporal structure of amyloid-$β$ progression.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42094273},
issn = {2331-8422},
abstract = {We introduce LNODE, a mechanism-based phenomenological model for amyloid beta (A$β$) dynamics, calibrated using positron emission tomography (PET) imaging. A$β$ is a key biomarker of Alzheimer's disease. LNODE is designed to support the fusion, harmonization, quantitative analysis, and interpretation of Abeta PET scans. We evaluate LNODE on 1461 subjects in the ADNI cohort and 1070 subjects in the A4 Study, using MUSE and DKT anatomical atlases. LNODE is formulated as a regional neural ordinary differential equation (ODE) model that is jointly calibrated on all available scans within a cohort. The model captures the spatial propagation, proliferation, and clearance of A$β$ and incorporates a latent-state representation that modulates A$β$ dynamics. The temporal evolution of these latent states is governed by cohort-shared parameters, enabling LNODE to represent both population-level trajectories and subject-specific deviations. The proposed model demonstrates strong parameter identifiability and stability properties, supported by synthetic experiments and analytical analysis of the Hessian condition number. To mitigate overfitting and reduce spurious correlations, LNODE is intentionally underparameterized, employing approximately five to ten parameters per subject. Despite this parsimonious parameterization, LNODE achieves $R^2 > 0.99$ in both the ADNI and A4 datasets. LNODE exhibits strong predictive performance: in the A4 cohort, it accurately forecasts the A$β$ PET signal in previously unseen follow-up scans, including cases with inter-scan intervals exceeding four years. Clustering in the learned latent-state space reveals distinct subgroups, consistent with the existence of different subtypes of Alzheimer's disease progression.},
}

@article {pmid42094347,
year = {2026},
author = {Zhao, Z and Locascio, JJ and Li, H and Gowravaram, N and Green, RJ and Kastanenka, K and Bacskai, B and Hyman, BT and Gomperts, SN},
title = {Amyloid plaques drive state-dependent long-range circuit reorganization in the hippocampus.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.22.720180},
pmid = {42094347},
issn = {2692-8205},
abstract = {Amyloid plaques are a pathological hallmark of Alzheimer's disease, but how they drive widespread neuronal dysfunction remains unclear. While studies in anesthetized animals show that plaques drive local hyperactivity [1,2] , it is unknown how this pathology shapes functional hippocampal maps in freely behaving animals. We combined chronic 1-photon calcium imaging, local field potential recordings, and post hoc 2-photon plaque imaging in freely behaving APP/PS1 mice across behavior and sleep to correlate real-time hippocampal activity and place coding with precise plaque topography. Here we show that plaques exert nonlocal, long-range effects on hippocampal activity that depend on plaque size, laminar position, and the animal's behavioral state. Place cells, which encode spatial position and are normally uniformly distributed, are preferentially enriched near plaques, revealing an aberrant reorganization of plaque-adjacent neurons into the hippocampal map of space. In longitudinal experiments, pre-existing place cell locations do not predict future plaque sites, whereas hyperactivity during slow-wave sleep weakly predicts future amyloid deposition. These findings identify a mechanism by which amyloid pathology reorganizes brain circuits, degrading the functional architecture of the hippocampus and contributing to widespread dysfunction and cognitive impairment in Alzheimer's disease.},
}

@article {pmid42094385,
year = {2026},
author = {Sanders, B and Korthauer, M and Singh Parihar, K and Ifergan, I},
title = {Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles attenuate neuroinflammation and Alzheimer's disease-related pathology in 5xFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.27.720934},
pmid = {42094385},
issn = {2692-8205},
abstract = {Alzheimer's disease is characterized by progressive cognitive decline, amyloid-β deposition, neuroinflammation, and neurodegeneration, yet effective and well-tolerated therapies remain limited. Because dysregulated myeloid responses are increasingly recognized as important drivers of disease progression, we investigated the therapeutic potential of poly(lactic-co-glycolic acid) immunomodulatory nanoparticles in the 5xFAD mouse model of amyloid-driven neurodegeneration. Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles and fluorescently labeled particles displayed the expected size range and negative surface charge. After intraperitoneal administration, fluorescent particles were preferentially associated with myeloid cells in the blood, spleen, and brain, with greater uptake by brain myeloid populations in 5xFAD mice than in wild-type controls. Therapeutic treatment of 6.5-month-old 5xFAD mice, a stage at which behavioral abnormalities are already established, resulted in significant improvement in elevated plus maze behavior and a more modest improvement in Barnes maze performance. Flow cytometric analysis performed 9 weeks after the final treatment demonstrated persistent changes in brain immune composition, with the most prominent effects observed in P2RY12 [+] microglial populations, particularly the CD11c [+] subset, and comparatively limited sustained effects in CD11b [+] P2RY12 [-] myeloid cells. These changes were accompanied by reduced expression of activation- and disease-associated markers and lower pro-inflammatory cytokine production within microglial populations. Histological analysis further showed reduced cortical amyloid plaque burden, decreased CD68 immunoreactivity, and reduced neurodegeneration in treated 5xFAD mice. Together, these findings show that systemically administered poly(lactic-co-glycolic acid) immunomodulatory nanoparticles produce durable behavioral, immunological, and pathological benefits in 5xFAD mice and support further investigation of this biodegradable myeloid-targeted platform as a therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42094407,
year = {2026},
author = {Flax, R and Lacigová, A and Howell, S and Li, H and Bashore, FM and Čajánek, L and Axtman, AD},
title = {Development of Potent and Cell Active 5-Azaindole-Based Tau Tubulin Kinase Inhibitors.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.27.721186},
pmid = {42094407},
issn = {2692-8205},
abstract = {We have developed and characterized a potent and cell active tau tubulin kinase 1 and 2 (TTBK1 and TTBK2) inhibitor, 13 . Compound 13 demonstrates in-cell, kinome-wide selectivity, and potently inhibits both TTBK1 and TTBK2. As part of our medicinal chemistry campaign, we also identified a structurally similar negative control, compound 5 , which lacks in-cell affinity for TTBK1 and TTBK2. Based on their substrates, which include TDP-43, tau, and tubulin, TTBK1 and TTBK2 inhibition has been pursued as a therapeutic approach for Alzheimer's disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. TTBK2 is also an effector of ciliogenesis, acting in concert with CEP164, CP110, and CEP83 to initiate the biogenesis of primary cilia. The development of selective chemical tools for these kinases facilitates investigation into TTBK1/2-mediated pathways and potential disease-altering ramifications linked to their pharmacological perturbation.},
}

@article {pmid42094412,
year = {2026},
author = {Tilahun, K and Parameswaran, J and Dudley, M and Pun, D and Ma, F and Zhang, J and Bold, T and Jiang, J},
title = {TMEM106B C-terminal fragments drive nucleocytoplasmic transport failure and TDP-43 mislocalization in the aging human brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.23.719939},
pmid = {42094412},
issn = {2692-8205},
abstract = {TMEM106B is a lysosomal membrane protein and major genetic modifier of multiple neurodegenerative diseases, including frontotemporal lobar degeneration, Alzheimer's disease, and amyotrophic lateral sclerosis. Proteolytically generated C-terminal fragments of TMEM106B assemble into amyloid fibrils that accumulate in the brains of individuals with neurodegenerative disease and in cognitively normal aged adults, yet how these fibrils produce neuronal dysfunction has remained unclear. Here, we show that cytosolic and lysosome-directed TMEM106B C-terminal fragments (CTF and gCTF) form detergent-insoluble amyloid aggregates, drive redistribution of endogenous TDP-43 from the nucleus to the cytoplasm, and accelerate neuronal death. Unbiased proximity proteomics identified the inner nuclear membrane LAP1-TorsinA axis as a fragment-specific interactome, and co-immunoprecipitation confirmed a direct physical interaction between gCTF and LAP1 that was not observed with full-length TMEM106B. Fragment expression disrupted Lamin B1 organization, mislocalized the nuclear import machinery KPNB1 and RanGAP1, and impaired importin-dependent nuclear transport in primary cortical neurons. Critically, neurons harboring endogenous TMEM106B fibrillar pathology in aged human frontal cortex exhibited the same phenotypes, namely disrupted Lamin B1 and LAP1 localization and cytoplasmic redistribution of TDP-43, whereas fibril-negative neurons from the same cases and younger control tissue retained intact nuclear envelope organization. These findings define TMEM106B proteinopathy as an upstream driver of nuclear envelope disruption and nucleocytoplasmic transport failure, linking a widespread feature of brain aging to a central mechanism of neurodegeneration.},
}

@article {pmid42094448,
year = {2026},
author = {Foiani, MS and Bourdenx, M and Kraller, L and Nirujogi, RS and Yiu, A and Davies, H and Patel, S and Damoc, LS and Mitchener, L and Jaunmuktane, Z and Coscia, F and Duff, KE},
title = {Spatial Single-Cell Proteomics Reveals Molecular Trajectories Of Tangle-Bearing Neurons In Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.26.720932},
pmid = {42094448},
issn = {2692-8205},
abstract = {Neurofibrillary tangles composed of hyperphosphorylated tau are a defining pathological hallmark of Alzheimer's disease (AD); however, the pathways and mechanisms associated with the transition from physiological tau to tangle pathology remain unclear. Here, we integrate laser microdissection of post-mortem, fixed human AD brain tissue labelled with an antibody recognizing tangle-associated phospho-tau (AT8) with mass spectrometry-based proteomics, applied to individual neurons and to small neuronal pools. This approach identified ∼2,000 and ∼5,000 proteins, respectively, and enabled direct detection of disease-associated tau phosphorylation sites without prior enrichment. A layered analysis of the proteome of tangle-positive and tangle-negative neurons revealed heterogeneous disease-associated states. Pseudotime analysis, combined with an AI-driven analytical framework, indicates that neurons do not segregate into discrete classes but instead organize along a continuum of proteomic changes that correlate with tau abundance. This organization enabled the construction of a trajectory of pathological neuronal responses that can be resolved within an individual brain. Early stages of this trajectory are characterized by coordinated remodeling of proteostasis networks, including reduced proteasome component abundance and increased lysosomal acidification machinery, followed by disruption of synaptic pathways. Notably, despite extensive proteomic remodeling, neurons bearing tangles show little evidence of activated cell-death programs, suggesting prolonged molecular adaptation rather than acute degeneration. Together, these findings establish a framework for single-cell-resolved proteome analysis of human brain disease in situ and define a continuum of neuronal states underlying tau pathogenesis, revealing early vulnerabilities and adaptive responses during AD progression.},
}

@article {pmid42094463,
year = {2026},
author = {Ahmed, W and Nogueras-Ortiz, C and Sagar, R and Dong, D and Boyd, RJ and Yao, PJ and Iliuk, A and Lyketsos, CG and Witwer, KW and Kapogiannis, D and Mahairaki, V},
title = {Proteomic identification and validation of novel neuronal EV-based markers for Alzheimer's disease biomarker discovery.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.26.720870},
pmid = {42094463},
issn = {2692-8205},
abstract = {Extracellular vesicles (EVs) circulate in biofluids and carry tissue-specific molecular cargo, offering significant potential for the discovery of minimally invasive biomarkers. However, translation in neurodegenerative diseases has been hindered by the lack of validated neuronal EV surface markers that enable selective isolation from plasma. We hypothesized that proteomic profiling of EVs released from human induced pluripotent stem cell (hiPSC)-derived neurons would identify 1. robust Alzheimer's disease (AD)-associated signatures that reflect disease pathogenesis, and 2. surface-accessible neuronal markers capable of enriching disease-relevant cargo. Neurons differentiated from AD patients and age-matched cognitively normal (CN) individuals were used to isolate EVs, which were characterized and analyzed by LC-MS proteomics in both total and membrane-enriched fractions. Proteomic profiling identified numerous dysregulated proteins, with a subset validated across independent AD datasets. We identified CNTNAP2 and STX1B as neuronal, brain-enriched EV surface proteins accessible for selective capture and confirmed their presence in EVs from post-mortem human brain, supporting them as bona fide brain-derived EV markers. Immuno-isolation of plasma EVs showed that CNTNAP2-positive EVs had a robust AD-associated increase in phosphorylated tau, identifying CNTNAP2 as a highly discriminative brain-derived EV marker and supporting its potential for blood-based AD diagnostics.},
}

@article {pmid42094473,
year = {2026},
author = {Gutierrez, JC and Chen, Y and Babaian, A and Dhindsa, RS and Lareau, CA},
title = {Resolving human neuronal herpesvirus reactivation via petabase-scale association studies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.29.721769},
pmid = {42094473},
issn = {2692-8205},
abstract = {Mounting evidence implicates herpesvirus reactivation in the etiology of Alzheimer's disease, yet we lack a refined molecular characterization of pathogenesis in neurodegeneration. Here, we mine over 10 petabytes of human sequencing data for viral transcripts, identifying recurrent herpes simplex virus 1 (HSV-1) reactivation in healthy but not pathological post-mortem human brain tissue. Integrative single-nucleus analyses resolve direct evidence of HSV-1 expression in RORB+ glutamatergic neurons, implicating viral reactivation in a neuronal population progressively lost during dementia.},
}