@article {pmid42646579,
year = {2026},
author = {Calabrò, RS and Calderone, A and Ravi, D and Galipò, C and Crupi, MF and Quartarone, A},
title = {Hospital-to-Home Neurological Transition Care: A Scoping Review Across Selected Chronic Neurological Disorders.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
pmid = {42646579},
issn = {2076-3271},
mesh = {Humans ; *Nervous System Diseases/therapy ; *Transitional Care ; Multiple Sclerosis ; Hospitalization ; Chronic Disease ; Amyotrophic Lateral Sclerosis ; },
abstract = {BACKGROUND: Returning home after neurological hospitalization, rehabilitation, or specialist care transfers responsibility to patients, caregivers, and community services. We mapped mechanisms and gaps across dementia/Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

METHODS: Following JBI guidance and PRISMA-ScR, eligibility was derived using population-concept-context. We included empirical reports involving adults with a target condition, a post-discharge, return-home, rehabilitation, telehealth, caregiver, treatment, respiratory, or palliative continuity component, and post-transition patient, caregiver, service, safety, rehabilitation, equity, or implementation outcomes. Five databases were searched through to 11 May 2026. Two reviewers independently screened records; charting and classification were verified by R.S.C., A.C., and A.Q.

RESULTS: Of 24,417 records, 69 reports were included: Dementia/ADRD, 28; PD, 10; MS, 9; and ALS, 22. Eighteen were core transition reports (26.1%), 14 return-home/community re-entry reports (20.3%), 16 adjacent continuity reports (23.2%), and 21 companion/secondary reports (30.4%). Dementia/ADRD provided discharge-anchored evidence; PD and MS mapped functional carry-over; ALS mapped adjacent respiratory, telehealth, and palliative continuity.

CONCLUSIONS: The main contribution is an operational cross-disease framework separating direct discharge, return-home, adjacent-continuity, and companion evidence while linking mechanisms to disease-specific pathways. This framework maps disease-specific functions, not comparative effectiveness. The proposed frameworks are author-derived and hypothesis-generating. Future studies should use explicit anchors, standardized outcomes, longer follow-up, and equity-sensitive implementation measures addressing caregiver workload, digital access, feasibility, and sustainability. They inform testable, context-sensitive intervention designs for future neurological transition-care research and practice.},
}

Humans
*Nervous System Diseases/therapy
*Transitional Care
Multiple Sclerosis
Hospitalization
Chronic Disease
Amyotrophic Lateral Sclerosis

@article {pmid42646820,
year = {2026},
author = {Liu, Y and Lu, J and Zhang, Z and Yao, D and Xia, Y and Chen, K},
title = {The Visual System in Alzheimer's Disease: A Multilevel Review of Pathology, Monitoring, and Intervention.},
journal = {Vision (Basel, Switzerland)},
volume = {10},
number = {3},
pages = {},
pmid = {42646820},
issn = {2411-5150},
support = {2022ZD0208500//National Science and Technology Major Project/ ; 2024YFHZ0359//Sichuan Science and Technology Program/ ; },
abstract = {Alzheimer's disease (AD) extends beyond the brain to the visual system, offering a promising window for pathology, monitoring, and intervention. This review synthesizes evidence on AD-related visual impairments across molecular, cellular, circuit, and cortical levels. We examine the eye-brain pathological relationship as a working framework, noting experimental evidence for brain-to-eye amyloid-β (Aβ) transport in mouse models and associations between retinal and cerebral pathology in humans, while emphasizing that bidirectional pathological transport has not been established. Structural and functional changes in the retina, optic nerve, and visual cortex are reviewed, alongside white matter damage and posterior cortical atrophy patterns. We evaluate emerging multimodal tools (OCTA, ERG, and hyperspectral imaging) that shift diagnosis toward an integrated "structure-vessel-function" assessment. We critically examine non-pharmacological interventions, including 40 Hz gamma stimulation and photobiomodulation, discussing their mechanisms, translational challenges, and the dissociation between structural and cognitive outcomes. We propose the visual system as a candidate pathological window, a quantitative monitoring platform, and an investigational intervention entry point in Alzheimer's disease. However, clinical translation of these applications requires standardized acquisition protocols, prospective longitudinal validation, and robust mechanistic evidence. To advance this agenda, we identify three priorities: multimodal data integration, closed-loop neuromodulation strategies, and methodologically rigorous validation frameworks.},
}

@article {pmid42646836,
year = {2026},
author = {Yang, HW and Han, JW and Oh, DJ and Kim, BJ and Lee, DW and Kim, JL and Jhoo, JH and Park, JH and Lee, JJ and Kwak, KP and Lee, SB and Moon, SW and Ryu, SH and Kim, SG and Kim, KW},
title = {Domain-Specific Cognitive Concordance in Older Married Couples.},
journal = {JAMA network open},
volume = {9},
number = {8},
pages = {e2631017},
pmid = {42646836},
issn = {2574-3805},
mesh = {Humans ; Female ; Male ; Cross-Sectional Studies ; Republic of Korea ; Aged ; *Spouses/psychology/statistics & numerical data ; *Cognition/physiology ; Longitudinal Studies ; Aged, 80 and over ; Neuropsychological Tests ; *Marriage/psychology ; },
abstract = {IMPORTANCE: Spousal similarity in late-life cognition has been reported, but whether concordance differs across cognitive domains remains unclear.

OBJECTIVE: To examine whether cognitive concordance among older married couples is domain specific by comparing real couples with demographically and genetically matched control pairs.

This nationwide, multicenter, community-based cross-sectional study was conducted from January 2019 to December 2020 and included married couples from the Korean Longitudinal Study of Cognitive Aging and Dementia. Each spouse was individually matched to an unrelated control based on sex, cognitive diagnosis, apolipoprotein E ε4 status, age, and education. Data were analyzed from March to April 2026.

EXPOSURE: Marital pairing within a 4-group matched design (real couples, spouse-control pairs, and matched null couples).

MAIN OUTCOMES AND MEASURES: For 9 subtests from the Korean version of the Consortium to Establish a Registry for Alzheimer Disease Assessment Packet, intraclass correlation coefficients (ICCs) were calculated within each group, and the spousal concordance (ICC difference) was defined as the difference between the ICC of real couples and that of matched null couples. Significance was assessed with 2-sided permutation tests and Benjamini-Hochberg false discovery rate correction.

RESULTS: The sample included 783 married couples (1566 individuals; 783 [50.0%] female and 783 [50.0%] male; mean [SD] age, 74.0 [5.5] years) and 783 matched control couples. Among the 783 married couples, 4 of 9 subtests showed significant ICC differences after false discovery rate correction in unadjusted analyses: Verbal Fluency (ICC difference, 0.232; 95% CI, 0.138-0.324), Constructional Praxis (ICC difference, 0.145; 95% CI, 0.039-0.252), Boston Naming Test (ICC difference, 0.134; 95% CI, 0.038-0.231), and Constructional Recall (ICC difference, 0.110; 95% CI, 0.017-0.200); all remained significant after covariate adjustment. In contrast, the Mini-Mental State Examination and verbal memory recall and recognition showed little concordance beyond demographically matched null pairs.

CONCLUSIONS AND RELEVANCE: In this cross-sectional study of 783 older married couples, spousal cognitive concordance was domain specific, with the greatest effect size estimates in language and visuospatial function rather than global cognition. These findings suggest that spousal cognitive similarity may be missed when analyses rely only on global screening measures, highlighting the need for longitudinal study of within-couple concordance.},
}

Humans
Female
Male
Cross-Sectional Studies
Republic of Korea
Aged
*Spouses/psychology/statistics & numerical data
*Cognition/physiology
Longitudinal Studies
Aged, 80 and over
Neuropsychological Tests
*Marriage/psychology

@article {pmid42646944,
year = {2026},
author = {Guo, B and Chang, J and Liu, A and Li, M and Guo, L and Cheng, S and Wang, H and Ba, Q},
title = {Environmental Cadmium Exposure Exacerbates Alzheimer's-like Pathology in a Gut Microbiota-Involved Manner.},
journal = {Toxics},
volume = {14},
number = {8},
pages = {},
pmid = {42646944},
issn = {2305-6304},
support = {2022YFF0606703//National Key R&D Program of China/ ; KF202330//the Open Foundation of Shaanxi University of Chinese Medi-cine Key Laboratory of Research & Development of Characteristic Qin Medicine Re-sources/ ; },
abstract = {Cadmium (Cd), a ubiquitous environmental toxicant, poses substantial health risks even at low-dose chronic exposures. In this study, we developed a mouse model with chronic low-dose dietary Cd exposure (100 nM CdCl2 in drinking water for eight months) to investigate its impacts on cognitive and neuropathological alterations. Behavioral assessments demonstrated that Cd-exposed mice exhibited pronounced deficits in spatial learning, memory retention, and working memory compared with control mice. Histopathological analyses of hippocampus uncovered accelerated Alzheimer's-like neuropathology, marked by elevated β-amyloid plaque immunoreactivity and tau hyperphosphorylation. Concurrently, neuroinflammatory responses were markedly upregulated, shown as astrocytes activation and pro-inflammatory Th17 cell signatures in parenchyma. Brain transcriptomic profiling revealed extracerebral prostaglandin signaling following Cd exposure, a finding consistent with elevated prostaglandins detected in the gut. Crucially, these outcomes were gut microbiota-involved: antibiotic-mediated microbiota depletion attenuated dietary Cd-enhanced cognitive impairments, neuroinflammation, and prostaglandin upregulation, underscoring the critical role of intestinal microbes in mediating Cd neurotoxicity. Furthermore, in vitro co-culture experiments demonstrated that Cd potentiated prostaglandin production in intestinal epithelial cells-an effect amplified by gut bacterial stimuli. This observation suggests a mechanism under which peripheral prostaglandins may contribute to central inflammatory cascades. Together, these findings support a gut-brain mechanism underlying dietary Cd-exacerbated neurodegeneration and highlight gut homeostasis and prostaglandin signaling as promising therapeutic targets for mitigating Cd-associated neurodegenerative disorders.},
}

@article {pmid42647155,
year = {2026},
author = {Ohara, K and Zhang, H and Shibata, H and Hasegawa, Y},
title = {Long-Term Dietary Supplementation with Pearl Oyster Shell-Derived Nacre Extract Improves Cognitive Performance and Attenuates Alzheimer's Disease-Like Pathology in APPNL-G-F/NL-G-F Knock-In Mice.},
journal = {Journal of dietary supplements},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/19390211.2026.2718077},
pmid = {42647155},
issn = {1939-022X},
abstract = {Alzheimer's disease is characterized by cognitive decline, amyloid-β deposition, tau-related pathology, neuroinflammation, and oxidative stress. Pearl oyster shell-derived nacre extract is used in dietary supplement-related applications, but evidence from animal models should be interpreted cautiously and its effects on Alzheimer's disease-like pathology remain incompletely defined. To evaluate whether long-term oral dietary supplementation with nacre extract is associated with changes in cognitive performance and Alzheimer's disease-like pathological features in APPNL-G-F/NL-G-F knock-in mice. A controlled preclinical animal study was performed using male C57BL/6 wild-type mice and male APP[NL-G-F/NL-G-F] knock-in mice over a 6-month dietary supplementation period. Six mice were assigned to each group. APP knock-in mice received a standard diet with or without 0.5% (w/w) nacre extract, corresponding to an estimated intake of approximately 20 mg/mouse/day or approximately 600 mg/kg/day. Cognitive performance was assessed using the Y-maze and novel object recognition tests. Brain pathology and molecular responses were evaluated by histology, immunohistochemistry, RNA sequencing, qPCR, Western blotting, and oxidative stress-related assays. Nacre supplementation was associated with improved performance in the Y-maze and novel object recognition tests, reduced amyloid-β deposition and Congo red-positive plaque burden, lower phosphorylated tau immunoreactivity, and fewer histologically degenerated hippocampal neurons. Exploratory RNA sequencing of non-microdissected brain tissue excluding the cerebellum (n = 3/group) identified 53 genes meeting the criteria of an absolute fold change ≥ 1.5 and a valid non-zero FDR-adjusted p value < 0.05. A2M showed a 1.51-fold increase (FDR-adjusted p = 0.00091), and increased A2M abundance was confirmed at the protein level. Iba1 and GFAP immunoreactivity was reduced, and oxidative stress-related parameters were altered in the nacre-supplemented group. Long-term nacre supplementation was associated with improvements in behavioral performance and attenuation of several Alzheimer's disease-like pathological features in male APP knock-in mice. These findings represent an exploratory preclinical signal and do not establish a causal mechanism, dose-response relationship, comprehensive safety profile, or efficacy as a dietary supplement in humans.},
}

@article {pmid42647218,
year = {2026},
author = {Malafaia, D and Melo, L and Silva, AMS and Albuquerque, HMT},
title = {Xanthones and Their Nitrogen and Sulfur Analogs in Alzheimer's Disease: Recent Progress Toward Multifunctional Therapeutics.},
journal = {ChemMedChem},
volume = {21},
number = {16},
pages = {e70453},
pmid = {42647218},
issn = {1860-7187},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Xanthones/chemistry/therapeutic use/pharmacology ; *Sulfur/chemistry ; *Nitrogen/chemistry ; Molecular Structure ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; Animals ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia among the elderly worldwide. In medicinal chemistry and drug discovery, heterocycles are widely recognized as privileged scaffolds due to their structural versatility and biological relevance. In the context of AD, heterocyclic compounds have been extensively investigated for the development of potential therapeutic agents. Among fused heterocyclic systems, oxygen-, nitrogen-, and sulfur-containing heterocycles are particularly prominent in approved drugs. This review focuses on recent advances in the exploration of xanthone derivatives, alongside with their nitrogen- and sulfur-containing analogs, as promising template scaffolds for the development of prospective anti-AD therapeutics.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Xanthones/chemistry/therapeutic use/pharmacology
*Sulfur/chemistry
*Nitrogen/chemistry
Molecular Structure
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use
Animals

@article {pmid42647276,
year = {2026},
author = {Papadopoulou, K and Tsokkou, S and Konstantinidis, I and Pavlidis, P and Sardeli, C and Kouvelas, D and Meditskou-Efthymiadou, S and Sioga, A and Papamitsou, T},
title = {Beyond the Central Nervous System: Uncovering Memantine's Modulatory Role in the Peripheral Nervous System.},
journal = {Medicines (Basel, Switzerland)},
volume = {13},
number = {3},
pages = {},
pmid = {42647276},
issn = {2305-6320},
abstract = {Background: Memantine, an uncompetitive and voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, is clinically established for moderate-to-severe Alzheimer's disease. Its pharmacodynamic profile, low-to-moderate affinity, rapid open-channel block, and strong voltage dependency allows selective inhibition of pathological NMDA overactivation while preserving physiological neurotransmission. Increasing evidence shows that these same mechanistic principles operate in the peripheral nervous system, where NMDA receptors contribute to excitotoxicity, oxidative stress, neuroinflammation, and maladaptive nociceptive signaling. Purpose: To synthesize emerging preclinical and clinical evidence demonstrating memantine's modulatory and neuroprotective actions in peripheral neurons and glia and to outline implications for drug repurposing across neurology, pain medicine, oncology, supportive care, and ophthalmology. Methodology: A narrative integration of mechanistic studies, in vivo preclinical models, and heterogeneous clinical trials evaluating memantine's effects on peripheral sensory neurons, autonomic neurons, Schwann cells, retinal ganglion cells, and neuromuscular junction physiology. Evidence was examined across conditions involving excitotoxicity, oxidative injury, mitochondrial dysfunction, apoptotic signaling, neuroinflammation, and neuropathic pain amplification. Results: Memantine consistently attenuates peripheral excitotoxic calcium influx, suppresses NOX-2-mediated ROS generation, stabilizes mitochondrial membrane potential, modulates Bax/Bcl-2 signaling, and reduces neuroinflammatory cytokine activity. It also inhibits dorsal horn wind-up selectively under neuropathic conditions. These convergent mechanisms yield protective effects across chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathy, traumatic nerve injury, phantom limb pain, retinal ganglion cell excitotoxicity, and organophosphate-induced neuromuscular toxicity. Clinical evidence includes improved multimodal neuropathy outcomes in diabetic neuropathy when combined with gabapentin, reduced phantom limb pain prevalence and intensity at six months, and a five-fold reduction in post-mastectomy neuropathic pain with pre-emptive administration. Conclusions: Memantine should be conceptually reframed as a system-wide neuroprotective agent with substantial translational potential beyond the CNS. Priorities for future development include NR2B-selective peripheral NMDA antagonists, peripherally restricted formulations, single-cell transcriptomic mapping of peripheral NMDA receptor subtypes, and adequately powered PNS-specific randomized trials.},
}

@article {pmid42647328,
year = {2026},
author = {Merino-País, M and López-Ortiz, S and Emanuele, E and Imbimbo, C and Imbimbo, BP and Lista, S and Santos-Lozano, A},
title = {Physical Exercise and Gut Microbiota: Implications for Alzheimer's Disease in Experimental Models: A Systematic Review and Meta-Analysis.},
journal = {Journal of functional morphology and kinesiology},
volume = {11},
number = {3},
pages = {},
pmid = {42647328},
issn = {2411-5142},
abstract = {Background and Objectives: The concept of the gut-muscle-brain axis encompasses the intricate, multidirectional interactions between the gut microbiota (GM), physical exercise (PE), and the central nervous system. Within this framework, gut dysbiosis has been implicated in the pathogenesis of Alzheimer's disease (AD). Given that cognitive functions in AD appear to benefit from PE, it is plausible to hypothesize that these improvements may be partially mediated by PE-induced alterations in GM taxonomy. Therefore, the objective of this study is to evaluate the potential effects of PE in the GM and their implications for AD. Methods: A systematic review was conducted in PubMed, Web of Science and Scopus following the PRISMA guidelines up to July 2025 for preclinical controlled trials that assessed the effects of PE on the GM of AD animal models. A random-effects model meta-analysis was performed to estimate the pooled effect of PE on GM frequency or composition. This study received no external funding. Results: Eight studies were included in the systematic review (sample size, n = 126), of which two could be meta-analyzed. We found that PE significantly reduced Actinobacteria abundance (MD = -0.005%; 95% CI, -0.008 to -0.002; p = 0.001) with no statistically significant evidence of heterogeneity (I[2] = 89.60%, Q = 0.102, p = 0.950) or publication bias observed (Begg's test, p = 0.296), but no significant effects were found for other phylums or genera. Conclusions: PE appears capable of modulating the GM of animal models with AD in a selective and heterogeneous manner. Further studies are needed to clarify the mechanisms by which this is possible and to determinate its impact on the pathogenesis of the disease.},
}

@article {pmid42647485,
year = {2026},
author = {, },
title = {Expression of Concern: Constipation in Tg2576 mice model for Alzheimer's disease associated with dysregulation of mechanism involving the mAChR signaling pathway and ER stress response.},
journal = {PloS one},
volume = {21},
number = {8},
pages = {e0356955},
pmid = {42647485},
issn = {1932-6203},
}

@article {pmid42647766,
year = {2026},
author = {Paranhos, T and Katsumi, Y and Brickhouse, MJ and Eloyan, A and Eckbo, R and Zaitsev, A and Du, A and La Joie, R and Thangarajah, M and Taurone, A and Vemuri, P and Jack, CR and , and Hammers, DB and Aisen, PS and Beckett, LA and Koeppe, R and Kukull, WA and Toga, AW and Atri, A and Clark, DG and Day, GS and Duara, R and Graff-Radford, NR and Grant, IM and Honig, LS and Johnson, E and Jones, DT and Masdeu, JC and Mendez, MF and Musiek, ES and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, T and Wolk, DA and Womack, KB and Carrillo, MC and Rabinovici, GD and Apostolova, LG and Dickerson, BC and Eldaief, MC and Touroutoglou, A},
title = {EOAD-Signature Atrophy Predicts Dementia in Early-Onset MCI due to Alzheimer Disease: An MRI-Based Prognostic Biomarker.},
journal = {Neurology},
volume = {107},
number = {7},
pages = {e218519},
doi = {10.1212/WNL.0000000000218519},
pmid = {42647766},
issn = {1526-632X},
mesh = {Humans ; Female ; Atrophy/pathology ; *Alzheimer Disease/diagnostic imaging/pathology/complications ; Magnetic Resonance Imaging ; Disease Progression ; *Cognitive Dysfunction/diagnostic imaging/pathology/etiology ; Prognosis ; Male ; Middle Aged ; Biomarkers ; Adult ; Longitudinal Studies ; *Dementia/diagnostic imaging ; },
abstract = {BACKGROUND AND OBJECTIVES: Early-onset Alzheimer disease (EOAD) is associated with substantial variability in clinical progression, and reliable biomarkers to predict the transition from mild cognitive impairment (MCI) to dementia remain limited. Structural MRI measures have demonstrated prognostic value in late-onset Alzheimer disease, but their utility for predicting progression in EOAD is less well understood. The goal was to examine whether baseline cortical atrophy predicts progression to dementia in patients with MCI because of EOAD.

METHODS: This study included a well-characterized cohort of patients with EOAD enrolled in the large multisite natural history Longitudinal Early-Onset Alzheimer's Disease Study. Participants underwent standardized clinical assessments and structural MRI at baseline. Participants were aged between 40 and 64 years with biomarker-supported sporadic EOAD at the MCI stage. Cortical atrophy was measured within the EOAD-signature, a set of predominantly parieto-temporal regions showing greater atrophy in EOAD than in controls. Clinical severity was measured with the global Clinical Dementia Rating. Cox proportional hazards models estimated the association between baseline EOAD-signature atrophy burden and the hazard of progression to dementia over time. We evaluated whether EOAD-signature atrophy improved prognostic performance beyond baseline clinical severity using likelihood ratio tests, Akaike Information Criterion (AIC), and Harrell concordance index.

RESULTS: A total of 130 patients with MCI due to EOAD (mean age 59.6 ± 4.1 years; 49% female) and 97 cognitively normal controls (mean age 56.9 ± 6.0 years; 64% female) were included. Greater baseline atrophy within the EOAD-signature predicted faster progression to dementia (hazard ratio [HR] = 1.24 per 1-SD increase in atrophy; 95% CI 1.13-1.37; p < 0.002). Adding EOAD-signature atrophy burden to a model including baseline clinical severity significantly improved model fit (ΔAIC = -4.5; likelihood ratio test p = 0.011).

DISCUSSION: Baseline cortical atrophy within the EOAD-signature predicts progression from MCI to dementia in EOAD and provides prognostic information beyond baseline clinical severity. These findings support the potential value of EOAD-signature atrophy as an MRI-based biomarker for individualized prognostication and clinical trial stratification.},
}

Humans
Female
Atrophy/pathology
*Alzheimer Disease/diagnostic imaging/pathology/complications
Magnetic Resonance Imaging
Disease Progression
*Cognitive Dysfunction/diagnostic imaging/pathology/etiology
Prognosis
Male
Middle Aged
Biomarkers
Adult
Longitudinal Studies
*Dementia/diagnostic imaging

@article {pmid42648141,
year = {2026},
author = {Gao, X and Ma, D and Liu, R and Guo, T and Dong, Z and Yan, J and Huang, J},
title = {Domain-specific deficits in categorical perception unveil the neural architecture of auditory agnosia in dementia.},
journal = {Hearing research},
volume = {481},
number = {},
pages = {109783},
doi = {10.1016/j.heares.2026.109783},
pmid = {42648141},
issn = {1878-5891},
abstract = {Auditory processing deficits are a prominent early feature of Alzheimer's disease (AD), yet whether they reflect generalized cognitive slowing or domain-specific neural degradation remains unclear. This study combined a categorical perception paradigm with high-temporal-resolution electroencephalography (EEG) to evaluate neural responses to distinct combinations of acoustic cues, rapid temporal dynamics (consonants) versus stable spectral configurations (lexical tones), across a continuum of healthy aging, mild cognitive impairment (MCI), and AD. Rather than a monolithic functional loss, behavioral analysis revealed a differential vulnerability: while psychomotor slowing was global, categorical precision collapsed specifically for rapid consonant cues but remained remarkably resilient for tones. Neurophysiologically, this divergence was underpinned by a distinct trajectory transitioning from successful compensatory hyper-activation in normal aging to a state of inefficient hyper-activation in clinical cohorts, characterized by sustained P300 amplitudes but severe temporal processing delays. Crucially, we demonstrated the clinical utility of these domain-specific electrophysiological signatures using a fivefold cross-validated machine learning approach. Advanced classification algorithms, notably the gradient boosting machine (GBM), distinguished participants with MCI from cognitively normal older adults with an area under the receiver operating characteristic curve (AUC) of 0.836. These findings reframe auditory deficits in dementia as a nuanced erosion of specific neural codes and highlight the efficacy of interpretable, EEG-based neurocomputational tools for the early clinical screening of pre-dementia states.},
}

@article {pmid42648288,
year = {2026},
author = {Quenez, O and Schramm, C and Cassinari, K and Nicolas, A and Groeneveld, J and Huguet, G and Grenier-Boley, B and Hulsman, M and Walters, GB and de Rojas, I and Rovelet-Lecrux, A and Feuillette, S and Miguel, L and Richard, AC and Rousseau, S and Ahmad, S and Amin, N and Amouyel, P and Belbin, O and Bellenguez, C and Berr, C and Bossù, P and Bouwman, F and Bras, J and Clarimon, J and Daniele, A and Dartigues, JF and Debette, S and Deleuze, JF and Denning, N and Dols-Icardo, O and van Duijn, CM and Fortea, J and Fox, NC and Frikke-Schmidt, R and Galimberti, D and Ghidoni, R and Giedraitis, V and Gille, JJP and Grozeva, D and Guerreiro, R and Grünblatt, E and Hardy, J and Riedel-Heller, SG and Hiltunen, M and Holmes, C and Hort, J and Hummerich, H and Ikram, MA and Ikram, MK and Ingelsson, M and Jansen, IE and Kawalia, A and Kraaij, R and Kehoe, PG and Lathrop, M and Lacour, M and Lemstra, AW and Lleó, A and Luckcuck, L and Mannens, MMAM and Marshall, R and Masullo, C and Mead, S and Mecocci, P and de Mendonça, A and Meggy, A and Mehrabian, S and Mol, MO and Morgan, K and Morin, A and Nacmias, B and Norsworthy, PJ and Olaso, R and Pasquier, F and Pastor, P and Piras, F and Popp, J and Ramirez, A and Raybould, R and Redon, R and Reinders, MJT and Rivadeneira, F and van Rooij, JGJ and Ryan, NS and Saad, S and Sanchez-Juan, P and Scarmeas, N and Scheltens, P and Schott, JM and Seripa, D and Sie, D and Sims, R and Sistermans, EA and Sorbi, S and Sleegers, K and van Spaendonk, R and van Swieten, JC and Tesi, N and Tijms, BM and Tsolaki, M and Uitterlinden, AG and Vijverberg, J and Visser, PJ and Wagner, M and Williams, J and Zarea, A and , and Génin, E and Holstege, H and Gudbjartsson, DF and Wallon, D and Lecourtois, M and Fernandez, MV and Stefansson, H and Jacquemont, S and Lambert, JC and van der Lee, SJ and Charbonnier, C and Nicolas, G},
title = {Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2026.07.013},
pmid = {42648288},
issn = {1537-6605},
abstract = {Copy-number variants (CNVs) are major contributors to human disease. In Alzheimer disease (AD), APP duplications cause autosomal-dominant forms, but the role of CNVs in non-monogenic AD remains poorly characterized. We analyzed rare CNVs (frequency <1%) from 22,319 exomes (4,150 early-onset AD [EOAD, ≤65 years], 8,519 late-onset AD [LOAD], 9,650 unaffected control subjects) using harmonized calling and quality control. After identifying 17 individuals with a pathogenic CNV, we performed exome-wide and gene-set burden analyses. EOAD-affected individuals showed increased burdens of rare CNVs affecting coding genes, particularly deletions in AD-related genes. Integrated loss-of-function (LoF) analysis gathering short truncating variants with deletions showed that ABCA1 (odds ratio [OR] = 5.77 [95% confidence interval 2.25; 17.06], p = 0.0002) and ABCA7 deletions contribute to this deletion burden (OR = 2.29 [1.44; 3.65], p = 0.0006), while CTSB LoF alleles appear as candidates (OR = 5.03 [1.50; 20.71], p = 0.0089). We then performed exome-wide gene-level dosage analysis and highlighted 18 genes across five loci with a false discovery rate of <10%, including the 22q11.21 central region, where deletions were restricted to EOAD (including one de novo event) and duplications were enriched in control individuals, with intermediate frequencies in LOAD. We narrowed this locus to the SCARF2-KLHL22-MED15 region after integrating short truncating variants. Replication in 33,977 affected individuals and 362,322 control subjects confirmed association for 22q11.21 dosage with exome-wide significance (ORSCARF2 = 0.34 [0.21; 0.53]; mega-p value = 5.52 × 10[-7]). SCARF2 overexpression significantly increased amyloid-β uptake, congruent with duplication-associated decreased AD risk. We conclude that rare coding CNVs in a proportion of AD-associated genes and 22q11.21 deletions, including some found in DiGeorge syndrome, increase AD risk. Conversely, we identify 22q11.21 duplication as a strong AD-risk-decreasing factor.},
}

@article {pmid42648310,
year = {2026},
author = {Chen, J and Ji, H and Yuan, Y},
title = {40 Hz noninvasive transcranial ultrasound stimulation modulates multiscale nonlinear dynamics of hippocampal CA1 neural oscillations of Alzheimer's mouse model.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae9eed},
pmid = {42648310},
issn = {1741-2552},
abstract = {Aberrant nonlinear dynamics of hippocampal neural oscillations are a hallmark of early network dysfunction in Alzheimer's disease (AD), with critical roles in memory processing. Although transcranial ultrasound stimulation (TUS) has shown cognitive benefits in AD models and patients, its effects on the nonlinear dynamics of hippocampal CA1 oscillations and their multiscale organization remain unclear. Approach. Here, we applied 40 Hz non-invasive TUS to the hippocampal CA1 region of AD mouse model and recorded local field potentials before, during, and after stimulation. Analyses integrated nonlinear dynamical metrics, power spectral dependencies, cross-frequency coupling, and event-level oscillatory features. Main results. We found that (1) 40 Hz TUS decreases complexity and irregularity of CA1 activity, and enhances dynamical activity and long-range temporal correlations in broadband and high-frequency ranges, increases complexity in the theta and beta bands. (2) TUS also significantly reduced theta-gamma and intra-gamma phase-amplitude coupling, while producing frequency-specific changes in the rate, amplitude, duration, and temporal organization of theta, gamma, and ripple events. (3) Furthermore, the relationship between nonlinear dynamics and power spectral density was modulated across stimulation phases. Significance. 40 Hz TUS can modulate multiscale nonlinear dynamics of neural oscillations in hippocampal CA1 of Alzheimer's mouse model, which lays a theoretical foundation for the clinical intervention of Alzheimer's disease via ultrasound stimulation. .},
}

@article {pmid42648361,
year = {2026},
author = {Maria de Campos, R and Carraro, MF and Brandão Bitencourt, AL and Jerisha, JJ and Ayon, NJ and Juska, VB and Pinheiro, NR and Johnson, EA and Nowar, RN and McGee, JP and Alfaro, ME and Oberholzer, MV and Grippo, V and Cline, EN and Viola, KL and Kelleher, NL and Habif, M and Jerusalinsky, DA and Shekhawat, GS and Elmor, MB and Lah, JJ and Levey, AI and Klein, WL and Sebollela, A},
title = {Use of high-affinity scFv antibody NUsc1 for isolation and sensitive detection of Alzheimer's-associated amyloid beta oligomers.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113499},
doi = {10.1016/j.jbc.2026.113499},
pmid = {42648361},
issn = {1083-351X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which soluble amyloid-beta oligomers (AβOs) play a key role in disease onset and progression. This study further explores NUsc1, a single-chain variable fragment (scFv) antibody with high specificity for neurotoxic AβOs over monomers or fibrils, to selectively isolate and assist characterization of AβO species. NUsc1 binds AβOs with a kinetic dissociation constant under 10nM, comparable to the affinity of Leqembi for protofibrils. NUsc1 inhibits aggregation of AβOs into protofibrillar and fibrillar structures and blocks AβO binding to cultured hippocampal neurons in a dose-dependent manner, with an IC50 of ∼100nM in experiments using 2.25ng/μL AβOs. Selectivity and high affinity of NUsc1 enabled immunoprecipitation of AβOs under non-denaturing conditions. Atomic force microscopy revealed globular NUsc1-AβO complexes with a z-height of ∼3-4 nm, while free NUsc1 measured ∼1.5nm. Mass spectrometry revealed a heterogeneous population of NUsc1-isolated AβOs, consistent with a stepwise species assembly, while non-denaturing size-exclusion chromatography revealed species of approximately 70kDa. In ELISA, phage-bound NUsc1 (pbNUsc1) detected ∼12pM AβOs, a 33-fold increase in detection sensitivity compared to a commercial anti-Aβ antibody. NUsc1 also detected AβOs from 5xFAD mouse brain extracts, cerebrospinal fluid from AD rats, and, notably, from CSF of human donors, demonstrating direct detection of AD-relevant oligomers in a clinically relevant human biofluid. Collectively, these results highlight NUsc1's promise not only as a powerful research tool for structural and mechanistic studies of AβOs but also as a highly sensitive diagnostic tool for clinical use.},
}

@article {pmid42648363,
year = {2026},
author = {Dodd, DA and LaCroix, MS and Valdez, C and Mendoza-Oliva, A and Beaver, JD and Vega, AR and Kumar, A and Xing, C and White, CL and Diamond, MI},
title = {Endolysosomal inhibition uncouples tau uptake from intracellular seeding.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113498},
doi = {10.1016/j.jbc.2026.113498},
pmid = {42648363},
issn = {1083-351X},
abstract = {Neurodegenerative tauopathies, including Alzheimer's disease, appear to be driven by propagation of tau assemblies, which must access the cytoplasm to recruit monomer and self-replicate, a process termed "seeding." The prevailing model holds that tau seeds enter cells via macropinocytosis and reach the cytosol through lysosomal rupture or micro-perforation. Our findings revise this model by revealing that endocytosis is not required for seeding. Using genome-scale CRISPR screening, we identified multiple v-ATPase components whose loss reduced tau uptake (measured by flow cytometry) yet paradoxically increased seeding (measured by FRET biosensors). Acute v-ATPase inhibition with bafilomycin A1 produced the same effect in v2L tau biosensors and iPSC-derived neurons. Among regulators of endosome maturation, dominant-negative Rab5a decreased internalization while enhancing cytoplasmic templating. Cholesterol depletion produced identical results. Strikingly, transient hypothermia eliminated virtually all detectable tau uptake and dramatically increased seeding, without affecting subsequent tau monomer or aggregate degradation. We conclude that efficient endolysosomal trafficking does not appear to be required for cytoplasmic seeding under the conditions studied here. Across diverse perturbations, reduced endolysosomal flux consistently enhanced tau seeding, consistent with prior work indicating that most internalized aggregates are routed toward degradation rather than amplification. To seed effectively, tau must cross the plasma or vesicular membranes into the cytoplasm. We have found that proper endolysosomal trafficking suppresses cytoplasmic tau seeding, as all perturbations augmented this process. These findings reframe the role of the endolysosomal system in tau seeding and identify membrane transit rather than macropinocytosis itself as a critical gateway to cytoplasmic tau amplification.},
}

@article {pmid42648539,
year = {2026},
author = {Shi, K and Luo, XY and Liu, TT and Liu, WZ and Dong, YF and Zheng, FB and Zhou, X and Xing, JS and Sun, ZH and Chen, QQ and Jiang, L and Tan, CC and Tan, L and Xu, W and , },
title = {Cerebral amyloid-β burden and white matter injury: associations, clues for underlying mechanisms, and implication on cognitive trajectory after lecanemab therapy.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.08.057},
pmid = {42648539},
issn = {2090-1224},
abstract = {INTRODUCTION: White matter hyperintensities (WMH) are linked to cognitive decline and risk of Alzheimer's disease (AD).

OBJECTIVES: To test whether amyloid-β (Aβ) deposition contributes to white matter injury and whether WMH dynamics can modulate the clinical efficacy of the anti-Aβ therapy.

METHODS: Twenty patients with early AD who are receiving lecanemab and a matched cohort of 110 untreated AD patients were followed. Linear mixed-effects models were used to examine the interplay between WMH trajectories and lecanemab on cognitive decline. The roles of Aβ burden in predicting baseline severity and progression rates of WMH were evaluated in a larger cohort of 1,031 adults. Finally, cerebrospinal fluid (CSF) proteomic and bioinformatic analyses were performed to identify potential candidate mediators and pathways linking Aβ to WMH progression.

RESULTS: Following lecanemab treatment (median = 13 times), 80 % of patients showed WMH reductions, predominantly in periventricular and frontoparietal regions. Compared to the reference cohort, WMH progression is significantly slower among those with anti-Aβ therapy. WMH trajectory significantly modified the relationship between anti-Aβ therapy and cognitive decline, with greater cognitive improvement observed among those with smaller WMH reductions. The levels of Aβ burden were correlated with higher burden and accelerated rates of WMH. Eight proteins in CSF were identified as candidate mediators linking WMH to Aβ. They were enriched in vascular-endothelial, neuro-cytoskeletal, and neuroinflammation pathways.

CONCLUSION: The interplay of Aβ with white matter integrity contributes to cognitive decline in the context of Alzheimer's disease.},
}

@article {pmid42648589,
year = {2026},
author = {Zhang, R and Yu, T and Hao, K and Yu, Y and Chen, L and Cheng, X},
title = {Non-linear association of blood urea nitrogen with low cognitive performance: Translational evidence from murine models and human population analysis.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115996},
doi = {10.1016/j.expneurol.2026.115996},
pmid = {42648589},
issn = {1090-2430},
abstract = {BACKGROUND: Cognitive impairment in Alzheimer's disease (AD) is increasingly recognized as a systemic metabolic disorder, yet early peripheral biomarkers remain elusive. The kidney-brain axis offers a novel perspective, but the association between blood urea nitrogen (BUN) and Cognitive function is poorly understood.

METHODS: We integrated murine models (5xFAD vs. wild-type), human NHANES data (n = 3435), and single-cell virtual knockout of the BUN-associated gene GLS in human kidney cells.

RESULTS: 5xFAD mice showed early renal histopathological damage and memory deficits; BUN positively correlated with fear memory retention, and reduced BUN in 5xFAD aligned with the low-BUN risk limb of the human non-linear association. In humans, restricted cubic splines revealed a significant inverse association between BUN and low cognitive performance (LCP), with the risk reduction plateauing at BUN levels above approximately 12 mg/dL. Subgroup analyses showed no significant interactions for any of the examined variables, indicating that the inverse association between BUN and LCP was consistent across population strata. Exploratory GLS knockout upregulated mitochondrial oxidative phosphorylation and ROS pathways, providing hypothesis-generating molecular clues.

CONCLUSIONS: Cross-species evidence links BUN to cognitive, with murine data consistent with human low-BUN risk and identifying a significant inverse association between BUN and LCP that plateaued above approximately 12 mg/dL in this older adult cohort in this cohort, which should be viewed as exploratory and requires validation in independent prospective cohorts. Virtual GLS knockout suggests a mitochondrial axis. BUN warrants further evaluation as an accessible biomarker for cognitive risk assessment.},
}

@article {pmid42648719,
year = {2026},
author = {Taniguchi, D and Tsuyama, K and Hatano, T and Ashizawa, K and Yao, T and Fujimaki, M and Kanai, K and Li, Y and Funayama, M and Hattori, N},
title = {Astrocyte-Predominant Tau Pathology in a Patient With VCP R191Q Variant.},
journal = {Neuropathology : official journal of the Japanese Society of Neuropathology},
volume = {46},
number = {5},
pages = {e70075},
doi = {10.1111/neup.70075},
pmid = {42648719},
issn = {1440-1789},
support = {JP25wm0625126//Japan Agency for Medical Research and Development/ ; JP25wm0625127//Japan Agency for Medical Research and Development/ ; JP25K18969//Japan Society for the Promotion of Science (JSPS)/ ; JP24K02373//Japan Society for the Promotion of Science (JSPS)/ ; },
mesh = {Humans ; Female ; *Valosin Containing Protein/genetics ; *tau Proteins/metabolism ; *Astrocytes/pathology/metabolism ; Middle Aged ; Frontotemporal Dementia/pathology/genetics ; Brain/pathology/metabolism ; },
abstract = {Variants in the valosin-containing protein (VCP) gene cause multisystem proteinopathy, typically characterized by TDP-43 pathology. However, there are few reports describing tau pathology in VCP variant carriers. Here, we report a Japanese woman carrying a heterozygous VCP R191Q variant, who developed progressive muscle weakness, frontotemporal dementia, and parkinsonism beginning in her mid-forties and died at the age of 61. Neuropathological examination demonstrated FTLD-TDP type D pathology involving the frontal and temporal cortices, limbic structures, brainstem, spinal cord, and skeletal muscle. In addition, a distinct pattern of tau pathology was identified, predominantly in astrocytes and extending from the lower brainstem throughout the spinal cord. Tau aggregates were distributed in perivascular, subpial, and central gray matter, with a rostrocaudal distribution. Immunohistochemistry and confocal microscopy demonstrated colocalization of 3-repeat (3R) and 4-repeat (4R) tau within astrocytes, with predominance of 3R tau. Western blot analysis confirmed these findings and showed a tau banding pattern similar to that in Alzheimer's disease. These features differ from those observed in disorders with astrocytic tau pathology, such as cervical spondylotic myelopathy, chronic traumatic encephalopathy, and aging-related tau astrogliopathy, which are typically characterized by predominance of 4R tau and minimal or absent 3R tau involvement. They also differ from the neuronal tau pathology observed in the frontotemporal cortex in patients with the VCP D395G variant. This case expands the neuropathological spectrum of VCP-related diseases and suggests a possible association between VCP variants and pathological tau aggregation.},
}

Humans
Female
*Valosin Containing Protein/genetics
*tau Proteins/metabolism
*Astrocytes/pathology/metabolism
Middle Aged
Frontotemporal Dementia/pathology/genetics
Brain/pathology/metabolism

@article {pmid42648816,
year = {2026},
author = {Xu, R and Chen, H and Zhao, C and Ding, X},
title = {A lyophilized CHA-lateral flow platform for point-of-care detection of miR-106b-5p from L1CAM-Immunocaptured small extracellular vesicles in Alzheimer's disease.},
journal = {Analytica chimica acta},
volume = {1420},
number = {},
pages = {345938},
doi = {10.1016/j.aca.2026.345938},
pmid = {42648816},
issn = {1873-4324},
mesh = {*MicroRNAs/blood ; Humans ; *Alzheimer Disease/diagnosis/blood ; *Point-of-Care Systems ; *Neural Cell Adhesion Molecule L1/immunology/chemistry ; *Extracellular Vesicles/chemistry/metabolism ; Immunoassay/methods ; Freeze Drying ; Limit of Detection ; Rapid Diagnostic Tests ; },
abstract = {The early, non-invasive diagnosis of Alzheimer's disease (AD) remains a significant clinical challenge. MicroRNAs carried by L1CAM-immunocaptured small extracellular vesicles (sEVs) in blood, particularly miR-106b-5p, have emerged as promising candidate biomarkers for AD. However, their detection requires methods that are sensitive, specific, stable, and suitable for point-of-care (POC) applications. Catalytic hairpin assembly (CHA) combined with lateral flow immunoassay (LFIA) offers a potential POC solution, but its practical application is limited by high background leakage caused by "DNA breathing" and poor probe stability. Herein, we propose an integrated POC platform that combines immunomagnetic enrichment of L1CAM-positive sEVs with a novel "Fold-Adsorb-Block-Immobilize-Lyophilize" (FABIL) process for CHA probe stabilization. The FABIL process utilizes magnetic graphene oxide (MGO) to adsorb and physically separate hairpin probes (H1 and H2), thereby suppressing nonspecific hybridization and generating lyophilized CHA microspheres with room-temperature stability. When integrated into a lateral flow test strip, the FABIL-NE-miR platform achieves a visual detection limit of 10 fM and a liquid-phase limit of detection of 1.14 fM, overcoming the traditional trade-off between low background and high sensitivity. Clinical validation using 100 serum samples, including 32 AD cases and 68 non-AD controls, demonstrated that FABIL-NE-miR outperformed traditional low-background CHA systems, with an area under the ROC curve (AUC) of 0.9563, a sensitivity of 90.63%, and a specificity of 94.12%. Overall, the FABIL-NE-miR platform enables rapid visual detection of low-abundance AD-associated miRNAs from L1CAM-immunocaptured sEV fractions. By addressing key challenges such as background leakage and probe instability, this study provides a practical tool for AD screening and supports the feasibility of the FABIL strategy as a universal platform for next-generation nucleic acid diagnostics.},
}

*MicroRNAs/blood
Humans
*Alzheimer Disease/diagnosis/blood
*Point-of-Care Systems
*Neural Cell Adhesion Molecule L1/immunology/chemistry
*Extracellular Vesicles/chemistry/metabolism
Immunoassay/methods
Freeze Drying
Limit of Detection
Rapid Diagnostic Tests

@article {pmid42648826,
year = {2026},
author = {Chien, SC and Chang, IY and Chen, YC and Lai, YZ and Chen, YF and Sun, PL and Li, BR and Wang, YL and Chen, JC},
title = {Multiplexed EDL-FET biosensor with tannic acid stabilization for simultaneous p-Tau217 and Aβ42/Aβ40 detection in plasma and whole blood from stroke patients.},
journal = {Analytica chimica acta},
volume = {1420},
number = {},
pages = {345949},
doi = {10.1016/j.aca.2026.345949},
pmid = {42648826},
issn = {1873-4324},
mesh = {Humans ; *Amyloid beta-Peptides/blood ; *Biosensing Techniques/methods/instrumentation ; *tau Proteins/blood ; *Stroke/blood ; *Tannins/chemistry ; Biomarkers/blood ; *Peptide Fragments/blood ; Female ; Male ; Aged ; Phosphorylation ; Polyphenols ; },
abstract = {Alzheimer's disease (AD) is a leading cause of disability in aging societies, underscoring the need for practical blood-based biomarker assays. Stroke patients face an elevated risk of AD-related cognitive impairment, yet reliable, scalable tools for early biomarker assessment in this population remain lacking. Current platforms are limited by low throughput, instability, and demanding sample preparation that restricts point-of-care translation. This study addresses the need for a multiplexed, clinically practical biosensor capable of simultaneously measuring AD-relevant biomarkers in both plasma and whole blood. An eight-channel electric double-layer field-effect transistor (EDL-FET) platform was developed to simultaneously measure phosphorylated tau (p-tau217) and the Aβ42/Aβ40 ratio in plasma and whole blood. Standardized surface modification with tannic acid (TA)-assisted antibody immobilization enabled stable chip performance under wet storage for at least 10 days. Clinically, 54 plasma and 32 whole-blood samples from stroke patients were stratified into cognitively impaired (MMSE ≤24) and unimpaired (MMSE >24) groups. p-tau217 significantly differentiated cognitive status in both matrices, with the strongest performance in plasma. Combining p-tau217 with Aβ42/Aβ40 in plasma yielded a receiver operating characteristic (ROC) area under the curve (AUC) of 0.938. Plasma p-tau217, alone or in combination, demonstrated higher sensitivity for detecting cognitive impairment, while whole-blood measurements offered practicality, with preserved sample integrity and minimal pre-analytical requirements. This work presents the first multiplexed EDL-FET platform for simultaneous AD biomarker profiling in stroke patients using both plasma and whole blood. The integration of p-tau217 and Aβ42/Aβ40 on a stable, multi-channel chip demonstrates a novel route toward point-of-care AD risk stratification in high-risk populations, pending validation in larger, multi-center cohorts.},
}

Humans
*Amyloid beta-Peptides/blood
*Biosensing Techniques/methods/instrumentation
*tau Proteins/blood
*Stroke/blood
*Tannins/chemistry
Biomarkers/blood
*Peptide Fragments/blood
Female
Male
Aged
Phosphorylation
Polyphenols

@article {pmid42649077,
year = {2026},
author = {Wang, Y and Li, H and Hao, L and Guo, P and Xu, B and Cai, M and Li, S},
title = {Cholinergic dysfunction in Alzheimer's disease: Mechanistic perspectives and multi-target effects of traditional Chinese medicine.},
journal = {Bioscience trends},
volume = {},
number = {},
pages = {},
doi = {10.5582/bst.2026.01106},
pmid = {42649077},
issn = {1881-7823},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and complex pathological changes. Cholinergic dysfunction is an early, clinically pivotal feature of AD closely associated with multiple pathological processes, including amyloid-β (Aβ) pathology, neuroinflammatory responses, mitochondrial dysfunction, metal-ion dyshomeostasis, and apolipoprotein E (APOE) ε4-related vulnerability. While disrupted cholinergic signaling impairs memory formation and synaptic function, its bidirectional interaction with AD-related pathological cascades further accelerates disease progression. Traditional Chinese medicine (TCM) has been investigated as a potential multitarget approach with which to modulate cholinergic deficits and related pathological processes. Some TCM-derived compounds, standardized extracts, and formulas have been reported to regulate cholinergic enzymes, acetylcholine levels, cholinergic receptors, oxidative stress, mitochondrial function, neuroinflammatory responses, and Aβ- or tau-related pathology. This review summarizes the role of cholinergic failure in AD pathophysiology and evaluates the evidence surrounding TCM-based interventions, with emphasis on direct cholinergic evidence, indirect collateral mechanisms, and current translational limitations. Indeed, the purpose of these insights is to inform future development of multitarget therapeutic strategies for AD.},
}

@article {pmid42649221,
year = {2026},
author = {Shuken, SR and Frere, GA and Beard, CR and McGann, CD and Canterbury, JD and Zuniga, NR and Gassaway, BM and Dawson, SL and Ooi, KH and Paulo, JA and McNerney, MW and Gygi, SP and Yu, Q},
title = {Next-generation multiplexed targeted proteomics quantifies post-translational modifications in disease and compound-protein interactions with high throughput.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42649221},
issn = {2041-1723},
support = {K99 AG088297/AG/NIA NIH HHS/United States ; GM67945/NH/NIH HHS/United States ; R01 GM132129/GM/NIGMS NIH HHS/United States ; K22 CA282268/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Proteomics/methods ; *Protein Processing, Post-Translational ; Phosphorylation ; *Alzheimer Disease/metabolism ; tau Proteins/metabolism ; High-Throughput Screening Assays/methods ; Brain/metabolism ; Mass Spectrometry ; },
abstract = {The GoDig platform enables sensitive, multiplexed targeted pathway proteomics without manual scheduling or synthetic standards. Here we present GoDig 2.0, which increases sample multiplexing to 35-fold, improves time efficiency and reduces scan delays for higher success rates, and allows flexible spectral and elution library generation from different mass spectrometry data types. GoDig 2.0 measures 2.4× more targets than GoDig 1.0, quantifying >99% of 800 peptides in a single run. We compile a library of 23,989 human phosphorylation sites from a phosphoproteomic dataset and use it to profile kinase signaling differences across cell lines. In human brain tissue, we establish a hyperphosphorylated tau assay including pTau127, revealing potential biomarkers for Alzheimer's disease. We also quantify diglycyl-lysine peptides to assess polyubiquitin branching. Finally, we build a library of 20,946 reactive cysteines and profile covalent compound-protein interactions spanning diverse pathways. GoDig 2.0 enables high-throughput analyses of site-specific protein modifications across many biological contexts.},
}

Humans
*Proteomics/methods
*Protein Processing, Post-Translational
Phosphorylation
*Alzheimer Disease/metabolism
tau Proteins/metabolism
High-Throughput Screening Assays/methods
Brain/metabolism
Mass Spectrometry

@article {pmid42649291,
year = {2026},
author = {Lee, SY and Park, E and Lee, HE and Kim, S and Yeo, Y and Park, J and Choi, YJ and Lee, K and Yoon, KJ and Park, S and Kim, E and Kim, JI and Chung, WS},
title = {Aberrant excitatory neuronal ERBB4 promotes Alzheimer's disease pathology.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42649291},
issn = {1476-4687},
abstract = {Neuroinflammation and synapse loss are associated with cognitive decline in Alzheimer's disease (AD). Although microglial hyperphagocytic activity has been implicated in synapse loss[1-4], the mechanisms underlying these pathologies remain obscure. Here we demonstrate that, during AD progression in mice, astrocytes and microglia increase phagocytic elimination of excitatory synapses while reducing elimination of inhibitory synapses, suggesting that neuroinflammation alone may be dispensable for early AD synapse loss. Instead, single-nucleus RNA-sequencing analysis identified the emergence of early-responsive excitatory neurons (EREN), characterized by expression of ectopic Erb-B2 receptor tyrosine kinase 4 (Erbb4), as one of the earliest major alterations in AD mouse models. Selective Erbb4 deletion in AD excitatory neurons abrogated abnormal neuronal network activities and synapse loss, as well as reactive gliosis, amyloid plaque deposition and cognitive deficits. Conversely, Erbb4 overexpression in wild-type excitatory neurons recapitulated these core AD-like phenotypes without amyloid plaques. Mechanistically, these effects required mammalian target of rapamycin (mTOR) signalling downstream of ERBB4. Subsequent transcriptomic analyses showed that excitatory neuronal Erbb4 is both necessary and sufficient to induce EREN and reactive gliosis. Directed mediation analysis of human AD transcriptomic data further support a model in which excitatory neuronal ERBB4 contributes to a pathogenic cascade that links amyloid pathology to tau propagation and cognitive decline. These findings identify aberrant Erbb4 expression in excitatory neurons as an early driver of AD pathophysiology and a potential therapeutic target across neurodegenerative diseases.},
}

@article {pmid42649434,
year = {2026},
author = {Yuan, C and Zhang, H and Chen, X and Zhu, L and Wang, Z and Wang, Y and Ge, S},
title = {Diagnostic accuracy of plasma p-tau217 against amyloid PET: A meta-analysis of technical platform variability and ratio versus single marker comparisons.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {9},
pages = {},
pmid = {42649434},
issn = {1590-3478},
mesh = {*tau Proteins/blood ; Humans ; *Alzheimer Disease/blood/diagnostic imaging/diagnosis ; *Positron-Emission Tomography/standards ; *Amyloid beta-Peptides/blood/metabolism ; Biomarkers/blood ; Sensitivity and Specificity ; Peptide Fragments/blood ; },
abstract = {OBJECTIVE: To systematically evaluate the diagnostic accuracy of plasma phosphorylated tau 217 (p-tau217) for detecting amyloid pathology in Alzheimer's disease (AD), compare performance across different technical platforms, and assess the incremental diagnostic value of the p-tau217/Aβ42 ratio relative to single p-tau217 measurements.

METHODS: In order to find diagnostic accuracy studies of plasma p-tau217 utilizing amyloid positron emission tomography (PET) as the reference standard, we conducted a systematic search of PubMed and EMBASE between January 2020 and February 2026. Random-effects models were used to compute pooled sensitivity, specificity, and diagnostic odds ratio (DOR). Technical platforms such as single-molecule array (Simoa), chemiluminescence immunoassay (CLIA), electrochemiluminescence immunoassay (ECLIA), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to stratify subgroup studies. Studies that reported both p-tau217 alone and p-tau217/Aβ42 ratios were subjected to paired meta-analyses.This systematic review was registered with PROSPERO (registration number: CRD420261371940).

RESULTS: Included were 25 studies with 18,073 participants. Platform-specific pooled diagnostic accuracy estimates were as follows: Simoa had sensitivity of 0.894 (95% CI 0.861-0.920) and specificity of 0.875 (0.845-0.900); CLIA had sensitivity of 0.886 (0.860-0.907) and specificity of 0.865 (0.826-0.896); ECLIA had the highest sensitivity of 0.933 (95% CI 0.918-0.946) but lower specificity (0.791, 95% CI 0.571-0.915); LC-MS/MS showed sensitivity of 0.827 (95% CI 0.725-0.897) and the highest specificity of 0.938 (95% CI 0.692-0.990).There was significant variation between the studies (I[2] = 63%-86%). The p-tau217/Aβ42 ratio approximately doubled the diagnostic odds ratio compared with p-tau217 alone (relative DOR 1.96, 95% CI 1.19-3.23), with mean sensitivity improvements of 3.6% and varying specificity changes (mean + 1.7%), according to paired meta-analyses of five studies.

CONCLUSIONS: For amyloid pathology, all technical platforms showed good diagnostic accuracy. While LC-MS/MS demonstrated the highest specificity, ECLIA demonstrated the maximum sensitivity. Its application in clinical practice is supported by the fact that the p-tau217/Aβ42 ratio performed much better than p-tau217 alone.},
}

*tau Proteins/blood
Humans
*Alzheimer Disease/blood/diagnostic imaging/diagnosis
*Positron-Emission Tomography/standards
*Amyloid beta-Peptides/blood/metabolism
Biomarkers/blood
Sensitivity and Specificity
Peptide Fragments/blood

@article {pmid42649465,
year = {2026},
author = {Rippert, AL and Arnadottir, GA and Bedinger, L and Brunetti-Pierri, N and Cech, J and Chen, X and Chen, Y and Chick, E and Dyack, S and Franchi, M and Frey, T and Genevieve, D and Glass, I and Granadillo, J and Keener, KA and MacKay, SB and McDunnah, P and Misra, VK and Monaghan, KG and Mullegama, SV and Peduto, C and Peterman-Prather, L and Rauch, A and Somerville, C and Stefansson, K and Steindl, K and Sulem, P and Sulem, T and Trapane, P and Zeuli, R and Zinner, S and Izumi, K},
title = {Heterozygous Variants in LRP1 Cause a Neurodevelopmental Disorder With Congenital Heart Defects.},
journal = {American journal of medical genetics. Part A},
volume = {},
number = {},
pages = {},
doi = {10.1002/ajmg.a.70261},
pmid = {42649465},
issn = {1552-4833},
support = {K02NS140483/NH/NIH HHS/United States ; GSP15001//Fondazione Telethon/ ; U24HG006834//National Human Genome Research Institute (NHGRI)/ ; },
abstract = {LRP1 encodes the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1), a transmembrane protein involved in endocytosis and activation of multiple signaling pathways. LRP1 variants have been implicated in the pathogenesis of congenital heart defects (CHD), Alzheimer's disease, and neurodevelopmental disorders (NDD). Biallelic LRP1 variants have also been reported in two siblings with CHD, hypotonia, dysmorphology, corneal clouding, and ascites. However, conclusive evidence supporting the role of LRP1 in human disease is still lacking. Individuals with heterozygous variants in LRP1 (NM_002332.3) were identified through genetic testing. GeneMatcher facilitated identification of participants and international collaboration. Comprehensive clinical and genotypic data were collected. Fifteen participants with heterozygous predicted loss-of-function (pLOF) or missense variants in LRP1 were identified. The most common phenotypes include NDD, CHD, musculoskeletal and gastrointestinal issues, and dysmorphic features. CHD was more common in participants with pLOF variants. Our findings suggest that LRP1 haploinsufficiency is associated with a syndromic NDD. Phenotypic differences in cardiac and neurologic involvement between participants with pLOF and missense variants suggest the possibility of alternate disease mechanisms.},
}

@article {pmid42649608,
year = {2026},
author = {Isaac, JI and Singh, PG and Lee, CU and Paget, JT and Fahradyan, V},
title = {Animal Models of Lymphaticovenous Anastomosis: A Systematic Review of Current Evidence and Future Directions in Translational Research.},
journal = {Microsurgery},
volume = {46},
number = {6},
pages = {e70283},
doi = {10.1002/micr.70283},
pmid = {42649608},
issn = {1098-2752},
mesh = {Animals ; Anastomosis, Surgical/methods ; *Translational Research, Biomedical ; *Lymphatic Vessels/surgery ; *Models, Animal ; Vascular Patency ; Dogs ; Rats ; Recipient Vessels ; Rabbits ; },
abstract = {BACKGROUND: Lymphovenous bypass (LVB) or lymphaticovenous anastomosis (LVA) is increasingly applied, including experimental use for Alzheimer's disease via cervical lymphatic pathways. However, literature on long-term patency and failure mechanisms is scarce, and no gold standard exists for evaluating durability. Robust, reproducible LVA models are essential to advance translational research. This review maps current animal models and proposes strategies for improving reliability and mechanistic insight.

METHODS: A PRISMA-guided search of PubMed, Scopus, and Google Scholar identified original animal studies reporting intra- or postoperative patency using functional or structural methods. Extracted data included species, anastomosis type, assessment tools, follow-up intervals, patency rates, and histology.

RESULTS: Of 107 records screened, 11 met criteria: rats (n = 7), rabbits (n = 1), piglets (n = 1), and canines (n = 2). Techniques were mainly end-to-end (n = 9) and end-to-side (n = 2), targeting femoral, iliolumbar, popliteal, mesenteric, cervical, and thoracic-duct outflows. Intraoperative patency was uniformly high (≥ 90%). Postoperative patency was reported in six studies, ranging from 80% to 100% at ≤ 7 days (ICG lymphography) to 67% at 1 month (canines). Histology (three studies) distinguished patent sites (smooth endothelium) from failed ones (irregular endothelium, thrombus, fibrosis). Follow-up was categorized as short-term (0-7 days), mid-term (2-4 weeks), and long-term (≥ 1 month), but standardized long-term outcomes were absent.

CONCLUSIONS: Future models should integrate noninvasive imaging, serial long-term follow-up, and detailed histologic and molecular analysis to clarify success and failure mechanisms. Standardized methodologies will enhance translational relevance, refine surgical techniques, and inform therapies to improve LVA durability.},
}

Animals
Anastomosis, Surgical/methods
*Translational Research, Biomedical
*Lymphatic Vessels/surgery
*Models, Animal
Vascular Patency
Dogs
Rats
Recipient Vessels
Rabbits

@article {pmid42649834,
year = {2026},
author = {Liu, Z and Ouyang, H and Liu, X and Mao, H and Dai, W and Kang, Y},
title = {Knowledge Graph and Large Language Model-Based Analysis of fMRI Brain Functional Neuroimaging Research.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {8},
pages = {},
doi = {10.3390/bioengineering13080945},
pmid = {42649834},
issn = {2306-5354},
support = {19JZD010//Ministry of Education of the People's Republic of China/ ; },
abstract = {The rapid growth of multimodal neuroimaging research has produced fragmented literature that limits systematic characterization of cross-modal relationships and disease-specific knowledge structures. To address this, we constructed a multimodal neuroimaging knowledge graph from 1838 peer-reviewed studies (2016-2026) spanning fMRI, EEG, fNIRS, and PET, using an LLM-based extraction and retrieval-augmented semantic merging pipeline. The resulting graph comprised 4190 nodes and 7007 edges, exhibiting a scale-free topology with a dominant connected component covering 76.6% of nodes. Alzheimer's disease, the hippocampus, and fMRI/PET emerged as the most central hubs linking disease, anatomical, and methodological dimensions. Louvain community detection identified 25 functional modules, with seven major communities-centered on Alzheimer's biomarker integration, molecular/fluid imaging, and psychiatric functional connectivity-forming the field's core structure. Cross-modal analysis revealed the strongest coupling between fMRI and PET, indicating high methodological convergence. At the disease level, Alzheimer's disease displayed a mature, hierarchically organized biomarker system, whereas major depressive disorder and chronic pain showed diffuse, less consolidated knowledge structures. These results reveal pronounced disparities across neuroimaging research domains and demonstrate that LLM-augmented knowledge graphs can systematically uncover latent structural organization relevant to multimodal integration and biomarker discovery.},
}

@article {pmid42650190,
year = {2026},
author = {Godos, J and Caruso, G and Mainas, G and Micek, A and Di Mauro, A and Buccarello, L and Martínez López, NM and Frias-Toral, E and Giampieri, F and Lehoczki, A and Isola, G and Galvano, F and Ungvari, Z and Quiles, JL and Battino, M and Grosso, G},
title = {Oral Microbiota, the Oral-Brain Axis, and Neurodegeneration: Mechanisms and Dietary Modulation.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/antiox15080925},
pmid = {42650190},
issn = {2076-3921},
support = {NA//Italian Ministry of Health/ ; },
abstract = {The oral microbiota represents a complex and dynamic microbial ecosystem that plays a critical role in preserving both oral and systemic homeostasis. Emerging evidence suggests that alterations in oral microbial milieu (dysbiosis) may contribute to the pathogenesis of neurodegenerative disorders, especially Alzheimer's disease (AD), through the oral-brain axis. This review synthesizes current evidence on the pathways linking oral microbiota to cognitive decline, integrating microbial, immunological, and vascular perspectives. Oral pathogens may access the central nervous system via hematogenous dissemination or neural routes, including the trigeminal nerve, while simultaneously promoting systemic inflammation, immune activation, and blood-brain barrier disruption. These processes converge on key neurodegenerative mechanisms, including chronic neuroinflammation, amyloid-β accumulation, and tau pathology. In parallel, alterations in oral microbial composition have been linked to disease severity, supporting a potential role of dysbiosis in both initiation and progression of cognitive impairment. Diet emerges as a critical modifiable determinant of oral microbial ecology. Diets rich in refined sugars may promote dysbiosis and inflammatory signaling, whereas (poly)phenols, probiotics, and prebiotics may support microbial eubiosis and exert neuroprotective effects through modulation of host-microbe interactions. Although current evidence remains largely observational and mechanistic, the diet-oral microbiota-brain axis represents a promising target for preventive and therapeutic strategies aimed at mitigating cognitive decline and promoting healthy aging. Future longitudinal and interventional studies are required to establish causality and translate these insights into clinical practice.},
}

@article {pmid42650212,
year = {2026},
author = {Varrassi, G and Tran, YV and Farì, G and Narvaez Encinas, M and Corriero, A and Puntillo, F and Pham, PV and Leoni, MLG},
title = {The Eye as a Window to Neurodegeneration: Oxidative Stress, Optic Nerve Vulnerability, and Retinal Biomarkers-A Scoping Review.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/antiox15080948},
pmid = {42650212},
issn = {2076-3921},
support = {//Tam Anh General Hospital, Ha Noi/ ; },
abstract = {Neurodegenerative diseases represent a major and growing global health burden characterized by progressive neuronal dysfunction, axonal degeneration, and irreversible neural tissue loss. Increasing evidence identifies oxidative stress as one of several interacting pathogenic mechanisms in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and several optic neuropathies. Interest has increasingly focused on the brain-retina axis, as the retina and optic nerve share structural, metabolic, and molecular features with the central nervous system and may provide accessible insights into neurodegeneration. This scoping review mapped current evidence on oxidative stress in neurodegeneration, emphasizing cranial nerve involvement, optic nerve vulnerability, retinal ganglion cell degeneration, visual dysfunction, oxidative biomarkers, and emerging therapeutic strategies. The review followed established methodological frameworks and PRISMA-ScR recommendations; no formal risk-of-bias appraisal was undertaken, consistent with scoping-review methodology. The literature shows that oxidative stress interacts with mitochondrial dysfunction, neuroinflammation, impaired mitophagy, ferroptosis, and altered bioenergetics, contributing to neuronal injury in cerebral and retinal disorders. Retinal ganglion cells appear particularly vulnerable because of their high metabolic demands and reliance on oxidative phosphorylation. Glaucoma and other optic neuropathies share molecular signatures with central neurodegenerative diseases. Retinal imaging and oxidative biomarkers show promise for diagnosis, monitoring, and stratification. The evidence base is nonetheless dominated by preclinical work; biomarker performance is inconsistent across matrices and assay platforms and most antioxidant clinical trials have been negative. Oxidative stress is therefore best regarded as one interacting node of a broader pathogenic network rather than a universal or predominant driver and the brain-retina continuum as a mechanistically plausible but not yet clinically validated framework for biomarker-guided neuroprotection.},
}

@article {pmid42650215,
year = {2026},
author = {Concetta, SM and Cinzia, L and Giulia, Z and Caterina, L and Gaetano, I and Nicolò, M and Angela, TS},
title = {Functional Foods and Micro- and Nanoplastics: Advances in Precision Nutritional Medicine for Oral-Gut-Brain Axis Health.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/antiox15080951},
pmid = {42650215},
issn = {2076-3921},
abstract = {Microplastics and nanoplastics (MNPs) are emerging environmental pollutants due to their persistence and bodily accumulation. Recently, functional foods have received much attention for their ability to reverse or block MNP damage for therapeutic purposes and the potential risk of developing oral-gut-brain axis disorders. Among these, artichoke, spirulina algae, Opuntia ficus-indica, pterostilbene, hydroxycinnamic acids, and quinic acid are rich sources of polyphenols. These bioactive ingredients, especially when combined with probiotics and prebiotics, exhibit significant antioxidant and anti-inflammatory potential by activating nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and cellular resilience enzymes. Nrf2 activation enhances cellular resilience response, and it may preserve oral epithelial barrier (OEB), intestinal epithelial barrier (IEB), and blood-brain barrier (BBB) integrity, while modulating oral pathogens, gut microbial dysbiosis, and neuroinflammatory processes. However, most of the available evidence supporting these mechanisms derives from in vitro and animal studies, whereas clinical evidence in humans remains limited. Perturbations of Nrf2 due to circulating MNPs may exacerbate selective susceptibility to oral, gut, and nervous system disorders, including Alzheimer's disease (AD). Although these findings are biologically plausible, the causal relationships and their clinical relevance have not yet been fully established. This review discusses the role of functional foods in maintaining oral-gut-brain health through Nrf2-mediated mechanisms that may mitigate MNP-induced inflammation and reactive oxygen species (ROS). The review also examines emerging concepts in precision nutritional medicine, including individual variability in dietary responses, microbiome-related factors, and future personalized strategies for populations exposed to MNPs. Finally, current knowledge gaps, the scarcity of human studies, and the challenges in translating preclinical findings into clinical practice are highlighted, emphasizing the need for further translational and clinical research.},
}

@article {pmid42650275,
year = {2026},
author = {Riccetti, R and Trentini, A and Mola, G and Brombo, G and di Paola, DF and Castellazzi, M and Candeloro, R and Manfrinato, MC and Zuliani, G and Cervellati, C},
title = {Reduced Serum PON1 Lactonase Activity Is Associated with Mild Cognitive Impairment and Mixed Dementia.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/antiox15081011},
pmid = {42650275},
issn = {2076-3921},
abstract = {High-density lipoprotein (HDL)-associated paraoxonase-1 (PON1) contributes substantially to the antioxidant and anti-inflammatory functions of HDL. Impairment of these protective properties has been associated with Alzheimer's disease (AD) and other forms of dementia, particularly those involving neurovascular dysregulation. In the present study, we investigated for the first time the potential involvement of the putative physiological lactonase activity of PON1 in serum samples from a large cohort of older adults (n = 691), including cognitively healthy controls and patients with mild cognitive impairment (MCI), AD, vascular dementia (VAD), mixed AD/VAD (MIXED dementia), and other forms of dementia. A difference was observed between controls and MCI patients (-34%, p < 0.001). The next largest differences were observed in the VAD and MIXED dementia groups, both showing a decrease of approximately 25% compared with controls (p < 0.05 and p < 0.001, respectively), and in AD patients (-14%, p < 0.05). After adjustment for confounding factors, only MCI and MIXED dementia remained significantly different from controls. These findings suggest that reduced serum PON1 lactonase activity is already detectable at the MCI stage and is particularly evident in conditions combining neurodegenerative and vascular pathology. Longitudinal studies are required to determine whether lower PON1 lactonase activity precedes, accompanies, or follows cognitive decline.},
}

@article {pmid42650743,
year = {2026},
author = {Zhou, Y and Diao, Y and Yan, Z and Shui, X and Huang, Z and Sun, Y and Wang, S and Xia, Y and Lee, TH and Wang, L},
title = {Development of a Novel AAV-Mediated microRNA Gene Therapy for Spatial Suppression of BACE1 to Improve Cognitive Function in Alzheimer's Disease Model Mice.},
journal = {Biomolecules},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/biom16081075},
pmid = {42650743},
issn = {2218-273X},
support = {82401642, 82404101, 82271449 and 82571556//National Natural Science Foundation of China/ ; 2022J01666//Fujian Provincial Department of Science and Technology/ ; 2025Y9117, 2024Y9094 and 2023Y9008//Fujian Provincial Department of Science and Technology/ ; },
mesh = {Animals ; *MicroRNAs/genetics/metabolism ; *Alzheimer Disease/therapy/genetics/metabolism ; *Amyloid Precursor Protein Secretases/genetics/metabolism/antagonists & inhibitors ; *Aspartic Acid Endopeptidases/genetics/metabolism/antagonists & inhibitors ; *Dependovirus/genetics ; *Genetic Therapy/methods ; Mice ; Disease Models, Animal ; Humans ; *Cognition ; Gene Therapy Agents ; Hippocampus/metabolism ; Male ; },
abstract = {The beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a promising and rational target for Alzheimer's disease (AD), but current clinical trials have been disappointing. Consequently, utilizing the intrinsic regulatory mechanisms of BACE1 during AD pathogenesis might provide valuable insights into the treatment of this devastating disease. In this study, we proposed a combination of AAV delivery and microRNA therapeutics targeting AD at its root by sustained and spatial inhibition of BACE1 with a single therapeutic injection. We demonstrate that upregulation of BACE1 is correlated with downregulation of miR-143-3p in the hippocampus of individuals with AD, and miR-143-3p can directly target BACE1 to inhibit Aβ generation. In the brains of 5×FAD model mice, BACE1 levels are found to be elevated with age in the cornu ammonis 1 (CA1) subfield of the hippocampus. AAV-mediated miR-143-3p restoration in the hippocampal CA1 subfield of AD mice can improve cognitive performance, attenuate BACE1 expression, reduce Aβ levels, induce microglia polarization toward the anti-inflammatory phenotype, modulate neural-related genes including Gal3, and promote synaptic functions. Collectively, the AAV-mediated microRNA gene therapy approach developed for spatial suppression of BACE1 can effectively enhance cognitive performance in AD model mice, offering an attractive therapeutic option for AD treatment with long-lasting efficacy.},
}

Animals
*MicroRNAs/genetics/metabolism
*Alzheimer Disease/therapy/genetics/metabolism
*Amyloid Precursor Protein Secretases/genetics/metabolism/antagonists & inhibitors
*Aspartic Acid Endopeptidases/genetics/metabolism/antagonists & inhibitors
*Dependovirus/genetics
*Genetic Therapy/methods
Mice
Disease Models, Animal
Humans
*Cognition
Gene Therapy Agents
Hippocampus/metabolism
Male

@article {pmid42650752,
year = {2026},
author = {Soto-Mercado, V and Arias-Loaiza, MP and Mendivil-Perez, M},
title = {Neuroprotective Potential of Sesamum indicum in a Multifactorial In Vitro Neuron-Astrocyte System Exposed to Chronic Stress Mediators.},
journal = {Biomolecules},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/biom16081084},
pmid = {42650752},
issn = {2218-273X},
support = {112721-201-2024 and 2024-77129//Fondo Nacional de Financiamiento para la Ciencia, la Tecnología y la Innovación Francisco José de Caldas, Minciencias; Comité para el Desarrollo de la Investigación (CODI); Programa Jóvenes Investigadores UdeA-2025/ ; },
mesh = {*Neuroprotective Agents/pharmacology/chemistry ; *Neurons/drug effects/metabolism/cytology ; *Sesamum/chemistry ; *Astrocytes/drug effects/metabolism/cytology ; Animals ; Oxidative Stress/drug effects ; *Plant Extracts/pharmacology/chemistry ; Tumor Necrosis Factor-alpha/metabolism ; Amyloid beta-Peptides/metabolism ; Dioxoles/pharmacology/chemistry ; Molecular Docking Simulation ; Membrane Potential, Mitochondrial/drug effects ; Lignans/pharmacology/chemistry ; Humans ; Mitochondria/drug effects/metabolism ; Coculture Techniques ; },
abstract = {Chronic stress is increasingly recognized as a major contributor to Alzheimer's disease (AD)-related neurodegeneration through mechanisms involving neuroinflammation, oxidative stress, mitochondrial dysfunction, excitotoxicity, and amyloidogenic processing. Here, we investigated the neuroprotective effects of Sesamum indicum whole paste extract (SIPE) using 2D neuron-astrocyte-like cell (ALC) co-cultures and 3D neuron-ALC spheroids exposed to a TNF-α/glutamate/cortisol (TGC) chronic stress paradigm. TGC exposure induced mitochondrial dysfunction, mitochondrial superoxide generation, astrocytic reactivity, NF-κB activation, reduced pro-BDNF expression, intracellular and extracellular Aβ42 accumulation, Tau phosphorylation, and caspase-3 activation, reproducing key hallmarks associated with chronic stress-related neurodegeneration. Among sesame-derived preparations evaluated, SIPE exhibited the strongest neuroprotective effects, preserving mitochondrial membrane potential, reducing oxidative stress, preventing neuronal loss, attenuating gliosis, and suppressing inflammatory, amyloidogenic, and apoptotic signaling. These effects were consistently reproduced in 3D spheroids. Phytochemical analysis revealed that SIPE contained the highest enrichment of sesamin, representing approximately 25% of the detected relative composition. Molecular docking analyses demonstrated favorable sesamin binding affinity toward TNF-α, DJ-1, Aβ42, and caspase-3. Collectively, these findings identify SIPE as a promising multitarget neuroprotective strategy against chronic stress-associated AD-related pathology.},
}

*Neuroprotective Agents/pharmacology/chemistry
*Neurons/drug effects/metabolism/cytology
*Sesamum/chemistry
*Astrocytes/drug effects/metabolism/cytology
Animals
Oxidative Stress/drug effects
*Plant Extracts/pharmacology/chemistry
Tumor Necrosis Factor-alpha/metabolism
Amyloid beta-Peptides/metabolism
Dioxoles/pharmacology/chemistry
Molecular Docking Simulation
Membrane Potential, Mitochondrial/drug effects
Lignans/pharmacology/chemistry
Humans
Mitochondria/drug effects/metabolism
Coculture Techniques

@article {pmid42650994,
year = {2026},
author = {Fossataro, C and Savastano, MC and Mottola, F and De Dominicis, F and Campaniello, G and Cocuzza, M and Rizzo, C and Amore, F and Salgarello, T and Giudiceandrea, A and Rizzo, S},
title = {Diagnostic Role of Multimodal Imaging in Optic Disc Diseases.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {16},
pages = {},
doi = {10.3390/diagnostics16162591},
pmid = {42650994},
issn = {2075-4418},
abstract = {The aim of this narrative review was to provide a disease-oriented diagnostic framework for selecting and integrating multimodal imaging techniques according to the suspected optic disc disorder. A non-systematic PubMed search was performed to identify relevant literature on optic disc diseases and related imaging appearances. Searches included a combination of terms related to disease features and imaging modalities. The recent introduction of non-invasive imaging devices, such as optical coherence tomography (OCT) and OCT angiography (OCTA), has allowed a remarkable step forward in the knowledge of the optic disc. OCT has revolutionized the diagnosis and monitoring of glaucomatous eyes, providing useful quantitative biomarkers. Fundus examination and color fundus photography are the first step for evaluation of optic disc edema, which requires further exams, including fundus autofluorescence, to exclude the presence of optic disc drusen, ocular ultrasound and in certain cases, fluorescein angiography. Although still limited, OCTA could give a support in the evaluation of vascular diseases that involve the optic disc, such as anterior ischemic optic neuropathy, retinal vein occlusion and proliferative diabetic retinopathy. Analyzing the radial peripapillary capillary plexus, OCTA can also highlight early vascular changes in degenerative diseases (i.e., glaucoma, Alzheimer's disease or multiple sclerosis). Multimodal imaging is a cornerstone in the neuro-ophthalmology field, offering unparalleled insight into optic nerve head architecture and vascular integrity in both normal and diseased states.},
}

@article {pmid42650999,
year = {2026},
author = {Alagoz, AN and Ozturk, S and Bunul, SD and Anık, Y and Ozer, T and Cetin Erci, G},
title = {Magnetic Resonance Imaging-Based Cortical and Subcortical Volumetric Changes in Alzheimer's Disease: Association with Clinical Severity.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {16},
pages = {},
doi = {10.3390/diagnostics16162596},
pmid = {42650999},
issn = {2075-4418},
abstract = {Background/Objectives: This study evaluated automated magnetic resonance imaging (MRI) volumetry for characterizing structural brain changes in Alzheimer's disease (AD), mild cognitive impairment (MCI), and cognitively healthy controls (HC), and examined its association with cognitive performance. Methods: This retrospective observational study included consecutively enrolled individuals aged ≥65 years. AD dementia and MCI were diagnosed according to the 2011 National Institute on Aging-Alzheimer's Association (NIA-AA) clinical criteria. Automated volumetric analysis of structural MRI was used to obtain the total intracranial volume-normalized cortical and subcortical volumes, cerebrospinal fluid (CSF) compartments, and hemispheric asymmetry indices. Between-group comparisons were corrected using the Benjamini-Hochberg false discovery rate. Prespecified volumetric markers were evaluated using receiver operating characteristic analysis and internally validated logistic regression models. Results: The study included 102 participants (34 per group). Compared with HC, the AD group showed lower total cerebrum, right hippocampal, and anterior cingulate gyrus (ACgG) volumes and higher CSF volumes. Compared with MCI, the AD group exhibited lower thalamic and caudate volumes. CSF volume showed the highest individual discriminative performance for differentiating AD from HC (AUC = 0.837), whereas the combined hippocampal-ACgG-CSF model showed the best performance for differentiating MCI from HC (AUC = 0.826). After adjustment for diagnostic group, cognitive performance remained positively associated with hippocampal volume and negatively with CSF and lateral ventricular volumes. Conclusions: Automated MRI volumetry may support the quantitative assessment of neurodegeneration in clinically defined AD and MCI. Combined volumetric markers improved discrimination between MCI and HC, although these findings require external validation in larger, longitudinal, biomarker-characterized cohorts.},
}

@article {pmid42651073,
year = {2026},
author = {Kulmaganbetov, M and Khaidarov, S and Bevan, R and Morgan, JE},
title = {The Machine Learning Classification of Retinal Ganglion Cell Dendritic Texture in a 3xTg-Alzheimer's Disease Mouse Model.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {16},
pages = {},
doi = {10.3390/diagnostics16162672},
pmid = {42651073},
issn = {2075-4418},
support = {G0800547/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Background/Objectives: Retinal imaging has considerable potential for monitoring Alzheimer's disease (AD) neurodegeneration, as retinal ganglion cell dendritic atrophy within the inner plexiform layer (IPL) is an early event. We tested whether quantitative optical coherence tomography (OCT) speckle texture analysis combined with supervised machine learning could discriminate AD-related IPL alterations without exogenous contrast agents in a mouse model. Methods: Retinal explants from triple-transgenic AD mice (n = 7, aged 12 months) and C57BL/6 controls (n = 3, aged 15 months) were imaged ex vivo using a custom 1040 nm spectral-domain OCT system. Five grey-level co-occurrence matrix (GLCM) features were extracted from IPL volumes of interest (VOIs) and classified using a linear support vector machine (SVM). Results: AD and control IPL textures formed two completely separable clusters in a two-dimensional feature space defined by contrast and entropy (0°), achieving 100% VOI-level classification accuracy (95% CI: 96.4-100%). However, given the small sample size, VOI-level rather than animal-level validation, lack of histological confirmation, non-interleaved image acquisition, and differences in age/strain between groups, these results represent exploratory dataset separability rather than a validated diagnostic test. Conclusions: These findings demonstrate the feasibility of the ligand-free, texture-based OCT discrimination of IPL alterations, indicating a strong underlying optical signal. Adequately powered, in vivo longitudinal studies with matched controls, interleaved acquisition, animal-level cross-validation, and histological validation are required before any clinical translation.},
}

@article {pmid42651097,
year = {2026},
author = {Heath, S and Ruzicka, M and McLoon, T and Gupta, D and Emeri, O and Nnabugwu, Z and Adeniji, A and Brackett, C and Slack, S and Agbowuro, A},
title = {The Role of the NMDA Receptor in the Treatment of Psychiatric and Neurological Diseases.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080786},
pmid = {42651097},
issn = {2076-3425},
abstract = {The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor widely expressed in the CNS and in peripheral tissues where it mediates crucial physiological functions and its dysregulation has been linked to a host of neurological and psychiatric disorders including Alzheimer's disease, schizophrenia, epilepsy, and chronic pain. This work highlights the therapeutic potential in targeting the NMDAR in these disease states by providing a holistic analysis of the existing literature focused on the molecular role of the receptor in applicable disease conditions. While several drugs targeting the NMDAR have been approved for clinical use, many more are in clinical and preclinical development. A significant part of this review assesses the chemical and pharmacological attributes of these molecules and provides a prognostic perspective for their use.},
}

@article {pmid42651103,
year = {2026},
author = {Costa, IM and Kanashiro, A and Barros, GSF and Monteiro, AJ and Bonilha, CS and Galdino, G and Veras, FP},
title = {Targeting Neutrophil Extracellular Traps in Neuroinflammation: A Therapeutic Perspective on Neurodegenerative Diseases.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080792},
pmid = {42651103},
issn = {2076-3425},
abstract = {Neuroinflammation is a complex process involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Neutrophils, although traditionally considered peripheral immune cells, have emerged as active participants in the immunopathology of the central nervous system (CNS) through the release of neutrophil extracellular traps (NETs), structures composed of decondensed chromatin embedded with pro-inflammatory proteins. Evidence suggests that NETs play a dual role: they are protective against pathogens but can also induce tissue damage when produced in excess. Several pathways are involved in their formation, including vesicle-mediated release (vital NETs), the lytic NADPH oxidase (NOX)-dependent pathway, and the mitochondrial pathway. Targeting NETs therapeutically, through the use of NETosis inhibitors, NET-degrading strategies, or blockade of neutrophil migration, has shown promise in reducing neuroinflammation/neurodegeneration and improving neurological outcomes in experimental models. This review aims to investigate both the protective and deleterious roles of NETs and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity, offering valuable insights for potential applications in clinical practice.},
}

@article {pmid42651118,
year = {2026},
author = {Kvašňák, E},
title = {Effects of 40 Hz Brain Stimulation Across Modalities: A Comparative Narrative Review.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080808},
pmid = {42651118},
issn = {2076-3425},
abstract = {Gamma-band oscillations centered around 40 Hz play an important role in cortical communication, and their disruption has been documented as a neurophysiological feature of several neurodegenerative and neuropsychiatric disorders. This narrative review synthesizes preclinical and early-phase clinical evidence for 40 Hz non-invasive brain stimulation across five delivery modalities: (1) auditory stimulation, which leverages the 40 Hz auditory steady-state response (ASSR) to probe parvalbumin-positive (PV[+]) interneuron circuits and serves as a validated neurophysiological biomarker in schizophrenia; (2) visual stimulation, using luminance or invisible spectral flicker to induce steady-state visually evoked potentials (SSVEPs) and, in animal models, to activate microglial phagocytosis; (3) transcranial alternating current stimulation (tACS), which delivers sinusoidal sub-threshold membrane polarization at gamma frequency, with preliminary case-series evidence suggesting tau burden reduction and EEG-based biomarker changes in Alzheimer's disease; (4) repetitive transcranial magnetic stimulation (rTMS), offering focal cortical entrainment that, when combined with tACS in phase-synchronized protocols, produces sustained gamma enhancement in the dorsolateral prefrontal cortex; and (5) multisensory combined stimulation, which engages multiple convergent pathways and currently represents the approach with the most promising early translational signal, including cognitive stabilization and hippocampal volume preservation in small AD trials. While single-session entrainment does not reliably yield cognitive gains, multi-week applications have shown neurophysiological and preliminary biomarker-level changes in selected populations. It should be emphasized, however, that the human evidence base remains early-phase and largely derived from small, often uncontrolled studies; 40 Hz stimulation should accordingly be regarded as a biologically plausible and well-tolerated investigational approach rather than an established therapeutic intervention. Adequately powered, randomized, sham-controlled trials are required before clinical conclusions can be drawn.},
}

@article {pmid42651122,
year = {2026},
author = {Rodriguez, C and Montandon, ML and Garibotto, V and Haller, S and Herrmann, FR and Giannakopoulos, P},
title = {Abnormal FDG-PET Patterns and Amyloid Positivity Predict Personality Changes in Cognitively Preserved Individuals.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080812},
pmid = {42651122},
issn = {2076-3425},
support = {320030-169390/SNSF_/Swiss National Science Foundation/Switzerland ; },
abstract = {Background/Objectives: Clinically overt Alzheimer's disease (AD) is associated with significant changes in personality factors. Earlier studies indicated that personality factors do not remain stable in elderly controls. Whether the early presence of AD neuroimaging markers may predict subsequent changes in personality factors is still debatable. Methods: To address this issue, we examined the association between Big Five factor scores and baseline AD and vascular imaging markers in a previously established cohort of 58 elderly controls with a 4.5-year follow-up. Personality was assessed with the Neuroticism-Extraversion-Openness Personality Inventory-Revised scale at inclusion and 55-month follow-up. Regression models were used to identify predictors of personality factor changes including time, age, sex, APOE epsilon 4 allele, baseline MMSE scores, amyloid PET positivity, abnormal FDG-PET patterns, mesial temporal lobe atrophy and Fazekas scores, and number of microbleeds. Results: In both univariate and multivariable models, the decrease in openness was related to abnormal FDG PET patterns. This single variable explained 15% of the variance of this personality factor. In univariate models, lower MMSE scores and amyloid positivity at baseline were associated with a subsequent decrease in agreeableness scores. In multivariable models, these two parameters explained 11% and 8% of variance respectively. The other personality factors were not associated with AD and cerebrovascular imaging markers. Conclusions: Personality patterns at baseline may impact the emergence of AD pathology but they may also change rapidly as a function of the presence of early AD-related PET abnormalities.},
}

@article {pmid42651126,
year = {2026},
author = {Wang, H and Wang, Y and Lv, Z and Deng, Y and Pan, C and Li, Y and Zhou, Z},
title = {State-Dependent Alterations of Hippocampal Theta-Gamma Coupling in 5xFAD Mice and Their Differential Modulation by Donepezil.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080816},
pmid = {42651126},
issn = {2076-3425},
support = {2025ZD1801202//National Science and Technology Major Project/ ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is associated with progressive hippocampal circuit dysfunction, but electrophysiological measures of state-dependent abnormalities and treatment responsiveness remain incompletely characterized. We examined hippocampal theta-gamma coupling in 5xFAD mice across behavioral states and after donepezil.

METHODS: Local field potentials were recorded from CA1 in freely behaving wild-type (WT) and 5xFAD mice during home-cage activity, open-field exploration, and Y-maze testing. Power spectral density and theta-gamma phase-amplitude coupling (PAC) were quantified at the animal level at baseline and after seven days of donepezil.

RESULTS: Untreated 5xFAD mice showed reduced theta-low-gamma coupling during home-cage and open-field activity, but not Y-maze exploration, and elevated theta-high-gamma coupling in all three contexts. Donepezil increased theta-low-gamma coupling during open-field and Y-maze exploration and produced a partial numerical shift toward WT levels in the home cage. For theta-high-gamma coupling, the treated group did not differ significantly from either comparator. Untreated 5xFAD mice also showed reduced center exploration and distance traveled in the open field, while Y-maze spontaneous alternation was unchanged. Theta-high-gamma coupling correlated positively with open-field center time in WT mice only.

CONCLUSIONS: Hippocampal theta-gamma coupling shows frequency- and context-dependent abnormalities in 5xFAD mice. Theta-low-gamma coupling is sensitive to short-term cholinergic modulation during exploration, whereas donepezil's effect on theta-high-gamma coupling remains inconclusive. Animal-level PAC may provide a candidate functional readout, but longitudinal and cross-model validation is required before biomarker claims are justified.},
}

@article {pmid42651131,
year = {2026},
author = {Xue, J and Yan, X and Wei, J and Gao, M and Liang, K},
title = {Altered Driving Structures and Controllability Patterns of Brain Effective Networks in Mild Cognitive Impairment and Alzheimer's Disease.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080820},
pmid = {42651131},
issn = {2076-3425},
support = {24YJCZH366 and 25YJCZH280//Youth Fund Project for Humanities and Social Sciences Research of the Ministry of Education/ ; 202403021212185 and 202503021212275//Youth Science Research Project of Basic Research Program of Shanxi Province/ ; 2024L158//Science and Technology Innovation Project of Higher Education Institutions of Shanxi Province/ ; },
abstract = {Background: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are associated with abnormalities in brain networks. However, differences in the control architecture of directed brain effective networks among normal controls (NC), patients with MCI, and patients with AD remain insufficiently characterized. This study investigated diagnostic-group differences in driving structures and controllability patterns in structurally constrained brain effective networks. Methods: Multimodal neuroimaging data, including diffusion MRI and resting-state functional MRI, were used to construct brain effective networks in the NC, MCI, and AD groups. Directed interregional interactions were estimated using multivariate autoregressive modeling under structural connectivity constraints. A structural controllability framework based on maximum matching was then applied to identify group-level driving nodes and driving edges. Controllability index was compared across groups separately at the whole-brain, resting-state network (RSN), and regional levels. Results: Group-level driving structures differed among the NC, MCI, and AD groups. Driving nodes were mainly distributed within the default mode network, with additional somatosensory and motor network drivers in MCI and a frontoparietal network driver in AD. The whole-brain controllability index decreased from NC to MCI and increased from MCI to AD. Similar nonmonotonic patterns were observed in the default mode and frontoparietal networks, whereas the somatosensory and motor and visual networks showed different group patterns. Regional node controllability was negatively associated with indegree and positively associated with outdegree, and driving nodes were more likely to correspond to outdegree hubs. Hub-level controllability showed a pattern opposite to that of the whole brain. Several regional indices were associated with cognitive scores, although these pooled cross-sectional associations may partly reflect diagnostic-group separation. Conclusions: MCI and AD were associated with differences in driving structures and controllability patterns in directed brain effective networks. These findings provide preliminary network-level observations on altered directed information propagation across the AD clinical spectrum and require validation in larger, independent, and longitudinal cohorts.},
}

@article {pmid42651138,
year = {2026},
author = {Lu, S and Chen, Z and Wang, Y and Bian, H and Yu, S and Huang, L},
title = {Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080828},
pmid = {42651138},
issn = {2076-3425},
support = {LH2019H106//Natural Science Foundation of Heilongjiang Province/ ; YQJH2023152//Excellent Young Teachers Basic Research Support Program" for Provincial Undergraduate Colleges in Heilongjiang Province/ ; ZHY2025-009//Heilongjiang Province Traditional Chinese Medicine Research Project/ ; },
abstract = {O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions.},
}

@article {pmid42651144,
year = {2026},
author = {Lee, S and Hong, SH and Nam, YJ and Cho, YH and Son, SJ and Hong, CH},
title = {An Integrated Model Based on Gut Microbiota and APOE Genotype for Predicting Dementia Risk.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080834},
pmid = {42651144},
issn = {2076-3425},
support = {6637-303//Korea Disease Control and Prevention Agency/ ; RS-2025-25303051//Korea Health Industry Development Institute/ ; RS-2022-KHI30309//Korea Health Industry Development Institute/ ; GRRCAjou2023-B02//Gyeonggi Provincal Medical Center/ ; RS-2021-NR056488//National Research Foundation of Korea/ ; },
abstract = {BACKGROUND: Dementia develops through the combined influence of genetic vulnerability, biological processes, and environmental exposures. The apolipoprotein E (APOE) ε4 allele is a well-known genetic contributor to dementia risk, and growing evidence links gut microbial alterations to cognitive decline and cerebrovascular-related pathology. Nevertheless, studies jointly evaluating genetic, microbiome, and clinical information remain relatively scarce. This study examined an integrated framework combining APOE genotype and gut microbiome data for cross-sectional dementia classification.

METHODS: We analyzed 292 participants representing three cognitive stages: subjective memory impairment (SMI), mild cognitive impairment, and dementia. Clinical variables, APOE genotype, and gut microbial metagenomic profiles were examined. Associations among genetic risk, Alzheimer's disease pathology, and brain structural changes were assessed, and multivariable models were used to distinguish participants with dementia from those with SMI or MCI.

RESULTS: APOE ε4 carriage was most frequent among participants with dementia, while no ε4 carriers were observed in the SMI group. Gut microbial profiles differed according to the dementia-related genetic-risk category (mild vs. moderate-to-high). The fully integrated model showed a numerically higher cross-validated AUC than models constructed from fewer data domains. Streptococcus, Akkermansia, and Fusicatenibacter were more abundant in the moderate-to-high genetic-risk group; these taxon-level findings were exploratory and based on nominal p-values.

CONCLUSIONS: The findings support an exploratory integrated framework for cross-sectional dementia classification based on genetic and gut microbiome information. Independent longitudinal and multicenter validation is required before the framework can be interpreted as predicting future dementia risk or supporting personalized clinical decisions.},
}

@article {pmid42651165,
year = {2026},
author = {Huang, L and Hu, Z and Zhang, Z and Gao, Y},
title = {Alzheimer's Disease Detection Using Combined EEG Source Connectivity and Microstate Features.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080856},
pmid = {42651165},
issn = {2076-3425},
support = {LZ25F010006//Zhejiang Provincial Natural Science Foundation/ ; 62371171//National Natural Science Foundation of China/ ; },
abstract = {Background/Objectives: Electroencephalography (EEG) connectivity and microstate analysis have shown great potential for Alzheimer's disease (AD) diagnosis; however, their clinical application remains limited by the low spatial resolution of EEG and the lack of standardized microstate analysis. To address these challenges, this study proposes a multi-domain feature fusion framework, namely Source-localized Microstate and Multi-frequency Synchronization (SMMS), which integrates EEG source localization (ESL)-based weighted phase lag index (wPLI) functional connectivity with EEG microstate features. Methods: Specifically, ESL was employed to improve the spatial resolution of EEG signals for constructing functional connectivity matrices, while multi-frequency-band wPLI features were extracted to characterize functional synchronization among cortical regions. Meanwhile, EEG microstate features were utilized to capture the temporal dynamics of brain functional states. The proposed framework was evaluated on a public OpenNeuro dataset comprising 36 AD patients, 23 frontotemporal dementia (FTD) patients, and 29 healthy controls (HCs), as well as an additional clinical dataset collected from 48 AD patients at Sir Run Run Shaw Hospital, Hangzhou, China. Results: Experimental results showed that the proposed SMMS framework achieved high classification performance on both datasets. Conclusions: These findings demonstrate its effectiveness for EEG-based Alzheimer's disease diagnosis.},
}

@article {pmid42651177,
year = {2026},
author = {Lu, B and Zhang, M and Ren, Z and Wang, T and Wang, Z and Ding, C},
title = {High-Frequency rTMS Improves Cognitive Deficits in APP/PS1 Mice with Attenuation of Ferroptosis-Related Oxidative Injury.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080868},
pmid = {42651177},
issn = {2076-3425},
support = {No. 52077057//National Natural Science Foundation of China/ ; },
abstract = {Background/Objectives: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulatory approach with potential therapeutic value for cognitive impairment in Alzheimer's disease (AD). Ferroptosis-related oxidative injury has been implicated in AD-associated neuronal dysfunction, but whether rTMS-induced functional improvement is accompanied by changes in ferroptosis-related oxidative injury remains unclear. This study evaluated the effects of high-frequency rTMS on cognitive function, hippocampal neuronal excitability, and ferroptosis-related oxidative injury in amyloid precursor protein/presenilin-1 (APP/PS1) mice, using Ferrostatin-1 (Fer-1) as a pharmacological comparator. Methods: Six-month-old female mice were used, including age-matched C57BL/6J controls and APP/PS1 mice assigned to the AD + Sham, AD + rTMS, and AD + Fer-1 groups (n = 6 per group). After 14 days of intervention, cognitive performance was assessed using behavioral tests. Whole-cell patch-clamp recordings were performed in hippocampal dentate gyrus granule neurons to evaluate neuronal excitability and voltage-gated sodium (Na[+]) and potassium (K[+]) channel properties. Biochemical assays and transmission electron microscopy were used to assess oxidative, iron-related, and mitochondrial changes, and mitochondrial ultrastructure was examined in an independent cohort (n = 3 per group) using transmission electron microscopy. Results: Compared with AD + Sham mice, high-frequency rTMS improved cognitive performance, increased evoked action potential firing, lowered the elevated action potential threshold, partially restored voltage-gated Na[+] and K[+] current amplitudes, and accelerated recovery of Na[+] currents from inactivation. Fer-1 produced partially overlapping, but not identical, effects across behavioral, electrophysiological, biochemical, and ultrastructural outcomes. Both interventions increased hippocampal glutathione (GSH) levels, reduced malondialdehyde (MDA) and total iron levels, partially restored superoxide dismutase (SOD) activity, and improved mitochondrial ultrastructure and reduced the prevalence of mitochondrial profiles with small cross-sectional areas. Conclusions: High-frequency rTMS improved cognitive and hippocampal neuronal outcomes in female APP/PS1 mice. These improvements were accompanied by biochemical and mitochondrial changes compatible with attenuation of ferroptosis-related injury. However, the findings do not establish ferroptosis inhibition as either necessary or sufficient for the effects of rTMS.},
}

@article {pmid42651198,
year = {2026},
author = {Harris, KE and Lascaratos, G and Chau, KY},
title = {Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?.},
journal = {Brain sciences},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/brainsci16080890},
pmid = {42651198},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: Mitochondrial Complex V (Complex V [CX-V], or ATP synthase) is the terminal enzyme of oxidative phosphorylation and is responsible for the majority of cellular ATP production. An increasing body of evidence suggests that CX-V dysfunction may contribute to mitochondrial impairment observed in neurodegenerative disease. This review evaluated current research on the structure, regulation, and function of CX-V, examined the consequences of CX-V dysfunction, and assessed its proposed role in neurodegenerative disorders.

METHODS: A comprehensive review of the published literature was carried out, with emphasis on primary research investigating CX-V structure and function, inherited CX-V disorders, and experimental evidence linking CX-V dysfunction to neurodegenerative disease. The reviewed studies used a range of experimental approaches, including structural biology, biochemical studies, patient-derived cellular models, animal models and post-mortem human tissue.

RESULTS: Current evidence demonstrates that disruption of CX-V impairs ATP production, alters mitochondrial membrane potential, and oxidative phosphorylation, and that pathogenic variants cause primary mitochondrial disease. Across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis/frontotemporal dementia, glaucoma and inherited optic neuropathies, alterations in CX-V activity, regulation and structural integrity are consistently associated with mitochondrial dysfunction. Direct evidence supporting CX-V as a primary driver of neurodegeneration remains very limited, with many observations originating from broader studies of general mitochondrial dysfunction.

CONCLUSIONS: CX-V dysfunction represents a recurring feature of mitochondrial impairment across a variety of neurodegenerative disorders and may exacerbate neuronal vulnerability by disrupting cellular bioenergetics. Current evidence indicates that CX-V may serve as a common downstream target of multiple pathological pathways rather than acting as a primary pathological factor. Future studies require direct assessment of CX-V activity in clinically relevant human models and patient tissues to determine its contribution to disease progression and examine its potential as a therapeutic target.},
}

@article {pmid42651370,
year = {2026},
author = {Lancaster, H and Hawes, F and Tang, EYH and Sabatini, S},
title = {Stakeholder Perspectives on Identifying and Managing Comorbid Health Conditions Among Nursing Home Residents with Dementia: A UK Single-Site Qualitative Study.},
journal = {Healthcare (Basel, Switzerland)},
volume = {14},
number = {16},
pages = {},
doi = {10.3390/healthcare14162601},
pmid = {42651370},
issn = {2227-9032},
support = {//National Institute for Health and Care Research/ ; //University of Wisconsin-Eau Claire/ ; },
abstract = {Background: This single-site qualitative interview study sought the opinions of 15 stakeholders from a nursing home based in the United Kingdom (UK) about identification and management of comorbidities in residents with dementia. Methods: Stakeholders were recruited through one of the nursing home owners, who acted as the gatekeeper. No residents with dementia were interviewed. Semi structured interviews were conducted online via Microsoft Teams in 2024. Data was analyzed using thematic analysis. Results: Stakeholders comprised four care assistants; three well-being companions; two nurses; a general practitioner (GP); two informal caregivers; a chaplain; the manager; and the owner of the nursing home. Stakeholders perceived that the identification and management of comorbidities in residents with dementia were shaped by interacting factors across four domains: the wider healthcare context, nursing home organization, staff capability and care practices, and resident-related challenges. Perceived healthcare under-resourcing increased complexity, while coordinated teamwork, continuous improvement, staff well-being, geriatric expertise, and person-centred, inclusive care were viewed as key facilitators. Conclusions: Overall, the perspectives of stakeholders interviewed in this single-site case study suggest that improving the identification and management of comorbidities in residents with dementia requires multilevel interventions that strengthen staff capability, organizational practices, and integration between nursing homes and the wider healthcare system.},
}

@article {pmid42651550,
year = {2026},
author = {Ye, F and Qu, X and Li, R and Wan, Y and Zhu, J and Yu, J and Qi, X},
title = {Oral Health Status, Knowledge, Hygiene Behavior and Cognitive Function Among Older Adults in Shanghai, China.},
journal = {Behavioral sciences (Basel, Switzerland)},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/bs16081373},
pmid = {42651550},
issn = {2076-328X},
abstract = {Cognitive impairment is a growing concern in rapidly aging societies, including China, and oral health has been proposed as a modifiable correlate of cognitive aging; however, few studies compare distinct oral health domains within the same older population or identify the subgroups in which associations are strongest. We analyzed data from 1707 community-dwelling adults aged 55+ in the 2022 Lifelong Learning and Productive Aging Survey of Shanghai (LEAP-SH) study. Cognitive problems were measured with the Ascertain Dementia 8 (AD8) total score (0-8; higher = worse). Self-reported oral health, oral health knowledge, and oral hygiene behavior were each standardized and entered in separate models adjusted for sociodemographic and health covariates; interaction models tested effect modification by six sociodemographic moderators. All three domains were associated with lower AD8 scores, most strongly oral health status (β = -0.26; p < 0.001), followed by oral health knowledge (β = -0.14; p = 0.004) and oral hygiene behavior (β = -0.10; p = 0.036). Associations were broadly consistent across subgroups; only two interactions, both involving knowledge, were nominally significant, and neither survived correction for multiple comparisons. Oral health may be a modifiable correlate of cognitive aging, although the cross-sectional design precludes causal inference.},
}

@article {pmid42651656,
year = {2026},
author = {Ding, X and Wang, P and Zhou, L and Li, X},
title = {Revealing the Mechanisms of Alzheimer's, Parkinson's and Huntington's Diseases Through Invertebrate Models.},
journal = {Biology},
volume = {15},
number = {16},
pages = {},
doi = {10.3390/biology15161351},
pmid = {42651656},
issn = {2079-7737},
support = {X2026161//College Students' Innovation and Entrepreneurship Training Program/ ; },
abstract = {The neural circuits of the human brain are highly complex (due to the number of neurons and the diversity of synaptic connections), hindering the analysis of the pathological mechanisms of neurodegenerative diseases. Invertebrates with simple yet well-differentiated nervous systems have a natural advantage over mammalian model organisms in the identification of pathogenic genes and functional studies of neurodegenerative diseases. They can provide unique and profound insights into the pathogenesis of complex human neurodegenerative diseases and the formulation of intervention strategies. This article reviews the conserved mechanisms of three neurodegenerative diseases across species, including protein homeostasis imbalance and aggregation toxicity, mitochondrial dysfunction and metabolic abnormalities, axonal transport defects, and loss of synaptic function. Based on research on three invertebrates in the field of neurodegeneration, namely Caenorhabditis elegans (C. elegans), Drosophila melanogaster (D. melanogaster), and Bombyx mori (B. mori), we cover three major types of neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The aim is to find important inspirations for the future prevention and treatment of neurodegenerative diseases from the aspects of the material basis and existing treatment strategies.},
}

@article {pmid42651727,
year = {2026},
author = {Feng, C and Zhang, T and Liu, X and Liu, Z and Zhao, Y and Zhang, P},
title = {Circulating Homocysteine and Choroid Plexus Volume Across the Alzheimer's Disease Continuum: Cross-Sectional and Progression-Related Associations.},
journal = {Biology},
volume = {15},
number = {16},
pages = {},
doi = {10.3390/biology15161423},
pmid = {42651727},
issn = {2079-7737},
support = {2023AAC05036//Natural Science Foundation of Ningxia Province/ ; 2024AAC03247//Natural Science Foundation of Ningxia Province/ ; 2024BEH04022//Natural Science Foundation of Ningxia Province/ ; XT2022024//the University-level scientific research project of Ningxia Medical University/ ; XJKF230109//the University-level scientific research project of Ningxia Medical University/ ; JCXK2025003//the University-level scientific research project of Ningxia Medical University/ ; XJKF230204//Ningxia Medical University/ ; },
abstract = {BACKGROUND: Elevated plasma homocysteine (HCY) is a risk factor for Alzheimer's disease (AD), but its relationship with structural brain changes across the AD continuum remains unclear. The choroid plexus (CP) regulates cerebrospinal fluid homeostasis and may interface with peripheral metabolic signals. Whether HCY relates to CP structural alterations and disease progression remains unknown.

METHODS: We analyzed 819 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (229 cognitively normal (CN), 397 with mild cognitive impairment (MCI), and 193 with AD dementia). Multinomial logistic regression assessed associations between HCY and diagnosis under stepwise covariate adjustment. Phenotype-wide structural magnetic resonance imaging (MRI) mapping identified HCY-associated signals. Cox models evaluated associations of CP volume (CPV) with CN-to-MCI and MCI-to-AD dementia conversion and whether CPV added prognostic discrimination beyond baseline disease-severity markers. Independent human CP single-nucleus and spatial transcriptomic datasets were reanalyzed to characterize epithelial expression states and their spatial organization in a hypothesis-generating analysis.

RESULTS: Higher HCY was associated with MCI and AD dementia; however, the AD association attenuated after adjustment for renal function, vitamin B12, and medications, whereas the MCI association remained stable. CPV was among the HCY-associated MRI signals that persisted after progressive covariate adjustment. Right and bilateral CPV showed model-dependent associations with MCI-to-AD dementia conversion. In the disease-severity sensitivity analysis, larger right and bilateral CPV remained associated with a higher risk of progression from MCI to AD dementia. Single-nucleus analysis identified two CP epithelial states with relatively high expression of one-carbon metabolism-related genes, termed one-carbon metabolism-enriched epithelial state A (OCM-Epi-A) and state B (OCM-Epi-B). Donor-level pseudobulk analysis did not identify pathway enrichment after false discovery rate correction, whereas OCM-Epi-A-like spots were located near endothelial spots more often than expected by chance in three of the four spatial samples.

CONCLUSIONS: Circulating HCY was associated with larger CPV, and larger CPV showed model-dependent associations with MCI-to-AD dementia progression. Independent transcriptomic reanalysis identified one-carbon metabolism-enriched epithelial states and their spatial organization in postmortem CP tissue, providing hypothesis-generating tissue-level context for the ADNI associations.},
}

@article {pmid42651806,
year = {2026},
author = {Andreadou, EG and Evangelopoulou, E and Tsolaki, M and Tsamesidis, I and Pessach, I and Mitka, S},
title = {Exosome-Based Therapeutics in Alzheimer's Disease: Translational Perspectives Beyond Conventional Therapies.},
journal = {Current issues in molecular biology},
volume = {48},
number = {8},
pages = {},
pmid = {42651806},
issn = {1467-3045},
abstract = {Alzheimer's disease (AD) remains a major neurodegenerative disorder lacking effective long-term disease-modifying therapies. Current pharmacological approaches provide primarily symptomatic benefit, while recently approved anti-amyloid monoclonal antibodies offer only modest clinical efficacy and are constrained by safety concerns, high costs, and limited blood-brain barrier (BBB) penetration. In this context, exosome-based strategies have emerged as potential therapeutic platforms in AD research. As endogenous nanovesicles, exosomes exhibit favorable biocompatibility, intrinsic BBB-crossing capacity, and the ability to deliver diverse therapeutic cargo across multiple pathological pathways. Through bioengineering approaches, exosomes may additionally be optimized for targeted brain delivery and therapeutic personalization. Nevertheless, despite their conceptual and preclinical advantages, exosome-based therapies remain at an early translational stage, with unresolved challenges related to large-scale production, standardization, biodistribution, and long-term safety. This review provides a comparative translational analysis of conventional and exosome-based therapeutic strategies in AD, focusing on mechanistic targeting, delivery efficiency, safety and tolerability, therapeutic personalization, and translational readiness. We critically evaluate the extent to which exosome-based platforms may address the limitations of current therapies while highlighting the key barriers that continue to limit their clinical translation and real-world applicability.},
}

@article {pmid42651826,
year = {2026},
author = {Cheng, Z and Bai, R and Diao, Y},
title = {Integrative Transcriptomics and Mendelian Randomization Identify RGS1 as a Causal Immune Regulator in Alzheimer's Disease.},
journal = {Current issues in molecular biology},
volume = {48},
number = {8},
pages = {},
pmid = {42651826},
issn = {1467-3045},
support = {2020NZ010008//the major and Special Projects of Fujian Province/ ; 2022C006R//High level Talent Innovation and Entrepreneurship Project of Quanzhou/ ; },
abstract = {Alzheimer's disease (AD) has a complex pathogenesis, involving molecular and neuroimmune dysregulation, but the causal drivers linking transcriptomic changes to immune remodeling are not yet clear. In a discovery cohort, differential expression analysis was performed, and it was independently validated in two external cohorts. Key genes were prioritized via LASSO/logistic regression, functionally annotated, and causally linked to AD using two-sample MR. The neuroimmune landscape was mapped by ssGSEA, and top candidates were validated in vitro. RGS1 is a key node in neuroinflammation and cytoskeletal dynamics, which is prioritized by the algorithmic intersection. MR analysis suggested a potential causal association between genetically predicted RGS1 expression and AD risk. RGS1 was consistently upregulated in both discovery and validation cohorts (AUC: 0.61-0.67) and was confirmed in vitro. Immune deconvolution showed that AD-specific enrichment profiles occur, and RGS1 is strongly correlated with activated CD4+ T cells and pro-inflammatory chemokines. RGS1 is identified as a robust key gene that may contribute to immune microenvironment dysregulation in AD, and combining discovery-validation transcriptomics, causal inference, and experimental validation, we find that RGS1 is a potential immunomodulatory target.},
}

@article {pmid42652092,
year = {2026},
author = {Surguchov, A},
title = {Caveolin-1 at the Crossroads of Diabetes and Alzheimer's Disease: New Mechanisms, Biomarkers, and Therapeutic Opportunities.},
journal = {Biomedicines},
volume = {14},
number = {8},
pages = {},
doi = {10.3390/biomedicines14081709},
pmid = {42652092},
issn = {2227-9059},
abstract = {Type 2 diabetes mellitus (T2D) is increasingly recognized as a major risk factor for Alzheimer's disease (AD), supporting the concept that chronic metabolic dysfunction contributes to neurodegeneration. Recent advances have identified caveolin-1 (CAV-1), the principal structural protein of caveolae, as an important regulator of insulin signaling, lipid metabolism, mitochondrial homeostasis, neurovascular integrity, and amyloid precursor protein processing. Since our previous review published in 2020, substantial evidence has demonstrated that altered CAV-1 expression and function are associated with AD-related pathology under diabetic conditions through multiple mechanisms, including endothelial dysfunction, impaired brain insulin signaling, disruption of mitochondria-endoplasmic reticulum contact sites (MERCSs), neuroinflammation, mitochondrial dysfunction, and defective autophagy. Experimental studies further show that restoring neuronal or endothelial CAV-1 expression improves insulin signaling, preserves synaptic function, attenuates amyloid pathology, and ameliorates cognitive decline in preclinical models. This review summarizes recent advances in understanding of the CAV-1-dependent mechanisms linking T2D and AD and discusses the emerging potential of CAV-1 as a biomarker and therapeutic target for diabetes-associated neurodegeneration. Collectively, current evidence identifies CAV-1 as a central molecular hub integrating metabolic, vascular, and neurodegenerative pathways and supports its further investigation as a promising therapeutic target.},
}

@article {pmid42652164,
year = {2026},
author = {Karbownik, M and Fidura, M and Perlikowska, R},
title = {Are Signal Peptides Hidden Regulators of Neurodegenerative Disease?.},
journal = {Biomedicines},
volume = {14},
number = {8},
pages = {},
doi = {10.3390/biomedicines14081781},
pmid = {42652164},
issn = {2227-9059},
support = {564-20-100//Medical University of Lodz/ ; },
abstract = {Canonical signal peptides (SPs) are short N-terminal sequences that direct nascent proteins into the secretory pathway, but their role extends far beyond protein targeting. Advances in sequencing and computational tools have enabled their systematic identification across proteomes, highlighting SPs as critical regulators of protein biogenesis, including endoplasmic reticulum (ER) targeting, translocation, folding, and proteostasis. Clinically, mutations affecting SP function underlie a distinct group of human disorders, while SP-derived fragments are emerging as diagnostic biomarkers and therapeutic targets. In biotechnology, SPs are engineered to enhance recombinant protein production and serve as molecular tags for intracellular delivery. Together, these developments position SPs at the intersection of fundamental cell biology, medicine, and biotechnology. While this review primarily focuses on canonical SPs, it also considers selected non-canonical targeting and topogenic sequences whose dysfunction contributes to protein misfolding, impaired ER translocation, disrupted degradation pathways, and altered intracellular trafficking in neurodegenerative diseases. Aberrations involving both conventional SPs and alternative targeting/topogenic elements contribute to pathological protein aggregation, a hallmark of major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington Disease (HD), prion diseases, and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); in multiple sclerosis (MS) is primarily an inflammatory demyelinating disease, where abnormal protein exposure, potentially linked to misprocessed SPs, can activate immune responses. By synthesizing current knowledge, the review explores how alterations in targeting determinants influence key proteostasis pathways, acting as upstream modulators of disease-relevant molecular cascades. It further discusses the emerging concept that SP-derived fragments may participate in intercellular communication, adding an additional layer of regulatory complexity.},
}

@article {pmid42652176,
year = {2026},
author = {Tarawneh, R},
title = {Glycation at the Gate: A Brain Endothelial Glycocalyx Model and Therapeutic Roadmap for Alzheimer's Disease.},
journal = {Biomedicines},
volume = {14},
number = {8},
pages = {},
doi = {10.3390/biomedicines14081794},
pmid = {42652176},
issn = {2227-9059},
support = {7RF1AG083744/AG/NIA NIH HHS/United States ; },
abstract = {While Alzheimer's disease (AD) is primarily considered a disorder of protein aggregation, converging evidence from clinical, neuropathological, and mechanistic studies strongly supports the notion that brain endothelial dysfunction is a primary and early event in AD pathogenesis. Brain endothelial pathways are among the most differentially expressed in human AD brains. Brain endothelial alterations precede amyloid deposition and cognitive deficits in experimental AD models and closely parallel the degree of neuronal loss in human AD brains. Despite growing evidence to support brain endothelial contributions to neurodegeneration, studies examining the potential of the brain endothelium as a druggable target in AD have been scarce. Further, there has been a relative paucity of validated fluid biomarkers that can reliably measure brain endothelial injury in AD, independently of overt vascular disease or disruption to other cerebrovascular constituents. In this perspective, we propose a brain endothelial glycocalyx-centric model of AD in which brain endothelial dysfunction, driven predominantly by non-enzymatic glycation and carbonyl stress, acts as a key upstream regulator of aberrant protein trafficking, blood-brain barrier instability, and dysregulated neuro-immune cascades. Further, recent evidence suggests the presence of direct interactions of the brain endothelium with key pathways involved in neuronal survival and synaptic signaling, highlighting potential direct contributions of brain endothelial disturbances to cognitive impairment. Within this framework, we identify several brain endothelial axes, including reduction in carbonyl stress, improved glycation-dependent signaling, attenuation of advanced glycation end-product (AGE)-mediated toxicity, and enhanced endothelial glycocalyx stability and resilience as potential therapeutic approaches in AD. Modulating brain endothelial glycation has potential as a novel therapeutic strategy in AD which may complement other disease-modifying treatments, particularly in the earliest preclinical stages. In conclusion, this framework positions the brain endothelium as a mechanistic hub linking metabolic stress to aberrant protein aggregation and neurodegeneration in AD with potential therapeutic implications in AD and other neurodegenerative disorders.},
}

@article {pmid42652205,
year = {2026},
author = {Alzweiri, M and Ali Agha, ASA and Qinna, NA and AlDabet, G and El Khassawna, T and Aburjai, T},
title = {Alzheimer's Disease as a Multi-Layer Network Disorder: A Systems Biology Framework Integrating Multi-Omics Mechanisms.},
journal = {Biomedicines},
volume = {14},
number = {8},
pages = {},
doi = {10.3390/biomedicines14081823},
pmid = {42652205},
issn = {2227-9059},
abstract = {Despite substantial progress in biomarker discovery and multi-omics profiling, several features of Alzheimer's disease (AD), including prolonged compensated states, heterogeneous clinical trajectories, and marked stage-dependent therapeutic responses, remain difficult to integrate into a single mechanistic framework. In this review, we propose an integrative and testable conceptual framework that reframes AD as a single, progressive multi-layer network disorder whose dynamics arise from hierarchical constraint propagation and progressive loss of cross-scale coordination. Integrating evidence from human genetics, epigenomics, transcriptomics, proteomics, metabolomics, spatial biology, connectomics, and longitudinal biomarker studies, we examine how molecular, cellular, and circuit-level processes interact over time to shape disease progression. Within this framework, different omics measurements are interpreted as complementary representations of disease-related changes, rather than as independent molecular signatures. Disease progression reflects the gradual convergence of immune, metabolic, proteostatic, cytoskeletal, and synaptic stress, with overt cognitive impairment emerging when compensatory capacity is exceeded, producing threshold-like network destabilization. By explicitly linking biological scale, temporal hierarchy, and network structure, this synthesis extends prior network-medicine, connectomic, and multi-omics approaches into a testable framework for state-aware stratification, integrative analysis, and stage-appropriate therapeutic investigation in AD.},
}

@article {pmid42652243,
year = {2026},
author = {Thoe, ES and Tan, HD and Fauzi, A and Chamyuang, S and Tang, YQ and Chia, AYY},
title = {Multi-Target Neuroprotective Effects of Cordycepin and Adenosine from Cordyceps militaris Against Amyloid-β-Induced Neurotoxicity.},
journal = {Biomedicines},
volume = {14},
number = {8},
pages = {},
doi = {10.3390/biomedicines14081862},
pmid = {42652243},
issn = {2227-9059},
abstract = {Background:Cordyceps militaris (C. militaris) is a medicinal mushroom recognized for its diverse pharmacological activities, largely attributed to its principal bioactive nucleosides, cordycepin and adenosine. Although accumulating evidence supports their neuroprotective potential, the molecular mechanisms underlying their effects against Alzheimer's disease (AD) remain incompletely understood. This study investigated the neuroprotective effects of cordycepin and adenosine against amyloid-β (Aβ42)-induced neurotoxicity and explored their potential molecular mechanisms using integrated experimental and computational approaches. Methods: SH-SY5Y neuroblastoma cells were pretreated with cordycepin (COR), adenosine (ADE), or donepezil (DNPZ) prior to Aβ42 exposure, and cell viability was assessed using the MTT assay. Drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were evaluated in silico, followed by network pharmacology to identify potential therapeutic targets and enriched biological pathways. Molecular docking and molecular dynamics simulations were performed to elucidate the interactions of the compounds with selected Alzheimer's disease-related proteins. Results: COR and ADE significantly attenuated Aβ42-induced cytotoxicity and improved SH-SY5Y cell viability. Network pharmacology identified 84 shared molecular targets, including 9 AD-associated genes. Protein-protein interaction analysis revealed hub genes involved in signal transduction, epigenetic regulation, and purine metabolism, while Gene Ontology and KEGG enrichment analyses highlighted pathways associated with neuroactive ligand-receptor interaction, calcium signaling, and inflammatory regulation. ADMET analysis predicted favorable pharmacokinetic properties for both compounds, although cordycepin was predicted to be AMES-positive. Molecular docking and molecular dynamics simulations demonstrated stable interactions of COR and ADE with liver X receptors (LXRα and LXRβ), whereas donepezil exhibited stronger binding affinity toward β-secretase (BACE1). Conclusions: COR and ADE exert neuroprotective effects through coordinated modulation of multiple AD-related signaling pathways rather than a single molecular target. These findings provide mechanistic insights into the neuroprotective activities of C. militaris-derived nucleosides and support further investigation of their potential as multi-target therapeutic candidates for AD and other neurodegenerative disorders.},
}

@article {pmid42652334,
year = {2026},
author = {Arthanat, S and Wang, J and LaRoche, D and Fritz, H and DiZazzo-Miller, R and Hussein, M and Ghattas, O and Akash, M and Begum, M},
title = {Systematic Co-Design of Artificial Intelligence-Enabled Innovations for Healthy Aging: A Demonstration Study Involving Socially Assistive Robots for Dementia Care.},
journal = {International journal of environmental research and public health},
volume = {23},
number = {8},
pages = {},
doi = {10.3390/ijerph23081019},
pmid = {42652334},
issn = {1660-4601},
support = {5R01AG075892-04/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Robotics ; *Artificial Intelligence ; Aged ; *Dementia/therapy ; Female ; *Healthy Aging ; Caregivers ; Male ; Pilot Projects ; Aged, 80 and over ; Self-Help Devices ; },
abstract = {Artificial intelligence-enabled technologies offer new opportunities to support healthy aging and the long-term care needs of older adults. However, inclusive practices are paramount to ensuring that accessibility, usability, privacy, and equitable use are factored into the design and deployment of these emerging technologies. This article explores the role of co-design in health technology development and highlights the application of three methodological tools-the NIH Stage Model for Behavioral Intervention Development, the Unified Theory of Acceptance and Use of Technology, and Goal Attainment Scaling-to create a smart-home-based socially assistive robot (SAR) for the care of individuals living with Alzheimer's disease and related dementias (ADRD). Ten participants (five caregiver-care recipient dyads) from an ongoing mixed-methods pilot feasibility study trialed the SAR in their homes for 1-6 months, with the robot personalized to their daily functioning, home layout, and caregiving needs. Qualitative analysis of monthly interviews derived themes pertaining to technical design, care protocol design, training management, and complementary care. These themes, combined with goal attainment analysis, offered several insights that allowed us to iteratively scale and refine the technology tailored to ADRD care. The study offers a practical framework for future co-design efforts aimed at enhancing the adoption of AI-enabled health technologies among older adults.},
}

Humans
*Robotics
*Artificial Intelligence
Aged
*Dementia/therapy
Female
*Healthy Aging
Caregivers
Male
Pilot Projects
Aged, 80 and over
Self-Help Devices

@article {pmid42652858,
year = {2026},
author = {Cabarkapa, S and Shelton, C and Faucie, P and Murgier, J},
title = {Objective Sleep Architecture Alterations and Sleep-Dependent Brain Clearance Dysfunction Across the Early Alzheimer's Disease Continuum: A Systematic Review.},
journal = {Journal of clinical medicine},
volume = {15},
number = {16},
pages = {},
doi = {10.3390/jcm15166454},
pmid = {42652858},
issn = {2077-0383},
abstract = {Background: Sleep-dependent glymphatic clearance has emerged as a potential mechanism linking sleep disruption with Alzheimer's Disease (AD) pathology. However, the relationship between objectively measured sleep and glymphatic function across the AD continuum remains unclear. Methods: Four databases (PubMed, Embase, Cochrane Library, and PsycINFO) were systematically searched for studies assessing objective sleep metrics and glymphatic-related biomarkers or clearance measures in humans across the AD continuum. Following peer review of the search strategy, supplementary searches of PubMed and Embase using expanded glymphatic and sleep electrophysiology terminology were undertaken to maximize sensitivity. The final database searches identified 416 records. After removal of 72 duplicates, 344 records were screened, 64 reports underwent full-text assessment, and four studies met the inclusion criteria. Results: Four studies involving participants across the AD continuum were included. Objective sleep assessment was performed using polysomnography or electroencephalography, while brain clearance was evaluated using direct or surrogate imaging measures including diffusion tensor image analysis along the perivascular space (DTI-ALPS), perivascular space burden, blood oxygen level-dependent-cerebrospinal fluid (BOLD-CSF) coupling, or direct tracer-based clearance imaging. Across studies, better preserved slow-wave sleep, slow-wave activity, and sleep oscillatory coupling were generally associated with more favorable glymphatic function or glymphatic-related biomarkers. Conversely, disrupted sleep architecture, reduced sleep efficiency, and altered sleep oscillatory coupling were associated with impaired glymphatic clearance or glymphatic dysfunction. Conclusions: Current evidence suggests that objectively measured sleep architecture, particularly slow-wave sleep and sleep oscillatory dynamics, may be associated with biomarkers of brain clearance across the AD continuum. However, the available evidence remains preliminary, is predominantly cross-sectional, and relies largely on indirect measures of brain clearance. Larger longitudinal studies incorporating standardized sleep assessment and validated measures of cerebral clearance are required to clarify temporal relationships, establish causality, and determine whether sleep-targeted interventions influence brain clearance or disease progression. Summary of findings: Preliminary evidence suggests that preserved slow-wave sleep and sleep oscillatory activity are associated with more favorable biomarkers of brain clearance, whereas disrupted sleep architecture is associated with less favorable clearance-related measures.},
}

@article {pmid42652920,
year = {2026},
author = {Jehu, DA and Hanson, M and Huang, Y and Soares, A and Hergott, C and Waller, JL and Young, L and Hall, W and Robinson-Johnson, D and Allen, C and Sams, R and Carrick, RM and Fulzele, S and Hamrick, M and Zhu, H and Dong, Y},
title = {Multifactorial Exercise and Inflammatory Responses in Dementia: Findings from a Randomized Controlled Trial Secondary Analysis.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/life16081230},
pmid = {42652920},
issn = {2075-1729},
support = {IGPCT00028//Augusta University/ ; IGPP00033//Augusta University/ ; P01 AG036675 (Core C)//NIA/ ; },
abstract = {The objective of this randomized controlled trial was to evaluate the impact of a multifactorial exercise program on circulating inflammation in people living with dementia (PWD) in residential care. This parallel-group, 6-month assessor-blinded trial (NCT05488951) allocated (1:1) 42 PWD to a multifactorial exercise intervention or usual care alone in residential care settings between July 2022 and January 2023. The exercise group engaged in 30 min of physical therapist-led strength and balance training, followed by 30 min of walking 3 x/week over 6 months, and received usual care. The usual care group only received care from healthcare providers, ongoing medical treatment, and opportunities to participate in social activities. Fasted blood was drawn at baseline and 6 months. Intention-to-treat (ITT) and per-protocol (PP; ≥2 x/week exercise vs. usual care) analyses were conducted. The ITT analysis revealed no differences between groups over time (p > 0.05). In adjusted PP analyses, there was a group-by-time interaction trend resulting in decreases in IL-1β (-3.6; +5.0 pg/mL) and IL-8 (-13.4; +14.0 pg/mL) in the exercise group compared with usual care (IL-1β: p = 0.089; IL-8: p = 0.087). Findings suggest adherence-dependent reductions in pro-inflammatory cytokines, indicating potential benefits of exercise. However, this trial was not powered for this secondary analysis, necessitating the need for larger, adequately powered trials.},
}

@article {pmid42652977,
year = {2026},
author = {Qadi, N and Aldakheel, A and Shosha, E},
title = {Midlife Vascular and Lifestyle Determinants of Late-Life Cognitive Decline and Dementia: A Life-Course Prevention Framework with a Gulf (GCC) Perspective.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/life16081289},
pmid = {42652977},
issn = {2075-1729},
abstract = {Dementia is a growing global health challenge, yet many determinants of late-life cognitive decline emerge decades before symptoms appear. Midlife is a practical window for prevention because hypertension, diabetes, obesity, dyslipidemia, smoking, physical inactivity, unhealthy diet, sleep disturbance, and social isolation can be identified and modified before substantial brain injury becomes apparent. This narrative review synthesizes evidence linking midlife vascular and lifestyle exposures to late-life cognitive impairment and dementia. The most consistent data support a life-course model in which cumulative vascular, metabolic, inflammatory, and behavioral risks interact with neurodegenerative pathology and cognitive reserve. Vascular and metabolic factors act largely through small-vessel disease, endothelial dysfunction, and inflammation, whereas physical activity, healthy diet, sleep, and social engagement may strengthen resilience. Although observational evidence is vulnerable to confounding and single-risk trials may underestimate cumulative benefit, multidomain prevention remains biologically plausible and clinically actionable, as recent trials reaffirm. These priorities are especially salient in the rapidly transitioning Gulf Cooperation Council (GCC) countries, where midlife cardiometabolic risk is high and local evidence is limited. Dementia prevention should be embedded in routine midlife care, with vascular risk management and sustained lifestyle support treated as core elements of lifelong brain health.},
}

@article {pmid42652978,
year = {2026},
author = {Michelin, W and Pinto, JO and Peixoto, B},
title = {Sex-Specific Structural Vulnerability in Alzheimer's Disease: Insights from APOE ε 4-Negative Patients.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/life16081290},
pmid = {42652978},
issn = {2075-1729},
abstract = {Background: The interaction between sex, APOE ε4 status, and clinical progression in Alzheimer's Disease (AD) remains a subject of debate. While females are often considered at higher risk for AD, the underlying structural neuroanatomical trajectories and how they are modulated by genotype are not fully elucidated. This study aims to evaluate how sex and the APOE ε4 genotype interact to influence longitudinal brain atrophy across three clinical groups. Methods: We analyzed longitudinal data from 2400 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), stratified by clinical group (i.e., cognitively normal, mild cognitive impairment, and AD), sex, and APOE ε4 carrier status. Using Type III Sum of Squares ANCOVA, we modeled the longitudinal variation in brain volume, controlling for baseline brain volume, and baseline severity of neurocognitive impairment and age at entry. Results: While main effects of sex and APOE genotype were not significant, the triple interaction (APOE * Sex * Clinical Group) was marginally significant (p = 0.051). Post hoc analysis revealed a distinct pattern of structural dimorphism within the AD cohort among APOE ε4-negative individuals with females exhibiting significantly greater structural preservation compared to males (Mean difference = 11.32, p = 0.051). Among APOE ε4 carriers, atrophy trajectories for males and females were statistically indistinguishable (p = 0.922), potentially suggesting that the ε4 allele exerts a dominant neurodegenerative influence that overrides sex-specific physiological differences. Conclusions: These emerging findings highlight the importance of jointly considering biological sex and APOE ε4 status to improve the characterization of Alzheimer's disease heterogeneity and support precision medicine approaches.},
}

@article {pmid42653013,
year = {2026},
author = {Apescaritei Apostol, LL and Ștefan, CS and Grecu, M and Moldovanu, S and Verga, GI and Lungu, M and Prada, GI and Romila, A},
title = {Comparative Analysis by Machine Learning of Geriatric Frailty and Alzheimer's Disease Classification Using Independent Datasets.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/life16081324},
pmid = {42653013},
issn = {2075-1729},
abstract = {Frailty syndrome and Alzheimer's disease are prevalent conditions in the elderly that are associated with aging, decreased quality of life, and a significant healthcare burden. Evidence for a relationship between physical frailty and neurodegenerative decline is accumulating. This study analyzed two independent datasets, a frailty dataset based on gait and mobility parameters and an AD dataset with clinical, functional and lifestyle variables, in order to evaluate and compare their classification performance using machine learning. Features were optimized using dimensionality reduction techniques to keep predictors of clinical significance and hyperparameter optimized Random Forest models were built to develop the best model. Evaluation was performed with Accuracy, F1-score, Matthews Correlation Coefficient and Area Under the Curve. The results showed that the models constructed on the whole AD dataset achieved maximum predictive power with an accuracy of 0.946, which was slightly increased to an accuracy of 0.948 after the selection of significant features. Diagnostic models based on frailty were able to demonstrate an ACC predictive capacity of 0.6418, and in terms of feature selection, improvements appeared in all indicators. Regarding the features derived from Alzheimer's disease associated with geriatric frailty, they managed to surpass the ACC frailty features of 0.741 alone, suggesting some intercalation mechanisms between neurodegeneration and physical vulnerability. These findings show that machine learning algorithms accompanied by feature selection improve clinical discrimination and prediction of frailty and neurodegenerative disorders, which offers a promising aspect for geriatric assessment. The frailty models analyzed demonstrated an ACC predictive capacity of 0.6418, even though feature selection improved all indicators. Alzheimer's disease-derived features associated with frailty outperformed features in the frailty dataset with an ACC of 0.741, suggesting the mechanism of overlap between neurodegeneration and physical vulnerability. These results support the theory of a motor-cognitive aging continuum, indicating that algorithmic machine learning techniques coupled with feature selection mainly provide computational validation for the biological intersection of neurodegeneration and physical frailty, rather than forming an independent predictive clinical model. Using these algorithms the study highlights shared pathophysiological mechanisms, providing a significant insight into systemic geriatric deterioration.},
}

@article {pmid42653081,
year = {2026},
author = {Aebisher, D and Krzysztofińska, A and Smolak, B and Bernat, P and Czajka, W and Kowal, M and Krasoń, S and Dynarowicz, K and Guz, W and Bartusik-Aebisher, D},
title = {MALDI Mass Spectrometry Imaging in Alzheimer's Disease Lipidomics: Matrix Selection, Spatial Lipid Pathology and Emerging Analytical Strategies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
doi = {10.3390/ijms27167074},
pmid = {42653081},
issn = {1422-0067},
mesh = {*Alzheimer Disease/metabolism/pathology/diagnostic imaging ; Humans ; *Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods ; *Lipidomics/methods ; Animals ; Lipid Metabolism ; *Lipids/analysis ; },
abstract = {Alzheimer's disease (AD) involves not only amyloid-β and tau pathology but also extensive disturbances in lipid metabolism, membrane organization, neuroinflammatory signaling, and tissue homeostasis. Conventional lipidomics has identified changes in phospholipids, sphingolipids, sulfatides, ceramides, gangliosides, and cholesterol-related pathways, but tissue homogenization removes their anatomical context. The aim of this review is to critically assess how matrix selection, sample preparation, ionization polarity, and emerging analytical strategies influence the detection and interpretation of spatial lipid alterations specifically associated with AD neuropathology. Current evidence shows that AD-related lipid remodeling is region- and lesion-specific, with recurrent findings including ganglioside accumulation, sulfatide depletion, ceramide-related alterations, phospholipid remodeling, lysosomal lipid changes, and disturbed cholesterol homeostasis within or around amyloid plaques. Matrix chemistry strongly influences lipid-class coverage, ionization efficiency, spectral background, adduct formation, spatial resolution, and biological interpretation. Matrix-Assisted Laser Desorption/Ionization with Laser-Induced Post-Ionization (MALDI-2), ion mobility, reactive matrices, on-tissue derivatization, structural lipidomics, single-cell imaging, and spatial multiomics are expanding molecular coverage and annotation confidence. However, broader translation requires standardized workflows, structurally validated assignments, quantitative quality control, larger human cohorts, and improved interlaboratory reproducibility. Collectively, the available evidence indicates that the principal value of Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) in AD lies not merely in detecting altered lipid abundance, but in resolving lesion-specific lipid microenvironments whose interpretation depends directly on matrix chemistry, spatial resolution, and structural validation.},
}

*Alzheimer Disease/metabolism/pathology/diagnostic imaging
Humans
*Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
*Lipidomics/methods
Animals
Lipid Metabolism
*Lipids/analysis

@article {pmid42653169,
year = {2026},
author = {Terribile, G and Pedrinazzi, M and Frigerio, I and Sancini, G and Combi, R},
title = {Theranostic Innovative Strategies for Brain Diseases: New Insights on Neurovascular Unit-Associated Pathological Changes in Neurodegenerative Disorders and Aging.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
doi = {10.3390/ijms27167165},
pmid = {42653169},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology/diagnosis ; *Aging/pathology ; Animals ; Blood-Brain Barrier/metabolism/pathology ; *Theranostic Nanomedicine/methods ; *Brain Diseases/therapy/diagnosis/pathology ; Nanoparticles ; MicroRNAs/genetics ; Nanotechnology ; },
abstract = {Central nervous system (CNS) disorders represent a significant healthcare challenge, with aging as the primary risk factor. Current clinical management remains predominantly symptomatic, as late-stage diagnosis and the blood-brain barrier (BBB) limit therapeutic efficacy. This review synthesizes emerging innovations in neurotheranostics-integrated diagnostic and therapeutic platforms-focusing on the neurovascular unit (NVU) as a central pathogenic driver and target. Evidence indicates that NVU and BBB dysfunction are early events in Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases, often preceding classic neuropathological hallmarks. The review highlights the potential of nanotechnology, engineered nanoparticles (NPs) and microRNAs (miRNAs) as precision tools for early detection and targeted CNS delivery. Additionally, it discusses the transformative impact of artificial intelligence (AI) in facilitating personalized, predictive care. Transitioning from a generic "one-pill-for-one-disease" model to a patient-centered strategy targeting early NVU alterations is essential. Integrating AI, nanotechnology and NVU-focused strategies offers a promising path toward effective, personalized disease-modifying therapies.},
}

Humans
*Neurodegenerative Diseases/therapy/pathology/diagnosis
*Aging/pathology
Animals
Blood-Brain Barrier/metabolism/pathology
*Theranostic Nanomedicine/methods
*Brain Diseases/therapy/diagnosis/pathology
Nanoparticles
MicroRNAs/genetics
Nanotechnology

@article {pmid42653267,
year = {2026},
author = {Li, L and Zhang, Y and Li, S and Zhao, M and Hu, W and Xiao, Y and Wen, J},
title = {Putative Modulation of OATP1A2 and P-gp Expression at the Blood-Brain Barrier by Nrf2-PXR: An Associative Hypothesis for Amyloid-β Transport in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
doi = {10.3390/ijms27167264},
pmid = {42653267},
issn = {1422-0067},
support = {82360734//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *NF-E2-Related Factor 2/metabolism ; *Blood-Brain Barrier/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism ; *Pregnane X Receptor/metabolism ; *ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism/genetics ; *Organic Anion Transporters/metabolism/genetics ; Biological Transport ; Gene Expression Regulation ; },
abstract = {Impaired amyloid-β (Aβ) clearance across the blood-brain barrier (BBB) is a major contributor to Aβ accumulation in Alzheimer's disease (AD). P-glycoprotein (P-gp) has been identified as a key BBB efflux transporter involved in Aβ clearance, whereas emerging evidence suggests that organic anion transporting polypeptide 1A2 (OATP1A2) and its rodent counterparts, such as Oatp1a4, may participate in the influx component of Aβ transport. Nuclear factor erythroid 2-related factor 2 (Nrf2) and pregnane X receptor (PXR) are important transcriptional regulators of oxidative stress responses, xenobiotic metabolism, and transporter expression and may therefore modulate OATP1A2 and P-gp expression at the BBB. However, the mechanisms by which Nrf2-PXR crosstalk may regulate OATP1A2/P-gp expression in BBB endothelial cells under AD-relevant pathological conditions, as well as the consequences of this regulation for Aβ transport homeostasis, remain incompletely understood. This review summarizes current evidence linking P-gp, OATP1A2/Oatp1a4, Nrf2, and PXR to BBB transporter homeostasis in AD. A "net-effect" model is further proposed, in which Nrf2-PXR crosstalk may shift the BBB transporter balance toward enhanced P-gp-mediated efflux and reduced OATP1A2-associated influx. Because several key components of this model, particularly OATP1A2-mediated Aβ influx and BBB-specific Nrf2-PXR regulation, remain insufficiently validated, this model should be regarded as a mechanistic framework for future experimental investigation rather than as an established pathogenic pathway. Clarifying this regulatory axis may provide new insights into BBB dysfunction and impaired Aβ clearance in AD and may help identify potential molecular targets for therapeutic intervention.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*NF-E2-Related Factor 2/metabolism
*Blood-Brain Barrier/metabolism
Animals
*Amyloid beta-Peptides/metabolism
*Pregnane X Receptor/metabolism
*ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism/genetics
*Organic Anion Transporters/metabolism/genetics
Biological Transport
Gene Expression Regulation

@article {pmid42653355,
year = {2026},
author = {Arbănași, EM and Arbănași, EM and Boghițoiu, TG and Cărare, SA and Cordoș, BA and Braysh, K and Suciu, N and Chinezu, L and Manu, DR and Montagne, A and Dewing, J and Russu, E and Bănescu, CV and Voidăzan, ST and Cărare, RO},
title = {Cerebral Intramural Cells: A Missing Cellular Link Between Vascular Aging and Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
doi = {10.3390/ijms27167353},
pmid = {42653355},
issn = {1422-0067},
support = {Fellowship No. 8370651-606/ALZS_/Alzheimer's Society/United Kingdom ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; Animals ; Pericytes/metabolism/pathology ; Blood-Brain Barrier/metabolism/pathology ; Cerebral Amyloid Angiopathy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Myocytes, Smooth Muscle/metabolism/pathology ; *Aging/pathology ; *Brain/pathology/blood supply/metabolism ; Muscle, Smooth, Vascular/pathology/metabolism ; },
abstract = {The pathological deposition of amyloid-β (Aβ) in the walls of cerebral blood vessels as cerebral amyloid angiopathy (CAA) is a key feature of Alzheimer's disease (AD) and is linked to impaired clearance of Aβ via intramural periarterial drainage (IPAD). The spontaneous contractions of cerebral smooth muscle cells (SMCs) are thought to drive IPAD, but the relationship between vascular aging and Aβ accumulation remains unclear. We propose a unified framework centered on cerebral intramural cells (CICs), including arterial SMCs, specialized pericyte subtypes, as mediators of vascular dysfunction and neurodegeneration. We integrate current evidence from studies of cerebral small vessel disease, blood-brain barrier (BBB) dysfunction, pericyte biology, vascular aging, cerebral perfusion, and IPAD. CICs regulate vasomotion, capillary flow, BBB integrity, and IPAD. Their dysfunction impairs perfusion and protein clearance, increasing vulnerability in white matter and the hippocampus. These vascular alterations interact with amyloid and inflammatory processes, contributing to synaptic dysfunction, network disconnection, and neurodegeneration. CICs represent potential therapeutic targets. A CIC-centered framework may help explain the links between vascular dysfunction, impaired Aβ clearance, and neurodegeneration in AD and CAA.},
}

Humans
*Alzheimer Disease/pathology/metabolism
Animals
Pericytes/metabolism/pathology
Blood-Brain Barrier/metabolism/pathology
Cerebral Amyloid Angiopathy/metabolism/pathology
Amyloid beta-Peptides/metabolism
Myocytes, Smooth Muscle/metabolism/pathology
*Aging/pathology
*Brain/pathology/blood supply/metabolism
Muscle, Smooth, Vascular/pathology/metabolism

@article {pmid42653368,
year = {2026},
author = {Summers, RA and Quang, D and Johnson, NR},
title = {Human Stem Cell-Derived Models of the Alzheimer's Disease Neuroimmune System.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
doi = {10.3390/ijms27167360},
pmid = {42653368},
issn = {1422-0067},
support = {1RF1AG078965-01A1/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Microglia/metabolism/immunology/pathology ; Astrocytes/metabolism/immunology/pathology ; Amyloid beta-Peptides/metabolism ; *Neuroimmunomodulation ; Animals ; Models, Biological ; },
abstract = {Mounting evidence implicates dysregulation of the neuroimmune system in Alzheimer's disease (AD). Neuroimmune cells, namely microglia and astrocytes, have the potential to contribute to AD through mechanisms such as promoting neuroinflammation and propagating amyloid-β (Aβ) and tau aggregates. Human induced pluripotent stem cell (hiPSC)-derived models offer advantages for studying the AD neuroimmune system, such as recapitulating genetic variants associated with the disease and allowing for precise manipulation of human cells in vitro. Here, we provide an overview of modern techniques for generating 2-dimensional (2D) monocultures and co-cultures, 3-dimensional (3D) organoids and assembloids, and chimeras containing hiPSC-derived microglia and astrocytes. Then, we highlight recent studies that have utilized hiPSC-derived neuroimmune models to investigate AD risk variants in genes encoding apolipoprotein E (APOE) and triggering receptor on myeloid cells 2 (TREM2), mutations known to cause familial AD in genes encoding presenilin 1 (PSEN1) and 2 (PSEN2) and amyloid precursor protein (APP), and trisomy 21 leading to Down syndrome-associated AD (DS-AD). We then briefly summarize recent studies that have utilized hiPSC-derived neuroimmune models lacking disease-associated variants to study the clearance of Aβ and tau aggregates. Finally, we discuss notable limitations of these models and reflect on future directions for this area of research, including the use of cultures with increasing cellular diversity and structural complexity, advancements in live-imaging techniques for detecting AD pathology in vitro, and drug screening.},
}

Humans
*Alzheimer Disease/immunology/pathology/metabolism/genetics
*Induced Pluripotent Stem Cells/metabolism/cytology
Microglia/metabolism/immunology/pathology
Astrocytes/metabolism/immunology/pathology
Amyloid beta-Peptides/metabolism
*Neuroimmunomodulation
Animals
Models, Biological

@article {pmid42653402,
year = {2026},
author = {Wang, G and Hiramoto, K and Ma, N and Ohnishi, S and Yoshikawa, N and Murata, M and Kawanishi, S},
title = {Glycyrrhizin Ameliorates Learning and Memory Impairment via Inhibition of Neuroinflammation in an Alzheimer's Disease Mouse Model SAMP8.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
doi = {10.3390/ijms27167399},
pmid = {42653402},
issn = {1422-0067},
support = {24K20202//Japan Society for the Promotion of Science/ ; 23K24589//Japan Society for the Promotion of Science/ ; 22KK0150//Japan Society for the Promotion of Science/ ; },
mesh = {Animals ; *Glycyrrhizic Acid/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; Disease Models, Animal ; Male ; *Memory Disorders/drug therapy ; *Neuroinflammatory Diseases/drug therapy ; Hippocampus/drug effects/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Microglia/drug effects/metabolism ; *Anti-Inflammatory Agents/pharmacology ; HMGB1 Protein ; *Learning/drug effects ; tau Proteins/metabolism ; Klotho Proteins ; },
abstract = {Neuroinflammation plays a central role in Alzheimer's disease (AD). Glycyrrhizin (GL), a major component of licorice, exhibits anti-inflammatory effects, but its effects on AD pathology remain unclear. To investigate the effects of GL (18β-glycyrrhizin, 18β-GL) and its stereoisomer (18α-glycyrrhizin, 18α-GL) on cognitive function, neuroinflammation, and AD pathology in senescence-accelerated mouse prone 8 (SAMP8; P8) mice, 40-week-old P8 male mice, an AD model due to aging, and the control (senescence-accelerated mouse resistant 1, SAMR1; R1) mice were treated with 18β-GL, 18α-GL and physiological saline (control) for 12 weeks (n = 6 in each group). Cognitive function was evaluated using a step-through passive avoidance test. Plasma levels of α-Klotho, IGF-1, 2',3'-cyclic GMP-AMP (2',3'-cGAMP), HMGB1, IL-6, and TNF-α were measured by ELISA. Hippocampal microglial activation (Iba1), amyloid-β (Aβ) deposition, and phosphorylated tau (p-Tau) were assessed by immunohistochemistry. Aged P8 mice showed impaired memory, decreased α-Klotho and IGF-1 levels, and increased inflammatory markers compared with R1 mice. GL significantly improved memory performance, reduced inflammatory markers, and suppressed Iba1 activation, as well as Aβ and p-Tau accumulation. These effects were associated with inhibition of the cGAS-STING pathway, as indicated by reduced 2',3'-cGAMP and HMGB1 levels. GL ameliorates AD pathology by inhibiting neuroinflammation, suggesting its therapeutic potential for AD.},
}

Animals
*Glycyrrhizic Acid/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
Disease Models, Animal
Male
*Memory Disorders/drug therapy
*Neuroinflammatory Diseases/drug therapy
Hippocampus/drug effects/metabolism/pathology
Amyloid beta-Peptides/metabolism
Microglia/drug effects/metabolism
*Anti-Inflammatory Agents/pharmacology
HMGB1 Protein
*Learning/drug effects
tau Proteins/metabolism
Klotho Proteins

@article {pmid42653437,
year = {2026},
author = {Khan, A and Khan, H and Park, IH and Aldahmash, BA and Khan, MS and Yang, G and Kang, KS},
title = {Alkaloids as Emerging Neuroprotective Agents for Neurodegenerative Disorders: Insights into Tryptanthrin and Its Derivatives.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
doi = {10.3390/ijms27167436},
pmid = {42653437},
issn = {1422-0067},
mesh = {Humans ; *Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Quinazolines/therapeutic use/chemistry/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; *Alkaloids/therapeutic use/pharmacology/chemistry ; },
abstract = {Neurodegenerative conditions are incurable, progressive disorders characterized by the slow and irreversible loss of neurons. This neuronal loss can lead to several neuropsychiatric disorders and long-term complications. Despite significant advances in understanding the mechanisms of neurodegenerative disease, currently, there is no cure for neurodegenerative diseases, highlighting the urgent need for novel neuroprotective strategies. Alkaloids are an important class of bioactive substances that exhibit neuroprotection against several neurodegenerative diseases. Tryptanthrin, an indoloquinazoline alkaloid, shows strong anti-inflammatory, antioxidant, and neuroprotective properties. In this review, we described the pathophysiology of neurodegenerative diseases and summarized several alkaloids' neuroprotective properties. Furthermore, we showed protective benefits of tryptanthrin and its derivatives against neurodegenerative illnesses, focusing on their modulation of oxidative stress, neuroinflammation, neuronal death, and related signaling pathways in cellular and animal models of neurodegenerative diseases. However, various challenges, such as clinical evidence, pharmacokinetic studies, and long-term treatment effects, are not well documented. Future research on tryptanthrin and its derivatives should focus on the optimization of drug delivery methodologies and clinical studies to establish its potential as a therapeutic candidate for neurodegenerative diseases.},
}

Humans
*Neuroprotective Agents/therapeutic use/pharmacology/chemistry
*Quinazolines/therapeutic use/chemistry/pharmacology
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
Oxidative Stress/drug effects
*Alkaloids/therapeutic use/pharmacology/chemistry

@article {pmid42653476,
year = {2026},
author = {Șerban, M and Toader, C and Covache-Busuioc, RA},
title = {ZBP1 in Neuroinflammation and Neurodegeneration: Z-Nucleic-Acid Sensing, RHIM Signalling and Therapeutic Targeting.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
doi = {10.3390/ijms27167478},
pmid = {42653476},
issn = {1422-0067},
mesh = {Humans ; *RNA-Binding Proteins/metabolism ; Signal Transduction ; Animals ; *RNA, Z-Form/metabolism ; *Neurodegenerative Diseases/metabolism ; *Neuroinflammatory Diseases/metabolism ; *DNA, Z-Form/metabolism ; Innate Immunity Recognition ; *DNA-Binding Proteins/metabolism ; Immunity, Innate ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; },
abstract = {In contrast to foreign nucleic acids, some of our own endogenously synthesized nucleic acids may become immunologically active without being considered "foreign". For example, abnormalities in chromatin organization, transcription termination, ribonucleic acid (RNA) splicing, and RNA editing, together with damage to mitochondrial integrity, may render normally functional deoxyribonucleic acid (DNA) and RNA persistently available and aberrantly structured ligands for innate immunity. Z-DNA-binding protein 1 (ZBP1), recently identified as an important component of this innate immune system, recognizes both left-handed DNA (Z-DNA) and left-handed RNA (Z-RNA) using its tandem Z-alpha (Zα) domains and couples recognition of these conformational states to receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-, receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-, and mixed-lineage kinase domain-like pseudokinase (MLKL)-dependent inflammatory and cell-death pathways. More recent studies have also shown that ZBP1 plays a role in recognizing damaged self-nucleic acids associated with tauopathies, Alzheimer's disease (AD), traumatic brain injury (TBI), and amyloid-associated neuroinflammation. The nucleic-acid forms associated with these conditions include transposable-element activation, extended repeat-containing transcripts, RNA-RNA duplexes or RNA:DNA hybrids, oxidized mitochondrial DNA (mtDNA), and intercellularly transferred nucleic acids, all of which may exhibit substrate structures compatible with Z-form formation. Signaling by ZBP1 does not occur simply based upon nucleic-acid abundance; rather, signaling occurs after prolonged exposure to a nucleic acid when it persists in a structurally competent state, sufficient receptors are present to bind its exposed regions, the receptor proteoforms are competent to participate in signaling, receptor-interacting protein homotypic interaction motif (RHIM)-dependent assembly occurs, and the appropriate adaptor molecules are present. Furthermore, the identity of the cell type expressing ZBP1 determines whether the response produces RIPK3-MLKL-dependent neuronal injury, microglia-mediated inflammation, apoptosis, or mixed cell death. Finally, competition with adenosine deaminase acting on RNA 1 (ADAR1), melanoma differentiation-associated protein 5 (MDA5), double-stranded RNA-dependent protein kinase (PKR), the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, and other nucleic-acid-sensing proteins divides the available pool of endogenous nucleic acids among the outcomes of immune tolerance, type I interferon (IFN-I) signaling, translational inhibition, neuroinflammation, and necroptosis.},
}

Humans
*RNA-Binding Proteins/metabolism
Signal Transduction
Animals
*RNA, Z-Form/metabolism
*Neurodegenerative Diseases/metabolism
*Neuroinflammatory Diseases/metabolism
*DNA, Z-Form/metabolism
Innate Immunity Recognition
*DNA-Binding Proteins/metabolism
Immunity, Innate
Receptor-Interacting Protein Serine-Threonine Kinases/metabolism

@article {pmid42653505,
year = {2026},
author = {Gromadzka, G and Kąkol, M and Klimkiewicz, M and Bendykowska, M},
title = {Glutathione Biology in Neurodegenerative and Metabolic Diseases: Molecular Mechanisms, Pathophysiological Roles, and Therapeutic Perspectives.},
journal = {International journal of molecular sciences},
volume = {27},
number = {16},
pages = {},
doi = {10.3390/ijms27167507},
pmid = {42653505},
issn = {1422-0067},
mesh = {Humans ; *Glutathione/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/physiopathology ; Animals ; *Metabolic Diseases/metabolism/therapy/physiopathology ; Signal Transduction ; Homeostasis ; Oxidative Stress ; NF-E2-Related Factor 2/metabolism ; Oxidation-Reduction ; Mitochondria/metabolism ; Antioxidants/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; },
abstract = {Glutathione is an abundant intracellular low-molecular-weight thiol that contributes importantly to cellular redox homeostasis. Besides its well-established role in the antioxidant defense of the cell, glutathione regulates mitochondrial function, metabolism of toxicants, protein thiol oxidation/reduction, redox signaling, and immunity. Disturbances in glutathione metabolism have been shown to play a role in various diseases; however, it has become clear that changes in glutathione metabolism are a part of a complex, multifactorial process. In this review, we summarize current knowledge of the molecular mechanisms governing glutathione synthesis, recycling, compartmentalization, and biological functions, with particular emphasis on redox signaling, the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway, and reversible protein S-glutathionylation. We further examine how disturbances in glutathione homeostasis interact with mitochondrial dysfunction, chronic inflammation, metabolic stress, and impaired cellular signaling in Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, Wilson's disease, type 2 diabetes, and nonalcoholic fatty liver disease. We also evaluate current translational interventions targeting restoration of glutathione balance through glutathione supplementation, precursor supplementation, pharmacological modulation of endogenous antioxidant mechanisms, dietary interventions, and changes in lifestyle. Despite the fact that many interventions have been promising at the mechanistic and experimental level, there are still insufficient clinical data because of the problems associated with glutathione availability, tissue specificity, disease variability, and a lack of sufficiently powered clinical trials. The conclusion of this review is that glutathione should not be viewed as a universal therapeutic target; instead, glutathione should be perceived as an important factor contributing to cellular resilience and able to help other disease-specific interventions. Future progress in glutathione-based interventions will likely depend on integrating redox biomarkers, patient stratification, and precision medicine strategies to identify individuals most likely to benefit from targeted modulation of glutathione homeostasis.},
}

Humans
*Glutathione/metabolism
*Neurodegenerative Diseases/metabolism/therapy/physiopathology
Animals
*Metabolic Diseases/metabolism/therapy/physiopathology
Signal Transduction
Homeostasis
Oxidative Stress
NF-E2-Related Factor 2/metabolism
Oxidation-Reduction
Mitochondria/metabolism
Antioxidants/metabolism
Kelch-Like ECH-Associated Protein 1/metabolism

@article {pmid42653650,
year = {2026},
author = {Odonkor, CA and Karpe, DA and Siddique, MU and Abd-Elsayed, A},
title = {Neuropharmacology of Cannabinoids: A Comprehensive Review of Preclinical and Clinical Evidence for Hemp-Derived Extracts and Active Compounds.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {8},
pages = {},
doi = {10.3390/ph19081151},
pmid = {42653650},
issn = {1424-8247},
abstract = {Cannabis sativa contains more than 120 phytocannabinoids, with Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being the best characterized. This review synthesizes preclinical and clinical evidence on hemp-derived extracts, cannabinoids, and active compounds. THC primarily acts as a partial agonist at cannabinoid receptor type 1 (CB1) and type 2 (CB2), producing psychoactive, appetite-stimulating, antiemetic, and analgesic effects. CBD is non-intoxicating and has a multimodal profile involving CB1 negative allosteric modulation, CB2 inverse agonism or antagonism, inhibition of anandamide inactivation, and activity at 5-HT1A receptors, transient receptor potential channels, GPR55, and peroxisome proliferator-activated receptor gamma. Preclinical models of Parkinson's disease, Alzheimer's disease, Huntington's disease, epilepsy, and pain support anti-inflammatory, antioxidant, anti-excitotoxic, and glial-modulating mechanisms, but clinical translation remains uneven. The strongest evidence supports FDA-approved cannabidiol for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex, and THC-based agents for refractory chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Moderate-certainty evidence supports nabiximols for multiple sclerosis spasticity and small benefits in selected chronic neuropathic pain populations. Evidence remains insufficient or negative for acute pain, insomnia, most psychiatric disorders, and many promoted indications. Key risks include cannabis use disorder, cognitive and psychiatric effects, cardiovascular events, sedation, high-dose CBD hepatotoxicity, and drug interactions. Rigorous, long-term, product-standardized trials are needed.},
}

@article {pmid42653654,
year = {2026},
author = {Choi, IA and Yun, JH and Lee, J and Choi, DH},
title = {Therapeutic Potential of 2-(2-Benzofuranyl)-2-Imidazoline in Preclinical CNS Models: A Systematic Review of Mechanisms, Disease Models, and Cellular Targets.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {8},
pages = {},
doi = {10.3390/ph19081155},
pmid = {42653654},
issn = {1424-8247},
support = {RS-2025-23963199//Ministry of Science and ICT/ ; },
abstract = {Background/Objectives: 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) is a selective imidazoline I2-site ligand that has shown neuroprotective and neuromodulatory effects in preclinical central nervous system (CNS) studies. However, the primary preclinical literature remains fragmented across disease models, outcome types, mechanistic endpoints, and cellular targets, making it difficult to define where its therapeutic-development potential is strongest and how disease- or model-specific functional effects relate to molecular, cellular, tissue, and blood-brain barrier/neurovascular unit (BBB/NVU)-related findings. Methods: This systematic review integrated preclinical evidence from 36 original studies identified in the PubMed, Web of Science, Embase, and Scopus databases through searches last updated on May 19, 2026, to evaluate the strength of evidence for 2-BFI across CNS-related models and to connect functional, molecular, cellular, and neurovascular findings. The evidence categories included ischemic stroke/neurovascular outcomes (n = 13), traumatic CNS injury (n = 2), neuroinflammatory/neurodegeneration-related models (n = 9), behavioral pharmacology (n = 8), and cellular mechanisms (n = 4). Eligible studies were original CNS-related animal, cellular, or behavioral/pharmacological studies that directly evaluated 2-BFI and reported neuroprotective, neurological, cellular, molecular, vascular, inflammatory, neurotransmitter-related, or behavioral outcomes. Findings were synthesized qualitatively, and risk of bias in in vivo animal studies was assessed using SYRCLE's risk-of-bias tool. Results: The most extensive preclinical evidence was found in ischemic stroke and neurovascular injury models, in which 2-BFI attenuated infarct size, neurological deficits, and edema, and suppressed apoptosis-related injury and blood-brain barrier/neurovascular unit (BBB/NVU) disruption. Across models, these effects are best interpreted as modulation of interconnected secondary injury processes involving N-methyl-D-aspartate receptor (NMDAR)/Ca[2+]-dependent excitotoxicity, oxidative and mitochondrial stress, inflammatory amplification, regulated cell death, and neurovascular destabilization. Evidence from traumatic CNS injury, autoimmune neuroinflammation, Alzheimer's disease-related models, chronic epilepsy, and cellular stress models broadened the CNS relevance of 2-BFI but remained less replicated or more mechanistically indirect than the stroke/neurovascular evidence. Behavioral and pharmacological studies additionally indicated that 2-BFI modulates neurotransmitter-related systems associated with pain-, affective-, addiction-, opioid-, and compulsivity-related outcomes, although these findings should be distinguished from disease-modifying neuroprotective evidence. Conclusions: Meta-analysis was not conducted because of heterogeneity in models, dosing regimens, treatment timing, and outcomes. Overall, the current evidence does not yet support definitive dosing, treatment timing, or clinical development recommendations for 2-BFI. The strongest preclinical therapeutic rationale is currently found in ischemic stroke and neurovascular injury settings, whereas other CNS indications require further validation. Future studies should define dose-response relationships, therapeutic windows, pharmacokinetic and safety profiles, sex- and age-related effects, and efficacy in clinically relevant comorbid models before clinical translation is considered. The review was not prospectively registered. Funding was provided by a National Research Foundation of Korea grant funded by the Korean government.},
}

@article {pmid42653713,
year = {2026},
author = {Mendes, GO and Bento, LDP and Oliveira, TM and Barbosa, DB and Tsui, GS and Gomes, EN and Sales, RO and Rocha, MSC and Silva, MPD and Oliveira, TA and Maia, EHB and Falkoski, DL and Marra, IFS and Andrade, LSM and Mendes, LCVP and Fonseca, BS and Oliveira, LMG and Silva, VDAD and Carvalho, PB and Silva, AMD and Taranto, AG and Damázio, LCM and Valle, MS and Leite, FHA},
title = {Design, Synthesis, In Vitro and In Vivo Evaluation of Novel Anti-Alzheimer's (1E,4E)-1,5-Bis[(het)aryl]penta-1,4-dien-3-one Derivatives.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {8},
pages = {},
doi = {10.3390/ph19081216},
pmid = {42653713},
issn = {1424-8247},
support = {APQ-04559-22//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; APQ-07852-25//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; APQ-03224-24//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 305452/2025-8//National Council for Scientific and Technological Development/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative condition characterized by neurofibrillary tangles, neuronal loss, cognitive impairment, and accumulation of β-amyloid plaques. Considering the limitations of current treatments, which present adverse effects and only alleviate symptoms without modifying disease progression, there is an urgent need for new therapeutic approaches. This study aimed to investigate the neuroprotective potential of synthetic derivatives of (1E,4E)-1,5-bis[(het)aryl]penta-1,4-dien-3-ones, focusing on the inhibition of the cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), targets directly related to the cholinergic deficit observed in AD. Methods: The compounds were initially synthesized by aldol condensation reactions, with subsequent physicochemical characterization. They were then subjected to in silico assays that demonstrated high binding affinity to the active sites of AChE and BChE. The derivatives were evaluated in vitro for their inhibitory activity on these enzymes and in vivo in an experimental model of AD induced by streptozotocin in Wistar rats. Results: The synthesized derivatives showed favorable predicted interactions with the active sites of AChE and BChE, supporting their potential as cholinesterase inhibitors. In vitro assays demonstrated inhibitory activity against both enzymes, with selected derivatives showing improved activity compared with the parent scaffold. In the in vivo model, treatment with the selected compounds was associated with neuroprotective effects, suggesting preservation of nervous tissue integrity under AD-like conditions. Conclusions: These findings indicate that derivatives may represent promising candidates for further investigation as multitarget agents for AD. The study reinforces the relevance of integrating organic synthesis, molecular modeling, enzymatic assays, and in vivo evaluation in the search for new therapeutic strategies for neurodegenerative diseases.},
}

@article {pmid42653715,
year = {2026},
author = {Yang, L and Yin, Y and Liu, X and Guo, B},
title = {Single-Chain Variable Fragment Fusion Proteins for Targeted Delivery and Therapy.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {8},
pages = {},
doi = {10.3390/ph19081218},
pmid = {42653715},
issn = {1424-8247},
support = {CA293945/CA/NCI NIH HHS/United States ; CPRIT RP260101//The University of Texas System/ ; X-E-0024-20260714//Welch Foundation/ ; },
abstract = {A single-chain variable fragment (scFv) is an engineered antibody derivative that retains antigen-binding specificity while having a much smaller size than an antibody, improved tissue penetration, and enhanced versatility for genetic manipulation. When an scFv is fused with diverse protein payloads, multifunctional biologics can be created for targeted delivery and therapy. Over the past decade, scFv fusion proteins have gained significant traction in oncology, where they have been incorporated into immunotoxins, immunocytokines, bispecific antibodies, Chimeric Antigen Receptor (CAR)-T cells constructs, and immune cell engagers. In addition, advances in blood-brain barrier (BBB)-targeting strategies have enabled the exploration of scFv-based therapeutics for neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Despite promising preclinical and clinical outcomes, challenges such as structural instability, short half-life, immunogenicity, and manufacturing complexity remain. This review provides an in-depth and up-to-date overview of scFv fusion protein engineering and its therapeutic applications in cancer and neurodegenerative disorders. We also highlight the clinical translations and design principles of scFv fusion proteins.},
}

@article {pmid42653735,
year = {2026},
author = {Șolea, R and Șerban, E and Călugăr-Solea, SF and Mathe, E and Blebea, NM and Hancu, G and Serban, G},
title = {Cannabis and Cannabinoids: The Medical Potential of Cannabidiol in Mental and Neurological Disorders.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {8},
pages = {},
doi = {10.3390/ph19081238},
pmid = {42653735},
issn = {1424-8247},
support = {//University of Oradea/ ; },
abstract = {Background/Objectives: Mental and neurological disorders contribute substantially to the global burden of disease, affecting people of all ages and backgrounds. As their prevalence increases with age, their overall impact is expected to grow in the coming decades. Although psychological and pharmacological treatments are available, many patients fail to achieve satisfactory outcomes, underscoring the need for improved therapeutic strategies. Cannabis sativa L. has been used for medicinal purposes for centuries, and cannabidiol (CBD) has attracted increasing attention because of its broad therapeutic potential. Scientific studies indicate that CBD may be beneficial in several mental and neurological disorders. Methods: A comprehensive literature search was conducted to identify articles investigating the therapeutic potential of CBD and cannabis in selected disorders. Results: Evidence from preclinical and clinical studies, together with findings from the broader cannabis literature, indicates that CBD may offer therapeutic benefits in a range of conditions, including Alzheimer's and Parkinson's disease, anxiety disorders, and epilepsy. Emerging data also support its potential use as an adjunctive therapy for COVID-19. Current research has improved understanding of the neurobiological mechanisms underlying these disorders and the molecular pathways through which CBD may exert its effects. CBD has demonstrated good tolerability, with predominantly mild adverse effects and a favorable safety profile. Conclusions: Despite promising findings, many available studies are preclinical or involve small patient cohorts, and the mechanisms underlying the therapeutic effects of CBD remain incompletely understood. Further well-designed, randomized, controlled, multicenter trials are needed to establish the efficacy and safety of CBD and support its integration into clinical practice.},
}

@article {pmid42653875,
year = {2026},
author = {Gao, J and Li, L and Li, Y},
title = {Honeysuckle as a Food-Medicine Resource: A Review of Its Multi-Target Pharmacological Effects and Emerging Applications.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {16},
pages = {},
doi = {10.3390/molecules31162792},
pmid = {42653875},
issn = {1420-3049},
support = {81202638//National Natural Science Foundation of China/ ; LBH-Q18115//Heilongjiang Postdoctoral Fund/ ; PL2025T010//Heilongjiang Academy of Sciences/ ; ZHY2024-012//Heilongjiang University of Chinese Medicine/ ; },
mesh = {*Lonicera/chemistry ; Humans ; Animals ; Neuroprotective Agents/pharmacology/chemistry ; *Plant Extracts/pharmacology/chemistry ; Functional Food ; Phytochemicals/pharmacology/chemistry ; },
abstract = {Lonicera japonica Thunb. (honeysuckle), a traditional herb with "food-medicine homology" status in Chinese medicine, is valued for its antipyretic and detoxifying properties. This review systematically summarizes its chemical composition-over 507 identified compounds, including phenylpropanoids, flavonoids, triterpenoids, saponins, and the plant-specific miR2911-as well as its multi-target pharmacological mechanisms and emerging translational applications, with particular emphasis on the gut-brain axis-mediated neuroprotective effects. Despite low oral bioavailability, honeysuckle polysaccharides and chlorogenic acid have been shown to exert significant neuroprotection in Alzheimer's disease models by modulating gut microbiota composition, increasing short-chain fatty acid production, and restoring intestinal barrier integrity-a mechanism that challenges conventional direct-action paradigms. We also outline the applications of honeysuckle in functional foods, pharmaceuticals, animal husbandry, and cosmetics, and propose future directions including precision fermentation and mechanism-driven clinical trials. By integrating phytochemistry, pharmacology, and biotechnology, this review provides a roadmap for the evidence-based development of honeysuckle as a precise medicinal and edible resource.},
}

*Lonicera/chemistry
Humans
Animals
Neuroprotective Agents/pharmacology/chemistry
*Plant Extracts/pharmacology/chemistry
Functional Food
Phytochemicals/pharmacology/chemistry

@article {pmid42653915,
year = {2026},
author = {Runfola, M and Polini, B and Mazzierli, A and Raffellini, L and Di Ricco, F and Cirone, I and Sagona, S and Gul, S and Lessi, M and Cuzzola, AR and D'Orsi, R and Bellina, F and Manera, C and Chiellini, G and Rapposelli, S},
title = {Novel Insights into the Pleiotropic Neuroprotective Action of Synthetic Halogen Free Thyronamine-like Analogues.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {16},
pages = {},
doi = {10.3390/molecules31162833},
pmid = {42653915},
issn = {1420-3049},
support = {DEM-AGING//Region of Tuscany/ ; ECS00000017 CUP I53C22000780001//PNRR Tuscany Health Ecosystem (THE) - Spoke n. 02 "Preventive and Predictive Medicine/ ; 67562227//Pfizer/ ; },
mesh = {Animals ; *Neuroprotective Agents/pharmacology/chemistry ; Caenorhabditis elegans/drug effects ; Humans ; *Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Autophagy/drug effects ; Microglia/drug effects/metabolism ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving metabolic impairment, neuroinflammation, synaptic failure, and comorbidities. Hence, therapeutic development for AD is rapidly shifting from a single-target approach, centred on amyloid-beta (Aβ) reduction, to multi-target strategies. In this study, we investigated the neuroprotective profile of two acetanilide derivatives, SG-22 and SG-23, originated from the halogen-free thyronamine-like lead compound SG-2. Their efficacy was evaluated through an integrated approach combining in vitro cellular models, in vivo phenotypic screening in a Caenorhabditis elegans AD model, and comprehensive ADME-Tox profiling. In U87MG cells, both SG-22 and SG-23 effectively prevented Aβ25-35-induced cytotoxicity and restored autophagy-related gene expression, including LC3, SIRT1, and SIRT6, while reducing mTOR and SIRT5 levels. Furthermore, all compounds exhibited anti-inflammatory effects in activated HMC3 microglial cells, reducing IL-6 and increasing IL-10 levels, with evidence suggesting partial involvement of TAAR1 signalling. ADME-Tox analyses revealed improved safety and metabolic profiles for the tested compounds, particularly SG-22, which showed reduced hERG liability and enhanced cytochrome P450 stability. However, in vivo studies demonstrated that only SG-2 and SG-23 improved motility and fitness in the C. elegans AD model, consistent with their ability to activate autophagy, whereas SG-22 was ineffective due to limited organismal uptake. Ultimately, the monoacetylated analogue SG-23 emerges as a promising candidate, balancing neuroprotective efficacy and drug-like properties, and supporting thyronamine-like analogues as multi-target agents for AD.},
}

Animals
*Neuroprotective Agents/pharmacology/chemistry
Caenorhabditis elegans/drug effects
Humans
*Alzheimer Disease/drug therapy/metabolism
Amyloid beta-Peptides/metabolism
Autophagy/drug effects
Microglia/drug effects/metabolism
Disease Models, Animal

@article {pmid42654012,
year = {2026},
author = {Karageçili, H and Yerlikaya, E and Ertürk, A and Aslan, K and Akıncıoglu, H and Gülçin, İ},
title = {Comprehensive Evaluation of Peonidin: Antioxidant and Multi-Enzyme Inhibitory Abilities with Molecular Docking Insights.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {16},
pages = {},
doi = {10.3390/molecules31162931},
pmid = {42654012},
issn = {1420-3049},
mesh = {*Molecular Docking Simulation ; *Antioxidants/chemistry/pharmacology ; *Anthocyanins/chemistry/pharmacology ; Free Radical Scavengers/chemistry/pharmacology ; Humans ; Biphenyl Compounds/chemistry ; Sulfonic Acids/chemistry ; },
abstract = {Anthocyanins are water-soluble plant pigments. They give many plants, fruits, vegetables, and cereal kernels their red, purple, and blue colors. This research aims to reveal the biological properties of peonidin as an anthocyanin. To comprehend the antioxidant capabilities of peonidin, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS[•+]), N,N-dimethyl-p-phenylenediamine dihydrochloride radical (DMPD[•+]), and 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH[•]) scavenging, Fe[3+]-2,4,6-tris(2-pyridyl)-s-triazine (TPTZ), and Cu[2+] reducing assays were recorded. The IC50 values for peonidin against ABTS[•+], DMPD[•+] and DPPH[•] scavenging capabilities were determined to compare with standard antioxidants. ABTS[•+] radical scavenging activity of peonidin had an IC50 value of 15.40 μg/mL, while the IC50 values for BHA, BHT, Trolox, and α-Tocopherol were 12.82, 11.78, 12.67, and 10.83 μg/mL, respectively. DPPH radical scavenging activity of peonidin had an IC50 value of 41.63 μg/mL, while the IC50 values for BHA, BHT, Trolox, and α-Tocopherol were 8.45, 23.10, 6.30, and 18.73 μg/mL, respectively. Enzyme inhibition was studied to investigate the effects of peonidin. The Ki values of peonidin were 114.33, 63.02, 2.99, 9.76, and 15.14 nM toward hCA I, hCA II, AChE, BChE, and α-glycosidase enzymes, respectively. Furthermore, peonidin's interactions with target enzymes BChE, hCA I, hCA II, AChE, and α-glycosidase were investigated by molecular docking. The results suggest that antioxidant-rich peonidin is a plant-based compound with potential use in the treatment of glaucoma, Alzheimer's disease, and diabetes.},
}

*Molecular Docking Simulation
*Antioxidants/chemistry/pharmacology
*Anthocyanins/chemistry/pharmacology
Free Radical Scavengers/chemistry/pharmacology
Humans
Biphenyl Compounds/chemistry
Sulfonic Acids/chemistry

@article {pmid42654097,
year = {2026},
author = {Chikamatsu, G and Nakagawa, S and Morofuji, Y and Shiozaki, E and Ogawa, Y and Okamura, K and Matsunaga, Y and Watanabe, D and Walter, FR and Izumo, T and Niwa, M and Deli, MA and Matsuo, T},
title = {Clazosentan Attenuates Endothelin-1-Induced ETA Protein Upregulation and Contractile Sensitization in Brain Pericytes.},
journal = {Pharmaceutics},
volume = {18},
number = {8},
pages = {},
doi = {10.3390/pharmaceutics18080980},
pmid = {42654097},
issn = {1999-4923},
support = {JPJSBP120203804//Japan Society for the Promotion of Science/ ; 20KK0254//Japan Society for the Promotion of Science/ ; 20K09351//Japan Society for the Promotion of Science/ ; NKM2022-9/2023//Hungarian Academy of Sciences/ ; NKM2025-7/2025//Hungarian Academy of Sciences/ ; },
abstract = {Background/Objectives: Brain pericytes are contractile mural cells of the neurovascular unit whose responses to endothelin-1 (ET-1) are mediated primarily by endothelin type A (ETA) receptors. ET-1/ETA signaling has been implicated in pathological pericyte contraction in neurovascular disorders such as Alzheimer's disease and in cerebrovascular dysfunction after subarachnoid hemorrhage, motivating pharmacological evaluation of selective ETA receptor antagonists at the pericyte level. Clazosentan is a selective ETA receptor antagonist used clinically for cerebral vasospasm; however, its pharmacodynamic effects on brain pericytes remain insufficiently characterized. Methods: Pericyte impedance-based contractile and recovery responses to ET-1 were evaluated by xCELLigence real-time cell index analysis. Pericyte viability, morphology, and ETA protein abundance were examined using Cell Counting Kit-8 assay, immunocytochemistry, and Western blotting. As a secondary barrier-related assessment, transendothelial electrical resistance (TEER) was measured in primary rat brain endothelial cell-based in vitro blood-brain barrier models. Results: ET-1 induced impedance-based contractile responses with a concentration-related trend, followed by recovery responses, and increased ETA protein abundance in a time- and concentration-related manner; clazosentan significantly attenuated ET-1-induced ETA upregulation. Repeated ET-1 exposure was associated with an enhanced subsequent ET-1-induced impedance-based contractile response and a more sustained response, suggesting contractile sensitization; both effects were significantly attenuated by clazosentan. Clazosentan did not overtly disrupt TEER-assessed barrier properties. Conclusions: These findings suggest that ET-1/ETA signaling may shift brain pericytes toward a sensitized contractile response state and that selective ETA blockade by clazosentan attenuates this process without overtly disrupting TEER-assessed barrier properties under the present in vitro conditions. These observations support further pharmacological characterization of clazosentan as a modulator of pericyte ET-1 responses.},
}

@article {pmid42654104,
year = {2026},
author = {Farias, G and Chahinian, H and Hauchard, N and Brunet, D and Fantini, J and Yahi, N and Fantini, D and Aulas, A},
title = {An Optimal Spray Device for the Nose-to-Brain Delivery of AmyP53, an Adaptive Therapeutic Peptide for Alzheimer's and Parkinson's Diseases.},
journal = {Pharmaceutics},
volume = {18},
number = {8},
pages = {},
doi = {10.3390/pharmaceutics18080987},
pmid = {42654104},
issn = {1999-4923},
abstract = {Background: Nose-to-brain delivery offers a noninvasive route to bypass the blood-brain barrier for the treatment of neurodegenerative diseases. AmyP53 is a first-in-class adaptive 12-mer peptide that prevents the formation of neurotoxic amyloid oligomers by competitively targeting lipid raft gangliosides on brain cell membranes, thereby blocking the shared pathological mechanism underlying both Alzheimer's and Parkinson's diseases. Objective: Here, we report the identification of optimal spray devices for the nose-to-brain delivery of AmyP53, ahead of a planned Phase 1 clinical trial. Method/Results: Among six devices evaluated (four commercial systems and two novel devices specifically engineered for nose-to-brain delivery), two systems were identified as optimal for further clinical development (narrower plume angles and significantly higher deposition in the olfactory region): the Neurospray™ and Neurospray™ Preservative-Free (PF). AmyP53 was quantitatively and reproducibly delivered by both Neurospray™ systems, retaining full recognition of its therapeutic target (gangliosides), as assessed by a surface pressure-based ganglioside-binding assay. In a rabbit preclinical model, intranasal administration of AmyP53 with the Neurospray™ resulted in rapid and sustained brain delivery, detectable at 10 min and persisting at 24 h post-administration, without significant systemic exposure. Conclusions: These results validate the Neurospray™ drug delivery systems as optimal drug delivery systems for the clinical development of AmyP53.},
}

@article {pmid42654155,
year = {2026},
author = {Al Kabbani, MA and Köhler, L and Wied, T and Adam, D and Klimek, J and Zempel, H},
title = {Targeting TTLL1 Alleviates Aβ-Induced Microtubule Disruption and TAU Pathology in Human iPSC-Derived Cortical Neurons.},
journal = {Pharmaceutics},
volume = {18},
number = {8},
pages = {},
doi = {10.3390/pharmaceutics18081038},
pmid = {42654155},
issn = {1999-4923},
support = {22039//Alzheimer Forschung Initiative/ ; },
abstract = {Background: Microtubules play a crucial role in neuronal structure and function, with their stability and dynamics regulated by posttranslational modifications (PTMs) such as polyglutamylation. In Alzheimer's disease (AD), the microtubule-associated protein TAU becomes mislocalized into the somatodendritic compartment ('TAU missorting'), dissociates from microtubules, aggregates into neurofibrillary tangles, and contributes to microtubule destabilization and neuronal death. Objectives and Methods: Here, we investigated the role of tubulin tyrosine ligase-like proteins (TTLLs) in TAU missorting and microtubule dysregulation using human-induced pluripotent stem cell (hiPSC)-derived cortical neurons treated with oligomeric amyloid-beta (oAβ) to replicate AD-like conditions. TTLL1, TTLL4, and TTLL6 were selectively knocked down (KD) to assess their impact on TAU missorting and microtubule stability. Fluorescence resonance energy transfer (FRET) microscopy was used to examine proximities between TAU and TTLL proteins. Results: We observed TAU missorting, increased tubulin polyglutamylation, decreased tubulin acetylation associated with microtubule destabilization, and synaptic declustering in oAβ-treated neurons. TTLL1 KD significantly reduced TAU missorting, tubulin polyglutamylation, and synaptic disintegration, while TTLL4 KD showed moderate effects, and TTLL6 KD restored microtubule acetylation. Importantly, TTLL KD did not impair neuritic networks, dendritic complexity, or neuronal activity. FRET microscopy in HEK293T cells revealed a close molecular proximity between TAU and TTLL1 consistent with a potential direct or complex-mediated association, but not with other TTLLs, suggesting a direct role of TTLL1 in TAU-mediated toxicity. Conclusions: Our findings identify TTLL1 as a promising therapeutic target for limiting TAU-associated cytoskeletal pathology in AD. These results support further development of pharmacological or genetic strategies targeting TTLL1 as a disease-modifying approach for AD and related tauopathies.},
}

@article {pmid42654172,
year = {2026},
author = {Blagojevic Castro, C and Gardener, SL and Jahan, F and Chen, J and Brown, BM and Loo, RL and Taddei, K and Rainey-Smith, SR and Weinborn, M and Reis, ACRD and Garg, ML and Martins, RN and Sohrabi, HR},
title = {Dietary Patterns and Cognitive Decline in Older Adults: Findings from the Western Australia Memory Study.},
journal = {Nutrients},
volume = {18},
number = {16},
pages = {},
doi = {10.3390/nu18162592},
pmid = {42654172},
issn = {2072-6643},
support = {#324100//Department of Jobs, Tourism, Science and Innovation/ ; },
mesh = {Humans ; Female ; Male ; Aged ; Western Australia ; *Diet, Western/adverse effects ; Apolipoprotein E4/genetics ; *Cognitive Dysfunction/genetics/prevention & control/epidemiology/psychology ; *Cognition ; Neuropsychological Tests ; Aged, 80 and over ; Longitudinal Studies ; Alzheimer Disease/genetics ; Risk Factors ; Memory ; Genotype ; Genetic Predisposition to Disease ; *Diet ; *Feeding Behavior ; },
abstract = {BACKGROUND: Preventive strategies, including adherence to specific dietary patterns, have received increasing attention as approaches to reduce cognitive decline and dementia risk. However, findings remain inconsistent, partly due to differences in dietary assessment methods, cognitive outcomes, and THE consideration of genetic susceptibility factors such as apolipoprotein E (APOE) genotype.

METHODS: This study examined associations between dietary patterns and longitudinal cognitive change in 185 older adults without dementia from the Western Australia Memory Study. Participants completed a food frequency questionnaire at baseline and underwent comprehensive neuropsychological assessments at baseline and up to five follow-up visits at 18-month intervals. Composite scores were generated for six cognitive domains and the Preclinical Alzheimer's Cognitive Composite (PACC).

RESULTS: Western and Prudent dietary pattern scores were analysed using linear mixed-effects models stratified by APOE ε4 carrier status. Among APOE ε4 carriers, greater adherence to a Western dietary pattern was associated with a faster decline in attention (p = 0.016), whereas no significant associations were observed for the Prudent dietary pattern or among APOE ε4 non-carriers. This association was attenuated after excluding participants with possible baseline cognitive impairment (MoCA < 23).

CONCLUSION: These findings suggest that adherence to a Western dietary pattern may accelerate cognitive decline in individuals genetically at risk for Alzheimer's disease, highlighting the importance of considering gene-diet interactions when developing dietary strategies for dementia prevention.},
}

Humans
Female
Male
Aged
Western Australia
*Diet, Western/adverse effects
Apolipoprotein E4/genetics
*Cognitive Dysfunction/genetics/prevention & control/epidemiology/psychology
*Cognition
Neuropsychological Tests
Aged, 80 and over
Longitudinal Studies
Alzheimer Disease/genetics
Risk Factors
Memory
Genotype
Genetic Predisposition to Disease
*Diet
*Feeding Behavior

@article {pmid42654386,
year = {2026},
author = {Rus Prelog, P and Zupan, M and Šabović, M and Frol, S and Kramberger, MG},
title = {Beyond Amyloid: Systemic and Brain Frailty as Determinants of Response to Anti-Amyloid Therapy in Alzheimer's Disease-A Conceptual Review.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {8},
pages = {},
doi = {10.3390/medicina62081489},
pmid = {42654386},
issn = {1648-9144},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/complications ; *Frailty/physiopathology/complications ; *Brain/physiopathology ; Antibodies, Monoclonal/therapeutic use ; Biomarkers/analysis ; Aged ; Magnetic Resonance Imaging/methods ; *Amyloid ; },
abstract = {Anti-amyloid therapy (AAT) with monoclonal antibodies (mAbs) modestly slow cognitive and functional decline in early Alzheimer's disease (AD). However, both the magnitude of clinical benefit and the risk of treatment-related complications vary substantially even among patients with similar biomarker profiles. Frailty, both brain and systemic, is highly prevalent in older adults with AD and affects a large proportion of those considered for AAT. Despite this, it has been largely absent from current decision frameworks. Brain frailty, defined by structural and microvascular damage (e.g., small-vessel disease, microbleeds, and atrophy), limits the clinical benefit of amyloid clearance and increases susceptibility to amyloid-related imaging abnormalities. In contrast, systemic frailty, reflecting reduced physiological reserve, mainly affects treatment tolerance and recovery from adverse events. In this narrative, conceptual review, we synthesize evidence that both forms of frailty act as biologically grounded modifiers of AAT efficacy and safety and may limit the clinical benefit while increasing susceptibility to complications and decompensation. Importantly, the precise empirical thresholds at which frailty begins to exert harmful effects remain unknown. We further outline how MRI-based markers of brain frailty, combined with brief systemic frailty measures, could support risk stratification, patient selection, monitoring intensity, and shared decision-making, including deferring treatment when the benefit-risk balance is unfavorable, while avoiding exclusion of patients who may still benefit. Taken together, we propose that future studies should incorporate frailty measures and perform precise assessments of both brain and systemic frailty, as this may improve patient stratification and better characterize the effects of AAT.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology/complications
*Frailty/physiopathology/complications
*Brain/physiopathology
Antibodies, Monoclonal/therapeutic use
Biomarkers/analysis
Aged
Magnetic Resonance Imaging/methods
*Amyloid

@article {pmid42654447,
year = {2026},
author = {Beg, MMA and Aalilil, M and Mishra, AK and Baek, KH and Vinayagam, R},
title = {Mechanisms of Forgetting: A Systematic Review of Neurocognitive and Clinical Determinants.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {8},
pages = {},
doi = {10.3390/medicina62081550},
pmid = {42654447},
issn = {1648-9144},
mesh = {Humans ; Stress Disorders, Post-Traumatic/psychology ; *Memory Disorders/physiopathology/psychology ; Major Depressive Disorder/psychology ; Memory/physiology ; Executive Function/physiology ; },
abstract = {Background and Objectives: Forgetting has been a passive process of memory failure; an active and controlled neurocognitive process is critical for cognitive efficiency, goal-directed behaviors, and emotional coping. This systematic review aims to provide a human-based summary of the scientific understanding of forgetting from neurobiological and psychological perspectives. Materials and Methods: A literature review from 2000 - 2025 was performed using PubMed/MEDLINE, PsycINFO, and Scopus. Original peer-reviewed human-based studies that used behavioral tasks, neuroimaging methods, electroencephalography, and physiological stress inductions were considered. Results: Active control processes have been identified in the forgetting paradigm, and intentional forgetting involved prefrontal-hippocampal downregulation, whereas unintentional forgetting occurred due to limited resources, interference, and competition at the stage of information retrieval. Stress-induced disruption of the ability to recall memories operated specifically via executive and inhibitory functions. Pathological forgetting in mild cognitive impairment was explained by encoding impairments and poor consolidation, but not by accelerated long-term decay. Post-Traumatic Stress Disorder (PTSD) and Major Depressive Disorder (MDD) featured pathological forgetting associated with decreased specificity, negative bias, and poor prefrontal-medial temporal lobe inhibition, resulting in asymmetrical memory retention. Forgetting has been recognized as a dynamic and multidetermined process, which involves executive control, hippocampal-cortical interactions, and emotional modulation. Different pathologies of forgetting occur depending on the disrupted domain, indicating that differential forgetting patterns specific to particular domains, such as encoding failures in Mild Cognitive Impairment (MCI) and inhibitory deficits in PTSD, may have implications for differential diagnoses and interventions. Conclusions: Executive and emotion-regulatory dysfunction leads to maladaptive forgetting and is characterized by less specificity, more interference, and weaker inhibition. Disrupted hippocampal amygdalar prefrontal networks, in disorders like PTSD and MDD, disrupt memory suppression, resulting in intrusive emotional memories with loss of context.},
}

Humans
Stress Disorders, Post-Traumatic/psychology
*Memory Disorders/physiopathology/psychology
Major Depressive Disorder/psychology
Memory/physiology
Executive Function/physiology

@article {pmid42654512,
year = {2026},
author = {Görgülü, FF and Görgülü, O},
title = {Olfactory Bulb and Gyrus Rectus Volumes in Alzheimer's Disease: Associations with Eating Disturbances.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {8},
pages = {},
doi = {10.3390/medicina62081615},
pmid = {42654512},
issn = {1648-9144},
mesh = {Humans ; *Alzheimer Disease/complications/physiopathology/pathology ; Female ; Male ; *Olfactory Bulb/pathology/physiopathology/diagnostic imaging ; Case-Control Studies ; Aged ; Magnetic Resonance Imaging/methods ; Retrospective Studies ; *Feeding and Eating Disorders/etiology ; ROC Curve ; Aged, 80 and over ; Organ Size ; },
abstract = {Background and Objectives: Olfactory dysfunction is an early non-cognitive feature of Alzheimer's disease (AD). The volumetric behavior of olfactory and related frontal structures and their link to eating disturbances remains unclear; we therefore compared olfactory bulb (OB) and gyrus rectus (GR) volumes between patients with AD and controls and examined their relationship with eating disturbances and their diagnostic value. Materials and Methods: In this single-center, retrospective, case-control study, 135 patients with AD and 49 age-matched controls underwent 3-Tesla MRI. Right, left, and total OB and GR volumes were measured. Groups were compared using the Mann-Whitney U test; age- and sex-adjusted logistic regression and receiver operating characteristic (ROC) analyses were performed; and OB and GR volumes were compared according to eating disturbance status in patients with AD, with adjustment for age and sex. p-Values were corrected for multiple comparisons using the Benjamini-Hochberg false discovery rate procedure. Results: All OB and GR volumes were significantly lower in patients with AD compared to controls (all p < 0.001), with the total OB volume nearly half that of the controls. Among patients with AD, all OB volumes were significantly lower in those with eating disturbances (all p < 0.001) and remained independently associated after adjustment for age and sex, whereas none of the GR volumes was significantly associated with eating disturbance status after adjustment. In adjusted models, every volumetric measure was independently associated with AD (all p < 0.001). The total OB volume showed the best diagnostic performance (AUC 0.940; sensitivity 0.82; specificity 0.98), while GR volumes performed less well (AUC 0.78-0.84). Conclusions: AD is associated with marked OB and GR atrophy. OB volume was associated with eating disturbances and discriminated AD from controls with high accuracy, supporting OB volumetry as an accessible candidate imaging marker that warrants prospective validation.},
}

Humans
*Alzheimer Disease/complications/physiopathology/pathology
Female
Male
*Olfactory Bulb/pathology/physiopathology/diagnostic imaging
Case-Control Studies
Aged
Magnetic Resonance Imaging/methods
Retrospective Studies
*Feeding and Eating Disorders/etiology
ROC Curve
Aged, 80 and over
Organ Size

@article {pmid42655419,
year = {2026},
author = {D'Alessandro, VI and Attivissimo, F and Basileo, T and De Palma, L and Lanzolla, AML and Di Nisio, A and The Alzheimer's Disease Neuroimaging Initiative, },
title = {Feature Selection Analysis and Robustness to Missing Data for Sensor-Based Prognostic Modeling of Alzheimer's Disease Progression.},
journal = {Sensors (Basel, Switzerland)},
volume = {26},
number = {16},
pages = {},
doi = {10.3390/s26165109},
pmid = {42655419},
issn = {1424-8220},
support = {CN000013//European Union/ ; },
mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging/pathology ; Humans ; Prognosis ; Disease Progression ; Neuroimaging ; Prediction Algorithms ; Algorithms ; Predictive Learning Models ; },
abstract = {Feature selection (FS) plays a critical role in sensor-based predictive modeling for Alzheimer's disease (AD), where heterogeneous clinical and neuroimaging measurements generate high-dimensional data with varying degrees of missingness due to incomplete clinical assessment of patients. Effective dimensionality reduction is essential to improve model interpretability, robustness, and generalization performance in sensor-driven healthcare applications. However, a systematic analysis of the interplay between FS strategies, missing-data handling, and prognostic modeling in sensor-derived AD data remains underexplored. In this study, we present a comprehensive and methodologically rigorous evaluation framework for AD prediction using multimodal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We jointly investigate multiple FS techniques and prognostic models on imputed datasets, systematically varying the number of top-ranked features. To ensure robustness, a K-fold cross-validation (CV) procedure is adopted and only features consistently selected across folds (intersection-based stability criterion) are retained. These stable feature subsets are subsequently evaluated on a test set. To further assess robustness to incomplete sensor measurements, we conduct a sensitivity analysis by varying the tolerated missingness thresholds for feature inclusion, reflecting realistic scenarios of incomplete clinical data availability. In this phase, XGBoost is employed both as a prognostic model and as an embedded FS method, exploiting its native capability to handle missing values and to provide feature-importance rankings based on predictive contribution. The proposed framework enables a systematic assessment of FS stability, predictive performance, and resilience to missing sensor data. Results provide practical methodological guidelines for the development of reliable and generalizable sensor-driven prognostic models for AD in real-world clinical environments.},
}

*Alzheimer Disease/diagnosis/diagnostic imaging/pathology
Humans
Prognosis
Disease Progression
Neuroimaging
Prediction Algorithms
Algorithms
Predictive Learning Models

@article {pmid42655528,
year = {2026},
author = {Liu, S and Wu, H and Sun, C and Qiu, Y and Wu, H and Wei, Y and Lv, Y and Yang, Z},
title = {Topological Data Analysis-Driven fNIRS Signal Processing for Alzheimer's Disease Stage Identification.},
journal = {Sensors (Basel, Switzerland)},
volume = {26},
number = {16},
pages = {},
doi = {10.3390/s26165221},
pmid = {42655528},
issn = {1424-8220},
support = {2026YFHZ0021//Science and Technology Department of Sichuan Province/ ; },
mesh = {*Alzheimer Disease/diagnosis ; Humans ; Spectroscopy, Near-Infrared/methods ; *Signal Processing, Computer-Assisted ; Brain ; Algorithms ; },
abstract = {This paper proposes a novel Topological Data Analysis (TDA) pipeline to extract robust structural features from functional near-infrared spectroscopy (fNIRS) signals for the classification of Alzheimer's Disease (AD) stages. Alzheimer's disease is increasingly understood as a disconnection syndrome, where the disruption of functional brain networks precedes gross anatomical atrophy. However, traditional graph-theoretic approaches rely on arbitrary connectivity thresholds, which can obscure critical multi-scale topological information, and are sensitive to noise. To address this, our framework leverages Persistent Homology (PH) to analyse the topological evolution of brain networks across a continuous range of scales. By modeling 48-channel hemoglobin concentration time-series as high-dimensional point clouds via Granger causality metrics, we construct filtration sequences of Vietoris-Rips complexes. The resulting topological invariants, including 0-dimensional connected components, 1-dimensional loops, and 2-dimensional voids, are first examined through Persistence Diagrams. For classification, significant H0 and H1 features are converted into Persistence Images using Gaussian kernel smoothing, while H2 features are retained for qualitative topological interpretation. This transformation enables the integration of complex topological features into standard machine learning workflows. Our experimental results were evaluated on a subject-level held-out test set consisting only of original, non-augmented recordings. Data augmentation was applied only to the training set to alleviate class imbalance. The proposed topology-driven feature extraction method achieved 86% accuracy in multi-class diagnosis (NC vs. MCI vs. AD). This study validates the efficacy of TDA as a sophisticated signal processing tool for revealing intrinsic neurodegenerative patterns in hemodynamic data, offering an exploratory methodological proof-of-concept for AD stage classification.},
}

*Alzheimer Disease/diagnosis
Humans
Spectroscopy, Near-Infrared/methods
*Signal Processing, Computer-Assisted
Brain
Algorithms

@article {pmid42655823,
year = {2026},
author = {Anghelinici, D and Musteata, M},
title = {qEEG and Functional Connectivity as a Translational Bridge Between Humans and Dogs in Epilepsy and Associated Disorders: From Spontaneous Model to Automatic Classification-An Integrative Review.},
journal = {Veterinary sciences},
volume = {13},
number = {8},
pages = {},
doi = {10.3390/vetsci13080803},
pmid = {42655823},
issn = {2306-7381},
abstract = {Quantitative electroencephalography (qEEG) converts the raw EEG signal into reproducible numerical descriptors (spectral power, hemispheric symmetry, coherence and signal complexity) and has emerged as a candidate translational biomarker linking human and canine neurology. This integrative review examined the diagnostic, prognostic, pharmacological and translational value of qEEG, with emphasis on functional connectivity, and assessed the comparability of the dog as a natural model of human disease. Seventy-five studies were included, spanning epilepsy, acute brain injury, neurodegeneration, rehabilitation and paroxysmal disorders. In both species, epilepsy was consistently associated with altered spectral power and with reduced or reorganized coherence, and interictal abnormalities were demonstrable even in the absence of visible epileptiform discharges. Dogs reproduced the human patterns closely: phenobarbital induced the spectral redistribution predicted by human pharmaco-EEG data, canine cognitive dysfunction reproduced the slowing and the sleep-architecture changes described in Alzheimer's disease, and a single machine-learning pipeline classified human and canine recordings with comparable accuracy. Conversely, acute brain injury remains virtually unexplored in the dog, and no canine normative database comparable to the human ones is yet available. The evidence was limited by heterogeneous acquisition protocols, small samples and scarce longitudinal veterinary data. qEEG, and coherence in particular, appears to be a promising cross-species biomarker of network dysfunction and supports the dog as a translational platform, although standardized validation remains necessary.},
}

@article {pmid42655989,
year = {2026},
author = {Sayyed, N and Afzal, M and Rafeeq, M and Omer, AB and Al-Abbasi, FA and Rahman, S and Al-Zharani, M and Alzarea, SI and Kazmi, I},
title = {Erucic acid arbitrates neuroprotection in streptozotocin-induced memory deficit via improving oxidative stress/neuroinflammatory indicators/cholinergic activity in rodents.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/1028415X.2026.2718394},
pmid = {42655989},
issn = {1476-8305},
abstract = {BACKGROUND: Erucic acid (EA), a monounsaturated omega-9 fatty acid derived from Raphanus sativus L. seeds, has antioxidant and anti-inflammatory properties. This study investigated its neuroprotective effects against streptozotocin (STZ)-induced diabetes-associated cognitive dysfunction in rats.

METHODS: Male Wistar rats were randomly assigned to five groups: normal control, STZ control (60 mg/kg), STZ + EA (10 mg/kg), STZ + EA (20 mg/kg), and EA (20 mg/kg) per se. EA was administered orally for 38 days. Blood glucose and body weight were measured before STZ administration and at the end of the study. Cognitive function was assessed using the Y-maze and Morris water maze (MWM). Cholinergic function, oxidative stress, neurotransmitters, inflammatory mediators, apoptosis, and cellular energy status were evaluated biochemically, and hippocampal histopathology was performed.

RESULTS: EA treatment significantly reduced hyperglycemia and attenuated diabetes-induced body weight loss. EA improved spontaneous alternation in the Y-maze and spatial learning and memory in the MWM, reducing escape latency and increasing target-quadrant time. EA decreased acetylcholinesterase activity while increasing choline acetyltransferase activity, restored antioxidant defenses, and reduced MDA, ROS, and NO levels. It also normalized neurotransmitter levels, suppressed TNF-α, IL-1β, IL-6, NF-κB, and caspase-3, increased IL-10, and improved the ATP/ADP ratio. Histopathology demonstrated preservation of hippocampal neuronal architecture.

CONCLUSIONS: EA ameliorated diabetes-associated cognitive dysfunction by improving learning and memory, preserving cholinergic neurotransmission, reducing oxidative stress and neuroinflammation, inhibiting neuronal apoptosis, and restoring cellular energy metabolism. These findings support the therapeutic potential of EA for managing cognitive impairment associated with diabetes.},
}

@article {pmid42656103,
year = {2026},
author = {Chen, Y and Yao, C and Yan, F and Xiao, P and Lu, X},
title = {[Noninvasive nanosecond transcranial pulsed electric fields: deep-penetrating, high-field stimulation for suppressing hippocampal amyloid-β and improving cognitive function in an Alzheimer's disease model].},
journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi},
volume = {43},
number = {4},
pages = {718-728},
pmid = {42656103},
issn = {1001-5515},
mesh = {Animals ; *Alzheimer Disease/therapy/metabolism ; *Hippocampus/metabolism ; *Amyloid beta-Peptides/metabolism ; Mice ; Disease Models, Animal ; *Cognition ; *Transcranial Direct Current Stimulation/methods ; Cognitive Enhancement ; Male ; },
abstract = {Abnormal deposition of amyloid-β (Aβ) in the deep-brain hippocampus can impair synaptic transmission and disrupt neural network activity, thereby inducing learning and memory deficits and accelerating cognitive decline in Alzheimer's disease (AD). Therefore, reducing hippocampal Aβ deposition is an important strategy for delaying AD progression. Existing transcranial electrical stimulation methods are limited by safety thresholds and are difficult to achieve effective field strength in deep brain regions under noninvasive conditions, thus failing to effectively intervene in hippocampal Aβ deposition. Nanosecond pulsed electric fields, which contain abundant high-frequency components and exhibit stronger transcranial penetration capability, may overcome this limitation. In this study, nanosecond transcranial pulsed electric field stimulation (ns-tPFS) was applied with parameters of 500 ns band width, 500 V amplitude, and 5 Hz frequency in a five familial AD mutations (5xFAD) mouse model. First, finite element simulation was performed to determine that the electric field strength generated by ns-tPFS in the hippocampal region could reach 3 × 10 [4] V/m. Then, molecular dynamics simulation was used to evaluate the disruptive effect of this field strength on the structural stability of Aβ multimers. Subsequently, Morris water maze and Y-maze behavioral tests, together with immunofluorescence detection, were conducted to assess the intervention effects of ns-tPFS on animal cognitive function and hippocampal Aβ deposition. The results showed that, under the above stimulation parameters, ns-tPFS could disrupt the structure of Aβ multimers, markedly reduce hippocampal Aβ deposition in 5xFAD mice, and effectively improve their cognitive function. In summary, this study demonstrates, from animal simulations and experiments, the feasibility of ns-tPFS for improving AD symptoms and provides a new research perspective and experimental basis for the noninvasive intervention of hippocampal Aβ pathology.},
}

Animals
*Alzheimer Disease/therapy/metabolism
*Hippocampus/metabolism
*Amyloid beta-Peptides/metabolism
Mice
Disease Models, Animal
*Cognition
*Transcranial Direct Current Stimulation/methods
Cognitive Enhancement
Male

@article {pmid42656334,
year = {2026},
author = {Gallmetzer, E and Mak, E and Kara, F and Zeydan, B and Kapoor, E and Shufelt, CL and Rocca, WA and Kantarci, K},
title = {Premature and early menopause and neuroimaging biomarkers of neurodegenerative diseases: a systematic review.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1912295},
pmid = {42656334},
issn = {2813-3919},
abstract = {BACKGROUND: Premature and early menopause involve ovarian hormone deprivation, which may contribute to later-life vulnerability to cognitive decline and neurodegenerative diseases. Multimodal neuroimaging biomarkers provide a means of detecting structural, microstructural, functional, and molecular brain changes before clinical symptoms emerge.

METHODS: Following PRISMA guidelines, we conducted a systematic search of PubMed. Study quality was assessed using the Newcastle-Ottawa Scale.

RESULTS: Neuroimaging modalities included in vivo structural magnetic resonance imaging (MRI) (n = 16), functional MRI (n = 2), diffusion tensor imaging (n = 4), and positron emission tomography (n = 3). Women with premature or early menopause showed regionally specific structural and microstructural brain abnormalities, including lower gray-matter volume or cortical thickness in medial temporal, frontal, and basal forebrain regions; white-matter microstructural abnormalities in the anterior corona radiata, corpus callosum, and fronto-occipital tracts; and reduced posterior hippocampal activation during memory encoding. In one study, earlier age at menopause was associated with higher amyloid-β (Aβ) burden in women who underwent premenopausal bilateral oophorectomy (PBO), and elevated tau deposition was reported predominantly among women with higher Aβ levels.

CONCLUSION: Converging multimodal neuroimaging evidence suggests that premature and early menopause may be associated with Alzheimer's disease-relevant brain changes. However, findings remain heterogeneous, and longitudinal studies are needed to clarify the temporal relationships between ovarian hormone deprivation and neurodegeneration, and to determine the clinical implication of these findings.},
}

@article {pmid42656410,
year = {2026},
author = {Gao, P and Chu, Y and Geng, M and Tian, N and Chen, D and Si, Y and Liu, H and Wang, P and Cao, J},
title = {Joint effects of leukocyte-albumin ratio and hypertension are associated with multidimensional cognitive decline and Alzheimer's disease risk in older adults: evidence from NHANES and a clinical AD validation cohort.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1826100},
pmid = {42656410},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) pathogenesis involves complex interactions between neuroinflammation and vascular dysfunction. While leukocyte-albumin ratio (LAR) and hypertension are independently linked to cognitive decline, their joint associations with multidimensional cognitive impairment and AD risk remain understudied.

METHODS: We analyzed two cohorts: 1,300 adults (≥ 60 years) from NHANES 2011-2014, and a clinical cohort (50 AD patients + 125 age-/gender-matched controls). LAR was calculated, hypertension was defined as per JNC7 criteria, and cognitive function was assessed via AD-sensitive tests standardized to z-scores. Restricted cubic spline (RCS) regression, multivariable linear regression, subgroup analysis, and Cox regression were used to examine LAR, hypertension, and their combined associations with cognitive outcomes.

RESULTS: In the NHANES cohort, LAR was significantly correlated with DSST performance; participants with co-occurring high LAR + hypertension had lower scores across three cognitive domains, with age- (65-74 years) and sex-specific patterns and a 2.17-fold higher all-cause mortality risk. In the validation cohort, AD patients had higher LAR, with the highest LAR quartile linked to a 3.92-fold increased AD risk (p = 0.015).

CONCLUSION: Our findings support an association between LAR, hypertension, and cognitive decline. Elevated LAR in conjunction with hypertension is associated with poorer cognitive performance across multiple domains in older adults, as observed in both the NHANES and a clinical AD cohort. As a low-cost, easily measurable biomarker, LAR may hold promise for early AD risk stratification in primary care, highlighting a potential target for combined anti-inflammatory and antihypertensive interventions. However, its modest discriminative ability (AUC = 0.61) indicates that LAR should not be used as a standalone diagnostic tool. Prospective longitudinal studies are warranted to validate these associations.},
}

@article {pmid42656493,
year = {2026},
author = {Mukwaya, A and Yin, Z and Yarcusko, R and Baldwin, G and Uddin, N and Venkat, H and Xue, Y and Van Arnam, NS and Kam, HT and Chen, DF and Krasemann, S and Lennikov, A and Margeta, MA},
title = {Assessing microglial phagocytosis of apoptotic neurons in vitro: a multimodal approach.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1813556},
pmid = {42656493},
issn = {1662-4548},
abstract = {Microglia are the resident immune cells of the central nervous system, responsible for defending against infections, responding to tissue damage, and maintaining homeostasis. Dysregulation of their phagocytic activity has been implicated in many neurodegenerative diseases of the brain and the eye, including Alzheimer's disease, multiple sclerosis, glaucoma, and age-related macular degeneration. Past work has shown that brain and retinal microglia switch to a disease-associated molecular phenotype (DAM) following phagocytosis of apoptotic neurons in vivo, but it is technically challenging to perform these assessments and isolate phagocytic cells for downstream analysis. Although several protocols exist for isolating and culturing microglia to evaluate their phagocytic activity in vitro, these approaches often fail to mimic the pathophysiology of neurodegeneration, where dysregulated phagocytosis of damaged or apoptotic neurons is a key feature. Here we describe a protocol for evaluating phosphatidylserine-mediated phagocytosis by primary mouse brain microglia in vitro. The procedure involves isolating primary mouse brain microglia, inducing apoptosis in a feeder neuronal cell line, labeling apoptotic cells with a fluorescent dye, feeding the labeled cells to the microglia, and analyzing phagocytosis using several complementary approaches. This protocol enables an accessible and high-throughput assessment of microglial phagocytic activity using a biologically relevant stimulus, offering improved insights into the regulation of this critical immune process in a disease-relevant context.},
}

@article {pmid42656509,
year = {2026},
author = {He, Y and Shi, Y and Hu, J and Wang, X and Su, J and Yang, Z and Zhang, Z and Liao, S and Lu, X and Zhu, X},
title = {MTHFR C677T and A1298C polymorphisms in dementia susceptibility: evidence from a meta-analytic investigation with disease-specific and ethnicity-stratified analyses.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1858837},
pmid = {42656509},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) and vascular dementia (VaD) have become significant global health challenges. Recent research evidence indicates a close comorbidity between AD and cerebral small vessel disease. The C677T (rs1801133, also known as c.665C > T) and A1298C (rs1801131) polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene have been associated with both conditions, though conclusions vary across studies.

METHODS: We conducted a systematic search of PubMed, Embase, Web of Science and the Cochrane Library, covering the period from the inception of these databases to January 2026. Studies reporting the distribution of MTHFR C677T and/or A1298C genotypes were included. A fixed-effects model was used to calculate the pooled odds ratio (OR) and its 95% confidence interval (CI). Sensitivity analyses using random-effects models were also performed to test the robustness of the findings. Subgroup analyses were performed according to type of dementia and ethnicity.

RESULTS: A total of 26 C677T studies and 8 A1298C studies were included. In the allele contrast model (T vs. C), C677T was significantly associated with dementia (OR = 1.40, 95% CI 1.05-1.87, p = 0.021) and AD (OR = 1.40, 95% CI 1.01-1.93, p = 0.043), but no statistically significant association was observed for VaD (OR = 1.42, 95% CI 0.76-2.66, p = 0.266). C677T showed no significant association under homozygous, heterozygous, dominant, or recessive inheritance models. No significant heterogeneity in association was observed across racial subgroups. A1298C showed no significant association with dementia under any genetic model.

CONCLUSION: This meta-analysis showed that the MTHFR C677T T allele is associated with the risk of AD in an allele-dependent model, with a similar but non-significant trend for VaD. The A1298C polymorphism shows no association with either type of dementia. These findings suggest that C677T genotyping may aid AD risk stratification in research, but it requires prospective validation and gene-environment studies before clinical use.},
}

@article {pmid42656566,
year = {2026},
author = {Phillips, WT and Schwartz, JG},
title = {The olfactory-glymphatic syndrome: linking smell dysfunction, cognitive impairment and sleep disturbances in neuropathological disorders.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1897376},
pmid = {42656566},
issn = {1662-4548},
abstract = {Olfactory dysfunction is a common feature of several neuropathological disorders - including Alzheimer's and Parkinson's diseases - whose shared profile often includes glymphatic dysfunction, cognitive impairment, and sleep disturbances. Importantly, smell loss frequently precedes cognitive or motor symptoms by years, highlighting its potential as an early clinical marker. This article reviews mechanisms that may link olfactory dysfunction to disease development in a wide range of neuropathological diseases and advances a research-based hypothesis for a shared etiologic pathway underlying these overlapping symptoms. In particular, it examines metabolic syndrome as a possible upstream driver that promotes nasal turbinate vasodilation, disrupts nasal lymphatic drainage, and culminates in an olfactory-glymphatic syndrome. Integrating glymphatic imaging or assessment with olfactory testing, cognitive evaluation, and metabolic risk profiling - hypertension, diabetes mellitus, hyperlipidemia, and elevated body mass index - may enable earlier detection and open new avenues for prevention and novel therapeutic opportunities for neuropathological disorders.},
}

@article {pmid42656575,
year = {2026},
author = {Xu, Y and Guan, W and Yang, Y and Yang, Y and Xia, Y and Peng, Y},
title = {The delta-opioid receptor: a therapeutic target for Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1891339},
pmid = {42656575},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) presents a complex pathogenesis involving amyloid-β (Aβ) plaques, tau tangles, and neuroinflammation. Recent evidence highlights δ-opioid receptor (DOR) as a unique and promising therapeutic target for AD. This review summarizes current knowledge on DOR's multifaceted neuroprotective role in AD pathology. While its involvement in Aβ regulation appears context-dependent, DOR activation consistently attenuates tau hyperphosphorylation, modulates microglial dysfunction, suppresses harmful neuroinflammation and inhibits complement-mediated synaptic pruning. All these findings have been well documented in in vitro and in vivo AD animal models. Furthermore, preclinical findings from general depression and anxiety models indicate that selective DOR agonists could help alleviate neuropsychiatric symptoms like depression and agitation, which are commonly seen in AD. DOR-associated genetic markers have also shown AD diagnostic potential. We conclude that targeting DOR offers a novel and integrative strategy impacting key AD pathological hallmarks: Aβ, tau, and neuroinflammation, as well as managing cognitive and emotional symptoms. Future research should focus on elucidating precise molecular mechanisms and translating these findings into clinical applications for AD diagnosis and therapy.},
}

@article {pmid42656592,
year = {2026},
author = {Riedel, EO and Bongratz, F and Zott, B and Berberich, C and Eichinger, P and Yakushev, I and Grimmer, T and Wachinger, C and Hedderich, DM},
title = {Deep learning-based cortical thickness maps for diagnosis of neurodegenerative diseases: a rater study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70458},
pmid = {42656592},
issn = {2352-8729},
abstract = {INTRODUCTION: Cortical atrophy patterns on magnetic resonance imaging (MRI) are essential for diagnosing neurodegenerative diseases (NDs), but remain challenging to assess visually. Deep learning enables quantitative evaluation of cortical thickness (CTh) and z-score maps.

METHODS: 3T three-dimensional T1 MRI from 40 ND patients (Alzheimer's dementia, posterior cortical atrophy, behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia) and 10 controls were retrospectively analyzed. Cortical surfaces were extracted with FreeSurfer and registered to fsaverage, and z-score maps were generated using stochastic cortical self-reconstruction (SCSR). Three neuroradiologists rated CTh or z-score maps, each with or without 3D T1 for ND presence and differential diagnosis. Conventional 3D T1 served as baseline reading condition.

RESULTS: Diagnostic accuracy (Acc) was quantitatively highest for z-score maps with 3D T1 (Acc = 0.98) for the detection of ND, though it did not reach statistical significance. However, diagnostic confidence improved for z-score maps versus baseline 3D T1 (adjusted p = 0.017 for Rater 2). Inter-rater agreement improved from κ = 0.525 (baseline 3D T1) to κ = 0.792 (z-score with 3D T1).

DISCUSSION: SCSR-generated z-score maps show promise for diagnostic evaluation of ND.},
}