@article {pmid42361864,
year = {2026},
author = {Galushkin, A and Giladi, E and Gozes, I},
title = {Aging ADNP syndrome mice exhibit mutation/sex-dependent disruption of motor behavior and circadian rhythmicity.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107509},
doi = {10.1016/j.nbd.2026.107509},
pmid = {42361864},
issn = {1095-953X},
abstract = {Circadian disruption is an early and clinically relevant feature of Alzheimer's disease and related neurodegenerative conditions, yet the molecular determinants underlying its emergence remain incompletely understood. Activity-dependent neuroprotective protein (ADNP) is a key regulator of neurodevelopment and neuroprotection, with de novo mutations driving the neurodevelopmental ADNP syndrome tauopathy and with somatic mutations implicated in tauopathy and neurodegeneration in Alzheimer's disease, but its role in circadian system function has not been systematically explored. Here, with Alzheimer's disease being twice as prevalent in women, we performed a comprehensive characterization of circadian locomotor activity, explicitly considering sex as a biological variable in aged mouse models of ADNP disruption, representing two key phenotypes of the syndrome. Using recordings of voluntary wheel-running activity combined with cosinor-based rhythmometry, we quantified parameters of circadian organization, including activity levels, timing, and rhythm integrity. We demonstrate that ADNP haploinsufficiency with late tau deposition was associated with impaired circadian organization in a strongly sex-dependent manner. In Adnp[+/-] mice, circadian alterations diverged between sexes: males exhibited a pronounced reduction in overall activity levels and rhythmic output, whereas females showed alterations in circadian timing (phase shift), and increased waveform complexity, indicative of fragmented activity patterns. Notably, reduced rhythm robustness was observed in both sexes, pointing to impaired stability of circadian output. In contrast to Adnp[+/-] mice, mice carrying a heterozygous Adnp p.Tyr718* mutation (with early tauopathy) exhibited marked vulnerability only under a circadian challenge paradigm. This was characterized by a high incidence of arrhythmicity based on cosinor-based zero-amplitude testing, with a particularly severe phenotype in a small exploratory cohort of males, in which all examined Tyr718* mice failed to exhibit detectable circadian rhythmicity. Importantly, the study was conducted in aged mice, a context relevant to age-associated neurodegenerative vulnerability. These findings position ADNP as a contributor to circadian system stability and highlight its associated signaling pathways as candidate targets for future mechanistic and therapeutic investigation.},
}

@article {pmid42361954,
year = {2026},
author = {Roy, KK and Mehta, DK and Das, R},
title = {Pregnancy and Alzheimer's disease: Understanding maternal and neonatal neurological risks.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111808},
doi = {10.1016/j.pnpbp.2026.111808},
pmid = {42361954},
issn = {1878-4216},
abstract = {Alzheimer's disease (AD) is the foremost cause of dementia globally, marked by progressive neurological decline and cognitive impairment. Risk arises from complex interactions between genetic and environmental factors. This review examines how prenatal health influences long-term brain outcomes in both mothers and offspring. Pregnancy triggers significant hormonal, immunological, and physiological changes that support fetal development but also increase the risk of complications such as gestational diabetes and preeclampsia. These conditions promote chronic inflammation, vascular dysfunction, and brain alterations associated with AD and vascular dementia. Maternal cardiovascular and metabolic health critically affect neurodevelopment and cognitive aging across generations. Postpartum hormones, notably progesterone and estrogen, provide neuroprotective and anti-inflammatory effects that may mitigate neurodegeneration. Additionally, reproductive factors including parity and reproductive lifespan modulate women's risk of AD. The immune adaptations and inflammatory processes during pregnancy further contribute to neurodegenerative pathways. This review highlights the importance of optimizing maternal health, implementing early detection of cognitive risks, and fostering interdisciplinary collaboration to improve outcomes. Integrating obstetric, neurological, and psychiatric care can enhance prevention and management strategies. Ultimately, these insights underscore the need for public health initiatives targeting maternal and offspring brain health to reduce the burden of neurological diseases over the lifespan.},
}

@article {pmid42362005,
year = {2026},
author = {Jayaram, S and Easwaran, V and Selvaraj, D and Gunasekaran, V and Soumya, V and Thiruselvi, M and Laxmana Prasanth, M and Singh, S and Ellaiyarasu, C and Karthik Rai, P and Gokula Priyan, G and Thahideen, A and Sabarieshwaran, K},
title = {Apolipoprotein E in Alzheimer's disease: A review of APOE receptors, signalling pathways and therapeutic opportunities.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104108},
doi = {10.1016/j.mcn.2026.104108},
pmid = {42362005},
issn = {1095-9327},
abstract = {Apolipoprotein E, a glycoprotein, is one of the strongest genetic risk factors for late-onset Alzheimer's disease. APOE is involved in the transport and metabolism of cholesterol, phospholipids and other lipids, synaptic function and neuroinflammation in the CNS. One of the key functions of APOE is to bind and deliver newly synthesized cholesterol and lipids to neurons through receptor-mediated endocytosis (LDLR, LRP1, VLDLR, APOER2). The APOE gene exists in three common isoforms: APOE2, APOE3, and APOE4, with distinct structural and functional properties. The three isoforms of APOE vary in their potential to bind and transport lipids and cholesterol, receptor affinity and clearance of Aβ. Among the three isoforms, APOE4 is one of the strongest risk factors for late-onset Alzheimer's disease, while APOE2 exerts a protective role highlighting the functional divergence among isoforms in CNS physiology. The functions of APOE are exerted through binding of APOE with members of the low-density lipoprotein receptor (LDLR) family, including LDLR, LRP1, VLDLR, and APOER2. So, therapeutic approaches that potentiate the protective effects of APOE, like APOE mimetics, ABCA1 agonists, targeting APOE receptors like LDLR, LRP1, APOER2, and TREM2, might offer significant therapeutic benefits in Alzheimer's disease.},
}

@article {pmid42362040,
year = {2026},
author = {Xu, W and Cao, J and Liu, Y and Wei, Z and Zha, X and Xie, S and Liu, X and Wang, W and Zhang, C and , },
title = {LPI alleviates Alzheimer's disease pathology via the GPR55 receptor.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.035},
pmid = {42362040},
issn = {1873-7544},
abstract = {Lysophosphatidylinositol (LPI) is an endogenous GPR55 agonist, yet its role in Alzheimer's disease (AD) remains unclear. Here, we performed serum metabolomic profiling in 5xFAD mice and observed a reduction in multiple LPI species prior to the onset of overt Aβ pathology, and this decrease was further corroborated in human cohort samples. Exogenous LPI treatment reduced cerebral Aβ deposition, improved performance in learning and memory behavioral tasks, reduced pathological microglial aggregation, inhibited astrocyte proliferation, and ameliorated hippocampal oxidative stress. Mechanistically, administration of the GPR55 antagonist ML191 blocked the protective effects of LPI, while the GPR55 agonist O-1602 recapitulated these benefits, indicating that LPI acts through GPR55. Collectively, our findings suggest that reduced LPI represents an early metabolic vulnerability in the 5xFAD model and establish the LPI-GPR55 axis as a potential therapeutic target for early intervention in AD.},
}

@article {pmid42362042,
year = {2026},
author = {Ohno, M},
title = {Accelerated long-term forgetting and relevant biomarkers for early detection in preclinical Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.020},
pmid = {42362042},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) commences with the preclinical stage where individuals remain cognitively unimpaired but already have AD pathology. As fluid and neuroimaging biomarker research progresses, AD has become defined biologically rather than based on traditional clinical symptoms. While the diagnosis of AD has been conceptually advanced by the AT(N) classification framework according to core biomarker profiles of amyloid-β (A), tau (T) and neurodegeneration (N), solely relying on biological diagnosis at an asymptomatic stage has limitations with potential ethical and psychosocial issues. Accelerated long-term forgetting (ALF) characterized by higher forgetting rates over longer delays (a week to months) captures substantial interest as one of the sensitive mnemonic measures. Remarkably, ALF assays have been increasingly applied to detecting subtle cognitive declines in preclinical AD individuals who are still normal on standard memory tests, which typically use ∼ 30 min delays to assess classical hippocampal amnesia. The findings suggest that ALF may reflect the impairment of systems memory consolidation, a process that is required to gradually transform memory traces temporarily stored in the hippocampus into cortical networks for long-term storage. This review provides an overview of recent progress in ALF research including the underlying mechanisms and fluid-based or brain imaging biomarkers, which have been explored not only in individuals at risk for developing AD but also in relevant animal models. The findings have important implications for how we can optimize the earlier and precise identification of patients at a preclinical stage of AD that is essential for designing effective preventive interventions.},
}

@article {pmid42362520,
year = {2026},
author = {Zheng, X and Feng, H and Ren, L and Zhang, Y},
title = {Multi-ancestry multi-trait analysis reveals shared genetics across major psychiatric disorders and Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04213-0},
pmid = {42362520},
issn = {2158-3188},
abstract = {The clinical overlap between major psychiatric disorders (MPDs) and Alzheimer's disease (AD) implicates complex shared etiology. Previous studies demonstrated that both diseases are genetically complex and highly heritable, suggesting that more endeavors are necessary to be made from the very bottom to understand their genetic basis. With the advance of post-genomic analysis, multi-ancestry meta-analysis allows the generalizability of the genetic architecture across different populations to uncover ancestry-specific variants, while multi-trait analysis enables the discovery of the co-colocalized risk genomic regions across diseases. Therefore, in this study, we leveraged published GWAS summary statistics from European, East Asian, Hispanic and African American populations to report schizophrenia, major depressive disorders, and Alzheimer's disease risk loci and further fine-mapping to credible sets with >95% PP inclusion of the causal variant. We distilled 2871 potential traits from publicly available and found 134 traits significantly genetically correlated with both MPDs and AD using batch LD score regression. We then prioritized the identified loci from multi-ancestry results for cross-trait colocalization analysis to assess shared genetic etiology and further nominated 2 colocalized loci across both conditions, including rs2532240 and rs6504163. In the end, we finalized our analysis by validation and functional inference of the underlying susceptibility genes as well as putative mechanisms using evidence from multiple resources, including FIVEx, Open Targets, and scQTLbase.},
}

@article {pmid42362546,
year = {2026},
author = {Vemuganti, V and Kang, JW and Zhang, Q and McGregor, ER and Hilser, JR and Aquino-Martinez, R and Harding, S and Harpt, JL and Beck, KR and Bussan, H and Kuehn, JF and Deming, Y and Studer, R and Johnson, SC and Asthana, S and Zetterberg, H and Blennow, K and Engelman, CD and Allayee, H and Anderson, RM and Ulland, TK and Bäckhed, F and Bendlin, BB and Rey, FE},
title = {Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-74744-z},
pmid = {42362546},
issn = {2041-1723},
abstract = {The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer's disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3β inhibition. Together, this study links ImP to hallmarks of neurodegeneration and suggests that targeting ImP may represent a potential strategy to modify ADRD risk.},
}

@article {pmid42362551,
year = {2026},
author = {Huang, Y and Xie, X and Huang, Z and Chen, R and Gangal, H and Wang, X and Souza, K and Hunter, J and Wu, X and Reddy, DS and Chin, J and Wang, J},
title = {Early-Stage Corticostriatal Hyperactivity Impairs Cognitive Flexibility Alongside Striatal Cholinergic Dysfunction in an Alzheimer's Disease Model.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-74817-z},
pmid = {42362551},
issn = {2041-1723},
support = {R01AA027768//U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA)/ ; U01AA025932//U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA)/ ; },
abstract = {Cognitive flexibility declines early in Alzheimer's disease, yet the underlying circuit mechanisms remain unknown. Here, we report that young 5xFAD mice exhibit deficits in instrumental reversal learning prior to spatial memory impairment. This behavioral inflexibility is associated with abnormal neuronal reactivation in the medial prefrontal cortex and dorsomedial striatum. Electrophysiological recordings reveal that medial prefrontal cortex neurons are hyperexcitable and receive increased excitatory input. Furthermore, glutamatergic transmission from the medial prefrontal cortex to striatal direct-pathway medium spiny neurons is enhanced and coincides with strengthened inhibitory transmission onto striatal cholinergic interneurons, reduced spontaneous firing, and diminished striatal acetylcholine release. Critically, sustained chemogenetic inhibition of this corticostriatal circuit attenuates cortical amyloid accumulation, reduces glutamatergic transmission, and increases acetylcholine levels. This also rescues reversal learning deficits in 5xFAD mice. Here, we show that pathological corticostriatal hyperactivity contributes to early cognitive inflexibility in a mouse model of Alzheimer's disease.},
}

@article {pmid42362650,
year = {2026},
author = {Ren, J and Yin, R and Zhao, J and Liu, J},
title = {Novel Alzheimer's disease-associated variants and genetic interactions identified from UK biobank whole-exome sequencing data using IBI-DT.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-58159-w},
pmid = {42362650},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) is a highly heritable neurodegenerative disorder whose genetic architecture remains incompletely understood, particularly with respect to rare variants and higher-order interactions. We applied Individualized Bayesian Inference-Decision Tree (IBI-DT) to 790,000 whole-exome sequencing variants from 8,292 unrelated White British individuals in the UK Biobank, using genome-wide association analysis (GWAS) based on Fisher's exact test as a marginal association comparator and evaluated the findings in an independent ADSP-Discovery ICE cohort of 1,560 unrelated individuals with 852,997 variants. In the discovery cohort, IBI-DT identified 178 significant variants using empirical null calibration, which mapped to 173 genes, whereas GWAS identified 16 significant variants that mapped to four genes. Compared with GWAS, IBI-DT prioritized more rare variants among the top 178 signals (147 vs. 66 with minor allele frequency ≤ 0.01) and identified variants with less correlated, less redundant linkage patterns. The IBI-DT-prioritized variants included established AD genes as well as additional biologically supported genes not prioritized by GWAS. Replication supported three variants and four genes across cohorts, including gene-level replication of KIF14 and ZNF90, which were replicated only by IBI-DT. IBI-DT also identified significant gene-gene and gene-environment interactions and biologically plausible enriched pathways. Neural networks trained on IBI-DT-prioritized variants outperformed GWAS-based models (AUC 0.67 vs. 0.63). Overall, these findings indicate that IBI-DT complements GWAS by recovering established AD signals while prioritizing rare, less redundant, and interaction-related AD-associated signals.},
}

@article {pmid42362728,
year = {2026},
author = {Das, R and Roy, S and Das, R and Mukhopadhyay, B},
title = {Photolytic disruption of Alzheimer's amyloid Aβ42-fibrils by sialic-acid decorated glycodendrimers.},
journal = {Communications chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42004-026-02098-0},
pmid = {42362728},
issn = {2399-3669},
support = {CRG/2022/005805//DST | Science and Engineering Research Board (SERB)/ ; },
abstract = {The formation of amyloid Aβ42-fibrils is linked to the pathology of cognitive dysfunction in Alzheimer's patients. There is a dire need for developing therapeutics to reverse Aβ42 fibrillation and to stop or slow down the disease progression. Here, we report rationally designed sialic acid functionalized porphyrin cored first and second-generation dendrimers, synthesized using "click chemistry." The glycoporphyrin dendrimer shows a promising ability to degrade Aβ42 fibrils to lower-order soluble oligomers upon irradiation. The gradual fragmentation of the β-sheet-rich Aβ42 fibrils to the unstructured forms by photoactivation of the dendrimers is evident from high-resolution imaging, particle size analysis, and peptide secondary structure distribution. Further, the glycodendrimers are non-toxic even when irradiated and can rescue the neuroblastoma cells from Aβ42 fibril-mediated cytotoxicity. We propose that the photoirradiated dendrimers degrade the Aβ42 fibrils by rupturing the H-bonds by the singlet oxygen species (ROS) generated from the excited porphyrin core.},
}

@article {pmid42362770,
year = {2026},
author = {Lee, S and Baratono, SR and Ha, J and Burt, GT and Palm, ST and Drew, WJ and Zide, BS and Chiulli, NM and Lariviere, S and Zhang, S and Yeo, BTT and Fox, MD and Sperling, RA and Donovan, NJ and Siddiqi, SH},
title = {Atrophy in preclinical Alzheimer's disease maps to a network that predicts longitudinal decline.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42362770},
issn = {1476-5578},
support = {2T32MH016259-34//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
abstract = {Brain atrophy may precede cognitive and functional impairment in Alzheimer's disease (AD), but at this "preclinical" stage, it remains unclear whether atrophy localizes to specific brain networks and whether such localization is associated with clinical outcomes. We investigated cortical thickness in 1778 cognitively unimpaired (CU) older adults with amyloid-β (Aβ) PET from the A4 (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) and LEARN (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration) studies, with a subset (N = 445) with tau PET. We estimated the networks disrupted by each individual's cortical thinning using a large normative connectome database (N = 1000), and tested whether this preclinical AD atrophy network is associated with clinical manifestations and longitudinal cognitive (PACC) and functional (CDR) trajectories. Distinct networks connected to atrophy patterns were associated with Aβ and regional tau in CU older adults. These networks were similar to a previously published atrophy network for AD dementia (Aβ: r = 0.817, P = 0.006; tau: r = 0.712, P = 0.046). Atrophy connectivity to this preclinical AD network was associated with higher Aβ and tau, independent of total cortical atrophy, and cross-sectionally with lower cognition, greater subjective cognitive decline, and increased anxiety; longitudinally, it predicted faster cognitive and functional decline over ~5 years. After tau adjustment, the functional-decline effect was preserved while the cognitive-slope effect was largely attenuated. Atrophy in preclinical AD localizes to a network resembling AD dementia, and is independently associated with AD pathologies, clinical outcomes, and longitudinal decline. Network-level neurodegeneration is detectable and clinically informative in preclinical AD, supporting future network-based research and therapeutic development.},
}

@article {pmid42362909,
year = {2026},
author = {Martí-Navia, A and López-Bellido, A and Balaguer, Á and Ballesta-Martínez, S and Álvarez-Sánchez, L and Peretó, M and García-Vallés, L and Raga, L and Baquero, M and Cháfer-Pericás, C},
title = {Baseline neuroimaging profiles and predictive modelling for early Alzheimer disease prognosis.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-60061-4},
pmid = {42362909},
issn = {2045-2322},
support = {PI22/00594//Instituto de Salud Carlos III/ ; CNS2022-135327//Ministerio de Ciencia e Innovación/ ; },
abstract = {Alzheimer's disease (AD) presents significant clinical heterogeneity in cognitive decline. Neuroimaging profiles and peripheral biomarkers, such as plasma oxidative stress biomarkers could provide information on AD progression. This study evaluates the contribution of baseline neuroimaging features and plasma lipid peroxidation biomarkers to modelling cognitive decline trajectories in early AD. Data were collected from patients with early AD (n = 195), and they were neuropsychologically evaluated to assess their progression. Baseline data included demographics, neuropsychological evaluations, neuroimaging measures and plasma lipid peroxidation levels. Follow-up neuropsychological evaluations were conducted biennially. Individual cognitive decline trajectories were estimated using MMSE and CDR Sum of Boxes (CDR-SB) scores. Multivariate modelling and hierarchical clustering analyses were applied to identify prognostic signatures and patient subgroups. Baseline neuroimaging variables showed significant associations with longitudinal cognitive trajectories, as reflected in MMSE and CDR Sum of Boxes slopes, whereas plasma lipid peroxidation biomarkers did not. Multivariate models based on neuroimaging features demonstrated substantial predictive contribution (conditional R[2] 0.825 for MMSE and 0.808 for CDR Sum of Boxes). Hierarchical clustering identified four distinct groups, primarily driven by left Koedam scores, enlarged perivascular spaces, and Fazekas scores. These clusters were significantly associated with differential rates of cognitive decline, particularly for MMSE. In conclusion, structural neuroimaging measures at baseline are robust indicators of cognitive decline in early AD, supporting its utility for individualized prognosis in early AD.},
}

@article {pmid42362958,
year = {2026},
author = {Karthika, C and Appu, AP and Akter, R and Rahman, MH and Tagde, P and Ashraf, GM and Abdel-Daim, MM and Hassan, SSU and Abid, A and Bungau, S},
title = {Retraction Note: Potential innovation against Alzheimer's disorder: a tricomponent combination of natural antioxidants (vitamin E, quercetin, and basil oil) and the development of its intranasal delivery.},
journal = {Environmental science and pollution research international},
volume = {},
number = {},
pages = {},
doi = {10.1007/s11356-026-37982-8},
pmid = {42362958},
issn = {1614-7499},
}

@article {pmid42363004,
year = {2026},
author = {Javonillo, DI and Furman, S and Le, L and Fernandez, K and Mulford, J and Singla, V and Jha, R and Tsourmas, KI and Kwang, NE and Green, KN and Lane, TE},
title = {Acute viral encephalitis impacts dense-core amyloid plaque pathology and dysregulates myeloid responses to amyloid plaques.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71637},
doi = {10.1002/alz.71637},
pmid = {42363004},
issn = {1552-5279},
support = {105190/ALZ/Alzheimer's Association/United States ; R01AG081599//National Institutes of Health (NIH-NIA)/ ; U54 AG054349/AG/NIA NIH HHS/United States ; T32 NS121727/NS/NINDS NIH HHS/United States ; R35NS116835//National Institutes of Health (NIH-NINDS)/ ; F31NS141599//National Institutes of Health (NIH-NINDS)/ ; /AG/NIA NIH HHS/United States ; /NS/NINDS NIH HHS/United States ; },
abstract = {INTRODUCTION: Recent epidemiological datasets have associated viral encephalitis exposure (i.e., viral-induced neuroinflammation) with increased risk of Alzheimer's disease (AD) and dementia, highlighting the need to uncover how it may impact AD neuropathology.

METHODS: Aged 5xFAD and wild-type (WT) mice were infected with the John Howard Mueller strain of murine hepatitis virus (JHMV), a neurotropic strain of murine coronavirus to comprehensively determine how coronavirus-induced encephalitis may induce molecular and cellular changes that impact beta-amyloid (Aβ) neuropathology.

RESULTS: JHMV-induced encephalitis at 12 days post-infection resulted in minimal changes to overall Aβ protein, despite increased CD4[+] and CD8[+] T-cell infiltration and Lgals3/MAC2-expressing macrophages surrounding more compact Aβ plaques in the brain. Spatial transcriptomic imaging and pathway analysis of differentially expressed genes (DEGs) within myeloid cells demonstrate down-regulated disease-associated (DAM) pathways involving Aβ clearance, response to lipids, and macrophage activation within infected 5xFAD brains.

CONCLUSIONS: JHMV encephalitis induces dysregulated gene expression and myeloid cell responses to Aβ plaque burden in 5xFAD mouse brains.},
}

@article {pmid42363162,
year = {2026},
author = {Ma, X and Yuan, M and Gao, Y and Guo, Z and Liang, J and Yan, F and Wang, S and Qiu, H and He, S and Li, Y and Wang, Y},
title = {40 Hz biparietal transcranial alternating current stimulation for Alzheimer's disease: a prospective study.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-04983-w},
pmid = {42363162},
issn = {1741-7015},
support = {2021ZD0201800 and 2021ZD0201801//the Brain Science and Brain-like Intelligence Technology Research Projects of China/ ; LNB202204//the senile disease prevention project of Hebei Province/ ; XH202402//the "Spark" Research Project Outstanding Fund of the First Hospital of Hebei Medical University/ ; 20231065//the Medica science research subject of Hebei Provincial Health Commission/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by dysfunction in multiple cognitive domains. Patients with AD demonstrate a relative attenuation and dysregulation of theta and gamma oscillations in the temporal and parietal lobes at an early stage. Transcranial alternating current stimulation (tACS) has been shown to modulate neural oscillations in different regions of the brain, affecting higher cognitive functions such as motor function, memory, and learning.

OBJECTIVE: To observe the clinical efficacy and after-effects of biparietal 40 Hz tACS in treating AD patients, to analyze its safety and feasibility, and to deeply explore the effects of tACS on time-varying brain networks and dynamic functional connectivity.

METHODS: In the study, patients with mild AD who were treated in the First Hospital of Hebei Medical University from October 2022 to August 2023 were recruited, randomly divided into tACS group or Sham group, and then respectively received either biparietal 40 Hz tACS or sham stimulation for 15 consecutive days, each lasting 30 min. Neuropsychological assessment scales were collected to assess the efficacy at three time points: pre-stimulation, post-stimulation, and 10-week follow-up. Additionally, transcranial magnetic stimulation with electroencephalography (TMS-EEG) and functional magnetic resonance imaging (fMRI) were collected to explore time-varying brain networks and functional connectivity.

RESULTS: Patients with AD exhibited improvements in global cognition, memory, language, attention, and executive functions following tACS treatment compared with those before treatment. Additionally, the neuropsychiatric inventory scores were decreased significantly after tACS treatment. The clinical efficacies were not obvious in Sham group. These results indicated that tACS treatment had significant short-term efficacy and good stability. The brain time-varying EEG network patterns were analyzed using the adaptive directed transfer function. The analysis showed enhanced information flows from the temporal and prefrontal regions and from the posterior to anterior regions after tACS treatment. In contrast, decreased information flow was observed from the left to right frontal regions. The fMRI analysis revealed enhanced connectivity within default mode network and between default mode network and Frontoparietal network after active treatment.

CONCLUSIONS: The 40 Hz biparietal tACS is a potentially safe and effective treatment for AD with certain long-term efficacy by modulating dynamic functional connectivity.

TRIAL REGISTRATION: The trial was retrospectively registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2500115019).},
}

@article {pmid42363270,
year = {2026},
author = {Bathini, P and Schilling, S and Rahfeld, JU and Holtzman, DM and Saido, TC and Lemere, CA},
title = {Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00965-x},
pmid = {42363270},
issn = {1750-1326},
support = {23AARF-1029815/ALZ/Alzheimer's Association/United States ; AG078106/NH/NIH HHS/United States ; 1RF1 AG058657, 1R01NS136122/NH/NIH HHS/United States ; },
abstract = {Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk.},
}

@article {pmid42363277,
year = {2026},
author = {Caminiti, SP and Fernandes, M and Zaccone, C and Malito, R and Chiaravalloti, A and Manfredi, N and Camedda, R and Giuliano, FD and D'Amelio, M and Mercuri, NB and Perani, D and Liguori, C},
title = {Altered brain glucose metabolism and connectivity in young adults with obstructive sleep apnea.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71211},
doi = {10.1002/alz.71211},
pmid = {42363277},
issn = {1552-5279},
support = {//Ministry of University and Research (MUR)/ ; //National Recovery and Resilience Plan (NRRP)/ ; //Ministero dell'Università e della Ricerca/ ; //NEXTGENERATIONEU/ ; },
abstract = {INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a recognized risk factor for neurodegenerative disorders. However, a causal link between OSAS and brain damage has yet to be established.

METHODS: Thirty cognitively normal patients with moderate-to-severe OSAS, free from systemic or neurological comorbidities, were enrolled and underwent [18]F-fluorodeoxyglucose positron emission tomography imaging. Their scans were compared to those of cognitively normal, OSAS-free controls from the Alzheimer's Disease Neuroimaging Initiative database. Additional analyses included commonality mapping, correlations with polysomnographic parameters, and seed-based metabolic connectivity of major resting-state networks.

RESULTS: Group-level analyses showed fronto-parietal glucose hypometabolism and cerebellar glucose hypermetabolism in patients with OSAS compared to controls. Cerebellar glucose hypermetabolism was associated with reduced rapid eye movement sleep latency and duration. Seed-based connectivity analysis revealed alterations in attentional and limbic networks.

DISCUSSION: Moderate-to-severe OSAS may represent a cause of brain dysfunction, highlighting the importance of its early diagnosis and appropriate treatment to prevent worsening brain damage and possible future neurodegenerative processes.

HIGHLIGHTS: Moderate-to-severe obstructive sleep apnea syndrome (OSAS) is associated with altered brain glucose metabolism. Cerebellar glucose hypermetabolism is associated with rapid eye movement sleep impairment. Attentional and limbic networks connectivity is disrupted in moderate-to-severe OSAS. Early recognition of patients with moderate-to-severe OSAS has the potential to overcome the risk of worsening brain damage that may lead to neurodegeneration.},
}

@article {pmid42363461,
year = {2026},
author = {Zhou, J and Liu, H and Luo, R},
title = {Genetically predicted childhood traits and parental health and risk of pediatric psychiatric disorders: A 2-sample Mendelian randomization study.},
journal = {Medicine},
volume = {105},
number = {26},
pages = {e49426},
doi = {10.1097/MD.0000000000049426},
pmid = {42363461},
issn = {1536-5964},
support = {No: 2023NSFSC1492//Sichuan Science and Technology Program/ ; },
abstract = {The etiology of pediatric psychiatric disorders is complex, involving intergenerational influences and a child's own developmental health. We aimed to investigate the potential effects of genetically predicted childhood traits (childhood obesity, absence epilepsy, intelligence) and parental health traits (longevity, Alzheimer disease, severe depression) on the risk of several childhood and adolescent psychiatric disorders. We employed a 2-sample Mendelian randomization (MR) design using summary statistics from large-scale genome-wide association studies. Data for parental health exposures were primarily from the UK Biobank. Data for childhood trait exposures were from various consortia. Data for outcomes - conduct disorder, mixed conduct and emotional disorders, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and broader behavioral/emotional and social disorders - were sourced from FinnGen and the Psychiatric Genomics Consortium, among others. We used the inverse-variance weighted method for the primary analysis, with MR-Egger, weighted median, and weighted mode as additional analyses. To test the robustness of the results, we conducted sensitivity analyses using MR-Egger regression, Cochran Q test for heterogeneity, the MR-pleiotropy residual sum and outlier test, and a leave-one-out analysis. Genetic liability for childhood obesity was associated with an increased risk of ASD (odds ratio = 1.06, P = .016) and ADHD (odds ratio = 1.09, P = .026), even though these associations did not withstand multiple testing correction. No other robust, statistically significant causal associations were identified. Sensitivity analyses showed limited evidence of bias from horizontal pleiotropy for the main findings. Our findings provide MR evidence supporting potential links from genetic liability for childhood obesity to increased risks of ASD and ADHD. These results highlight the importance of considering a child's early-life health trajectory in the etiology of pediatric psychiatric disorders.},
}

@article {pmid42363608,
year = {2026},
author = {Ostovan, VR and Gholami, S and SoukhakLari, R and Moosavi, M},
title = {Cholinergic regulation of memory retrieval: scopolamine reduces hippocampal neurotrophic and metabolic support.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/01616412.2026.2695820},
pmid = {42363608},
issn = {1743-1328},
abstract = {BACKGROUND: Impairment of cholinergic neurotransmission is a defining neurochemical feature of Alzheimer's disease and is closely associated with altered synaptic function and cerebral energy metabolism. Although acetylcholine influences multiple stages of memory processing, the biological substrates supporting the expression of previously acquired recognition memory remain insufficiently characterized.

OBJECTIVE: This study examined whether acute antagonism of muscarinic acetylcholine receptors during the test phase of the novel object recognition (NOR) task alters retrieval performance and whether such behavioral effects are accompanied by changes in hippocampal brain-derived neurotrophic factor (BDNF) and glucose transporter-1 (GLUT-1).

METHODS: Adult male SWR/J mice underwent NOR training and received intraperitoneal scopolamine (1 mg/kg) or saline 30 min before the test session. Recognition performance was quantified using discrimination index and object exploration measures. Hippocampal tissue was collected immediately after testing for Western blot analysis of BDNF and GLUT-1 expression.

RESULTS: Muscarinic receptor blockade significantly reduced the ability of mice to preferentially explore the novel object, while total exploration time was increased versus controls. This behavioral deficit coincided with a decrease in hippocampal pro-brain-derived neurotrophic factor (pro-BDNF) and GLUT-1 protein levels.

CONCLUSIONS: These data indicate that cholinergic modulation during recognition memory expression is associated with coordinated neurotrophic and metabolic alterations in the hippocampus. Effective retrieval depends on the integrity of molecular systems supporting plasticity and energy supply, and cholinergic dysfunction may compromise memory expression partly through reducing hippocampal pro-BDNF, providing a mechanistic framework relevant to early cognitive dysfunction in neurodegenerative disease.},
}

@article {pmid42363707,
year = {2026},
author = {Valdivia-Aviña, K and Ochoa-Hugo, SE and Hernández-Sapiéns, MA and Canales-Aguirre, AA},
title = {Advances in 3D cell culture models for alzheimer's disease drug discovery.},
journal = {Expert opinion on drug discovery},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17460441.2026.2691833},
pmid = {42363707},
issn = {1746-045X},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) affects more than 57 million people, yet drug development faces high failure rates due to the limited translational validity of conventional models. This review analyzes how 3D (three-dimensional) systems provide a technical validation platform that more accurately replicates the human brain microenvironment.

AREAS COVERED: This review analyzes the evolution of 3D culture systems, including spheroids, organoids, hydrogels, and microfluidics. A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and ScienceDirect, covering publications from January 2014 to March 2026. The analysis synthesizes evidence on the capacity of these models to reproduce beta-amyloid (β-amyloid) aggregation and tau hyperphosphorylation, while exploring the integration of artificial intelligence to optimize compound screening.

EXPERT OPINION: 3D models serve as high-fidelity biological filters that complement current preclinical methodologies, improving early identification of toxicities and therapeutic efficacy. Their strategic integration and technical standardization are essential steps to refine predictive accuracy and optimize the transition to clinical trials.},
}

@article {pmid42363714,
year = {2026},
author = {Preitner, N and Dehlinger, V and Rodriguez, P and Fabbri, K and Varisco, Y and Pigni, M and Lovison, A and Münzenmaier, L and Piorkowska, K and Fuchs, A and Ait-Bouziad, N and Fournier, N and Jepaul, S and Molette, J and Gabellieri, E and Darmency, V and Poli, S and Pfeifer, A and Kosco-Vilbois, M and Capotosti, F},
title = {Elimination of tau tangles and soluble aggregates with the small molecule ACI-16664 prevents neurodegeneration in vivo.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71572},
doi = {10.1002/alz.71572},
pmid = {42363714},
issn = {1552-5279},
support = {//AC Immune SA/ ; },
mesh = {Animals ; *tau Proteins/metabolism/drug effects ; *Neurofibrillary Tangles/drug effects/pathology/metabolism ; Humans ; Mice ; *Tauopathies/pathology/drug therapy ; Mice, Transgenic ; Disease Models, Animal ; Neurons/drug effects/pathology ; Brain/pathology/drug effects ; Alzheimer Disease/pathology ; Protein Aggregation, Pathological/drug therapy ; *Nerve Degeneration/pathology ; },
abstract = {INTRODUCTION: Pathological tau aggregates are key therapeutic targets in Alzheimer's disease (AD), but current approaches face limitations including poor intracellular penetration, lack of selectivity for aggregated over physiological tau, or reliance on invasive administration.

METHODS: ACI-16664, an orally available brain penetrant tau aggregation inhibitor, was identified through medicinal chemistry optimization of the Morphomer library and characterized using biochemical assays, neuronal cultures, and the Tg4510 tauopathy mouse model.

RESULTS: ACI-16664 selectively bound aggregated tau with high apparent affinity, destabilized its β-sheet structures, blocked intracellular seeding by both soluble and insoluble tau, and prevented tau-induced neurotoxicity. In Tg4510 mice, ACI-16664 reduced both soluble tau aggregates and tangles, and prevented neuronal loss, synaptic degeneration, and cortical atrophy.

DISCUSSION: These findings demonstrate the therapeutic value of targeting tau aggregation across its diverse pathological forms and cellular compartments, supporting the potential of this approach to benefit patients with AD and other tauopathies across disease stages.},
}

Animals
*tau Proteins/metabolism/drug effects
*Neurofibrillary Tangles/drug effects/pathology/metabolism
Humans
Mice
*Tauopathies/pathology/drug therapy
Mice, Transgenic
Disease Models, Animal
Neurons/drug effects/pathology
Brain/pathology/drug effects
Alzheimer Disease/pathology
Protein Aggregation, Pathological/drug therapy
*Nerve Degeneration/pathology

@article {pmid42363721,
year = {2026},
author = {Wugalter, KA and Thurston, RC and Wu, M and Aizenstein, HJ and Kamboh, MI and Karikari, TK and Maki, PM},
title = {Evidence of APOE4-related brain vulnerabilities in verbal memory systems in midlife women.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71635},
doi = {10.1002/alz.71635},
pmid = {42363721},
issn = {1552-5279},
support = {R01AG053504/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; *Apolipoprotein E4/genetics ; Magnetic Resonance Imaging ; Middle Aged ; *Brain/physiology/diagnostic imaging ; *Memory/physiology ; Neuropsychological Tests ; Postmenopause ; Biomarkers/blood ; },
abstract = {INTRODUCTION: Women carrying the apolipoprotein E4 (APOE4) allele have a greater risk of Alzheimer's disease (AD) from ages 65-75 years compared to men, yet the effects of APOE4 on cognitive and neuroimaging outcomes among midlife women remain poorly understood. We investigated APOE4-related differences in memory-based functional neuroimaging outcomes in cognitively normal, midlife postmenopausal women.

METHODS: We measured blood-oxygen-level-dependent activation and hippocampal functional connectivity during a functional magnetic resonance imaging verbal encoding task. Linear regression models tested APOE4 differences (carriers vs. non-carriers) and associations of neuroimaging indices with verbal memory measures and plasma AD biomarkers, adjusting for age, race, and education.

RESULTS: Among 145 women from MsBrain, APOE4 carriers and non-carriers did not differ in verbal memory performance or AD biomarker levels. During verbal encoding, APOE4 carriers had significantly decreased activation and hippocampal functional connectivity in several regions compared to non-carriers.

DISCUSSION: APOE4-related functional brain differences are present by midlife in postmenopausal women.},
}

Humans
Female
*Apolipoprotein E4/genetics
Magnetic Resonance Imaging
Middle Aged
*Brain/physiology/diagnostic imaging
*Memory/physiology
Neuropsychological Tests
Postmenopause
Biomarkers/blood

@article {pmid42363728,
year = {2026},
author = {Birditt, KR and Mavromati, K and Swann, P and Quinn, T and Hainsworth, AH and Hughes, L and O'Brien, JT and McEwan, W and Malpetti, M},
title = {Inflammation profiles in Alzheimer's disease relate to cognition and neurodegeneration.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71642},
doi = {10.1002/alz.71642},
pmid = {42363728},
issn = {1552-5279},
support = {ARUK-RADF2021A-010//Race Against Dementia Alzheimer's Research UK/ ; NIHR203312//National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre/ ; /MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Alzheimer Disease/blood/immunology/complications ; Female ; Male ; *Inflammation/blood ; Aged ; *Cytokines/blood ; Biomarkers/blood ; *Cognitive Dysfunction/blood/immunology ; tau Proteins/blood ; *Cognition/physiology ; Neurofilament Proteins/blood ; Cohort Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Immune signaling alterations have been implicated in Alzheimer's disease (AD) pathophysiology, but their heterogeneity across the disease continuum in real-world cohorts is poorly characterized, limiting the development of stratified immunomodulatory approaches.

METHODS: In a diverse multicenter cohort (BioHermes) of 176 amyloid-positive individuals with AD/mild cognitive impairment (MCI) and 173 age and sex-matched controls, principal component analysis was performed on Luminex-measured plasma cytokines to derive inflammatory signatures, and their direct/indirect associations with cognition and neurodegeneration.

RESULTS: Two components were identified. Proinflammatory Component 2 was elevated in AD/MCI and in Black/African American participants, and strongly associated with poorer cognition (independently of neurofilament light [NfL], phosphorylated tau 217 [p-tau217], and glial fibrillary acidic protein [GFAP]). Inflammatory Component 1 showed an indirect association with cognition, mediated by neurodegeneration (plasma NfL).

DISCUSSION: Plasma inflammation profiles were associated with poorer cognition via direct and neurodegeneration-mediated pathways, supporting their potential use as stratification markers in AD therapeutics.},
}

Humans
*Alzheimer Disease/blood/immunology/complications
Female
Male
*Inflammation/blood
Aged
*Cytokines/blood
Biomarkers/blood
*Cognitive Dysfunction/blood/immunology
tau Proteins/blood
*Cognition/physiology
Neurofilament Proteins/blood
Cohort Studies
Aged, 80 and over

@article {pmid42349605,
year = {2026},
author = {Sandoz, M and Schaffner, E and Allali, G and Fossard, M},
title = {From Past Recall to Future Projection: What Does Verb Tense Production Reveal About Mental Time Travel in Alzheimer's disease?.},
journal = {Neuropsychologia},
volume = {},
number = {},
pages = {109538},
doi = {10.1016/j.neuropsychologia.2026.109538},
pmid = {42349605},
issn = {1873-3514},
}

@article {pmid42349617,
year = {2026},
author = {Li, Q and Liu, X and Xing, R and Qi, F and Li, X and Wang, K and Chen, L},
title = {5-Methoxyseselin inhibits neuronal ferroptosis and β-amyloid production in female APP/PS1 transgenic mice.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118188},
doi = {10.1016/j.bcp.2026.118188},
pmid = {42349617},
issn = {1873-2968},
abstract = {Nrf2 signaling dysregulation drives progressive cognitive decline in Alzheimer's disease (AD), as the brain's endogenous defenses fail to neutralize oxidative stress and ferroptotic neuronal attrition. Here, we report that 5-Methoxyseselin (5-Met), a natural coumarin derivative, is a nuclear factor erythroid 2-related factor 2 (Nrf2) inducer that facilitates glutathione peroxidase 4 (GPX4)-mediated lipid-repair machinery. Mechanistically, 5-Met may bind to Kelch-like ECH-associated protein 1 (Keap1), thereby disrupting the Keap1-Nrf2 inhibitory interaction and promoting Nrf2 stabilization. This leads to upregulated GPX4 expression and subsequent suppression of neuronal ferroptosis in APP/PS1 mice. Consistently, 5-Met treatment effectively protected N2a cells from ferroptotic challenges induced by ferric ammonium citrate (FAC), erastin, or RSL3 via upregulating GPX4 expression. Furthermore, 5-Met modulated β-amyloid (Aβ) homeostasis by inhibiting β-amyloid precursor protein-cleaving enzyme 1 (BACE1)-mediated Aβ production and enhancing low-density lipoprotein receptor-related protein 1 (LRP1)-mediated Aβ efflux. In addition, 5-Met treatment improved cognitive performance in APP/PS1 mice. Collectively, these findings identify 5-Met as a multi-target neuroprotective agent that restores Aβ homeostasis and inhibits neuronal ferroptosis, suggesting it may be a therapeutic compound for AD.},
}

@article {pmid42349673,
year = {2026},
author = {Adeboye, O and Gonda, BL and Gulati, N and Hu, K and Karp, AR and McNally, DC and Tsai, W and Zarate, JG and Holmes, M and Johnson-Kleinpeter, L and Kwok, HY and Miranda, VJ and Nguyen, JH and Patel, KA and Polagoni, A and Ramirez, B and Da Costa, RT and Love, CR and Grigoriev, A and Solesio, ME},
title = {Sensory decline in aging and neurodegeneration: A mitochondrial perspective.},
journal = {Pharmacological research},
volume = {230},
number = {},
pages = {108322},
doi = {10.1016/j.phrs.2026.108322},
pmid = {42349673},
issn = {1096-1186},
abstract = {Sensory organs (touch, sight, hearing, smell, and taste) are the primary way humans perceive the environment. Accordingly, sensory decline deleteriously affects patients' quality of life, and it is often associated with a worse prognosis of related pathologies. This decline has been broadly described in aging and in the main aging-related neurodegenerative disorders, even though it is often understudied and considered a minor symptom. The molecular pathways that drive aging-associated sensory decline are broad and diverse; however, mitochondrial dysfunction has been described at the intersection of many of these mechanisms. Mitochondria have robust mechanisms to maintain their homeostasis. These mechanisms include, for example, the unfolded protein response, the antioxidant systems, and mitophagy. During aging, these mechanisms are dysregulated, which contributes to the dysfunction of the organelle. For example, increased reactive oxygen species generation and mitochondrial DNA mutations are present in cells and tissues, the dysregulation of which is crucial for the onset of sensory decline. In this bibliographical review, we systematically and comprehensively discuss the most significant and recent findings in the field. The studies we describe here suggest that targeting mitochondrial dysfunction could be a valid, innovative, and promising pharmacological target against sensory decline in aging and aging-related neurodegenerative disorders. Moreover, targeting mitochondrial dysfunction might have positive effects on other symptoms of aging and associated pathologies, including Parkinson's and Alzheimer's Diseases. Further research in the field could significantly contribute to decreasing sensory decline, which could positively impact both lifespan and healthspan.},
}

@article {pmid42349722,
year = {2026},
author = {Kumari, S and Dhapola, R and Sharma, P and Paidlewar, M and Vellingiri, B and Cho, SG and Dayem, AA and Medhi, B and Harikrishnareddy, D},
title = {From Plastics to Pathology: The Neurodegenerative Impact of Bisphenol-A on Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103219},
doi = {10.1016/j.arr.2026.103219},
pmid = {42349722},
issn = {1872-9649},
abstract = {Bisphenol-A (BPA), a ubiquitous component of polycarbonate plastics and epoxy resins, has emerged as a significant environmental risk factor for neurodegenerative diseases, particularly Alzheimer's disease (AD). It is widely detected in the environment and humans due to its extensive use in plastics and epoxy resins for consumer products such as bottles, containers, and tableware. This review synthesizes current evidence on the molecular and cellular mechanisms by which BPA exposure may contribute to neurotoxicity and AD pathogenesis. We discuss how BPA disrupts endocrine signalling, induces oxidative stress, promotes neuroinflammation, and impairs synaptic plasticity, all of which are implicated in the development and progression of AD. The review also examines the impact of BPA on amyloid-beta accumulation, tau pathology, and cognitive decline, integrating findings from animal models, in vitro studies, and epidemiological research. Furthermore, we address the limitations of BPA alternatives and highlight emerging therapeutic and preventive strategies. This study highlights the pathogenic molecular mechanisms involved, offering a foundation for understanding BPA-induced neurodegenerative processes. By bridging the gap between environmental exposure and neuropathology, this article underscores the urgent need for regulatory action and further research to mitigate the neurodegenerative risks associated with BPA in plastics.},
}

@article {pmid42349730,
year = {2026},
author = {Jafari, A and Manhães, AC and Abreu-Villaça, Y},
title = {Flexible Time-Series Analysis: A Dynamically Aware Method for Inferring Directed Dependencies in Behavioral Data.},
journal = {Behavioural processes},
volume = {},
number = {},
pages = {105406},
doi = {10.1016/j.beproc.2026.105406},
pmid = {42349730},
issn = {1872-8308},
abstract = {Animal models remain essential in translational research, particularly in neuroscience, where behavioral assessments are used to investigate brain function and disease mechanisms. However, conventional statistical approaches, focused on frequencies, durations, and correlations, provide limited insight into the temporal organization and dependency structure of behavior. These methods treat behaviors as isolated or aggregated events, often overlooking the sequential, hierarchical, and dynamic nature of behavioral expression. This perspective advocates the adoption of analytical frameworks that integrate pattern-oriented and time-series dependency inference approaches. Tools such as THEME enable the detection of non-random, temporally structured behavioral sequences (T-patterns), revealing how behaviors are hierarchically organized over time. To further incorporate the possibility of assessing directed dependencies in behavioral sequences, tools such as Tigramite can be useful. Under specific assumptions, this tool allows the estimation of time-lagged, confounder-controlled, conditionally independent relationships between behaviors, representing them as dynamic interactions established over time. By combining these approaches, researchers can move beyond descriptive analyses toward generating hypotheses about the temporal organization and interdependence of behavioral events. Animal models of conditions such as drug addiction, autism spectrum disorder, anxiety disorders, and Alzheimer's disease, among others, in which traditional measures incompletely capture the richness of behavioral interactions, could benefit from this approach. Time-series inference methods may help identify candidate behavioral predictors and generate testable hypotheses about underlying pathophysiology. Overall, adopting this integrative, time-resolved analytical strategy may enable more comprehensive, reproducible, and biologically meaningful insights from animal models.},
}

@article {pmid42349803,
year = {2026},
author = {Chong, JR and Cheah, IK and Tang, RM and Halliwell, B and Chen, CP and Lai, MKP},
title = {Metabolism of the antioxidant micronutrient ergothioneine as a plasma biomarker of cognitive resilience in older people with Alzheimer's disease amyloid pathology.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.06.043},
pmid = {42349803},
issn = {1873-4596},
abstract = {BACKGROUND: Associations between dietary micronutrients and cognitive resilience to Alzheimer's disease (AD) amyloid pathology is currently unknown. We investigated whether plasma levels of L-ergothioneine (ET), its metabolite L-hercynine (HC), and their ratio (HC:ET, as an index of ET metabolism) affect known associations between biomarkers of amyloid pathology (p-Tau181 or p-Tau217) and cognitive decline.

METHODS: 259 initially dementia-free participants recruited from memory clinics and the community in Singapore had baseline measurements of plasma p-Tau, ET, HC, as well as annual neuropsychological assessments for up to 5 years to derive cognitive trajectories based on Clinical Dementia Rating-Sum of Boxes (CDR-SB) slopes.

RESULTS: High HC:ET attenuated the positive correlations between plasma p-Tau and CDR-SB slopes. Compared with participants with low amyloid burden, participants with high amyloid burden had higher risk of cognitive decline when HC:ET was low (Hazard ratio [HR] = 2.33, p = 0.002), but not when HC:ET was high (HR = 1.47, p = 0.32).

CONCLUSION: The identification of ET metabolism as a novel biomarker of cognitive resilience supports further investigations into mechanisms underlying its neuroprotectant properties. ET should be further assessed as a potential candidate for countering amyloid pathology-associated cognitive decline.},
}

@article {pmid42349816,
year = {2026},
author = {Abdel-Aal, RA and Abdelnabi, S and Badary, DM and Hussein, AMR},
title = {Effect of Metformin on Anti-Alzheimer Activity of Rivastigmine in Aluminum Chloride-Induced Alzheimer's Disease in Rats: A Behavioral, Biochemical, Immunohistopathological Evidence of Crosstalk between Amyloid, Tau, Autophagy, and Apoptosis.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179087},
doi = {10.1016/j.ejphar.2026.179087},
pmid = {42349816},
issn = {1879-0712},
abstract = {AIM: This study investigates how the anti-Alzheimer's effectiveness of rivastigmine (RIVA) is affected by the antidiabetic drug metformin (MET).

METHOD: ology: Male rats were randomly divided into a control group, an Alzheimer's disease (AD) group receiving aluminum chloride (AlCl3), a RIVA-treated group, a MET-treated group, and a RIVA+MET combination group. Cognitive performance was assessed using passive avoidance (PA), the radial arm maze (RAM), the Morris water maze (MWM), and novel object recognition (NOR) tests. Hippocampal microtubule-associated protein tau (MAPT), beta-site APP cleaving enzyme 1 (BACE1), acetylcholinesterase (AChE), and autophagy marker Sequestosome 1 (SQSTM1/p62) were measured, while amyloid-beta (Aβ) and caspase-3 expression were analyzed immunohistochemically. Histopathology and electron microscopy were used to assess neuronal integrity.

RESULTS: MET, RIVA, and their combined treatment mitigated the neurodegenerative alterations induced by AlCl3. The combination of MET+RIVA failed to yield significant differences in behavioral performance [PA, RAM, MWM, and NORT], MAPT levels, and AChE activity compared with the treatment with RIVA monotherapy. However, the combination therapy showed significant reductions in hippocampal BACE1, Aβ deposition, and SQSTM1/p62 levels, indicating enhanced suppression of amyloidogenic processing and improved autophagy. Although differences between MET+RIVA combination and RIVA monotherapy were not statistically significant for these markers, the combination markedly reduced caspase-3 immunoreactivity compared with the diseased group, indicating greater attenuation of apoptosis.

CONCLUSION: These results highlight the crosstalk among the amyloid, tau, autophagy, and apoptotic pathways in AD and suggest that the MET+RIVA combination showed promising molecular improvements but no clear behavioral superiority, indicating the need for further optimization.},
}

@article {pmid42350157,
year = {2026},
author = {Li, Y and Du, A and Zhang, Q and Xu, G and Xu, X and Ma, X and Chu, JCH and Thiyagarajan, V and Yu, Z and Chu, IK and Siu, KWM},
title = {The Cerebrospinal Fluid Proteome of Alzheimer's Disease Patients: Differentiation and Prediction of Responders and Non-Responders to Lymphatic-Venous Anastomosis.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c01031},
pmid = {42350157},
issn = {1520-6882},
abstract = {Herein, we describe the identification of protein biomarkers in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients that enable the differentiation of Responders from Non-Responders to lymphatic-venous anastomosis (LVA). Discovery of these potential biomarkers was achieved by deep proteomic analysis on the pre-LVA cerebrospinal fluid in a cohort of 90 patients. A combination of two CSF processing modalities and two computational platforms allowed us to secure the largest CSF proteome ever reported (6711 proteins identified with 4506 proteins quantified at a false-discovery rate of ≤1%). Importantly, we discovered 16 CSF proteins that are expressed differentially between patients who showed documented improvements after LVA (the Responders) and those who showed no improvements (the Non-Responders). Pairing of two of the best-performing potential biomarkers─NPTX2 and IGSF10─gave an accuracy of 0.790 (AUC = 0.854) in correctly identifying Responders and Non-Responders, which improved to 0.827 (AUC = 0.880) after we added a second pair of classical AD biomarkers─p-tau181 and Aβ42─to the test. We found that the classical ELISA biomarker ratio p-tau181/Aβ42 has, by itself, a marginally acceptable accuracy of 0.644 (AUC = 0.662). Our reported observation (in 2025) of a correlation between elevated p-tau181/Aβ42 and responding to LVA is in accordance with the interpretation that Responders have a higher abundance of NPTX2, which indicates better synaptic health. Apparently, the Responders are more resilient, despite an indication of more advanced pathology. In a simulation of the performance in future testing, we performed a 5-fold cross-validation that gave an AUC of 0.859 ± 0.074 and an accuracy of 0.740 ± 0.048 for the small testing group.},
}

@article {pmid42350204,
year = {2026},
author = {Rosenberg, PB and Forester, BP},
title = {Cannabinoid Treatments for Agitation in Alzheimer's Disease.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.06.001},
pmid = {42350204},
issn = {1545-7214},
}

@article {pmid42350221,
year = {2026},
author = {Pan, C and Ma, J and Yuan, X and Li, R and Zheng, X and Yan, J and Xie, Z and Liu, M and Xu, J and Su, Y and Li, J and Li, Y},
title = {Atrophy of specific amygdala subregion precedes the conversion from mild cognitive impairment with neuropsychiatric symptoms to dementia.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100234},
doi = {10.1016/j.inpsyc.2026.100234},
pmid = {42350221},
issn = {1741-203X},
abstract = {BACKGROUND: The amygdala is known to exhibit early signs of Alzheimer's disease (AD) pathology. However, it remains unclear whether atrophy in its specific subregions contributes to the transition from mild cognitive impairment (MCI) with neuropsychiatric symptoms (NPS) to dementia.

METHODS: We recruited 376 participants at baseline: 130 MCI with NPS (MCI+NPS), 154 MCI without NPS (MCI-NPS), and 92 cognitively unimpaired (CU) individuals. Upon clinical follow-up, the MCI cohort was classified into 17 converters who progressed to dementia (MCI-c) and 96 non-converters who remained stable (MCI-nc). All participants underwent baseline and follow-up neuropsychological evaluations and multimodal magnetic resonance imaging (MRI). From the MRI data, we extracted volumes of amygdala subregions and used partial Spearman's correlations to assess their associations with NPS and cognitive alterations.

RESULTS: Compared to the CU group, the MCI + NPS group exhibited more extensive bilateral amygdala atrophy, involving all subregions, whereas the MCI-NPS group showed atrophy confined to the bilateral centromedial (CeM) amygdala. Furthermore, relative to the MCI-nc group, the MCI-c group exhibited greater annual volume loss in the bilateral amygdalae and their subregions, except for the right CeM. The annual atrophy rate of the right basolateral (BLA) amygdala correlated with more severe affective (r = -0.274, p = 0.005) and hyperactivity symptoms (r = -0.343, p < 0.001). The annual atrophy rate of the left superficial (SUP) amygdala correlated with more severe affective symptoms (r = -0.273, p = 0.011).

CONCLUSIONS: Progressive atrophy of the BLA and SUP is associated with NPS-related cognitive decline in MCI, suggesting a potential mechanistic role for these subregions and highlighting them as candidates for future targeted intervention.},
}

@article {pmid42350373,
year = {2026},
author = {Casterton, R and Martinez-Cotrina, A and Barnard, J and Wycherley, E and Hu, Y and Anderson, R and Janel, S and Byun, J and Houghton, O and Solomon, DA and Alcalde, J and Lafont, F and Ruepp, MD and Hirth, F and Tummers, B and Cho, YY and De Nicola, G and Mizielinska, S and Fanto, M},
title = {Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42350373},
issn = {2041-1723},
support = {ARUK-PG2019B-008//Alzheimer's Research UK (ARUK)/ ; },
mesh = {Proteotoxic Stress ; Animals ; Humans ; Cell Death ; Neurons/metabolism/pathology ; Lamin Type B/metabolism/genetics ; Phosphorylation ; Alzheimer Disease/pathology/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Nuclear Lamina/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; Mice ; Frontotemporal Dementia/pathology/metabolism ; Cell Nucleus/metabolism ; },
abstract = {Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cortex of FTD and Alzheimer's disease (AD) patients. Together these findings characterise a form of cell death directly linked to proteotoxic stress and nuclear lamina stability that is associated with neurodegeneration.},
}

Proteotoxic Stress
Animals
Humans
Cell Death
Neurons/metabolism/pathology
Lamin Type B/metabolism/genetics
Phosphorylation
Alzheimer Disease/pathology/metabolism
*Neurodegenerative Diseases/metabolism/pathology
Nuclear Lamina/metabolism
p38 Mitogen-Activated Protein Kinases/metabolism
Mice
Frontotemporal Dementia/pathology/metabolism
Cell Nucleus/metabolism

@article {pmid42350389,
year = {2026},
author = {Karunakaran, KB and Purushottam, M and Balakrishnan, N and Viswanath, B and Amemori, KI and Jain, S},
title = {Expression patterns of risk genes associated with three evolutionarily relevant syndromes in rhesus macaque and human brains.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04198-w},
pmid = {42350389},
issn = {2158-3188},
support = {IA/CPHI/20/1/505266//DBT India Alliance (Wellcome Trust/DBT India Alliance)/ ; JP22H04998//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP24H02163//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP25K02377//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP24gm6910012//Japan Agency for Medical Research and Development (AMED)/ ; JP24wm0625210//Japan Agency for Medical Research and Development (AMED)/ ; BT/PR17316/MED/31/326/2015//Department of Biotechnology, Ministry of Science and Technology (DBT)/ ; },
abstract = {Depressive disorder (DD), Alzheimer's disease (AD), and schizophrenia (SZ) are evolutionarily relevant traits that disrupt neural networks supporting affect and cognition. While genome-wide association studies have identified risk-related genes for these diseases, how the expression of these genes compare across species remains unclear. In this study, we examined the spatial and temporal expression of ~2000 disease-associated genes in human and rhesus macaque brains. Distinct cross-species signatures emerged. DD-linked genes showed broad cortical-subcortical expression in humans but were confined to subcortical regions in macaques. The divergent subset was enriched for neuron differentiation, migration, synaptic signalling, and cognition. SZ-linked genes were expressed across cortical-subcortical-cerebellar structures in humans. AD-linked genes showed postnatal cortical-hippocampal macaque expression, and broader cortical-subcortical human expression. Cross-species spatial comparisons revealed a significant negative correlation for DD genes, suggesting a broader spatial distribution of DD-related gene expression in humans, extending to distributed emotion-cognition networks, compared to affective hubs in macaques. SZ genes exhibited a similar, though non-significant, negative trend, while AD genes showed a weak, non-significant correlation, indicating an absence of systematic expression shifts. Together, evolutionary shifts in gene expression may have shaped emotional and cognitive functions in humans, and susceptibility to psychiatric and neurodegenerative disorders.},
}

@article {pmid42350564,
year = {2026},
author = {Rejer, I and Gago, I and Marozas, V},
title = {Aggregating XAI-based explanations to identify spectral-spatial patterns in CNN-based resting-state EEG classification.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-59478-8},
pmid = {42350564},
issn = {2045-2322},
abstract = {Convolutional neural networks (CNNs) achieve high performance in electroencephalographic (EEG) classification tasks; however, their decision-making mechanisms remain difficult to interpret. Explainable artificial intelligence (XAI) methods are typically applied to provide insight into individual model decisions, yet such explanations do not reveal the overall structure of the patterns learned by the network. In this study, we hypothesize that, in EEG analysis, XAI can serve a deeper role: when appropriately applied, it can expose the general patterns learned by a trained CNN, thereby transforming it from a purely predictive model into a framework capable of revealing candidate discriminative structures that may form the basis for future neuroscientific hypotheses. This shift is enabled by structured aggregation of local explanations, through which instance-level insights are consolidated into cross-subject patterns. To implement this strategy, we employ averagedLIME, an extension of Local Interpretable Model-agnostic Explanations, which aggregates sample-level explanations into global class-level saliency maps. In trial-based EEG paradigms, such aggregation reinforces consistent patterns across samples analogously to event-related potentials averaging. In this study, we examine whether this strategy remains effective in a temporally unaligned resting-state setting, taking subject-independent classification of Alzheimer's disease and cognitively normal controls as a case study. Four neural architectures are compared, with spectral CNN yielding the most robust performance (95.81% test accuracy). The best-performing model is subsequently analyzed using averagedLIME, while SHapley Additive exPlanations (SHAP) and Grad-CAM are employed as complementary explanation techniques. Quantitative analyses demonstrated that the averagedLIME patterns were stable across cross-validation folds, robust to perturbation parameter selection, reproducible on unseen test data, and strongly supported by independent SHAP explanations. When interpreted in conjunction with the averaged input representations, the resulting saliency maps reproduced established EEG slowing patterns in Alzheimer's disease, while also highlighting localized spatial-spectral structures that were less apparent in the averaged EEG representations alone. These findings demonstrate that structured aggregation of CNN explanations enables extraction of stable cross-subject patterns from resting-state EEG and may reveal candidate discriminative structures that can motivate future neuroscientific hypotheses.},
}

@article {pmid42350884,
year = {2026},
author = {Mohammed, HE and Haseeb, ME and Nasser, M and Hanen, G and Abdelkader, MS and Yaser, H and Yaser, S and Samir, A and Arafeh, Y and Wagdy, M and Darwish, MK},
title = {Diagnostic accuracy of CSF and plasma pTau-181, pTau-217, and pTau-231 for Alzheimer's disease: a diagnostic meta-analysis.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42350884},
issn = {2240-2993},
abstract = {BACKGROUND: Alzheimer's disease (AD) remains the most common cause of dementia worldwide, yet achieving an accurate early diagnosis continues to pose a major challenge. Recent advances highlight phosphorylated tau (pTau) isoforms-pTau-181, pTau-217, and pTau-231-detected in cerebrospinal fluid (CSF) and plasma as promising biomarkers capable of distinguishing AD from non-Alzheimer's dementias and cognitively healthy individuals (HC). This study aimed to comprehensively assess the diagnostic accuracy of these pTau isoforms through a systematic review and diagnostic meta-analysis.

METHODS: Following PRISMA 2020 guidelines and PROSPERO registration (CRD42025632278), we performed a systematic search of PubMed, Scopus, and Web of Science databases through September 2025. Eligible studies evaluated the diagnostic performance of pTau-181, pTau-217, or pTau-231 in CSF or plasma using established AD reference standards. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated using random-effects models. Clinical applicability was assessed via Fagan's nomogram, and publication bias was examined using Deeks' funnel plot asymmetry test.

RESULTS: Forty-eight studies encompassing diverse international cohorts met inclusion criteria. In differentiating AD from HC, CSF pTau-217 demonstrated the highest diagnostic precision (sensitivity = 0.95; specificity = 0.91), outperforming pTau-181 and pTau-231 (AUC = 0.90 each). Plasma biomarkers also exhibited strong diagnostic value: plasma pTau-181 achieved sensitivity of 0.88, specificity of 0.81, and AUC of 0.91, while plasma pTau-231 displayed sensitivity of 0.84, specificity of 0.87, and AUC of 0.86, with low interstudy heterogeneity. Comparative analyses confirmed significantly higher pTau concentrations in AD relative to both non-AD dementias and healthy controls. The overall certainty of evidence ranged from moderate to high, supporting the robustness of these findings.

CONCLUSIONS: This meta-analysis supports the strong diagnostic performance of pTau isoforms, particularly CSF pTau-217, in distinguishing Alzheimer's disease from healthy controls and non-Alzheimer's dementias. However, evidence for CSF pTau-217 is limited and largely derived from limited number of studies. Although plasma pTau-181 and pTau-231 show promising diagnostic accuracy, further real-world validation, assay standardization, and assessment within established diagnostic pathways are needed.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid42350980,
year = {2026},
author = {Knox, S and Horn, J and Simpson, K and Wolf, B},
title = {Methodological advances in claims-based dementia algorithms: integrating medication and clinical data for medicare populations.},
journal = {BMC medical research methodology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12874-026-02929-7},
pmid = {42350980},
issn = {1471-2288},
support = {UL1 TR001450/TR/NCATS NIH HHS/United States ; K01AG073538/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Accurate identification of Alzheimer's Disease and Related Dementias (ADRD) in Medicare data is essential for research, policy, and care planning. Existing approaches, including the Centers for Medicare & Medicaid Services (CMS) Chronic Conditions Warehouse (CCW) algorithm, rely primarily on International Classification of Diseases, Tenth Revision (ICD-10) codes and are subject to misclassification and potential bias across populations.

METHODS: We evaluated whether incorporating neuropsychiatric symptom (NPS) ICD-10 codes and medication data improves prediction of algorithm-defined ADRD classificaitons. We analyzed 269,214 Medicare beneficiaries receiving home health services in 2019 using claims, assessment, and prescription drug files. Two classification algorithms were examined: (1) the CCW binary classification algorithm and (2) a clinically informed ADRD ternary classification algorithm (ADRD-highly likely, ADRD-possible, ADRD-unlikely). Predictive models were developed for each algorithm using stacked elastic net regression, incorporating demographics, healthcare utilization, psychiatric and cognitive indicators, and medication use. Models were trained on beneficiaries with definitive ADRD status and evaluated in an independent test set using area under the curve (AUC), sensitivity, specificity, and predictive values. Thresholds were selected to prioritize specificity (≥ 80%) while maximizing sensitivity.

RESULTS: In the test dataset, the CCW predictive model achieved an AUC of 0.863 for predicting CCW binary-defined ADRD status. The ADRD predictive model achieved a higher AUC of 0.906 when predicting ADRD ternary-defined classifications. Both models demonstrated strong discrimination for their respective outcomes, but performance characteristics differed. Among beneficiaries classified as ADRD-possible, the ADRD predictive model more frequently classified individuals as ADRD-negative, indicating a more conservative approach to ambiguous cases.

CONCLUSIONS: Incorporating NPS codes and medication data improves prediction of algorithm-defined ADRD classifications, particularly among individuals with uncertain status. Models aligned with the ADRD ternary algorithm demonstrated more specific and conservative classification patterns, suggesting that integrating behavioral, cognitive, and medication data may enhance the validity of claims-based phenotyping. Further validations against clinical diagnosis are needed.},
}

@article {pmid42351167,
year = {2026},
author = {Yan, C and Chen, Z and Yan, Y and Wang, M and Chen, W and Zhou, F and Liu, Q},
title = {Integrative transcriptomic analysis identifies meningeal-hippocampal immune communication in Alzheimer's disease.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-08414-5},
pmid = {42351167},
issn = {1479-5876},
support = {2022ZD0212200//Ministry of Science and Technology of the People's Republic of China/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) exhibits spatial heterogeneity, yet the mechanisms by which immune-active meninges communicate with vulnerable brain regions during disease progression remain unclear. This study aimed to investigate meninges-hippocampus crosstalk and map the communication patterns during AD pathology development.

METHODS: We employed 5xFAD transgenic and PS19 tau-pathology mouse models and integrated bulk RNA sequencing, proteomics, and spatial transcriptomics across time-course analyses to distinguish AD pathology from normal aging processes. Transcription factor activity inference was coupled with ligand-receptor dynamics analysis to examine regulatory modules in homeostatic and disease-associated microglia.

RESULTS: We identified structure-specific disease genes, including a robust 19-gene hippocampal signature that was reproducible across an independent 5xFAD dataset and PS19 tau-pathology dataset. Spatial analysis defined a disease progression axis that transferred to the independent spatial dataset, where meningeal spots were enriched in advanced disease progression layers and disease modules showed consistent gradients. Ligand-receptor and microglial-state LRaxis analyses further supported candidate communication axes associated with pathology gradients and state-specific regulatory modules in both homeostatic and disease-associated microglia.

CONCLUSIONS: Our spatial framework supports the meninges as a candidate modulatory interface associated with hippocampal pathology in AD mouse models. These mouse-derived, computationally inferred ligand-receptor and regulatory modules should be considered hypothesis-generating candidates that require validation in human AD tissues and functional perturbation studies before translational relevance can be inferred.},
}

@article {pmid42351176,
year = {2026},
author = {Liu, Y and Yao, Z and Zhu, L and Peng, W},
title = {Extracellular vesicle-mediated bidirectional communication between the brain and peripheral organs in Alzheimer's disease: evidence, mechanisms, and translational perspectives.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04705-7},
pmid = {42351176},
issn = {1477-3155},
support = {No.825B20009//National Natural Science Foundation of China for PhD Students/ ; No.82374552//National Natural Science Foundation of China/ ; No.2024JJ2086//Hunan Provincial Natural Science Foundation for Distinguished Young Scholars/ ; No.20240304076//Support Plan for High-level Health and Medical Talents in Hunan Province/ ; },
abstract = {Alzheimer's disease (AD) has traditionally been conceptualized as a brain-centered neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau pathology, synaptic dysfunction, and progressive neuronal loss. However, accumulating evidence suggests that AD is also shaped by systemic disturbances and reciprocal communication between the central nervous system and peripheral organs. Extracellular vesicles (EVs), which transport proteins, lipids, metabolites, and nucleic acids across biological fluids and barriers, have emerged as plausible mediators of this inter-organ crosstalk. In this Review, current evidence for EV-mediated bidirectional communication between the brain and peripheral organs is synthesized, with particular attention to the liver-brain, heart-brain, gut-brain, lung-brain, bone-brain, and adipose-brain axes. The strength of evidence across these axes is compared, and the ways in which organ-derived EVs may influence neuroinflammation, neurovascular dysfunction, metabolic homeostasis, blood-brain barrier integrity, and Aβ/tau-related processes are discussed, while also considering how brain-derived EVs (BDEVs) may affect peripheral physiology. The translational potential of EVs as diagnostic biomarkers, therapeutic carriers, and candidate targets for systemic intervention in AD is further evaluated. Current evidence most strongly supports the gut-brain, liver-brain, and adipose-brain axes, whereas several other axes remain supported primarily by experimental models or engineered EV studies. Major barriers to progress include EV heterogeneity, limited source specificity, insufficient standardization of isolation and quantification workflows, and a continuing reliance on associative human data and preclinical models. Overall, EVs are best viewed as one candidate signaling layer within a broader systemic network linking peripheral physiology to brain pathology. Clarifying the magnitude, directionality, and causal significance of these interactions will require rigorous EV characterization, source-resolved in vivo trafficking studies, and longitudinal clinical investigation.},
}

@article {pmid42351233,
year = {2026},
author = {Alotaibi, Y and Rajendran, S},
title = {Reinforcement learning-driven adaptive game therapy for cognitive impairment patients with improved vision transformer based detection model.},
journal = {BMC psychology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40359-026-05043-x},
pmid = {42351233},
issn = {2050-7283},
support = {26UQU4281768GSSR01//Umm Al-Qura University, Saudi Arabia/ ; },
abstract = {BACKGROUND: Cognitive impairment is the growing challenge that requires early diagnosis and personalized management of neurodegenerative conditions like Alzheimer's disease. Neuroimaging modalities like Magnetic Resonance Imaging (MRI) provide valuable structural and functional insights into brain changes associated with cognitive decline. However, existing deep learning (DL) based diagnostic models have the challenges in non-consideration of long-range spatial dependencies and contextual information across brain slices that lead to suboptimal classification accuracy.

METHODS: To overcome the limitations, this research introduces the framework that combines an Improved Vision Transformer (Im-ViT) with the Residual Simple Recurrent Unit (ResNet-SRU) based Multilayer Perceptron (MLP) to capture spatial and temporal dependencies in neuroimaging data. Preprocessing using Multiscale Gaussian Filter (MGF) enhances feature clarity by removing multiscale noise. In addition, the system integrates the Visual Working Memory (VWM)-based game therapy, where difficulty levels dynamically adapt using the proposed Iterative Hiking-based Reinforcement Learning (ItHRL) approach.

RESULTS: The analysis of the proposed model based on various assessment measures like Accuracy, Recall, Precision, F-Score, Specificity, and Mean Squared Error (MSE) acquired the values of 99.62%, 99.33%, 98.97%, 99.56%, 99.62% and 0.018 respectively.

CONCLUSIONS: The proposed model with combined detection and game therapy approach yield higher classification accuracy, faster convergence and patient engagement.},
}

@article {pmid42351234,
year = {2026},
author = {Jin, B and Li, A and Xu, F and Chen, C and Dong, J and Wang, J and Tang, D and Gu, Y and Liu, H},
title = {Age-dependent diagnostic and correlational architecture of multiplex plasma biomarkers in Alzheimer's disease: a cross-ethnic, cross-platform validation study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02119-z},
pmid = {42351234},
issn = {1758-9193},
support = {2024-BS-038//Doctoral Start-up Foundation of Liaoning Province/ ; 2024JH2/102600308//Joint Program of Science and Technology Plan of Liaoning Province/ ; },
abstract = {BACKGROUND: Plasma phosphorylated tau-217 (p-tau217) is one of the most accurate blood-based biomarkers for Alzheimer's disease (AD), yet whether its diagnostic and correlational properties vary with age at onset has not been systematically examined.

METHODS: We measured eight plasma biomarkers (tau, amyloid, neurodegeneration, neuroinflammation) via automated chemiluminescence immunoassay in a Chinese memory clinic cohort (n = 604; amyloid positron emission tomography (PET) reference), with validation in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1,615; amyloid and tau PET). Diagnostic accuracy and biomarker-clinical correlations were compared between early-onset (EO < 65 years) and late-onset (LO ≥ 65 years) subgroups.

RESULTS: Overall accuracy was high (primary area under the curve (AUC) 0.923; ADNI 0.904). In ADNI, p-tau217 showed higher accuracy in EO than LO (AUC 0.940 vs 0.892, P = 0.012), most pronounced at age 60 and absent by 70. The optimal biomarker shifted from tau-centric markers in LO to Aβ42/Aβ40 in EO. Tau biomarker-clinical correlations diverged sharply by onset age and were stronger in EO for cognitive and neuropsychiatric outcomes, whereas glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) showed no age-dependent heterogeneity. Opposing-direction associations were observed for p-tau217%, which correlated negatively with onset age in AD but positively in Non-AD cognitive impairment. In an exploratory analysis, baseline p-tau217 was associated with longitudinal cognitive decline, numerically greater in EO though based on a small subgroup. Cross-ethnic generalizability was supported by the ADNI-Asian subgroup.

CONCLUSIONS: This cross-ethnic, cross-platform study demonstrates that the diagnostic accuracy, biomarker-clinical correlation architecture, and optimal analyte selection of plasma p-tau217 vary systematically with age at onset, most markedly for tau-related measures. These findings challenge universal threshold paradigms and support age-stratified biomarker interpretation in clinical practice and therapeutic trial design.},
}

@article {pmid42351318,
year = {2026},
author = {Naranjo-Galvis, CA and Zabaleta, J and Alliey-Rodriguez, N and Salamanca-Duque, LM},
title = {Challenge-based ex vivo immune profiling reveals stimulus-dependent peripheral immune reprogramming in Alzheimer's disease.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag166},
pmid = {42351318},
issn = {1758-535X},
abstract = {Altered immune function is increasingly recognized as a contributor to Alzheimer's disease (AD); however, it remains unclear whether peripheral immune alterations reflect constitutive inflammation or stimulus-dependent changes in immune responsiveness. Addressing this distinction is critical for understanding immune dysregulation in neurodegenerative diseases. In this study, we applied a challenge-based ex vivo immune profiling approach to characterize functional immune responsiveness in patients with AD and in cognitively healthy older adults. Peripheral blood mononuclear cells were exposed to defined innate, antigenic, and mitogenic stimuli, and cytokine and β-amyloid responses were quantified in culture supernatants. Diagnosis-by-stimulus interaction effects were assessed using generalized estimating equation models, adjusted for age and sex. In parallel, exploratory correlation-based immune-amyloid network analyses and hypothesis-driven immunogenetic stratification were performed to investigate biomarker coordination patterns and context-dependent genetic influence. Baseline cytokine concentrations showed limited between-group differences, whereas ex vivo immune challenge revealed selective stimulus-dependent alterations in cytokine production. In contrast, immune stimulation revealed selective amplification of stimulus-evoked responses in AD, particularly involving IFN-γ, IL-4, and IL-10, whereas classical proinflammatory cytokines retained preserved inducibility. Exploratory genotype-stratified analyses suggested potential context-dependent differences in functional immune and β-amyloid responses to immune challenges. Together, these findings indicate that peripheral immune dysregulation in AD is characterized by stimulus-dependent differences in cytokine production that become apparent under immune challenge conditions, highlighting the value of ex vivo immune stimulation assays in translational immunology in neurodegenerative diseases.},
}

@article {pmid42351415,
year = {2026},
author = {Xu, J and Costen, F},
title = {Machine Learning-Based Multiclass Classification of Cognitive Stages Using Plasma Biomarkers, Clinical Assessments, and Genetic Features: A Repeated, Nested Cross-Validation Study in ADNI with External Evaluation in CNTN.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {12},
pages = {},
doi = {10.3390/diagnostics16121755},
pmid = {42351415},
issn = {2075-4418},
abstract = {Background: Plasma biomarkers are promoted as scalable tools for the staging of Alzheimer's disease (AD), yet head-to-head comparisons against the clinical scales used to define diagnostic labels remain scarce. Reported gains from machine learning fusion of clinical and biomarker features may reflect label circularity rather than biological signals, and quantifying this circularity is a central aim of the present work. Methods: From the Alzheimer's Disease Neuroimaging Initiative (ADNI), we assembled 655 participants (CN = 296, MCI = 168, and AD = 191) with concurrent plasma biomarkers (pT217, Aβ42/40, NfL, and GFAP), clinical scales (MMSE, CDR-SB, and FAQ), APOE genotype, and demographics. Three pre-specified feature sets (clinical-only, biomarker plus demographic-genetic, and full fusion) were compared across four classifiers (Logistic Regression, SVM, Random Forest, and XGBoost) using repeated, nested cross-validation (5-fold × 3 outer, 5-fold inner) with balanced class weighting. Because the external Center for Neurodegeneration and Translational Neuroscience (CNTN) cohort (n=130) measures pT181 rather than pT217 and lacks Aβ42/40, external evaluation used a separate reduced feature panel (NfL, GFAP, APOE, age, sex, and education), not the proposed pT217-inclusive panel. Results: Clinical scales alone reached a three-class AUC-OVR of 0.9539±0.0041, and fusion reached 0.9559±0.0046, an indistinguishable gain. Because MMSE, CDR-SB, and FAQ partly determine ADNI diagnostic labels, both estimates are circularity-inflated upper bounds and do not reflect independent classification power. Independent of this circularity, the internal plasma plus demographic-genetic model still achieved AUC-OVR =0.7455±0.0150, with pT217 as the dominant contributor. Pairwise discrimination was excellent for CN vs. AD (1.0000) and MCI vs. AD (0.9739) but markedly weaker for CN vs. MCI (0.9302 for fused and 0.6972 for plasma only). The separate reduced-feature model, which contains neither pT217 nor Aβ42/40, transferred to CNTN with AUC-OVR =0.702 (95% CI 0.635-0.764). Conclusions: Apparent fusion gains in ADNI are largely a consequence of label circularity. After removing the circular clinical features, the internal pT217-inclusive plasma model supports three-class CN/MCI/AD screening at AUC ≈0.74 and a reduced panel without pT217 transfers to an independent cohort at AUC ≈0.70. These values provide a realistic performance estimate for blood-based AD staging under the current feature set, diagnostic label structure, and cohort design, and richer feature sets or pathology-anchored labels may shift this estimate. MCI detection remains the principal bottleneck.},
}

@article {pmid42351427,
year = {2026},
author = {Kim, S and Kwon, SR and Lee, JH and Lee, K and Song, SH and Song, J},
title = {Diagnostic Performance and Clinical Utility of Automated Plasma Amyloid-β 1-42/1-40 Assay.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {12},
pages = {},
doi = {10.3390/diagnostics16121767},
pmid = {42351427},
issn = {2075-4418},
support = {05-2025-0064//Seoul National University Bundang Hospital/ ; },
abstract = {Background: Blood-based biomarkers offer an accessible alternative to cerebrospinal fluid or positron emission tomography (PET) imaging for Alzheimer's disease (AD) screening and diagnosis. This study evaluated the diagnostic performance of the fully automated HISCL plasma Aβ42/40 assay in a real-world clinical setting. Methods: We retrospectively enrolled 127 participants, stratified into cognitively normal (CN), mild cognitive impairment (MCI), AD, and Non-AD subgroups. Plasma Aβ42/40 levels were quantified using the HISCL and Simoa platforms. Additionally, plasma oligomerized Aβ (OAβ), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured. Results: The HISCL plasma Aβ42/40 ratio was significantly lower in the AD continuum (MCI + AD) compared to the CN subgroup (p < 0.001). The HISCL assay demonstrated robust diagnostic performance (AUC = 0.747), yielding a comparably higher AUC value compared to the Simoa Aβ42/40 ratio (AUC = 0.687). Although method comparison showed a proportional difference between HISCL and Simoa, the HISCL assay maintained high discriminative capability. Notably, integrating plasma GFAP and NfL with the HISCL Aβ42/40 ratio significantly enhanced the diagnostic accuracy (AUC = 0.823, p = 0.046). Method comparison between heparinized and EDTA plasma in the HISCL assay confirmed assay stability, showing a significant correlation and a regression slope near unity. Conclusions: The HISCL plasma Aβ42/40 assay demonstrates reliable diagnostic performance for identifying AD pathology in clinical practice, showing stability across sample types. Furthermore, its combination with neurodegeneration markers significantly improves predictive accuracy, supporting its utility as a robust screening tool and foundational component of future multimarker diagnostic panels.},
}

@article {pmid42351553,
year = {2026},
author = {Hong, B and Tao, T and Li, Y and Gu, Z and Zhang, H and Chen, J and Yue, L},
title = {Prediction of Antipsychotic Drug Doses for BPSD in Alzheimer's Disease Using Deep Learning Techniques.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {12},
pages = {},
doi = {10.3390/diagnostics16121894},
pmid = {42351553},
issn = {2075-4418},
support = {STI2030-Major Projects-2022ZD0213100//National Natural Science Foundation of China/ ; STI2030-Major Projects-2022ZD029000//National Natural Science Foundation of China/ ; NA//the integrated innovation team project of Shanghai Mental Health Center/ ; JCYJ-SHFY-2022-014//Shanghai Pilot Program for Basic Research-Chinese Academy of Science, Shanghai Branch/ ; 20Y11906800//Shanghai Science and Technology Committee/ ; No.KCXFZ20211020163408012//Shenzhen Science and Technology Program/ ; NA//the Program of High-Level Medical Talents, National Health Commission of China/ ; 2023-TX-018//the Programe of Chen Frontier Lab for AI and Mental Health (TCCI) - Shanghai Mental Health Center (SMHC)/ ; SHDC12025118//Shanghai Shen-Kang Hospital Development Center/ ; SHDC22025303//Shanghai Shen-Kang Hospital Development Center/ ; NA//the Integrated Innovation Team Project of Shanghai Mental Health Center/ ; NA//The Scientific Research Program of FuRong Laboratory/ ; 19MC1911100//Shanghai Clinical Research Center for Mental Health/ ; 13dz2260500//Shanghai Key Laboratory of Psychotic Disorders/ ; },
abstract = {Background/Objectives: Antipsychotic dosing for behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease remains empirical and variable. This study develops a deep learning model to predict individualized antipsychotic doses from structural MRI. Methods: A transfer learning approach with a cascaded ResNet (Cas-ResNet) was used. The model was first pre-trained on a large healthy aging dataset (CBMFM, n = 646) for brain age prediction, then fine-tuned on a BPSD dataset (SMHC, n = 86) to predict the defined daily dose (DDD) of antipsychotics. Model interpretability was performed using Grad CAM to identify predictive brain regions. Results: The proposed model achieved a mean absolute error of 0.19 and a Pearson correlation of 0.66 between predicted and actual doses, outperforming baseline 3DCNN, VGG, and DenseNet. Key contributing regions included the left inferior temporal gyrus, right parahippocampal gyrus, right putamen, left middle temporal gyrus, and left caudate. Conclusions: This proof-of-concept study demonstrates that deep learning can predict personalized antipsychotic doses from structural MRI, offering an objective tool to standardize BPSD pharmacotherapy and reduce empirical prescribing. The identified brain regions provide neurobiological insights into treatment response.},
}

@article {pmid42351685,
year = {2026},
author = {Stavrovskaya, AV and Pavlova, AK and Voronkov, DN and Olshanskiy, AS and Romanenko, AS and Fedorova, EN and Simonenko, AV and Sukhorukov, VS and Illarioshkin, SN},
title = {Impact of Semaglutide on Hippocampal Injury in a Streptozotocin-Induced Model of Alzheimer's Disease.},
journal = {Biomedicines},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biomedicines14061257},
pmid = {42351685},
issn = {2227-9059},
support = {grant for major scientific projects in priority areas of scientific and technological developmentProject No. 075-15-2024-638//Ministry of Science and Higher Education of the Russian Federation: grant for major scientific projects in priority areas of scientific and technological development/ ; },
abstract = {Background: Glucagon-like peptide-1 receptor (GLP1R) agonists, particularly semaglutide, show neuroprotective effects in genetic models of Alzheimer's disease (AD). However, their delayed and long-term effects in sporadic AD, such as the intracerebroventricular streptozotocin (STZ) injection, remain insufficient. It is unclear how long the effects of GLP1R agonists persist after discontinuation and whether a single course can suppress progressive neurodegeneration. This study aimed to evaluate the delayed effects of semaglutide administration on morphological changes in neurons and glial cells in the hippocampus associated with cognitive impairment in an STZ-induced rat model of AD. Methods: Rats received bilateral intracerebroventricular STZ injections (3 mg/kg) followed by a 5-week course of intraperitoneal administration of semaglutide (0.1 mg/kg, every other day), and were euthanized 60 days after discontinuation of semaglutide administration. Immunomorphological methods were used to detect neuronal, astrocytic and microglial alterations. A novel object recognition test was performed to assess behavioral effects. Results: STZ-treated animals demonstrated cognitive impairments, ventriculomegaly, a significant increase in p-tau protein fluorescence intensity (p = 0.02), a decrease in CA1-CA3 field area (by 23%, p = 0.008), and reduced hippocampal neuronal density. Decreases in TOMM20 (mitochondrial marker) and synaptophysin levels were accompanied by significant glial activation in the hippocampal CA3 field. Semaglutide administration significantly reduced the enlarged ventricular lumen (by 43.5%), decreased p-tau fluorescence intensity, reduced vimentin-positive reactive astrocytes (by 68.4%), and increased synaptophysin fluorescence intensity. Furthermore, it reduced microglial activation (decreasing IBA1 cell density and elongation) and alleviated the disrupted AQP4 distribution. However, semaglutide did not completely halt the neurodegenerative process and showed no effect on the number of doublecortin-positive cells in the dentate gyrus. Conclusions: Hippocampal changes assessment revealed that course administration of semaglutide exerts prolonged effects, attenuating the severity of pathomorphological alterations and behavioral changes in a sporadic AD model after drug discontinuation.},
}

@article {pmid42351711,
year = {2026},
author = {Khan, FF and Kwon, GR},
title = {APOE ε4 Allele Dose and Time to Clinical Conversion from Mild Cognitive Impairment to Alzheimer's Disease Dementia: An ADNI Survival Analysis.},
journal = {Biomedicines},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biomedicines14061280},
pmid = {42351711},
issn = {2227-9059},
abstract = {Background/Objectives: Existing Alzheimer's disease (AD) prediction studies often treat APOE ε4 as a binary carrier variable and emphasize classification rather than time-to-event progression. This study evaluated whether APOE ε4 allele dose predicts clinical conversion from mild cognitive impairment (MCI) to AD dementia/probable AD in a longitudinal survival framework adjusted for hippocampal volume and baseline cognition. Methods: We analyzed 1115 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with baseline MCI, APOE genotype data, and at least one follow-up visit, grouped by APOE ε4 allele count (0, 1, or 2). Kaplan-Meier curves, Bonferroni-corrected log-rank tests, nested Cox models, interaction testing, and twelve sensitivity and robustness analyses were performed. Results: During 3.73 ± 3.38 years of mean follow-up, 399 participants (35.8%) clinically converted. Median conversion-free survival was 18.47 years for non-carriers, 4.32 years for heterozygotes, and 3.41 years for homozygotes, although the non-carrier median occurred late in follow-up. In the fully adjusted Cox model, APOE ε4 dose remained associated with conversion hazard (HR = 1.580, 95% CI 1.362-1.834, p < 0.0001). Intracranial Volume (ICV)-adjusted hippocampal volume was protective (HR = 0.620, 95% CI 0.566-0.680, p < 0.0001), and the model achieved a Concordance Index (C-index) of 0.805. The APOE ε4 × hippocampal volume interaction was not significant (likelihood ratio test p = 0.098). Sensitivity analyses supported robustness, although the APOE ε4 association was attenuated in the exploratory amyloid-positive CSF subgroup. Conclusions: These findings support APOE ε4 allele dose as a statistical marker of clinical progression risk in ADNI, not as evidence of biomarker-confirmed AD progression or distinct mechanisms.},
}

@article {pmid42351734,
year = {2026},
author = {Dragomir, AF and Barbu, AC and Stoleru, S and Zugravu, A and Dumitrescu, MC and Bazar, G and Ghita, CIV and Fratea, S and Stoleru, CM and Coman, OA and Fulga, I},
title = {Comparative Effects of Donepezil and Tacrine on Recall-Related Exploratory Behavior in a Subacute Lipopolysaccharide-Induced Neuroinflammatory Model of Cognitive Impairment.},
journal = {Biomedicines},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biomedicines14061306},
pmid = {42351734},
issn = {2227-9059},
abstract = {Background/Objectives: Neuroinflammation is increasingly recognized as an important contributor to Alzheimer-like cognitive impairment. Lipopolysaccharide (LPS) is commonly used in experimental models to trigger systemic immune activation and behavioral alterations associated with neuroinflammation. This study aimed to validate a subacute LPS-induced model of recall-phase impairment and to compare the effects of donepezil and tacrine on recall-related exploratory behavior in rats. Methods: Male Wistar rats were tested in a two-trial Y-maze paradigm consisting of an acquisition trial followed by a recall trial 24 h later. In the validation experiment, rats received saline or LPS 1 mg/kg intraperitoneally for four consecutive days. In the intervention experiment, rats received saline, LPS, or LPS combined with donepezil 1 or 3 mg/kg or tacrine 3 or 5 mg/kg. The primary recall-phase outcome was the unknown/known arm time ratio (U/K time ratio). Additional outcomes included arm times, arm entries, U/K entry ratios, discrimination indices, and mean time per entry. Results: Repeated LPS administration significantly reduced the U/K time ratio, decreased time- and entry-based discrimination indices, reduced time spent in the unknown arm, and decreased unknown-arm entries, without significantly altering acquisition-phase behavior, total entries, or mean time per entry. In the intervention experiment, donepezil 1 mg/kg and tacrine 5 mg/kg significantly increased the U/K time ratio compared with LPS. Discrimination indices and entry-based measures further supported a treatment-related shift toward novelty-directed exploration, while total arm entries and mean time per entry were not significantly changed. Conclusions: Subacute LPS administration produced a measurable recall-phase exploratory impairment in the Y-maze. Donepezil and tacrine attenuated several components of this impairment, with partially distinct dose-related behavioral profiles.},
}

@article {pmid42351738,
year = {2026},
author = {Sarwar, T and Rehman, AA and Arif, H and Alwanian, WM and Alharbi, HOA and Rahmani, AH},
title = {Biophysical and Computational Insights into Alpha-1 Antitrypsin Aggregation and Its Inhibition by Natural Polyphenols.},
journal = {Biomedicines},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biomedicines14061310},
pmid = {42351738},
issn = {2227-9059},
abstract = {Background/Objectives: Protein misfolding and amyloid fibril formation underlie several degenerative diseases, including Alzheimer's disease and Parkinson's disease. Alpha-1 antitrypsin (A1AT), a serpin protein, is particularly prone to misfolding, with polymerization and aggregation implicated in alpha-1 antitrypsin deficiency and associated hepatic and pulmonary disorders. In this study, we examined the structural changes in A1AT induced by the fluorinated alcohol, trifluoroethanol (TFE), and assessed the inhibitory effects of two natural polyphenols, amentoflavone (AMF) and theaflavin (TF), on aggregation and fibril formation. Methods: A library of selected phytocompounds was virtually screened against the crystal structure of A1AT (PDB 3NE4) using AutoDock Vina to elucidate their binding affinity towards it. Based on binding affinities, two compounds, AMF and TF, were selected for further studies. Protein aggregation was induced with TFE, and the protective effects of AMF and TF were evaluated using protease inhibitory activity, intrinsic fluorescence, turbidity, Rayleigh scattering, ANS fluorescence, and ThT fluorescence assays. Furthermore, 100 ns molecular dynamics simulation and MM-PBSA calculations were performed to assess the stability and binding interactions of the A1AT-ligand complexes. Results: Pre-treatment of A1AT with AMF or TF significantly inhibited TFE-induced aggregation in a dose-dependent manner, with AMF being consistently more effective. ThT fluorescence analysis revealed a ~60-65% decrease in aggregate formation upon treatment with polyphenols, with IC50 values estimated at ~40 µM for AMF and ~50 µM for TF, both of which are statistically significant. Molecular docking and 100 ns molecular dynamics simulation also revealed stable A1AT-polyphenol interactions, with AMF exhibiting greater binding affinity and greater attenuation of solvent-induced conformational perturbation. Conclusions: Collectively, our findings show that TFE causes A1AT misfolding via a molten globule-like intermediate, resulting in fibril formation at 30-40% TFE, and natural polyphenols AMF and TF inhibited aggregation in a concentration-dependent manner. These observations suggest the potential of AMF and TF as lead scaffolds for anti-aggregation strategies, as modulators of amyloidogenic processes.},
}

@article {pmid42351744,
year = {2026},
author = {Chen, K and Shi, H and Bai, Y and Shi, S and Gao, B and Duan, H and Hao, P and Zhao, W and Gao, Y and Yang, Z and Li, X},
title = {BDNF-Hyaluronic Acid Hydrogel Promotes Neuronal Differentiation of Neural Stem Cells in Aβ-Induced Injury and 5×FAD Mice.},
journal = {Biomedicines},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biomedicines14061316},
pmid = {42351744},
issn = {2227-9059},
support = {82271403//National Natural Science Foundation of China/ ; 82272171//National Natural Science Foundation of China/ ; 31730030//National Natural Science Foundation of China/ ; 81941011//National Natural Science Foundation of China/ ; 31971279//National Natural Science Foundation of China/ ; },
abstract = {Objectives: Alzheimer's disease (AD) is associated with impaired adult hippocampal neurogenesis (AHN). This study aimed to establish an in vitro model of Aβ1-42 oligomer-damaged neural stem cells (NSCs) and to employ the 5×FAD mouse model of AD in vivo, and to evaluate the therapeutic effects of brain-derived neurotrophic factor-loaded hyaluronic acid hydrogel (BDNF-HA gel) on AHN. Methods: In vitro, BDNF-HA gel was co-cultured with Aβ1-42 oligomer-impaired NSC spheres and evaluate NSC proliferation, migration, and differentiation. In vivo, BDNF-HA gel was infused intracerebroventricularly into 5×FAD mice. Using BrdU labeling, immunofluorescence, anterograde transsynaptic viral tracing, and behavioral tests, we assessed the effects of BDNF-HA gel on adult neurogenesis, newborn neuron integration into memory circuits, and cognitive function. Results: In vitro, BDNF-HA gel attenuated Aβ1-42-induced NSC apoptosis, restored proliferation and migration, promoted differentiation into neuroblasts, newborn neurons, and oligodendrocytes, and alleviated mitochondrial depolarization and loss of mitochondrial mass. In vivo, despite the absence of significant Aβ plaques reduction in 5×FAD mice, BDNF-HA gel markedly enhanced NSC proliferation and neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ). Behavioral tests further revealed significant improvements in object recognition, spatial working memory, and spatial reference memory. Conclusions: BDNF-HA gel can effectively counteract the toxic microenvironment induced by Aβ oligomers, promoting NSC proliferation, migration, and differentiation into neurons. Without altering the Aβ burden, it significantly enhances adult neurogenesis and rescues cognitive deficits in AD mice.},
}

@article {pmid42351804,
year = {2026},
author = {Edem, EE and Soja, SB and Abba, MR and Chinyere, KF and Enye, LA},
title = {Not All Sleep Loss Is Equal: A Comprehensive Evaluation of Rodent Models, Their Neurobiological Validity, and Translational Relevance to Neurological Disease.},
journal = {Biomedicines},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/biomedicines14061376},
pmid = {42351804},
issn = {2227-9059},
abstract = {Not all sleep loss is equal, and overlooking this limits progress in sleep and neurological disease research. We compared nine rodent sleep deprivation paradigms, gentle handling, multiple platform variants, disk-over-water, the Unpredictable Chronic Sleep Deprivation (UCSD) paradigm, novel object introduction, curling prevention by water, automated systems, and head-lifting, evaluating stress confounds, sleep stage specificity, chronicity, and neurobiological outcomes. Effects included hippocampal plasticity, prefrontal chemistry, glymphatic clearance, neuroinflammation, oxidative stress, neurogenesis, and circadian regulation, linked to Alzheimer's, Parkinson's, and psychiatric comorbidities. UCSD with caffeine produced antioxidant depletion, serotonin reduction, acetylcholinesterase upregulation, and synaptophysin loss, early neurodegeneration markers. We propose a disease-targeted framework with six translational priorities and reporting standards.},
}

@article {pmid42351874,
year = {2026},
author = {Wang, Q and Wu, M},
title = {Cross-Lingual Alzheimer's Disease Speech Detection: Polarity Inversion and Few-Shot Calibration Strategies.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/bioengineering13060629},
pmid = {42351874},
issn = {2306-5354},
support = {(Grant No. 2025J01001)//the Natural Science Foundation of Fujian Province/ ; },
abstract = {Speech-based non-invasive screening offers a cost-effective and scalable approach for the early detection of Alzheimer's disease (AD). However, the clinical utility of deep learning models remains severely constrained by the scarcity of labeled speech data in low-resource languages, necessitating cross-lingual transfer learning. Conventional domain adaptation paradigms typically assume semantically consistent feature domains and focus heavily on aligning marginal distributions; however, they suffer catastrophic performance degradation when applied to cross-lingual pathologic speech. By analyzing disease-associated representation vectors within a self-supervised HuBERT space, we uncover a systematic mechanism driving this failure, a phenomenon we term cross-lingual polarity flip, where the direction of disease-relative-to-control feature offsets fundamentally reverses between languages. While prior multilingual studies have largely discarded such dimensional inconsistencies as ungeneralizable noise, a 500-round Monte Carlo stability analysis demonstrates that these flips occur in a highly stable, structural manner across 18.3% of top discriminative dimensions. Leveraging this insight, we introduce Monte Carlo Polarity Flip Calibration (MC-PFC), a few-shot framework designed to explicitly rectify flip orientations. Requiring only five labeled support samples per class from the target domain, MC-PFC robustly estimates direction flips via a separability-weighted ensemble voting mechanism. Evaluated on a strictly held-out Chinese blind test set, MC-PFC achieves an area under the receiver operating characteristic curve (AUC) of 0.871, recovering 99.5% of the performance achieved by a full in-domain trained upper bound (AUC = 0.875). Ablation experiments confirm that direction calibration yields a substantial +0.361 AUC gain, vastly outperforming standard distribution alignment (+0.081). This work establishes a data-efficient paradigm for cross-lingual medical analysis, shifting the clinical AI focus from discarding cross-lingual discrepancies to actively modeling and calibrating them.},
}

@article {pmid42351911,
year = {2026},
author = {Habeb, MH and Alnanih, RA and Elrefaei, LA},
title = {ACross-Paradigm CNN-Swin Transformer Ensemble with Super-Resolution Enhancement for Multi-Class Alzheimer's Disease Classification.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/bioengineering13060666},
pmid = {42351911},
issn = {2306-5354},
abstract = {Alzheimer's disease (AD) is a global health challenge requiring early and accurate diagnosis, yet current clinical methods struggle with early stages. Deep learning approaches for MRI-based diagnosis face persistent challenges related to image quality issues, limited model generalization, and subtle inter-class variations. To address these limitations, this paper proposes a robust, end-to-end brain MRI-based framework for multi-class classification of AD stages. Positioned within the broader research priority of artificial intelligence and intelligent healthcare technologies, the proposed methodology incorporates an attention-based ensemble of deep learning models alongside an enhanced image preprocessing that uses Real-ESRGAN to mitigate common compression and resolution degradations in 2-D MRI slices. The ensemble makes use of the superior capabilities of the Swin Transformer to capture global contextual dependencies and EfficientNet-B3/MobileNetV2 for effective multi-scale feature extraction, with feature fusion performed using a Squeeze-and-Excitation attention mechanism. The experiments were performed on a publicly available Alzheimer's MRI dataset, resulting in classification accuracy of 94.47% and 92.28% for the two proposed frameworks. The robustness and clinical interpretability of the framework are emphasized through comprehensive metrics and qualitative analysis. This framework demonstrates promising benchmark performance on a standardized public dataset, highlighting the potential of cross-paradigm ensembles combined with super-resolution preprocessing.},
}

@article {pmid42351942,
year = {2026},
author = {Kathilankal Jis, J and Chen, K and Zhao, C and Chen, L and Pouriyeh, S and Xie, Z and Xie, Y},
title = {Centralized Review of Alzheimer's Disease and Related Dementias Biomedical Repositories and Computational Methods.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/bioengineering13060698},
pmid = {42351942},
issn = {2306-5354},
support = {#2138259, #2138286, #2138307, #2137603, #2138296//Kennesaw State University/ ; },
abstract = {Alzheimer's disease and related dementias (ADRD) are neurodegenerative conditions characterized by progressive cognitive and functional decline. AD pathology is associated with extracellular amyloid-β plaques, intracellular tau neurofibrillary tangles, synaptic dysfunction, and neuronal loss. AD accounts for approximately 60-80% of dementia cases globally. In 2022, AD was the seventh leading cause of death in the United States, and the number of Americans aged 65 and older living with Alzheimer's dementia is projected to increase substantially by 2060. Despite decades of research, AD/ADRD data resources remain fragmented across clinical, imaging, genetic, genomic, and therapeutic domains. This paper addresses that gap by providing a centralized review of widely used AD/ADRD databases and computational methods. We first summarize computational approaches used to analyze these datasets, including machine learning (ML), natural language processing (NLP), and biomedical imaging. We then review eight databases classified into three categories: Clinical and Population Data, Genetics and Genomics, and Drug Discovery and Therapeutics. Finally, we discuss real-world applications, including early diagnosis, clinical decision support, personalized medicine, and drug-mechanism analysis. This review identifies opportunities for future work in data harmonization, cross-database compatibility, and robust, generalizable AI models for AD/ADRD research.},
}

@article {pmid42352004,
year = {2026},
author = {Garcia-Baucells, P and Bartra, C and Sarroca, S and Reinoite, F and Senserrich, J and Corpas, R and Griñán-Ferré, C and Sanfeliu, C},
title = {Translational Insights into Exercise-Induced Protective Adaptations in 5XFAD Mice and Middle-Aged Amateur Sportsmen.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/antiox15060698},
pmid = {42352004},
issn = {2076-3921},
abstract = {The increase in antioxidant defenses mediated by physical exercise signaling is proposed to be a protective factor against brain aging and neurodegeneration. However, the processes involved, particularly the response of senescence markers and cell fitness status in the context of Alzheimer's disease (AD) pathology, remain unclear. We analyzed male and female 5XFAD transgenic AD mice subjected to 6 months of voluntary wheel running using molecular and behavioral techniques. Levels of mRNA of selected genes, mitochondrial complex proteins, and proteasomal function, were analyzed in the cerebral cortex or hippocampus. In an exploratory translational approach, proteasomal dynamics- and senescence-related genes were analyzed in peripheral blood from middle-aged amateur sportsmen. Physical exercise increased expression of antioxidant genes and modulated epigenetic genes in 5XFAD male and female mice. An increase in protein levels of hippocampal mitochondrial complexes CIII and CV was also induced in males. Both exercised 5XFAD mice and veteran sportsmen showed improved proteasomal status and decreased expression of senescence genes. Exercised mice showed memory and behavior preservation, as well as increases in brain metabolic fitness and gene modulation. These changes may contribute to the neuroprotective effect of physical exercise.},
}

@article {pmid42352232,
year = {2026},
author = {Ding, S and Li, J and Chen, Z and Bai, W and Li, K},
title = {Calcium at the Helm: Mechanisms and Therapeutic Targets in the Retinal Neurovascular Unit.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060763},
pmid = {42352232},
issn = {2218-273X},
support = {82571232//National Natural Science Foundation of China/ ; BK20240122//Natural Science Foundation of Jiangsu Province/ ; },
mesh = {Humans ; Animals ; *Calcium/metabolism ; Diabetic Retinopathy/metabolism/drug therapy/pathology ; *Retina/metabolism/drug effects/pathology ; Glaucoma/metabolism/drug therapy/pathology ; Blood-Retinal Barrier/metabolism ; *Retinal Diseases/metabolism/drug therapy ; Calcium Channel Blockers/pharmacology/therapeutic use ; Retinal Ganglion Cells/metabolism/pathology ; },
abstract = {Retinal neurovascular unit (RNVU) dysfunction underlies major blinding and neurodegenerative conditions including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal ischemia-reperfusion (RIR) injury, and Alzheimer's disease (AD)-associated retinopathy. Within the RNVU, calcium ions coordinate neurotransmission, glial activation, vascular tone, and blood-retinal barrier maintenance, and calcium dysregulation is emerging as a unifying pathogenic hub across these conditions. Although upstream triggers differ, including mechanical stress in glaucoma, hyperglycemia in DR, oxidative damage in AMD, ischemic energy failure in RIR, and amyloid-β-driven endoplasmic reticulum stress in AD, all converge on disruption of intracellular calcium homeostasis, producing shared downstream consequences including excitotoxic injury of retinal ganglion cells (RGCs), Müller cell reactive gliosis, and pericyte hypercontraction. Broad-spectrum calcium channel blockade has shown limited clinical success, underscoring the need for cell-type-specific and pathway-selective approaches. This review therefore catalogs key interventional nodes, including transient receptor potential (TRP) channel antagonists, T-type calcium channel inhibitors, calcium/calmodulin-dependent protein kinase II (CaMKII) suppressors, and mitochondrial permeability transition pore (mPTP) inhibitors, and discusses how precision targeting of these pathways may restore RNVU homeostasis and open a therapeutic window into central nervous system (CNS) degenerative disorders.},
}

Humans
Animals
*Calcium/metabolism
Diabetic Retinopathy/metabolism/drug therapy/pathology
*Retina/metabolism/drug effects/pathology
Glaucoma/metabolism/drug therapy/pathology
Blood-Retinal Barrier/metabolism
*Retinal Diseases/metabolism/drug therapy
Calcium Channel Blockers/pharmacology/therapeutic use
Retinal Ganglion Cells/metabolism/pathology

@article {pmid42352258,
year = {2026},
author = {Singh, AA and Khan, F and Song, M},
title = {Role of Microbial Toxins in Neurodegenerative Diseases: Insights and Future Perspectives.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060790},
pmid = {42352258},
issn = {2218-273X},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/microbiology/pathology ; Animals ; *Bacterial Toxins/metabolism/toxicity ; Oxidative Stress ; *Mycotoxins/metabolism/toxicity ; },
abstract = {Neurodegenerative disorders, including Parkinson's, Alzheimer's, and multiple sclerosis, are significant global health issues characterized by escalating neuronal dysfunction and cognitive decline. Studies suggest that microbial toxins originating from fungi and bacteria may contribute to neurodegenerative processes by altering neuronal homeostasis in several ways. Toxins formerly associated with infectious diseases have now been associated with neuroinflammation, oxidative stress, and protein misfolding, all of which are common in neurodegenerative diseases. According to recent studies, microbial toxins generated by the gut microbiota may cross the blood-brain barrier and possibly contribute to neuroinflammatory cascades linked to the development of neurodegenerative diseases. The complex interplay of microbial metabolites, microbial responses, and mitochondrial dysfunction demonstrates the diverse character of neurodegenerative processes. This review delves into the current understanding of microbial toxins, which are produced by diverse bacteria and can have a direct or indirect impact on neuronal health via multiple signaling pathways. Understanding the signaling mechanisms of microbial and toxin-mediated neurodegenerative diseases could result in the development of effective alternative therapeutics for neurological disorders.},
}

Humans
*Neurodegenerative Diseases/metabolism/microbiology/pathology
Animals
*Bacterial Toxins/metabolism/toxicity
Oxidative Stress
*Mycotoxins/metabolism/toxicity

@article {pmid42352263,
year = {2026},
author = {Lei, Q and He, Y and Fang, B},
title = {Glycolysis: The Bridge Between Cellular Interaction and Alzheimer's Disease.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060796},
pmid = {42352263},
issn = {2218-273X},
support = {81971152//National Natural Science Foundation of China/ ; 2900025016//Liaoning Red Cross Foundation/ ; XLYC2412063//The Health Commission of Liaoning Province/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Glycolysis ; *Cell Communication ; Animals ; Neurons/metabolism/pathology ; Astrocytes/metabolism/pathology ; Microglia/metabolism/pathology ; Energy Metabolism ; },
abstract = {The pathological progression of Alzheimer's disease (AD) involves not only intrinsic neuronal lesions but is also closely associated with dysregulation of intercellular communication within the neuroimmune microenvironment. Glycolysis, as a central pathway in cellular energy metabolism, exhibits significant abnormalities in AD, and changes in its activity may further influence disease progression by modulating interactions between neurons. This article aims to systematically elucidate how glycolysis, as a key component of metabolic regulation, participates in the regulation of cellular interactions during the progression of AD, and to explore its potential mechanisms and therapeutic implications. Firstly, it systematically reviews the key changes in interactions between cells in AD, including microglia, astrocytes, oligodendrocytes, and neurons, and their roles in neuroinflammation, synaptic loss, and amyloid deposition. Secondly, by analysing alterations in the glycolytic metabolic profiles of various neuronal cell types in AD, we explore in depth how glycolysis regulates cellular signalling, inflammatory responses, and cellular function, thereby influencing cell-cell interactions. Lastly, by combining current research on the control of the glycolytic pathway in AD with possible therapeutic methods, we propose a novel way to stop the progression of the disease by focusing on cell interactions through mediating glycolysis. By tracing the causal chain in AD through which glycolysis acts as a bridge via altered cell-cell interactions, this paper aims to provide a theoretical basis for the development of disease-modifying therapies based on metabolic reprogramming.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Glycolysis
*Cell Communication
Animals
Neurons/metabolism/pathology
Astrocytes/metabolism/pathology
Microglia/metabolism/pathology
Energy Metabolism

@article {pmid42352265,
year = {2026},
author = {Tian, M and Feng, R and Gong, C and Ben, X and Ma, Z and Yi, X and Guo, Q},
title = {Intranasal Adipose-Derived MSC Extracellular Vesicles Confer Sustained Cognitive Improvement and Suppress Alzheimer's Pathology in APP/PS1 Mice.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060798},
pmid = {42352265},
issn = {2218-273X},
support = {ZDYF2024SHFZ137//Department of Science and Technology of Hainan Province/ ; 823QN246//Department of Science and Technology of Hainan Province/ ; 82301632//National Natural Science Foundation of China/ ; QCQTXM202213//Department of Science and Technology of Hainan Province/ ; },
mesh = {Animals ; *Alzheimer Disease/therapy/pathology/metabolism/genetics ; *Extracellular Vesicles/metabolism/transplantation ; Administration, Intranasal ; Mice ; Female ; Mice, Transgenic ; *Mesenchymal Stem Cells/metabolism/cytology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; Presenilin-1/genetics/metabolism ; Cognition ; Disease Models, Animal ; *Adipose Tissue/cytology ; Hippocampus/metabolism/pathology ; Humans ; Cognitive Enhancement ; },
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapies, and extracellular vesicles (EVs) derived from adipose-derived mesenchymal stromal cells (ADMSCs) have emerged as promising therapeutic candidates. In this study, we investigated the brain biodistribution and dose-dependent effects of intranasally administered ADMSC-EVs in female APP/PS1 mice, with age-matched wild-type mice and vehicle-treated transgenic mice serving as controls. EV biodistribution was assessed using PKH26 labeling, cognitive performance was evaluated using the Morris water maze, Y-maze, and novel object recognition tests, and hippocampal amyloid pathology and plasma AD-related biomarkers were analyzed. Intranasally delivered ADMSC-EVs rapidly reached multiple brain regions, including the hippocampus, improved learning and memory performance, and reduced hippocampal amyloid-β 1-42 (Aβ42) deposition and plaque burden. These effects followed a nonlinear dose-response pattern, with reduced efficacy at low doses and no additional benefits at high doses. Notably, partial behavioral and pathological benefits persisted after treatment cessation. Together, these findings show that intranasal ADMSC-EVs exert therapeutic effects in APP/PS1 mice and support the importance of dose optimization and post-treatment durability in the development of EV-based interventions for AD.},
}

Animals
*Alzheimer Disease/therapy/pathology/metabolism/genetics
*Extracellular Vesicles/metabolism/transplantation
Administration, Intranasal
Mice
Female
Mice, Transgenic
*Mesenchymal Stem Cells/metabolism/cytology
Amyloid beta-Protein Precursor/genetics/metabolism
Amyloid beta-Peptides/metabolism
Presenilin-1/genetics/metabolism
Cognition
Disease Models, Animal
*Adipose Tissue/cytology
Hippocampus/metabolism/pathology
Humans
Cognitive Enhancement

@article {pmid42352275,
year = {2026},
author = {Fehér, Á and Boldizsár, A and Pákáski, M and Janka, Z and Kálmán, J},
title = {The Variant T Allele of SLC2A1 rs841847 Confers Moderate Protection Against Late-Onset Alzheimer's Disease.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060808},
pmid = {42352275},
issn = {2218-273X},
mesh = {Humans ; *Alzheimer Disease/genetics ; Female ; *Polymorphism, Single Nucleotide ; *Alleles ; Male ; Case-Control Studies ; Aged ; *Glucose Transporter Type 1/genetics ; Genetic Predisposition to Disease ; Aged, 80 and over ; Age of Onset ; Gene Frequency ; Genotype ; },
abstract = {Epidemiological and biological evidence indicate a close connection between Alzheimer's disease (AD) and type-2 diabetes mellitus. Glucose transporter 1 (GLUT1), encoded by the SLC2A1 gene, has a major role in glucose metabolism, the dysregulation of which has been implicated in both diseases. We conducted a case-control association study in a sample of 439 non-diabetic patients with late-onset AD and 304 cognitively healthy, non-diabetic elderly controls to determine the potential risk for developing AD associated with SLC2A1 rs841847 polymorphism. The rs841847 C/C genotype occurrence was higher in the AD group (AD: 60.4%, controls: 50.7%), while the minor T allele-containing genotypes were more frequent among controls (AD: 39.6%, controls: 49.3%). A multivariate logistic regression model adjusted for age, sex, and apolipoprotein E (APOE) ε4 status (ε4 allele carriers versus non-carriers) demonstrated that carriers of the T allele had a significantly reduced risk for AD compared to C/C homozygotes (OR = 0.672; 95% CI: 0.493-0.916; p = 0.012). Although the rs841847 polymorphism has been linked to type-2 diabetes mellitus, the present study investigated this gene variant in AD for the first time. Our findings indicate a moderate protective effect for the rs841847 T allele on the susceptibility to AD. We demonstrated the rs841847 polymorphism as a candidate single nucleotide polymorphism for further examination as a predisposing genetic factor for AD.},
}

Humans
*Alzheimer Disease/genetics
Female
*Polymorphism, Single Nucleotide
*Alleles
Male
Case-Control Studies
Aged
*Glucose Transporter Type 1/genetics
Genetic Predisposition to Disease
Aged, 80 and over
Age of Onset
Gene Frequency
Genotype

@article {pmid42352309,
year = {2026},
author = {Morciano, G and Gorgoglione, R and Porcelli, V and Ahmed, A and Scarcia, P and Vozza, A and Lasorsa, FM and Fiermonte, G and Palmieri, L},
title = {Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060842},
pmid = {42352309},
issn = {2218-273X},
support = {2020RRJP5L//Ministry of Universities and Research/ ; 2022ZY7ATN//Ministry of Universities and Research/ ; GR-2019-12369862//Italian Ministry of Health/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; *Mitochondrial Dynamics ; *Mitochondria/metabolism ; Animals ; *Mitochondrial Proteins/metabolism ; Energy Metabolism ; Mitochondrial Membrane Transport Proteins/metabolism ; },
abstract = {Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology/drug therapy
*Mitochondrial Dynamics
*Mitochondria/metabolism
Animals
*Mitochondrial Proteins/metabolism
Energy Metabolism
Mitochondrial Membrane Transport Proteins/metabolism

@article {pmid42352321,
year = {2026},
author = {Merino, JJ and Rodríguez-Arellano, JJ and Busquets, X and Álvarez-Vicente, I and Cabaña-Muñoz, ME and Flores, AI and Gasca, AT},
title = {The Immune-Chemokine Axis in Alzheimer's Disease: Roles of Adaptive Immune System in Neuroinflammation and Disease Progression.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060855},
pmid = {42352321},
issn = {2218-273X},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/metabolism ; Animals ; *Adaptive Immunity ; Disease Progression ; *Chemokines/immunology/metabolism ; *Neuroinflammatory Diseases/immunology/pathology ; Brain/immunology/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; T-Lymphocytes/immunology ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) and the accumulation of tau in the brain, which triggers robust innate immune responses. Growing evidence indicates that neuroinflammation contributes to AD progression by overactivating microglia through the release of cytokines and chemokines. In general, chemokines can disrupt neuronal communication and promote blood-brain barrier permeability. Peripheral immune cells are mobilized into the brain by a gradient of chemokines. These processes link peripheral immune responses with substantial T-cell infiltration into the CNS parenchyma, leptomeninges and cerebrospinal fluid of both AD mice and AD patients. This finding underscores the relevance of the adaptive immune system, particularly T and B cells, in AD neuropathology. T-cell infiltration into the brain can influence amyloid clearance through chemokine signalling. However, chemokines play a critical role in AD by either promoting or suppressing disease progression. The infiltration of peripheral T and B cells into the brain parenchyma can exacerbate neuronal loss, yet it may also exert neuroprotective effects. Despite the presence of CD4[+] and CD8[+] T cells in postmortem brains of AD patients, debate continues about their role in AD brains, in terms of whether they are protective or detrimental. Understanding the complex role of chemokines in controlling innate and adaptive immune responses by modulating neuron-glia interactions (involving astrocytes and microglia) may provide novel therapeutic approaches for AD. Targeting chemokine signalling or treating with drugs that can prevent the recruitment of immune cells may be promising strategies for treating AD neuropathology. Therapies that prevent the overactivation of T cells in the brain could lead to protective strategies against AD. In fact, regulatory T cells (Tregs) could delay the onset of cognitive symptoms, because they suppress inflammation and slow the accumulation of Aβ plaques and p-Tau in the brain. Complementary strategies, such as photobiomodulation, nanoparticle, and T-cell-based approaches, could mitigate AD progression in patients.},
}

Humans
*Alzheimer Disease/immunology/pathology/metabolism
Animals
*Adaptive Immunity
Disease Progression
*Chemokines/immunology/metabolism
*Neuroinflammatory Diseases/immunology/pathology
Brain/immunology/pathology/metabolism
Amyloid beta-Peptides/metabolism
T-Lymphocytes/immunology

@article {pmid42352337,
year = {2026},
author = {Abd El-Fattah, W and Guesmi, A and Hamadi, NB and Alshehri, KM and Abdella, EM and Mohamed, RR and Elshaarawy, RFM and Hafez, HS},
title = {Chitosan Nanoparticles Co-Encapsulating Selegiline Analogue and L-Tyrosine Mitigate Depression-Related Pathology and Cognitive Decline in Rats.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060871},
pmid = {42352337},
issn = {2218-273X},
support = {IMSIU-DDRSP2601//Imam Mohammad ibn Saud Islamic University/ ; },
mesh = {Animals ; *Tyrosine/chemistry/pharmacology/administration & dosage ; Rats ; *Nanoparticles/chemistry ; *Depression/drug therapy/pathology/metabolism ; *Chitosan/chemistry ; Male ; *Selegiline/chemistry/pharmacology/analogs & derivatives/administration & dosage ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; Hippocampus/metabolism/drug effects ; Oxidative Stress/drug effects ; Monoamine Oxidase/metabolism ; },
abstract = {Chronic depression is associated with oxidative stress, neuroinflammation, neurotransmitter imbalance, and Alzheimer's-like changes. Current monoamine oxidase inhibitors have limited cognitive benefits and disease-modifying properties. A new nanotherapeutic, combining chitosan nanoparticles, propargylamino-1-(4-methylthiophenyl) propane (PAMTP), and L-tyrosine (En@PAMTP_Tyr), was developed. En@PAMTP_Tyr nanoparticles were ~140 nm in diameter, with a zeta potential of +27 mV and entrapment efficiencies of 73.45% for PAMTP and 90.85% for L-tyrosine. Drug release was pH-sensitive, favoring acidity. Intraperitoneal administration of En@PAMTP_Tyr reduced anhedonia, despair, cognitive deficits, and neuromuscular weakness, with efficacy matching or exceeding that of selegiline. In treated rats' hippocampal tissue, En@PAMTP_Tyr increased superoxide dismutase and glutathione, normalized MAO and acetylcholinesterase activities, and corrected CUSD-induced TNF-α and IL-10 changes, showing antioxidant and anti-inflammatory effects. Histological analyses revealed that En@PAMTP_Tyr preserved CA1 pyramidal neurons, reduced β-amyloid levels, restored tau protein, and improved brain-derived neurotrophic factor levels, indicating reduced neurodegeneration. Molecular docking studies showed that PAMTP had high affinity for monoamine oxidase and acetylcholinesterase, supporting its role as an MAO-B inhibitor and cholinergic modulator. These findings suggest that En@PAMTP_Tyr is a promising nanoplatform for targeting MAO-B in depression, addressing mood, cognitive function, oxidative stress, inflammation, and Alzheimer-like pathology in the hippocampus.},
}

Animals
*Tyrosine/chemistry/pharmacology/administration & dosage
Rats
*Nanoparticles/chemistry
*Depression/drug therapy/pathology/metabolism
*Chitosan/chemistry
Male
*Selegiline/chemistry/pharmacology/analogs & derivatives/administration & dosage
*Cognitive Dysfunction/drug therapy/metabolism/pathology
Hippocampus/metabolism/drug effects
Oxidative Stress/drug effects
Monoamine Oxidase/metabolism

@article {pmid42352386,
year = {2026},
author = {Matsushita, A and Kimura, M and Tajima, N and Yamanaka, T and Inazu, M},
title = {Polyphenols Suppress Intracellular Zinc Deficiency-Induced ROS Production and NLRP3 Inflammasome Activation in Microglial and Neuronal Cells.},
journal = {Biomolecules},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/biom16060920},
pmid = {42352386},
issn = {2218-273X},
support = {24K10042//Japan Society for the Promotion of Science/ ; },
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Reactive Oxygen Species/metabolism ; *Microglia/metabolism/drug effects ; *Zinc/deficiency/metabolism ; *Polyphenols/pharmacology ; *Inflammasomes/metabolism/drug effects ; *Neurons/metabolism/drug effects ; Humans ; Oxidative Stress/drug effects ; Antioxidants/pharmacology ; Cell Survival/drug effects ; },
abstract = {Zinc deficiency is increasingly recognized as a risk factor for neurodegenerative diseases, yet the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the impact of intracellular zinc depletion on oxidative stress and inflammasome activation in microglial (SIM-A9) and neuronal (SH-SY5Y) cell models, and evaluated the protective effects of polyphenolic compounds. Intracellular zinc chelation with the membrane-permeable chelator TPEN markedly increased reactive oxygen species (ROS) production, reduced cell viability, and upregulated the mRNA expression of NLRP3 inflammasome-related genes and pro-inflammatory cytokines. In contrast, extracellular zinc chelation had no effect, highlighting the critical role of intracellular zinc homeostasis in maintaining redox balance. Zinc supplementation significantly attenuated these responses. Among 32 polyphenols screened by DPPH radical scavenging assay, caffeic acid derivatives-chicoric acid (ChA), rosmarinic acid (RA), and caffeic acid phenethyl ester (CAPE)-exhibited the most potent antioxidant activity, surpassing that of edaravone. These compounds suppressed ROS production and differentially protected against zinc deficiency-induced cellular damage. ChA showed the strongest ROS inhibitory activity (IC50: 1.9 µM in SIM-A9), RA provided robust cytoprotection even at low concentrations, and CAPE most effectively suppressed inflammasome-related gene expression and inhibited aggregation of both Aβ1-42 and the highly neurotoxic pyroglutamate-modified variant pEAβ3-42. These findings demonstrate that intracellular zinc deficiency drives ROS-dependent upregulation of NLRP3 inflammasome-related genes, and suggest that caffeic acid derivative polyphenols may serve as complementary agents for mitigating neuroinflammatory and amyloidogenic processes relevant to Alzheimer's disease.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Reactive Oxygen Species/metabolism
*Microglia/metabolism/drug effects
*Zinc/deficiency/metabolism
*Polyphenols/pharmacology
*Inflammasomes/metabolism/drug effects
*Neurons/metabolism/drug effects
Humans
Oxidative Stress/drug effects
Antioxidants/pharmacology
Cell Survival/drug effects

@article {pmid42352564,
year = {2026},
author = {Anigbogu, C and Svalina, MN and Hoffman, GR and Kumar, A and Tyner, K and Thompson, JA and Kramer, DR},
title = {Theta Oscillations, Oculomotor Processing, and Neural Synchronization: A Review.},
journal = {Brain sciences},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/brainsci16060555},
pmid = {42352564},
issn = {2076-3425},
abstract = {Theta oscillations, neural activity within the 4-8 Hz range, are implicated in a wide range of cognitive functions, including oculomotor and sensory processing, attention, memory, and motor planning and execution across diverse brain regions. Saccadic eye movements (SEMs), which are integral to visual perception and cognition, occur within a similar frequency range. This review explores how theta oscillations contribute to oculomotor and cognitive processing, emphasizing their role in coordinated motor and sensory functions. We synthesize foundational and contemporary studies into a working model describing neural synchronization across cognitive networks. We discuss the complex interplay between theta oscillations, SEMs, and cognition, summarizing the current state of our knowledge.},
}

@article {pmid42352579,
year = {2026},
author = {Crompton, J and Cuthell, R and Steward, TGJ and Watts, WW and Alqahtani, A and Whitcomb, DJ},
title = {Transcranial Focused Ultrasound Stimulation for Alzheimer's Disease-A Scoping Review.},
journal = {Brain sciences},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/brainsci16060570},
pmid = {42352579},
issn = {2076-3425},
abstract = {Background/Objectives: Alzheimer's disease (AD) remains a significant global health challenge, characterised by a persistent resistance to traditional pharmacological interventions. While non-invasive brain stimulation (NIBS) techniques like transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) show therapeutic promise, their limited depth of penetration restricts their efficacy in targeting deep-brain AD pathology. Transcranial focused ultrasound stimulation (tFUS) has emerged as a novel, non-invasive neuromodulatory tool capable of precise deep-brain targeting. This scoping review aims to systematically map the current evidence base regarding the neuromodulatory application of tFUS in AD. Methods: Following PRISMA-ScR guidelines, a scoping search was conducted across four major databases (Ovid MEDLINE, Embase, Web of Science, and CENTRAL). Studies were included if they investigated focused ultrasound stimulation (FUS) as a neuromodulatory intervention for AD, excluding applications involving blood-brain-barrier disruption via microbubbles. Two independent reviewers performed screening and data extraction, with inter-rater reliability assessed via Cohen's kappa. Results: Our analysis indicates that tFUS represents a safe and potent multi-modal intervention for AD that addresses both pathological protein aggregation and electrophysiological network failure. Its ability to modulate neuroplasticity and metabolic recovery suggests a promising therapeutic trajectory. Conclusions: Future research should prioritise the standardisation of acoustic protocols and the pursuit of longitudinal clinical cohorts to establish the long-term efficacy of this non-invasive technology.},
}

@article {pmid42352624,
year = {2026},
author = {Hung, M and Chriss, H and Nelson, M and O'Callaghan, J and Ward, C and Parry, A and Marx, J and Lipsky, MS},
title = {Mapping the Evidence on Oral Health Interventions and Cognitive Status in Alzheimer's Disease: A Scoping Review.},
journal = {Brain sciences},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/brainsci16060615},
pmid = {42352624},
issn = {2076-3425},
abstract = {BACKGROUND: Oral health is increasingly recognized as a potentially modifiable factor in Alzheimer's disease (AD), although its influence on cognitive outcomes remains uncertain.

METHODS: This scoping review followed the Arksey and O'Malley framework and was reported in accordance with PRISMA-ScR guidelines. Searches were conducted in PubMed, Scopus, and Web of Science through August 2025. Eleven studies met the inclusion criteria: one randomized controlled trial, one nonrandomized trial, and nine observational studies.

RESULTS: Poor oral health, including tooth loss, periodontal disease, and impaired mastication, was consistently associated with worse cognitive and dementia-related outcomes. Interventions improved oral and functional measures but yielded limited and inconsistent evidence of cognitive benefit. Proposed mechanisms, including systemic inflammation and microbiome alterations, were infrequently evaluated directly.

CONCLUSIONS: Overall, oral health correlates with cognitive status in AD, but the causal impact of interventions remains uncertain, highlighting the need for rigorous trials with standardized cognitive and mechanistic outcomes.},
}

@article {pmid42352655,
year = {2026},
author = {Baiamonte, L and Bellante, G and Allegra, P and Tarantino, D and Migliazzo, C and Lodico, M and Maniscalco, L and Piccoli, T and Vanacore, N and Matranga, D and Salemi, G},
title = {Attention Deficit/Hyperactivity Disorder and Risk of Dementia: A Systematic Review and Meta-Analysis.},
journal = {Brain sciences},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/brainsci16060646},
pmid = {42352655},
issn = {2076-3425},
abstract = {INTRODUCTION: The significant impact of attention deficit/hyperactivity disorder (ADHD) on health in adult life has been widely recognized. Among the comorbidities of this disorder in later life, dementia is one of the most relevant ones. We performed a systematic review and meta-analysis to explore the impact of previous ADHD diagnosis on dementia risk.

MATERIALS AND METHODS: We systematically searched Pubmed, Embase and Scopus for the relevant literature. Cohort and case-control studies were included in our review. Retrieved records were selected by title and abstract and then by full text reading. For quality appraisal, the Newcastle-Ottawa scale was used. A meta-analysis of hazard ratios (HRs) was performed for each type of dementia.

RESULTS: Four cohort studies and one case-control study were included, for a total of 3,703,877 and 400 participants, respectively. For all-cause dementia, the pooled HR was 2.52 (95%CI 1.51-4.22, p < 0.001), pointing out a significantly higher hazard in subjects with ADHD. For Alzheimer's disease, vascular dementia and Lewy body dementia, no meta-analysis was performed due to the low number of available studies.

DISCUSSION AND CONCLUSIONS: Our results support a significant association between ADHD and risk of dementia. The results regarding specific types of dementia are more challenging to interpret and could have been influenced by sample size issues. These findings show that ADHD deserves attention in future research on cognitive disorders of the elderly; in particular, more studies are needed to reveal if a true causal relationship links ADHD and dementia.},
}

@article {pmid42352664,
year = {2026},
author = {Qiu, Y and Jiao, C},
title = {The Association Between Changes in White Matter Microstructure and Cognitive Function in Older Adults with Mild Cognitive Impairment.},
journal = {Brain sciences},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/brainsci16060655},
pmid = {42352664},
issn = {2076-3425},
support = {22&ZD185//Research on the Innovation and Development of Social Organizations of People with Disabilities under the Background of Healthy China Strategy/ ; },
abstract = {Background: Mild Cognitive Impairment (MCI) is a clinical state between normal aging and dementia. It may involve impairment in one or several cognitive domains. MCI offers a key window for maintaining cognitive function and studying how deficits develop in the elderly, making it of great research value. Measurement tools for screening MCI are not yet standardized in China. The accuracy of diagnostic criteria and threshold values needs improvement. Previous studies on the neural mechanisms of MCI have examined various aspects, but the changes in the white matter microstructure in older adults with MCI remain unclear. Most past studies used Fractional Anisotropy (FA) analysis to examine changes in white matter fiber orientation, often ignoring fiber density. As a result, findings are often contradictory or difficult to interpret. Therefore, it is necessary to assess cognitive function in MCI populations using more comprehensive and standardized measurement tools. It is also important to explore the association between changes in white matter microstructure and cognitive function in MCI by analyzing FA and Mean Diffusivity (MD). Methods: First, we assessed cognitive function using the Cognitive Function Measurement Scale for the Elderly, developed by Beijing Normal University, with diagnoses based on the NIA-AA (National Institute on Aging-Alzheimer's Association) criteria. Second, we employed Diffusion Tensor Imaging (DTI) combined with Tract-Based Spatial Statistics (TBSS) to investigate alterations in the white matter fiber tract integrity in individuals with MCI. Based on the metrics used, this study was divided into two analytical approaches: Analysis Mode 1 utilized FA to explore changes in white matter fiber orientation in the MCI group. Analysis Mode 2 utilized MD to examine changes in white matter fiber density in the MCI group. Third, we further explored the association between alterations in the white matter fiber tract integrity and cognitive function in individuals with MCI. Specifically, FA and MD values from brain regions showing significant differences between the MCI and normal control groups were extracted and correlated with cognitive test scores. Results: According to the results of the community measurement survey, the prevalence of MCI among the elderly in Shenzhen is approximately 21.54%. Individuals with MCI exhibited functional decline in memory, attention, language, executive function, and spatial processing. DTI results indicated that (1) FA values across the brain's white matter fiber tracts showed a decreasing trend in the elderly with MCI, with no areas exhibiting significantly higher FA values. Specifically, FA values were significantly lower in the corpus callosum, internal capsule, corona radiata, thalamic radiation, external capsule, superior fronto-occipital fasciculus, and cingulum (cingulate gyrus). (2) White matter fiber tracts with significantly reduced FA values also demonstrated significantly increased MD values. Additionally, MD values in the cingulum (hippocampus), inferior cerebellar peduncle, and corticospinal tract were significantly reduced in the MCI group. (3) Correlation analysis revealed that the significant differences in FA and MD values within the white matter fiber tracts of older adults with MCI were correlated with scores on several cognitive tests. Conclusions: In the present study, older adults with MCI tended to exhibit functional decline across multiple cognitive domains and relatively extensive microstructural white matter damage. Observations suggested that white matter fiber density may be informative regarding these microstructural alterations, indicating that diffusion biomarkers in key regions such as the cingulum (hippocampus) warrant further investigation.},
}

@article {pmid42352894,
year = {2026},
author = {Janpaijit, S and Verma, K and Widoyanti, AAE and Tencomnao, T and Prasansuklab, A},
title = {Exploring Mechanistic Targets of Areca catechu Against Neurodegenerative Diseases Through an Integrated Network Pharmacology, Molecular Docking, and Experimental Approaches.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125169},
pmid = {42352894},
issn = {1422-0067},
support = {Fundamental Fund//Thailand Science Research and Innovation Fund, Chulalongkorn University/ ; },
mesh = {Molecular Docking Simulation ; Animals ; Network Pharmacology/methods ; *Areca/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry ; Humans ; Caenorhabditis elegans/drug effects ; *Plant Extracts/pharmacology/chemistry ; Mice ; Microglia/drug effects/metabolism ; Alzheimer Disease/drug therapy/metabolism ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders, while the therapeutic efficacy of current drugs for both diseases remains limited, with unfavourable side effects. The fruit of Areca catechu L. (AC) is recognised as a popular chewing item across China and Southeast Asia and has been used for centuries as a traditional remedy, ranging from relieving digestive issues to depression. The neuroprotective role of AC has been underscored in previous studies; however, its mechanisms of action remain unclear. The present study aimed to investigate anti-neurodegenerative mechanisms of AC for the treatment of AD and PD. An integrated approach combining untargeted metabolite profiling, network pharmacology, bioinformatics analysis, and molecular docking was utilised. Experimental validation was performed using in vitro cell-based and in vivo models. The study revealed TNF-α, IL-1β, IL-6, CASP3, MAPK3, and AKT1 as top-ranked hub targets by which AC exerts its action on AD and PD. Enrichment analyses of these genes identified significant biological and functional pathways involved in neuroinflammation, apoptosis, and AD. Experimental validation showed that AC extracts significantly downregulated hub gene expressions in the neuroinflammatory BV-2 microglia cell model and prolonged the survival of the transgenic Caenorhabditis elegans AD model. Docking analysis suggested lucidine B, oxolucidine B, solanocapsine, evodiamine, and liquiritigenin are the principal phytocompounds underlying the neuroprotective properties of AC. The findings revealed the pharmacological mechanisms of AC and highlighted its potential value as an effective, multitargeting natural agent to address challenges in AD and PD therapies.},
}

Molecular Docking Simulation
Animals
Network Pharmacology/methods
*Areca/chemistry
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/chemistry
Humans
Caenorhabditis elegans/drug effects
*Plant Extracts/pharmacology/chemistry
Mice
Microglia/drug effects/metabolism
Alzheimer Disease/drug therapy/metabolism

@article {pmid42352907,
year = {2026},
author = {Scrivo, A and Bernardino, L and Consiglio, A},
title = {The Dual Role of Glial Extracellular Vesicles in Neurodegeneration: Insights from iPSC-Based Models.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125182},
pmid = {42352907},
issn = {1422-0067},
support = {2023 BP 00242//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; },
abstract = {Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication in the brain, with glial cell-derived EVs increasingly recognized for their roles in maintaining brain homeostasis and contributing to the progression of neurodegenerative diseases. By transferring a diverse cargo of bioactive molecules, including proteins, RNAs, and organelles, EVs influence recipient cell behavior and overall brain function. In neurodegenerative conditions, glial EVs can either propagate pathogenic signals or deliver neuroprotective and regenerative cues, depending on their cellular origin and molecular composition. This context-dependent heterogeneity highlights the need for physiologically relevant human models to investigate EVs biology. Human induced pluripotent stem cell (iPSC)-derived glial models provide a disease-relevant platform, as they recapitulate key pathological features of Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). When further integrated with brain organoid platforms, these iPSC-based systems enable the generation of three-dimensional environments that closely resemble in vivo EVs dynamics. Importantly, glial EVs can modulate cellular pathways involved in neuronal survival and function. Indeed, their potential to interact with and, under specific experimental conditions, traverse the blood-brain barrier (BBB) has contributed to growing interest in their application for biomarker discovery and therapeutic development. Engineered and patient-specific EVs derived from iPSCs are emerging as promising tools for targeted, cell type-specific, therapeutic approaches, although their clinical applicability still requires further validation. This review discusses the emerging evidence supporting the dual role of iPSC-derived glial EVs in health and disease, underscores the translational potential of iPSC-based platforms for mechanistic studies, and outlines their promise as precision medicine tools for diagnostics and therapy.},
}

@article {pmid42352925,
year = {2026},
author = {Czubowicz, K and Motyl, JA and Wencel, A and Strosznajder, RP},
title = {The Role of Sphingosine-1-Phosphate Signaling in Cerebral Ischemia/Reperfusion Injury and Alzheimer's Disease Pathology.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125200},
pmid = {42352925},
issn = {1422-0067},
support = {the statutory budget of MMRI PAS, under theme No. 7//Mossakowski Medical Research Institute, Polish Academy of Sciences/ ; },
abstract = {Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that regulates key cellular processes, like proliferation, apoptosis, inflammation, and vascular homeostasis. S1P acts as a signaling molecule both inside and outside cells by interacting with five G-protein-coupled S1P receptors (S1PR1-S1PR5). Accumulating evidence indicates that dysregulation of S1P signaling is implicated in the pathophysiology of cerebral ischemia/reperfusion (I/R) injury and Alzheimer's disease (AD). In I/R injury, S1P signaling regulates vascular permeability, immune cell infiltration, and neuronal survival and death. In AD, alterations in S1P metabolism are associated with β-amyloid deposition, tau hyperphosphorylation, synaptic dysfunction, and sustained neuroinflammation. S1P receptor (S1PR) modulators represent promising therapeutic agents in both preclinical and clinical studies. Fingolimod was the first oral disease-modifying therapy approved for the treatment of multiple sclerosis and, at the same time, the first S1PR modulator introduced into clinical practice. New selective S1PR-targeting agents, including siponimod and ozanimod (S1PR1 and S1PR5), as well as the S1PR1-selective agent ponesimod, have also been approved for clinical use. In addition to their immunomodulatory properties, S1PR modulators have direct effects in the central nervous system, facilitating the maintenance of blood-brain barrier integrity, reducing microglial activation, and enhancing neuronal survival pathways. Building on this knowledge, we discuss the role of S1P signaling, highlighting recent advances in S1PR modulators as promising therapeutic agents for cerebral I/R injury and AD.},
}

@article {pmid42353002,
year = {2026},
author = {Kanubaddi, KR and Yaung, CL and Harn, HJ and Chiou, TW and Hsu, SX and Wijaya, I and Lin, SZ and Wuli, W},
title = {Astragalus and Cordyceps Derivatives in the Treatment of Aging-Related Chronic Diseases and Neurodegenerative Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125273},
pmid = {42353002},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Cordyceps/chemistry ; Animals ; *Aging/drug effects ; Chronic Disease/drug therapy ; *Astragalus Plant/chemistry ; *Drugs, Chinese Herbal/therapeutic use/chemistry ; },
abstract = {Aging is associated with a rising burden of chronic metabolic, cardiovascular, musculoskeletal, and neurodegenerative diseases that share interconnected pathological mechanisms, including oxidative stress, chronic inflammation, mitochondrial dysfunction, metabolic imbalance, and immune dysregulation. Because these disorders arise from complex and overlapping biological disturbances, conventional single-target therapies often provide only limited benefit. In this context, traditional Chinese herbal medicines, characterized by multi-component and multi-target actions, are being re-evaluated using modern pharmacological and systems biology approaches. Among these, Astragalus membranaceus and Cordyceps species have attracted attention as representative tonic medicines with long-standing traditional use and growing biomedical relevance. Their principal bioactive constituents, including polysaccharides, saponins, flavonoids, sterols, and nucleoside derivatives such as cordycepin, exert pleiotropic effects on inflammatory signaling, redox homeostasis, mitochondrial function, metabolic regulation, and immune responses. This review summarizes current evidence on bioactive derivatives from Astragalus and Cordyceps in aging-related chronic and neurodegenerative disorders, including diabetes, cardiovascular dysfunction, osteoarthritis, cancer, Alzheimer's disease, and Parkinson's disease. It focuses on mechanistic findings from cellular and animal studies and critically discusses key translational challenges, such as compositional variability, poor bioavailability, lack of standardized preparation, limited clinical validation, and safety concerns related to toxicity and herb-drug interactions.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
*Cordyceps/chemistry
Animals
*Aging/drug effects
Chronic Disease/drug therapy
*Astragalus Plant/chemistry
*Drugs, Chinese Herbal/therapeutic use/chemistry

@article {pmid42353021,
year = {2026},
author = {Amadea, G and Youn, K and Jun, M},
title = {Systems Biology and Atomistic Simulations Reveal Multi-Target Modulation of Alzheimer's Disease and Type 2 Diabetes by Caesalpinia sappan Bioactives.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125300},
pmid = {42353021},
issn = {1422-0067},
support = {No. RS-2026-25483801//National Research Foundation of Korea/ ; RS-2025-25440216//National Research Foundation of Korea/ ; },
abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are major global health burdens that share interconnected pathological mechanisms involving impaired insulin signaling, metabolic stress, and chronic neuroinflammation. This study applied an integrative systems biology and atomistic simulation framework to investigate bioactive compounds from Caesalpinia sappan L. targeting shared molecular regulators linking AD and T2DM. Network topology analysis identified four central hub genes, STAT3, SRC, HSP90AA1, and TP53, representing key regulatory nodes involved in inflammatory signaling, kinase regulation, proteostasis, and cellular stress responses. Compound-specific interaction analysis revealed distinct target preferences among phytochemical subclasses. Protosappanin B showed strong binding toward both STAT3 and HSP90α, whereas flavonols including quercetin and rhamnetin exhibited high affinity for SRC, and the chalcone derivative sappanchalcone preferentially interacted with TP53. Atomistic molecular dynamics simulations and MM-PBSA calculations supported stable protein ligand interactions and favorable binding energetics, while density functional theory analysis indicated electronic properties consistent with sustained intermolecular interactions. Collectively, these findings suggest that structurally distinct subclasses of C. sappan phytochemicals converge on complementary regulatory hubs within the shared AD and T2DM molecular network, supporting coordinated multi-target modulation of interconnected inflammatory, kinase signaling, proteostasis, and cellular stress pathways underlying AD-T2DM comorbidity.},
}

@article {pmid42353032,
year = {2026},
author = {Shahabian, L and Kynigopoulos, D and Papacharalambous, R and Ioannou, E and Dionysiou, S and Christou, S and Picolos, M and Pipis, M and Panayiotou, E},
title = {Semaglutide Selectively Improves Metabolic and Cognitive Function in 5xFAD Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125311},
pmid = {42353032},
issn = {1422-0067},
mesh = {Animals ; Semaglutide ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Male ; *Cognition/drug effects ; Female ; Disease Models, Animal ; *Glucagon-Like Peptides/pharmacology ; Mice, Transgenic ; Diet, High-Fat/adverse effects ; Amyloid beta-Peptides/metabolism ; Adiponectin/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; Hippocampus/metabolism/drug effects ; Body Weight/drug effects ; },
abstract = {Alzheimer's disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease's progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required.},
}

Animals
Semaglutide
*Alzheimer Disease/drug therapy/metabolism
Mice
Male
*Cognition/drug effects
Female
Disease Models, Animal
*Glucagon-Like Peptides/pharmacology
Mice, Transgenic
Diet, High-Fat/adverse effects
Amyloid beta-Peptides/metabolism
Adiponectin/metabolism
Glucagon-Like Peptide-1 Receptor/metabolism
Hippocampus/metabolism/drug effects
Body Weight/drug effects

@article {pmid42353146,
year = {2026},
author = {Muraleva, NA and Stefanova, NA and Kolosova, NG},
title = {Features of Alteration in MAPK Pathway Activity in the Postnatal Brain of a Rat Model of Sporadic Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125430},
pmid = {42353146},
issn = {1422-0067},
support = {FWNR-2026-0025//Russian Foundation for Basic Research/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; Rats ; Disease Models, Animal ; *MAP Kinase Signaling System ; Rats, Wistar ; *Brain/metabolism ; Hippocampus/metabolism/pathology ; p38 Mitogen-Activated Protein Kinases/metabolism ; Male ; Prefrontal Cortex/metabolism ; Phosphorylation ; },
abstract = {Early-life factors influence adult-brain vulnerability to sporadic Alzheimer's disease (AD), but the underlying molecular mechanisms are unknown. In this study, we performed an integrated analysis of mitogen-activated protein kinases (MAPK) pathways' (ERK1/2, JNK, and p38 MAPK) activity in the hippocampus and prefrontal cortex of OXYS rats (a model of sporadic AD) on postnatal days 3 and 10 (P3 and P10): critical periods of brain maturation. Wistar rats (healthy controls) showed extensive developmental transcriptional remodeling of all MAPK pathways. OXYS rats exhibited alterations, most pronounced in the prefrontal cortex at P3, with the JNK pathway showing the greatest divergence. At the protein level, OXYS rats failed to show the normal age-related increase in hippocampal ERK1/2 phosphorylation and in JNK1/2 levels in both regions, indicating developmental signaling deficits. p38 MAPK remained stable among Wistar and OXYS rats. Thus, delayed brain maturation, which contributes to accelerated brain aging and neurodegeneration in OXYS rats, occurs simultaneously with alterations in MAPK signaling. These aberrations potentially are able to increase brain susceptibility to age-related pathologies later in life.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
Rats
Disease Models, Animal
*MAP Kinase Signaling System
Rats, Wistar
*Brain/metabolism
Hippocampus/metabolism/pathology
p38 Mitogen-Activated Protein Kinases/metabolism
Male
Prefrontal Cortex/metabolism
Phosphorylation

@article {pmid42353174,
year = {2026},
author = {Lee, S and Yoo, YJ and Kim, G and Kim, E and Yun, S and Kim, J and Ryu, H and Chung, W},
title = {Kilovoltage Energy Significantly Enhances the Therapeutic Efficacy of Low-Dose Radiation in a 3xTg-AD Mouse Model of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125458},
pmid = {42353174},
issn = {1422-0067},
support = {RS-2023-00253427//Ministry of Science and ICT/ ; RS-2022-NR070632, RS-2026-255417//Ministry of Science and ICT/ ; RS-2024-00467661//Ministry of SMEs and Startups/ ; RS-2024-00441564//Ministry of SMEs and Startups/ ; RS-2025-02317308//Ministry of Science and ICT/ ; BT250232//Seoul R&BD Program/ ; KHU-20251295//Kyung Hee University in 2025/ ; },
mesh = {Animals ; *Alzheimer Disease/radiotherapy/metabolism/pathology ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Brain/metabolism/radiation effects/pathology ; Male ; },
abstract = {Low-dose radiation (LDR) has emerged as a promising therapeutic modality for Alzheimer's Disease (AD). Although different irradiation protocols have been explored, the optimal parameters for maximizing therapeutic efficacy remain unclear. Radiation energy has been shown to influence radiobiological responses, with more pronounced effects at lower energy ranges. We therefore investigated whether kilovoltage LDR (KLDR) provides superior therapeutic efficacy compared with megavoltage LDR (MLDR) in a murine model of AD(3xTg-AD). To this end, we directly compared the efficacy of MLDR and KLDR in AD model mice to identify an optimal irradiation strategy for LDR treatment with potential relevance to clinical translation in AD. X-rays with 110-kV or 6-MV energy were applied to the brain of AD model mice at an early-stage of disease progression (26-28 weeks age; 0.6 Gy × 5 fractions for 2.5 weeks). After LDR treatment, cognitive function was assessed in AD model mice using passive avoidance (PA) test and novel object recognition (NOR) test. In addition, different molecular markers associated with inflammation, amyloid-beta (Aβ) plaques, tau burden, and neuronal and synaptic degeneration were analyzed in the brain of AD model mice. KLDR (110 kV) significantly inhibited cognitive decline in AD model mice, as demonstrated by both the PA and NOR tests. In addition, KLDR significantly reduced hippocampal levels of GFAP, Iba-1, and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), while increasing anti-inflammatory cytokines (TGF-α, TGF-β, and IL-10), and was associated with marked reductions in Aβ and tau levels. Furthermore, the expression levels of Aβ40 and Aβ42 were quantified by ELISA following KLDR and MLDR treatment, revealing a statistically significant reduction in the KLDR group. The degeneration of neurons and synapses was significantly suppressed also at the kilovoltage energy level. Conversely, MLDR (6 MV) exerted minimal effects and did not produce statistically significant improvements. Taken together, our findings demonstrate that radiation energy level is a key determinant of LDR therapeutic efficacy in AD model mice, with KLDR showing significantly greater effectiveness in improving AD-related pathological features than MLDR. Therefore, KLDR may be recommended as a novel radiation protocol for AD treatment.},
}

Animals
*Alzheimer Disease/radiotherapy/metabolism/pathology
Disease Models, Animal
Mice
Mice, Transgenic
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Brain/metabolism/radiation effects/pathology
Male

@article {pmid42353177,
year = {2026},
author = {Asti, AL},
title = {β-Amyloid (Aβ) and Human Cathelicidin LL-37: Two Sides of the Same Coin?.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125460},
pmid = {42353177},
issn = {1422-0067},
mesh = {Humans ; *Amyloid beta-Peptides/metabolism ; Cathelicidins ; *Antimicrobial Cationic Peptides/metabolism/chemistry ; Alzheimer Disease/metabolism/pathology ; Animals ; Microglia/metabolism ; Antimicrobial Peptides/metabolism ; Parkinson Disease/metabolism/pathology ; Immunity, Innate ; },
abstract = {Physiologically produced circulating β-amyloid (Aβ) exerts critical physiological functions. Although Aβ is a key player in Alzheimer's disease (AD), it may initially be beneficial at the onset of infection. As an evolutionary conserved antimicrobial peptide (AMP), Aβ contributes to innate immune defense against pathogens. Host defense peptides such as Aβ and human cathelicidin (LL-37) not only kill pathogens through their antimicrobial activity but also exhibit high affinity for bacterial lipopolysaccharides (LPSs) and membrane receptors. LL-37, which is upregulated in the brain, binds to Aβ, modulating its aggregation; Aβ and LL-37 are protective under physiological conditions, but during chronic infection or dysregulation, their interaction becomes toxic and contributes to AD pathology. Similarly to Aβ, LL-37 can induce neuroinflammation by stimulating human microglia to release inflammatory cytokines, such as TNF-α and IL-6. Neuroinflammation is essential for protecting the brain from pathogens-when prolonged, it drives pathological processes underlying AD, Parkinson's disease (PD), and other neurodegenerative disorders.},
}

Humans
*Amyloid beta-Peptides/metabolism
Cathelicidins
*Antimicrobial Cationic Peptides/metabolism/chemistry
Alzheimer Disease/metabolism/pathology
Animals
Microglia/metabolism
Antimicrobial Peptides/metabolism
Parkinson Disease/metabolism/pathology
Immunity, Innate

@article {pmid42353182,
year = {2026},
author = {Hasan, M and Abd-ElRaouf, K and Moran, SR and Lo, CH},
title = {Dysregulation of the Tau-Microtubule-End-Binding Protein Axis in Alzheimer's Disease and Related Tauopathies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125467},
pmid = {42353182},
issn = {1422-0067},
support = {Start-up fund//Syracuse University/ ; },
abstract = {Alzheimer's disease (AD) and related tauopathies are marked by progressive cognitive decline, synaptic dysfunction, and neuronal loss. The microtubule (MT)-associated protein tau, encoded by the MAPT gene, plays a central role in neurodegenerative pathology. Although the dissociation of hyperphosphorylated tau from MTs and their subsequent aggregation has been extensively studied, the broader landscape of other MT-associated proteins remains largely underexplored. Among these, the end-binding protein (EBP) family, which comprises MT plus-end-tracking proteins, has emerged as a critical regulator of MT dynamics and stability. EBPs modulate MT polymerization, interact with various MT-associated proteins, and influence cytoskeletal organization. Recent studies suggest that pathological tau impairs end-binding protein 3 (EB3) function by limiting its localization to MT plus-ends and inhibiting EB3-mediated MT elongation and stability. In addition, EB1 appears to interfere with tau aggregation in an in vitro study involving biomolecular condensates. Dysregulation of dynamic tau-MT-EBP interactions may result in structural and functional consequences throughout the entire network, potentially increasing MT instability under neurodegenerative conditions. Hence, the tau-MT-EBP network is an emerging mechanistic axis for advancing the understanding of physiological processes, disease pathology, and therapeutic interventions. In this review, we summarize recent advances in understanding the tau-MT-EBP axis and highlight the molecular mechanisms underlying key pathological interactions within this network. Finally, we discuss current therapeutic strategies and future directions for targeting this dynamic axis to mitigate AD and related tauopathies.},
}

@article {pmid42353197,
year = {2026},
author = {Honjo, A and Yako, H and Kasai, M and Chiba, M and Satsuka, A and Kato, T and Yagi, M and Nishi, A and Miyamoto, Y and Yamauchi, J},
title = {Hesperetin Rescues Amyloid Beta-Induced Defects in Neurite Outgrowth Under In Vitro Mild Cognitive Impairment-like Cellular Conditions.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125481},
pmid = {42353197},
issn = {1422-0067},
mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; Animals ; *Hesperidin/pharmacology ; *Neuronal Outgrowth/drug effects ; *Cognitive Dysfunction/metabolism/drug therapy/pathology ; *Peptide Fragments ; Mice ; Neurons/drug effects/metabolism ; *Neurites/drug effects/metabolism ; Cell Differentiation/drug effects ; Cell Line ; },
abstract = {Accumulation of aggregated amyloid beta (Aβ) species is a defining pathological hallmark of Alzheimer's disease and is associated with extensive neuronal structural abnormalities. Mild cognitive impairment (MCI), a transitional stage between normal aging and the onset of dementia, is thought to represent an early phase of this pathological continuum. Studies at the cellular level suggest that the conditions impair the maintenance of established neuronal processes/networks and restrict their capacity for elongation or re-elongation. They may also attenuate the activation and process extension of quiescent neural progenitor or stem-like cells. These early cellular changes precede overt neurodegeneration in neural tissue and are likely to contribute to cognitive decline. They highlight the importance of in vitro models for identifying molecular targets involved in recovery from disease. In this study, we investigated the effects of aggregated Aβ (25-35) on neuronal process elongation and associated intracellular events in the N1E-115 cell line, a widely used model of neuronal differentiation. Addition of aggregated Aβ to cultured N1E-115 cells attenuated process elongation in a concentration-dependent manner. This morphological impairment was accompanied by decreased expression of neuronal differentiation markers. In contrast, at the half-maximal inhibitory concentration for process elongation, long-term cultured cells did not exhibit apparent process retraction or degenerative morphology. This mild but progressive impairment, without extensive cell death, is consistent with the cellular features of early-stage conditions rather than advanced Alzheimer's pathologies. Similar results were observed in primary cortical neurons. Aβ also decreased the level of GTP-bound Ras and phosphorylation of the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). Furthermore, treatment with hesperetin, a bioactive flavonoid compound, recovered the Aβ-induced inhibition of neuronal process elongation. Hesperetin also restored Ras and MAPK/ERK states, suggesting that its effects are associated, at least in part, with modulation of signaling through Ras and MAPK/ERK. Our findings suggest that hesperetin may serve as a useful molecular probe for modulating early cellular responses associated with Alzheimer's disease-related pathology. This in vitro model might serve as a useful platform for investigating the molecular target candidates involved in recovery from nervous system disorders.},
}

*Amyloid beta-Peptides/metabolism/toxicity
Animals
*Hesperidin/pharmacology
*Neuronal Outgrowth/drug effects
*Cognitive Dysfunction/metabolism/drug therapy/pathology
*Peptide Fragments
Mice
Neurons/drug effects/metabolism
*Neurites/drug effects/metabolism
Cell Differentiation/drug effects
Cell Line

@article {pmid42353204,
year = {2026},
author = {Olajide, AT and Aunsorn, S and Kehinde, SA and Kaewmanee, T and Chusri, S},
title = {From Tradition to Translation: A Critical Appraisal of Bacopa monnieri for Neuroprotection from Preclinical and Clinical Perspectives and Challenges in Utilization.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125488},
pmid = {42353204},
issn = {1422-0067},
support = {67A307000040//National Science, Research, and Innovation Fund (NSRF) and Mae Fah Luang University (Fundamental Fund Grant)/ ; },
mesh = {*Bacopa/chemistry ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; *Plant Extracts/therapeutic use/pharmacology/chemistry ; *Neuroprotection/drug effects ; Cognitive Enhancement ; },
abstract = {Dementia, and more specifically Alzheimer's disease (AD), is a progressive neurodegenerative disorder that has become a growing health menace in the world with an escalation in incidence as well as enormous social and economic consequences. Existing pharmacological treatment including cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists are not very effective in reducing the symptoms and fail to prevent the disease process. The non-pharmacological treatment interventions such as diet, exercise and cognitive training have supportive effects and cannot be used as standalone treatments. Therapeutic gap has resulted in increased interest in complementary and alternative therapies, especially that of pleiotropic action of herbal medicines. Bacopa monnieri (BM) is an Ayurvedic herb that has historically been used to treat memory enhancement and now has both preclinical and clinical evidence supporting its ability to modulate neurotransmission, reduce oxidative stress and suppress neuroinflammation. However, such difficulties as low bioavailability, instability of the environmental factors, and variations in formulations restrict its clinical applicability. New technologies with a lot of potential such as microencapsulation technology can provide the solution to this problem by increasing stability, solubility, and targeted delivery of compounds that will increase treatment efficacy. This narrative review is a synthesis of the existing information on the pathogenesis of dementia, therapeutic approaches, and the effectiveness of BM as a complementary intervention. It points out links between traditional medicine and modern neuroscience, strengths and limitations of on-going evidence, gaps that need further research, such as long-term clinical trials, standardized formulations, and discovery of the role of BM in the gut-brain axis. BM is a prime example of how herbal medicines can be used as a complement to conventional treatment and play a role in multi-modal approaches aimed at reducing the cognitive impairment associated with dementia.},
}

*Bacopa/chemistry
Humans
Animals
*Neuroprotective Agents/therapeutic use/pharmacology/chemistry
*Alzheimer Disease/drug therapy
*Plant Extracts/therapeutic use/pharmacology/chemistry
*Neuroprotection/drug effects
Cognitive Enhancement

@article {pmid42353205,
year = {2026},
author = {Morishita, S and Hane, M and Wu, D and Kitajima, K and Ohno, S and Yamaguchi, Y and Sato, C},
title = {Prediction of Novel Disease-Related Regions in SIGLEC-7 by In Silico and Biochemical Analyses.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125489},
pmid = {42353205},
issn = {1422-0067},
support = {Grant-in-Aid for Scientific Research(B) (KAKENHI 21H02425, 23K21291, and 25K02224)//Japan Society for the Promotion of Science/ ; Nagoya University Interdisciplinary Frontier Fellowship//Nagoya University/ ; J-glyconet//Ministry of Education, Culture, Sports, Science and Technology/ ; },
mesh = {Humans ; *Antigens, Differentiation, Myelomonocytic/chemistry/genetics/metabolism ; *Lectins/chemistry/genetics/metabolism ; Models, Molecular ; Amino Acid Motifs ; *Antigens, CD/chemistry/genetics/metabolism ; Amino Acid Sequence ; Computer Simulation ; Mutation ; Protein Binding ; Amino Acid Substitution ; Sialic Acid Binding Ig-like Lectin 3/metabolism/chemistry/genetics ; *Antigens, Differentiation, B-Lymphocyte/chemistry/genetics/metabolism ; Sialic Acid Binding Immunoglobulin-like Lectins/chemistry/genetics/metabolism ; },
abstract = {SIGLECs are well-known receptors that distinguish self from non-self by binding to sialic acid-containing glycoconjugates, thereby regulating normal immune functions. They have also been associated with several diseases, including systemic sclerosis, leukemia, and Alzheimer's disease. To identify pathogenic regions related to ligand binding in SIGLECs using a novel approach, we employed the in silico Individual Meta Random Forest (InMeRF) program, which predicts disease-related amino acid substitutions. InMeRF predicted a novel three-amino-acid motif (LSI) consisting of highly pathogenic amino acid residues in SIGLEC-7 and other CD33-related SIGLECs. Alanine substitution experiments and point-mutation energy calculations using SIGLEC-7 as a representative model member of the SIGLEC family showed that mutations in the LSI motif altered binding to ganglioside ligands compared with the wild type (WT) and affected structural stability, as reflected by changes in mutation energy. Structural analysis based on the crystal structure of SIGLEC-7 revealed that the LSI motif forms a buried β-strand located beneath the previously identified sialic acid-binding region (Site 2) in CD33-related SIGLEC-7. Taken together, these findings demonstrate the utility of InMeRF for identifying previously unrecognized pathogenic regions and provide new structural and functional insights into the SIGLEC family.},
}

Humans
*Antigens, Differentiation, Myelomonocytic/chemistry/genetics/metabolism
*Lectins/chemistry/genetics/metabolism
Models, Molecular
Amino Acid Motifs
*Antigens, CD/chemistry/genetics/metabolism
Amino Acid Sequence
Computer Simulation
Mutation
Protein Binding
Amino Acid Substitution
Sialic Acid Binding Ig-like Lectin 3/metabolism/chemistry/genetics
*Antigens, Differentiation, B-Lymphocyte/chemistry/genetics/metabolism
Sialic Acid Binding Immunoglobulin-like Lectins/chemistry/genetics/metabolism

@article {pmid42353247,
year = {2026},
author = {Lamprou, S and Mavromati, K and Gunn-Moore, FJ and Quinn, TJ},
title = {Discovery-Driven Plasma Proteomics Identifies a Multi-Protein Signature for Amyloid PET Positivity: A Machine Learning Analysis of the Bio-Hermes Cohort.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125533},
pmid = {42353247},
issn = {1422-0067},
support = {324008-01//Race Against Dementia/ ; },
mesh = {Humans ; *Proteomics/methods ; *Positron-Emission Tomography/methods ; *Alzheimer Disease/blood/diagnostic imaging/metabolism ; *Machine Learning ; Biomarkers/blood ; *Amyloid/metabolism ; Female ; Boosting Machine Learning Algorithms ; Random Forest ; Cohort Studies ; *Blood Proteins/metabolism ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder in which early detection remains limited by the cost and invasiveness of positron emission tomography and cerebrospinal fluid testing. We evaluated whether plasma proteomic profiles could distinguish amyloid PET-positive from amyloid PET-negative individuals using the Bio-Hermes cohort. After quality control and missing-data filtering, 988 participants and 295 proteins were analysed; 31 proteins showing group differences were used for supervised classification. Random Forest, Gradient Boosting, and Neural Network models were trained across four train/test splits with repeated cross-validation and class downsampling. Amyloid-positive and amyloid-negative groups differed across a subset of proteins, with five remaining significant after false discovery rate correction. Tree-based models performed most consistently, with Random Forest and Gradient Boosting achieving AUC values of 0.79-0.81 and balanced accuracy of 0.68-0.73. Eight proteins (SERPINA1, C3, CRP, APOE4, CFH, VTN, C1QTNF5, and PON1) emerged as recurring high-importance features. These findings indicate that discovery-driven plasma proteomics can identify multi-protein signatures associated with amyloid status and can complement established single-analyte blood biomarkers by adding pathway-level information.},
}

Humans
*Proteomics/methods
*Positron-Emission Tomography/methods
*Alzheimer Disease/blood/diagnostic imaging/metabolism
*Machine Learning
Biomarkers/blood
*Amyloid/metabolism
Female
Boosting Machine Learning Algorithms
Random Forest
Cohort Studies
*Blood Proteins/metabolism

@article {pmid42353264,
year = {2026},
author = {Gualerzi, A and Mangolini, V and Forleo, L and Cabrini, C and Picciolini, S and Bedoni, M},
title = {Raman Spectroscopy for Probing Pathological Protein Aggregates: Potential and Perspectives for Advanced Diagnostic Applications.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125550},
pmid = {42353264},
issn = {1422-0067},
support = {B/2023/0213//Fondo di Beneficenza Intesa San Paolo/ ; },
mesh = {Humans ; *Spectrum Analysis, Raman/methods ; *alpha-Synuclein/metabolism/chemistry ; *Protein Aggregation, Pathological/metabolism/diagnosis ; *Amyloid beta-Peptides/metabolism/chemistry ; *Protein Aggregates ; Animals ; *Parkinson Disease/diagnosis/metabolism ; *Alzheimer Disease/metabolism/diagnosis ; *Neurodegenerative Diseases/diagnosis/metabolism ; },
abstract = {Parkinson's disease and Alzheimer's disease are currently classified as a major global health burden, sharing a defining pathological hallmark represented by insoluble protein aggregates of α-synuclein (α-syn) and amyloid-β (Aβ), respectively. A defining characteristic of all amyloids is a highly ordered, unbranched filamentous morphology, where individual β-strands align perpendicularly to the filament axis. Despite recent technological advances, direct observation of protein conformational changes and amyloid formation in biological samples remains a challenge as well as the quantification of pathological aggregates in liquid biopsies. This review critically recapitulates the major advances in the application of Raman spectroscopy (RS) and surface-enhanced Raman spectroscopy (SERS) in the investigation of pathological protein aggregates in neurological disorders, with a focus on α-syn and Aβ. We discuss both in vitro structural characterization and the applications to biological and clinical samples, outlining the main challenges for clinical translation, including the need for standardized protocols. Recent achievements in the use of RS and SERS on liquid biopsies and other clinical samples are paving the way for further implementation of Raman-based approaches for the diagnosis of neurodegenerative disorders.},
}

Humans
*Spectrum Analysis, Raman/methods
*alpha-Synuclein/metabolism/chemistry
*Protein Aggregation, Pathological/metabolism/diagnosis
*Amyloid beta-Peptides/metabolism/chemistry
*Protein Aggregates
Animals
*Parkinson Disease/diagnosis/metabolism
*Alzheimer Disease/metabolism/diagnosis
*Neurodegenerative Diseases/diagnosis/metabolism

@article {pmid42353279,
year = {2026},
author = {Jorda, A and Alvarez-Gamez, K and Vergani, S and Paba, I and Perez, M and Aldasoro, M and Vila, JM and Valles, SL},
title = {Insulin Regulates AKT/GSK-3β Signalling, Tau Phosphorylation, and Redox Homeostasis in SH-SY5Y Neuroblastoma Cells.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125565},
pmid = {42353279},
issn = {1422-0067},
support = {CIAICO/2023/143//Generalitat Valenciana/ ; },
mesh = {Humans ; *Glycogen Synthase Kinase 3 beta/metabolism ; *tau Proteins/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Insulin/pharmacology/metabolism ; Phosphorylation/drug effects ; *Signal Transduction/drug effects ; Cell Line, Tumor ; *Neuroblastoma/metabolism/pathology ; Oxidative Stress/drug effects ; Oxidation-Reduction/drug effects ; Homeostasis/drug effects ; Apoptosis/drug effects ; Cell Survival/drug effects ; NF-E2-Related Factor 2/metabolism ; },
abstract = {Insulin (Ins) regulates multiple intracellular signalling pathways involved in cell survival, oxidative stress responses, and tau phosphorylation. Dysregulation of these pathways has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD). The present study evaluated the effects of insulin on protein kinase B/glycogen synthase kinase-3 beta (AKT/GSK-3β) signalling, tau phosphorylation, and oxidative stress-related markers in SH-SY5Y neuroblastoma cells. Cell metabolic activity was assessed using the (diphenyltetrazolium bromide) MTT assay, while cell number and viability were evaluated by Trypan Blue exclusion, necrosis by lactate dehydrogenase (LDH) release, and apoptosis by Caspase-3 activity. Western blot analysis was performed to evaluate the expression of phosphorylated AKT (p-AKT), phosphorylated GSK-3β (p-GSK-3β Ser9), phosphorylated TAU (pTAU), nuclear factor erythroid 2-related factor 2 (NRF2), manganese superoxide dismutase (Mn-SOD), and copper/zinc superoxide dismutase (Cu/Zn-SOD). Lipid peroxidation was determined by measuring malondialdehyde (MDA) levels using a colorimetric/fluorometric assay. Insulin treatment increased MTT reduction (31.25%) and cell metabolic activity (119.15%) while reducing LDH release (19.2%) and Caspase-3 activity (31.26%). In addition, insulin significantly increased p-AKT (34.2%) and p-GSK-3β (Ser9) (19.9%) levels. A reduction in pTAU levels (53.39%) was also observed following insulin treatment. Furthermore, insulin increased NRF2 expression (18.77%), Cu/Zn-SOD (37.29%), and Mn-SOD (50.16%) and reduced MDA levels (13.95%). These findings indicate that insulin modulates signalling pathways associated with tau phosphorylation and cellular redox regulation in SH-SY5Y cells. Insulin treatment was associated with increased AKT and GSK-3β phosphorylation, reduced tau phosphorylation, and changes in oxidative stress-related markers in SH-SY5Y neuroblastoma cells. These findings support a role for insulin in the modulation of molecular pathways implicated in cellular stress responses and tau regulation. Further studies using differentiated neuronal models and disease-relevant conditions are required to determine the relevance of these observations to neurodegenerative disorders.},
}

Humans
*Glycogen Synthase Kinase 3 beta/metabolism
*tau Proteins/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
*Insulin/pharmacology/metabolism
Phosphorylation/drug effects
*Signal Transduction/drug effects
Cell Line, Tumor
*Neuroblastoma/metabolism/pathology
Oxidative Stress/drug effects
Oxidation-Reduction/drug effects
Homeostasis/drug effects
Apoptosis/drug effects
Cell Survival/drug effects
NF-E2-Related Factor 2/metabolism

@article {pmid42353303,
year = {2026},
author = {Shao, W and Wang, K and Liu, Y and Zhang, H and Sun, Z and Zhou, R},
title = {Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125580},
pmid = {42353303},
issn = {1422-0067},
support = {zyyzdxk-2023272//State Administration of Traditional Chinese Medicine of the People's Republic of China/ ; },
mesh = {Humans ; *Lipid Metabolism ; Animals ; *Aging/metabolism/pathology ; *Brain/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Neuroglia/metabolism/pathology ; Metabolic Reprogramming ; Apolipoproteins E/metabolism ; },
abstract = {The mammalian brain fundamentally relies on precise lipid homeostasis to maintain structural integrity and complex neural signaling. Emerging evidence positions lipid metabolism reprogramming not merely as a secondary pathological byproduct but as a core initiating driver of age-related neurodegenerative diseases. This review systematically evaluates the mechanisms of cerebral lipid dyshomeostasis during brain aging, highlighting glial cells as the central mediators of this pathological cascade. We comprehensively dissect the age-associated "lipid drift", emphasizing apolipoprotein E (APOE)-induced cholesterol transport defects and lipid raft pathology, the accumulation of lipid droplets that triggers microglial metabolic stress (LDAMs), and ceramide-driven neuronal apoptosis coupled with the exosome-mediated propagation of pathogenic proteins. Furthermore, we map these aberrant lipid networks to specific pathological signatures in Alzheimer's, Parkinson's, and demyelinating diseases. Finally, we critically evaluate promising therapeutic interventions, including nutritional strategies, LXR/RXR agonists, and nanotechnology-enabled delivery systems designed to bypass the blood-brain barrier. By integrating high-throughput lipidomics for early diagnostic biomarker discovery, we underscore the translational imperative of restoring cerebral lipid homeostasis as a disease-modifying strategy for neurodegeneration.},
}

Humans
*Lipid Metabolism
Animals
*Aging/metabolism/pathology
*Brain/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
*Neuroglia/metabolism/pathology
Metabolic Reprogramming
Apolipoproteins E/metabolism

@article {pmid42353342,
year = {2026},
author = {Dey, A and Sanyal, D and Chattopadhyay, K and Maulik, U and Uversky, VN and Sen, S},
title = {IMMUND: A Diagnostic and Therapeutic Pipeline to Uncover the Convergence in Functional Perturbation at Early Stages of Neurodegenerative Diseases and Multiple Sclerosis Based on Protein Markers.},
journal = {International journal of molecular sciences},
volume = {27},
number = {12},
pages = {},
doi = {10.3390/ijms27125627},
pmid = {42353342},
issn = {1422-0067},
mesh = {Humans ; *Multiple Sclerosis/diagnosis/metabolism/immunology/therapy ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/metabolism/immunology/therapy ; Blood-Brain Barrier/metabolism ; Leukocytes, Mononuclear/metabolism ; Alzheimer Disease/diagnosis/metabolism/immunology ; },
abstract = {Neuroinflammation is a key hallmark of both neurodegenerative and neurospecific autoimmune diseases, including multiple sclerosis (MS), where immune dysregulation contributes to cellular stress, autophagy, and disease progression in Alzheimer's disease (AD), Parkinson's disease (PD), and MS. Emerging evidence suggests a shared mechanism behind MS, AD, and PD, driven by chronic interaction between the peripheral immune system and the central nervous system (CNS). While MS was traditionally viewed as a primary autoimmune condition, recent research indicated that all three disorders involve a breakdown of the blood-brain barrier (BBB). This structural failure enables peripheral immune cells and cytokines to enter the brain, causing sustained neuroinflammation and accelerating disease progression. Here, we propose an end-to-end framework for identification of the diagnostic and therapeutic cell-specific protein markers commonly regulated in mild-moderate AD (MMAD), early-stage PD (ESPD), and MS within peripheral blood mononuclear cells (PBMCs). PBMC markers were first identified based on shared differential protein expression, followed by filtering for BBB permeability. Subsequently, sorted cell markers were mapped to disease-specific neural cell types. Our analysis suggests that PBMC-derived cells, including astrocyte- and monocyte-like populations, share overlapping transcriptional signatures and functional similarity with macrophages and neuroglial cells, indicating potential transcriptional similarity or functional convergence. Furthermore, intra- and inter-cellular pathway analysis suggested both shared and disease-specific signaling mechanisms, with kinase-integrin interactions emerging as key regulatory factors. Selected potential seed markers, primarily kinases and immunoglobulins, were further analyzed through evolutionary sequence-structure space to identify druggable structural features. Next, protein moonlighting possibilities were tested to enhance the temporal functional trajectory of the markers for precise therapeutic impact. Hence, the framework provides a robust strategy to identify immune-based disease-specificcandidate diagnostic andpotential therapeutic targets.},
}

Humans
*Multiple Sclerosis/diagnosis/metabolism/immunology/therapy
*Biomarkers/metabolism
*Neurodegenerative Diseases/diagnosis/metabolism/immunology/therapy
Blood-Brain Barrier/metabolism
Leukocytes, Mononuclear/metabolism
Alzheimer Disease/diagnosis/metabolism/immunology

@article {pmid42353615,
year = {2026},
author = {ALNasser, MN and Carter, WG},
title = {Phytochemicals as NMDA Receptor Inhibitors and Their Potential for Treating Excitotoxicity-Related Neurotoxicity: A Systematic Review.},
journal = {Current issues in molecular biology},
volume = {48},
number = {6},
pages = {},
doi = {10.3390/cimb48060611},
pmid = {42353615},
issn = {1467-3045},
support = {KFU260924//King Faisal University/ ; },
abstract = {Excitotoxicity caused by excessive activation of glutamate receptors, particularly N-methyl-D-aspartate receptors (NMDARs), significantly contributes to neuronal damage in neurodegenerative diseases (NDDs), such as Alzheimer's, Parkinson's, and Huntington's diseases. This systematic review aimed to evaluate the effects of plant extracts and phytochemicals on NMDAR-mediated excitotoxicity and to summarize their proposed neuroprotective mechanisms. The review protocol was registered in PROSPERO (CRD42024528160). A systematic search of Medline, Embase, Web of Science Core Collection, and PubMed identified 323 records, with an additional 7 records identified through manual searching that specifically considered in vitro and in vivo inhibitors of NMDAR excitotoxicity using plant extracts and isolated phytochemicals. Twenty-seven studies demonstrated that plant extracts and phytochemicals attenuate excitotoxicity through multiple mechanisms, including inhibition of NMDAR-induced currents, reduction of intracellular calcium influx, modulation of NMDAR expression, attenuation of oxidative stress, and mitochondrial dysfunction. However, the evidence base was largely dominated by in vitro and ex vivo studies, with limited in vivo validation, restricting translational relevance. Risk-of-bias assessment using an adapted version of the Office of Health Assessment and Translation (OHAT) Risk of Bias Tool indicated that 4 studies had a low overall risk of bias, 12 had low to moderate risk, and 11 were at moderate risk, with key limitations related to inadequate reporting of blinding, randomization, and allocation concealment. In contrast, exposure characterization, outcome assessment, and confounding control were generally strong across studies. Although the findings support the mechanistic neuroprotective potential of certain plant extracts and phytochemicals against NMDAR-mediated excitotoxicity, further well-designed in vivo and clinical studies are required to establish their therapeutic relevance for the treatment of neurodegenerative diseases.},
}

@article {pmid42353637,
year = {2026},
author = {Di Gerlando, R and Dragoni, F and Minucchi, E and Garofalo, M and Perini, G and Costa, A and Pisani, A and Morasso, C and Cotta Ramusino, M and Gagliardi, S},
title = {Plasma-Derived miRNAs as Fluid Biomarkers to Differentiate Alzheimer's and Frontotemporal Dementia.},
journal = {Current issues in molecular biology},
volume = {48},
number = {6},
pages = {},
doi = {10.3390/cimb48060633},
pmid = {42353637},
issn = {1467-3045},
support = {GR-2021-12374436/PNC-E.3//Ministry of Health/ ; },
abstract = {Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) are complex neurodegenerative disorders, often sharing overlapping symptoms. Non-coding RNAs may be involved in pathological processes in these conditions, hence the study of miRNAs isolated from plasma-derived extracellular vesicles (EVs) could provide exploratory insights into the molecular background. The main aim of this work was to identify shared deregulated miRNAs presenting different expression patterns in the two pathologies. A selection of the identified deregulated miRNAs was further studied with the purpose of identifying their mRNA targets and generating hypotheses on their potential pathological involvement. A total of 340 and 291 differentially expressed miRNAs were found in FTD and AD, respectively. Among the commonly deregulated miRNAs with opposite expression patterns between the two conditions, miR-638 emerged as a candidate of interest, showing consistent patterns across our experimental analyses. Nevertheless, these findings are preliminary and intended to be interpreted cautiously, requiring validation in larger cohorts. In addition, the expression of two of its predicted targets in peripheral blood mononuclear cells (PBMCs) appeared to align with miR-638 expression in the same cell type and may reflect potential differences in underlying brain pathological states.},
}

@article {pmid42353761,
year = {2026},
author = {Xu, J and Ashebir, YA and Shao, Y},
title = {Molecular Basis of Synergistic Causal Effect of Dual GLP-1R and GIPR Agonists for Risk Reduction in Diabetic Retinopathy, Alzheimer Disease, and Coronary Artery Disease in Diabetic Patients.},
journal = {Genes},
volume = {17},
number = {6},
pages = {},
doi = {10.3390/genes17060602},
pmid = {42353761},
issn = {2073-4425},
support = {U01OH012486/CC/CDC HHS/United States ; P30AG066512/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Coronary Artery Disease/genetics/drug therapy/prevention & control ; *Alzheimer Disease/genetics/drug therapy/prevention & control ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetic Retinopathy/genetics/drug therapy/prevention & control ; *Diabetes Mellitus, Type 2/drug therapy/genetics/complications ; *Receptors, Gastrointestinal Hormone/agonists/genetics ; Glucagon-Like Peptide-1 Receptor/genetics ; Glycated Hemoglobin/metabolism ; Male ; Hypoglycemic Agents/therapeutic use/pharmacology ; Female ; },
abstract = {Background: The dual agonism of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) becomes a groundbreaking treatment for type 2 diabetes (T2D) that achieves robust glycemic control and maintains body weight. It also induces potential risk reduction in diabetic retinopathy (DR), Alzheimer disease (AD), and heart diseases including coronary artery disease (CAD) in treated T2D patients. To date, the molecular basis underpinning the remarkable causal treatment effects and synergy of the dual agonism of GLP-1R and GIPR on risk reduction in T2D, CAD, DR and AD has not been systematically investigated. Methods: To elucidate the treatment effects and potential synergy of dual GLP-1R/GIPR agonism on risk reduction in T2D, CAD, DR and AD while minimizing the impact of confounders, we used a robust cis-Mendelian randomization (cis-MR) with a principal component-based generalized method of moments (PC-GMM) where blood-based glycated hemoglobin (HbA1c), high- and low-density lipoprotein cholesterol (HDL-c, LDL-c), and BMI were used as mediating biomarkers. Results: Our cis-MR analyses confirmed a synergistic causal protective effect of dual GLP-1R/GIPR agonism on T2D via HbA1c reduction [OR = 0.17; 95% CI = (0.11, 0.26); p = 3.68 × 10[-17]] which is more significant than either GLP-1R agonism or GIPR agonism alone. Similarly, the causal protective effect of dual GLP-1R/GIPR agonism via HbA1c reduction was also significant for DR [OR = 0.20; 95% CI = (0.11, 0.36); p = 9.22 × 10[-8]]. Further, our multivariate cis-MR (or cis-MVMR) analyses revealed that after adjusting for HbA1c, a synergistic protective effect on DR via a reduction in LDL-c is significant in dual GLP-1R/GIPR agonism [OR = 0.57; 95% CI = (0.29, 0.94)], while the protective effect on DR of LDL-c reduction is non-significant in either GLP-1R agonism or GIPR agonism alone. Also, after adjusting for HbA1c, the multivariate cis-MR results showed significant protective effects on AD via a reduction in LDL-c in GLP-1R/GIPR agonism [OR = 0.44; 95% CI = (0.25, 0.81)]. Importantly, the multivariate cis-MR results also revealed that dual GLP-1R/GIPR agonism has significant protective effects on CAD via both a reduction in BMI [OR = 0.46; 95% CI = (0.28, 0.75)] and an improvement in HDL [OR = 0.59; 95% CI = (0.39, 0.90)]. This is in support of the hypothesis that dual GLP-1R/GIPR agonism has a synergistic protective effect on CAD that is stronger than that of GLP-1R agonism alone, which yielded a non-significant causal effect for both HDL and BMI, and GIPR agonism alone also yielded a non-significant causal effect for HDL when adjusted for BMI. Conclusions: These novel findings have significant implications for repurposing dual incretin agonism in terms of diabetic drugs to serve as a unifying, precision prevention strategy against CAD, DR and AD as leading drivers of mortality and morbidity in diabetic patients.},
}

Humans
*Coronary Artery Disease/genetics/drug therapy/prevention & control
*Alzheimer Disease/genetics/drug therapy/prevention & control
*Glucagon-Like Peptide-1 Receptor Agonists
*Diabetic Retinopathy/genetics/drug therapy/prevention & control
*Diabetes Mellitus, Type 2/drug therapy/genetics/complications
*Receptors, Gastrointestinal Hormone/agonists/genetics
Glucagon-Like Peptide-1 Receptor/genetics
Glycated Hemoglobin/metabolism
Male
Hypoglycemic Agents/therapeutic use/pharmacology
Female

@article {pmid42353831,
year = {2026},
author = {Rusek, M and Pitucha, M},
title = {From Genes to Imaging Phenotypes: Radiomics and Machine Learning as Tools to Decode Molecular Pathways in Alzheimer's Disease.},
journal = {Genes},
volume = {17},
number = {6},
pages = {},
doi = {10.3390/genes17060672},
pmid = {42353831},
issn = {2073-4425},
mesh = {*Alzheimer Disease/genetics/diagnostic imaging/pathology/metabolism ; Humans ; *Machine Learning ; Radiomics ; Phenotype ; tau Proteins/genetics/metabolism ; Apolipoproteins E/genetics ; Amyloid beta-Peptides/genetics/metabolism ; Molecular Imaging/methods ; },
abstract = {Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder driven by complex interactions between genetic susceptibility, molecular pathways, and progressive brain alterations. Key genetic factors, including APOE, TREM2, and MAPT, contribute to pathological processes such as amyloid-β accumulation, tau aggregation, neuroinflammation, and synaptic dysfunction. Despite substantial advances in understanding these mechanisms, translating molecular insights into clinically accessible biomarkers remains a major challenge. Radiomics and machine learning (ML) have emerged as promising approaches for extracting high-dimensional quantitative features from medical imaging data and identifying complex patterns associated with disease processes. Radiomic features capture spatial heterogeneity and subtle characteristics of neurodegeneration that are not discernible using conventional imaging analysis. When integrated with ML, these features may serve as noninvasive surrogates of molecular activity, enabling the identification of imaging signatures associated with specific genetic backgrounds and biological pathways. This review aims to explore how radiomics and ML can bridge the gap between genetic and molecular mechanisms and in vivo imaging phenotypes in AD. We summarize current knowledge on genetic determinants and molecular pathways and discuss advances in molecular imaging, particularly tracers targeting amyloid and tau pathology. Furthermore, we analyze the emerging role of radiomics and ML in linking imaging phenotypes with underlying biological processes. This integrative framework may support improved disease stratification, early diagnosis, and prediction of therapeutic response, contributing to the development of precision medicine strategies and future theranostic approaches in Alzheimer's disease.},
}

*Alzheimer Disease/genetics/diagnostic imaging/pathology/metabolism
Humans
*Machine Learning
Radiomics
Phenotype
tau Proteins/genetics/metabolism
Apolipoproteins E/genetics
Amyloid beta-Peptides/genetics/metabolism
Molecular Imaging/methods

@article {pmid42354076,
year = {2026},
author = {Nakamura, K and Kawamura-Yamagishi, M and Kuragano, M and Uwai, K and Tokuraku, K},
title = {Cross-Category Screening of Food Samples for Amyloid-β42 Aggregation-Inhibitory Activity Using a Microliter-Scale High-Throughput Screening System with Quantum-Dot-Labeled Aβ.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/foods15122108},
pmid = {42354076},
issn = {2304-8158},
support = {JPMJPF2213//Japan Science and Technology Agency/ ; JP24K08627//Japan Society for the Promotion of Science/ ; },
abstract = {Alzheimer's disease (AD) is associated with the aggregation and deposition of amyloid-β (Aβ), making Aβ aggregation an important target in AD-related research. Food-derived components have attracted attention as potential modulators of Aβ-related processes, but the direct effects of diverse food samples on Aβ42 aggregation remain unclear. Here, we screened 120 food-sample preparations derived from 115 food items for inhibitory activity against Aβ42 aggregation using an automated microliter-scale high-throughput screening system with quantum-dot-labeled Aβ (QDAβ). Among primary screening samples, 34 showed detectable Aβ42 aggregation-inhibitory activity, and 12 were classified as highly active (1/EC50 ≥ 10 mL/mg). Within the present screening set, highly active samples were frequently observed among tea-related samples. Black tea, Camembert, Red perilla, and Black soybean were selected as representative hits for further validation. Automated MSHTS images and dose-response data showed concentration-dependent suppression of Aβ42 aggregate formation. These inhibitory effects were further supported by thioflavin T (ThT) assays and transmission electron microscopy, which showed suppression of ThT-positive fibrillar aggregation and reduced fibrillar aggregate formation. In differentiated PC12 cells, selected food samples increased cell viability in Aβ42-treated cells at some concentrations. These findings provide a basis for functional food research and active component analysis of food-derived Aβ42 aggregation modulators.},
}

@article {pmid42354226,
year = {2026},
author = {Crowley, P and Henry, AL and O'Donovan, M and Sheehan, R and Flanagan, E and O'Caoimh, R},
title = {Randomised Evaluation of Sleep in Cognitive Impairment Trial (REST)-Protocol for a Feasibility Study of a Digital Cognitive Behavioural Therapy for Insomnia Intervention.},
journal = {International journal of environmental research and public health},
volume = {23},
number = {6},
pages = {},
doi = {10.3390/ijerph23060695},
pmid = {42354226},
issn = {1660-4601},
support = {DTICTN-2021-003/HRBI_/Health Research Board/Ireland ; },
mesh = {Humans ; *Sleep Initiation and Maintenance Disorders/therapy ; *Cognitive Behavioral Therapy/methods ; Feasibility Studies ; *Cognitive Dysfunction/complications/therapy ; Middle Aged ; Aged ; Female ; Pilot Projects ; Randomized Controlled Trials as Topic ; Male ; Dementia/complications ; Quality of Life ; *Sleep ; },
abstract = {Dementia is a leading and growing cause of disability worldwide. Insomnia is highly prevalent in mild cognitive impairment (MCI) and dementia and is associated with impaired cognition, functional decline, and reduced quality of life (QoL). Although sleep disturbance represents a potentially modifiable risk factor within the trajectory of cognitive impairment, there have not been many studies conducted to examine the feasibility or preliminary efficacy of digital cognitive behavioural therapy for insomnia (dCBT-I) in this population. The aim of this pilot randomised controlled feasibility study is to evaluate the acceptability, adherence, and potential clinical effects of a multi-component dCBT-I programme (Sleepio) in adults with MCI or mild dementia and comorbid insomnia. Thirty community-dwelling adults aged ≥50 years with established MCI or mild dementia (Mini-Mental State Examination ≥18; Clinical Dementia Rating 0.5-1.0) and insomnia (Sleep Condition Indicator ≤16) will be randomised (1:1) to Sleepio or a wait-list control. Feasibility outcomes include recruitment and retention rates, intervention adherence (completion of ≥4/6 sessions), and acceptability measured using validated usability scales. Secondary outcomes include changes in sleep, mood, QoL, cognition, and function over 10 weeks. Adverse events will be monitored to assess safety. Findings will inform the design of a future definitive trial evaluating digital sleep interventions in cognitively impaired populations. Ethical approval has been granted. The trial is registered at ClinicalTrials.gov (NCT07363928).},
}

Humans
*Sleep Initiation and Maintenance Disorders/therapy
*Cognitive Behavioral Therapy/methods
Feasibility Studies
*Cognitive Dysfunction/complications/therapy
Middle Aged
Aged
Female
Pilot Projects
Randomized Controlled Trials as Topic
Male
Dementia/complications
Quality of Life
*Sleep

@article {pmid42354250,
year = {2026},
author = {Ginossar, T and Partridge, EL and Adair, JC and Ghahate, DM and Quam, MM and Prestopnik, JL and Knoefel, JA and Ryman, SG and Rosenberg, GA and Shah, VO},
title = {"When the Worlds Change and We Get Old": Indigenous Older Adults Reflecting on Dementia and Aging.},
journal = {International journal of environmental research and public health},
volume = {23},
number = {6},
pages = {},
doi = {10.3390/ijerph23060720},
pmid = {42354250},
issn = {1660-4601},
support = {015003-2125/GF/NIH HHS/United States ; },
mesh = {Humans ; *Dementia/psychology ; *Aging/psychology ; COVID-19 ; Aged ; Focus Groups ; Female ; SARS-CoV-2 ; Aged, 80 and over ; Qualitative Research ; Pandemics ; },
abstract = {BACKGROUND: Understanding the perspectives of Indigenous older adults about aging and dementia in different Indigenous communities can inform the provision of culturally grounded services and advance equity. However, the experiences and perspectives of Southwestern Pueblo communities are under-researched.

METHODS: Approved by the Zuni Tribal Government and IRB, this community-engaged, qualitative research explored Zuni older adults' perceptions, experiences, and support needs. Two co-authors who are community members co-led four focus groups and transcribed them.

RESULTS: Twenty participants in four focus groups shared holistic perceptions of dementia. Whereas they often described dementia as a part of aging, they also expressed a strong desire for specialized dementia care and information. They expressed a strong commitment to caregiving as a cultural value, along with challenges and the need for resources to support caregiving as part of specialized dementia healthcare. The challenges experienced by community members were exacerbated by the devastating impact of the COVID-19 pandemic, including the loss of loved ones, long-term COVID-19, disruption of gatherings, loneliness and social isolation.

CONCLUSIONS: The need for culturally grounded services is inseparable from Zuni participants' requests for specialized dementia services (including prevention, screening, and caregiving). As the first study to report on the impact of the COVID-19 pandemic on Zuni aging, it highlights the importance of re-building social services and gatherings in planning of service provision.},
}

Humans
*Dementia/psychology
*Aging/psychology
COVID-19
Aged
Focus Groups
Female
SARS-CoV-2
Aged, 80 and over
Qualitative Research
Pandemics

@article {pmid42354294,
year = {2026},
author = {Vasan, SS and Anand, S and Lee, M and Fluck, NC},
title = {On Burden of Diseases, Prevention, Medical Research and Health Service Delivery: Grampian Case Study.},
journal = {International journal of environmental research and public health},
volume = {23},
number = {6},
pages = {},
doi = {10.3390/ijerph23060763},
pmid = {42354294},
issn = {1660-4601},
mesh = {Humans ; Female ; Male ; Scotland/epidemiology ; *Cost of Illness ; *Biomedical Research ; *Delivery of Health Care ; Disability-Adjusted Life Years ; Adult ; *COVID-19/epidemiology ; Aged ; Adolescent ; Middle Aged ; Young Adult ; },
abstract = {Burden of diseases measured as disability-adjusted life years (DALYs) per 100,000 people can be mined from public domain data, when they are made available by population health surveillance systems. This can be analysed to allow insightful comparisons with the national average, and to understand differences in trends between the sexes, age groups, time periods, geographic regions, and sub-regions. In this illustrative case study, we have analysed the Scottish burden of disease database to understand what ailed the population of the Grampian region before the COVID-19 pandemic. We have identified that selected cancers, ischaemic heart disease, Alzheimer's disease and other dementias are amongst the highest contributors to the burden; that drug use disorders and colorectal cancer are showing worsening trends and require health promotion and disease prevention measures from ages 15 and 25, respectively, especially in Aberdeen City; and that males are more vulnerable to atrial fibrillation and flutter, diabetes mellitus, oesophageal cancer, and self-harm, while females are more vulnerable to cerebrovascular and chronic obstructive pulmonary diseases. We demonstrate the usefulness of our analysis and methodology for the wider health system, allowing targeted medical research investments and coordinated response from public health and health service delivery. We also show the need for up-to-date surveillance data, forecasts, and evidence on the impact of interventions to be made available widely.},
}

Humans
Female
Male
Scotland/epidemiology
*Cost of Illness
*Biomedical Research
*Delivery of Health Care
Disability-Adjusted Life Years
Adult
*COVID-19/epidemiology
Aged
Adolescent
Middle Aged
Young Adult

@article {pmid42354579,
year = {2026},
author = {Emdad, FB and Rahman, MI and Nabil, HR and Rayed, E and Ovi, PR and Emdad, EB and Rahman, MT and Talukdar, MR and Hossain, MR},
title = {A Generalized Responsible AI Framework for Trustworthy Clinical Prediction: Explainability, Fairness, Performance, and Uncertainty in Alzheimer's Disease Modeling.},
journal = {Healthcare (Basel, Switzerland)},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/healthcare14121721},
pmid = {42354579},
issn = {2227-9032},
abstract = {Objectives: Alzheimer's disease (AD) remains one of the most prevalent neurodegenerative conditions among older adults, underscoring the urgent need for accurate and ethically grounded early detection methods. Artificial intelligence (AI) techniques, particularly machine learning and deep learning models, show promise in leveraging neuroimaging biomarkers to support early diagnosis. However, significant challenges persist regarding model explainability, accountability, and responsible implementation in real-world healthcare settings. This study presents a generalized Responsible AI (RAI) framework composed of four core components-explainability, fairness, predictive performance, and uncertainty quantification-to address these challenges. Method: Using the TADPOLE neuroimaging dataset, we implemented a Feedforward Neural Network (FNN) within a unified Responsible AI (RAI) framework integrating explainability, fairness, predictive performance, and uncertainty quantification. Although Random Forest achieved slightly higher predictive accuracy (95%), the FNN was selected as the primary model because it better supports end-to-end uncertainty estimation through Monte Carlo Dropout, enabling more reliable clinical decision support. Results: The proposed framework demonstrated strong predictive performance (92% accuracy), improved fairness reflected by an equalized odds difference of 0.124, and progressively lower predictive entropy across training iterations, indicating enhanced confidence in predictions. The framework further enabled model transparency through explainability analyses and supported the identification of low-confidence predictions for potential clinical review. Conclusions: Our findings highlight not only the feasibility of integrating RAI principles into AD prediction pipelines but also the persistent challenges of applying such frameworks to real-world clinical data. This work contributes practical insights toward operationalizing Responsible AI in healthcare contexts.},
}

@article {pmid42356119,
year = {2026},
author = {Persely, A and Piroska, M and Zoldi, L and Beszedics, B and Juhasz, J and Makra, N and Dunai, ZA and Szabo, D and Tarnoki, DL and Tarnoki, AD},
title = {The Role of Gut Microbiome in Mild Cognitive Impairment: A Twin Study.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {6},
pages = {},
doi = {10.3390/medicina62061106},
pmid = {42356119},
issn = {1648-9144},
mesh = {Humans ; Male ; *Cognitive Dysfunction/microbiology/physiopathology ; *Gastrointestinal Microbiome/physiology ; Aged ; Female ; RNA, Ribosomal, 16S/analysis ; Feces/microbiology ; Aged, 80 and over ; Twins, Monozygotic ; },
abstract = {Background and Objectives: Recent studies have revealed the potential roles of gut microbiota and microbial metabolites in influencing mild cognitive impairment (MCI) and Alzheimer's disease via the gut-brain axis. This relationship has not yet been investigated in monozygotic twin pairs, which represent an ideal model for minimizing genetic confounding. Materials and Methods: Seven twin pairs discordant for ACE and 15 for MoCA were enrolled. Stool samples were subjected to 16S ribosomal RNA-based microbiome analysis. Results: No significant differences in alpha or beta diversity were observed between MCI-discordant twin pairs at the genus or family level. The most robust finding was a significantly lower abundance of Lachnospiraceae in MCI-affected twins, identified independently by ANCOM-BC and LEfSe. Additional exploratory findings included higher abundances of Sutterella, Succinivibrio, Odoribacter, and Ruminococcus. However, several taxa showed opposing patterns between ACE- and MoCA-derived cohorts, highlighting the methodological impact of cognitive instrument selection. Conclusions: The convergent reduction of Lachnospiraceae across two independent analytical methods represents the most substantive finding. The remaining results are exploratory, limited by small sample size, restricted statistical power, and lack of availability to fully control for dietary habits, physical activity, and medication use. Validation in larger longitudinal twin cohorts with a standardized cognitive assessment is warranted.},
}

Humans
Male
*Cognitive Dysfunction/microbiology/physiopathology
*Gastrointestinal Microbiome/physiology
Aged
Female
RNA, Ribosomal, 16S/analysis
Feces/microbiology
Aged, 80 and over
Twins, Monozygotic

@article {pmid42356271,
year = {2026},
author = {Sarti, G and Tognozzi, G and Magni, G and Lana, D and Rossi, F and Traini, C and Vannucchi, MG},
title = {The Multiple Functions of Amyloid Beta in the Gut Epithelium and the Role of the Microbiota: A Study in the APP/PS1 Animal Model Subjected to Chronic Synbiotic Treatment.},
journal = {Nutrients},
volume = {18},
number = {12},
pages = {},
doi = {10.3390/nu18121883},
pmid = {42356271},
issn = {2072-6643},
support = {PRIN2022SC_VANNUCCHI//Ministero dell'università e della ricerca/ ; VANMBANCAITALIA23//Bank of Italy/ ; 58513_CHIARA TRAINIRICATEN24//University of Florence/ ; },
mesh = {Animals ; *Synbiotics/administration & dosage ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Intestinal Mucosa/metabolism/microbiology ; *Alzheimer Disease/microbiology/metabolism ; Mice, Transgenic ; *Gastrointestinal Microbiome/physiology ; Intestinal Barrier Function ; Colon/metabolism/microbiology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice ; Presenilin-1/genetics ; Ileum/metabolism/microbiology ; Tight Junctions/metabolism ; Male ; },
abstract = {Background:/ Over the past decade, increasing evidence has shifted attention from the brain to the gut microbiota (MB) as a source and site of systemic dissemination of amyloid-β (Aβ), an APP derivative responsible for plaque formation in the brains of Alzheimer's disease (AD) patients. Furthermore, AD patients and APP/PS1 mice, a transgenic model of AD, exhibit dysbiosis. Objectives: Using APP/PS1 mice treated from 2 to 8 months of age, we studied ileal and colonic epithelial integrity, intestinal barrier (IB) integrity assessed through tight junction (TJ) protein expression, local immune system, the presence/increase in Aβ expression in enterocytes, and the protective effects of synbiotic treatment. Methods: The tissue was stained with Periodic Acid-Schiff and Alcian Blue to evaluate epithelial morphology and mucus production, and immunohistochemistry was performed to assess TJs, immune markers, and Aβ expression. Results: Our results demonstrate that colonic and ileal epithelium of 8-month-old APP/PS1 mice displays IB impairment in term of alterations of goblet cells staining and TJ protein expression and signs of immune involvement. The ileum was more severely affected, showing a reduced epithelial surface area, decreased lysozyme production, and fewer tuft cells. Long-term synbiotic treatment largely prevented APP/PS1 mouse changes and caused a significant increase in Aβ expression in all treated mice. Conclusions: These findings support the belief in early intestinal involvement in AD and highlight the potential of the microbiota as a target for early intervention aimed at modifying the progression to neurodegeneration. Increased epithelial Aβ labeling after treatment raises the possibility of intestinal management of Aβ, which requires further validation.},
}

Animals
*Synbiotics/administration & dosage
*Amyloid beta-Peptides/metabolism
Disease Models, Animal
*Intestinal Mucosa/metabolism/microbiology
*Alzheimer Disease/microbiology/metabolism
Mice, Transgenic
*Gastrointestinal Microbiome/physiology
Intestinal Barrier Function
Colon/metabolism/microbiology
Amyloid beta-Protein Precursor/genetics/metabolism
Mice
Presenilin-1/genetics
Ileum/metabolism/microbiology
Tight Junctions/metabolism
Male

@article {pmid42356332,
year = {2026},
author = {Mosiej, W and Kruk, M and Królikowski, T and Oczkowski, M and Glegoła, K and Zielińska, D},
title = {Functional and Psychobiotic Potential of a Food-Derived Multi-Strain Lactic Acid Bacteria Consortium: An In Vitro Evaluation Using Static Digestion and SHIME[®] Models.},
journal = {Nutrients},
volume = {18},
number = {12},
pages = {},
doi = {10.3390/nu18121946},
pmid = {42356332},
issn = {2072-6643},
support = {2021/43/O/NZ9/02468//National Science Centre/ ; },
mesh = {Humans ; *Digestion/physiology ; *Lactobacillales/physiology ; *Gastrointestinal Microbiome/physiology ; *Fermented Foods/microbiology ; *Probiotics ; *Microbial Consortia/physiology ; Models, Biological ; *Food Microbiology ; Bacterial Adhesion ; Amino Acids/metabolism ; },
abstract = {BACKGROUND/OBJECTIVES: The microbiota-gut-brain axis (MGBA) plays a pivotal role in cognitive function, making psychobiotics a promising strategy for managing neurodegenerative diseases. Lactic acid bacteria (LAB) from traditional fermented foods represent a valuable source of candidate strains, and multi-strain consortia may offer enhanced therapeutic efficacy through synergistic effects. This study evaluated the functional and psychobiotic potential of three lactic acid bacteria (LAB) strains isolated from fermented foods, assessed as monocultures and a multi-strain consortium (MIX).

METHODS: The research encompassed an initial screening of the individual strains and the MIX, assessing their adhesion to mucin, stability in a static in vitro digestion model, and amino acid profiling. Subsequently, the LAB MIX underwent long-term evaluation in a dynamic gastrointestinal model (SHIME[®]) inoculated with microbiota from a patient with Alzheimer's disease, during which alterations in gut microbiota composition and amino acid metabolism were analyzed.

RESULTS: The LAB MIX demonstrated high stability under digestive stress and effective mucoadhesive properties. Furthermore, the consortium demonstrated a distinct metabolic signature, driving enhanced functional effects that complemented or exceeded those observed in individual monocultures. In the SHIME[®] model, the MIX induced significant, site-specific shifts in microbial composition, notably increasing lactobacilli abundance. These taxonomic changes correlated with an enriched metabolic profile, including elevated levels of GABA precursors and amino acids with antioxidant potential, which are crucial for MGBA modulation.

CONCLUSIONS: These results identify the LAB consortium as a compelling psychobiotic candidate. Further in-depth in vivo and clinical studies are required to validate its therapeutic potential for MGBA modulation.},
}

Humans
*Digestion/physiology
*Lactobacillales/physiology
*Gastrointestinal Microbiome/physiology
*Fermented Foods/microbiology
*Probiotics
*Microbial Consortia/physiology
Models, Biological
*Food Microbiology
Bacterial Adhesion
Amino Acids/metabolism