@article {pmid41714635,
year = {2026},
author = {Sun, J and Han, JJ and Chen, W},
title = {Deep learning models identify brain changes during the progression of Alzheimer's disease.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00666-7},
pmid = {41714635},
issn = {2056-7189},
support = {92049302, 32088101, 32330017//National Natural Science Foundation of China/ ; 12026210//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder whose progression is closely associated with time. However, most diagnostic models are based on single time-point data, overlooking longitudinal disease characteristics. Structural magnetic resonance imaging (sMRI) has been widely utilized in the study of AD. To address the need for multi-time series analysis in longitudinal AD research and the integration of features from different brain tissues, we propose a Multi-Branch Fusion Channel Attention Network (MBFCA-Net) for disease diagnosis. This network leverages the temporal correlations across longitudinal scans for effective AD detection. We further conduct retrospective interpretability analysis to quantify the contributions of brain regions across disease stages. This enables a detailed investigation of dynamic changes in brain regions associated with AD and normal aging. The results indicate that the importance of regions such as the amygdala, parahippocampal gyrus, and temporal lobe undergoes dynamic changes throughout the progression of AD. Furthermore, AD-related voxel clusters exhibit a developmental trend, shifting from the hippocampus to the temporal lobe and transitioning from a dispersed to a more aggregated distribution. Our study provides novel insights into the longitudinal patterns of AD-related changes, offering valuable contributions to early diagnosis and pathological understanding of the disease.},
}

@article {pmid41714576,
year = {2026},
author = {Lu, X and Xu, K and Zhou, Z and Ding, G and Zhang, Y and Liang, Y and Zhou, J and Jia, M and Zhang, Y and Shen, L and Li, H},
title = {Chaetoglobosin F Attenuates Amyloid-β-Induced Neurotoxicity in Caenorhabditis elegans by Regulating Autophagy and Oxidative Stress Via the Insulin/IGF-1 and p38 MAPK Pathways.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {80},
pmid = {41714576},
issn = {1573-6903},
mesh = {Animals ; Caenorhabditis elegans/drug effects ; *Amyloid beta-Peptides/toxicity ; *Oxidative Stress/drug effects/physiology ; *Autophagy/drug effects/physiology ; p38 Mitogen-Activated Protein Kinases/metabolism ; Insulin-Like Growth Factor I/metabolism ; Insulin/metabolism ; Animals, Genetically Modified ; *Indole Alkaloids/pharmacology ; *MAP Kinase Signaling System/drug effects/physiology ; Caenorhabditis elegans Proteins/metabolism ; Neuroprotective Agents/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease for which no effective clinical therapies currently exist. The neuroprotective potential of Chaetoglobosin F (CF), a fungal secondary metabolite, was investigated in this study using a Caenorhabditis elegans (C. elegans) model of AD that are transgenic nematodes expressing amyloid-beta (Aβ). Key parameters evaluated included paralysis rate, lifespan, motor and cognitive functions, Aβ plaque aggregation, intracellular reactive oxygen species (ROS), and autophagosome formation. The transcriptional levels of genes were examined by real time PCR. Results showed that treatment with CF significantly delayed paralysis, extended lifespan, and ameliorated Aβ-induced deficits in locomotion and chemotaxis. CF markedly reduced Aβ plaque accumulation, suppressed intracellular ROS levels, and promoted autophagosome formation. Furthermore, CF had potent inhibitory effects on acetylcholinesterase (AChE) activity. These beneficial effects were correlated with the upregulation of crucial genes, including daf-16, skn-1, pmk-1, mtl-1, unc-51, bec-1, lgg-1, sod-1 and sod-3, which confirmed the improving antioxidant defenses and autophagy. Our findings demonstrate that CF confers strong neuroprotection against Aβ-induced toxicity in C. elegans by co-regulating oxidative stress and autophagy through the Insulin/IGF-1 (IIS) and p38 MAPK signaling pathways. These results suggest that CF is a promising natural compound for further investigation as a potential therapeutic agent for AD.},
}

Animals
Caenorhabditis elegans/drug effects
*Amyloid beta-Peptides/toxicity
*Oxidative Stress/drug effects/physiology
*Autophagy/drug effects/physiology
p38 Mitogen-Activated Protein Kinases/metabolism
Insulin-Like Growth Factor I/metabolism
Insulin/metabolism
Animals, Genetically Modified
*Indole Alkaloids/pharmacology
*MAP Kinase Signaling System/drug effects/physiology
Caenorhabditis elegans Proteins/metabolism
Neuroprotective Agents/pharmacology

@article {pmid41714374,
year = {2026},
author = {Chauhan, N and Jain, S and Gupta, P and Dwivedi, J and Paliwal, S and Sharma, S and Mishra, A and Singh, S and Beth, MRM and Arunraj, M},
title = {Identification of a novel GSK-3β inhibitor for Alzheimer's disease using In-Silico prediction and experiment cycling, validated in a streptozotocin-induced Alzheimer's disease mouse model.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41714374},
issn = {1432-1912},
abstract = {GSK-3β has been a key target in Alzheimer's disease (AD) research for over two decades. To identify novel GSK-3β inhibitors, 333 compounds from the National Cancer Institute (NCI) database were screened using a validated ligand-based pharmacophore model with four essential features (two hydrogen bond acceptors, one hydrophobic, and one aromatic ring). After tapering screening with refined boundaries, two top compounds (NSC 275 and NSC 3198) were identified. Molecular docking and simulation studies confirmed their strong binding affinity to GSK-3β. ELISA analysis revealed that their half maximal inhibitory concentration (IC50) values were comparable to the standard GSK-3β inhibitor, CHIR99021. Subsequent in-vivo studies assessed the efficacy of these chemical entities in tested mouse model. Acute toxicity studies demonstrated no observed adverse effect level (NOAEL). Whereas behavioral tests, using the Morris water maze, the tested compounds (5 mg/kg and 10 mg/kg) exhibited cognitive improvements comparable to those of the donepezil group (1 mg/kg), an approved AD treatment. Further analysis of oxidative stress, histopathology, and immune responses in the hippocampus (CA1) indicated that the NSC 275 and NSC 3198 reversed cognitive deficits similarly to the donepezil treated group. The results suggested that combination of in-silico, in-vitro, and in-vivo approaches demonstrates the potential of NSC 275 and NSC 3198 as promising GSK-3β inhibitors for AD treatment.},
}

@article {pmid41714121,
year = {2026},
author = {Koo, H and Mattay, V and Hofling, AA and Wang, SJ and Krainak, D and Kim, Y and Krudys, K and Buracchio, T and Marzella, L},
title = {Advancing Theranostics in Alzheimer Disease: FDA Approval of Amyloid-β PET Drugs for Selection of Patients for Amyloid-β-Directed Therapies and Other Labeling Updates.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.271312},
pmid = {41714121},
issn = {1535-5667},
}

@article {pmid41713702,
year = {2026},
author = {Keil, SA and Li, Y and Krieger, AC and Wang, XH and Nguyen, TD and Ivanidze, J and Chiang, GC and Butler, TA and Zhou, L},
title = {Increased MRI-derived parenchymal cerebral spinal fluid mapping in untreated obstructive sleep apnea patients.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107325},
doi = {10.1016/j.nbd.2026.107325},
pmid = {41713702},
issn = {1095-953X},
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent disorder associated with increased risk of Alzheimer's disease (AD) and cognitive decline. The mechanisms underlying the relationship between OSA and disease progression remain undefined, but may involve impairment in the glymphatic system, a perivascular network responsible for cerebrospinal fluid and interstitial fluid exchange and waste clearance. This study evaluated MRI-visible perivascular spaces (PVS) and parenchymal CSF mapping (pCSF) as non-invasive proxies of glymphatic function in untreated and CPAP-treated OSA relative to healthy controls.

METHODS: Forty-two adults (n = 16 healthy controls, n = 14 untreated OSA, n = 12 CPAP-treated OSA) were retrospectively evaluated. Participants underwent MRI and cognitive testing, and a sub-cohort (n = 25) received [11]C-PIB amyloid PET. Enhanced PVS contrast (EPC) mapping segmentation quantified MRI-visible PVS, while multi-echo FAST-T2 MR derived pCSF mapping provided voxelwise quantification of glymphatic fluid distribution. Between-group differences were assessed using nonparametric statistics and multivariable regression analyses controlled for age and sex.

RESULTS: Segmented MR-visible PVS did not differ between groups. Comparatively, untreated OSA subjects had higher ADmask pCSF versus than controls (p = 0.0155), with exploratory analyses displaying a similar relationship across regions including cerebral grey and white matter. Intriguingly, CPAP-treated individuals exhibited pCSF levels statistically comparable to controls. In the sub-cohort, higher ADmask pCSF independently predicted greater amyloid burden on PET (β = 0.616, p = 0.007).

CONCLUSIONS: Untreated OSA is associated with higher parenchymal glymphatic fluid burden consistent with impaired perivascular fluid dynamics. CPAP-treated participants exhibited pCSF levels comparable to controls. pCSF mapping represents a sensitive biomarker for evaluating perivascular fluid distribution, a positive association with amyloid deposition, and monitoring potential treatment-related differences in OSA.},
}

@article {pmid41713500,
year = {2026},
author = {Liu, S and Cheng, Y and Zhang, X and Shen, Y and Wu, S and Chen, Y and Shi, D and Zhuang, C and Chen, B and Zhong, Y and Wang, X and Wen, Y and Zheng, X and Jia, Y and Guan, J and Yan, G and Wu, R},
title = {Assessing Effects of Microwave Electromagnetic Field in APP/PS1 Mice by In Vivo GABA-weighted Imaging via Variable delay Multipulse-Chemical Exchange Saturation Transfer MRI.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106131},
doi = {10.1016/j.neuint.2026.106131},
pmid = {41713500},
issn = {1872-9754},
abstract = {Electromagnetic fields (EMFs) have been shown to be beneficial in treating Alzheimer's disease (AD), but the underlying neurophysiological mechanisms remain unclear. It has been proposed that EMF promotes GABAergic neurogenesis and that abnormal GABA levels are an important influence on the progression of AD. To achieve in vivo GABA-weighted imaging in the brain in APP/PS1 mice, we utilized variable delay multi-pulse (VDMP)-chemical exchange saturation transfer (CEST)- magnetic resonance imaging (MRI) and pathological validation to measure GABA levels in APP/PS1 mice under microwave EMF and explore the therapeutic mechanism. The APP/PS1 mice received a 4-week microwave EMF treatment. The findings show that microwave EMF stimulation significantly increased GABA-weighted signals on MRI of APP/PS1 mouse hippocampus. VDMP-CEST was sensitive in detecting GABA-weighted signals. ELISA showed that microwave EMF stimulation elevated GABA levels in the hippocampus. Compared to in vitro levels, VDMP-CEST accurately detected GABA-weighted signal changes. With the pathological validations, we found that microwave EMF exposure can elevate hippocampal GABA levels by promoting AQP4 polarizion, reducing Aβ accumulation and neuronal degeneration, improving cognitive impairment, and may have slowed AD progression. Collectively, microwave EMF treatment could increase GABA-related changes, which corresponded to the accumulation of Aβ and improvement in the water maze. VDMP-CEST detected levels are highly consistent with pathological evidence, implying that VDMP-CEST is an effective modality for in vivo GABA-weighted imaging during microwave EMF treatment, providing more objective imaging-based diagnostic evidence for monitoring GABA-related pathological changes in AD.},
}

@article {pmid41713452,
year = {2026},
author = {Bray, NW and Adriano, DAC and Grant, S and Kendall, KD and Hill, MD and Stewart Longman, R and Matar, AA and Alghasab, N and Mahdi, N and Afshar, EE and Bruce Pike, G and Poulin, MJ and Eskes, GA},
title = {Sex-Specific Contributions to Single- and Dual-Task Walking in Adults at Risk of Alzheimer Disease and Related Dementias.},
journal = {Journal of aging and physical activity},
volume = {},
number = {},
pages = {1-12},
doi = {10.1123/japa.2025-0148},
pmid = {41713452},
issn = {1543-267X},
abstract = {BACKGROUND/OBJECTIVE: Walking reflects a complex interaction between physiological systems that deteriorate with age and do so more rapidly in those living with diseases. We conducted a sex-specific cross-sectional analysis to determine the contribution of modifiable (risk) factors to single- and dual-task gait performance in older adults at risk of Alzheimer disease and related dementias.

METHODS: We included participants (n = 103; 60.4% female; mean age 63.7 ± 6.2) who had completed a preintervention assessment for a randomized controlled trial. We used the following factors in hierarchical regressions while controlling for age, muscle strength, cardiorespiratory fitness, and global cognition. Participants walked at their usual pace on an electronic walkway and completed the two-back version of the n-back test either separately or together.

RESULTS: Males and females demonstrated reduced gait speed when comparing single to dual tasking (p < .001), but only females demonstrated increasing (i.e., worse) gait variability (p = .007). In females, the dual-task velocity model was significant, F(3, 56) = 5.173, with muscle strength (p = .006) and cardiorespiratory fitness (p = .049) contributing significantly. For males, the models were significant across all conditions, but muscle strength was the only significant (modifiable) factor (single task, p = .023; dual task, p = .046).

CONCLUSION: Dual-task gait velocity is associated with a combination of modifiable factors. However, the importance of each factor differs between males and females. Significance/Implications: Such findings have implications for understanding gait decline and potential sex-specific intervention strategies in those at risk of Alzheimer disease and related dementias.},
}

@article {pmid41713228,
year = {2026},
author = {Pulok, MMH and Akter, F and Islam, MT and Kumar, P and Enan, ME and Khaled Bhuiyan, AFM and Azmi, AM and Ahammed, T and Billah, MM and Das, SK and Islam, MS and Abdullah, M and Khanom, T and Hossain, MS and Faruk, MAZ},
title = {Integrative structure-based approach for phytocompound-based dual therapeutics targeting Alzheimer's and Parkinson's disease.},
journal = {Journal of molecular graphics & modelling},
volume = {144},
number = {},
pages = {109319},
doi = {10.1016/j.jmgm.2026.109319},
pmid = {41713228},
issn = {1873-4243},
abstract = {Neurodegenerative diseases like Alzheimer's and Parkinson's are growing global health concerns with limited treatment options. In this study, we explored four natural compounds-Baicalein, Vincarubine, Rutin, and Luteolin-for their potential as multi-target drugs using computational methods. These compounds were tested against key proteins involved in disease progression, including LRRK2, APP, and Tau kinase. Molecular docking showed that Vincarubine had the strongest binding with LRRK2 and APP, while Rutin interacted best with Tau kinase. Molecular dynamics simulations further supported Rutin's strong and stable binding, with low fluctuation and deviation values. Although Vincarubine showed high binding affinity, it also displayed greater structural flexibility, suggesting it may need some modifications for better stability. Pharmacokinetic analysis revealed that most of the compounds followed drug-likeness rules, but Rutin and Vincarubine had some limitations in size and brain permeability, meaning advanced delivery systems like nanoparticles may be needed. Toxicity tests showed that Baicalein and Rutin were generally safe, while Vincarubine had potential risks for the kidneys and lungs. When compared to commonly used drugs like Donepezil, Memantine, and Levodopa, these natural compounds showed even better binding strength and stability in simulations. Overall, the results suggest these phytocompounds could be promising candidates for treating neurodegenerative diseases. However, further lab-based studies, both in cells and animals, are essential to confirm their real-world potential. Future research should be focused on improving their structures, delivery methods, and possible combinations to boost their effectiveness.},
}

@article {pmid41714582,
year = {2026},
author = {Li, N and Look, KA and Chou, LN},
title = {Dementia Family Caregivers' Involvement and Perceived Challenges in Health Care Interactions: Informing the GUIDE Model.},
journal = {Journal of general internal medicine},
volume = {},
number = {},
pages = {},
pmid = {41714582},
issn = {1525-1497},
abstract = {BACKGROUND: Health care interaction tasks, such as making appointments and coordinating care, are vital but often overlooked caregiver tasks. The Guiding an Improved Dementia Experience (GUIDE) Model began in 2024 and aims to support dementia family caregivers through care coordination.

OBJECTIVE: This observational study described the characteristics of dementia family caregivers and their perceived challenges in performing health care interaction tasks before the start of the GUIDE Model.

DESIGN: Cross-sectional nationally representative survey.

PARTICIPANTS: Primary family caregivers for those with probable dementia from the National Study of Caregiving (NSOC) Round 13 and the National Health and Aging Trends Study (NHATS). We also conducted subgroup analyses examining caregivers' difficulty performing health care interaction tasks.

MAIN MEASURES: Dementia family caregivers were asked whether they had helped with any of the nine health care interaction tasks. Only caregivers who answered yes to the task questions were asked about their difficulty performing the respective health care interaction tasks. We compared the characteristics of caregivers who performed versus did not perform these tasks, as well as those who reported any difficulty versus no difficulty.

KEY RESULTS: Our study included 467 caregivers. Most (92.5%) caregivers performed at least one health care interaction task. The most frequently performed health care interaction tasks were speaking to providers (82.2%), making appointments (79.0%), and sitting in on doctor appointments (68.4%). The tasks caregivers rated as being most difficult were transitioning care after a hospital stay (58.9%), coordinating care (43.0%), and handling insurance matters (39.8%). Over half of caregivers assisting after an overnight hospital stay received post-hospital training (58.2%).

CONCLUSIONS: Family caregivers commonly perform health care interaction tasks, and their difficulties, particularly transitioning care after a hospital stay, should be recognized and assessed across care settings and providers in the GUIDE Model.},
}

@article {pmid41714332,
year = {2026},
author = {Li, C and Chia, XW and Xu, G and Ang, LF and Makino, H},
title = {Vulnerability of short-term memory in a mouse model of Alzheimer's disease.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-69619-2},
pmid = {41714332},
issn = {2041-1723},
support = {MOE2017-T3-1-002//Ministry of Education - Singapore (MOE)/ ; JP25H01750//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP25H02511//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; },
abstract = {Interference from distracting stimuli renders short-term memory vulnerable. While behavioral evidence suggests short-term memory deficits in Alzheimer's disease (AD), the underlying neural mechanisms remain poorly understood. Using a mouse model of AD (APP-KI), we identified increased susceptibility of short-term memory to sensory perturbations. Simultaneous two-photon calcium imaging across eight cortical regions during a delayed-response task showed that distractors disrupted neural selectivity at both single-neuron and population levels in APP-KI mice. Recurrent neural network models replicating the neural activity of APP-KI mice exhibited decreased stability, consistent with reduced functional connectivity across the dorsal cortex. Furthermore, analyses of multi-regional corticocortical communication revealed reduced spatiotemporal degeneracy in activity transmission within the dorsal cortex of APP-KI mice, which could account for their attenuated robustness during sensorimotor transformations. Collectively, these findings identify reduced functional connectivity and impaired spatiotemporal degeneracy as central mechanisms of short-term memory deficits in the APP-KI mouse model of AD.},
}

@article {pmid41714304,
year = {2026},
author = {Ruankham, W and Prachayasittikul, V and Pingaew, R and Jeungprasopsuk, W and Tantimongcolwat, T and Prachayasittikul, V and Prachayasittikul, S and Phopin, K},
title = {Unraveling Network Pharmacology-Based Therapeutics of Anthranilate Sulfonamides via Sirtuins/FOXO3a Cascade in Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {2},
pages = {e70377},
doi = {10.1111/jnc.70377},
pmid = {41714304},
issn = {1471-4159},
support = {//National Science Research and Innovation Fund (NSRF)), Thailand/ ; },
mesh = {Humans ; *Sirtuins/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Forkhead Box Protein O3/metabolism ; *Sulfonamides/pharmacology/chemistry/therapeutic use ; *Network Pharmacology/methods ; Molecular Docking Simulation ; *Neuroprotective Agents/pharmacology ; *ortho-Aminobenzoates/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Cell Line, Tumor ; Animals ; },
abstract = {Sulfonamide-based compounds have been a clinically attractive scaffold for drug development and proven as antioxidant and antimicrobial agents, but their pharmacological derivatives containing anthranilates (SA1-4) and therapeutic targets are not clearly clarified. To unravel the neuroprotective roles and underlying mechanisms of SA1-4 against oxidative injury and healthy longevity crosstalk, a combination of in vitro experiments, in silico modeling, and network pharmacology was employed. Pretreatment with SA1-4 in human neuronal SH-SY5Y cells significantly regulated sirtuins (SIRTs)/forkhead box class O 3a (FOXO3a)-mediated longevity signaling pathway via targeting endogenous antioxidant enzymes (i.e., superoxide dismutase 2 [SOD2] and catalase [CAT]), apoptotic cascades (i.e., Bcl-2-associated X-protein [BAX] and B-cell lymphoma-2 [BCL-2]), mitochondrial balance, and ultimately led to the neuronal rescue. Molecular docking simulations support the possibility of the SA1-4 modulatory effect within the active binding site of SIRT1. Importantly, in silico predictions of pharmacokinetic profiles suggested that the synthetic compounds possessed preferable drug-like properties, good oral bioavailability, and safety profiles. Network pharmacology also revealed the involvement of SA1-4 and key targets-regulated SIRTs in neurodegeneration, including non-amyloidogenic cascade, tau phosphorylation, calcium homeostasis, insulin-mediated glucose uptake, and neuroinflammation. Therefore, SA1-4 exert promising multi-target therapeutic strategies against oxidative damage, potentially offering alternative anti-Alzheimer candidates for further clinical neurodegenerative and anti-aging therapeutics.},
}

Humans
*Sirtuins/metabolism
*Alzheimer Disease/drug therapy/metabolism
*Forkhead Box Protein O3/metabolism
*Sulfonamides/pharmacology/chemistry/therapeutic use
*Network Pharmacology/methods
Molecular Docking Simulation
*Neuroprotective Agents/pharmacology
*ortho-Aminobenzoates/pharmacology/therapeutic use
Signal Transduction/drug effects
Cell Line, Tumor
Animals

@article {pmid41713755,
year = {2026},
author = {Liu, S and Dang, B and Kang, Z and Wei, R and Yang, Z and Guo, X and Shao, F and Li, Z and Xing, L and Hu, J and Chen, X},
title = {Discovery of tetrahydroisoquinoline derivatives as selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting activities and neuroprotective activities.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130593},
doi = {10.1016/j.bmcl.2026.130593},
pmid = {41713755},
issn = {1464-3405},
abstract = {Recently, histone deacetylase 6 (HDAC6) has attracted considerable attention for its potential in treating neurodegenerative disorders. In this paper, a series of tetrahydroisoquinoline derivatives were designed and synthesized as selective HDAC6 inhibitors. 4-((7-chloro-3, 4-dihydroisoquinolin-2(1H)-yl)methyl)-3-fluoro-N-hydroxybenzamide (8g), the most promising compound, potently inhibited HDAC6 (IC50 = 7.0 nM) and exhibited >2000 ~ fold selectivity over HDAC1. Molecular simulation indicated its molecular basis of HDAC6 inhibition. In vitro, 8g showed no significant toxicity on rat dopaminergic pheochromocytoma PC-12 cells. Furthermore, we demonstrated that 8g induced neurite outgrowth and showed good neuroprotective activity in PC-12 cells. Our research provided a new promising structure for the development of HDAC6is against Alzheimer's disease.},
}

@article {pmid41713678,
year = {2026},
author = {Li, A and Xing, Y and Xie, S and Meng, W and Wu, Z and Wu, N and Wang, Z and Zhu, W and Shi, X and Xie, B and Yin, Y and Mi, Y and Wei, T and Qiao, Y and Wei, J and Zhang, G and Tang, Y},
title = {Simulated Default Mode Network Electric Fields are Associated with Cognitive Response to Transcranial Alternating Current Stimulation in Mild Alzheimer's Disease.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103056},
doi = {10.1016/j.brs.2026.103056},
pmid = {41713678},
issn = {1876-4754},
}

@article {pmid41713416,
year = {2026},
author = {Xu, YKT and Bush, A and Musheyev, E and Umans, J and Zhang, L and Kim, AA and Zhang, S and Eugenin von Bernhardi, J and Yan, Y and Sulam, J and Bergles, DE},
title = {Brain-wide mapping of oligodendrocyte organization, oligodendrogenesis, and myelin injury.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.01.025},
pmid = {41713416},
issn = {1097-4172},
abstract = {Insulating sheaths of myelin accelerate neuronal communication in the mammalian brain. Oligodendrocytes that produce myelin are generated throughout life to gradually increase myelin coverage, but these dynamics have not been defined brain-wide across the lifespan. We developed a cellular mapping pipeline involving tissue clearing, lightsheet microscopy, and AI-assisted analysis to identify the precise location of millions of oligodendrocytes and assess regional myelin density in the mouse brain. These atlases revealed the diversity of oligodendrocyte patterning, which was consistent between brain hemispheres, individuals, and sexes but displayed both age- and region-specific differences. Integration of these atlases with transcriptomic and ultrastructural datasets highlighted underlying mechanisms that may control this patterning. In models of demyelination and disease, we identified regions of enhanced oligodendrocyte resilience and vulnerability and white matter injury near β-amyloid plaques, demonstrating the utility of this pipeline for defining brain-wide oligodendrocyte dynamics in both health and disease.},
}

@article {pmid41713415,
year = {2026},
author = {Bieri, G and Pratt, KJB and Fuseya, Y and Aghayev, T and Sucharov, J and Horowitz, AM and Philp, AR and Fonseca-Valencia, K and Chu, R and Phan, M and Remesal, L and Wang, SJ and Yang, AC and Casaletto, KB and Villeda, SA},
title = {Liver exerkine reverses aging- and Alzheimer's-related memory loss via vasculature.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.01.024},
pmid = {41713415},
issn = {1097-4172},
abstract = {Blood factors transfer the benefits of exercise to the aged brain independent of physical activity. Here, we show that the liver-derived exercise factor (exerkine) glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (GPLD1), a GPI-degrading enzyme, reverses aging- and Alzheimer's-related memory loss by targeting the brain vasculature. GPLD1 has the potential to cleave over 100 putative GPI-anchored proteins, necessitating the identification of downstream targets that mediate cognitive rejuvenation for translational application. We identified GPI-anchored tissue-nonspecific alkaline phosphatase (TNAP) on the brain vasculature as a GPLD1 substrate. Mimicking age-related increases in cerebrovascular TNAP impaired blood-brain transport and cognition in young mice and mitigated GPLD1-induced cognitive benefits in aged mice. Inhibiting TNAP recapitulated the benefits of GPLD1 in old age, restoring youthful hippocampal transcriptional signatures and rescuing cognition. In an Alzheimer's disease model, increasing GPLD1 or inhibiting TNAP ameliorated Aβ pathology and improved cognitive deficits. We thus identify brain vasculature as a mediator of the cognitive benefits of a liver-to-brain exercise axis.},
}

@article {pmid41713294,
year = {2026},
author = {Guerrero, S and Hassan, N and Salas-Huenuleo, E and Moglia, I and Prades, R and Massa, S and Teixido, M and Guzman, F and Giralt, E and Albericio, F and de Oliveira, E and Araya, E and Kogan, MJ},
title = {Apolipoprotein E-enriched protein corona enhances the blood-brain barrier transport of β-sheet-breaker peptide-functionalized gold nanoparticles.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {262},
number = {},
pages = {115538},
doi = {10.1016/j.colsurfb.2026.115538},
pmid = {41713294},
issn = {1873-4367},
abstract = {The transient, heterogeneous nano-bio interface defined by the protein corona in biological environments dictates the biodistribution, immune recognition, metabolism, and clearance of nanomaterials. Far from being a drawback, this corona can be harnessed for targeted nanodrug delivery when its composition is predictably tuned or deliberately modulated. We hypothesized that preloading apolipoprotein E (ApoE), previously identified as a constituent of the corona of β-sheet-breaker peptide-functionalized gold nanoparticles (AuNPs), would enhance transport across the blood-brain barrier (BBB) and increase brain uptake. To test this, we synthesized AuNPs (approximately 12 nm) functionalized (AuNP-f) with CLPFFD or THRPPMWSPVWPCLPFFD peptides, both containing the β-sheet-breaker motif LPFFD, which recognizes β-amyloid aggregates implicated in Alzheimer's disease. After incubation with human plasma, hard-corona proteins were profiled by 2D IEF/SDS-PAGE and LC-MS/MS. Proteins were ranked based on their roles in nanoparticle trafficking and BBB transcytosis, and ApoE was selected for deliberate enrichment due to its recurrent presence. ApoE-decorated AuNP-f were evaluated in an in vitro BBB model and in vivo biodistribution assays using Sprague-Dawley rats. Brain accumulation was assessed ex vivo. Preloading ApoE onto AuNP-f significantly enhanced nanoparticle transport across the BBB in vitro and increased brain accumulation in rats. These results demonstrate that rational corona enrichment with ApoE improves BBB transit and brain accumulation without altering nanoparticle surface chemistry. Corona engineering thus offers a pragmatic route to brain-targeted nanodrug delivery and may be extended to other protein-receptor axes for organ-specific targeting.},
}

@article {pmid41712998,
year = {2026},
author = {Pavilek, B and Hajduová, D and Bortňák, D and Milata, V},
title = {Kynurenic acid derivatives in treatment for Alzheimer's disease.},
journal = {Bioorganic & medicinal chemistry},
volume = {136},
number = {},
pages = {118601},
doi = {10.1016/j.bmc.2026.118601},
pmid = {41712998},
issn = {1464-3391},
abstract = {This review provides a comprehensive overview of kynurenic acid (KYNA) derivatives with specific focus on KYNA amides as an emerging class of multi-target directing drugs (MTDDs) for the treatment of Alzheimer's disease (AD). It highlights the urgent need for novel AD therapies, discusses the key structural and pharmacological attributes that position KYNA as a promising candidate for this role, outlines laboratory synthesis for KYNA scaffold. Furthermore, the review summarizes the most promising KYNA derivatives reported in the literature, critically evaluates the results from conducted bioassays, and establishes future prospectives for KYNA MTDDs. Overall, eleven leading structures (compounds 1-11) were identified whose MTDD profiles usually combine the neuroprotective and anti-inflammatory features of KYNA with neurotransmitter modulation, anti-amyloid-beta (Aβ) aggregation activity, and, less frequently, antioxidant properties and the maintenance of ion homeostasis. Comparative analysis of the bioassay data identifies compounds 2 and 6 as MTDDs with superior translational validity, evidenced by their demonstrated efficacy in vivo models (Caenorhabditis elegans). Conversely, compounds 7 and 8 emerged as the candidates with the highest potency and broadest pharmacological scope. These derivatives effectively modulated five distinct pathological hallmarks of AD: Aβ accumulation, oxidative stress, neurotransmitter imbalance, and neuroinflammation. Notably, they exhibit disease-modifying potential by functioning not only as neuroprotective agents but also as promoters of neurogenesis. Synthetically, amidation represents the predominant strategy for achieving an MTDD profile, facilitating the efficient modification of pharmacological activity in a single step via the incorporation of bioactive amines.},
}

@article {pmid41712850,
year = {2026},
author = {Piyaamornpan, N and Srisuwannanukorn, S and Tangthamrongthanawat, K and Mekhasingharak, P and Rattanabannakit, C and Hunnangkul, S and Wongkom, N and Senanarong, V},
title = {Web-Based Application for Cognitive and Functional Assessments in Dementia Screening: Mixed Methods, User-Centered Development Approach.},
journal = {JMIR human factors},
volume = {13},
number = {},
pages = {e85454},
doi = {10.2196/85454},
pmid = {41712850},
issn = {2292-9495},
mesh = {Humans ; Female ; *Dementia/diagnosis ; Aged ; Male ; Thailand ; *Internet ; *Mass Screening/methods ; Aged, 80 and over ; Middle Aged ; Neuropsychological Tests ; User-Centered Design ; Cognitive Dysfunction/diagnosis ; },
abstract = {BACKGROUND: Digital health technologies offer new opportunities for cognitive screening and monitoring among older adults. In Thailand, where dementia prevalence is rising, accessible web-based cognitive tools remain limited despite their potential to facilitate early detection and community-based assessment. Understanding usability and validity is critical to ensure successful implementation in real-world contexts.

OBJECTIVE: This study aimed to develop and validate a web-based application, Healthy Brain Test, for cognitive and functional assessments in dementia screening among older Thai adults. Specific objectives were to (1) design user-centered cognitive modules covering key cognitive domains and (2) evaluate correlations between the web-based assessments and conventional clinical tools to determine diagnostic cutoffs for cognitive impairment.

METHODS: We designed Healthy Brain Test as a self-administered web application suitable for older users and their caregivers. The platform includes digital versions of the Thai Mental State Examination (e-TMSE), a clock drawing test, and a category verbal fluency test, along with electronic versions of the short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE-16) and cognitive instrumental activities of daily living (IADLs). Participants completed both web-based and paper-based assessments. Correlations between modalities were analyzed, and receiver operating characteristic (ROC) curves were generated to determine sensitivity and specificity. Data were analyzed using SPSS for Windows, version 30.0 (IBM Corp) and MedCalc Statistical Software (MedCalc Software Ltd).

RESULTS: A total of 198 older adults participated (women: 137/198, 69.2%; median age 69.4 years), with 57.1% (113/198) having more than 6 years of education. Of the 198 participants, 44 were diagnosed with major neurocognitive disorder, 58 were diagnosed with mild neurocognitive disorder, and 96 were cognitively normal. The e-TMSE showed strong agreement with the traditional TMSE (r=0.837; P<.001). Category verbal fluency, IQCODE-16, and IADL modules also demonstrated significant correlations (P<.001). The e-TMSE achieved an area under the ROC curve of 0.84 (bootstrapped 95% CI 0.78-0.89); a cutoff ≤23 provided 88.6% sensitivity and 70.1% specificity for identifying major neurocognitive disorder. Participants reported high ease of use and engagement during pilot testing.

CONCLUSIONS: Healthy Brain Test demonstrated strong validity and usability as a web-based cognitive and functional assessment platform for dementia screening. Its integration of established cognitive measures into a digital interface enables remote, accessible, and user-friendly evaluation for older adults and caregivers. Future research should assess long-term feasibility, user adherence, and integration with clinical workflows to support large-scale screening initiatives.},
}

Humans
Female
*Dementia/diagnosis
Aged
Male
Thailand
*Internet
*Mass Screening/methods
Aged, 80 and over
Middle Aged
Neuropsychological Tests
User-Centered Design
Cognitive Dysfunction/diagnosis

@article {pmid41712108,
year = {2026},
author = {Grasso, M and Fidilio, A and L'Episcopo, F and Recupero, M and Barone, C and Lovino, M and Alboni, S and Bacalini, MG and Caruso, G and Greco, D and Buono, S and De La Torre, R and Tascedda, F and Blom, JM and Benatti, C and Caraci, F},
title = {Searching for New Possible Peripheral Biomarkers of Cognitive Decline in Down Syndrome: The Role of IL-18 Pathway and its Interaction with TGF-β1 and TNF-α.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {12},
pmid = {41712108},
issn = {1559-1174},
support = {GR-2019-12369983//Ministero della Salute/ ; GR-2019-12369983//Ministero della Salute/ ; grant agreement no. 899986//European Union's Horizon 2020 research and innovation program/ ; },
mesh = {Humans ; *Interleukin-18/blood/physiology ; Biomarkers/blood ; Adult ; Male ; Female ; *Down Syndrome/blood/complications/psychology ; *Transforming Growth Factor beta1/blood/physiology ; Young Adult ; *Tumor Necrosis Factor-alpha/blood/physiology ; *Cognitive Dysfunction/blood/etiology ; Middle Aged ; Alzheimer Disease/blood/diagnosis ; Signal Transduction ; Aged ; },
abstract = {Down syndrome (DS) represents one of the most common genetic disorders attributable to a partial or complete trisomy of chromosome 21 that affects about 1 in 700 individuals at birth. The diagnosis of Alzheimer's Disease (AD)-correlated cognitive decline in this population requires new approaches and new biomarkers that comprehensively assess health status and early cognitive decline. In this observational study, we explored for the first time the relation of IL-18, a cytokine member of IL-1 family involved in both innate and acquired immune responses, with DS associated cognitive decline. We observed that plasma total IL-18, in subjects with DS over 35 with and without AD-related cognitive decline, and plasma concentrations of its binding protein in subjects with DS (19-35 years) were correlated with lower plasma concentrations of Transforming Growth Factor (TGF-β1), which are linked to an increased rate of cognitive decline in adults with DS. In addition, we found a significant association between low baseline concentrations of Free IL-18, the active form of the cytokine, and an increased rate of cognitive decline at 12 months, calculated as delta of the Test for Severe Impairment (dTSI), in individuals with DS (19-35 years). Finally, we demonstrated a reduction of Free IL-18/TNF-α ratio, considered as a new possible double biomarker, in both young and older adult DS subjects without AD-related cognitive decline (area under the receiver operating curve (AUC) was 0.82 and 0.71, respectively), suggesting the advantage of the composite biomarkers in the discrimination of patients from healthy people over single biomarkers.},
}

Humans
*Interleukin-18/blood/physiology
Biomarkers/blood
Adult
Male
Female
*Down Syndrome/blood/complications/psychology
*Transforming Growth Factor beta1/blood/physiology
Young Adult
*Tumor Necrosis Factor-alpha/blood/physiology
*Cognitive Dysfunction/blood/etiology
Middle Aged
Alzheimer Disease/blood/diagnosis
Signal Transduction
Aged

@article {pmid41712029,
year = {2026},
author = {Ahmad, HA and Zafar, M and Khan, T and Khan, MI},
title = {Current progress in pathway-targeted therapeutics for Alzheimer's disease: mechanistic insights and windows of opportunity.},
journal = {Molecular and cellular biochemistry},
volume = {},
number = {},
pages = {},
pmid = {41712029},
issn = {1573-4919},
}

@article {pmid41711970,
year = {2026},
author = {Pham, HB and Tong, MT and Tran, NTL and Tran, TT and Phan, TL and Ching, CTS and Huynh, CK and Ha, TTH and Tran, CT},
title = {Development and human samples validation of a plasma pTau‑217 electrochemical sensor for Alzheimer's detection in Vietnamese patients.},
journal = {Mikrochimica acta},
volume = {193},
number = {3},
pages = {170},
pmid = {41711970},
issn = {1436-5073},
support = {B2024-28-06//Vietnam National University HoChiMinh City (VNU-HCM)/ ; },
}

@article {pmid41711262,
year = {2026},
author = {Keshavan, A and Wiltshire, K and Wee, R and Belio, IG and Tucker, K and Hart, M and Lunn, MP and David, MCB and Rizzo, L and Sadeghi-Alavijeh, O and Wilson, P and Gale, DP and Heslegrave, AJ and Zetterberg, H and Fox, NC and Malhotra, P and Schott, JM},
title = {The Alzheimer's Disease Diagnosis and Plasma Phospho-Tau217 (ADAPT) study stage 1: Validating clinical cut-points against CSF and amyloid PET.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71147},
doi = {10.1002/alz.71147},
pmid = {41711262},
issn = {1552-5279},
support = {ARUK-BBC2023-002//Blood Biomarker Challenge/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/cerebrospinal fluid/blood/diagnostic imaging ; *tau Proteins/blood/cerebrospinal fluid ; *Positron-Emission Tomography ; Male ; Female ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Phosphorylation ; Sensitivity and Specificity ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; Cohort Studies ; },
abstract = {INTRODUCTION: We validated plasma phosphorylated tau (p-tau)217 cut-points for Alzheimer's disease (AD) diagnosis using two commercial assays in two biomarker-defined cohorts and examined influences of pre-analytical factors and chronic kidney disease (CKD) on p-tau217 concentrations.

METHODS: Lumipulse (Fujirebio) and ALZpath (Quanterix) assays quantified plasma p-tau217 in symptomatic patients (AD status definition cerebrospinal fluid [CSF] n = 257; amyloid positron emission tomography [PET] n = 76). Receiver operating characteristic (ROC) analyses established ≥ 95% sensitivity/specificity cut-points. In separate cohorts we evaluated the impact of pre-analytical handling/transport variations (n = 40/10) and cognitively normal (CN)-CKD individuals (n = 58).

RESULTS: Diagnostic accuracy was similar (area under the ROC Lumipulse 0.947; ALZpath 0.940). Lumipulse p-tau217 achieved 95% sensitivity and 97% specificity using dual cut-points (0.153/0.422 pg/mL), producing indeterminate results in 19.4% (CSF defined) and 34.2% (PET defined). P-tau217 concentrations were stable across handling conditions and kit lots, and mostly in the low-to-intermediate range in CN-CKD.

DISCUSSION: Lumipulse plasma p-tau217, now available in our United Kingdom Accreditation Service-accredited clinical National Health Service laboratory, will be used in a randomized trial of p-tau217 result disclosure in memory services.},
}

Humans
*Alzheimer Disease/diagnosis/cerebrospinal fluid/blood/diagnostic imaging
*tau Proteins/blood/cerebrospinal fluid
*Positron-Emission Tomography
Male
Female
Aged
Biomarkers/blood/cerebrospinal fluid
Phosphorylation
Sensitivity and Specificity
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Aged, 80 and over
Cohort Studies

@article {pmid41711160,
year = {2026},
author = {Zerbini, E and Riva, D and Maffioli, E and Tedeschi, G and Sacchi, S and Pollegioni, L},
title = {Post-translational regulation of human D-3-phosphoglycerate dehydrogenase in Alzheimer's disease.},
journal = {Protein science : a publication of the Protein Society},
volume = {35},
number = {3},
pages = {e70505},
doi = {10.1002/pro.70505},
pmid = {41711160},
issn = {1469-896X},
support = {PRIN 2017 (2017H4J3AS)//Ministero dell'Università e della Ricerca/ ; },
mesh = {Humans ; *Alzheimer Disease/enzymology/genetics/metabolism ; *Phosphoglycerate Dehydrogenase/metabolism/chemistry/genetics ; *Protein Processing, Post-Translational ; Female ; Male ; Phosphorylation ; Acetylation ; Hippocampus/enzymology ; Aged ; },
abstract = {Emerging evidence suggests that sex-specific differences in L-serine (L-Ser) metabolism play a key role in Alzheimer's disease (AD). While disruptions in amino acid balance are well known, recent findings point to a dimorphic regulation of the serine biosynthetic pathway. To explore this, we examined post-translational modifications (PTMs) of D-3-phosphoglycerate dehydrogenase (PHGDH)-the rate-limiting enzyme for de novo L-Ser synthesis-as a potentialmechanism underlying this difference. PHGDH was immunoprecipitated from hippocampal tissue of healthy and AD-affected males and females and analyzed by mass spectrometry. Five phosphorylation sites (S55, T60, T78, S383, and S473) were shared across all groups, but a unique deacetylation at K289 appeared exclusively in AD males. Functional assays using recombinant PHGDH variants revealed that changes at solvent-exposed sites (K289, S383, and S473) reduced solubility, while phosphomimetic substitutions at S55 and T78 within the catalytic cleft strongly impaired activity. Notably, mimicking acetylation at K289 improved protein stability. Overall, these PTMs act both as subtle modulators and as on/off switches, fine-tuning PHGDH function and potentially contributing to sex-dependent metabolic vulnerability in AD.},
}

Humans
*Alzheimer Disease/enzymology/genetics/metabolism
*Phosphoglycerate Dehydrogenase/metabolism/chemistry/genetics
*Protein Processing, Post-Translational
Female
Male
Phosphorylation
Acetylation
Hippocampus/enzymology
Aged

@article {pmid41711094,
year = {2026},
author = {Gaugler, JE and Albers, EA and Birkeland, RW and Urbanski, DP},
title = {A mixed methods evaluation of the Residential Care Transition Module.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/13607863.2026.2631437},
pmid = {41711094},
issn = {1364-6915},
abstract = {OBJECTIVES: A post-hoc, mixed methods analysis of a randomized controlled trial of a 12-month psychosocial and psychoeducational telehealth intervention to support dementia caregivers of cognitively impaired relatives living in residential long-term care settings (the Residential Care Transition Module/RCTM) was conducted to identify and test potentially new mechanisms and outcomes of the RCTM.

METHOD: Two hundred and forty caregivers were randomly assigned to the RCTM treatment condition or to usual care as the control group and were administered quarterly surveys. Participants in the treatment condition provided qualitative data on perceptions of intervention benefits on follow-up surveys and semi-structured interviews conducted after the 12-month intervention (n = 30). New mechanisms and outcomes identified in the qualitative analysis were mapped onto existing items and scales (e.g. single items from the Short Sense of Competence Questionnaire) and re-analyzed quantitatively using general linear models.

RESULTS: The mixed methods analysis suggested that dementia caregivers in the RCTM group were more confident in their ability to obtain information about and arrange services (e.g. legal and financial planning, long-term care ombudsman) than controls and were less likely to report annoyance with care recipients' behaviors.

CONCLUSION: The mixed methods results advance our understanding of the RCTM's potential efficacy, and the adoption of similar methodologies may yield greater insights into how and why dementia care interventions are beneficial, even in the face of initial null findings.},
}

@article {pmid41711012,
year = {2026},
author = {Sheibani, N and Yadollahikhales, G and Simpkins, AN},
title = {Guidelines in Action: Cognitive Outcomes and Blood Pressure Control.},
journal = {Stroke},
volume = {},
number = {},
pages = {},
doi = {10.1161/STROKEAHA.125.053501},
pmid = {41711012},
issn = {1524-4628},
}

@article {pmid41710946,
year = {2026},
author = {Schwab, D and Hofmann, C and Justies, N and Dickerson, DS and Keshavarz, A and van Iersel, T and Martens, K and Bittner, B},
title = {Bioequivalence Between a Gantenerumab Disposable Syringe and an Autoinjector: A Randomized Controlled Trial in Healthy Volunteers.},
journal = {Clinical pharmacology in drug development},
volume = {15},
number = {2},
pages = {e70038},
doi = {10.1002/cpdd.70038},
pmid = {41710946},
issn = {2160-7648},
support = {//F. Hoffmann-La Roche/ ; },
mesh = {Humans ; Therapeutic Equivalency ; Male ; Female ; Adult ; Healthy Volunteers ; Syringes ; Middle Aged ; Injections, Subcutaneous ; Area Under Curve ; *Antibodies, Monoclonal, Humanized/administration & dosage/pharmacokinetics/adverse effects ; Young Adult ; Disposable Equipment ; },
abstract = {Gantenerumab, a monoclonal antibody targeting amyloid beta plaques in the brain, reduces plaque accumulation and was developed to slow Alzheimer's disease progression. Results from the pivotal GRADUATE I and II studies evaluating gantenerumab in people with early Alzheimer's disease were announced in 2022. The studies did not meet their primary endpoint of slowing clinical decline. This study evaluated the pharmacokinetics, immunogenicity, and safety of a high concentration liquid formulation of gantenerumab administered subcutaneously as a single dose using an autoinjector (AI) or a disposable syringe (DS). The DS was employed in pivotal clinical trials, while the AI was developed in parallel to ease SC administration. The study aimed to demonstrate bioequivalence (BE) between AI and DS administration in healthy participants, defined by 90% confidence intervals (CIs) for geometric least square (LS) mean ratios being within the 0.80-1.25 range for maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC). Among the 266 healthy participants, 135 received 255 mg gantenerumab via AI and 131 received 255 mg via DS in a parallel group design. BE between AI and DS SC administration was demonstrated with geometric LS mean ratios (90% CIs) for Cmax, AUC0-inf, and AUC0-last of 1.078 (1.006, 1.155), 1.053 (0.986, 1.124), and 1.054 (0.992, 1.121), respectively, all within the 0.80-1.25 BE range. Safety findings were consistent with the known safety profile of gantenerumab.},
}

Humans
Therapeutic Equivalency
Male
Female
Adult
Healthy Volunteers
Syringes
Middle Aged
Injections, Subcutaneous
Area Under Curve
*Antibodies, Monoclonal, Humanized/administration & dosage/pharmacokinetics/adverse effects
Young Adult
Disposable Equipment

@article {pmid41710892,
year = {2026},
author = {Peng, L and Zhang, Z and Hu, Y and Chen, H and Tian, Y and Ling, H},
title = {Regulating the crosstalk between Bifidobacterium and the brain: a potential therapeutic strategy for Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1706811},
pmid = {41710892},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/therapy/microbiology/metabolism ; *Bifidobacterium/physiology/immunology ; *Gastrointestinal Microbiome ; *Brain/metabolism/microbiology ; *Probiotics/therapeutic use ; Animals ; },
abstract = {Alzheimer's disease (AD) is a common dementia in the elderly population, typically manifested through symptoms of cognitive impairment (CI) and memory loss. Pathologically, it is characterized by abnormally elevated levels of amyloid-β (Aβ) deposition and tau phosphorylation. Given the rapid rate of population aging, many scientists are investigating AD, focusing on its pathogenic mechanisms and potential treatments. Unfortunately, to date, no highly effective therapeutic strategies have emerged. Intriguingly, multiple studies have revealed alterations in the gut microbiome of individuals with AD, suggesting it may serve as a novel avenue for investigating AD pathogenesis. Bifidobacterium, a pivotal probiotic in the gastrointestinal tract, is crucial in upholding the equilibrium of gut flora. Notably, marked deficiencies in Bifidobacterium have been observed in the guts of AD patients, underscoring the potential of further inquiry into the impact of Bifidobacteria on AD via the gut-microbe-brain axis. However, current research on the mechanisms through which Bifidobacteria can alleviate AD is limited, warranting further investigation. This review examines Bifidobacterial alterations in Alzheimer's disease patients and the underlying mechanisms, with the aim of evaluating their potential as a therapeutic strategy for Alzheimer's disease.},
}

Humans
*Alzheimer Disease/therapy/microbiology/metabolism
*Bifidobacterium/physiology/immunology
*Gastrointestinal Microbiome
*Brain/metabolism/microbiology
*Probiotics/therapeutic use
Animals

@article {pmid41710720,
year = {2026},
author = {Qiao, Y and Zhou, F and Mao, T and Gao, L},
title = {Revitalizing GIP: Therapeutic Potential in Metabolic and Neurodegenerative Disorders.},
journal = {Diabetes, metabolic syndrome and obesity : targets and therapy},
volume = {19},
number = {},
pages = {559587},
pmid = {41710720},
issn = {1178-7007},
abstract = {Glucose-dependent insulinotropic polypeptide (GIP), once the overlooked sibling of the incretin family, is now experiencing a research renaissance. Historically, its therapeutic development was hindered by a seemingly diminished insulinotropic effect in type 2 diabetes (T2DM), its paradoxical stimulation of glucagon during hyperglycemia, and translational gaps between rodent and human physiology. This review highlights the renewed interest in GIP, driven by a deeper understanding of its pleiotropic actions. GIP stimulates glucose-dependent insulin secretion and, uniquely, also stimulates glucagon secretion during hyperglycemia. Emerging evidence suggests this glucagon release may subsequently enhance insulin secretion through intra-islet α-β cell communication, revealing a more complex role in glucose homeostasis than previously appreciated. Beyond the pancreas, GIP promotes lipid storage in adipose tissue, reduces ectopic fat deposition, modulates bone remodeling, influences cardiovascular lipid metabolism, and exhibits neuroprotective properties. Preclinical and clinical studies indicate that GIP-based therapies can improve glycemic control, alleviate obesity-related inflammation, and enhance insulin sensitivity. Notably, GIP exhibits synergistic effects with GLP-1, exemplified by the dual receptor agonist Tirzepatide, which has demonstrated superior efficacy in clinical trials. Compared to the selective GLP-1 receptor agonist semaglutide (1 mg), the highest dose (15 mg) of tirzepatide achieved a greater reduction in glycated hemoglobin (-2.30 vs -1.86 percentage points) and body weight (an additional 5.5 kg reduction) over 40 weeks. Furthermore, GIP and its analogs show promise in ameliorating pathology and cognitive deficits in neurodegenerative models like Alzheimer's disease, suggesting a potential new therapeutic avenue for central nervous system disorders. This review synthesizes the evolving narrative of GIP from a challenging target to a multifaceted therapeutic agent and identifies key research gaps, particularly in understanding its tissue-specific signaling and optimizing its synergy within multi-agonist therapies for metabolic and neurodegenerative diseases.},
}

@article {pmid41710622,
year = {2026},
author = {Alsalhi, AA and Almazyad, FH and Alharbi, AZ and AlDhuwaihy, A and AlSulaim, YB},
title = {Evaluating the dementia risk associated with anesthesia and surgery: A comprehensive systematic review and meta-analysis.},
journal = {Saudi journal of anaesthesia},
volume = {20},
number = {1},
pages = {156-165},
pmid = {41710622},
issn = {1658-354X},
abstract = {Increasing global life expectancy has expanded the surgical population, raising concerns about postoperative outcomes. Dementia, especially Alzheimer's disease (AD), poses a significant public health challenge. This meta-analysis investigates anesthesia exposure and AD risk. Following PRISMA 2020 guidelines, we systematically searched five databases (2014-2022) for observational studies evaluating dementia risk in adults ≥60 years undergoing surgery with anesthesia. Two reviewers independently screened studies, extracted data, and assessed quality using the Newcastle-Ottawa Scale. Pooled odds ratios were calculated using a random-effects model, with subgroup and publication bias analyses conducted. Significant associations with dementia included hypertension (OR 1.36, 95% CI [1.16, 1.59]), hyperlipidemia (OR 1.19 [1.16, 1.22]), coronary artery disease (OR 2.45 [1.72, 3.50]), depression (OR 1.70 [1.27, 2.27]), and head injury (OR 1.31 [1.14, 1.51]). Subgroup analyses showed mixed results for age, surgery, and medication. Kidney-ureter-bladder surgery increased risk substantially (OR 2.52 [1.10, 5.76]). Publication bias was observed. No statistically significant association was found between general anesthesia and AD risk. However, significant heterogeneity, potential publication bias, inconsistent subgroups, and challenges in isolating anesthesia effects from surgery necessitate cautious interpretation. Large prospective cohort studies with standardized methods, adequate lag time, and rigorous confounder adjustments are imperative. Perioperative care optimization for older adults at risk of cognitive decline is clinically warranted.},
}

@article {pmid41710481,
year = {2026},
author = {Rizvi, SMO and Thakur, A and Sharma, S and Kaur, H and Kaur, S and Dan, P},
title = {Hydroxyapatite nanoparticles as a vehicle for drug delivery approach in Alzheimer's disease.},
journal = {3 Biotech},
volume = {16},
number = {3},
pages = {92},
pmid = {41710481},
issn = {2190-572X},
abstract = {Hydroxyapatite (HAp) nanoparticles are gaining attention as potential drug delivery systems for Alzheimer's Disease (AD) because of their compatibility with biological systems, stability, and adaptable surfaces. Their small size facilitates effective drug encapsulation and controlled release, while surface alterations with ligands or antibodies enable precise targeting of delivery to the blood-brain barrier (BBB) and to areas affected by amyloid-beta (Aβ) plaques and tau accumulations. HAp nanoparticles are capable of transporting anti-amyloid, anti-tau, and neuroprotective drugs, which increases therapeutic levels and reduces systemic adverse effects. Research shows that HAp nanoparticles can pass through the BBB using adsorptive-mediated and receptor-mediated transcytosis, and methods such as temporarily opening tight junctions or modifying surface charges can further improve their permeability. Drugs can be integrated via co-precipitation, adsorption, or encapsulation techniques, often allowing for pH-responsive release in the acidic environment of diseased brain tissue. Nevertheless, there are still obstacles to address regarding the scalability of production, stability and clearance in living organisms, and the long-term compatibility and safety in neural tissue.},
}

@article {pmid41710476,
year = {2026},
author = {Baghel, B and Purohit, P and Roy, B and Pareek, V and Sharma, S and Roy, PK},
title = {Enhanced neuroprotective ability of human cerebellum during ageing: the interplay of neuroplasticity, neurodegeneration and life-time trajectory-a pilot study.},
journal = {3 Biotech},
volume = {16},
number = {3},
pages = {89},
pmid = {41710476},
issn = {2190-572X},
abstract = {The neurodegenerative decline of brain with ageing is an acute global demographic problem, as elderly population surges worldwide. However, ageing effect has not been systematically studied for cerebellum, an autonomous part of brain having motor, cognition, language and memory functions. By magnetic resonance investigation, we study brain-ageing process: 177 normal subjects, aged 20-80, with focus on cerebellum, the first larger-scale analysis as we know. We found that for whole brain, both grey-matter/GM and white-matter/WM) volumes deceases with ageing (by ~ 15%). Contrastingly, these volumes remain unexpectedly stable in ageing cerebellum, indicating neuroprotective ability. To estimate neuroplasticity resilience of brain-tissue, we evaluated GM/WM interrelationship, assessed by GM-volume/WM axial-diffusivity. During ageing, the GM/WM interrelationship is comparatively stable in cerebellum, while in whole brain this relationship is much variable (230% increase). We validated the cerebellar neuroprotective ability by epigenetic tissue ageing analysis (DNA-methylation). Ageing retardation-level (years) of brain-tissue follows the neurodevelopmental caudal-rostral-rhinal axis: cerebellum (maximum retardation/neuroprotection), occipital, frontal, and temporal region (minimum). We log-normally plotted ageing-retardation against phylogenic age of that brain region (million-years ago/MYA), and found linear relationship, implying a quantitative evolutionary behaviour, indicating cerebellum's phylogenic antiquity (Cambrian-era ~ 510MYA), which adapted the cerebellum to withstand degenerative damage. Finally, we investigated cerebellum's neurocognitive resilience, enabling focussed development of coordination, tool-making and language, while present-day humans evolutionarily progressed over Neanderthals. We found that humans show maximal cerebellar expansion and depth. Of seminal significance is that cerebellum is a unique paradoxical brain region with peak neuroprotective behaviour, and may have substantial therapeutic rehabilitative biotechnological implications in neurodegenerative disorders.},
}

@article {pmid41710449,
year = {2026},
author = {MacLennan, RJ and Chapin, BA and Solberg, LM and Clark, DJ},
title = {Cognitive decline in U.S. military veterans: risk factors and clinical implications.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1704367},
pmid = {41710449},
issn = {2813-3919},
abstract = {Military veterans have higher aggregate prevalence of risk factors for cognitive decline than non-veterans. This includes risk factors like diabetes, chronic pain, smoking, depression, and more. The disparity in prevalences is due in part to the unique experiences and exposures of their military service. Alzheimer's disease and other dementias are debilitating diseases with large financial and logistical burdens. These burdens are held by the patient, their family, friends, and caregivers, as well as healthcare professionals, and healthcare systems. Standardized screening for these risk factors may be helpful for understanding risk profiles that lead to cognitive decline. Additionally, screening must occur early to encourage early intervention and behavioral modifications and to reduce these burdens. This perspective presents the prevalence of risk factors for cognitive decline in the Veteran and non-veteran populations and proposes an approach to managing risk factors in Veterans.},
}

@article {pmid41710299,
year = {2026},
author = {Anicin, L and Andjelic, S and Markovic Blagojevic, M and Bulaja, D and Zivkovic, M and Zivkovic, T and Antonijevic, M and Bacanin, N},
title = {Metaheuristic-driven dual-layer model for classifying Alzheimer's disease stages.},
journal = {Frontiers in computational neuroscience},
volume = {20},
number = {},
pages = {1731812},
pmid = {41710299},
issn = {1662-5188},
abstract = {INTRODUCTION: Accurate determination of the progression phase of Alzheimer's disease (AD) is crucial for timely clinical decision-making, improved patient management, and personalized therapeutic interventions. However, reliably distinguishing between multiple disease stages using neuroimaging data remains a challenging task.

METHODS: This study proposes an advanced machine learning framework for multi-stage AD classification using magnetic resonance imaging (MRI) data. The architecture follows a two-tier design. In the first stage, convolutional neural networks (CNNs) are employed to extract deep and discriminative feature representations from MRI images. In the second stage, these features are classified using ensemble learning models, specifically XGBoost and LightGBM. Metaheuristic optimization strategies are applied to further enhance model performance. The proposed framework was evaluated using a publicly available Alzheimer's disease dataset under three different experimental configurations.

RESULTS: Experimental results demonstrate that the proposed approach effectively addresses the multi-class classification problem across different AD progression stages. The optimized models achieved a maximum classification accuracy of 89.55%, indicating robust predictive performance and strong generalization capability.

DISCUSSION: To improve transparency and clinical relevance, explainable artificial intelligence (XAI) techniques were incorporated to interpret model predictions and highlight feature importance. The results provide meaningful insights into neuroimaging biomarkers associated with AD progression and support the development of more interpretable and trustworthy diagnostic systems. Overall, the proposed framework contributes to improved data-driven decision support and offers a promising direction for future Alzheimer's disease diagnosis and staging research.},
}

@article {pmid41710159,
year = {2026},
author = {Pang, Y and Yang, J and Liu, J and Xie, Z and Wang, J},
title = {Metabolic interactions in the brain: the crucial roles of neurons, astrocytes, and microglia in health and disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1731771},
pmid = {41710159},
issn = {1662-4548},
abstract = {This review provides an in-depth exploration of the intricate energy metabolism pathways within the brain, with a particular focus on the dynamic interplay between neurons, astrocytes, and microglia. Neurons, with their high energy demands, primarily rely on oxidative phosphorylation and the tricarboxylic acid (TCA) cycle to sustain synaptic activity and neurotransmitter synthesis. In contrast, astrocytes predominantly engage in glycolysis, producing lactate and glutathione, which are essential for supporting neuronal function and protecting against oxidative stress. Additionally, microglia, the brain's resident immune cells, exhibit a metabolic flexibility that allows them to shift between oxidative phosphorylation and glycolysis, depending on their activation state, which significantly influences neuroinflammation and synaptic plasticity. The review highlights the critical role of astrocyte-neuron metabolic coupling, particularly through the lactate shuttle and glutathione metabolism, in maintaining neuronal homeostasis and facilitating synaptic function. It also delves into the metabolic underpinnings of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis, illustrating how disruptions in brain energy metabolism contribute to disease progression. By synthesizing recent findings, this review not only underscores the centrality of brain energy metabolism in both normal and pathological conditions but also identifies potential therapeutic targets aimed at modulating these metabolic pathways to mitigate the effects of neurodegenerative disorders. This comprehensive analysis offers valuable insights that could propel further research and innovation in the field of neurology, making it essential reading for experts interested in the molecular mechanisms underlying brain function and disease.},
}

@article {pmid41710117,
year = {2026},
author = {Sergio, J and Price, A and Snyder, PJ and Doster, SA and Durkin, M and Strenger, JR and Thompson, LI and Stradtman, M and Sinoff, S and Alber, J},
title = {The Relationship Between Gait Task Performance and Plasma Biomarkers for Alzheimer's Disease in Cognitively Unimpaired Older Adults and Patients with Mild Cognitive Impairment.},
journal = {Clinical interventions in aging},
volume = {21},
number = {},
pages = {562194},
pmid = {41710117},
issn = {1178-1998},
mesh = {Humans ; Aged ; *Alzheimer Disease/blood/diagnosis/genetics/physiopathology ; *Cognitive Dysfunction/blood/physiopathology/genetics ; Male ; Female ; Biomarkers/blood ; Aged, 80 and over ; *Gait/physiology ; Middle Aged ; Genotype ; Apolipoproteins E/genetics ; Task Performance and Analysis ; },
abstract = {PURPOSE: The Timed Up and Go (TUG) is a 20-foot gait assessment, with TUG-dual task (DT) serial subtractions to determine dual-task cost. Alzheimer's disease (AD) risk is established using plasma biomarkers and APOE genotyping.

METHODS: We investigated: 1) TUG/TUG-DT differences between AD low-risk cognitively unimpaired (CU) older adults (N = 74), AD high-risk CU older adults (N = 87), and mild cognitively impaired (MCI) older adults (N = 33) and 2) the relationship between TUG/TUG-DT performance and plasma biomarkers. One hundred and ninety-four older adults ages 55-80 completed TUG/TUG-DT, a fasting blood draw, and APOE genotyping. Scores on the Clinical Dementia Rating Scale (CU = 0; CI = ≥0.5) and Montreal Cognitive Assessment (CU ≥ 24; CI = ≤23) determined whether participants were placed into the CU low-risk, CU high-risk, or MCI groups. Risk level for CU participants were assessed by APOE genotyping. Those participants who carried at least one copy of the APOE ε4 allele were designated to the high-risk group (n = 87). Participants with no APOE ε4 allele were assigned to the low-risk group (n = 75).

RESULTS: MCI participants took longer to perform the TUG than CU participants (p < 0.001). CU high-risk and MCI group performed similarly on step counts, while the CU low-risk took significantly fewer steps (p<0.001). Speed predicted whether someone was below an AD-risk threshold for pTau217 in CU participants (n = 150). Exploratory generalized additive models showed plasma biomarkers predicted gait metrics in CU groups.

CONCLUSION: Step count may be more sensitive, compared to speed alone, in identifying those in preclinical AD stages. Gait metrics (speed and efficiency) played a key role as a clinical manifestation of early AD pathophysiology determined by blood-based biomarker concentration. Combining these assessments offers a multidimensional, cost-effective approach for preclinical-AD screening and potential early intervention.},
}

Humans
Aged
*Alzheimer Disease/blood/diagnosis/genetics/physiopathology
*Cognitive Dysfunction/blood/physiopathology/genetics
Male
Female
Biomarkers/blood
Aged, 80 and over
*Gait/physiology
Middle Aged
Genotype
Apolipoproteins E/genetics
Task Performance and Analysis

@article {pmid41710069,
year = {2026},
author = {Pronk, NP and Wang, S and Woodard, C and Bhatt, T and Arena, R},
title = {Multilevel prediction of Alzheimer's disease dementia in the United States: An artificial intelligence analysis.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70274},
pmid = {41710069},
issn = {2352-8729},
abstract = {INTRODUCTION: Variables predicting Alzheimer's disease (AD) are not limited to individual-level risk factors. The purpose of this investigation is to assess multilevel predictors of AD prevalence.

METHODS: US county-level datasets incorporating 45 predictor variables were analyzed cross-sectionally using artificial intelligence analytical methods. A Light Gradient-Boosting Machine model was trained to predict county-level AD after which model performance and feature importance were evaluated.

RESULTS: The final model retained 20 features and explained 75% (R [2] = 0.75) of the variance in AD prevalence. Racial and ethnic minority status showed the highest importance value (0.848), far exceeding all other features (e.g., poor sleep ranked second with importance value of 0.153).

DISCUSSION: This study confirmed upstream factors as being significant predictors of AD prevalence and racial and ethnic minority status as being the most important. From a policy perspective, efforts to reduce population levels of AD prevalence should consider addressing racial and ethnic disparities.},
}

@article {pmid41709918,
year = {2026},
author = {Lin, YR and Chang, MC and Wang, WF and Tung, YC and Jhang, KM},
title = {The Association of Thyroid Function on Cognition and Neuropsychiatric Symptoms in Patients with Cognitive Impairment.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {575834},
pmid = {41709918},
issn = {1176-6328},
abstract = {INTRODUCTION: This study aims to investigate the association between thyroid function, cognitive status, and neuropsychiatric symptoms (NPSs) in patients with mild cognitive impairment or dementia.

METHODS: This cross-sectional analysis enrolled 2,289 patients newly diagnosed with mild cognitive impairment or dementia. Based on thyroid-stimulating hormone and free thyroxine levels, patients were classified into euthyroid, hypothyroid, and hyperthyroid groups, with subclinical and overt forms incorporated into their respective categories due to group size distribution. NPSs were assessed using the Neuropsychiatric Inventory. Multivariate logistic regression evaluated associations between thyroid function and NPSs, while linear regression examined relationships with cognitive status.

RESULTS: Significant differences in Clinical Dementia Rating-Sum of Boxes (CDRSOB) and Cognitive Abilities Screening Instrument (CASI) scores were observed across the three thyroid function groups (mean CDRSOB: euthyroid = 4.6, hyperthyroidism = 5.4, hypothyroidism = 5.3, p = 0.013; mean CASI: euthyroid = 51.6, hyperthyroidism = 47.2, hypothyroidism = 49.0, p = 0.028). Patients in the hyperthyroid group demonstrated higher odds of experiencing delusion (odds ratio (OR) = 1.61, 95% confidence interval (CI) = 1.12-2.31, p = 0.009), agitation (OR = 1.47, 95% CI = 1.00-2.13, p = 0.048), and moderate to severe hallucination (OR = 1.76, 95% CI = 1.01-2.92, p = 0.037). After adjusting for age, education, and dementia subtypes, patients in the hyperthyroid group had significantly worse CDRSOB scores than those in the euthyroid group (β = 0.66, 95% CI = 0.03-1.3, p = 0.040).

CONCLUSION: This study provides the first structured evaluation of behavioral and psychological symptoms of dementia across thyroid function states in patients with cognitive impairment. Hyperthyroidism was associated with worse global function and a higher prevalence of delusions, agitation, and moderate-to-severe hallucinations. These findings highlight an association between thyroid dysfunction and BPSD (behavioral and psychological symptoms of dementia) in cognitively impaired populations and underscore the importance of careful clinical evaluation of thyroid status.},
}

@article {pmid41709913,
year = {2026},
author = {Daniels, AJ and McDade, E and Llibre-Guerra, JJ and Xiong, C and Perrin, RJ and Ibanez, L and Supnet-Bell, C and Cruchaga, C and Goate, A and Renton, AE and Benzinger, TLS and Gordon, BA and Hassenstab, J and Karch, C and Levey, A and Morris, JC and Buckles, V and Allegri, RF and Chrem, P and Berman, SB and Chhatwal, JP and Farlow, MR and Fox, NC and Day, GS and Ikeuchi, T and Jucker, M and Levin, J and Lee, JH and Aguillon, D and Takada, L and Sosa, AL and Martins, R and Mori, H and Noble, JM and Salloway, S and Huey, E and Sánchez-Valle, R and Schofield, PR and Roh, JH and Bateman, RJ and , },
title = {15 years of longitudinal genetic, clinical, cognitive, imaging, and biochemical measures in DIAN.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {13},
pmid = {41709913},
issn = {3005-1940},
abstract = {The Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs) is a longitudinal, global cohort study investigating brain aging and autosomal dominant Alzheimer's disease (ADAD), a rare monogenic form of Alzheimer's disease (AD). Established in 2008 with support from the National Institute on Aging (NIA), DIAN Obs is designed to collect comprehensive and uniform data with the aim to characterize brain biology and clinical trajectory of individuals at risk for ADAD. Mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes cause ADAD with virtually full penetrance and a predictable age at symptomatic onset. Participants, both mutation carriers and non-carriers from affected families, undergo longitudinal clinical and cognitive assessments, neurologic and physical examinations, structural and functional neuro-imaging, and amyloid and tau positron emission tomography (PET). Biospecimens include cerebrospinal fluid, plasma, serum, and whole blood for biochemical, genetic and multi-omic analyses, with brain donation upon death. This dataset enables one of the most detailed longitudinal examinations of the human brain across the continuum from presymptomatic to symptomatic AD. The extensive DIAN Obs data and biospecimen repository provides a globally accessible resource to advance understanding of AD pathophysiology, aging, and the development of preventive and therapeutic interventions.},
}

@article {pmid41709891,
year = {2026},
author = {Yadav, TC and Yadav-Samudrala, BJ and Fitting, S},
title = {Editorial: Nanomedicine targeting central nervous system.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1755137},
doi = {10.3389/fmed.2026.1755137},
pmid = {41709891},
issn = {2296-858X},
}

@article {pmid41709697,
year = {2026},
author = {Lagartos-Donate, MJ and Escobar-Doncel, B and Zhang, SQ and Pan, JP and Villaseca González, N and Anisimov, A and Montaldo, NP and Jensen, V and Mao, L and Li, B and Banzon-Pereira, N and Shi, L and Cao, SQ and Caponio, D and Wang, P and Nair, RR and Luo, OJ and Chen, G and Nevado-Holgado, AJ and Buckley, N and Nilsen, HL and Fang, EF},
title = {Loss of REST associated with Alzheimer's disease pathology is ameliorated by NAD.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf261},
pmid = {41709697},
issn = {1460-2156},
support = {#281931//Civitan Norges Forskningsfond for Alzheimers sykdom/ ; #282952//Cure Alzheimer's Fund/ ; #284930//Cure Alzheimer's Fund/ ; #2020001//Helse Sør-Øst/ ; #2021021//Helse Sør-Øst/ ; #2023093//Helse Sør-Øst/ ; #262175//Research Council of Norway/ ; #334361//Research Council of Norway/ ; #282942//Molecule AG/VITADAO/ ; #119986//NordForsk Foundation/ ; #81971327//National Natural Science Foundation of China/ ; #82301422//National Natural Science Foundation of China/ ; #269901//Akershus University Hospital/ ; #261973//Akershus University Hospital/ ; #262960//Akershus University Hospital/ ; #TO01000215//Czech Republic-Norway KAPPA programme/ ; #101073251//Czech Republic-Norway KAPPA programme/ ; #104617//Wellcome Leap's Dynamic Resilience Program/ ; #35590//Nasjonalforeningen for folkehelse/ ; },
abstract = {Downregulation and inactivation of the Repressor Element 1-Silencing Transcription factor (REST) is shown in Alzheimer's disease (AD) and likely contributes to its progression, but the exact molecular mechanism linking REST reduction to AD remains unclear. We examined changes in REST expression in the entorhinal cortex and hippocampus across different Braak stages of tauopathy. We show that alterations in REST expression and sub-cellular localization are partially responsible for AD pathology, as REST overexpression improves cognition, reduces amyloid-β and phosphorylated Tau deposition, and restores mitochondrial and synaptic homeostasis. Mechanistically, the NAD+/SIRT1 axis modulates REST expression through chromatin remodelling in the promoter region of REST, leading to changes in the expression of REST target genes involved in mitophagy and synaptic function. These findings reveal a new mechanism of action for NAD+ and highlight REST as a promising therapeutic target for AD therapy.},
}

@article {pmid41709695,
year = {2026},
author = {Das, S and Hyman, BT and Serrano-Pozo, A},
title = {A critical appraisal of the link between apolipoprotein E and Tau.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
pmid = {41709695},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: The apolipoprotein E (APOE) genotype has traditionally been associated with Alzheimer's disease (AD) and, more specifically, with the severity of cerebral β-amyloidosis in the form of Aβ plaques and cerebral amyloid angiopathy (CAA). However, a growing body of research has examined its potential impact on Tau pathology.

RECENT FINDINGS: Here we critically review the evidence supporting a differential effect of APOE alleles on Tau in the context of AD and non-AD tauopathies, from genetic, neuropathological, and biomarker studies to preclinical studies in mouse models and human inducible pluripotent stem-cells (hiPSCs)-derived brain cells.

SUMMARY: Genetic, neuropathological, and preclinical studies in transgenic mice have yielded somewhat conflicting results, whereas most multitracer PET imaging studies on individuals along the normal aging to AD dementia continuum support an Aβ-independent effect of the APOEε4 allele on the tauopathy of AD. More clinical and preclinical research is needed to elucidate the link between APOE and Tau.},
}

@article {pmid41709686,
year = {2026},
author = {Russell, JK and Schlachetzki, Z and Rafii, MS},
title = {Decoding Alzheimer's disease through down syndrome: insights from a genetically defined population.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
doi = {10.1097/WCO.0000000000001461},
pmid = {41709686},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: This review explores Alzheimer's disease (AD) in individuals with Down syndrome (DS), a genetically defined population with near-universal development of AD neuropathology by age 40. We examine the genetic basis of DS-AD, epidemiology, biomarker trajectories, and clinical trial innovations, highlighting how insights from DS research inform broader AD pathogenesis, early detection, and therapeutic strategies.

RECENT FINDINGS: Advances in biomarker research, including longitudinal studies such as ABC-DS, have mapped predictable trajectories of amyloid, tau, and neurodegeneration in DS-AD, aligning closely with clinical staging. Plasma and CSF biomarkers (Aβ42, p-tau, NfL, GFAP) and neuroimaging modalities (amyloid/tau PET, MRI) demonstrate early and sequential changes decades before dementia onset. Revised AD diagnostic criteria now classify DS individuals as Stage 0 from birth, acknowledging genetic determinism and enabling earlier intervention. Comparative analyses between DS-AD, autosomal-dominant AD, and sporadic AD reveal shared pathological features but distinct timing and distribution of amyloid and tau. Clinical trials targeting amyloid and APP pathways in DS are underway, leveraging predictable disease progression to accelerate therapeutic development.

SUMMARY: Studying AD in DS provides a unique lens into the natural history of Alzheimer's disease, offering critical insights into genetic drivers, biomarker evolution, and therapeutic opportunities. The genetically defined and biologically concordant nature of DS-AD enables precise staging and early intervention strategies that can be translated to sporadic and familial AD. Continued investment in DS research will advance biomarker validation, refine clinical trial design, and inform personalized treatment approaches for the broader AD population.},
}

@article {pmid41709676,
year = {2026},
author = {Skjellegrind, HK and Thingstad, P and Gjøra, L and Kolberg, M and Kjelvik, G and Ernstsen, L and Fagerhaug, TN and Langhammer, A and Krokstad, S and Åsvold, BO and Næss, M and Selbæk, G},
title = {Cohort Profile Update: HUNT4 70.},
journal = {International journal of epidemiology},
volume = {55},
number = {2},
pages = {},
doi = {10.1093/ije/dyag011},
pmid = {41709676},
issn = {1464-3685},
support = {//Norwegian National Centre for Ageing and Health and Center for Oral Health Services and Research (TkMidt)/ ; },
}

@article {pmid41709596,
year = {2026},
author = {Okoye, O and Aguzzoli, CS and Battista, P and Ramos, C and Meenan, K and Abu Raya, M and Ratnasiri, B and Rojas, JC and de Leon, J and Miller, B and Gorno-Tempini, ML and La Joie, R and Spina, S},
title = {Mixed primary progressive aphasia and alcohol use disorder: a case of detailed clinical phenotyping outperforming molecular imaging.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13554794.2026.2623906},
pmid = {41709596},
issn = {1465-3656},
abstract = {Primary progressive aphasia (PPA) refers to a group of clinically and pathologically heterogeneous syndromes characterized by progressive and relatively selective impairment in speech and language as the main cognitive domain in the early disease stage. The main clinical variants of PPA based on current diagnostic criteria include logopenic variant PPA (lvPPA), nonfluent variant PPA (nfvPPA), and semantic variant PPA (svPPA). Identification of speech/language and non-language abilities and in vivo biomarkers (such as neuroimaging, genetic, and biofluid studies) facilitates the correct classification of the main variants. PPA variants clinical presentation may overlap leading to a diagnosis of mixed or unclassified PPA. We report the case of a trilingual patient with a 10-year history of word-finding difficulties initially attributed to chronic alcohol abuse. Her clinical presentation was evocative of lvPPA with features of svPPA, while her neuropsychological testing and MRI data were suggestive of a diagnosis of svPPA. While β-amyloid PET brain imaging was negative, postmortem immunohistochemical analysis of the brain showed unequivocal evidence of Alzheimer's disease. We describe this case of complex PPA for which clinical data outperformed imaging biomarkers in predicting the underlying neuropathology and discuss chronic alcohol abuse as a potential risk factor for neurodegeneration.},
}

@article {pmid41709460,
year = {2026},
author = {Temple, SD and Chapman, NH and Choi, SH and DeStefano, AL and Thornton, TA and Wijsman, EM and Blue, EE},
title = {Multiple-testing corrections in case-control studies using identity-by-descent segments.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2026.01.013},
pmid = {41709460},
issn = {1537-6605},
abstract = {Identity-by-descent (IBD) mapping provides complementary signals to genome-wide association studies (GWASs) when multiple causal haplotypes or variants are present but not directly tested. We propose the difference between affected-affected and control-control IBD rates as an IBD mapping statistic. For our hypothesis test, we use a computationally efficient approach from the stochastic processes literature to derive genome-wide significance levels that control the family-wise error rate (FWER). Whole-genome simulations indicate that our method conservatively controls the FWER. We pair our IBD mapping approach with a selection scan and a validation procedure via phenotype randomization so that one can contrast results for evidence of confounding due to positive selection, sequencing artifacts, or population structure. We developed automated and reproducible workflows to phase haplotypes, call local ancestry probabilities, and perform the IBD mapping scan, the former two tasks being important preprocessing steps for haplotype analyses. We applied our methods to search for Alzheimer disease (AD) risk loci in the Alzheimer's Disease Sequencing Project (ADSP) genome data. We identified six genome-wide significant signals of AD risk among samples genetically similar to African and European reference populations and self-identified Amish samples. Some variants in the six risk loci we detected have previously been associated with AD, dementia, and memory decline, and four genes at two of these loci have already been nominated as therapeutic targets for AD. Overall, our scalable approach makes further use of large consortia resources, which are expensive to collect but provide insights into disease mechanisms.},
}

@article {pmid41709289,
year = {2026},
author = {Koivumäki, M and Martiskainen, H and Takalo, M and Lehtisalo, J and Ngandu, T and , and Snellman, A and Hiltunen, M and Rinne, JO},
title = {Genetic validation of ABI3 p.Ser209Phe variant and its effects on early brain pathology in asymptomatic elderly individuals.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01984-y},
pmid = {41709289},
issn = {1758-9193},
abstract = {BACKGROUND: Alzheimer's disease (AD) has a strong genetic component, with APOE ε4 being the most established risk factor through its effects on beta-amyloid (Aβ) metabolism and microglial function. Recent genetic studies have also implicated microglial genes, such as the ABI3[S209F] variant, to increased AD risk. As APOE ε4 and ABI3[S209F] influence microglial pathways through distinct mechanisms, their combined analysis may provide novel insights into AD pathophysiology. Therefore, we investigated ABI3[S209F] in the Finnish FinnGen cohort and in an imaging study of cognitively healthy older adults.

METHODS: We used FinnGen R12 data (> 500,000 individuals), including 8,490 ABI3[S209F] carriers and 511,670 non-carriers, with survival analyses matched by sex and birth year. Disease endpoints (AD, dementia, neurodegenerative disorder) were defined from national health registries using harmonized ICD codes, medication, and reimbursement records. For the imaging study, 58 participants aged ≥ 50 years were recruited into three genotype-based groups (ABI3[S209F]/APOE ε4, ABI3[S209F]/APOE ε3, non-carriers). All imaging participants underwent structural MRI, [[11]C]PiB PET for amyloid beta, [[11]C]PK11195 PET for microglial activity, and a comprehensive neuropsychological battery.

RESULTS: ABI3[S209F] was significantly associated with increased risk of AD (OR = 1.22, p = 0.0012) and neurodegenerative disorders (OR = 1.21, p = 0.00023), but not with dementia (OR = 1.10, p = 0.06). Survival analyses indicated that ABI3[S209F] carriers developed AD at an earlier age than non-carriers with the same APOE genotype. The carriers of ABI3[S209F] and APOE ε4 had higher brain Aβ burden when compared to the ABI3[S209F] carriers without APOE ε4 (SUVR 2.0 (0.7) vs. 1.67 (0.5); mean (sd), p = 0.017), but there was no difference in Aβ between the ABI3[S209F] carriers and controls (1.67 (0.5) vs 1.75 (0.6), p = 0.75 (HST)). ABI3[S209F] was not associated with global neuroinflammation, although subtle regional increases in [[11]C]PK11195 binding were observed in ABI3[S209F] ε4 carriers. No differences were found in brain volumes or cognition.

CONCLUSIONS: ABI3[S209F] increases AD risk and is associated with earlier disease onset. The variant alone does not significantly influence cortical Aβ deposition, neuroinflammation, or brain structure. Its effect may be pronounced in combination with APOEε4.},
}

@article {pmid41709227,
year = {2026},
author = {Siedlecki-Wullich, D and Ayral, AM and Iohan, L and Lemeu, C and Buiche, V and Blary, K and Chapuis, J and Eysert, F and Beury, D and Delacre, M and Hot, D and Masuda, T and Knobeloch, KP and Prinz, M and Lambert, JC and Kilinc, D},
title = {Inflammatory stimulus enhances synaptic material uptake by adult APP microglia in a microfluidic neuron-microglia co-culture model.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03748-9},
pmid = {41709227},
issn = {1742-2094},
support = {MIB; AMRC//CURE:JPMXP1323015486/ ; JP23gm1910004; JP23jf0126004; JP24zf0127012//Japan Agency for Medical Research and Development/ ; JP25H01009; JP25K02573//JSPS KAKENHI/ ; 3DMiniBrain; PMG-AD//EU Joint Programme ̶ Neurodegenerative Disease Research (JPND)/ ; 196026//Sanofi i-Awards Europe 2019/ ; AARG-22-926152/ALZ/Alzheimer's Association/United States ; P-21-03626//French Renatech network/ ; },
}

@article {pmid41709060,
year = {2026},
author = {Yadav, AK and Verma, P and Srivastava, A and Srivastava, P and Rai, R and Rathour, S},
title = {Molecular insights into glial neuroimmune cross reactivity with CNS antigens and its role in neuroinflammation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41709060},
issn = {1568-5608},
abstract = {Neuroinflammation has been increasingly considered a key player of neurodegenerative as well as psychiatric disorders. This review integrates existing knowledge on glial-neuroimmune interactions, emphasizing the roles of cytokine signaling, glial activation, and BBB modulation in neuro-pathogenesis. A systematic review was performed studying peer-reviewed literature on molecular pathways of microglia, astrocytes, endothelial cells, and peripheral immune mediators. A possible explanation of this finding could be that the model is based on the underlying pathophysiology, and this is shared across disease contexts, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury. Novel in vitro platforms, including the organ-on-a-chip and brain organoids, were also discussed for their translational potential. Microglia M1/M2 polarization and astrocyte reactivity appeared to be a common feature in neurotoxicity as well as excitotoxicity and chronic inflammation. Cytokine cascade of TNF-α, IL-1β, and IL-6 led to the disrupted BBB, allowing for peripheral immune cells to infiltrate. Both the NLRP3 inflammasome and mitochondrial dysfunction were identified as enhancers of neuroimmune signaling. Comparing across disease models, shared relationships emerged between glia-cytokines-BBB. Advanced in vitro systems proved to be useful to model these interactions and screen prescription drugs. This review highlights existing insights into glia-neuroimmune cross-reactivity and its critical role in CNS disease. The molecular interactions between these molecules could represent promising targets for novel therapeutic options. We suggests integrative systems platforms and AI-driven strategies to expedite clinical translation in neuroinflammation.},
}

@article {pmid41708936,
year = {2026},
author = {Du, Y and Prinkey, K and Pham, AQ and Lawrence, A and Morales, C and Dinata, M and Gutierrez, M and Khalil, A and Sharma, M and Rissman, RA and Manikkoth, M and Baick, I and Karthikeyan, H and Dore, K},
title = {Sex-dependent rescue of memory and synaptic deficits in AD model mice by increasing PSD-95 palmitoylation.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-09702-y},
pmid = {41708936},
issn = {2399-3642},
support = {AG067049//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {PSD-95, a major scaffolding protein, requires palmitoylation to remain at synapses where it plays critical roles in synaptic structure and function. Here, we show that PSD-95 palmitoylation is specifically reduced in the hippocampus of female Alzheimer's disease (AD) model mice. Accordingly, these mice have significant memory deficits that are not observed in male AD model mice. Systemic injections of Palmostatin B, a depalmitoylating enzyme inhibitor (including the one acting on PSD-95), rescues memory deficits in female AD model mice and restores PSD-95 palmitoylation levels. Importantly, both synaptic structure and function are impaired in female AD model mice, and these deficits are normalized in Palmostatin B injected animals. This drug has no effects on amyloid plaques or GFAP levels, indicating that the rescue of behavioral and synaptic deficits is not due to effects on plaque or astrogliosis related AD pathology. Our data instead suggest that the sex-dependent rescue we observe is mediated by the stabilization of small, vulnerable dendritic spines. This study demonstrates that increasing PSD-95 palmitoylation might be an effective way to protect synapses from AD pathology and therefore a promising therapy for AD.},
}

@article {pmid41708600,
year = {2026},
author = {Hu, J and Scheidt, T and Thacker, D and Axell, E and Stemme, E and Łapińska, U and Wennmalm, S and Meisl, G and Curk, S and Andreasen, M and Vendruscolo, M and Arosio, P and Šarić, A and Schmit, JD and Knowles, TPJ and Sparr, E and Linse, S and Michaels, TCT and Dear, AJ},
title = {Structural defects in amyloid-β fibrils drive secondary nucleation.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-69377-1},
pmid = {41708600},
issn = {2041-1723},
support = {219703//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; NNF19OC0054635//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; 2019-02397//Vetenskapsrådet (Swedish Research Council)/ ; 2015-00143//Vetenskapsrådet (Swedish Research Council)/ ; 2022-06641//Vetenskapsrådet (Swedish Research Council)/ ; 945378//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; 337969//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; FNU-11-113326//Det Frie Forskningsråd (Danish Council for Independent Research)/ ; },
abstract = {Formation of new amyloid fibrils and oligomers from monomeric protein on the surfaces of existing fibrils is an important driver of many disorders such as Alzheimer's and Parkinson's diseases. The structural basis of this secondary nucleation process, however, is poorly understood. Here, we ask whether secondary nucleation sites are found predominantly at rare growth defects: irregularities in the fibril core structure incorporated during their original assembly. We first demonstrate using the specific inhibitor of secondary nucleation, Brichos, that secondary nucleation sites on Alzheimer's disease-associated fibrils composed of Aβ40 and Aβ42 peptides are rare compared to the number of protein molecules they contain. We then grow Aβ40 fibrils under conditions designed to eliminate most growth defects while leaving the regular fibril morphology unchanged, and confirm the latter using cryo-electron microscopy. We measure both the ability of these annealed fibrils to promote secondary nucleation and the stoichiometry of their secondary nucleation sites, finding that both are greatly reduced as predicted. Re-analysis of published data for other proteins suggests that fibril growth defects may also drive secondary nucleation generally across most amyloids. These findings could unlock structure-based drug design of therapeutics that aim to halt amyloid disorders by inhibiting secondary nucleation sites.},
}

@article {pmid41708563,
year = {2026},
author = {Ono, D and Kondrakunta, S and Mak, E and Przybelski, SA and Fought, AJ and Schwarz, CG and Murray, ME and Nguyen, A and Reichard, RR and Senjem, ML and Gunter, JL and Jack, CR and Miyagawa, T and Forsberg, LK and Fields, JA and Savica, R and Ramanan, VK and Jones, DT and Botha, H and Louis, EKS and Knopman, DS and Graff-Radford, NR and Day, GS and Ferman, TJ and Kremers, WK and Lowe, VJ and Petersen, RC and Boeve, BF and Dickson, DW and Kantarci, K},
title = {Neuropathologic basis of quantitative susceptibility mapping in the substantia nigra: contributions of tau, pigmented neurons, and iron.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {17},
pmid = {41708563},
issn = {1432-0533},
mesh = {Humans ; *Substantia Nigra/pathology/metabolism/diagnostic imaging ; Male ; *Iron/metabolism ; Female ; Aged ; *tau Proteins/metabolism ; Aged, 80 and over ; Magnetic Resonance Imaging/methods ; *Neurons/pathology/metabolism ; Alzheimer Disease/pathology/metabolism/diagnostic imaging ; Lewy Body Disease/pathology/metabolism/diagnostic imaging ; Cognitive Dysfunction/pathology/metabolism/diagnostic imaging ; Middle Aged ; },
abstract = {Quantitative susceptibility mapping (QSM) on MRI quantifies tissue magnetic susceptibility, which increases with iron accumulation, myelin loss, and neuroinflammation. Elevated QSM in the substantia nigra (SN) has been reported in Lewy body disease and other parkinsonian disorders, but from existing literature it remains unclear whether these findings are driven by neurodegeneration-related iron deposition or other neuropathologic features. We studied 59 autopsied participants who underwent antemortem 3 T MRI with QSM (median age at death, 78.5 years; MRI-to-death interval, 2.0 years), including clinical diagnoses of 18 with Alzheimer's-type dementia, 15 cognitively unimpaired, 9 with mild cognitive impairment, and 9 with dementia with Lewy bodies. A machine learning-incorporated digital histopathology pipeline quantified tau burden, iron deposition, and neuronal densities. The SN was divided into geometric quadrants, and QSM values were analyzed in relation to corresponding neuropathologic measures within each quadrant. Iron deposition correlated with QSM in all quadrants (ρ = 0.41-0.56, all P < 0.005). Tau burden correlated with QSM in the ventromedial (VM) quadrant (ρ = 0.45, P = 0.002), whereas lower pigmented neuron density was associated with higher QSM in the dorsomedial quadrant (ρ = - 0.35, P = 0.007). Rank regression analysis confirmed iron as the strongest predictor of QSM across all quadrants (β = 0.35-1.06, P ≤ 0.026), with tau independently associated with QSM in the VM (β = 0.45, P = 0.015). Mediation analysis demonstrated that tau exerted direct (0.45, P = 0.018) and indirect effects via iron (0.12, P = 0.046) on QSM in the VM, with 80% of the effect being direct. These findings underscore the contributions of tau pathology, pigmented neuron density, and iron deposition to nigral magnetic susceptibility and highlight the potential for QSM to serve as a sensitive biomarker for diverse neuropathologies.},
}

Humans
*Substantia Nigra/pathology/metabolism/diagnostic imaging
Male
*Iron/metabolism
Female
Aged
*tau Proteins/metabolism
Aged, 80 and over
Magnetic Resonance Imaging/methods
*Neurons/pathology/metabolism
Alzheimer Disease/pathology/metabolism/diagnostic imaging
Lewy Body Disease/pathology/metabolism/diagnostic imaging
Cognitive Dysfunction/pathology/metabolism/diagnostic imaging
Middle Aged

@article {pmid41708549,
year = {2026},
author = {Zeng, Q and Wang, M and Wang, E and Zhou, X and Xu, P and Haroutunian, V and Cai, D and Zhang, B and , },
title = {Sex and APOE genotype specific brain regional vulnerability to Alzheimer's Disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41708549},
issn = {2509-2723},
abstract = {Alzheimer's disease (AD) disproportionately affects women and carriers of the apolipoprotein E ε4 allele (APOE4), yet little is known about how sex and APOE interact to influence white matter (WM) integrity during disease progression. We integrated diffusion MRI and matched blood transcriptomic data to investigate these interactions and their underlying biological mechanisms. WM microstructure was quantified using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), and regional vulnerability was assessed with a composite vulnerability score (CVS) derived from associations between diffusion features and AD severity across clinical traits in each of the four sex-APOE groups (female or male, with or without APOE4). Brain parcellation with the Eve atlas revealed regions consistently affected across sex-APOE groups (e.g., parahippocampal and superior temporal gyri) and regions specific to individual groups (e.g., the cingulum in females with APOE4 and the middle frontal gyrus in males without APOE4). Gene co-expression network analysis of the matched blood expression data identified gene subnetworks linked to group-specific regional vulnerability, including a muscle tissue morphogenesis module regulated by NEURL1B and HIST1H2BN associated with middle frontal gyrus vulnerability. These findings demonstrate that sex and APOE genotype jointly shape region-specific WM vulnerability and its molecular signatures in AD. Understanding these interactions provides novel mechanistic insights and may inform precision approaches to drug development, biomarker discovery, and clinical trial design for AD.},
}

@article {pmid41708418,
year = {2026},
author = {Jomeiri, A and Navin, AH and Shamsi, M},
title = {Corrigendum to "Regional attention-enhanced vision transformer for accurate Alzheimer's disease classification using sMRI data" [Comput. Biol. Med. 197 (2025) 111065].},
journal = {Computers in biology and medicine},
volume = {},
number = {},
pages = {111559},
doi = {10.1016/j.compbiomed.2026.111559},
pmid = {41708418},
issn = {1879-0534},
}

@article {pmid41708398,
year = {2026},
author = {Dyer, AH and Dolphin, H and Morrison, L and Kenny, T and Fallon, PG and Cunningham, C and O'Connor, A and Lawlor, B and O'Farrelly, C and Bourke, NM and Kennelly, SP and , },
title = {Systemic inflammation, delirium and clinical progression in mild-moderate Alzheimer disease.},
journal = {EBioMedicine},
volume = {},
number = {},
pages = {106159},
doi = {10.1016/j.ebiom.2026.106159},
pmid = {41708398},
issn = {2352-3964},
abstract = {BACKGROUND: Both low-grade systemic inflammation and acute inflammatory events may contribute to Alzheimer Disease (AD) progression. However, studies examining the prognostic utility of systemic inflammatory biomarkers in AD, and how systemic inflammatory events may contribute to clinical trajectories in AD, have yielded conflicting results.

METHODS: We quantified plasma cytokines/chemokines in 333 individuals with mild-moderate AD at baseline, 12 and 18 months alongside baseline neurodegenerative biomarkers. AD severity was assessed using the Alzheimer Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating Scale (CDR-Sb) and Disability Assessment for Dementia (DAD).

FINDINGS: Systemic inflammatory biomarkers were primarily associated with age/socio-demographic characteristics, remained strikingly stable over time, and were not associated with AD progression. Rather, higher baseline plasma p-tau217 was associated with greater yearly progression on both the ADAS-Cog (β: 2.82; 95% CI: 1.12, 4.52; nominal p = 0.001) and DAD (β: -2.34; 95% CI: -3.86, -0.82; nominal p = 0.003). Higher baseline GFAP was also associated with subsequent decline on both the CDR-Sb (β: 1.02; 95% CI: 0.38, 1.67; nominal p = 0.002) and DAD (β: 1.91; 95% CI: -3.45, -0.37; nominal p = 0.02). Experiencing one or more episodes of delirium was associated with accelerated decline on the CDR-Sb at 18-months (β: 2.63; 95% CI: 1.55, 3.71; adjusted p < 0.001).

INTERPRETATION: Biomarkers of neuroinflammation (GFAP), neurodegeneration (p-tau217) and incident delirium, rather than systemic inflammatory biomarkers, were associated with clinically-significant decline in mild-moderate AD.

FUNDING: European Commission (FP7 grant; 279093); Meath Foundation (MFRG 121/2021); Wellcome Trust (227946/Z/23/Z & 203930/B/16/Z); Health Research Board (203930/B/16/Z; ECSA-2024-003).},
}

@article {pmid41708382,
year = {2026},
author = {Yasuno, F and Kimura, Y and Nihashi, T and Minami, H and Minami, H and Takeda, A and Sakurai, T and Kato, T},
title = {Frontostriatal volumes and anterior thalamic mediation of late-life depressive symptoms across the cognitive spectrum from normal aging to Alzheimer's disease: A structural equation modelling study.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100199},
doi = {10.1016/j.inpsyc.2026.100199},
pmid = {41708382},
issn = {1741-203X},
abstract = {BACKGROUND: Late-life depression has been linked to cortico-striato-thalamo-cortical (CSTC) dysfunction. We examined whether the volumes of the thalamic subregions, frontal cortex, and striatum are related to depressive symptoms across cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD) groups.

METHODS: Fifty-four psychotropic-naïve older adults (CN:16; MCI:19; AD:19) underwent T1-weighted MRI, neuropsychological assessments, and Geriatric Depression Scale (GDS) ratings. Cortical and subcortical volumes were obtained using FreeSurfer, and the thalamic nuclei were segmented using the Iglesias Probabilistic Atlas and grouped into six subregions. The intracranial volume-adjusted regional volumes were compared across the groups. Stepwise regression identified volumetric predictors of the GDS, and structural equation modelling tested CSTC-based pathways linking cognition, regional volumes, and depressive symptoms.

RESULTS: Thalamic subregional volumes did not differ significantly between groups, whereas the frontal and subcortical regions showed diagnostic effects. Lower volumes of the anterior thalamic subregions, frontal gyrus, and putamen were associated with higher GDS scores. Path analysis showed excellent fit and demonstrated that frontal and putaminal atrophy had direct effects on the GDS, whereas anterior thalamic volume indirectly influenced the GDS via its association with these frontostriatal nodes.

CONCLUSION: These findings suggest a CSTC network account of late-life depression, wherein frontostriatal atrophy show proximal associations with depressive symptoms, whereas anterior thalamic volume shows an indirect association. Future longitudinal, multimodal studies are needed to determine temporal ordering and causality, including whether protecting anterior thalamic integrity or enhancing frontostriatal function might be associated with attenuation of depressive symptoms in older adults.},
}

@article {pmid41708354,
year = {2026},
author = {Recupero, M and Zagaria, T and Elia, F and Grasso, M and Caraci, F and Barone, C and Greco, D and Ferri, R and Serretti, A and Buono, S},
title = {Habilitative and rehabilitative educational interventions as protective factors against cognitive decline in adults with Down syndrome: A retrospective study.},
journal = {L'Encephale},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.encep.2025.10.009},
pmid = {41708354},
issn = {0013-7006},
abstract = {BACKGROUND AND OBJECTIVES: Adults with Down syndrome (DS) face a markedly elevated risk of Alzheimer's disease (AD), yet modifiable environmental factors that modulate cognitive decline remain under-explored. We aimed to determine whether formal education and lifelong habilitative/rehabilitative educational interventions (HREI) preserve neuropsychological functioning in DS.

METHODS: We retrospectively reviewed records of 50 adults with DS (median=41 years). Global cognition and seven Test for Severe Impairment (TSI) domains were compared between individuals with dementia (n=25) and matched controls without dementia (n=25). Participants were further stratified by schooling (0-5 vs. 8-13years) and HREI exposure/duration.

RESULTS: The dementia group performed significantly worse in praxis, language comprehension, immediate memory, general knowledge, conceptualisation and total TSI score (P<0.01). Within this group,≥8years of schooling and HREI exposure were each associated with higher global cognition and superior performance across up to five domains; no benefit was evident when interventions ceased after age 18. Schooling and HREI did not differentiate participants without dementia.

CONCLUSION: Formal education and sustained HREI appear to confer cognitive reserve in DS, attenuating AD-related decline. These findings support policies that guarantee educational inclusion and lifelong, structured cognitive-motor enrichment for individuals with DS. Prospective larger-scale studies are warranted to delineate optimal dosage and timing of enrichment programmes in DS.},
}

@article {pmid41708206,
year = {2026},
author = {Chinnathambi, S and Velmurugan, G and Kumarappan, M and Chandrashekar, M},
title = {Interacting partners of Tau protein in Alzheimer's disease.},
journal = {Advances in clinical chemistry},
volume = {131},
number = {},
pages = {87-102},
doi = {10.1016/bs.acc.2025.10.005},
pmid = {41708206},
issn = {2162-9471},
mesh = {*tau Proteins/metabolism/chemistry ; Humans ; *Alzheimer Disease/metabolism/pathology ; Animals ; Phosphorylation ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative condition causes noticeable symptoms including impaired memory and cognitive decline. In AD, the intracellular aggregation of Tau into NFTs is the histopathological indicator that impairs the neuronal function. Tau is a highly soluble, intrinsically disordered in nature, allowing it to adopt multiple conformation. Tau, a microtubule-associated protein, it interacts with tubulin subunits and plays a critical role in stabilizing microtubule network. Tau protein interacts with numerous proteins in physiological and pathological conditions. This interaction facilitating either biological function or contribute to Tau-mediated pathogenic changes. Tau interacting partners and related molecular crossroads can either propagate Tau pathogenesis, or they have neuroprotective role, lowering toxic Tau species or inflammation. In the central nervous system, Tau function is regulated by posttranslational modification at many sites within the protein. Tau in functioning neurons contains numerous phosphate groups, the majority of which are found in the microtubule assembly domain. Hyperphosphorylation and aggregation of Tau are the significant pathological markers of AD. This review focuses on Tau as a multifunctional protein and its known interaction partners involved in the control of several processes.},
}

*tau Proteins/metabolism/chemistry
Humans
*Alzheimer Disease/metabolism/pathology
Animals
Phosphorylation

@article {pmid41708012,
year = {2026},
author = {Sambhariya, WS and Rickman, CB and D'Amore, PA and Corradetti, G and Hageman, GS and Howell, GR and Marola, OJ and Phatnani, H and Philp, NJ and Sinha, D and Toomey, CB and Stone, F and Eberhart, C and Handa, JT},
title = {Age-related macular degeneration and cerebral amyloid angiopathy have similar pathologies from cholesterol-APOE-amyloid-β-complement mediated inflammation.},
journal = {Progress in retinal and eye research},
volume = {},
number = {},
pages = {101449},
doi = {10.1016/j.preteyeres.2026.101449},
pmid = {41708012},
issn = {1873-1635},
abstract = {Age-related macular degeneration (AMD) and Alzheimer's disease (AD) are neurodegenerative conditions that afflict millions of elderly people around the world. AMD is a progressive retinal disorder that leads to central vision loss whereas AD primarily causes cognitive decline and behavioral changes. While each disease has distinct clinical manifestations, the accumulation of extracellular amyloid-β is a common histopathologic finding. Similarly, cerebral amyloid angiopathy (CAA), a vascular condition that can exist independent or with AD, is characterized by the accumulation of amyloid-β in cerebral blood vessels. While significant investigation of the pathophysiologic links between AMD and AD has been conducted, the underlying similarities and differences in the pathobiology of AMD and CAA has not been considered. In this review, we discuss the common pathological features of these two conditions. We then discuss the similar pathobiology that involves cholesterol metabolism, apolipoprotein E, amyloid-β, and complement mediated inflammation. At the same time, we discuss key differences in their pathobiology. This discussion sheds new perspective and insights of their pathobiology.},
}

@article {pmid41708000,
year = {2026},
author = {Koles, K and Repnikova, E and Novikov, B and Panin, V},
title = {Sialylation in the Nervous System: Functions and Mechanisms.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {111288},
doi = {10.1016/j.jbc.2026.111288},
pmid = {41708000},
issn = {1083-351X},
abstract = {Glycoprotein sialylation represents a critical post-translational modification with diverse biological roles in animals. This review explores its multifaceted functions in the nervous system, with particular emphasis on neurophysiology, homeostasis, and associated neurological disorders. The sialylation pathway modulates key neural processes through effects on glycoprotein stability, localization, activity, and molecular interactions. Examples include a crucial role in regulation of neuronal excitability by modulating the functions of voltage-gated ion channels. Recent studies have uncovered remarkably rapid, activity-dependent changes in synaptic sialylation, suggesting dynamic sialylation-mediated regulation of neural transmission and highlighting the importance of neuraminidases in these processes. Beyond synaptic function, sialylation mediates neuron-glia interactions by multiple mechanisms. It modulates immune functions regulated by siglecs and complement pathways while controlling microglial activation and neuroinflammation. The critical importance of proper sialylation is underscored by severe neurological manifestations associated with genetic defects in the sialylation pathway, including cognitive impairment, ataxia, and epilepsy. Furthermore, aberrant sialylation of glycoproteins and gangliosides has been implicated in neurodegenerative diseases (Alzheimer's and Parkinson's), brain cancers, and psychiatric disorders including schizophrenia and autism. Preclinical research has identified promising therapeutic strategies targeting sialylation. Studies demonstrate that polysialic acid administration reduces neurodegeneration, while siglec modulation alleviates age-related cognitive decline. Recent discoveries, including sialylated glycoRNA and insights from Drosophila models revealing unique sialylation-mediated glia-neuron crosstalk, have significantly expanded our understanding of this important regulatory system. These advances position sialylation as a promising therapeutic target for neurological disorders.},
}

@article {pmid41707918,
year = {2026},
author = {Alami, M and Berrougui, H and Boumezough, K and Salih, I and Sadki, K and Laurent, B and van Tellingen, O and Bunt, T and Khalil, A and Fulop, T},
title = {Antiretroviral Raltegravir, a Selective Human Immunodeficiency Virus Type 1 Integrase Inhibitor, Shows Anti-Alzheimer's Potential against Amyloid-Beta1-42-Induced Neurodegeneration.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {112161},
doi = {10.1016/j.mad.2026.112161},
pmid = {41707918},
issn = {1872-6216},
abstract = {There is growing evidence supporting the potential role of microbial infections in the aetiology of Alzheimer's disease (AD) and the protective role of anti-viral therapies. However, not much is known about the molecular mechanisms underlying their effects. We aimed to explore the modulatory role of raltegravir on monomeric amyloid beta 1-42 (m-Aβ1-42)-induced molecular alterations in cellular models of AD. Here we show, using the flow cytometry technique combined with specific monoclonal antibodies, that raltegravir significantly abolishes the m-Aβ1-42-stimulating effect on p-tau 181, and that this effect involves the upregulation of PP2Aα+β. This effect does not appear to be mediated by GSK-3β and CdK5 modulation, since no significant effect was observed on these kinases. Furthermore, raltegravir treatment significantly reduced CD86 expression without any impact on CD163, suggesting a possible affinity towards reducing the microglia M1-phenotype rather than improving the M2 state. Additionally, raltegravir significantly attenuated IL-1β production, likely through the downregulation of the NLRP3-inflammasome signaling pathway, indicating an important anti-inflammatory activity. Collectively, our in vitro findings are preliminary mechanistic observations that support raltegravir's repurposing for AD, thus soliciting further complementary research, especially in relevant animal models of AD, to accelerate the translation of these findings into the clinical setting.},
}

@article {pmid41707907,
year = {2026},
author = {Minauro-Sanmiguel, F and Vargas-Perez, H},
title = {Mitochondria-associated membranes and hallucinogenic therapy in Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.02.028},
pmid = {41707907},
issn = {1873-7544},
abstract = {Mitochondrial dysfunction is increasingly recognized as a central driver of Alzheimer's disease (AD), contributing to neuroinflammation, synaptic failure, and energy collapse.Emerging preclinical evidence suggests that classic hallucinogens, such as psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), mescaline, may restore mitochondrial integrity by activating Serotonin 2A (5-HT2A) and sigma-1(Sig-1R) receptors. In experimental models, these pathways are associated with enhanced mitochondrial biogenesis, reduced oxidative stress, and preservation of ER-mitochondrial coupling. DMT and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) specifically engage Sig-1R at mitochondria-associated membranes, improving calcium homeostasis and cellular resilience. While these mechanisms are mechanistically compelling, evidence for clinical efficacy in AD remains limited and largely preclinical. Accordingly, this framework is presented as a hypothesis-generating model suggesting that mitochondrial-centered psychedelic mechanisms warrant further investigation,provided that neuropsychiatric safety, patient selection, and translational feasibility are carefully addressed.},
}

@article {pmid41707905,
year = {2026},
author = {He, L and Xiaopeng, Z and Juan, D and Yan, L},
title = {Anti-ASC antibodies alleviate Alzheimer's disease-type pathology in APP/PS1 mice.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.02.023},
pmid = {41707905},
issn = {1873-7544},
abstract = {BACKGROUNDAND PURPOSE: Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) may contribute to Alzheimer's disease (AD) pathogenesis by promoting amyloid-β (Aβ) aggregation. ASC protein is mainly composed of the N-terminal pyrin domain (PYD) and the C-terminal caspase recruitment domain (CARD). This study aims to explore the different roles of the two domains of ASC in AD.

METHODS: The SH-SY5Y-APP695 cells were treated with ASC neutralizing antibodies against the N-terminal domain (anti-ASC N-terminal antibodies) or C-terminal domain(anti-ASC C-terminal antibodies). The cell apoptosis and Aβ production were detected. The eight-month-old APP/PS1 mice received lateral ventricle injections of anti-ASC N-terminal antibodies or anti-ASC C-terminal antibodies. The cognitive function and AD-like pathology of APP/PS1 mice were assessed.

RESULTS: The anti-ASC N-terminal and C-terminal antibodies attenuated apoptosis and mitochondrial damage, and reduced Aβ production by inhibiting BACE1 in vitro. Furthermore, intracerebroventricular administration of anti-ASC N-terminal and C-terminal antibodies improved cognitive impairment and reduced Aβ deposition, tau hyperphosphorylation, and neuroinflammation in the APP/PS1 mice.

CONCLUSIONS: The anti-ASC N-terminal and C-terminal antibodies may have neuroprotective effects, which are manifested as reducing cell apoptosis, improving cognitive function, and alleviating AD-like pathology in AD mice. Immunotherapies targeting ASC are promising for treating AD.},
}

@article {pmid41707903,
year = {2026},
author = {Nasiri, H and Mohammadtaheri, B and Khosravi, F and Ghadiminia, N and Saberian, P and Mohammadian, M and Shakeri, S and Hendudari, F and Siyah Rood, YK and Hassanpoor, A and Sadat, S and Bagheri, F and Mayeli, M and , },
title = {Default mode network connectivity relates to executive and language performance in patients with mild cognitive impairment.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138545},
doi = {10.1016/j.neulet.2026.138545},
pmid = {41707903},
issn = {1872-7972},
abstract = {Disruptions in default mode network (DMN) connectivity are well documented in Alzheimer's disease (AD), yet their associations with specific cognitive domains remain unclear. This study examined relationships between anterior and posterior DMN functional connectivity and memory, executive function, and language performance across the AD continuum. We conducted a cross-sectional analysis of resting-state fMRI and composite cognitive scores from 154 participants (61 cognitively normal, 68 mild cognitive impairment [MCI], and 25 AD). DMN connectivity metrics were derived from region-of-interest-to-voxel correlations within anterior (aDMN) and posterior (pDMN) subdivisions. Associations between DMN measures and cognitive domains were assessed using multiple linear regression adjusted for age, sex, and years of education, with correction for multiple comparisons. No DMN measure was significantly associated with memory performance in any diagnostic group after correction. In the MCI group, executive and language performance were associated with anterior-posterior DMN connectivity, with weaker coupling linked to poorer performance across these domains. No significant DMN-cognition associations were observed in the cognitively normal or AD groups. After additional adjustment for white matter hyperintensities, only anterior-posterior DMN connectivity remained significantly associated with executive and language performance in the MCI group. Overall, DMN connectivity-cognition relationships were domain-specific and most evident in MCI, supporting the concept of a transitional stage in which network-level functional organization is related to cognitive performance.},
}

@article {pmid41707701,
year = {2026},
author = {Anderson, YT and Priest, K and Zastre, J},
title = {Vitamin B1 Protects Against Aβ1-42-Induced HIF-1α Activation and Neurotoxicity.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106130},
doi = {10.1016/j.neuint.2026.106130},
pmid = {41707701},
issn = {1872-9754},
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and extensive neuronal loss, largely driven by amyloid beta (Aβ) accumulation and associated cellular stress. Vitamin B1 (thiamine) supplementation has demonstrated cognitive benefits in clinical AD studies, however, the mechanisms underlying thiamine's neuroprotective effects remain unclear. Here, we investigated whether thiamine mitigates Aβ1-42-induced neurotoxicity by suppressing hypoxia-inducible factor-1 alpha (HIF-1α), a transcriptional stress factor regulating many proapoptotic and progressive amyloidogenic pathways. Exposure of neuronal cells to Aβ1-42 oligomers increased reactive oxygen species (ROS) accumulation, decreased intracellular Fe[2+], and induced HIF-1α stabilization. HIF-1α activation by Aβ1-42 promoted apoptosis through increased endoplasmic reticulum (ER) stress and increased mitochondrial dimerization of BNIP3. Thiamine supplementation significantly reduced cellular ROS levels, preserved intracellular Fe[2+] levels, and restored prolyl hydroxylase (PHD) activity to promote HIF-1α hydroxylation and degradation. Suppression of HIF-1α by thiamine attenuated ER and BNIP3-driven apoptotic pathways and preserved neuronal viability. Thiamine further mitigated HIF-1α-mediated amyloidogenic progression, limiting feedback toxicity caused by Aβ1-42. These results demonstrate that thiamine protects against Aβ1-42-mediated neurotoxicity by reducing ROS, preserving Fe[2+], and inhibiting HIF-1α-driven pathological cascades. Overall, this study identified a novel mechanism for thiamine's neuroprotective role, further supporting its therapeutic potential to limit neurodegenerative progression in AD.},
}

@article {pmid41707644,
year = {2026},
author = {Li, F and Bai, S and Liu, Y and Chen, Z and Zhao, S and Ding, Z and Xie, F and Xu, Y and Yue, L and Zhang, H and Zhang, Y and Sun, K and Shen, D},
title = {Enhancing diagnosis of mild cognitive impairment through brain-heart-gut metabolic networks in whole-body PET imaging.},
journal = {Cell reports. Medicine},
volume = {7},
number = {2},
pages = {102629},
doi = {10.1016/j.xcrm.2026.102629},
pmid = {41707644},
issn = {2666-3791},
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/diagnosis/metabolism ; *Positron-Emission Tomography/methods ; *Brain/diagnostic imaging/metabolism ; Male ; Aged ; Female ; Gastrointestinal Microbiome ; *Heart/diagnostic imaging ; *Myocardium/metabolism ; *Whole Body Imaging/methods ; *Metabolic Networks and Pathways ; },
abstract = {Mild cognitive impairment (MCI) is the prodromal stage of dementia involving complex interactions between the brain and peripheral organs. Emerging evidence indicates that heart dysfunction and gut microbiota dysbiosis contribute to MCI pathogenesis. Here, we present a framework integrating brain-heart-gut interactions using whole-body positron emission tomography (PET) to enhance brain-only diagnostic performance. Our brain-only model achieves diagnostic performance comparable to that of whole-body PET and shows promising generalizability across four datasets comprising 1,543 whole-body PET and 1,721 brain PET images. We identify key brain regions involving the limbic, parietal, frontal, and temporal cortices that engage the default mode, central autonomic, and sensorimotor networks. These regions, along with specific myocardium and distal colon, constitute an integrated brain-heart-gut metabolic network, underscoring multi-organ crosstalk mediated by neural, biochemical, and mechanical pathways. Overall, our generalizable framework not only shows great potential for clinical translation in MCI diagnosis but also provides broad applicability to other systemic diseases beyond MCI.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/diagnosis/metabolism
*Positron-Emission Tomography/methods
*Brain/diagnostic imaging/metabolism
Male
Aged
Female
Gastrointestinal Microbiome
*Heart/diagnostic imaging
*Myocardium/metabolism
*Whole Body Imaging/methods
*Metabolic Networks and Pathways

@article {pmid41707523,
year = {2026},
author = {Lish, AM and Young-Pearse, TL},
title = {Decoding Alzheimer's genetic risk through intercellular communication in the human brain: Lessons from Clusterin.},
journal = {Current opinion in neurobiology},
volume = {97},
number = {},
pages = {103165},
doi = {10.1016/j.conb.2026.103165},
pmid = {41707523},
issn = {1873-6882},
abstract = {Late-onset Alzheimer's disease (AD) arises in part from a complex genetic architecture dominated by common, low-penetrance variants, many of which are enriched in glial cells and remain mechanistically unresolved. Unlike the rare coding mutations that contribute to early-onset AD, these common variants often lie in noncoding regions, complicating efforts to link genetic risk to cellular function. Emerging evidence suggests that many glial-enriched risk genes contribute to disease by disrupting communication between glia and neurons. Such interactions are essential for preserving synaptic health and modulating immune responses to pathology. Understanding how polygenic variation perturbs these pathways requires integrative strategies that combine large-scale postmortem brain datasets with experimentally tractable human cellular models. In this review, we highlight recent progress in decoding the cellular impact of AD risk variants through the lens of glial-neuronal communication. We first illustrate how human brain studies have mapped cell-type-specific gene expression and intercellular networks associated with genetic risk. We then discuss how human stem cell-derived co-culture and 3D models are being used to test these hypotheses in controlled experimental systems. As a case study, we focus on CLU (Clusterin), a well-replicated risk locus that modulates glial inflammation, lipid exchange, and neuronal vulnerability. Together, these studies build a scalable, human-centric framework for linking genotype to function and point toward new opportunities for therapeutic discovery rooted in intercellular biology.},
}

@article {pmid41707471,
year = {2026},
author = {Wu, G and Wang, F and Chen, Z and Zheng, N and Zhou, Q and Xie, L and Yang, X and Song, D and Sun, Q and Lin, J and Li, L},
title = {Betaine alleviates neuronal impairment in glutamate-injured SH-SY5Y neuroblastoma cells via Nrf2 signaling pathway related ferroptosis.},
journal = {Journal of neuroimmunology},
volume = {414},
number = {},
pages = {578886},
doi = {10.1016/j.jneuroim.2026.578886},
pmid = {41707471},
issn = {1872-8421},
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder that currently lacks efficacious therapeutic interventions. It's well documented that ferroptosis is extensively involved in the progression and pathogenesis of AD. Betaine, a critical nutrient for mammal health, is reported to possess neuroprotective actions. The objective of the current research was to investigate whether betaine could mitigate neuronal impairments by suppressing ferroptosis in SH-SY5Y neuroblastoma cells injured by glutamate. The results indicate that betaine improved the survival rate and reversed morphology changes of glutamate-damaged SH-SY5Y cells. Additionally, betaine reduced the intracellular accumulation of Fe[2+], malondialdehyde (MDA), lipid reactive oxygen species (ROS), and lactate dehydrogenase (LDH) release induced by glutamate. And reversed the decreased glutathione (GSH) content and downregulation of ferroptosis inhibitor glutathione peroxidase 4 (GPX4) expression were observed upon betaine administration. Additionally, betaine facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus in SH-SY5Y cells induced by glutamate. Molecular docking validated high-affinity binding between betaine and Nrf2. Collectively, betaine could exert neuroprotective effects by alleviating ferroptosis via activation of the Nrf2 pathway, thereby positioning it as a potential candidate for targeting ferroptosis-driven neurodegeneration in AD.},
}

@article {pmid41707445,
year = {2026},
author = {Khodabukus, L and Bourgeais, A and Corvaisier, M and Bourreau, L and Brière, O and Annweiler, C},
title = {Motor imagery and executive dysfunction in the older population: Difference between realized and imagined Timed-Up and Go is associated with executive dysfunction.},
journal = {Gait & posture},
volume = {126},
number = {},
pages = {110130},
doi = {10.1016/j.gaitpost.2026.110130},
pmid = {41707445},
issn = {1879-2219},
abstract = {PURPOSE: Functional independence and neurocognitive disorders are major issues in geriatric medicine. The Timed-Up and Go (TUG) test has been validated for predicting the risk of serious falls. Motor imagery could be impaired when there is a neurocognitive disorder, notably executive. The aim of this study was to evaluate the association between executive disorders assessed by the Frontal Assessment Battery (FAB) and the difference between imagined and realized TUG.

METHODS: The Gait and Alzheimer Interactions Tracking (GAIT) study is a cross-sectional study. One hundred twenty-three patients aged over 60 were included. For each patient, a FAB, a TUG and an imagined TUG (iTUG) were performed, enabling a delta-TUG to be calculated. The association was studied using univariate and multivariate linear regression models.

RESULTS: There was a significant association between delta-TUG and FAB score. The delta-TUG was significantly higher (p < 0.001) in subjects with an executive impairment than in subjects without, 62.73 % ± 41.88 vs. 31.40 % ± 33.20, respectively.

CONCLUSIONS: Motor imagery assessment, using iTUG, may provide relevant information related to cognitive-motor processes. This is an area for further research.},
}

@article {pmid41707372,
year = {2026},
author = {Mao, Y and Chen, L and Liu, Y and Song, J and Liu, P and Zhang, M and Wu, S and Guan, J and Zhang, X and Zhang, Y and Mao, S},
title = {Enhanced brain targeting and improved Alzheimer's disease therapy via intranasal delivery of Ginsenoside F1-loaded mixed micelles.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {262},
number = {},
pages = {115551},
doi = {10.1016/j.colsurfb.2026.115551},
pmid = {41707372},
issn = {1873-4367},
abstract = {Alzheimer's disease (AD) progressively impairs cognition and memory, is pathologically localized in the cortex and hippocampus. Ginsenoside F1 (GF1), a rare ginsenoside, exerts great potential for AD treatment. However, the clinical translation is limited by its poor solubility and extremely low oral bioavailability (<1 %), which restricts its central nervous system (CNS) delivery and pathological site distribution via conventional formulations. Thus, the objective of this study is to explore the feasibility of increasing GF1 concentration in the brain via intranasal delivery, utilizing the solubilizing and permeation-enhancing capacity of nanomicelle in combination with borneol coadministration as a 'guider' to further enrich GF1 at the brain pathological sites. GF1-loaded single (GF1-M) and mixed micelles (GF1-MM) were successfully prepared and characterized. All the micelles had particle size less than 100 nm, with enhanced nasal mucosal permeability, and significantly increased GF1 concentration in the brain. The mixed micelles (GF1-1-BOR-MM) in combination with borneol further enhanced brain targeting efficiency of GF1, with a brain targeting index (DTI) of 1032.84 % and a nose-to-brain direct transport percentage (DTP) of 90.13 %. Borneol also significantly promoted GF1 distribution in the cortex and hippocampus, the pathological sites of AD. Pharmacodynamics studies demonstrated that after intranasal delivery, GF1-1-BOR-MM group showed substantial cognitive function improvement in AD model mice. In conclusion, intranasal drug delivery combined with nanomicelles breaks the deadlock of effective poorly soluble drug delivery to the brain. By combining with borneol, it can further enhance drug distribution to the pathologic site of AD, which holds great potential as a platform for treating CNS-related diseases.},
}

@article {pmid41707281,
year = {2026},
author = {Jiang, H and Jadhav, SB and Soda, AK and Zhou, W and Chen, H and Xu, S and Qiu, L and Huang, T and Xing, Z and Zhao, L and Lee, JJ and Ni, R and Wong, DF and Peng, G and Perlmutter, JS and Benzinger, TLS and Tu, Z},
title = {Design, synthesis, and characterization of F-18 sigma-1 receptor radiotracers for Alzheimer disease.},
journal = {European journal of medicinal chemistry},
volume = {307},
number = {},
pages = {118647},
doi = {10.1016/j.ejmech.2026.118647},
pmid = {41707281},
issn = {1768-3254},
abstract = {Sigma-1 receptor (σ1R) has been implicated in the pathogenesis of Alzheimer disease (AD). Positron emission tomography (PET) imaging of σ1R presents a novel strategy for the diagnosis and prognosis of AD. We previously reported a group of promising σ1R radiotracers. Continuing our efforts, we utilized an alternative labeling approach of our lead radiotracer (-)-[[18]F]TZ3108 to (-)-[[18]F]15, and facilitated the synthesis of three new radiotracers: (-)-[[18]F]13, (-)-[[18]F]14, and (-)-[[18]F]21. We performed systematic characterizations of these radiotracers including in vitro potency and selectivity, ex vivo biodistributions, autoradiography, immunohistology, PET for in vivo specificity, PET to assess σ1R expression in 3xTg-AD mice, PET in macaque brain, and radiometabolite analysis. We successfully synthesized all new F-18 labeled σ1R radiotracers with high yield and purity. In vitro and in vivo evaluations demonstrated all candidates were potent and selective for σ1R. PET studies in CD1 mice revealed high brain uptake and specificity for σ1R in vivo of all radiotracers. PET studies of 3xTg-AD and age-matched control mice showed reduced brain uptake of all σ1R radiotracers in AD mice. Immunohistology confirmed decreased expression of neuronal σ1R in 3xTg-AD mice. PET studies in macaque demonstrated (-)-[[18]F]13 has high brain uptake alongside elimination pharmacokinetics that are especially clinically favorable. Overall, our σ1R radiotracers can successfully quantify the reduction of σ1R in 3xTg-AD mice. (-)-[[18]F]13 is the most promising σ1R radiotracer of our discovery group, exhibiting high brain uptake, good in vivo specificity and stability, and clinically favorable brain washout pharmacokinetics that resolve prominent limitations of previously reported σ1R radiotracers.},
}

@article {pmid41707279,
year = {2026},
author = {Lin, Y and Lin, X and Zhu, J and Li, M and Xi, Y and Lu, D and Zhang, Y and Fu, L and Jiang, F},
title = {Design, synthesis, and investigation of anti-Alzheimer's activity and molecular mechanisms of phosphatidylserine derivatives.},
journal = {European journal of medicinal chemistry},
volume = {307},
number = {},
pages = {118676},
doi = {10.1016/j.ejmech.2026.118676},
pmid = {41707279},
issn = {1768-3254},
abstract = {Although phosphatidylserine (PS) mixtures exhibit neuroprotective properties, the development of PS-based Alzheimer's disease (AD) therapeutics has been constrained by incomplete structure-activity relationship (SAR) data and poorly defined mechanisms. Herein, 34 novel PS derivatives were designed, synthesized, and evaluated for neuroprotective effects in vitro and in vivo. Most compounds exhibited excellent safety with IC50 values greater than 200 μM in normal cells and potent in vitro neurotrophic activity, exemplified by A18, which enhanced neuronal proliferation (increased by 29.4 ± 3.3%), rescued rotenone-injured neurons (cell survival increased by 42.5 ± 1.9%), and promoted synaptogenesis in primary neurons. Synaptogenesis was quantified by an increase of MAP2-positive neurite length (42.0 ± 2.3 μm in A18-treated neurons vs. 27.6 ± 2.9 μm in the control group, ∗∗p < 0.01), with further synergistic effects observed when combined with Neurotrophin Growth Factor (NGF). In Aβ1-42-induced AD mice, A18 (25 mg/kg/day) demonstrated multimodal efficacy: restoring spatial memory(as evidenced by an increase in platform crossings, ∗∗∗∗p < 0.0001), preserving synaptic ultrastructure, and reducing neuroinflammation (decreasing TNF-α/IL-6 levels by 40-60%, ∗p < 0.05). Mechanistic studies have revealed that A18 activates the PI3K/AKT and ERK-CREB signaling pathways while suppressing neuroinflammatory pathways. Critical SAR principles establish para-benzoates with nitro groups (e.g., A18) as optimal pharmacophores and glycerol backbone integrity as essential. These findings provide a foundation for future PS-based AD drug development.},
}

@article {pmid41706850,
year = {2026},
author = {Cuklanz, KW and Stein, A and Chouinard, VA and Ongur, D and Du, F},
title = {Redox therapy for neuropsychiatric disorders: Molecular mechanisms and biomarker development.},
journal = {Science advances},
volume = {12},
number = {8},
pages = {eaea9014},
doi = {10.1126/sciadv.aea9014},
pmid = {41706850},
issn = {2375-2548},
mesh = {Humans ; *Biomarkers/metabolism ; Oxidation-Reduction ; NAD/metabolism ; Mitochondria/metabolism ; *Mental Disorders/metabolism/drug therapy/therapy ; Oxidative Stress/drug effects ; Animals ; Alzheimer Disease/metabolism/drug therapy ; Energy Metabolism ; Schizophrenia/metabolism ; Brain/metabolism ; },
abstract = {Redox dysregulation, characterized by an imbalance in the NAD[+] [nicotinamide adenine dinucleotide (oxidized form)]/NADH (reduced form of NAD[+]) ratio, is implicated in neurodegenerative and psychiatric disorders such as Alzheimer's disease and schizophrenia. This imbalance contributes to mitochondrial dysregulation, oxidative stress, and inflammation. Despite promising preclinical studies supporting therapeutic strategies aimed at restoring redox balance and thereby rescuing brain bioenergetic deficits, clinical outcomes and efficacy remain limited. Progress has been hindered by the incomplete understanding of NAD[+] subcellular cycling, as well as a lack of in vivo biomarkers measuring target engagement of redox status and mitochondrial function. Thus, this review examines molecular mechanisms of NAD (nicotinamide adenine dinucleotide)-related bioenergetic deficits, current and emerging NAD-targeted therapies, and recent advances in the development of neuroimaging biomarkers, emphasizing personalized and mechanism-driven approaches.},
}

Humans
*Biomarkers/metabolism
Oxidation-Reduction
NAD/metabolism
Mitochondria/metabolism
*Mental Disorders/metabolism/drug therapy/therapy
Oxidative Stress/drug effects
Animals
Alzheimer Disease/metabolism/drug therapy
Energy Metabolism
Schizophrenia/metabolism
Brain/metabolism

@article {pmid41706741,
year = {2026},
author = {Thomas, P and Nguyen, V and Weaver, R and Hansen, K and Sacharidou, A and Banks, WA and Mineo, C and Shaul, PW and Rhea, EM},
title = {Role of the endothelial cell apolipoprotein E receptor 2 in modulating the effects of apoE3 and apoE4 on insulin blood-brain barrier transport.},
journal = {PloS one},
volume = {21},
number = {2},
pages = {e0343155},
doi = {10.1371/journal.pone.0343155},
pmid = {41706741},
issn = {1932-6203},
mesh = {Animals ; *Blood-Brain Barrier/metabolism ; *Apolipoprotein E4/metabolism/genetics ; *Apolipoprotein E3/metabolism/genetics ; *Insulin/metabolism ; Mice ; Humans ; *Endothelial Cells/metabolism ; *Receptors, Lipoprotein/metabolism/genetics ; Biological Transport ; Mice, Transgenic ; Male ; Brain/metabolism ; Protein Isoforms/metabolism ; LDL-Receptor Related Proteins ; },
abstract = {Apolipoprotein E receptor 2 (apoER2), a primary receptor for apoE, has recently been linked to Alzheimer's disease. Compared with the most common form of apoE, apoE3, the apoE4 isoform increases the risk for developing Alzheimer's disease. ApoE4 impairs brain insulin signaling, a feature of Alzheimer's disease that correlates with cognitive decline. Insulin availability in the brain largely depends on blood-brain barrier (BBB) transport and contributes to brain insulin signaling. We have previously shown that the apoE4 isoform leads to regional reductions in insulin BBB transport in mice on a Western diet compared to apoE3 isoform. However, how insulin transport across the BBB is regulated by apoE isoforms is not well understood. Here we investigated a role of endothelial apoER2 in the effects of apoE isoforms on insulin BBB transport, using mice genetically expressing human apoE3 or apoE4 and expressing or lacking endothelial apoER2. We found that a loss of endothelial apoER2 did not overtly affect insulin BBB transport in either apoE3- or apoE4-expressing mice, except in the frontal cortex and pons/medulla, where decreased transport was observed in apoE3 mice lacking endothelial apoER2. These findings indicate that the effect of apoE4 on insulin BBB transport is largely independent of endothelial apoER2. In contrast, endothelial apoER2 may regulate insulin BBB transport in limited regions of the brain through its binding to apoE3.},
}

Animals
*Blood-Brain Barrier/metabolism
*Apolipoprotein E4/metabolism/genetics
*Apolipoprotein E3/metabolism/genetics
*Insulin/metabolism
Mice
Humans
*Endothelial Cells/metabolism
*Receptors, Lipoprotein/metabolism/genetics
Biological Transport
Mice, Transgenic
Male
Brain/metabolism
Protein Isoforms/metabolism
LDL-Receptor Related Proteins

@article {pmid41706640,
year = {2026},
author = {Hernandez, NM and Silva-Pérez, M and Chin, J},
title = {Noradrenergic innervation across brain regions is altered by aging and by disease progression in a mouse model of Alzheimer's disease neuropathology.},
journal = {PloS one},
volume = {21},
number = {2},
pages = {e0340611},
doi = {10.1371/journal.pone.0340611},
pmid = {41706640},
issn = {1932-6203},
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism ; Mice ; Disease Models, Animal ; *Aging/pathology ; Mice, Transgenic ; Disease Progression ; *Brain/pathology/metabolism ; Locus Coeruleus/pathology/metabolism ; *Adrenergic Neurons/pathology/metabolism ; *Norepinephrine/metabolism ; Humans ; Amyloid beta-Protein Precursor/genetics/metabolism ; Hippocampus/pathology/metabolism ; Male ; },
abstract = {Norepinephrine plays critical roles in modulating arousal and attention, is highly dynamic in awake, behaving individuals, and has anti-inflammatory and neuroprotective actions. Notably, the locus coeruleus (LC), the primary source of norepinephrine in the central nervous system, is among the first brain regions to show pathological alterations in early stages of Alzheimer's disease (AD). LC neuronal loss and associated reductions in norepinephrine in the brain have therefore been postulated to play a key role in AD pathophysiology. LC neurons and their axons have been studied in several mouse models of AD-related neuropathology to investigate their contribution to brain dysfunction in AD. However, the time course and spatial distribution of alterations in noradrenergic (norepinephrine-containing) LC projections are not fully understood. We therefore evaluated the density of noradrenergic axonal projections in the cortex and across subregions of the hippocampus in transgenic mice expressing mutant human amyloid precursor protein (APP) and in nontransgenic wild-type littermate controls at 2, 6, 12 and 20 months of age. In comparison to age-matched controls, APP mice displayed region-specific alterations in hippocampal noradrenergic fiber density that followed distinct age-related trajectories, along with subtle decreases in cortical noradrenergic fiber density. The alterations in noradrenergic innervation in APP mice were not associated with the extent of amyloid-β (Aβ) plaque load in the hippocampus or cortex and occurred in the absence of neuronal loss or Aβ plaques in the LC. In wild-type mice, there were subtle but robust alterations in noradrenergic fiber density across the brain between 2-20 months of age. These results reveal the presence of spatiotemporally complex alterations in noradrenergic innervation in the brain across both normal aging and disease progression.},
}

Animals
*Alzheimer Disease/pathology/metabolism
Mice
Disease Models, Animal
*Aging/pathology
Mice, Transgenic
Disease Progression
*Brain/pathology/metabolism
Locus Coeruleus/pathology/metabolism
*Adrenergic Neurons/pathology/metabolism
*Norepinephrine/metabolism
Humans
Amyloid beta-Protein Precursor/genetics/metabolism
Hippocampus/pathology/metabolism
Male

@article {pmid41706609,
year = {2026},
author = {Xu, J and Zhang, Y and Mao, Z},
title = {Potential benefits and concerns of surgical treatment for severe Alzheimer's disease: a decade of experience.},
journal = {International journal of surgery (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1097/JS9.0000000000004897},
pmid = {41706609},
issn = {1743-9159},
}

@article {pmid41706531,
year = {2026},
author = {Gul, G},
title = {Modeling β-sheet breaker peptides across multiple resolutions: from neurological targets to liposomal membranes.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5nr05060j},
pmid = {41706531},
issn = {2040-3372},
abstract = {β-Sheet-breaker peptides can destabilize protein aggregates associated with neurological disorders, thereby interfering with fibril formation. Given the pivotal role of misfolded protein oligomers such as amyloid-β and α-synuclein in Alzheimer's and Parkinson's diseases, respectively, strategies that block β-sheet formation or perturb β-sheet-rich interactions are promising therapeutic approaches to mitigate neurotoxicity and slow disease progression. However, cross-applicability of inhibitor peptides between these diseases remains largely unexplored. Moreover, the clinical potential of β-sheet-breaker peptides is often limited by enzymatic degradation and restricted blood-brain barrier permeability, necessitating effective delivery systems. To address these challenges, lipid-based nanocarriers offer versatile platforms for peptide encapsulation and controlled release. Therefore, in this study, we collected 50 experimentally validated β-sheet-breaker peptides and examined their binding to amyloid-β and α-synuclein fibrils using molecular docking and molecular dynamics simulations. The selected peptide was further evaluated via atomistic and coarse-grained simulations within PEGylated phosphatidylcholine bilayers at varying cholesterol concentrations to assess peptide-lipid interactions and encapsulation potential. Our results indicate that certain peptides may target multiple misfolded proteins, supporting their potential for cross-disease repurposing. Among the candidates, KR peptides exhibited the highest binding free energy toward both targets, while RR peptides demonstrated robust binding with comparable affinity. Multiscale simulations revealed that RR peptides predominantly localize within PEG corona regions and interact with lipid phosphate headgroups, suggesting preferential surface adsorption on pre-formed liposomal fragments. Peptide insertion was more pronounced in unsaturated membranes, whereas cholesterol-rich, saturated membranes hindered permeation and bilayer-to-vesicle transition. Overall, this study provides the first molecular-level insight into the potential of experimentally validated peptides against different neurodegenerative targets and presents a lipid-based delivery strategy to enhance their bioavailability by elucidating the underlying molecular interactions.},
}

@article {pmid41706377,
year = {2026},
author = {Singh, G and Maparu, K and Aran, KR},
title = {Neuro-renin-angiotensin-aldosterone system axis in alzheimer's disease: from molecular dysregulation to therapeutic redirection.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {36},
pmid = {41706377},
issn = {1573-7365},
mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Renin-Angiotensin System/physiology/drug effects ; Animals ; Blood-Brain Barrier/metabolism ; *Brain/metabolism/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration marked by tau hyperphosphorylation, amyloid-beta (Aβ) buildup, neuroinflammation, and blood-brain barrier (BBB) dysfunction. Although much attention is paid to understanding amyloid and tau pathologies, there are still no disease-modifying solutions. Recent evidence indicates that the brain-specific Renin-Angiotensin-Aldosterone System (RAAS), conventionally involved in the regulation of cardiovascular diseases, could be central in controlling the key neuropathological alterations in AD. This review explains the binary roles of the classical (ACE/Ang II/AT1R) and alternative (ACE 2 /Ang-(1-7)/MasR) axis of the RAAS in the central nervous system (CNS), including how overactivation of the classical axis intensifies oxidative stress and Aβ plaque formation, tau hyperphosphorylation, and BBB disruption, and how the alternative axis is neuroprotective, anti-inflammatory, and vasodilatory effects. We integrate molecular, cellular, and translational information about RAAS-mediated regulation of neurovascular integrity, glial activation, and synaptic resilience. We also discuss the repurposing of centrally acting ACE inhibitors and angiotensin II receptor blockers (ARBs), as well as next-generation MasR agonists and recombinant ACE2, as promising tools to re-establish neuro-RAAS balance. These findings together support a paradigm shift of the RAAS as a system-level therapeutic axis in AD. Conclusively, there is a need to highlight the necessity of specific CNS biomarkers and the accuracy of medicine models that can direct interventions on RAAS-related actions and redesign AD administration beyond symptom resolution to modify the disease.},
}

*Alzheimer Disease/metabolism/drug therapy
Humans
*Renin-Angiotensin System/physiology/drug effects
Animals
Blood-Brain Barrier/metabolism
*Brain/metabolism/drug effects

@article {pmid41706344,
year = {2026},
author = {Yu, JX and Zhang, WX and Li, PY and Yang, YL and Huang, HC},
title = {Curcumin Rescues Oxidative Stress-Induced Impairment of PINK1/Parkin Pathway-Mediated Mitophagy in APOE4-Expressing Astrocytes.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {454},
pmid = {41706344},
issn = {1559-1182},
support = {ZKZD202304 and ZK70202101//This study was supported by the Academic Research Projects of Beijing Union University/ ; },
mesh = {*Curcumin/pharmacology ; *Oxidative Stress/drug effects ; *Mitophagy/drug effects ; Animals ; *Astrocytes/metabolism/drug effects/pathology ; *Ubiquitin-Protein Ligases/metabolism ; Mitochondria/metabolism/drug effects ; *Apolipoprotein E4/metabolism/genetics ; *Protein Kinases/metabolism ; *Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Mice, Transgenic ; Humans ; Apoptosis/drug effects ; Autophagy/drug effects ; Mice ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized primarily by deterioration in memory, cognition, and learning ability. Its etiology is complex and influenced by multiple factors, including genetics and environment. With advancing research into mitochondrial function and mechanisms, impaired mitophagy has been proposed as a significant mechanism contributing to AD. The ApoE ε4 allele, a high-risk genetic factor for AD, may play a key role in disease pathogenesis by inducing mitophagy dysfunction and apoptosis. From the perspective of APOE gene polymorphisms, this study investigates abnormal changes in mitochondrial function and autophagy in humanized APOE4 mice primary astrocytes under oxidative stress, as well as the regulatory effect of curcumin (Cur) on mitophagy and oxidative stress-induced apoptosis, thereby exploring its potential to ameliorate AD through targeting mitophagy. Mitochondrial function analysis revealed that APOE4 expression reduced the antioxidant capacity and respiratory function of primary astrocytes, leading to mitochondrial membrane damage, intracellular reactive oxygen species (ROS) accumulation, and decreased ATP production. Curcumin effectively protected mitochondrial integrity, reduced the number of damaged mitochondria, improved overall mitochondrial function, and helped maintain mitochondrial homeostasis involving in PINK1/Parkin pathway. Regarding autophagy and apoptosis, curcumin was shown to restore autophagic flux, mitigate autophagy disruption caused by oxidative stress, and reverse early-stage apoptosis.},
}

*Curcumin/pharmacology
*Oxidative Stress/drug effects
*Mitophagy/drug effects
Animals
*Astrocytes/metabolism/drug effects/pathology
*Ubiquitin-Protein Ligases/metabolism
Mitochondria/metabolism/drug effects
*Apolipoprotein E4/metabolism/genetics
*Protein Kinases/metabolism
*Signal Transduction/drug effects
Reactive Oxygen Species/metabolism
Mice, Transgenic
Humans
Apoptosis/drug effects
Autophagy/drug effects
Mice

@article {pmid41706263,
year = {2026},
author = {Çakır, A and Şehzade, S and Koç, C and Çilingir, S and Acar, D and Süyen, G and Bican Demir, A and Kahveci, N},
title = {The Impact of REM Sleep Deprivation on ER Stress and Alzheimer-Like Pathology: Therapeutic Potential of Melatonin.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {79},
pmid = {41706263},
issn = {1573-6903},
}

@article {pmid41706165,
year = {2026},
author = {Bamford, AR and Logan, C and Do, QT and Nguyen, K and McMillan, LC and Yassa, MA and Shankle, WR and Thomas, EA},
title = {Salivary total tau: a clinically practical measure of tau neuropathology in Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {149},
pmid = {41706165},
issn = {1432-1459},
mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/diagnosis/pathology ; Female ; Male ; Aged ; *Saliva/metabolism ; Biomarkers/metabolism ; Neurofilament Proteins/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Aged, 80 and over ; Middle Aged ; Cognitive Dysfunction/metabolism/diagnosis ; },
abstract = {Neurofibrillary tangles, consisting of intracellular accumulations of the protein tau, are a hallmark feature of Alzheimer's disease (AD), and are thought to contribute to neuronal dysfunction and death during the disease process. The quantification of tau proteins in cerebrospinal fluid (CSF) or plasma has enormous utility for AD diagnosis; however, validated non-invasive measures of tau protein are lacking and would have added value for widespread screening. In this study, we quantified the levels of total tau (t-tau), along with neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), in saliva samples from 111 participants, including those with CSF biomarker-confirmed AD, mild AD, non-AD cognitively impaired (CI) and cognitively unimpaired (CU) older adults, using immunoassays on the Meso Scale Discovery platform. We find that salivary levels of t-tau were significantly elevated in AD and mild AD, but not other CI patients, compared to CU adults, while salivary levels of NfL and GFAP showed no significant differences across cohorts. In addition, we found that salivary t-tau was significantly correlated with CSF biomarker measures, including significant positive correlations with CSF t-tau and p-tau 181 (0.257; p = 0.016 and 0.276; p = 0.009 for t-tau and p-tau 181, respectively). Salivary t-tau was also found to predict AD cases compared to CU individuals with an area under the curve of 0.834 (95% CI 0.74-0.93; p < 0.0001). Finally, we observed that salivary t-tau levels were significantly negatively correlated with cognitive performance in AD patients, as well as all individuals together. These findings suggest that salivary t-tau might represent a non-invasive biomarker specific to AD pathology and could aid in early detection of AD or for clinical screening purposes.},
}

Humans
*tau Proteins/metabolism
*Alzheimer Disease/metabolism/diagnosis/pathology
Female
Male
Aged
*Saliva/metabolism
Biomarkers/metabolism
Neurofilament Proteins/metabolism
Glial Fibrillary Acidic Protein/metabolism
Aged, 80 and over
Middle Aged
Cognitive Dysfunction/metabolism/diagnosis

@article {pmid41705602,
year = {2026},
author = {Li, A and Klinger, HM and Seto, M and Birkenbihl, C and Properzi, MJ and Farrell, M and Thibault, E and Schultz, AP and Townsend, DL and Cuppels, M and Brown, JA and Papp, KV and Amariglio, RE and Yang, HS and Donohue, MC and Rissman, RA and Betthauser, TJ and Langhough, RE and Jonaitis, EM and Cody, K and Johnson, SC and Rentz, DM and Johnson, KA and Sperling, RA and Buckley, RF and Coughlan, GT and , },
title = {Elevated temporal tau PET predicts faster cognitive decline in women than men: A meta-analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71031},
doi = {10.1002/alz.71031},
pmid = {41705602},
issn = {1552-5279},
support = {U19AG010483//National Institutes of Health (NIH)-National Institute on Aging/ ; R01AG063689//National Institutes of Health (NIH)-National Institute on Aging/ ; P01AG036694//National Institutes of Health (NIH)-National Institute on Aging/ ; AG027161//National Institutes of Health (NIH)-National Institute on Aging/ ; AG021155//National Institutes of Health (NIH)-National Institute on Aging/ ; R01AG079142//National Institutes of Health (NIH)-National Institute on Aging/ ; U24AG057437//National Institutes of Health (NIH)-National Institute on Aging/ ; //Eli Lilly and Company/ ; //Accelerating Medicines Partnership/ ; //GHR Foundation/ ; AARF-23-1151259/ALZ/Alzheimer's Association/United States ; DP2AG082342//NIH New Innovator Award/ ; K99AG083063//NIH Pathway to Independence Award/ ; },
mesh = {Humans ; *tau Proteins/metabolism ; *Positron-Emission Tomography ; *Cognitive Dysfunction/diagnostic imaging/metabolism/genetics ; Female ; Male ; Aged ; Amyloid beta-Peptides/metabolism ; Sex Factors ; Disease Progression ; Alzheimer Disease/diagnostic imaging ; *Temporal Lobe/diagnostic imaging/metabolism ; Apolipoprotein E4/genetics ; Sex Characteristics ; Longitudinal Studies ; Middle Aged ; },
abstract = {INTRODUCTION: Women show higher levels of Alzheimer's disease (AD) pathology than men, but the implications for cognitive decline remain unclear. Determining the extent to which tau burden differentially accelerates cognitive decline in men and women will provide critical insights into sex-specific pathways of disease progression.

METHODS: We leveraged tau positron emission tomography (PET), amyloid beta (Aβ) PET, apolipoprotein E (APOE) ε4 genotyping, and longitudinal cognitive data over approximately 8.6 (standard deviation [SD] = 3.8) years from 1007 cognitively unimpaired adults across three cohorts. Cognitive trajectories were modeled with linear mixed-effects regression including sex × tau × time interactions, and results were synthesized using random-effects meta-analysis.

RESULTS: Higher tau burden in medial and lateral temporal regions was associated with faster cognitive decline in women than in men.

DISCUSSION: High tau burden carries a disproportionately greater cognitive cost for women, underscoring the need for sex-specific approaches to early detection and therapeutic intervention in AD.

HIGHLIGHTS: A meta-analysis across three independent cohorts shows that female cognitive advantage at low tau shifts to vulnerability at higher tau. Sex differences in tau-related cognitive decline were consistent after accounting for amyloid burden. Sex-specific rates of cognitive decline should be considered in clinical trial design.},
}

Humans
*tau Proteins/metabolism
*Positron-Emission Tomography
*Cognitive Dysfunction/diagnostic imaging/metabolism/genetics
Female
Male
Aged
Amyloid beta-Peptides/metabolism
Sex Factors
Disease Progression
Alzheimer Disease/diagnostic imaging
*Temporal Lobe/diagnostic imaging/metabolism
Apolipoprotein E4/genetics
Sex Characteristics
Longitudinal Studies
Middle Aged

@article {pmid41705505,
year = {2026},
author = {Malkoc, Z and Stopps, E and Asamoah, PMK and McCalla, SE and Kunze, A},
title = {Sub-Neuronal Network Profiling of Extracellular Vesicle Release Using a Compartmentalized Neurofluidic Platform.},
journal = {Advanced biology},
volume = {10},
number = {2},
pages = {e00381},
doi = {10.1002/adbi.202500381},
pmid = {41705505},
issn = {2701-0198},
support = {ED19HDQ0200091//Montana State University Catalyst Gap Fund/ ; 1R21AG071691-01//National Institute of Aging/ ; //Montana Nanotechnology Facility/ ; //National Nanotechnology Coordinated Infrastructure/ ; 1828765//National Science Foundation/ ; SCR_026324//Montana State University Cryo-EM Core Facility/ ; P20GM103474/GM/NIGMS NIH HHS/United States ; 1847245//Directorate for Engineering/ ; },
mesh = {*Extracellular Vesicles/metabolism ; *Neurons/metabolism ; Animals ; Cells, Cultured ; Okadaic Acid/pharmacology ; MicroRNAs/metabolism/genetics ; },
abstract = {Extracellular vesicles (EVs) are membrane-bound vesicles that are secreted by a wide range of organisms and cells, carrying cell-specific receptors and molecular cargo such as proteins and nucleic acids. EVs have emerged as promising biomarkers for cancer and neurodegenerative disorders like Alzheimer's Disease (AD). Traditional methods for isolating neuron-derived EVs from bodily fluids or conditioned media are based on bulk analysis methods, such as ultracentrifugation, isolation reagents, and immunoaffinity-based techniques, and lack spatial resolution to capture localized secretion dynamics. Here, our neurofluidic platform compartmentalizes neuronal networks and enables spatially resolved analysis of EV profiling before subsequent traditional isolation and content screening. This intermediate resolution provides critical insights into localized sub-neuronal EV secretion dynamics in cortical, hippocampal, and brainstem neurons. Using our platform, the influence of growth environment, cell maturation time, and exogenous stressors such as shear and biochemical stress can be unraveled. Biochemical stress is induced through okadaic acid (OA), a PP1A/PP2A inhibitor, which leads to hyperphosphorylation of proteins. In parallel, microRNA expression profiles are shown after OA treatment in primary neuron cultures, indicating an additional transcriptional response. These findings reveal regional differences in EV secretion dynamics associated with neuronal development and external stressors, including shear forces and PP1A/PP2A inhibition.},
}

*Extracellular Vesicles/metabolism
*Neurons/metabolism
Animals
Cells, Cultured
Okadaic Acid/pharmacology
MicroRNAs/metabolism/genetics

@article {pmid41705137,
year = {2026},
author = {Gu, L and Liu, J and Wang, C and Shan, X and Li, S and Zhang, X and Xia, L and Li, J},
title = {Brain-targeted delivery of siRNA via non-viral delivery systems, the therapeutic strategy for Alzheimer's disease-Unveiling challenges and prospects.},
journal = {International journal of pharmaceutics: X},
volume = {11},
number = {},
pages = {100503},
pmid = {41705137},
issn = {2590-1567},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral issues, posing significant public health challenges. Small interfering RNAs (siRNAs) offer the potential to selectively silence AD-related pathogenic genes. This review first outlines the diverse pathogenic mechanisms and hallmark pathologies of AD, then spotlights the key genes now being silenced by siRNA for therapeutic intervention. These genes encompass those directly implicated in amyloidogenesis, tau phosphorylation, and neuroinflammation, along with those aberrantly up-regulated and associated with AD pathology. Finally, it summarizes recent research on non-viral and local siRNA delivery strategies including lipid, polymer, quantum dots, inorganic materials, extracellular vesicles, and conjugates aimed at effectively penetrating the blood-brain barrier while overcoming intra- and extracellular barriers to target key AD pathways. These findings underscore the promise of siRNA therapy in addressing AD pathology and provide valuable insights into overcoming delivery challenges.},
}

@article {pmid41705110,
year = {2026},
author = {Choi, H and Lee, SM and Lee, JA},
title = {Decoding the brain's ATG8 paralog code: LC3-GABARAP specialization at synapses and the astrocyte-neuron interface.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1762891},
pmid = {41705110},
issn = {2296-634X},
abstract = {Macroautophagy is essential for the long-term health of neurons and astrocytes in the central nervous system (CNS). The six mammalian ATG8 paralogs (LC3A/B/C and GABARAP/GABARAPL1/L2) exhibit an emerging "ATG8 code"-a division of labor among these proteins that assigns specialized roles in the autophagy pathway to each paralog, enabling fine-tuned proteostasis at synapses and the astrocyte-neuron interface. This review synthesizes how LC3 versus GABARAP mediate distinct steps of autophagy (LC3 primarily governs cargo recruitment and phagophore expansion, whereas GABARAP drives autophagosome maturation, transport, and lysosomal fusion) and how these molecular distinctions translate into functional differences in neurons versus astrocytes. Neurons coordinate autophagy across long axons and synapses: presynaptic autophagy clears aging synaptic vesicles and organelles, while postsynaptic autophagy modulates receptor turnover and synaptic plasticity. Astrocytes, by contrast, leverage autophagy for metabolic support and clearance of extracellular debris (e.g., amyloid-β plaques), interfacing with neuronal autophagy via transcellular mechanisms. Dysregulation of these processes underlies diverse CNS disorders: impaired autophagic flux and aggregate clearance contribute to neurodegenerative diseases (Alzheimer's and Parkinson's), whereas selective autophagy deficits at synapses disrupt circuit homeostasis (implicated in epilepsy and autism). Finally, we highlight emerging methodologies-from multi-omics and live imaging to optogenetics and targeted therapeutics-that are illuminating this specialized autophagy network and opening novel avenues for intervention.},
}

@article {pmid41704851,
year = {2025},
author = {Soriano, S and Marshall, A and Holcomb, M and Flinn, H and Burke, M and Kara, G and Scalzo, P and Villapol, S},
title = {Sex-specific effects of fecal microbiota transplantation on TBI-exacerbated Alzheimer's disease pathology in mice.},
journal = {Frontiers in microbiology},
volume = {16},
number = {},
pages = {1703708},
pmid = {41704851},
issn = {1664-302X},
abstract = {BACKGROUND: Traumatic brain injury (TBI) accelerates Alzheimer's disease (AD) pathology and neuroinflammation, potentially via gut-brain axis disruptions. Whether restoring gut microbial homeostasis mitigates TBI-exacerbated AD features remains unclear, particularly with respect to sex differences.

OBJECTIVE: The goal of our study was to test whether fecal microbiota transplantation (FMT) modifies amyloid pathology, neuroinflammation, gut microbial composition, metabolites, and motor outcomes in male and female 5xFAD mice subjected to TBI.

METHODS: Male and female 5xFAD mice received sham treatments or controlled cortical impact, followed 24 h later by vehicle (VH) or sex-matched FMT from C57BL/6 donors. Assessments at baseline, 1-, and 3-days post-injury (dpi) included Thioflavin-S and 6E10 immunostaining for Aβ, Iba-1 and GFAP for glial activation, lesion volume, rotarod performance, 16S rRNA sequencing for microbiome profiling, serum short-chain fatty acids (SCFAs), and gut histology.

RESULTS: TBI increased cortical and dentate gyrus Aβ burden, with females showing greater vulnerability. FMT reduced Aβ deposition in sham animals and shifted plaque morphology but did not attenuate TBI-induced amyloid escalation. FMT differentially modulated glial responses by sex and region (reduced microgliosis in males) without altering lesion volume at 3 dpi. Rotarod performance was better in sham females compared to males and declined in FMT-treated TBI females. Fecal microbiome alpha diversity and richness were unchanged, while beta diversity revealed marked, time-dependent community shifts after TBI that were slightly altered by FMT. Gut morphology remained broadly intact, but crypt width increased after TBI, particularly in males.

CONCLUSION: In 5xFAD mice, TBI drives sex-dependent worsening of amyloid pathology, neuroinflammation, and dysbiosis. Acute FMT partially restores microbial composition and plaque features in sham animals but fails to reverse TBI-induced neuroinflammation or motor deficits. These findings underscore the context- and sex-dependence of microbiome interventions and support longer-term, sex-specific strategies for AD with comorbid TBI.},
}

@article {pmid41704845,
year = {2025},
author = {Villegas-Llerena, C and Paredes-Moscosso, SR and Guevara-Fujita, ML and Obispo, D and Custodio, N and Montesinos, R and Parodi, JF and Flores-Flores, O and Hardy, J and Fujita, R},
title = {Heterozygous TREM2 (p.W44X) and PSEN1 (p.A431T) mutations in two Peruvian families with familial Alzheimer's disease: expanding the genetic landscape in underrepresented populations.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1724380},
pmid = {41704845},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) accounts for up to 70% of all dementia cases, affecting an estimated 23-35 million people worldwide. According to the World Health Organization (WHO), the number of AD cases in Latin America, including Peru, is expected to quadruple by 2050. However, these populations remain underrepresented in research, diagnostics, and care. Early-onset Alzheimer's disease (EOAD), characterized by symptom onset before the age of 65, has been shown to have a strong genetic component, making it valuable for genetic studies. Identifying EOAD-associated mutations in underrepresented populations is crucial for uncovering pathogenic variants that may provide new insights into the disease's mechanisms. In this article, we present two Peruvian families with early and late onset AD in whom whole-exome sequencing (WES) revealed heterozygous variants associated with AD. In family AD002, we found a heterozygous variant in TREM2 (c.132G > A; p.W44X), a protein-truncating mutation. The proband and 17 family members participated in genetic testing, of which 04 members were carriers of the mutation. This is the first TREM2-associated mutation reported in the Peruvian population. In family AD009, a novel heterozygous variant in PSEN1 (c.1291G > A; p.A431T) is reported. The proband and 11 family members participated in genetic testing, of which 05 were carriers of the mutation (02 affected siblings and 03 unaffected relatives). This is the first report of PSEN1 A431T associated with AD. Overall, our findings suggest that TREM2 p.W44X is a likely-pathogenic variant while PSEN1 p.A431T is a candidate variant of uncertain significance (VUS) associated with AD; both genetic variants warrant further investigation.},
}

@article {pmid41704840,
year = {2026},
author = {Lang, Y and Ma, Q and Chen, R and Yang, D and Hu, X and Zhang, C and Shi, C and Guo, Z},
title = {Analysis of Fingerprint Profiles of Flavonoid Compounds in Rock Tea of Different Ages.},
journal = {International journal of analytical chemistry},
volume = {2026},
number = {},
pages = {8845352},
pmid = {41704840},
issn = {1687-8760},
abstract = {This study established a chromatographic fingerprint analysis method for aged rock tea using ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) technology to profile its chemical components. The chromatographic separation showed excellent performance, with more than 30 chemical components of common peaks identified. Comparative analysis of fingerprint profiles from different vintage-aged teas revealed significant differences in similarity, allowing classification into three distinct categories based on similarity indices. This method facilitates the classification of aged teas and quality evaluation of traditional Chinese medicinal materials. Component analysis of aged tea demonstrated that tea extracts are rich in flavonoid compounds, both in content and diversity, serving as a primary dietary source of total flavonoids. In subsequent animal experiments, functional flavonoids derived from aged tea extracts exhibited positive regulatory effects against multiple free radicals, including ·OH, H2O2, DPPH[-], and ABTS, in vitro. In vivo studies showed that these flavonoids reduced malondialdehyde (MDA) levels in the cerebral cortex of Alzheimer's disease (AD) mice, enhanced the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), mitigated oxidative damage, and improved cognitive dysfunction in AD mice. This research provides crucial references for future studies on traditional Chinese medicines aimed at ameliorating cognitive dysfunction.},
}

@article {pmid41704760,
year = {2026},
author = {Nakanishi Usuda, J and Nóbile, AL and Nery do Vale, FY and Corrêa, YLG and Adri, AS and Nava, RG and de Albuquerque Freitas, DG and Santos, RS and Schimke, LF and Fonseca, DLM and Cabral-Miranda, G and Khan, TA and Câmara, NO and Moll, G and Marques, AHC and Dalmolin, RJS and Nakaya, HI and Riemekasten, G and Filgueiras, IS and Dias, HD and Cabral-Marques, O},
title = {Integrative analysis reveals the autoantibodyome neuroimmune signature of neurodegeneration.},
journal = {iScience},
volume = {29},
number = {2},
pages = {114781},
pmid = {41704760},
issn = {2589-0042},
abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), are complex conditions driven by systemic dysregulation that transcends the central nervous system. An integrative systems immunology framework was applied to characterize the neuroimmune "autoantibodyome" across neurodegeneration through an individual participant data meta-analysis of five protein microarray datasets, comprising 596 samples from patients with AD, PD, or MS and healthy controls. We mapped differentially reactive autoantibodies stratified by their targets, unveiling shared features among diseases, such as blood-brain barrier impairment and amplified pro-inflammatory activation, alongside disease-specific perturbations in neuroimmune processes, including short-term memory (AD), skeletal muscle contraction (PD), and pain perception (MS). We identified convergent dysregulation of various autoantibodies targeting diverse synaptic transmission pathways, including gamma-aminobutyric acid (GABA)ergic and glutamatergic signaling. These results indicate the potential of the autoantibodyome to interact with and report on central alterations, suggesting that neurodegeneration may be better understood as a systemic dyshomeostasis.},
}

@article {pmid41704741,
year = {2026},
author = {Abdullah, LB and Khandakar, I and Douglas, A and Nance, R and Zhou, Z and Hall, J and O'Bryant, S and , },
title = {Predicting low premorbid cognitive ability with social determinants: A machine learning approach.},
journal = {JAR life},
volume = {15},
number = {},
pages = {100062},
pmid = {41704741},
issn = {2534-773X},
abstract = {BACKGROUND: Social determinants of health and biological processes are shaped by the exposome, which provides a framework for understanding how social adversity drives molecular and cellular mechanisms underlying Alzheimer's disease risk. Individuals with low premorbid intellectual ability (pIQ ≤70) may be particularly vulnerable to adverse social determinants of health due to reduced cognitive reserve, yet this relationship is understudied.

METHODS: Data from the Health and Aging Brain Study-Health Disparities (n = 2691) were analyzed. Participants were classified as low pIQ (IQ ≤70) or average pIQ (IQ 90-100) via word reading scores. Using a machine learning approach, an XGBoost model evaluated education, income, Area Deprivation Index (ADI), social support, stress, health status, and worry in prediction of pIQ grouping.

RESULTS: The model achieved and AUC of 0.72 [0.64, 0.81]. Top predictors included worry, ADI, income, high school completion, and tangible support. Low pIQ was associated with greater neighborhood deprivation, lower income, and reduced support resources.

CONCLUSION: Low pIQ, when combined with SDoH factors reflects a vulnerable psychosocial-cognitive phenotype that may accelerate pathways to cognitive decline potentially through inflammatory mechanisms.},
}

@article {pmid41704641,
year = {2026},
author = {Bach, DH and Nguyen, TL},
title = {Alzheimer's disease as a systems-level timing disorder: Circadian disruption of glial immunometabolism, brain clearance, and therapeutic responsiveness.},
journal = {Neurobiology of sleep and circadian rhythms},
volume = {20},
number = {},
pages = {100145},
pmid = {41704641},
issn = {2451-9944},
abstract = {Alzheimer's disease (AD) is traditionally conceptualized as a disorder of protein aggregation and neurodegeneration, yet growing evidence indicates that fundamental temporal organization of brain physiology is also disrupted. In the healthy brain, circadian clocks coordinate sleep-wake behavior, glial immunometabolism, astrocytic aquaporin-4 polarity, and glymphatic-lymphatic clearance, aligning immune readiness and proteostasis with daily activity-rest cycles. In AD, this temporal coordination progressively deteriorates, manifesting as sleep fragmentation, instability of rest-activity rhythms, vulnerability of central clock structures, and loss of circadian gating of glial and clearance pathways. These disruptions create phase-inappropriate immune and metabolic states, impair protein clearance, and alter the fate of extracellular vesicles, which may shift from mediators of waste export to facilitators of proteopathic spread. Importantly, circadian failure also constrains therapeutic delivery and biomarker interpretation by modulating blood-brain barrier transport, brain fluid dynamics, and brain-to-blood signal export. We propose that AD can be reframed as a systems-level timing disorder, in which loss of temporal coherence integrates molecular pathology, glial dysfunction, clearance failure, therapeutic inefficacy, and biomarker variability. This framework highlights chrono-pharmacology, chrono-neurotherapeutics, and circadian-informed biomarkers as essential components of precision strategies for AD prevention and treatment.},
}

@article {pmid41704453,
year = {2026},
author = {Esmkhani, M and Mahdavi, M and Javanshir, S and Iraji, A},
title = {Novel cinnamic acid-based N-benzyl pyridinium analogs: potent dual cholinesterase inhibitors with neuroprotective properties for Alzheimer's disease.},
journal = {RSC advances},
volume = {16},
number = {10},
pages = {9293-9306},
pmid = {41704453},
issn = {2046-2069},
abstract = {This study reports the design and synthesis of a novel series of cinnamic acid-based analogs bearing an N-benzyl pyridinium moiety against Alzheimer's disease (AD), aiming at dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside neuroprotective effects. A total of 15 derivatives were synthesized, among which compound 7b exhibited the most potent dual inhibition (AChE IC50 = 0.89 µM; BChE IC50 = 0.11 µM), and significant neuroprotection against H2O2-induced oxidative stress in SH-SY5Y cells, with no cytotoxicity under the tested concentration. Structure-activity relationship (SAR) analysis revealed that small electron-withdrawing substituents (e.g. ortho-fluoro, methyl) enhanced inhibitory activity, whereas meta and para substitutions generally reduced potency. Enzyme kinetics also determined compound 7b to be a competitive inhibitor of AChE (K i = 0.49 µM). Furthermore, molecular docking and molecular dynamics simulations identified stable binding interactions in the active sites of AChE and BChE. All these findings support the potential of these compounds as effective multi-target-directed ligands (MTDLs) for AD, displaying coordinated inhibition of cholinesterase, neuroprotection, and low toxicity.},
}

@article {pmid41704371,
year = {2026},
author = {Li, Y and Song, Z and Shi, H and Zhao, T and Chen, J and Zhou, X and Hu, Q and Li, X and Meng, L and Song, R and Sun, Z and Li, C and Haider, A and Yuan, H and Liang, SH},
title = {Radiosynthesis and Evaluation of [18]F‑Labeled Deuterated Radioligand for Positron Emission Tomography Imaging of Cholesterol 24-Hydroxylase.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {2},
pages = {538-546},
pmid = {41704371},
issn = {1948-5875},
abstract = {Brain cholesterol homeostasis is critical for neuronal function and primarily regulated by cholesterol 24-hydroxylase (CYP46A1). Dysregulation of CYP46A1 has been implicated in Alzheimer's disease (AD) and Huntington's disease (HD). Building on the clinically validated positron emission tomography (PET) tracer [[18]F]-CHL-2205, we designed a deuterated isotopologue, CHL-2205-d 3, targeting the amide N-methyl group to enhance stability and enable mechanistic studies. Compound 5 exhibited high CYP46A1 affinity (IC50 = 0.38 nM; K i = 0.22 nM). Radiosynthesis via copper-mediated [[18]F]-fluorination afforded [[18]F]5 in 31.5 ± 1.5% non-decay-corrected radiochemical yield and high molar activity (>95 GBq/μmol). Autoradiography and PET imaging in mice demonstrated robust brain uptake, heterogeneous regional distribution, and specific target engagement. Radiometabolite analysis confirmed that brain radioactivity was mainly attributable to intact [[18]F]5, with a pharmacokinetics comparable to that of [[18]F]-CHL-2205. [[18]F]5 preserves [[18]F]-CHL-2205 imaging performance and provides a deuterated PET tool for quantitative bioanalysis and integrated PET-deuterium metabolic imaging (DMI) studies of brain cholesterol metabolism.},
}

@article {pmid41704361,
year = {2026},
author = {Cho, S and Szalai, TV and El Gaamouch, F and Bajusz, D and Keserű, GM and Gabr, M},
title = {AI-Assisted Discovery and Optimization of Small-Molecule TREM2 Agonists with Functional Microglial Activity.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {2},
pages = {366-373},
pmid = {41704361},
issn = {1948-5875},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose loss-of-function variants increase Alzheimer's disease (AD) risk. While antibody-based agonists have shown promise, their translation is hindered by poor brain penetration and high cost. Here, we report the discovery and optimization of small-molecule TREM2 agonists through an AI-assisted virtual screening strategy. Deep docking of over five million purchasable compounds identified a structurally novel hit, T2K-014, which engaged TREM2 with modest affinity. A SAR-by-catalog campaign led to the identification of T2M-010 as a potent binder. T2M-010 demonstrated favorable in vitro PK properties, including high solubility, passive BBB permeability, moderate metabolic stability, and minimal safety liabilities. Functionally, T2M-010 activated receptor-proximal signaling, inducing SYK phosphorylation in TREM2-expressing cells, and promoted microglial phagocytosis. Together, these findings establish T2M-010 as the most potent small-molecule TREM2 binder reported to date capable of driving protective microglial responses relevant to AD.},
}

@article {pmid41704318,
year = {2026},
author = {Fang, S and Xi, H and Zhang, K and Fang, X and Yang, Y and Li, J and Yang, W},
title = {Zhinao Capsule improves learning and memory impairment in APP/PS1 mice through gut-brain axis-mediated inhibition of neuroinflammation.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1735765},
pmid = {41704318},
issn = {1664-302X},
abstract = {Traditional Chinese Medicine (TCM) interventions have attracted increasing attention in recent years, with a growing body of evidence supporting their efficacy in the treatment of Alzheimer's disease (AD). Zhinao Capsule (ZNJN), a proprietary TCM formulation, has demonstrated promising clinical outcomes, particularly in enhancing cognitive function and alleviating AD-related pathology in rodent models. This study aimed to evaluate the neuroprotective effects of ZNJN in APP/PS1 transgenic mice. Behavioral assessments indicated that ZNJN, especially at the high dose, significantly improved learning and memory abilities. Histopathological analysis revealed a marked reduction in hippocampal Aβ1-42 deposition and decreased activation of microglia and astrocytes, as evidenced by lower expression levels of Iba-1 and GFAP. In addition to central effects, ZNJN alleviated colonic inflammation and improved mucosal integrity. Systemic inflammatory responses were also suppressed, with significant reductions in serum levels of TNF-α, IL-6, IL-1β, and LPS. Furthermore, 16S rRNA gene sequencing showed that ZNJN modulated the gut microbiota by decreasing the abundance of pro-inflammatory genera and enriching potentially beneficial. These findings suggest that ZNJN exerts neuroprotective effects by modulating the gut microbiota and reducing neuroinflammation through the gut-brain axis. These findings suggest that ZNJN exerts neuroprotective effects by modulating the gut microbiota and reducing neuroinflammation through the gut-brain axis. This study provides experimental evidence supporting the potential of ZNJN as a multi-target therapeutic agent for AD intervention.},
}

@article {pmid41704186,
year = {2026},
author = {Piquero Lanciego, C and Tan, WY and Tee, M and Robert, C and Chen, C and Hilal, S},
title = {Brain age prediction in a multiethnic Asian population: A comparison of machine learning algorithms and their application for early-stage cognitive impairment diagnosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418556},
doi = {10.1177/13872877261418556},
pmid = {41704186},
issn = {1875-8908},
abstract = {BackgroundNeuroimaging-derived brain age is a promising biomarker of early neurodegeneration, but methodological variation in machine learning (ML) algorithms and input features as well as scarce evidence from various ethnic populations limit clinical translation.ObjectiveTo identify an accurate and interpretable machine learning-based brain age model for a multiethnic Asian population and examine its utility as a biomarker of early cognitive declineMethodsNine brain age prediction models were developed using 406 cognitively normal individuals (45-86 years) from two population-based studies using structural MRI features. Prediction performance was evaluated using mean absolute error (MAE) and Pearson's correlation coefficient (R[2]). Feature importance was assessed using the SHapley Additive exPlanations (SHAP) analysis based on best performing model. The model was applied to an independent cohort with no cognitive impairment (NCI), mild and moderate cognitive impairment no dementia (CIND), and dementia. Differences in BrainAGE across cognitive groups were examined using an ANOVA test.ResultsThe chosen ensemble model, comprised of linear regression, lasso and SVR, was trained on 17 features (11 subcortical volumes and 6 lobe-level cortical thickness measures) and achieved an overall bias-corrected MAE and R[2] of 4.04 years and 0.59 respectively. Feature importance analysis found thalamic, lateral ventricle, accumbens area and gray matter volume as important features for brain age prediction.ConclusionsAn interpretable ensemble ML model using structural MRI provides a robust BrainAGE biomarker capable of detecting early cognitive decline in multiethnic Asian populations.},
}

@article {pmid41704175,
year = {2026},
author = {Sun, Z and Han, J and Liu, H and Zeng, H and Li, R and Ji, W and Mao, D and Tian, X and Shang, Q},
title = {Characteristic activation pattern and network connectivity of brain in type 2 diabetes mellitus patients with mild cognitive impairment: A functional near-infrared spectroscopy study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418992},
doi = {10.1177/13872877261418992},
pmid = {41704175},
issn = {1875-8908},
abstract = {BackgroundType 2 diabetes mellitus (T2DM) and mild cognitive impairment (MCI) are prevalent conditions in the aging population, with growing evidence indicating a synergistic detrimental effect on brain function when comorbid. However, the distinct neurofunctional signatures of comorbid T2DM-MCI remain poorly characterized.ObjectiveThis study aimed to investigate the characteristic brain activation patterns and functional network connectivity in elderly patients with comorbid T2DM-MCI, compared to those with T2DM alone or MCI alone.MethodsIn this cross-sectional study,75 elderly participants (T2DM = 25, MCI = 25, T2DM-MCI = 25) underwent functional near-infrared spectroscopy (fNIRS) during a verbal fluency task, a 2-back task, single walking, and a dual-task (2-back while walking), followed by 8-min resting-state recording. Task-evoked cortical activation and resting-state functional connectivity were analyzed and compared across groups.ResultsDuring cognitive tasks, the T2DM-MCI group showed significantly reduced activation in prefrontal and motor cortices compared to single-disease groups. Dual-task performance specifically revealed hypoactivation in ventrolateral prefrontal and occipital regions in T2DM-MCI. Resting-state analysis demonstrated globally diminished functional connectivity in T2DM-MCI, particularly within prefrontal-motor networks and interhemispheric connections, whereas no significant differences were found between T2DM and MCI groups alone.ConclusionsComorbid T2DM-MCI exhibits a unique dual-pathology profile characterized by concurrent reductions in task-evoked activation and resting-state network connectivity, suggesting compromised neural efficiency from synergistic metabolic and neurodegenerative processes. These impairments may serve as sensitive biomarkers for early detection of diabetes-associated cognitive decline.Trial registration: The Chinese Clinical Trial Registry (ChiCTR) registration # ChiCTR2400084469 (https://www.chictr.org.cn).},
}

@article {pmid41704171,
year = {2026},
author = {Li, X and Zhang, Y and Shi, X and Li, D and Yang, W and Ma, A},
title = {A novel presenilin 1 nucleotide mutation (M139I) and its pathological function in a Chinese family with early-onset Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418314},
doi = {10.1177/13872877261418314},
pmid = {41704171},
issn = {1875-8908},
abstract = {BackgroundThe majority of early-onset familial Alzheimer's disease is caused by mutations in the presenilin 1 (PSEN1) gene.ObjectiveTo investigate the pathogenic mechanism of the novel nucleotide mutations of the PSEN1 gene in early-onset familial Alzheimer's disease.MethodsWe describe a Chinese family with autosomal dominant early-onset Alzheimer's disease. Gene sequencing revealed that the 417th nucleotide in the exon 5 of the PSEN1 gene had changed from G to C. This resulted in methionine being substituted by isoleucine at codon 139. To support that the novel mutation was pathological, we transfected lentiviruses that overexpressed wild-type and mutant PSEN1 gene sequences into SH-SY5Y cells to construct a cell model.ResultsThe present study showed that the PSEN1 M139I mutation led to an increase in the Aβ42/Aβ40 ratio. In addition, this mutation induced the expression of β-site APP-cleaving enzyme 1 (BACE-1). Analysis of the steady-state mechanism showed that the PSEN1 M139I mutation cells were more susceptible to endoplasmic reticulum stress and apoptosis under hydrogen peroxide induction than the wild type cells were.ConclusionsIn this study, we demonstrate that the PSEN1 M139I nucleotide mutation a new mutation that, can increase the ratio of intracellular Aβ42 and Aβ42/Aβ40, and increase endoplasmic reticulum stress to promote apoptosis. This supports that the PSEN1 M139I mutation is a pathological mutation.},
}

@article {pmid41703957,
year = {2026},
author = {Özkurt, Ç and Kelicen-Uğur, P},
title = {Prognostic Value of Plasma NfL and GFAP for Conversion to Alzheimer's Disease and Dementia in MCI: A Systematic Review and Robust Bayesian Meta-Analysis.},
journal = {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/1354750X.2026.2633568},
pmid = {41703957},
issn = {1366-5804},
abstract = {BACKGROUND: Accessible biomarkers to predict conversion to Alzheimer's disease and other dementias in Mild Cognitive Impairment (MCI) are urgently needed. Plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) are leading candidates, but their utility remains debated.

OBJECTIVE: We systematically reviewed the prognostic value of plasma NfL and GFAP in MCI using Robust Bayesian Meta-Analysis (RoBMA) to formally model and adjust for publication bias.

METHODS: We searched major databases through September 2025 for longitudinal cohort studies (Protocol: OSF 10.17605/OSF.IO/974ZD). RoBMA synthesized hazard ratios while adjusting for small-study effects. Risk of bias (QUIPS) and certainty (GRADE) were assessed.

RESULTS: We included 63 studies. For plasma GFAP (k = 3), Bayesian meta-analysis found moderate evidence for an association with dementia conversion (HR: 1.58, 95% CrI [1.00, 2.24]; Inclusion BF = 9.03). Conversely, for plasma NfL, the prognostic signal was driven by decisive publication bias (Bias BF > 4,000,000). After bias adjustment, the effect of NfL on conversion was null (HR: 1.00; Inclusion BF = 0.011). Evidence certainty was Low to Very Low.

CONCLUSIONS: The prognostic value of plasma NfL for dementia conversion appears to be an artifact of publication bias. Plasma GFAP shows a promising but preliminary signal requiring high-quality validation.},
}

@article {pmid41703636,
year = {2026},
author = {Genius, P and Fernández-Bonet, A and Rodríguez-Fernández, B and Gallay, C and Gonzalez-Escalante, A and Sánchez-Benavides, G and López-Martos, D and Esteller, M and Navarro, A and Gispert, JD and Brugulat-Serrat, A and Vilor-Tejedor, N and , },
title = {Sex-specific early cognitive changes are linked to global and pathway-specific genetic risk for Alzheimer's disease in at-risk individuals.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-025-00800-w},
pmid = {41703636},
issn = {2042-6410},
support = {(AACSF-23-1145154)./ALZ/Alzheimer's Association/United States ; RYC2022-038136-I//Spanish Ministry of Science and Innovation - State Research Agency/ ; Cohort I//William H. Gates Sr. Fellowship from the Alzheimer's Disease Data Initiative/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition in which genetic predisposition plays a key role, yet the sex-specific mechanisms linking genetic risk to early cognitive changes remain unclear. This study examined the impact of polygenic risk scores (PRS) on early cognitive changes in 318 cognitively unimpaired participants from the ALFA+ cohort, a nested longitudinal cohort from the ALFA study (see details in Study Participants Section, Methods). Participants were followed for three years, with assessments across five cognitive domains and a preclinical composite (PACC). Global AD PRS, including and excluding the apolipoprotein E (APOE) gene, alongside five biologically informed pathway-specific PRS (amyloid, immune, external stimuli signaling, cholesterol efflux, lipoprotein metabolism) were computed. Generalized linear models including interaction by sex and stratified by sex and amyloid status (CSF Aβ42/40 < 0.071) assessed associations between PRS and cognitive change. In women, APOE-independent AD genetic risk predicted worse executive function, particularly via cholesterol efflux and external stimuli signaling pathways. Among Aβ + women, PRS also predicted lower memory performance, partially modulated by reproductive span. In Aβ - women, worse executive functioning performance was linked to amyloid, immune, and signaling pathways. In contrast, men showed associations between AD PRS and worse visual (Aβ-) and attentional (Aβ+) performance, independent of pathway-specific mechanisms. These findings reveal distinct, domain-specific cognitive vulnerabilities to AD genetic risk by sex and amyloid status, highlighting APOE-independent and mechanistic contributions to early and subtle cognitive changes. Results support the need for sex-aware, biologically informed genetic models in preclinical AD for risk stratification and early intervention.},
}

@article {pmid41703303,
year = {2026},
author = {De Schepper, S and Ge, JZ and Sierksma, A and Crowley, G and Ferreira, LSS and Garceau, D and Toomey, CE and Sokolova, D and Rueda-Carrasco, J and Shin, SH and Kim, JS and Childs, T and Lashley, T and Burden, JJ and Sasner, M and Sala Frigerio, C and Jung, S and Hong, S},
title = {Author Correction: Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41593-025-02197-6},
pmid = {41703303},
issn = {1546-1726},
}