@article {pmid41792880,
year = {2026},
author = {Zahran, A and Abu-Khazneh, O and Bdair, M and Hajjeh, O and AbuBaha, M and Shehadeh, W and Awashra, A and Alazizi, I and Fuqha, R and Saife, S and Fuqha, H and Milhem, F and Hamshary, H and Abuzahra, D and Shuaib, U},
title = {Glymphatic System Dysfunction in Central Nervous System Diseases.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {3},
pages = {e70810},
doi = {10.1002/cns.70810},
pmid = {41792880},
issn = {1755-5949},
abstract = {BACKGROUND: The glymphatic system is a perivascular cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange pathway that supports brain homeostasis by clearing metabolic waste and neurotoxic proteins. Across central nervous system diseases, converging evidence indicates that glymphatic dysfunction represents a shared pathophysiological axis linking vascular, astroglial, inflammatory, and sleep-related disturbances to impaired solute clearance.

RESULTS AND CONCLUSION: In this review, we synthesize mechanistic and clinical evidence for glymphatic impairment in acute brain injury (ischemic and hemorrhagic stroke, traumatic brain injury) and chronic neurological disorders (Alzheimer's disease, Parkinson's disease, cerebral small vessel disease, multiple sclerosis, idiopathic normal pressure hydrocephalus, idiopathic intracranial hypertension, epilepsy, and headache disorders). Major mechanisms include (i) aquaporin-4 (AQP4) depolarization/mislocalization at astrocytic endfeet, reducing perivascular water transport; (ii) perivascular space compression or obstruction from cytotoxic/vasogenic edema, blood-derived products, protein aggregates, or altered extracellular matrix; (iii) loss of arterial pulsatility and vascular stiffening, weakening the driving forces for convective exchange; (iv) blood-brain barrier disruption and neuroinflammation, which remodel perivascular architecture and amplify clearance failure; and (v) sleep and autonomic dysregulation, including altered noradrenergic tone, which suppresses glymphatic activity during periods when clearance is normally maximal. Clinically, glymphatic dysfunction can be probed using diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS), contrast-enhanced MRI approaches, and structural surrogates such as enlarged perivascular spaces, with emerging associations to cognition, mood, and disease severity. Finally, we discuss translational strategies aimed at restoring clearance, including sleep/circadian optimization, vascular risk control, anti-inflammatory approaches, AQP4- and TRPV4-oriented targets, and neuromodulation. Mechanism-guided, standardized imaging and longitudinal interventional studies are needed to establish glymphatic biomarkers as actionable therapeutic and prognostic tools.},
}

@article {pmid41792827,
year = {2026},
author = {Mastrangelo, A and Caldera, S and Baiardi, S and Magliocchetti, F and Mammana, A and Testa, M and Ranieri, A and Ruggeri, E and Bentivenga, GM and Mastrangelo, V and Mometto, N and Ferri, C and Marti, A and Santangelo, M and Longoni, M and Mazzoli, S and Chiari, A and Biscetti, L and Capellari, S and Parchi, P},
title = {Prevalence and clinical effects of Lewy Body pathology in non-prion rapidly progressive dementias: a retrospective cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02004-9},
pmid = {41792827},
issn = {1758-9193},
support = {MNESYS (PE0000006)//Ministero dell'Università e della Ricerca/ ; RF-2021-12374386//Ministero della Salute/ ; },
}

@article {pmid41792667,
year = {2026},
author = {Kiene, F and Notbohm, A and Roheger, M and Duning, T and Hildebrandt, H},
title = {Cognitive tests distinguish biomarker-verified early Alzheimer's disease from other patients.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04742-7},
pmid = {41792667},
issn = {1471-2377},
}

@article {pmid41792456,
year = {2026},
author = {Abdulkhaliq, AA and Alasiri, G and Kim, B and Khan, J and Ajoolabady, A and Yousof, SM and Ren, J and Tuomilehto, J and Borai, A and Alrfaei, BM and Pratico, D},
title = {TREM2 in neurodegeneration and diseases.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41792456},
issn = {1476-5578},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface transmembrane receptor from the TREM receptor family, predominantly expressed on the microglia in the central nervous system (CNS). TREM2-initiated signaling plays a crucial role in regulating neuroinflammation and neurodegeneration, particularly in the context of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), through the activation of downstream signaling pathways and transcriptional regulation of relevant genes. In this review, we aim to provide a concise review of the role and mechanistic implications of TREM2 in neurodegeneration and neuroinflammation, with a specific focus on AD and PD. We will discuss the most recent preclinical studies to highlight current advancements in the field. This review is intended to support both basic researchers and clinicians by enhancing their understanding of microglial function in the pathophysiology of AD and PD, as well as its role in neuroinflammation and neurodegeneration. Ultimately, we hope this contribution will pave the way for new discoveries and the development of potential therapeutic interventions.},
}

@article {pmid41792386,
year = {2026},
author = {Kaczmarek, B and Ilkowska-Adamczewska, Z and Remlinger-Molenda, A and Kaluzniak-Szymanowska, A and Stachnik, K and Wieczorowska-Tobis, K and Tobis, S},
title = {The use of screening tests in panel studies to monitor cognitive functioning in senior participation programme groups using ACE-III and M-ACE.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-42595-9},
pmid = {41792386},
issn = {2045-2322},
}

@article {pmid41792369,
year = {2026},
author = {Huang, S and Zhang, T and Wang, Y and Du, H and He, J and Zeng, H and Ma, L and Deng, D and Zhou, Y and Liu, S and Zhao, W and Yang, X and Han, L and Zhao, S and Shu, S and Yao, S and Zhong, Q and Chen, X and Wang, J},
title = {Interaction between transient receptor potential vanilloid 4 and glutamate NMDA receptor subunit 1 mediates endoplasmic reticulum stress and neuroinflammation in postoperative delirium.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {41792369},
issn = {2662-8651},
support = {82471504//National Natural Science Foundation of China/ ; 32271148//National Natural Science Foundation of China/ ; 82471251//National Natural Science Foundation of China/ ; 82201350//National Natural Science Foundation of China/ ; 82401847//National Natural Science Foundation of China/ ; 23SWAQ24//Biosecurity Research Project/ ; 2024MZFS002//Research Grant of Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education/ ; },
abstract = {Postoperative delirium (POD) is a serious and prevalent neurocognitive complication that poses a major clinical challenge because its mechanism is unclear. This study identifies a pathogenic pathway centred on the direct interaction between transient receptor potential vanilloid 4 (TRPV4) and the essential N-methyl-D-aspartate receptor (NMDAR) subunit GluN1. Using a murine POD model, the neuron-centric glutamatergic dysfunction in the hippocampus was initially confirmed through ex vivo metabolic kinetic analysis. Transcriptomic analysis revealed upregulation of Trpv4, predominantly in neurons. Co-immunoprecipitation coupled with mass spectrometry revealed that TRPV4 directly interacts with GluN1. This enhanced TRPV4-GluN1 coupling promoted GluN1 phosphorylation at serine 896 and hyperactivated NMDAR signalling. We subsequently observed the concurrent induction of endoplasmic reticulum (ER) stress, as evidenced by a dilated ER ultrastructure and the upregulation of the expression of UPR markers (ATF6, p-PERK, p-IRE1α, and CHOP), as well as neuroinflammation, characterized by microglial activation and elevated expression of proinflammatory mediators (IL-6, IL-1β, and ICAM-1). These molecular pathologies were associated with decreased neuronal activity and the characteristic cognitive-affective deficits associated with POD. Critically, both pharmacological inhibition of TRPV4 (HC067047) and hippocampal CA3-specific Trpv4 knockdown reversed these pathologies and rescued the behaviour. Inhibiting NMDAR with MK801 recapitulated these therapeutic benefits. Furthermore, TRPV4 was significantly upregulated in early-onset Alzheimer's disease patients. Our study defines a novel TRPV4-GluN1 axis that drives POD pathogenesis, suggesting that it is a promising therapeutic target.},
}

@article {pmid41792330,
year = {2026},
author = {Song, Z and Hu, H and Zhang, W and Zheng, X and Liang, L and Zhao, B and Song, G and Li, J and Li, S and Wen, Y and Zhang, B and Wang, W and Deng, G and Zhang, C and Jiang, H and Hu, S and Tu, H and Wu, M and Li, H},
title = {The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41792330},
issn = {2662-8465},
support = {32341003//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.},
}

@article {pmid41792234,
year = {2026},
author = {Yu, H and Wang, F and Yuan, JQ and Chen, J and Zhang, KY and Jia, D and Gong, J and Mao, Y and Bi, S and Zhang, YQ and Lan, ZC and Yu, HY and Chai, GS},
title = {HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer's disease.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41792234},
issn = {2092-6413},
support = {82401671//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82505712//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81601121//National Natural Science Foundation of China (National Science Foundation of China)/ ; BK20211238//Natural Science Foundation of Jiangsu Province (Jiangsu Provincial Natural Science Foundation)/ ; },
abstract = {Ketogenic diet (KD) can significantly ameliorate cognition in Alzheimer's disease (AD), but the specific mechanism is not clear. Histone3-lysine9-β-hydroxybutyrylation (H3k9bhb), a novel histone modification mark induced by ketogenesis-generated β-hydroxybutyrate (β-OHB), may be involved in the prevention and treatment of AD. Here we report that β-OHB and H3K9bhb were reduced in the hippocampus of triple transgenic AD male mice (3xTg-AD) mice. Reduced H3K9bhb levels were also observed in patients with AD. The 3xTg-AD mice exhibited a low enrichment of H3K9bhb on the promoters of NMDA receptor subunits and Syn1 and axon-related genes together with impaired synaptic plasticity, all of which were rescued by 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2, a rate-limiting enzyme of β-OHB synthesis) upregulation. Moreover, β-OHB replenishment enhanced H3K9bhb in 3xTg-AD mice, leading to an increase of NMDA receptor subunits and Syn1 and cognitive function in an HMGCS2-dependent manner. Thus, HMGCS2 is a key molecular switch of cognitive impairment, and targeting HMGCS2 or β-OHB replenishment appropriately may serve as a novel therapeutic strategy for AD treatment.},
}

@article {pmid41792133,
year = {2026},
author = {Xu, Q and Li, G and Zhang, H and Jiang, Z and Gao, X and Li, Z and Langhi Prata, LGP and Kirkland, JL and Zhang, G and Sun, Y},
title = {The natural flavonoid dihydromyricetin targets senescent cells via PRDX2 and alleviates age-related diseases.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-70302-9},
pmid = {41792133},
issn = {2041-1723},
support = {82130045, 82350710221 and 82571777//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Aging is a primary risk factor for chronic diseases, with cellular senescence as an effective target to delay, prevent or alleviate age-related disorders. Here we report in vitro screening outputs from a natural medicinal agent library, wherein dihydromyricetin, a natural flavonoid, showed senotherapeutic potential. Dihydromyricetin protects senescent fibroblasts against further DNA damage and attenuates the senescence-associated secretory phenotype, acting as a senomorphic agent. Proteomics suggests that dihydromyricetin promotes nuclear translocation of peroxiredoxin 2 (PRDX2) to facilitate DNA repair in senescent cells. In prematurely aged mice, dihydromyricetin administration mitigates tissue aging and age-related physiological decline. In anticancer regimens, dihydromyricetin improves outcomes of chemotherapy. However, dihydromyricetin demonstrates senolytic activity against senescent microglial cells, whose basal PRDX2 expression remains low, by impairing mitochondrial function to promote apoptosis. In mice developing Alzheimer's disease, dihydromyricetin eliminates senescent microglial cells from amyloid β-protein plaques and alleviates neurodegenerative symptoms. Together, our study proposes dihydromyricetin as a natural senotherapeutic agent for mitigating age-related morbidities, including but not limited to cancers and Alzheimer's disease.},
}

@article {pmid41792131,
year = {2026},
author = {Cao, Y and Willis, BA and Horie, K and Wildsmith, KR and Koyama, A and Sachdev, P and Penner, N and Charil, A and Irizarry, M and Reyderman, L},
title = {Neuro-Dynamic Quantitative Systems Pharmacology (QSP) model describing Alzheimer's disease pathophysiology and treatment effects.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00677-4},
pmid = {41792131},
issn = {2056-7189},
abstract = {Lecanemab, an anti-amyloid antibody, has demonstrated a significant clinical benefit in slowing cognitive decline in early Alzheimer's disease (AD). A mechanistic Neuro-Dynamic Quantitative Systems Pharmacology (QSP) model was developed to capture the temporal and biological complexity of AD progression. This QSP model incorporates three interlinked modules reflecting core aspects of AD pathology: Aβ accumulation, tau pathology, and cognitive decline, where Aβ accumulation promotes tau pathology, which leads to neuronal damage and cognitive impairment. A large multivariate dataset was assembled from 4056 subjects participating in lecanemab studies and the Alzheimer's Disease Neuroimaging Initiative (ADNI) to inform and validate the model. Virtual populations-based model simulations successfully reproduced the hallmark cascade of AD pathology, consistent with the well-known Jack curve, from amyloid buildup to tau spread and cognitive decline over decades. Simulations accurately predicted all endpoints evaluated from the lecanemab trials and were further validated against data from other anti-Aβ therapies. Importantly, the model revealed that Aβ protofibrils are more potent drivers of tau pathology than plaques. In summary, the Neuro-Dynamic QSP model is the first of its kind to mechanistically link amyloid accumulation, tau pathology, and cognitive decline in AD, providing a powerful framework for simulating clinical scenarios and understanding disease mechanisms.},
}

@article {pmid41791567,
year = {2026},
author = {Guo, P and Zhao, J and Wang, C and Bai, Y and Zhang, B and Liu, A},
title = {Effect of DL0410 and tetrahydrocurcumin (LG0367) alone and in combination on learning and memory in vascular dementia.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178730},
doi = {10.1016/j.ejphar.2026.178730},
pmid = {41791567},
issn = {1879-0712},
abstract = {Vascular dementia (VaD) is one of the most common neurodegenerative diseases, and there is no effective therapy to prevent or cure VaD to date. 1,1'-(1,1'-Biphenyl-4,4'-diyl)bis(3-piperidino-1-propanone) dihydrochloride (DL0410) is a novel multi-target small-molecule drug against Alzheimer's disease (AD), with particularly outstanding acetylcholinesterase (AChE) inhibitory activity and Histamine H3 receptor (H3R) inhibitory activity. Natural derivative 1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (LG0367) is a metabolite of curcumin. Previous studies have demonstrated that LG0367 exhibited better pharmacokinetic properties and therefore displayed better pharmacological activity than curcumin. Here, using bilateral common carotid artery occlusion (2VO) rat model, we found that the combined treatment of DL0410 and LG0367 had a much better effect on improving cognitive function in rats than single-drug treatment or donepezil, suggesting a synergistic effect between the small-molecule drug DL0410 and the natural derivertive LG0367. In addition, we found that the combined DL0410 and LG0367 treatment had significant synergic effects on inhibiting AChE production in cortex of 2VO rats. Furthermore, compound-target network and enrichment analyses revealed that DL0410 and LG0367 exhibit synergistic potential against VaD based on multiple mechanisms. In addition, the study also showed that the combination treatment had remarkable synergic effects on decreasing inflammatory responses and oxidative stress, protecting mitochondrial structure, reducing the release of astrocytes, and decreasing neuronal damage and activating the expression of SHH protein in the cortex and hippocampus of 2VO rats. Our findings not only demonstrated a potent synergistic effect between the synthetic small-molecule DL0410 and the natural derivative LG0367, but also illuminate a promising "symptom-to-root" therapeutic strategy for VaD, providing a systematic and evidence-based model for modernizing phytotherapy. Ultimately, this study will provide important information for future clinical trials aimed at translating this synergistic combination into a tangible "multi-target, multi-mechanism" treatment option for VaD patients.},
}

@article {pmid41791565,
year = {2026},
author = {Cui, J and Huang, R and Dong, X},
title = {Efficacy and mechanisms of Icariin in the treatment of Alzheimer's disease: a systematic review and Meta-analysis of a preclinical study.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178706},
doi = {10.1016/j.ejphar.2026.178706},
pmid = {41791565},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition that predominantly affects elderly individuals, characterised by progressive cognitive dysfunction, memory impairment and behavioural changes. Icariin (ICA), the primary active ingredient of the traditional Chinese medicine Epimedium spp., has demonstrated significant potential in the treatment of neurological disorders. Nevertheless, the precise mechanisms through which it exerts its anti-AD effects remain to be elucidated. And this meta-analysis aimed to discuss the mechanisms by which ICA exerts its anti-AD effects and the differences in the efficacy of different doses of ICA by evaluating behavioral indicators and biochemical characteristics. A total of 31 pre-clinical studies were included, and the results showed that ICA treatment significantly improved cognitive dysfunction in animal models of AD in terms of resistance to neurotoxic substances, inhibition of oxidative stress, anti-inflammation, inhibition of apoptosis, modulation of neuronal autophagy, and protection of nerves to promote regeneration. Furthermore, 68 mg/kg of ICA was identified as the most effective doses in terms of improving cognition. However, further research is required, incorporating studies of higher quality and larger sample sizes, in addition to clinical trials, in order to verify the efficacy and safety of this approach in neurological disorders.},
}

@article {pmid41791447,
year = {2026},
author = {Pettis, JA and Orshoski, M and Pal, S and Allen, AM and Ortega Zepeda, M and Wysocki, VH and Kuret, J},
title = {Efficient tag-less purification of recombinant human tau proteins.},
journal = {Analytical biochemistry},
volume = {},
number = {},
pages = {116095},
doi = {10.1016/j.ab.2026.116095},
pmid = {41791447},
issn = {1096-0309},
abstract = {Tau proteins normally function as part of the neuronal cytoskeleton but aggregate to form filamentous inclusions in tauopathies such as Alzheimer's disease. The diverse functions of tau protein are frequently interrogated using biochemical assays that require highly purified tau as substrate. Conventional recombinant tau purification leverages polyhistidine (His6) tags to enable rapid and efficient isolation through immobilized metal affinity chromatography (IMAC). Preparation of native tau by this approach requires removal of His6 tags through additional processing steps. Here we report a protocol for purifying native recombinant full-length tau protein that retains the speed, convenience, broad availability and scalability of IMAC while eliminating the need for post-purification proteolytic cleavage. The method has been validated across a wide array of tau constructs, including full-length isoforms, missense mutants, and a truncation construct containing an aggregation-prone region of the microtubule-binding domain. Owing to its scalability and reproducibility, the method is well suited for structure-activity relationship investigations involving curated tau variant libraries.},
}

@article {pmid41791248,
year = {2026},
author = {Yuki, A and Nishita, Y and Nakamura, A and Kato, T and Tange, C and Zhang, S and Ando, F and Shimokata, H and Otsuka, R},
title = {Ten-year longitudinal effects of physical activity and apolipoprotein E ..4 genotype on precuneus atrophy in Japanese older adults.},
journal = {Archives of gerontology and geriatrics},
volume = {145},
number = {},
pages = {106194},
doi = {10.1016/j.archger.2026.106194},
pmid = {41791248},
issn = {1872-6976},
abstract = {BACKGROUND: The apolipoprotein E ε4 (APOE ε4) allele, a major genetic risk factor for Alzheimer's disease, is associated with early atrophy in the precuneus and posterior cingulate cortex. Whether physical activity can mitigate this atrophy in high-risk APOE ε4 carriers remains unclear. This study aimed to determine whether physical activity can reduce such neurodegenerative changes in older adults carrying this allele.

METHODS: This 10-year longitudinal study included 295 community-dwelling older adults (154 men and 141 women; age ≥65 years). Baseline physical activity was measured using accelerometers and analyzed according to activity intensity. Participants were categorized as APOE ε4 carriers or non-carriers. Volumes of the precuneus and posterior cingulate cortex were assessed using longitudinal magnetic resonance imaging. Sex-stratified linear mixed models examined the interaction between physical activity and APOE ε4 status on brain volume changes, adjusting for relevant covariates.

RESULTS: The moderate-to-vigorous physical activity (MVPA) × APOE ε4 × year effect in women's left precuneus was significant unadjusted but not after false discovery rate (FDR; 16 models) and exploratory. Left precuneus volume declined significantly over 10 years regardless of MVPA level or APOE ε4 genotype (each p < 0.0001). However, among APOE ε4 carriers, greater time spent in MVPA slowed the rate of volume decline. No similar effect was observed in men.

CONCLUSIONS: Higher habitual MVPA may be associated with slower left precuneus decline in APOE ε4-positive women. As this exploratory three‑way effect was FDR‑nonsignificant, targeted replication is needed to clarify the role of everyday activity in genetically vulnerable groups.},
}

@article {pmid41791120,
year = {2026},
author = {Peng, Y and Yao, SY and Wu, SL and Yang, H and Zhang, X and Kazuo, S and Liu, J and Du, MQ and Lin, LX and Kang, XH and Jiang, DY},
title = {New Perspective: Bench to Bedside Evidence of the Role of CD8+ T Cells in Alzheimer's Disease.},
journal = {Immunity, inflammation and disease},
volume = {14},
number = {3},
pages = {e70380},
doi = {10.1002/iid3.70380},
pmid = {41791120},
issn = {2050-4527},
support = {C202303076574//Scientific Research Project of the Hunan Provincial Health Commission, People's Republic of China/ ; 2023039//Key Plans of Hunan Administration Traditional Chinese Medicine, PR China/ ; 2022XYLH19//University-Hospital Joint Fund of Hunan University of Chinese Medicine, PR China/ ; 2021B-003//Fund for Creative Research Groups at the Affiliated First Hospital of Hunan Traditional Chinese Medical College, PR China/ ; 2021-009//Technology Plan Project of Zhuzhou City, Hunan Province, PR China/ ; //Fund for Research Chief of Clinical Department of Affiliated First Hospital of Hunan Traditional Chinese Medical College, PR China/ ; },
abstract = {INTRODUCTION: Amyloid beta plaques and tau tangles are the primary hallmarks of Alzheimer's disease (AD). Recently, passive anti-Aβ immunotherapy for AD has markedly advanced, as supported by evidence from AD animal models and clinical trials. Whereas innate immunity significantly contributes to AD pathology, it does not fully represent the immune mechanisms linked to this condition. Therefore, focus should be directed toward adaptive immunity, encompassing both humoral and cellular immunity.

METHODS: Relevant publications and clinical trial data up to February 2026 were systematically reviewed to summarize the mechanisms, therapeutic targets, safety profiles, and translational applications of CD8+ T cells in AD.

RESULTS: Clinical and animal studies have particularly suggested a potential involvement of T cells in AD pathogenesis. T cells that infiltrate the central nervous system (CNS) exert both protective and detrimental effects on neural tissue in AD. Because autoreactive CD8+ T cells are generally expected to have cytotoxic effects on CNS cells, they have received less attention. Nevertheless, accumulating evidence suggests that CD8+ Treg cells are involved in various diseases.

CONCLUSION: However, the function of anti-Aβ-specific CD8+ T cells in Alzheimer's disease (AD) remains ambiguous. Many subsets of CD8+ T cells have been well-studied in autoimmunity. We suggest that CD8+ T cell subsets identified in AD studies may constitute a promising area for future AD research.},
}

@article {pmid41791118,
year = {2026},
author = {Al-Hindawi, F and Wu, T and Wen, Y and Serhan, P and Forzani, E and Tsow, F and Geda, YE},
title = {Leveraging Naturalistic Driving Digital Biomarkers for Early Mild Cognitive Impairment Detection: Deep Learning Strategies.},
journal = {JMIR medical informatics},
volume = {14},
number = {},
pages = {e83622},
doi = {10.2196/83622},
pmid = {41791118},
issn = {2291-9694},
abstract = {BACKGROUND: Alzheimer disease and related dementias are increasing worldwide, with early detection during the mild cognitive impairment (MCI) stage critical for timely intervention. Driving behavior, which reflects everyday cognitive functioning, has emerged as a promising, noninvasive, and inexpensive digital biomarker when paired with machine learning. However, prior research has often relied on controlled settings, high-level features, or assumptions that fail to capture the sporadic nature of MCI, leaving a gap in modeling naturalistic driving data for robust early detection.

OBJECTIVE: This study aims to address the limitations of prior work by developing deep learning strategies that leverage driving data collected in a naturalistic setting as digital biomarkers for early detection of MCI.

METHODS: Clinically classified participants (8 with MCI and 14 cognitively normal; N=22) drove their personal vehicles under naturalistic conditions for several consecutive days. A total of 3 participants (2 cognitively normal and 1 MCI) withdrew before completing the experiments. In-vehicle sensors recorded GPS, accelerometer, and gyroscope signals, which were segmented into full trips and turning maneuvers. Three modeling strategies were compared: (1) single-view, (2) feature-level fusion, and (3) model-level late fusion. Classification models were trained and evaluated to assess their accuracy, discriminative ability, and participant-level performance.

RESULTS: Models using full-trip data consistently outperformed turn-only inputs, with the best-performing model achieving 78% accuracy and an area under the receiver operating characteristic curve of 77%. Turn-based inputs alone demonstrated limited discriminative power; however, combining them with trip data through late fusion improved performance, though not beyond the full-trip baseline. Participant-level analysis indicated that classification accuracy improved with increased data volume, and trip-wise modeling more effectively captured the episodic nature of MCI than majority-vote aggregation. A frequency-based risk score was proposed as an interpretable and flexible output, enabling practical application in clinical and community settings.

CONCLUSIONS: Naturalistic driving behavior offers a scalable and noninvasive approach for early cognitive screening. Deep learning models using full-trip naturalistic driving data show promise for detecting MCI, with fusion strategies providing supplementary insights. This framework supports proactive, real-world monitoring of cognitive decline, laying the foundation for digital health interventions in dementia prevention.},
}

@article {pmid41791097,
year = {2026},
author = {Salma, SU and Renduchintala, CR and Siddique, I and Sterling, E and Sneha, S and Sakib, N},
title = {AI-Driven Mental Health Support for Caregivers of Individuals With Alzheimer Disease: Systematic Literature Review and Development of a Conceptual Framework.},
journal = {JMIR mental health},
volume = {13},
number = {},
pages = {e79973},
doi = {10.2196/79973},
pmid = {41791097},
issn = {2368-7959},
abstract = {BACKGROUND: Caregivers supporting individuals with Alzheimer disease and related dementias (AD/ADRD) frequently encounter prolonged emotional strain, psychological distress, and social isolation, yet their needs are largely overlooked in current technological and clinical interventions. The special routines and obligations of caregivers of individuals with AD/ADRD are frequently not well-suited to the many artificial intelligence-driven (AI-driven) mental health solutions that are currently available. This reveals a critical need for sophisticated, customized solutions created especially to help the mental health of caregivers for patients with AD/ADRD.

OBJECTIVE: To address the existing limitations of personalized mental health interventions, we aimed to identify existing literature on personalized mental health interventions using AI for specific purposes and to develop a new framework for the caregivers of individuals with AD/ADRD.

METHODS: We followed an iterative approach to design the new framework. First, we did a systematic literature review of current literature to identify data analysis, AI methods, and personalized interventions. Second, we focused on the underlying gaps of this research, and by synthesizing our findings from the review, we proposed a conceptual framework.

RESULTS: The systematic literature review identified 73 unique results, and from external sources, we found 3 unique potential papers. Of these, 28 papers were eligible for inclusion, on which we performed our analysis. Based on the findings, we developed a new conceptual framework with 3 special features that are specifically for caregivers of patients with AD/ADRD. The 3 unique features are a personalized daily routine scheduler, which will take both patients with AD/ADRD and caregiver's information to make it personalized, a daily reward system to keep patients motivated, and an educational repository to get the bite-sized knowledge for the lesson of handling patients in an efficient manner and taking care of one's own mental health.

CONCLUSIONS: The proposed framework provides a chance for caregivers to receive mental health care, which will be personalized. The framework is developed with more updated methods than existing approaches, with a lack of personalization in this sector. This framework can be implemented with a goal of personalization and explainable approaches and can undergo further iterations to ensure it is appropriate for specific purposes.},
}

@article {pmid41790889,
year = {2026},
author = {Smits, JFM and Ligthart, TW and Jorge-Oliva, M and Middelhoff, S and Schipper, F and Pita-Illobre, D and Li, KW and Scheper, W},
title = {Neurons with granulovacuolar degeneration bodies are resilient to tau-induced protein synthesis impairment.},
journal = {Science advances},
volume = {12},
number = {10},
pages = {eaea8940},
doi = {10.1126/sciadv.aea8940},
pmid = {41790889},
issn = {2375-2548},
abstract = {In Alzheimer's disease, many surviving neurons with tau pathology contain granulovacuolar degeneration bodies (GVBs), neuron-specific lysosomal structures induced by pathological tau assemblies. This could indicate a neuroprotective role for GVBs; however, the mechanism of GVB formation and its functional implications are elusive. Here, we demonstrate that casein kinase 1δ (CK1δ) activity is required for GVB formation. CK1δ is sequestered in the GVB during this process in an autophagy-dependent manner. We show that neurons with GVBs (GVB[+]) are resilient to tau-induced impairment of global protein synthesis and are protected against tau-mediated neurodegeneration. GVB[+] neurons do not exhibit differential activation of transient translational stress responses but have increased ribosomal content. Unlike neurons without GVBs, GVB[+] neurons fully retain the capacity to induce long-term potentiation-induced protein synthesis in the presence of tau pathology. Our results have identified CK1δ as a key regulator of GVB formation that confers a protective neuron-specific stress response to tau pathology. These findings provide opportunities for targeting neuronal resilience in tauopathies.},
}

@article {pmid41790841,
year = {2026},
author = {Mao, Z and Peng, Y and Lin, R and Guo, X and Cui, X and Yu, Y and Zheng, X},
title = {Association of intraindividual differences in estimated glomerular filtration rates based on cystatin C and creatinine with dementia: A cohort study of the UK Biobank.},
journal = {PloS one},
volume = {21},
number = {3},
pages = {e0344566},
doi = {10.1371/journal.pone.0344566},
pmid = {41790841},
issn = {1932-6203},
abstract = {BACKGROUND: Dementia is a leading cause of cognitive decline, with Alzheimer's disease (AD) and vascular dementia (VaD) being the most common subtypes. The intraindividual difference between the estimated glomerular filtration rate based on cystatin C and creatinine (eGFRdiff) may serve as an indicator of the overall health status of an individual. However, the relationships between the eGFRdiff and dementia risk, dementia subtypes, dementia-related neuroimaging changes, and cognitive functions remain unclear.

METHODS: This study analysed data from over 450,000 participants in the UK Biobank who were followed for up to 15 years. The estimated glomerular filtration rate based on cystatin C (eGFRcys) and creatinine (eGFRcr) was calculated using the CKD-EPI equation, and eGFRdiff was defined as the difference between these values (eGFRdiff = eGFRcys - eGFRcr). Multivariate Cox regression models were used to evaluate the associations between the eGFRdiff and all-cause dementia (ACD), AD, and VaD, whereas cross-sectional analysis were used to examine the relationship among the eGFRdiff, dementia-related neuroimaging changes, and cognitive functions.

RESULTS: Over a median follow-up of 13.5 years, 8,710 participants developed dementia, including 3,910 with AD and 1,893 with VaD. Each one standard deviation increase in eGFRdiff was associated with a reduced risk of dementia, with hazard ratios (95% confidence intervals) of 0.92 (0.90-0.94) for ACD, 0.94 (0.91-0.98) for AD, and 0.90 (0.85-0.94) for VaD. A negative eGFRdiff was associated with adverse neuroimaging changes, including lower total brain and gray matter volumes and higher white matter hyperintensities. Additionally, a negative eGFRdiff was associated with poorer performance across multiple cognitive domains.

CONCLUSION: A negative eGFRdiff was associated with an increased risk of dementia, adverse neuroimaging outcomes, and cognitive decline. These findings suggest that the eGFRdiff might be considered a potential associative indicator for dementia and cognitive impairment, suggesting potential clinical value in risk assessment and early intervention strategies.},
}

@article {pmid41790768,
year = {2026},
author = {Brady, JJR and Bartlett, L and Roccati, E and Norris, K and Vickers, JC and Sinclair, D},
title = {Psychosocial hierarchies of modifiable risk for Alzheimer's disease: A networks analysis.},
journal = {PloS one},
volume = {21},
number = {3},
pages = {e0333148},
doi = {10.1371/journal.pone.0333148},
pmid = {41790768},
issn = {1932-6203},
abstract = {Thirty per-cent of multidomain risk reduction trials for Alzheimer's disease and related dementias (ADRD) report limited efficacy. Identifying potential cascading influences between psychosocial ADRD risk factors is a promising strategy for increasing this efficacy rate. We aimed to identify relational hierarchies among modifiable ADRD risk factors to inform temporally optimized prevention strategies. We applied a dual network approach-regularized partial correlation network (RPCN) and a Bayesian directed acyclic graph (DAG) generated via a novel ensemble method-to cross-sectional data from 898 community-dwelling older adults enrolled in an ADRD prevention initiative. The RPCN revealed clustering among mental health domains. The DAG suggested directional associations from stress, anxiety, and coping to downstream factors including depression, social support, cognitive activity, and cardiometabolic domains (physical activity, BMI, blood pressure, and MIND diet adherence). This dual-network framework highlights upstream psychosocial factors statistically associated with multiple ADRD-related risks. Models suggest targeting stress and coping may offer broad, cascading, benefits for ADRD risk reduction. Further exploration of strategically staggered and/or needs-based individualization of future modifiable ADRD prevention initiatives is warranted.},
}

@article {pmid41790706,
year = {2026},
author = {Wang, X and Liu, Y and Yin, Y and Huang, H and Chen, J and Chen, Z and Liu, S and Xiao, L and Chen, S and Peng, C},
title = {The effects of structured aerobic exercise and mind-body exercise on cognitive function in older adults with MCI: Systematic review and meta-analysis.},
journal = {Medicine},
volume = {105},
number = {10},
pages = {e47633},
doi = {10.1097/MD.0000000000047633},
pmid = {41790706},
issn = {1536-5964},
abstract = {BACKGROUND: Global aging has increased the prevalence of dementia, with mild cognitive impairment (MCI) representing a critical window for intervention. While exercise is recognized for mitigating cognitive decline, the comparative effectiveness of mind-body versus structured aerobic exercise remains unclear.

METHODS: Search sources included PubMed, Web of Science, and the Cochrane Library. Randomized controlled trials (RCTs) assessing mind-body exercise (tai chi, yoga, and dance) or structured aerobic exercise (walking and cycling) in patients with MCI aged over 50 years were included. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were used as outcome measures. Random- or fixed-effects meta-analyses were conducted using RevMan 5.4.1. Heterogeneity was assessed using the I2 statistic. Subgroup analyses examined intervention parameters.

RESULTS: Twenty-six randomized controlled trials (n = 2,555) were included. Mind-body exercise significantly improved MMSE (mean difference [MD] = 1.27, 95% confidence interval [CI]: 0.99-1.55, P < .01), MoCA (MD = 1.89, 95% CI: 0.78-3.00, P = .0008), and ADAS-Cog (MD = -2.09, 95% CI: -2.94 to -1.25, P < .00001) versus controls. Structured aerobic exercise showed non-significant effects on MMSE (MD = 0.37, P = .21) and MoCA (MD = -0.49, P = .26), with modest improvement on ADAS-Cog (MD = -1.41, P = .002). Optimal mind-body parameters include ≥20 weeks' duration, ≥60 minutes per session, and ≥3 times per week.

CONCLUSIONS: Mind-body exercise demonstrates superior cognitive benefits compared with structured aerobic exercise in older adults with MCI. It is advised to prioritize mind-body exercise interventions at least 3 times per week, for 60 minutes per session, for at least 20 weeks. Limitations include heterogeneity and geographic bias; these findings warrant confirmation through multicenter trials.},
}

@article {pmid41790675,
year = {2026},
author = {Alnazari, M and Bakhsh, A and Abdullah, S and Al Qahtani, S and Borhan, W and Rajih, E and Alshehri, AM},
title = {Biological implications and therapeutic potential of phosphodiesterase inhibitors: A review.},
journal = {Medicine},
volume = {105},
number = {10},
pages = {e47683},
doi = {10.1097/MD.0000000000047683},
pmid = {41790675},
issn = {1536-5964},
support = {IF2/PSAU/2022/03/22660//The Deputyship for Research &Innovation, Ministry of Education in Saudi Arabia/ ; },
abstract = {Phosphodiesterase (PDE) inhibitors regulate cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways, which influence neurodevelopment, cardiovascular function, and immune responses. Multiple PDE families exist, classified as dual-substrate (PDE1, PDE2, PDE3, PDE10, PDE11) or non-dual-substrate (PDE4, PDE5, PDE6, PDE7, PDE8, PDE9), each with distinct biological roles. This review summarizes the therapeutic applications of PDE inhibitors, evaluates evidence across different disease domains, and highlights challenges and future research priorities. A narrative review of published studies and clinical trial data was conducted, focusing on pharmacological properties, therapeutic relevance, and safety profiles of PDE inhibitors. Sources included PubMed, ClinicalTrials.gov, and regulatory reports. Dual-substrate PDEs demonstrate therapeutic potential in Alzheimer disease (PDE1), anxiety and memory enhancement (PDE2), and heart failure (PDE3), although chronic PDE3 inhibition may increase risks. Non-dual-substrate PDEs, such as PDE4 and PDE5, are clinically established for asthma, chronic obstructive pulmonary disease, psoriasis, erectile dysfunction, and pulmonary hypertension. Advances in structure-activity relationship studies have produced more selective and potent inhibitors. However, adverse effects, such as nausea (PDE4 inhibitors) and cardiovascular risks (long-term PDE3 inhibitors), remain limiting factors. PDE inhibitors represent a rapidly evolving therapeutic class with broad clinical applications. Their further development requires strategies to minimize adverse effects, improve selectivity, and better define disease-specific roles. Future research should focus on precision medicine approaches to fully harness their therapeutic potential.},
}

@article {pmid41790569,
year = {2026},
author = {Bubu, OM and Mullins, AE and Shah, S and Gills, JL and Kam, K and Parekh, A and Umasabor-Bubu, OQ and Turner, AD and Bernard, M and Briggs, A and Ramos-Cejudo, J and Valkanova, E and Mbah, AK and Pahari, P and Debure, L and Ghuman, M and Boutajangout, A and Williams, NJ and Hwang, J and Williams, MK and Rapoport, DM and Ayappa, I and de Léon, M and Jean-Louis, G and Varga, AW and Osorio, RS},
title = {Obstructive sleep apnea severity, Alzheimer's disease plasma markers, and CSF brain amyloidosis and tau pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71270},
doi = {10.1002/alz.71270},
pmid = {41790569},
issn = {1552-5279},
support = {L30-AG064670/NH/NIH HHS/United States ; P30AG059303/NH/NIH HHS/United States ; T32HL129953/NH/NIH HHS/United States ; K23AG068534/NH/NIH HHS/United States ; R01AG082278/NH/NIH HHS/United States ; RF1AG083975/NH/NIH HHS/United States ; R01HL118624/NH/NIH HHS/United States ; R21AG049348/NH/NIH HHS/United States ; R21AG055002/NH/NIH HHS/United States ; R01AG056031/NH/NIH HHS/United States ; R01AG022374/NH/NIH HHS/United States ; R01AG066970/NH/NIH HHS/United States ; R01AG080609/NH/NIH HHS/United States ; R01AG056531/NH/NIH HHS/United States ; K07AG05268503/NH/NIH HHS/United States ; K23HL125939/NH/NIH HHS/United States ; AARG-21-848397/ALZ/Alzheimer's Association/United States ; A2022033S//BrightFocus Foundation/ ; SCN-25-1474727//Alzheimer's Association/Michael J. Fox Foundation/CurePSP/ ; },
abstract = {INTRODUCTION: We examined obstructive sleep apnea (OSA) severity's association with Alzheimer's disease (AD) plasma biomarkers, independent or synergistic with cerebrospinal fluid (CSF) amyloid, and as a proof of concept, whether plasma amyloid beta (Aβ)42/Aβ40 with OSA severity improves detection of amyloidosis and tau pathology.

METHODS: In 120 cognitively normal older adults (70 with CSF data) from New York University sleep and aging studies (2013-2021), OSA severity was measured using apnea/hypopnea index with 4% desaturation; plasma Aβ40, Aβ42, tau, and neurofilament light chain (NfL) via single molecule array; CSF amyloid and tau via enzyme-linked immunosorbent assay. Associations evaluated adjusted correlations and generalized models; receiver operating characteristic analyses evaluated diagnostic accuracy.

RESULTS: OSA severity correlated with plasma Aβ40 (r = 0.21), Aβ42 (r = 0.26), and Aβ42/Aβ40 (r = 0.20). Plasma tau and NfL associations depended on CSF-Aβ42. OSA severity with Aβ42/Aβ40 improved CSF amyloidosis (area under the curve [AUC] = 0.78) and tau pathology (AUC = 0.71) detection.

DISCUSSION: OSA severity relates to elevated plasma Aβ and, with CSF amyloid, to tau/NfL. Combined plasma and OSA measures aid non-invasive AD associations' detection.},
}

@article {pmid41790564,
year = {2026},
author = {Horton, M and Whiley, DJ and Mayhew, M and McLean, S},
title = {Association between spirochaetal infection and neurodegenerative diseases: a systematic review and quantitative synthesis of observational studies.},
journal = {Journal of medical microbiology},
volume = {75},
number = {3},
pages = {},
doi = {10.1099/jmm.0.002136},
pmid = {41790564},
issn = {1473-5644},
abstract = {Introduction. Neurodegenerative diseases, including Alzheimer's and Parkinson's, are a growing global health concern. While age remains the primary risk factor, infectious agents have been proposed as potential contributors to disease onset or progression.Gap statement. Spirochaetal bacteria, such as Treponema pallidum, Borrelia burgdorferi and Leptospira spp., can invade the central nervous system, yet the extent to which these infections influence neurodegenerative outcomes remains unclear.Aim. This systematic review aimed to evaluate observational evidence on the association between spirochaetal infections and neurodegenerative diseases and to identify gaps in the literature to inform future research.Methodology. A systematic search of SCOPUS, EMBASE, PubMed/MEDLINE, Web of Science and CINAHL was conducted for studies published between January 2000 and May 2025. Eligible studies were observational, involved adult human populations and reported both spirochaetal infection and cognitive or neurodegenerative outcomes using standardized methods. Data were extracted using a standardized form. Owing to heterogeneity in study design, diagnostic approaches, outcome measures and reporting formats, an overall pooled meta-analysis was not feasible; however, a quantitative synthesis using meta-analytic methods was conducted for studies reporting mini-mental state examination data. Risk of bias was assessed using the Newcastle-Ottawa Scale.Results. Twenty-seven studies met the inclusion criteria: 13 on T. pallidum, 13 on B. burgdorferi and one on Leptospira spp. No eligible studies were found for Brachyspira spp., and studies involving Treponema denticola were excluded due to confounding by periodontitis. Studies investigating syphilis and leptospirosis consistently reported cognitive impairment and increased dementia risk. In contrast, findings for Lyme disease were heterogeneous, with some studies reporting persistent symptoms or increased Alzheimer's risk, while others found no long-term cognitive effects.Conclusion. This review highlights a potential link between spirochaetal infections and neurodegenerative outcomes, particularly for syphilis and leptospirosis. Evidence for Lyme disease remains inconclusive. Future research should prioritize longitudinal studies with standardized diagnostic criteria, integration of neuroimaging and biomarker data and improved diagnostic accuracy for spirochaetal infections.},
}

@article {pmid41790563,
year = {2026},
author = {Tee, BL and Spat-Lemus, J and Zhang, SX and Upendra, S and Zhao, X and Chen, G and Chen, Y and Wen, X and Yao, A and Leng, F and Li, C},
title = {Advancing global precision in dementia research: Examining Normative Heterogeneity of Aging and Neurodegeneration in Chinese Elders (ENHANCE).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71166},
doi = {10.1002/alz.71166},
pmid = {41790563},
issn = {1552-5279},
support = {R61AG083582 to C.L/NH/NIH HHS/United States ; R01AG083840 to C.L/NH/NIH HHS/United States ; R01AG080469 to C.L/NH/NIH HHS/United States ; R21AG077649 to C.L/NH/NIH HHS/United States ; UH3AG083258 to C.L/NH/NIH HHS/United States ; R01AG095513 to C.L/NH/NIH HHS/United States ; R01AG080469 to B.L.T./NH/NIH HHS/United States ; R01AG083840 to B.L.T./NH/NIH HHS/United States ; U19AG079774 to B.L.T./NH/NIH HHS/United States ; P01AG019724 to B.L.T./NH/NIH HHS/United States ; U01NS128913 to B.L.T./NH/NIH HHS/United States ; AACSFD-22-972143 to B.L.T./ALZ/Alzheimer's Association/United States ; K24DC015544 to B.L.T./DC/NIDCD NIH HHS/United States ; RF1NS050915 to B.L.T./DC/NIDCD NIH HHS/United States ; R01 NS100440-01 to B.L.T./DC/NIDCD NIH HHS/United States ; R01AG058233 to B.L.T./DC/NIDCD NIH HHS/United States ; P30 AG062422 to B.L.T.//Alzheimer's Disease Research Center of California/ ; },
abstract = {The Examining Normative Heterogeneity of Aging and Neurodegeneration in Chinese Elders (ENHANCE) project addresses gaps in Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD) research by prioritizing Chinese-speaking communities-an underrepresented but rapidly growing population in the United States (US) and globally. ENHANCE uses a transadaptation approach to develop cognitive assessments that reflect the language and culture of Cantonese and Mandarin speakers, making tools more relevant and appropriate. The project brings together data from older Chinese American participants at University of California San Francisco (UCSF) and Icahn School of Medicine at Mount Sinai (ISMMS), guided by community input and pilot testing results of research instruments. By combining data from ISMMS, UCSF, and the National Alzheimer's Coordinating Center (NACC), ENHANCE explores meaningful cross-cultural differences in AD/ADRD risk and progression. The goal is to improve diagnostic accuracy and representation in AD/ADRD research. ENHANCE helps make AD/ADRD research more responsive to language and cultural backgrounds in the older Chinese American community, supporting the goal of precision medicine in diverse population.},
}

@article {pmid41790486,
year = {2026},
author = {Ruuth, J and Tamminen, T and Toropainen, E and Tanila, H and Hyttinen, JMT and Malm, T and Kaarniranta, K and Koskela, A},
title = {Overproduction of 42 Amino Acids Long Amyloid Beta Leads to Activation of Secretory Autophagy and Development of Drusen-Like Structures Originating From Retinal Pigment Epithelium.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {5},
pages = {e71608},
doi = {10.1096/fj.202502464RRR},
pmid = {41790486},
issn = {1530-6860},
support = {333302//Academy of Finland/ ; //GeneCellNano/ ; //Paivikki ja Sakari Sohlberg Foundation/ ; 5503770//Kuopio University Hospital district/ ; //Sigrid Juséliuksen Säätiö (Sigrid Jusélius Stiftelse)/ ; //Silmäsäätiö (Finnish Eye Foundation)/ ; //De Blindas Vänner (DBV)/ ; //Finnish eye and Tissue Bank Foundation/ ; //Mary and Georg C. Ehrnrooths Foundation/ ; //Finnish Cultural Foundation-North-Savo/ ; },
abstract = {Age-related macular degeneration (AMD) is a global vision threatening disease affecting the macular region of the retina. AMD is classified into two forms: dry and wet AMD. There are no effective treatment options available for dry AMD (80% of cases). The cellular pathology includes oxidative stress and dysfunctional autophagy challenging the homeostasis of the retinal pigment epithelial (RPE) cells. Clinical findings include the formation of drusen deposits beneath the RPE cells consisting of 42 amino acids long amyloid beta (Aβ) among other components. However, the origin of drusen remains elusive. The 5xFAD (familiar Alzheimer's disease) mouse model of Alzheimer's disease produces abundant levels of Aβ making it an interesting model to study the possible relationship of Aβ to the formation of extracellular deposits and AMD-like pathology. An immunohistology analysis of the 5xFAD mouse model showed accumulation of autophagic markers SQSTM1 (sequestosome 1) and ubiquitin in the RPE. Concurrently, the markers of secretory autophagy enabling the delivery of the intracellular material to the extracellular lumen were upregulated. Aβ, SQSTM1, ubiquitin, catalase, and TRIM16 (tripartite motif containing 16) shifted age-dependently from intracellular origin to drusen-like deposits beneath the RPE cells. Additionally, classical proteins secreted via secretory autophagy, IL-1β (interleukin 1β), HMGB1 (high mobility group box-1), and ferritin showed similar accumulation which became visible in fundus age-dependently. These findings suggest a role for Aβ in the cellular pathogenesis of AMD. Furthermore, this model showed activated secretory autophagy pathway suggesting a role for Aβ in drusen-like deposition formation.},
}

@article {pmid41790466,
year = {2026},
author = {Chung, YE and Chung, RH and Hsu, CC and Liu, YL and Lai, RH and Hung, WJ and Wu, RC and Jiang, YJ and Chuang, SY and Tsai, SF and Kuo, CC and Hsiung, CA and Chen, WJ},
title = {APOE ε4 and Accelerated Cognitive Decline Among Cognitively Healthy Middle-Aged and Older Adults.},
journal = {JAMA network open},
volume = {9},
number = {3},
pages = {e260853},
doi = {10.1001/jamanetworkopen.2026.0853},
pmid = {41790466},
issn = {2574-3805},
abstract = {IMPORTANCE: Alzheimer disease (AD) pathology may begin decades before symptoms. Genetic factors, such as APOE ε4 carrier status and polygenic risk scores (PRS), influence AD risk, but their roles in cognitive decline among Asian populations remain unclear.

OBJECTIVE: To evaluate whether APOE ε4 carrier status and a non-APOE polygenic risk score (PRS_ADnapoe) are associated with age-related cognitive decline in community-dwelling older adults in Taiwan.

This prospective cohort study used data from 2 assessment waves of the Healthy Aging Longitudinal Study in Taiwan, spanning 2009 to 2019. Participants were aged 55 years and older and had both genetic data and Mini-Mental State Examination (MMSE) scores. Data analyses were conducted from August to December 2025.

EXPOSURES: APOE ε4 carrier status (noncarrier, heterozygote, homozygote) and PRS_ADnapoe score, derived from genome-wide association summary statistics excluding APOE variants.

MAIN OUTCOMES AND MEASURES: The primary outcome was change in MMSE scores, which were assessed cross-sectionally and longitudinally, modeled with mixed-effects regression accounting for age-related effects and covariates including sex, education, smoking, and population structure.

RESULTS: Among 4392 participants (mean [SD] age, 68.2 [7.8] years; 2359 [53.7%] women), 723 (16.5%) were APOE ε4 heterozygotes and 33 (0.8%) were APOE ε4 homozygotes. Over a mean (SD) follow-up of 6.3 (0.9) years, the mean (SD) annual MMSE decline was -0.2 (0.5). APOE ε4 carriage was associated with a significantly steeper quadratic age-associated decline in MMSE scores compared with noncarriers (estimate, -0.005; SE, 0.001; P = .001). This association was strongest among homozygotes (estimate, -0.017; SE, 0.008; P = .03), with MMSE trajectories diverging after approximately age 70 years. In contrast, PRS_ADnapoe scores were not associated with MMSE decline. Sensitivity analyses restricted to participants with 2-wave data and adjusted with inverse probability of censoring weighting confirmed these findings.

CONCLUSIONS AND RELEVANCE: In this cohort study of middle-aged and older adults in Taiwan, APOE ε4 carriage, particularly homozygosity, was associated with accelerated age-related cognitive decline detectable after age 70 years, whereas non-APOE polygenic risk was not associated with cognitive decline over the current follow-up. These results highlight the potential utility of early genetic risk awareness and support consideration of targeted preventive strategies for APOE ε4 carriers.},
}

@article {pmid41790409,
year = {2026},
author = {Zhang, X and Wu, L and Hua, D and Zhang, B and Wang, X and Li, L and Wang, Y and Zhu, J},
title = {Bisphenol S and Neurological Health: An Integrated Overview of Neurotoxicity and Underlying Mechanisms.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41790409},
issn = {1559-1182},
support = {82504453//the National Natural Science Foundation of China/ ; 24YF2757800//the Yangfan Program of the Shanghai Science and Technology Commission/ ; 20244Y0040//the Youth Clinical Research Program of the Shanghai Municipal Health Commission/ ; },
abstract = {Bisphenol S (BPS), a pervasive contaminant used in consumer and industrial products, has been widely detected in human serum, urine, hair, placenta, and breast milk. Although initially studied mainly as an endocrine disruptor, accumulating evidence indicates that BPS also exerts neurotoxicity by perturbing neuroinflammatory responses, neuroendocrine regulation, and neuronal development. However, its neurotoxic profile and mechanistic basis remain incompletely defined. This review systematically retrieved and synthesized epidemiological, animal, and cellular studies published between 2000 and February 2026 across multiple databases to delineate the neurotoxic features and mechanisms of BPS. Evidence from 14 epidemiological and 76 experimental studies consistently indicates neurotoxic risk. Epidemiological data associate BPS exposure with increased risks of neuropsychiatric outcomes, including attention-deficit/hyperactivity disorder (ADHD), Alzheimer's disease (AD), and depression, often with sex-specific patterns. Animal studies show that exposure across life stages induces behavioral impairments, encompassing social deficits, cognitive and emotional disturbances, motor dysfunction, and memory decline. In vitro studies further elucidate molecular underpinnings. Mechanistically, BPS neurotoxicity involves endocrine-axis disruption, neurotransmitter imbalance, oxidative stress, and transcriptional dysregulation and extends to gut-brain axis perturbation, brain region-specific vulnerability, and neural circuit dysfunction. These pathways interact and are modified by toxicokinetics, exposure dose and timing, sex, and species. Future work should integrate longitudinal human cohorts with mechanistic studies to clarify BPS's contribution to neurological disease development and inform regulation. We propose an integrative framework summarizing BPS neurotoxicity and its key modifying factors.},
}

@article {pmid41790404,
year = {2026},
author = {Emam, M and Albadri, S and Ahmed, AM and Mirza, IM and Hafiz, HA and Elnaeem, M and Alzamil, Y and Alazzam, MB and , },
title = {Higher Total Omega-3 PUFA Levels and a Lower Omega-6:Omega-3 Ratio Are Associated with Lower Temporal Lobe Volume in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41790404},
issn = {1559-1182},
abstract = {Research suggests varying effects of fatty acids on cognitive function and brain structure in neurocognitive disorders, but inconsistent findings call for further investigation and advanced neuroimaging techniques. This study investigated the relationship between serum fatty acid levels (omega-3 PUFAs, omega-6 PUFAs, omega-6:omega-3 ratio, MUFAs, and SFAs) and temporal lobe volume in cognitively normal (CN) individuals, those with mild cognitive impairment (MCI), and those with Alzheimer's disease (AD). The results indicated that, as expected, there was a significant difference in temporal lobe volumes (p < 0.001), with the AD group showing more pronounced reductions in volume compared to both the CN and MCI groups. Unexpectedly, higher plasma omega-3 PUFA levels were associated with reduced temporal lobe volume (β = - 0.31, p = 0.021), and a lower omega-6:omega-3 ratio was also associated with diminished temporal lobe volume (β = 0.26, p = 0.039), both observed only in the AD group, after adjustment for age, gender, education, and APOE ε4 allele status as potential confounders. No significant associations were observed for any lipids with temporal lobe volumes in the CN or MCI groups. Interestingly, the only significant association observed between fatty acids and cognitive function was in the CN group, where higher MUFAs and SFAs were both associated with worse cognitive scores. In short, higher omega-3 PUFA levels and a lower omega-6:omega-3 ratio were associated with reduced temporal lobe volume in Alzheimer's patients not using fatty acid supplements. Notably, this observational cross-sectional study cannot establish causality and should be interpreted cautiously, as the findings may be influenced by residual confounding, non-fasting sampling, potential reverse causality, lack of detailed dietary and longitudinal data, and methodological constraints including limited lipid characterization and region-specific morphometric analysis. Further research is needed to confirm these findings and investigate potential mechanisms.},
}

@article {pmid41790170,
year = {2026},
author = {Bousiges, O and Cretin, B and Battista, L and Schaeffer-Agalède, C and Philippi, N and Hamied, L and Ravier, A and Demuynck, C and Muller, C and Blanc, F},
title = {CSF elevated Tau and P-Tau and normal Aβ42 mainly corresponds to Alzheimer's disease with dementia with Lewy bodies.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41790170},
issn = {2509-2723},
abstract = {Some cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker profiles are difficult to interpret. We investigated one such case: normal Aβ42 and pathologically increased levels of Tau and P-Tau (Tau&PTau profile). We first extracted details of 184 patients with a Tau&PTau profile who had been followed up in Strasbourg, France (cohort 1) and whose diagnosis has been reviewed. Secondly, we recovered and analyzed the AD biomarker results and clinical diagnoses of a cohort of 1199 patients also followed up in Strasbourg (cohort 2). In cohort 1, 57% of patients were patients with comorbidity: they had both Alzheimer's disease and dementia with Lewy bodies (DLB) (AD+DLB). In cohort 2, among patients with a Tau&PTau profile: between 39.6 and 53.1% had comorbidity with AD, with more than half of the comorbidities being DLB. In cohort 2, among patients with AD+DLB, the majority (64.4%) had a Tau&PTau profile. These results show that patients with AD+DLB comorbidity mainly have a Tau&PTau profile. These results are relatively counterintuitive, given that AD and DLB are two diseases in which it is common, even systematic, to find a CSF Aβ42 decrease. However, the combination of the two diseases, or more broadly, AD comorbidity, indicates higher levels of Aβ42 than in pure AD.},
}

@article {pmid41790026,
year = {2026},
author = {Napolitano, E and Marino, C and Grimaldi, M and Buonocore, M and Santoro, A and D'Ursi, AM},
title = {Analyzing Nicotine Action Against Amyloid Toxicity by NMR-Pharmacometabolomics: An Exploratory Study.},
journal = {NMR in biomedicine},
volume = {39},
number = {4},
pages = {e70255},
doi = {10.1002/nbm.70255},
pmid = {41790026},
issn = {1099-1492},
abstract = {Alzheimer's disease (AD) is the primary neurodegenerative disease spread worldwide. One of the main histopathological hallmarks of AD is the deposition of amyloid plaques in the brain. Despite some epidemiological studies demonstrating that cigarette smoke is a factor in predisposing people to AD, nicotine, the principal alkaloid of Nicotiana Tobacco, has been widely studied for its ability to improve cognitive performance, both in animal models and in human studies. Several hypotheses have been proposed to explain the mechanism of action underlying the beneficial effect of nicotine in AD; however, this is still questioned. To gain new insights into the molecular mechanism underlying nicotine's neuroprotective action in AD, we performed NMR metabolomics on SH-SY5Y neuroblastoma cells treated with Aβ(1-42) in the presence of nicotine. Our data show that the neuroprotective action of nicotine resides in its ability to restore the systemic unbalanced metabolism associated with AD. In particular, nicotine reverses most Aβ(1-42)-induced metabolic impairments, including those related to amino acid metabolism, especially neurotransmission, as well as alterations in energy and membrane phospholipid metabolism.},
}

@article {pmid41789871,
year = {2026},
author = {Lv, M and Wang, Q and Yu, G and Chen, J and Zhou, X and Chen, Z and Li, R and Huang, S and Liang, Y and Que, Y and He, W and Xia, J and , },
title = {Choroid plexus-glymphatic axis disruption in Alzheimer's disease: Cerebrospinal fluid expansion as a mediator of metabolic dysfunction and cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261426578},
doi = {10.1177/13872877261426578},
pmid = {41789871},
issn = {1875-8908},
abstract = {BackgroundThe choroid plexus (ChP) and glymphatic system are crucial for cerebrospinal fluid (CSF) homeostasis and brain waste clearance. While their individual roles in Alzheimer's disease (AD) are recognized, the mechanisms linking ChP structural changes, glymphatic dysfunction, and CSF dynamics to metabolic and cognitive decline remain unclear.ObjectiveWe aimed to investigate the interrelationships among ChP volume, glymphatic function, CSF volumetric changes, cerebral glucose metabolism, and cognitive status across the AD spectrum.MethodsThis cross-sectional study included 142 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, categorized as cognitively normal (NC, n = 38), early mild cognitive impairment (EMCI, n = 31), late mild cognitive impairment (LMCI, n = 31), and AD (n = 42). We analyzed multimodal neuroimaging data, including normalized ChP volume (nChP), CSF sub-volumes, the diffusion tensor imaging along the perivascular space (DTI-ALPS) index, and [18F]-FDG-PET standardized uptake value ratios. Partial correlation and mediation analyses were performed, adjusting for covariates.ResultsIncreased nChP correlated with larger CSF (nTotal-CSF: r = 0.324, FDR-p = 0.004), lower DTI-ALPS, and reduced FDG. nChP drove cognitive decline via two paths: "nChP→nTotal-CSF→ Mini-Mental State Examination (MMSE)" (44.1% total effect) and "nChP→DTI-ALPS→FDG→MMSE" (9.9%, p < 0.001). CSF showed spatial mediation: nCSF-LV (66.20% on metabolism) outperformed external CSF (38.90%); DTI-ALPS negatively correlated with nCSF-LV (r = -0.406, FDR-p < 0.01).ConclusionsOur findings demonstrate that ChP enlargement is linked to cognitive impairment through pathways involving CSF dynamics and glymphatic function, with cerebral hypometabolism as a key downstream effector. This study posits a "CSF dynamics imbalance" cascade in AD, highlighting the potential of targeting Choroid Plexus-CSF-glymphatic axis for early diagnosis and intervention.},
}

@article {pmid41789867,
year = {2026},
author = {Balsliemke, AL and Ahlemeyer, B and Schmidl, E and Acker, T and Schänzer, A and Baumgart-Vogt, E},
title = {Region-specific ups and downs in mitochondrial numerical densities during Alzheimer's disease progression: A pilot study in human brains.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418994},
doi = {10.1177/13872877261418994},
pmid = {41789867},
issn = {1875-8908},
abstract = {BackgroundMitochondrial dysfunction is an important pathogenic factor in Alzheimer´s disease (AD) progression. Most studies analysed disturbances in the mitochondrial metabolism and oxidative stress or focussed on mitochondrial dynamics such as mitochondrial trafficking, fusion-fission and mitophagy.ObjectiveVery limited data exist regarding changes in the mitochondrial numerical density at different levels of AD neuropathologic changes (ADNC) in human brains.MethodsMitochondrial numerical densities were analysed by morphometry using the marker protein ATP5B in sections of 13 brain areas of 8 patients with either low, mid or high ADNC, 6 patients with tauopathy and 10 control patients. Patient samples were classified according to the ABC score.ResultsIn comparison to control patients, we detected increases in mitochondrial densities at low (not in all cases), mid and high ADNC in neurons of the frontal (25%) and temporal (11%) neocortices, pontine nuclei (30%) and Purkinje neurons of the cerebellum (30%). Contrarily, mitochondrial densities decreased by 20% in hippocampal neurons of the entorhinal cortex and CA3 region at mid and high ADNC. Only minor changes occurred in other brain regions investigated (e.g., parietal and occipital neocortices, inferior olive, substantia nigra, striatum). In tauopathy patients, changes in mitochondrial densities were comparable to those in AD patients, except for a stronger decrease in the entorhinal cortex (40%) and a greater increase in the temporal neocortex (30%).ConclusionsIn the neocortex, primarily affected by extracellular amyloid-β (Aβ) deposits, mitochondrial densities in neurons increased, whereas they decreased in the hippocampus, at first enriched in intracellular neurofibrillary tangles.},
}

@article {pmid41789865,
year = {2026},
author = {Li, Z and Wang, D and Xia, F and Liu, Y and Liu, Y},
title = {Identification of causally linked blood biomarkers for Alzheimer's disease via reverse transcriptome-wide Mendelian randomization.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261422501},
doi = {10.1177/13872877261422501},
pmid = {41789865},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder with poorly understood molecular mechanisms and limited early detection biomarkers.ObjectiveTo identify genes causally associated with AD risk using reverse transcriptome-wide Mendelian randomization (revTWMR) and bulk RNA-sequencing (RNA-seq).MethodsWe analyzed publicly available RNA-seq data from peripheral blood samples of patients with clinically diagnosed AD and cognitively normal controls, obtained from the GEO database. Differential expression analysis was performed to identify differentially expressed genes (DEGs). We used revTWMR by integrating genome-wide association study (GWAS) summary statistics with expression quantitative trait loci (eQTL) data to infer causal relationships between gene expression and AD risk.ResultsUsing RNA-seq data from peripheral blood samples of AD patients and cognitively normal controls, we identified 126 DEGs. Through revTWMR analysis, we narrowed down to 91 genes with significant causal associations with AD, and further prioritized 5 genes with strong causal effects (|α| ≥ 0.8). Among these, PSMA6, CD19, and CMTM6 have potential roles in AD pathogenesis and may serve as promising blood-based biomarkers for early detection and therapeutic targeting.ConclusionsOur findings highlight the utility of revTWMR in identifying causally relevant genes in AD and suggest several blood-based candidate biomarkers for early detection and therapeutic development. This integrative approach provides novel insights into the molecular underpinnings of AD.},
}

@article {pmid41789863,
year = {2026},
author = {Gibbs, D and Black, B and Petersen, M and Johnson, L and Hall, J and O'Bryant, SE and Zhang, F and , },
title = {Exploring feature importance in machine learning for neuroimaging traits in Alzheimer's disease across a multiethnic cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261426563},
doi = {10.1177/13872877261426563},
pmid = {41789863},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) affects 55 million people worldwide, projected to reach 139 million by 2050; yet, most machine learning (ML)-based AD classifiers have been developed in Non-Hispanic White (NHW) cohorts, limiting generalizability.ObjectiveAssess ethnic differences in AD prediction using classification performance and feature importance derived from multimodal neuroimaging biomarkers across African American (AA), Hispanic, and NHW participants.MethodsSupport vector machine classifiers were applied to multimodal neuroimaging data from a multi-ethnic cohort, incorporating structural magnetic resonance imaging measures, diffusion tensor imaging metrics, and positron emission tomography-based amyloid and tau measures. Models classified cognitively unimpaired (CU) versus cognitively impaired (CI) individuals and mild cognitive impairment (MCI) versus AD dementia, with and without adjustment for age, sex, and education.ResultsClassification performance varied by ethnicity and disease stage. NHW participants showed the strongest overall performance, particularly for CU versus CI, while Hispanic participants demonstrated high sensitivity and balanced performance for MCI versus AD. AA participants exhibited lower AUC and accuracy across tasks but maintained high negative predictive value. Demographic adjustment improved performance primarily for AA and NHW participants. Feature importance analyses revealed shared and population-specific patterns: tau positron emission tomography (PET) measures, especially posterior cingulate and lateral parietal standardized uptake value ratios, consistently ranked highest for CU versus CI across groups, whereas MCI versus AD classification diverged, with amyloid PET predominating in AA participants, tau PET in NHW participants, and mixed medial temporal atrophy and white matter signatures in Hispanics.ConclusionsShared early AD neuroimaging signatures exist across ethnic groups, but biomarker importance diverges at later disease stages, underscoring the need for ethnicity-aware ML models to improve prediction and equitable clinical translation.},
}

@article {pmid41789852,
year = {2026},
author = {Driscoll, I and Wilson, RE and Johnson, SC and Asthana, S and Gallagher, CL and Hermann, BP and Sager, MA and Carlsson, CM and Blennow, K and Zetterberg, H and Dubal, DB and Okonkwo, OC},
title = {Age-related alterations in plasma biomarkers of relevance to Alzheimer's disease are attenuated in KLOTHO KL-VS heterozygotes.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261422411},
doi = {10.1177/13872877261422411},
pmid = {41789852},
issn = {1875-8908},
abstract = {BackgroundThe literature supports an attenuation of unfavorable age-related changes, in both cognitive performance and CSF biomarkers of significance to Alzheimer's disease (AD), in association with a functionally advantageous KLOTHO KL-VS genotype (KL-VSHET).ObjectiveTo examine whether KL-VSHET attenuation of unfavorable age-related biomolecular changes is detectable in AD-relevant plasma biomarkers.MethodsSample consisted of 298 cognitively unimpaired adults (MeanAGE = 65 ± 6.8, 67% female) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies with available data of interest. Covariate (sex, education, APOE4+/- status, parental history of AD)-adjusted multivariate regression examined relationships between age group (Younger (N = 140), Older (N = 158); mean split at age 65) and AD-relevant plasma biomarkers [amyloid-β (Aβ) 42/40, phosphorylated tau (pTau)181, pTau217, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)] and whether these relationships differ for KL-VSHET [N = 86; Younger = 51 (59%), Older = 35 (41%)] compared to non-carriers [KL-VSNC: N = 212; Younger = 89 (42%), Older = 123 (58%)].ResultsIn the pooled sample, older age was associated with less favorable plasma biomarker profiles (all ps ≤ 0.001), except Aβ42 (p = 0.39). When the analyses were stratified by genotype, KL-VSNC continued to exhibit the same age-related pattern of changes in plasma biomarkers (all ps ≤ 0.009; except Aβ42, p = 0.63), which was attenuated in KL-VSHET for Aβ40, Aβ40/42, pTau181, pTau217, and pTau231 (all ps ≥ 0.1).ConclusionsUnfavorable age-associated changes in core AD plasma biomarkers were attenuated in KLOTHO KL-VSHET. KL-VSHET seems to be protective against age-related biomolecular alterations known to confer risk for developing AD.},
}

@article {pmid41789850,
year = {2026},
author = {Yang, Y and Yang, F and Yao, M and Li, L and Li, H},
title = {Decoding the key mechanisms of ferroptosis and inflammation: Emerging therapeutic targets for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427028},
doi = {10.1177/13872877261427028},
pmid = {41789850},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a common progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) deposition leading to the formation of senile plaques and hyperphosphorylation of tau protein resulting in NFTs. Ferroptosis, a newly identified form of programmed cell death, promotes neuroinflammation through mechanisms such as iron metabolism dysregulation, lipid peroxidation, and redox imbalance. Neuroinflammation, in turn, accelerates ferroptotic processes, creating a vicious cycle that drives the progression of neurodegenerative diseases. Recent studies have revealed a close association between ferroptosis and neuroinflammation in AD, and several ferroptosis-targeted agents have shown promising therapeutic effects in AD cell and animal models. This review explores the pathogenesis of ferroptosis in AD and elucidates the mechanistic role of the regulatory interplay between ferroptosis and neuroinflammation in AD, recent advances in ferroptosis-targeted therapeutic strategies are also discussed. Together, these insights may offer new perspectives for treating this devastating disorder.},
}

@article {pmid41789727,
year = {2026},
author = {Lee, J and Cho, Y and Choi, BY and Kim, HK and Lee, Y and Kim, E and Han, J and Sul, JH and Kim, JS and Baek, SH and Cho, Y and Park, J and Bahn, G and Bae, HG and Jun, JH and Lai, MKP and Arumugam, TV and Jo, DG},
title = {HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag089},
pmid = {41789727},
issn = {1460-2156},
abstract = {Alzheimer's disease (AD) is marked by amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation. The β-site APP cleaving enzyme 1 (BACE1) is a key driver of Aβ production, while the NLRP3 inflammasome mediates microglial inflammatory responses. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase, is upregulated in AD, yet its role in disease mechanisms remains unclear. Here, we show that HDAC6 promotes BACE1 protein stability through direct deacetylation of its C-terminal lysine (K501), thereby increasing Aβ production. HDAC6 also facilitated NLRP3 inflammasome activation in microglia, increasing IL-1β production in a catalytic domain-dependent manner. HDAC6 deficiency in 5xFAD mice reduced BACE1 accumulation, Aβ deposition, ASC speck formation, and IL-1β levels, accompanied by improved cognitive performance. Transcriptomic profiling further revealed downregulation of disease-associated microglial and neurotoxic astrocyte signatures alongside enrichment of synaptic pathways. These findings establish HDAC6 as a dual regulator of Aβ production and neuroinflammation, highlighting it as a promising therapeutic target in AD.},
}

@article {pmid41789717,
year = {2026},
author = {Yuste, R},
title = {Neuronal ensembles in cortical function and disease.},
journal = {Physiological reviews},
volume = {},
number = {},
pages = {},
doi = {10.1152/physrev.00003.2025},
pmid = {41789717},
issn = {1522-1210},
support = {RM1NS132981//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01EY035248//HHS | NIH | National Eye Institute (NEI)/ ; R01MH115900//HHS | NIH | National Institute of Mental Health (NIMH)/ ; 2203119//National Science Foundation (NSF)/ ; N000142012828//DOD | USN | Office of Naval Research (ONR)/ ; },
abstract = {Neuronal ensembles, defined as groups of coactive neurons, are physiological modules of the cerebral cortex. Calcium imaging and optogenetics have enabled mapping and manipulating ensembles with single cell resolution in mouse visual cortex, providing evidence of their importance. Ensembles dominate cortical activity, are generated endogenously or by sensory stimulation. Ensembles are imprinted by activating neurons synchronously and can be reactivated by "pattern completion" trigger cells. Intrinsic excitability mediates ensemble coactivation and reactivation, while UP states shield ongoing ensembles from external inputs. Neurons can belong to different ensembles, forming a combinatorial system that encodes visual stimuli accurately and stably. Ensembles contain pyramidal neurons and interneurons and inhibited "offsemble" cells. Cross-inhibition makes ensembles orthogonal from one another, while astrocytic activation increases ensemble occurrence. Ensembles can last for weeks, providing a substrate for long-term information storage, and they capture the recent history of stimulus presentation, implementing short-term memory. Optogenetic manipulation of ensembles demonstrates that they are necessary and sufficient for visual discrimination and perceptual states. Ensembles are altered in mouse models of epilepsy, schizophrenia, Alzheimer's disease, autism spectrum disorders and medically-induced loss of consciousness. An ensemble model of the cortex is proposed in which ensembles are functional units that activate each other via trigger cells and silence non-desired ensembles by cross-inhibition. This generates a map of orthogonal attractor states, forming a computationally powerful memory and processing system. Ensembles are likely involved in many brain diseases, so manipulating them could offer avenues for new therapeutics.},
}

@article {pmid41789706,
year = {2026},
author = {Levin, S and Engel, B and Carlson, C and Hinson, J and Holland, M and Figdore, D and Lim, HK and Tiers, L and Bhatt, K and Schlichtmann, B and Hoffmann, K and Bae, YE and Szabo, M and Lehmann, S and Um, YH and Algeciras-Schimnich, A},
title = {An automated plasma-based proteotyping immunoassay for APOE ε4 zygosity classification in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71143},
doi = {10.1002/alz.71143},
pmid = {41789706},
issn = {1552-5279},
support = {//Beckman Coulter/ ; },
abstract = {INTRODUCTION: Determining apolipoprotein E (APOE) ε4 allele status, a key genetic risk factor for Alzheimer's disease (AD), requires molecular genotyping infrastructure not widely accessible beyond specialized centers.

METHODS: A fully automated high-throughput apoE E4 proteotyping immunoassay was evaluated for clinical performance (460 participants across three cohorts) and analytical validity. Concordance with polymerase chain reaction (PCR)-based genotyping and measures of analytical validity were reported.

RESULTS: The apoE E4 immunoassay demonstrated 99.6% (95% confidence interval [CI]: 98.4% to 99.9%) concordance with PCR-based APOE ε4 genotype results across the pooled clinical cohort; 100.0% (95% CI: 97.1% to 100.0%) in those with AD (N = 127) and 99.4% (95% CI: 97.8% to 99.8%) in those without AD (333). The assay met analytical validity criteria for E4 isoform specificity, interference, precision, and stability.

DISCUSSION: The apoE E4 immunoassay demonstrated high concordance with PCR-based genotyping and robust analytical validity, offering an accessible alternative for APOE ε4 zygosity assessment.

HIGHLIGHTS: A novel high-throughput plasma-based proteotyping immunoassay for APOE ε4 zygosity classification was developed and evaluated for clinical performance and analytical validity. The apoE E4 immunoassay demonstrated high concordance (99.6%) with PCR-based APOE ε4 genotyping across a diverse international cohort, and a robust analytical profile. An apoE E4 immunoassay may offer a more cost-effective and accessible alternative to DNA genotyping approaches currently used for AD risk evaluation and anti-amyloid treatment decisions.},
}

@article {pmid41789587,
year = {2026},
author = {Talmasov, D and Santillo, AF and Hof, PR},
title = {Von Economo Neuron Loss in Frontotemporal Dementia: A Meta-Analysis of Neuropathological Studies.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70362},
pmid = {41789587},
issn = {2328-9503},
support = {25AACSF-1411581/ALZ/Alzheimer's Association/United States ; P30AG066514/AG/NIA NIH HHS/United States ; 5T32MH020004/MH/NIMH NIH HHS/United States ; },
abstract = {Von Economo neurons (VENs) have been reported to be vulnerable to neurodegeneration in frontotemporal dementia (FTD), particularly the behavioral variant (bvFTD), but these findings have not been systematically assessed across independent brain banks. We conducted a meta-analysis of neuropathological studies measuring VEN density in the anterior cingulate cortex or frontoinsular cortex in FTD using random-effects models with cluster-robust variance estimation. Seven studies (135 FTD, 68 controls) from four international brain banks showed significantly reduced VEN density in FTD with a large effect size (g = -1.45, 95% CI [-1.69, -1.21], p < 0.001) and remarkable consistency (I[2] = 0%). VEN loss was greater in FTD than Alzheimer's disease and occurred across TDP-43 and tau pathological subtypes.},
}

@article {pmid41789476,
year = {2026},
author = {Rajicic, A and Mol, MO and Melhem, S and Kisic, H and van Swieten, JC and Seelaar, H and van Rooij, JGJ},
title = {Transcriptomic signature of frontotemporal lobar degeneration with TDP-43 type C pathology.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag085},
pmid = {41789476},
issn = {1460-2156},
abstract = {Semantic variant of primary progressive aphasia is a clinical subtype of frontotemporal lobar degeneration and is marked by TDP-43 subtype C pathology (FTLD-TDP C). It is a sporadic disease, yet has a strikingly homogeneous clinicopathological presentation, suggesting a common pathophysiology. The aim of this study was to discover dysregulated pathways in FTLD-TDP C through transcriptomics of the temporal cortex, its most affected region. Bulk RNA sequencing was conducted on temporal cortices of a post-mortem cohort of 18 FTLD-TDP C patients and 23 sex- and age-matched controls. Differential expression and functional analyses were run to detect differentially expressed genes with FDR<0.05 (DEG) and functionally annotate them. We assessed enrichment of TARDBP's protein interactors and RNA targets in DEG. Our findings were compared to other published RNA sequencing data of tauopathies (Alzheimer's dementia, progressive supranuclear palsy and FTLD with MAPT), FTLD-TDP (subtypes A&B) and available proteomics of this cohort. Furthermore, we performed weighted gene co-expression network analysis (WGCNA). We adjusted for differences in cell type composition between cases and controls using cell deconvolution, and removed genes dysregulated in temporal cortices of other datasets. In DEG of FTLD-TDP we focused on enrichment of synaptic processes using SynGO. We found upregulation of damage response, cell structure, RNA splicing processes and downregulation of synaptic processes in 6322 DEG and five disease-related WGCNA modules. TARDBP-related genes were enriched in DEG. Additionally, transmembrane transport across the neurovascular unit was dysregulated. After cell deconvolution and removal of common tau-genes, postsynaptic processes remained dysregulated, specifically gene ontology terms 'modulation of chemical synaptic transmission' and 'neurotransmitter receptor localisation to postsynaptic specialisation membrane'. We found eleven synaptic FTLD-TDP C-specific genes affected on both RNA- and protein-level in the temporal cortex, which were involved in synaptic adhesion (CADM1, NCAN), signal transmission (COMT, RGS144, SLC1A2, TUBB2B) and synaptic plasticity (BEGAIN, ITPKA, LRFN1, RAB3B, SYNPO). In conclusion, a wide range of processes were dysregulated on RNA-level in the temporal cortex of FTLD-TDP C, including commonly affected processes in neurodegeneration, such as structural cell alterations. Dysregulation of TARDBP-related genes and RNA splicing has also been observed in other TDP-43 proteinopathies. Importantly, we found that postsynaptic processes were downregulated in FTLD-TDP C, after removing tauopathy-related genes and after cell deconvolution. In particular, assembly of receptors at the postsynaptic membrane and synaptic signal transmission were affected, both on RNA and protein level. Future research on these pathways could elucidate distinct pathophysiological mechanisms and guide targeted clinical approaches.},
}

@article {pmid41789119,
year = {2026},
author = {Höglinger, G and Vandenberghe, W and Woitalla, D and Corvol, JC and Van Tricht, H and Ewen, C and Van Den Steen, B and Rebollo Mesa, I and Germani, M and Garric, E and Arnould, T and Jose, J and Strong, N and De Bruyn, S and Buchanan, TJ},
title = {Safety, tolerability and biomarker results of bepranemab in participants with progressive supranuclear palsy: a randomised, multicentre, double-blind, placebo-controlled, phase 1b trial.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001396},
pmid = {41789119},
issn = {2632-6140},
abstract = {BACKGROUND: Preclinical evidence suggests targeting the mid-region of tau as a viable therapeutic strategy in diseases such as progressive supranuclear palsy (PSP): a rare, fatal, neurodegenerative tauopathy with no currently approved treatments. Bepranemab is a recombinant, humanised, full-length immunoglobulin G4 monoclonal antibody binding to a mid-region tau epitope. We assessed safety, tolerability and pharmacokinetics of bepranemab in participants with PSP.

METHODS: PSP003 (NCT04185415), a multicentre, double-blind, placebo-controlled, phase 1b study, recruited participants in hospital settings across 13 centres. Participants (aged ≥40 years) met Movement Disorder Society-PSP criteria for possible/probable PSP, could walk ≥5 steps with minimal/no assistance and were stable on treatment for ≥2 weeks prior to baseline. Participants were randomised 3:1 to receive intravenous bepranemab (90 mg/kg) or placebo every 4 weeks for 52 weeks. Primary endpoint: incidence of treatment-emergent adverse events (TEAEs) from baseline to last visit.

RESULTS: Twenty-five participants were enrolled (male: 44%; bepranemab n=18, placebo n=7). Seventeen (94.4%) in the bepranemab group reported ≥1 TEAE (five participants; ten investigational medicinal product (IMP)-related TEAEs), versus placebo (n=7; 100%). In the bepranemab and placebo groups, respectively, three participants (16.7%) and one participant (14.3%) discontinued due to TEAEs. Incidence of IMP-related TEAEs and severe TEAEs was similar between groups; no deaths were reported. Reduction (80.41%) in mean free tau cerebrospinal fluid levels was observed in the bepranemab group.

CONCLUSIONS: Multiple doses of bepranemab 90 mg/kg were well tolerated with an acceptable safety profile in participants with PSP. High target occupancy was observed.},
}

@article {pmid41789102,
year = {2026},
author = {Wang, T and Liu, X and Wang, X and Hua, F and Yan, L},
title = {TREM2 and microglial immunity in Alzheimer's disease: mechanisms, genetics, and therapeutic opportunities.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1739875},
pmid = {41789102},
issn = {1664-3224},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder of innate immune dysregulation within the central nervous system. The triggering receptor expressed on myeloid cells 2 (TREM2), a microglial immunoreceptor, has emerged as a pivotal genetic risk factor for late-onset AD, underscoring the critical role of neuroimmune interactions in disease pathogenesis. This review synthesizes recent advances concerning TREM2's modulation of core microglial functions, including phagocytosis, inflammatory signaling, cellular metabolism, and survival, processes that are essential for responding to amyloid-β plaques and neuronal damage. We highlight the TREM2-APOE pathway as a central mechanism driving the disease-associated microglia (DAM) phenotype and examine how loss-of-function mutations such as R47H disrupt immune surveillance, aggravate amyloid pathology, and promote neuroinflammation. Additionally, we explore the diagnostic and therapeutic potential of soluble TREM2 (sTREM2) and TREM2-targeted immunotherapies, which enhance plaque encapsulation and cognitive outcomes in preclinical models. By integrating genetic, molecular, and clinical evidence, this review establishes TREM2 as a keystone regulator linking amyloidosis, tauopathy, and neuroinflammation, highlighting its promise as a target for disease-modifying therapies.},
}

@article {pmid41788972,
year = {2026},
author = {Distefano, A and Calcagno, D and Grasso, G and Monasson, O and Peroni, E and Oliveri, V},
title = {Tolcapone Interferes With Key Pathological Features in Alzheimer's Disease.},
journal = {Bioinorganic chemistry and applications},
volume = {2026},
number = {},
pages = {1036276},
pmid = {41788972},
issn = {1565-3633},
abstract = {Tolcapone, a clinically approved drug for the treatment of Parkinson's disease as an adjunct therapy, has recently emerged as a potential modulator of amyloid-β aggregation and toxicity, which are hallmark features of Alzheimer's disease and are also involved in ocular neurodegenerative disorders, including glaucoma and age-related macular degeneration. Despite these noteworthy findings, the molecular basis of the interaction between amyloid-β and tolcapone remains poorly understood, and the mechanisms by which tolcapone affects metal-amyloid-β species have yet to be explored. In this work, we investigate the binding interactions of tolcapone with both copper-free amyloid-β and copper-associated amyloid-β complexes, using a combination of techniques including UV-vis spectroscopy, circular dichroism, mass spectrometry, and surface plasmon resonance. The results reveal that tolcapone binds directly to amyloid-β monomers. Furthermore, in vitro assays confirm the capacity of tolcapone to act as a radical scavenger and to compete with amyloid-β for the binding of copper ions. Altogether, our findings suggest that tolcapone exerts a multifaceted protective effect, potentially inhibiting toxic metal-free and metal aggregation pathways by preventing metal coordination to amyloid-β or disrupting preformed amyloid-β-metal complexes, thus offering new perspectives to explore and develop its analogs for the treatment of neurodegenerative disorders.},
}

@article {pmid41788921,
year = {2026},
author = {Raj, AP and Simon, M and Bhat, RM and Vaishnav, R and Al Siyabi, MY and Al Maamari, YI and Amr, M},
title = {Knowledge, awareness, and practice of undergraduate medical students on Alzheimer's disease and dementia in Oman.},
journal = {Journal of education and health promotion},
volume = {15},
number = {},
pages = {16},
pmid = {41788921},
issn = {2277-9531},
abstract = {BACKGROUND: Dementia is an acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. Alzheimer's disease is the most common type of dementia, which accounts for 60% to 70% of cases. There are no accurate statistics yet on the percentage of Alzheimer's patients in Oman, and it is expected that the number of patients with this disease will increase. Medical students are exposed to different aspects of Alzheimer's disease very late in their medical curriculum. Early exposure to the disease will increase the level of awareness and interest in the disease. The study might also help in the curricular changes in terms of integration of Dementia-related topics in neurobiology and other relevant preclinical courses. To assess first-year medical students' knowledge and attitude toward Alzheimer's disease and related dementias.

MATERIALS AND METHOD: A cross-sectional survey was carried out among first-year students at the College of Medicine and Health Sciences, National University, Oman, after getting their consent. The sociodemographic data will be collected from the students initially. We also adapted components from the published and previously tested Alzheimer's Disease Knowledge Scale, the Alzheimer's Disease Awareness Scale, and the Dementia Attitudes Scale, in addition to incorporating questions to specifically assess the local practices related to management of the disease.

RESULTS: 127 students participated in the study. 82.7% were females (n = 105), and 17.3% (n = 22) were males. The average age of participants was 19.30 years (SD = 0.769). In our sample, 54.4% of the respondents had correctly identified that loss of memory and forgetting names, appointments, and task repetition in the elderly need medical attention. Approximately half of the students, 47.6%, disagreed that Alzheimer's disease could be caused by black magic or evil eye. As a whole, 53.1% of participants were against hiding diagnoses and advocated for transparency. On the other hand, 73.4% of participants expressed strong disapproval of socially isolating Alzheimer's disease patients to prevent them from experiencing personal embarrassment. 56.7% of the students acknowledged the possibility that certain foods, such as fish, leafy greens, and berries, could reduce the chance of developing Alzheimer's disease. There is a moderate tendency toward belief in the existence of traditional remedies in Oman (45.3%), according to the data, which indicate that there is a mixed assessment of the availability of traditional remedies in Oman.

CONCLUSION: The study indicates a well-informed understanding of Alzheimer's disease and dementia within the studied community, especially concerning dietary influences and the possibilities of medicinal interventions. The divergent opinions on standard and alternative medicines suggest that additional education and study could be advantageous. As Alzheimer's disease research progresses, continuous public education initiatives will be essential to align attitudes with the most recent scientific findings and accessible treatment alternatives.},
}

@article {pmid41788860,
year = {2026},
author = {Mehmood, A and Farman, M and Afzal, F and Nisar, KS and Ahmed, MA and Hafez, M},
title = {A Physics Informed Neural Network (PINN) framework for fractional order modeling of Alzheimer's disease.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1748481},
pmid = {41788860},
issn = {1662-5196},
abstract = {This study presents a novel fractional order model of Alzheimer's disease (mental disorder) using the Caputo derivative to accurately capture long term memory and hereditary effects in neurodegeneration. The mathematical model incorporates key pathological constituents including neurons, amyloid beta (A β), tau proteins and microglial responses, allowing detailed simulation of their dynamic interactions. Fundamental properties of the model, including positivity, boundedness, invariant regions and equilibrium points, are rigorously analyzed to ensure biological feasibility. Sensitivity analysis identifies amyloid toxicity as the most influential driver of neuronal loss underscoring its central role in AD progression. Furthermore, a Physics Informed Neural Network (PINN) is developed to approximate system dynamics from noisy observations while ensuring compliance with biological and physical constraints. Compared to standard neural networks the PINN exhibits superior accuracy and robustness especially under data scarcity. By integrating fractional calculus, optimal control and machine learning, this work advances computational modeling of Alzheimer's disease and offers insights into therapeutic optimization.},
}

@article {pmid41788548,
year = {2026},
author = {Zheng, Y and Zhou, W and Chang, H and Zheng, K},
title = {Brain organoids as precision models for neurodegenerative diseases: from disease modeling to drug discovery.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1764964},
pmid = {41788548},
issn = {1662-4548},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have become major global causes of disability and mortality. Their complex pathogenic mechanisms remain incompletely understood, and effective disease-modifying therapies are still lacking. Traditional animal models and two-dimensional (2D) cell culture systems exhibit notable limitations in structural complexity, human relevance, and translational validity, making it difficult to faithfully recapitulate human-specific neuropathology. In recent years, brain organoid technology derived from induced pluripotent stem cells (iPSCs) has advanced rapidly, enabling the self-organization of diverse neuronal and glial cell types within a three-dimensional (3D) architecture that partially mimics human brain development and disease-related pathological events. When integrated with CRISPR-Cas9-based genome editing and multi-omics profiling, organoids support causal mechanism studies, target validation, and individualized drug-response prediction, highlighting their growing value in early-stage drug discovery. Despite current challenges-including insufficient maturation, lack of vascularization and immune components, and batch variability-the continuous progress in bioengineering, microfluidic systems, and artificial intelligence (AI)-driven multimodal data analysis is steadily expanding the translational potential of organoids as human-relevant preclinical models. Overall, brain organoids provide an essential foundation for constructing physiologically relevant and predictive research platforms for neurodegenerative diseases, offering new opportunities for therapeutic development and precision medicine.},
}

@article {pmid41788409,
year = {2026},
author = {Chen, R and Fan, S and Di, C and Wu, H and Shi, Z and Liu, F and Lv, Z and Liu, S and Ji, Y},
title = {Insulin resistance (TyG index) and body mass index as metabolic biomarker combined with ApoE genotype to diagnose Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1731547},
pmid = {41788409},
issn = {1663-4365},
abstract = {BACKGROUND: Growing evidence suggests that both ApoE genotype and metabolic disturbances including insulin resistance (IR) and obesity constitute risk factors for Alzheimer's disease (AD). However, large-scale studies investigating whether ApoE genotype interacts with metabolic abnormalities to indirectly impair cognitive function in AD remain scarce.

OBJECTIVE: This cross-sectional study aimed to explore the associations between ApoE genotype, metabolic disturbances [IR assessed by triglyceride-glucose (TyG) index and body mass index (BMI)], and cognitive function in AD patients.

METHODS: We analyzed 1,162 clinically diagnosed probable AD patients from the Cognitive Impairment Clinic at Tianjin Huanhu Hospital. Participants were categorized by ApoE ε4 carrier status. Metabolic parameters were evaluated using the TyG index and BMI. Mediation effect models were employed to assess the relationships between ApoE genotype, metabolic indices, and cognitive function.

RESULTS: ApoE ε4 carriers exhibited significantly lower BMI (P < 0.001) and higher TyG index (P < 0.001) compared to non-ApoE ε4 carriers. Significant TyG index elevation in ApoE ε4 carriers was observed in AD patients with Mini-Mental State Examination (MMSE) > 20 (P = 0.0036) and MMSE 10-20 (P = 0.009). Mediation analysis revealed that ApoE ε4 exerted 73.4% of its negative effect on cognition through direct pathways, while 9.7 and 16.9% were mediated through BMI reduction and TyG elevation, respectively.

CONCLUSION: ApoE ε4 carriers demonstrate a distinct metabolic profile characterized by lower BMI and elevated TyG index, associated with poorer cognitive performance. Our findings suggest that ApoE ε4 may indirectly influence AD cognition through metabolic pathways, highlighting early interventions targeting ApoE-related metabolic dysregulation as potential strategies to delay AD progression.},
}

@article {pmid41788296,
year = {2026},
author = {Guo, ZL and Cui, MW and Dong, YL and Wang, S},
title = {The oral microbiome as a regulatory hub for systemic health: a systematic review of mechanistic links and clinical implications.},
journal = {Journal of oral microbiology},
volume = {18},
number = {1},
pages = {2635233},
pmid = {41788296},
issn = {2000-2297},
abstract = {BACKGROUND: The human oral microbiome is a highly diverse ecosystem with important roles in oral and systemic health. Beyond dental caries and periodontitis, oral dysbiosis has been increasingly implicated in the development of multiple non-communicable diseases.

OBJECTIVE: To systematically synthesize evidence on the mechanisms linking oral dysbiosis to systemic diseases and to summarize its diagnostic and therapeutic implications.

DESIGN: A systematic review was performed using major electronic databases. We screened 1,128 records and included 104 studies that met predefined eligibility criteria.

RESULTS: Evidence indicates that oral dysbiosis may influence systemic health through several mechanisms, including hematogenous dissemination of oral pathogens and virulence factors (e.g. lipopolysaccharide), chronic systemic inflammation, molecular mimicry in autoimmune disorders, and microbial metabolic byproducts. The reviewed studies support associations between oral microbiome alterations and atherosclerotic cardiovascular disease, type 2 diabetes, Alzheimer's disease, rheumatoid arthritis, and gastrointestinal cancers. The literature also highlights the promise of non-invasive oral microbiome-based biomarkers for early detection and disease monitoring. Emerging microbiome-modulating interventions, including probiotics, prebiotics, and bacteriophage therapy, show potential for restoring oral eubiosis and improving systemic outcomes.

CONCLUSIONS: Oral dysbiosis is an important regulator of systemic disease processes and a promising target for diagnosis, prevention, and therapy. Integrating oral health and oral microbiome assessment into broader disease management may improve outcomes, although methodological standardization and stronger causal evidence are still needed.},
}

@article {pmid41788194,
year = {2026},
author = {Municio, C and Sapidou, K and Apsley, EJ and Fernandez-Otero, M and Arber, CE and Wray, S and Carro, E and Pellegrini, L},
title = {Choroid plexus organoids mimic amyloid uptake at the blood-cerebrospinal fluid-barrier.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1769911},
pmid = {41788194},
issn = {1662-5102},
abstract = {The choroid plexus (ChP) is a specialised tissue of the central nervous system that produces cerebrospinal fluid (CSF), maintains cerebral homeostasis and forms the blood-CSF barrier (B-CSF-B), a key interface that regulates the exchange of substances between the blood and the brain. Despite its physiological importance, the involvement of the ChP in neurodegenerative diseases such as Alzheimer's disease (AD), remains poorly understood. This is largely due to the reliance on murine models and the limited availability of human brain tissue. Recent advances in human stem-cell derived ChP organoids now offer a more physiologically relevant model to interrogate ChP role in human health and disease. Given that in AD pathology beta-amyloid (Aβ) accumulation has been linked to early disruption of brain barriers, studying the B-CSF-B is particularly relevant. Transthyretin (TTR), the predominant protein secreted by the ChP, is thought to play a role in the transport and clearance of Aβ, although its exact mechanisms are not yet fully elucidated. Here, we propose the use of ChP organoids to investigate the role of the B-CSF-B in amyloid uptake which may contribute to barrier dysfunction and disease progression in AD.},
}

@article {pmid41788190,
year = {2026},
author = {Matsuura, S and Tagai, K and Tatebe, H and Goto, R and Matsumoto, H and Oyama, A and Momota, Y and Ichihashi, M and Kataoka, Y and Matsuoka, K and Kokubo, N and Kamada, T and Osawa, K and Chishiki, Y and Moriguchi, S and Komatsu, Y and Seki, C and Takahata, K and Endo, H and Kudo, T and Higuchi, M and Tokuda, T},
title = {Comparison of three plasma p-tau217 assays to detect PET-confirmed Alzheimer's pathologies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70294},
pmid = {41788190},
issn = {2352-8729},
abstract = {INTRODUCTION: Plasma phosphorylated tau 217 (p-tau217) has emerged as a promising blood-based biomarker for Alzheimer's disease (AD) diagnosis, but cross-platform comparability remains unclear. We evaluated three platforms-single-molecule array (Simoa), Ella, and Lumipulse.

METHODS: We measured plasma p-tau217 from 113 participants underwent amyloid and tau positron emission tomography (PET; 55 AD, 36 controls, 22 non-AD; classified by amyloid PET status). Diagnostic performance and PET correlations were assessed across all three platforms.

RESULTS: All assays distinguished amyloid-positive from -negative individuals with high accuracy (89%-95%). Simoa showed superior sensitivity, Ella the smallest gray zone in a two-cutoff framework, and Lumipulse strongest tau correlation (r = 0.770). Multiple regression revealed higher amyloid β-values for Simoa/Ella (0.420-0.518) and higher tau β-values for Lumipulse (0.630). All platforms detected elevated p-tau217 in amyloid-positive individuals with substantial tau pathology despite relatively low Centiloid.

DISCUSSION: All platforms accurately detect AD with platform-specific differences, which inform platform selection for clinical and research applications.

TRIAL REGISTRATION: Clinical Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR), Trial ID: UMIN000057548, Registration Date: April 8, 2025.},
}

@article {pmid41788162,
year = {2026},
author = {Tomlin, M and Podpolny, M and Salinas, PC},
title = {Progressive changes in synapses and glial cells in App[NL-G-F] mice, a model of Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcaf484},
pmid = {41788162},
issn = {2632-1297},
abstract = {It is well documented that synapse loss correlates with cognitive decline in Alzheimer's disease. However, the mechanisms that contribute to synapse loss remain poorly understood. Studies have shown that amyloid-β directly signals to neurons to trigger changes in synaptic function leading to the subsequent loss of synapses. Other studies have demonstrated that glial cells directly target synapses in Alzheimer's disease. In this study, we determine the temporal relationship between changes in synapses and glial cells (microglia and astrocytes) in the NL-G-F knock-in mouse model of Alzheimer's disease. We evaluated synapse number and histological changes in glial cells in the hippocampus of NL-G-F mice using confocal microscopy across three timepoints, 2, 5, and 9 months, compared to their wild-type littermates. Using real-time quantitative PCR, we also evaluated molecular changes in glial cells. At 2 months of age, when very few amyloid-β plaques are present, inhibitory synapse number was transiently increased by more than 50% in NL-G-F mice, accompanied by a small increase in the microglial marker, Cx3cr1, and considerable changes in astrocyte markers, including a decreased level of Thbs1/2. At 5 months, when amyloid-β plaque load is notable, excitatory synapse number was decreased immediately proximal to plaques, whereas inhibitory synapse number was no different between NL-G-F and wild-type mice. At the cellular level, changes in microglia and astrocytes were also observed in NL-G-F mice in regions closely surrounding plaques. From 5 months, PCR analyses indicated marked and progressive changes in microglia and astrocyte markers, including increased Trem2 and Gfap expression. By 9 months, changes in excitatory synapse number and microglia at the cellular level were exacerbated, with evident synapse loss extending up to 30 µm away from plaques. Together, our data show that inhibitory synapses are the earliest change in NL-G-F mice occurring concomitantly with molecular changes in glial cells and preceding substantial plaque deposition, excitatory synapse loss, and glial cellular alterations.},
}

@article {pmid41788154,
year = {2026},
author = {Wu, Y and Mai, N},
title = {Structural Alterations and Cognitive Impairment in Late-Onset Depression: A Reverse Correlation Analysis.},
journal = {Alpha psychiatry},
volume = {27},
number = {1},
pages = {44585},
pmid = {41788154},
issn = {2757-8038},
abstract = {BACKGROUND: Late-onset depression (LOD), particularly when accompanied by cognitive impairment, represents a significant risk factor for dementia. Prevailing perspectives emphasize that cognitive impairment arises from interactions among multiple brain regions. However, current approaches to identifying brain network patterns associated with cognitive impairment largely rely on group-level analyses with multiple-comparison corrections, which may obscure complex and interconnected relationships between brain regions. Our previous research demonstrated that alterations in brain network properties in patients with LOD are closely associated with cognitive function. We therefore hypothesised that aberrant interactions among multiple brain regions in LOD lead to changes in network properties and subsequent cognitive dysfunction.

METHODS: This study aimed to investigate the interregional brain interactions underlying cognitive impairment in LOD by leveraging the robust interpretability of neural network models. Specifically, we sought to: (1) develop a neural network model of LOD-related cognitive impairment based on brain network properties; and (2) apply a reverse correlation approach to identify connectivity features associated with cognitive impairment in LOD.

RESULTS: No statistically significant differences were observed in tthe structural network properties when comparing the LOD and control participant groups across various thresholds. Using a neural network-based reverse correlation method, the most prominent differences were identified in the inferior, middle, and anterior regions of the left temporal pole when comparing patients with LOD with and without mild cognitive impairment (MCI).

CONCLUSION: Alterations in the internal structure of the temporal lobe may represent potential anatomical biomarkers for the early prediction of Alzheimer's disease, providing novel insights into the pathophysiological mechanisms underlying LOD-related MCI. The research framework proposed in this study effectively addresses the challenge of detecting subtle intergroup anatomical differences in studies with limited sample sizes. Moreover, the reverse correlation approach is not restricted to multilayer neural networks; as machine learning models become increasingly powerful and accessible, this method offers a practical and interpretable alternative for exploratory neuroimaging research.},
}

@article {pmid41788046,
year = {2026},
author = {Ledingham, D and Sathyanarayana, S and Stewart, CB and Iredale, R and Foster, V and Galley, D and Lad, M and Baker, MR and Pavese, N},
title = {Alzheimer's Biomarkers and Visuospatial Cognition in Parkinson's Disease: Modification by α-Synuclein and Mediation of Age Effects.},
journal = {Movement disorders clinical practice},
volume = {},
number = {},
pages = {},
doi = {10.1002/mdc3.70576},
pmid = {41788046},
issn = {2330-1619},
abstract = {BACKGROUND: Visuospatial deficits in Parkinson's disease (PD) often precede dementia and complicate daily functioning. Alzheimer's disease (AD) pathology and α-synuclein aggregation frequently co-occur in PD, but their combined impact on cognition is unclear.

OBJECTIVES: To examine whether AD biomarker burden relates to visuospatial performance in PD, whether this effect differs by α-synuclein status, and whether AD biomarkers mediate age-related decline.

METHODS: We analyzed 416 participants from the Parkinson's Progression Markers Initiative. AD biomarker burden was indexed by the cerebrospinal fluid pTau181/Aβ42 ratio; α-synuclein aggregation was assessed using seed amplification assay. Models adjusted for age, sex, education, and motor severity. Sensitivity analyses included genetic stratification and subgroup exclusion.

RESULTS: Higher AD biomarker burden was associated with poorer visuospatial performance and delayed recall. In participants with concurrent biomarker data (n = 246), AD burden interacted with α-synuclein status to predict worse visuospatial outcomes, with the greatest impairment observed in individual's positive for both biomarkers. Mediation analysis indicated that AD biomarker burden accounts for approximately 10-14% of the age effect on visuospatial performance.

CONCLUSIONS: AD and α-synuclein biomarkers show associations consistent with synergistic effects on visuospatial cognition in PD. These findings are exploratory and require replication in pre-specified independent cohorts. However, if validated, testing both biomarkers could help identify individuals at higher risk of early visuospatial decline and inform hypothesis-driven stratification in future clinical trials.},
}

@article {pmid41787981,
year = {2026},
author = {Huang, T and Zhang, M and Zhang, Y and Su, C and He, E and Wang, J and Yang, J and Liu, Y and Zeng, Y and Chen, X},
title = {Hippocampal Hap1 downregulation exacerbates Alzheimer's disease-related neuropathology through impairment of glucocorticoid receptor nuclear translocation in APP/PS1 mice.},
journal = {Zoological research},
volume = {},
number = {},
pages = {},
doi = {10.24272/j.issn.2095-8137.2025.436},
pmid = {41787981},
issn = {2095-8137},
abstract = {Although impaired nuclear translocation of glucocorticoid receptor (GR) contributes to hippocampal vulnerability in Alzheimer's disease (AD), its regulatory mechanisms remain poorly understood.Here, we identify Huntingtin-associated protein 1 (Hap1) as a critical regulator of GR nuclear translocation in the hippocampus. Specifically, Hap1 expression progressively declines in the APP/PS1 mouse hippocampus with aging and pathological progression. Hippocampal Hap1 knockdown induces cognitive deficits and synaptic loss, manifested as reduced dendritic complexity and spine density alongside impaired long-term potentiation (LTP), while exacerbating Aβ deposition in APP/PS1 mice. Crucially, Hap1 deficiency promotes GR ubiquitination and proteasomal degradation and, more critically, disrupts ligand-dependent GR nuclear translocation, thereby impairing GR-dependent BDNF transcription. Additionally, Hap1 knockdown elevates corticosterone levels and induces depressive-like behaviors, confirming hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Our results establish disruption of Hap1-mediated GR nuclear translocation as a key pathomechanism linking intracellular transport defects to synaptic failure in AD, suggesting Hap1 modulation as a potential therapeutic avenue.},
}

@article {pmid41787940,
year = {2026},
author = {Conti, M and Teghil, A and Schettino, M and D'Antonio, F and Sepe Monti, M and Talarico, G and Bruno, G and Di Vita, A and Alessandri, G and Guariglia, C and Boccia, M},
title = {Subtle alterations of autobiographical memory and spatiotemporal processing in subjective cognitive decline.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/13803395.2026.2637509},
pmid = {41787940},
issn = {1744-411X},
abstract = {INTRODUCTION: The deterioration of autobiographical memory (AM) and autonoetic consciousness is central in Alzheimer's Disease (AD). Here, we investigated the presence of AM alterations in a potential preclinical stage of AD known as Subjective Cognitive Decline (SCD), characterized by a self-reported worsening in cognitive functioning without an objective cognitive impairment. Considering the key role of spatial and temporal components in episodic features of AM, we further hypothesized that alterations in such components may be highlighted in SCD, and investigated possible modifications in these functions with tasks tapping environmental navigation and duration processing. Finally, the level of cognitive complaints was also considered a factor that may modulate performance.

METHOD: Performance of 31 individuals with SCD was compared with that of 31 healthy control participants matched for age, gender, and education. AM was assessed using the Autobiographical Interview and the Autobiographical Fluency Task (AFT). Environmental navigation was investigated using a battery assessing route, landmark, and survey knowledge, and landmark ordering. Temporal processing was assessed with computerized tasks investigating retrospective and prospective duration processing.

RESULTS: SCD produced more items in the personal semantics condition of the AFT compared with healthy controls, while showing reduced performance in landmark recognition and survey knowledge. When considering cognitive complaints, which are known to play a role in modulating performances in SCD, results showed a positive association between scores on the Cognitive Failure Questionnaire and scores on the semantic condition of the AFT, and a significant negative correlation between scores on the Cognitive Failure Questionnaire and performance in retrospective duration processing.

CONCLUSIONS: Findings suggest that subtle alteration of AM and spatiotemporal processing can be identified in SCD, and that the level of cognitive complaints may be a relevant factor in modulating spatiotemporal processing and autobiographical memory in this population.},
}

@article {pmid41787649,
year = {2026},
author = {Seok, J and Lee, H and Seo, J},
title = {Investigating the Causal Links between the Aging Process and Alzheimer's Disease Pathogenesis.},
journal = {International journal of stem cells},
volume = {},
number = {},
pages = {},
doi = {10.15283/ijsc25100},
pmid = {41787649},
issn = {2005-3606},
abstract = {As global societies age, the prevalence of neurodegenerative disorders, such as Alzheimer's disease, is rapidly increasing, intensifying the need to understand the mechanisms of aging and their contribution to these conditions. Consequently, the focus of aging research has shifted from the traditional concept of chronological age to a more nuanced understanding of biological age. This has spurred active investigation into robust biomarkers, including cellular senescence. However, the application of classical senescence markers to the brain presents a substantial challenge, as their validity in post-mitotic cells, such as neurons, remains unclear. In this review, we highlight the limitations of the current metrics for cellular senescence as indicators of biological aging, and propose a path forward focused on identifying and modeling cell-type-specific aging markers within the brain.},
}

@article {pmid41787549,
year = {2026},
author = {Tan, YJ and Mohammadi, R and Saffari, SE and Tan, NI and Lim, LS and Low, SH and Tan, LC and Chiew, HJ and Ng, KP and Hameed, S and Ting, SK and Ng, AS},
title = {Evaluating the real-world performance of plasma pTau217 and pTau181 in a Southeast Asian tertiary memory clinic.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02008-5},
pmid = {41787549},
issn = {1758-9193},
support = {MOH-CNIG22jul-0006//National Medical Research Council/ ; MOH-OFLCG18May-0002//National Medical Research Council/ ; MOH-CSAINV21-0005, NMRC/CG2/005a/2022-NNI//National Medical Research Council/ ; SHF(U)/22/GC-5C/007(EC), SHF(U)/23/GC-2C/002(EC)//SingHealth Fund- NNI Fund/ ; },
}

@article {pmid41787516,
year = {2026},
author = {Horikoshi, K and Nakajima, M and Miyajima, M and Miyahara, R and Sakamoto, K and Kawamura, K and Akiba, C and Kamohara, C and Ogino, I and Tsunemi, T and Karagiozov, K and Kondo, A},
title = {Plasma p-Tau217 and amyloid-β oligomers as complementary biomarkers for differential diagnosis, comorbidity detection and disease monitoring in idiopathic normal pressure hydrocephalus.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00784-8},
pmid = {41787516},
issn = {2045-8118},
support = {22GB1002//Juntendo Research Branding Project, Health, Labor and Welfare Sciences Research Grants/ ; 20K09355, 20K09398, and 24K10497//Japan Society for the Promotion of Science under Grants-in-Aid for Scientific Research/ ; },
}

@article {pmid41787435,
year = {2026},
author = {Bermudez, C and Hofrenning, E and Fought, AJ and Gunter, JL and Cogswell, PM and Jones, DT and Schwarz, CG and Lowe, V and Elder, BD and Petersen, RC and Vemuri, P and Algeciras-Schimnich, A and Mielke, MM and Knopman, DS and Graff-Radford, NR and Jack, CR and Graff-Radford, J},
title = {Plasma biomarkers of Alzheimer's disease and their association with disproportionately enlarged subarachnoid space hydrocephalus.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00789-3},
pmid = {41787435},
issn = {2045-8118},
support = {P30 AG062677/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; RF1 AG069052/AG/NIA NIH HHS/United States ; },
}

@article {pmid41787238,
year = {2026},
author = {Mayeri, Z and Woods, G and Rane, A and Kifle, A and Chamoli, M and Shukla, S and Walton, CC and Andersen, JK},
title = {A compound enhancing lysosomal function reduces tau pathology, microglial reactivity and rescues working memory in 3xTg AD mice.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41787238},
issn = {2509-2723},
support = {R01AG067325/AG/NIA NIH HHS/United States ; },
abstract = {Recent advancements in Alzheimer's disease (AD) therapeutics have validated the use of amyloid beta (Aβ)-clearing antibodies, which reduce Aβ pathology but leave other disease hallmarks largely unaddressed. Since AD involves multiple pathological processes, additional strategies are needed to target complementary mechanisms. One such target is autophagy, a lysosomal mediated degradation pathway essential for cellular homeostasis that removes toxic protein aggregates and damaged organelles. This process is implicated in AD, as impaired lysosomal function promotes Aβ and tau accumulation. Our laboratory recently identified a novel natural mitophagy inducing compound (MIC) that may serve as a therapeutic intervention for AD. We evaluated the effects of MIC in aged 3xTgAD mice, a transgenic model displaying both Aβ and tau pathology. Mice received either standard diet or diet containing MIC beginning at age 4 months until 20 months on alternating weeks. Age-matched non-transgenic (NonTg) controls were included under standard and MIC-supplemented diets to assess compound effects during normal aging. Neuropathological changes were assessed using immunohistochemistry (IHC) for Aβ, phosphorylated tau (pTau), and microglial reactivity. Cognitive performance was evaluated using the Morris Water Maze (MWM) to assess spatial learning and memory and the Y-maze to measure working memory. At 20 months of age, our neuropathological assessment showed that 3xTgAD mice fed an MIC-supplemented diet had a significant reduction in pTau accumulation and microglial reactivity, although Aβ burden remained unchanged. At 15 months, MIC diet also improved spatial learning and memory in aged NonTg controls but not in 3xTgAD mice. However, in younger 8 month-old 3xTgAD mice, MIC restored working memory performance to NonTg levels, indicating an age-dependent therapeutic response. MIC emerges as a potential modulator of tau pathology and neuroinflammation. As a naturally derived compound, MIC offers potential for combination therapy with FDA-approved Aβ-clearing antibodies, enabling a multimodal approach to AD treatment that addresses amyloid, tau, and microglia-related pathology.},
}

@article {pmid41787187,
year = {2026},
author = {Zhu, Z and Ni, M and Lv, X and Peng, J and Gao, F and Pan, B and Shen, Y and Wang, S and Shi, J},
title = {Regional cerebral hypometabolism and pathological heterogeneity in sporadic early onset alzheimer's disease: China Aging and Neurodegenerative Initiative (CANDI) study.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {41787187},
issn = {1619-7089},
support = {XDB39000000//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; YD9100002033//the Joint Fund for New Medicine of USTC/ ; 2308085QH265//the Natural Science Foundation of Anhui Province/ ; 202304295107020056//the Anhui Provincial Key R&D Programmes/ ; 20230429510702 0053//the Anhui Provincial Key R&D Programmes/ ; MAI2023Q024//the Joint Fund for Medical Artificial Intelligence/ ; },
}

@article {pmid41787137,
year = {2026},
author = {Marano, G and Da Cas, R and Ippoliti, I and Caffarra, P and Locuratolo, N and Vanacore, N and Ancidoni, A},
title = {Regulatory, clinical, and post-marketing challenges of lecanemab for Alzheimer's disease: insights from real-world data.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {4},
pages = {},
pmid = {41787137},
issn = {1590-3478},
}

@article {pmid41787135,
year = {2026},
author = {Rekha, D and Kamala Kumari, PV and Thummala, UK and Dastagiri Reddy, Y and Prasanth, D and Praveen Kumar, P},
title = {Machine Learning-Integrated Pharmacophore, DFT Analysis, and molecular dynamics of Diosmetin as a potent ache inhibitor with neuroprotective activity in a Scopolamine-Induced alzheimer's zebrafish model.},
journal = {Journal of computer-aided molecular design},
volume = {40},
number = {1},
pages = {},
pmid = {41787135},
issn = {1573-4951},
abstract = {Alzheimer's Disease (AD) is a degenerative disorder of the brain that causes a gradual loss of cognitive function. The cholinergic hypothesis suggests that acetylcholine deficiency is the main cause of AD, which explains why blocking acetylcholinesterase (AChE) is the most effective way to treat AD. Nevertheless, there are some drawbacks to the currently available AChE inhibitors; thus, new molecules with better therapeutic effects and fewer side effects are needed. In this study, the anti-Alzheimer activity of diosmetin, a natural flavonoid, was investigated via an integrated computational and experimental approach. Pharmacophore mapping revealed that the essential chemical features of diosmetin are responsible for AChE inhibition, and density functional theory calculations were employed to investigate its electronic properties and chemical behavior. Molecular docking experiments indicated that diosmetin could bind firmly to AChE with a binding energy of -9.49 kcal/mol. Molecular dynamics simulations strengthened this hypothesis by showing that the diosmetin-AChE complex remained stable over time. In vivo verification using a scopolamine-induced zebrafish model of Alzheimer's disease revealed that diosmetin administration notably enhanced learning and memory abilities in zebrafish. Various behavioral paradigms, including the light/dark preference test, novel tank diving test, T-maze test, and novel object recognition test, have been used to assess cognitive function. Biochemistry revealed that diosmetin counteracted the scopolamine-induced increase in AChE activity, increased oxidative stress, increased myeloperoxidase inflammatory markers, decreased antioxidant activity, and restored normal histology in the brains of the zebrafish. Most importantly, high-dose diosmetin demonstrated comparable neuroprotective efficacy to donepezil in behavioral and biochemical assays while exhibiting weaker molecular binding affinity toward AChE, as indicated by MM-PBSA analysis, underscoring that similar in vivo outcomes do not necessarily imply molecular equivalence at the binding level.},
}

@article {pmid41787100,
year = {2026},
author = {Fieldhouse, R},
title = {These brain cells clear proteins that contribute to Alzheimer's.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41787100},
issn = {1476-4687},
}

@article {pmid41787076,
year = {2026},
author = {Mummery, CJ and Mayorga, AJ and Simmons, A and Chow, TW and Burgess, B and Nguyen, T and Gao, J and Budda, B and Park, LQ and Gupta, R and Li, C and Shi, L and Kenkare-Mitra, S and Rosenthal, A and Paul, R and Ward, M and Purcell, DD and Salloway, S and Grundman, M and Romano, G and Salvadore, G},
title = {The TREM2 agonistic antibody AL002 in early Alzheimer's disease: a phase 2 randomized trial.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41787076},
issn = {1546-170X},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial function and is implicated in Alzheimer's disease (AD) pathogenesis. Here we conducted a phase 2, randomized, double-blind, placebo-controlled trial of a humanized TREM2 agonistic monoclonal antibody in 381 participants with early AD. Participants were randomized (1:1:1:1) to receive AL002 (15 mg kg[-1], 40 mg kg[-1] or 60 mg kg[-1]) or placebo intravenously every 4 weeks for 48-96 weeks. AL002 demonstrated sustained target engagement and pharmacodynamic responses in the central nervous system, as demonstrated by reductions in soluble TREM2 and increases in osteopontin in cerebrospinal fluid, respectively. The study did not meet the primary endpoint of change from baseline in the Clinical Dementia Rating-Sum of Boxes score (versus placebo) (least squares mean difference versus placebo (95% confidence interval) at week 96: 15 mg kg[-1] -0.31 (-1.61 to 0.98), 40 mg kg[-1] 0.13 (-1.18 to 1.43) and 60 mg kg[-1] -0.17 (-1.49 to 1.15); P > 0.05 from mixed-effects model for repeated measures). The most frequent treatment-emergent adverse events were magnetic resonance imaging changes resembling amyloid-related imaging abnormalities (ARIA). This first trial of a TREM2 agonistic antibody in early AD was negative but provides findings relevant to the study of TREM2 therapeutics and ARIA. ClinicalTrials.gov: NCT04592874 .},
}

@article {pmid41787071,
year = {2026},
author = {Haapala, EA and Heinonen, S and Mykkänen, J and Niinikoski, H and Lagström, H and Salo, P and Jula, A and Rönnemaa, T and Viikari, JS and Raitakari, OT and Pahkala, K and Rovio, S},
title = {Genetic susceptibility to Alzheimer's disease and cardiometabolic risk from childhood.},
journal = {Pediatric research},
volume = {},
number = {},
pages = {},
pmid = {41787071},
issn = {1530-0447},
abstract = {BACKGROUND: We investigated the associations of genetic risk score for Alzheimer's disease (GRS-AD) with cardiometabolic risk from early childhood over a 20-year follow-up.

METHODS: The STRIP study included 1062 children at baseline. GRS-AD was calculated for 631 participants using 22 independent genetic risk variants, including APOE ε2 and ε4 alleles, and excluding them (non-APOE-GRS-AD). We repeatedly measured waist circumference, high-density (HDL-C) and low-density (LDL-C) lipoprotein cholesterol, triglycerides, glucose, insulin, and blood pressure. The data were analysed with generalised additive mixed models.

RESULTS: GRS-AD was directly associated with serum LDL-C (unstandardised β = 0.140, 95% CI = 0.084 to 0.195) and inversely with HDL-C (β = -0.026, 95% CI = -0.044 to -0.009). GRS-AD was inversely associated with serum HDL-C in males (β = -0.044, 95% CI = -0.070 to -0.018) but not in females (β = -0.010, 95% CI = -0.032 to 0.012). The associations were diluted when the non-APOE-GRS-AD was applied.

CONCLUSION: A genetic predisposition to AD may alter lipid metabolism from early childhood.

IMPACT: While Alzheimer's disease and cardiometabolic diseases may have shared genetic determinants, the associations between genetic susceptibility for Alzheimer's disease and increased cardiometabolic risk from childhood to young adulthood are poorly understood. We investigated the associations of genetic risk score for Alzheimer's disease with cardiometabolic risk from early childhood over a 20-year follow-up. We found that a higher genetic risk score for Alzheimer's disease was associated with higher LDL cholesterol, non-HDL cholesterol, and ApoB, and with lower serum HDL cholesterol and ApoA1. These findings suggest that a genetic predisposition to Alzheimer's disease may alter lipid metabolism from early childhood.},
}

@article {pmid41787066,
year = {2026},
author = {Colombo, G and Minta, K and Taylor, WR and Grübel, J and Chong, E and Chong, JR and Lim, MJH and Gonzales, PNG and Lai, MKP and Chen, CP and Schinazi, VR},
title = {Spatial navigation as a digital marker for clinically differentiating cognitive impairment severity.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01484-y},
pmid = {41787066},
issn = {2730-664X},
abstract = {BACKGROUND: Spatial navigation impairments emerge early in Alzheimer's disease, but assessments targeting these deficits remain underutilised or impractical for cognitive screening. The Spatial Performance Assessment for Cognitive Evaluation (SPACE) is a newly developed digital tool that evaluates spatial navigation deficits associated with cognitive impairment.

METHODS: We assessed spatial navigation ability using SPACE in 300 older adults recruited from memory clinics and the general community. Participants were classified across different levels of cognitive impairment using the Clinical Dementia Rating (CDR) scale. Performance in SPACE was compared with clinical diagnosis, standard cognitive assessments, and demographic models using Area Under the ROC Curve (AUC), sensitivity, and specificity.

RESULTS: We show that SPACE reliably distinguishes CDR levels, exceeding the accuracy of demographic models and matching or surpassing most traditional neuropsychological tests. Including SPACE significantly increases the AUC for distinguishing between no dementia from mild dementia (0.76 to 0.94), no dementia from moderate dementia (0.79 to 0.95), and questionable dementia from mild dementia (0.70 to 0.91), all with consistently high sensitivity and specificity. A shortened version of SPACE, lasting less than 11 minutes, reduces administration time by 40% while maintaining high diagnostic accuracy. Cross-validation analyses confirm the reliability and robustness of these models.

CONCLUSIONS: These findings highlight the potential of digital spatial navigation assessments to advance early detection, contributing to scalable and accessible healthcare.},
}

@article {pmid41786925,
year = {2026},
author = {Iqbal, S and Nisar, H and Yeap, KH},
title = {Quantitative EEG signatures of power and functional connectivity alterations in Alzheimer's disease and frontotemporal dementia.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-42452-9},
pmid = {41786925},
issn = {2045-2322},
support = {IPSR/RMC/UTARRF/2023-C2/H01//Universiti Tunku Abdul Rahman/ ; },
abstract = {Dementia is a common neurodegenerative disease in the elderly, which affects the structural and functional connectivity of the brain. Recent studies indicate that electrophysiological measures, such as power spectral features and functional connectivity (FC), show promise for the diagnosis and classification of dementia. However, findings across studies remain inconsistent, and distinct electrophysiological patterns separating dementia subtypes, as well as Frontotemporal Dementia (FTD) and cognitively normal (CN) individuals, are not yet well established. This study focuses on spectral power and functional connectivity (FC) analyses of the Electroencephalography (EEG) frequency bands (delta, theta, alpha, beta, and gamma) in Alzheimer's Disease (AD) and FTD. A publicly available eyes-closed (EC), resting-state (RS) EEG dataset comprising 88 age-matched participants, 36 with AD, 29 CN, and 23 with FTD, was used in this study. Absolute power was computed using Welch's method, while FC within each frequency band was assessed using Inter-Site Phase Clustering (ISPC) and network-based statistics, edge and node strength. The global power analysis revealed a significantly higher alpha power in CN compared to both AD and FTD. Regional analysis revealed a significantly lower temporal and parietal alpha in AD relative to CN and a significantly lower occipital alpha and beta in both AD and FTD compared to CN. Topographical power analysis showed unique significant differences within lobes in delta, theta, alpha, and gamma bands in AD and FTD, with AD illustrating a relatively more heterogeneous power distribution than FTD. Furthermore, FC analysis indicated that compared with CN, AD exhibited significantly lower edge strength in delta, theta, beta, and gamma bands, while significantly lower node strength in delta, theta, and gamma bands. Likewise, compared with CN, FTD showed significantly lower edge and node strength in the delta and theta bands, while significantly higher in the beta band. Furthermore, when compared to FTD, AD revealed a significantly lower edge and node strength in the delta, beta, and gamma bands. In conclusion, AD was associated with widespread FC disruptions, while FTD retained partially preserved connectivity, with the temporal lobe more affected than the frontal lobe. These findings suggest that band power and FC alterations may serve as potential biomarkers for diagnosing and classifying dementia into AD and FTD.},
}

@article {pmid41786890,
year = {2026},
author = {Brossaud, R and Oullier, T and Bessard, A and Aubert, P and Brossard, L and Mahé, MM and Caillaud, M and Delfino, G and Paillusson, S and Falentin, H and Naveilhan, P and Le-Loir, Y and Paillé, V and Neunlist, M and Cissé, M},
title = {The short-chain fatty acid butyrate prevents gut-brain amyloid-β pathology and neuroinflammation in an Alzheimer mouse model.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41786890},
issn = {1476-5578},
abstract = {Amyloid-β (Aβ) plays a critical role in Alzheimer's disease (AD) and its accumulation in the brain is pivotal to disease progression and precedes memory and neuronal loss. Besides the severely handicapping brain symptoms, AD patients display early gastro-intestinal (GI) manifestations such as upper and lower GI dysmotility, in particular constipation. Although there is increasing evidence of Aβ accumulation in the gut, its pathogenic effects on enteric nervous system (ENS) connectivity and gut function as well as underlying pathophysiological mechanisms are poorly understood. Furthermore, studies have reported a gut to brain transmission of Aβ that causes memory deficits in mice. Therefore, identifying therapeutics which can reduce Aβ accumulation in the gut at an early stage of the disease could have the advantage of slowing or even reversing disease progression before severe alterations or irreversible damages at both intestinal and brain levels. Hence, in this study, we investigated the capacity of the short-fatty acid butyrate to restore Aβ-driven alteration of ENS connectivity and gut-brain functions in the SAMP8 mouse model of AD. Here we show that SAMP8 mice display a gut amyloid pathology, an alteration of ENS connectivity and gut defects prior to memory decline. BACE1, an Aβ-producing enzyme, expression and activity are increased whereas neprilysin, an Aβ-degrading enzyme, is decreased in the gut of SAMP8 mice, indicating a rise in the Amyloid Precursor Protein (APP) holoprotein processing and a reduction of Aβ clearance which promote an amyloidosis. In primary ENS cultures, Aβ causes a degradation of synaptic-associated proteins EphB2 and synaptophysin, leading to an alteration of ENS connectivity. In wild-type mice, intra-colon delivery of Aβ alters ENS connectivity and causes subsequent GI symptoms, recapitulating the phenotype of the SAMP8 mouse model of aging and AD. Moreover, Aβ impairs ENS connectivity in human induced pluripotent stem cell (iPSC)-derived intestinal organoids and explant cultures of human colon, indicating that Aβ causes ENS lesions in models of the human gut. Butyrate, a short-chain fatty acid derived from bacterial metabolism, reduces Aβ secretion and preserves enteric neuronal connectivity in vitro and in vivo, and blocks Aβ accumulation in the gut, brain and plasma in SAMP8 mice. In addition, butyrate ameliorates neuroinflammation and prevents gut dysfunction and memory deficit. Collectively, these findings suggest that Aβ promotes gut symptoms through alteration of ENS connectivity and butyrate counteracts these impairments with an amelioration of neuroinflammation and memory function in AD model.},
}

@article {pmid41786716,
year = {2026},
author = {Jara, C and Venegas-Zamora, L and Park-Kang, HS and Lira, M and Ricca, M and Valenzuela, S and Tapia-Rojas, C},
title = {Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-026-00351-3},
pmid = {41786716},
issn = {2731-6068},
support = {11241376//Agencia Nacional de Investigación y Desarrollo/ ; 1221178//Agencia Nacional de Investigación y Desarrollo/ ; },
abstract = {The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.},
}

@article {pmid41786594,
year = {2026},
author = {Landi, G and Scaravelli, A and Tesi, MC and Testa, C},
title = {Spreading of pathological proteins through brain networks: A case study for Alzheimer's disease.},
journal = {Mathematical biosciences and engineering : MBE},
volume = {23},
number = {3},
pages = {619-635},
doi = {10.3934/mbe.2026024},
pmid = {41786594},
issn = {1551-0018},
abstract = {Given the complexity, unknown causes, and lack of effective treatments for Alzheimer's disease (AD), mathematical modeling offers a valuable approach to its understanding. Models, once validated, offer a powerful tool to test medical hypotheses that are otherwise difficult to directly verify. Here, our focus is to elucidate the spread of misfolded $ \tau $ protein, a critical hallmark of AD alongside A$ \beta $ protein, while taking the synergistic interaction between the two proteins into account. We consider distinct modeling choices, all employing network frameworks for protein evolution, differentiated by their network architecture and diffusion operators. By carefully comparing these models against clinical $ \tau $ concentration data, gathered through advanced multimodal analysis techniques, we show that certain models replicate better the protein's dynamics. This investigation underscores a crucial insight: when modeling complex pathologies, the precision with which the mathematical framework is chosen is crucial, especially when validation against clinical data is considered decisive.},
}

@article {pmid41786476,
year = {2026},
author = {Bezprozvanny, I},
title = {Calcium Signaling and Pathogenesis of Neurodegenerative Disorders: Potential Therapeutic Opportunities.},
journal = {Cold Spring Harbor perspectives in biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/cshperspect.a041758},
pmid = {41786476},
issn = {1943-0264},
abstract = {Alzheimer's disease and other neurodegenerative disorders are major health and economic problems. The main emphasis on treating these disorders has been based on the idea of targeting the amyloid pathway, but these efforts have not yielded effective disease-modifying therapies. In this article, I review arguments in favor of "calcium hypothesis of neurodegeneration" that offer additional targets that may potentially be explored. The main limitation in translation of this idea to the clinic has been concern about potential side effects of calcium channel blockers and inhibitors of calcium signaling enzymes in nonneuronal tissues. I reason that recently developed positive allosteric modulators of sarco-endoplasmic reticulum calcium (SERCA) pump may be able to solve this problem and briefly review results supporting this claim. If this class of compounds is proven safe in humans in clinical trials, they would offer promising therapeutic leads for developing disease-modifying therapy for a variety of neurodegenerative disorders.},
}

@article {pmid41786070,
year = {2026},
author = {Chen, Y and Wu, Y and Liu, X and Wan, J and Shen, M and Zhang, Q},
title = {Bridging Protein Quality Control and Epigenetic Dysregulation: The HDAC6 Paradox in Neurological Disorders and Therapeutic Targeting.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178721},
doi = {10.1016/j.ejphar.2026.178721},
pmid = {41786070},
issn = {1879-0712},
abstract = {Acetylation, a key post-translational modification, is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among HDACs, HDAC6-a class II deacetylase with predominant cytoplasmic localization-plays a unique role in cellular processes that extend beyond histone modification. It is ubiquitously expressed throughout the central and peripheral nervous systems and is integral to key physiological functions including protein quality control, autophagy, mitochondrial transport, and oxidative stress responses. Notably, under pathological conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and peripheral nerve injury, HDAC6 undergoes nuclear translocation and contributes to epigenetic dysregulation by modulating the transcription of genes such as brain-derived neurotrophic factor, thereby impairing synaptic integrity and function. This dual role-cytoplasmic in protein homeostasis and nuclear in transcriptional regulation-highlights the HDAC6 paradox in neurological disorders. This review summarizes recent understanding of HDAC6's structure, expression, and functions within the nervous system, and discuss how targeting HDAC6 with selective inhibitors offers a promising therapeutic strategy for mitigating neurological disease pathogenesis. The goal is to provide insights that bridge HDAC6's roles in protein quality control and epigenetic regulation, fostering further exploration of HDAC6 inhibition in neurologic therapeutics.},
}

@article {pmid41786019,
year = {2026},
author = {Guso, E and Lupoli, A and Olivieri, E and Bottoni, A and Gironi, M and Missarelli, DM and Toosy, AT and Rossi, E and Furlan, R},
title = {Trained immunity in neuroinflammation: emerging evidence, clinical perspectives, and future directions.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.02.047},
pmid = {41786019},
issn = {1873-7544},
abstract = {Trained immunity is the ability of the innate immune system to mount a heightened response to an environmental stimulus after a previous encounter with a noxious trigger. This effect is mediated by metabolic rewiring and epigenetic reprogramming in innate immune cells. In the context of neuroinflammation, trained immunity may represent a major contributor to the pathogenesis of neurological diseases, exerting both detrimental and potentially beneficial effects. While the general mechanisms and systemic implications of trained immunity are widely discussed, evidence in central nervous system (CNS) diseases remains fragmented and largely confined to individual pathological conditions. As a result, a comprehensive framework integrating these findings and identifying shared mechanisms across neurological disorders is still lacking. In this review, we explore the concept of trained immunity with a focus on neuroinflammatory and neurodegenerative diseases, synthetizing evidence from multiple CNS pathologies, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and cerebrovascular disorders. We first critically examine preclinical and experimental studies addressing innate immune memory in the CNS and subsequently integrate these findings with emerging clinical evidence, aiming to identify convergent mechanisms and disease-relevant immune memory signatures. Finally, we discuss potential therapeutic targets identified in preclinical settings and outline key unresolved issues, including the nature of triggering stimuli, thresholds, and temporal dynamics shaping innate immune memory in the CNS. By highlighting current limitations and defining critical questions for future research, this review presents a unifying perspective on trained immunity in neurological diseases and underscores the translational potential to modulate neuroinflammation and to influence disease progression.},
}

@article {pmid41786013,
year = {2026},
author = {Frenzel, S and Teipel, SJ and Grabe, HJ and , },
title = {Associations between structural neuroimaging markers and neuropathology of Alzheimer's Disease.},
journal = {NeuroImage},
volume = {329},
number = {},
pages = {121841},
doi = {10.1016/j.neuroimage.2026.121841},
pmid = {41786013},
issn = {1095-9572},
abstract = {Structural MRI is widely used for assessing the progression of Alzheimer's disease (AD). However, postmortem pathological examination remains the gold standard for confirming the diagnosis. We systematically investigated associations of structural MRI markers with AD neuropathology in well-characterized cohorts from Alzheimer's Disease Research Centres and the Alzheimer's Disease Neuroimaging Initiative. Data of 805 individuals who died between 2006 and 2024 were included. Markers of medial temporal lobe (MTL) and whole brain atrophy were determined from T1-weighted images acquired shortly before death. Two aggregate indices of AD-related brain atrophy (FSAD) and brain ageing (brainageR) were also included. Associations with neuropathology ratings were examined using ordinal logistic regression with proportional odds. At the time of MRI, median age was 78.5 years and 61 % had dementia. The median time between MRI and death was 4.6 years. At autopsy, 52 % had high Alzheimer's disease neuropathologic change (ADNC). In unadjusted analyses, ADNC most strongly correlated with volume of the MTL and the FSAD score (Spearman's ρ=-0.28 and 0.43). In adjusted analyses, the odds ratio associating low MTL volume with ADNC was 5.0 (95 % CI: 3.0-8.3); for a high FSAD score it was 11.0 (95 % CI: 6.6-18.0). MRI markers of AD generally were more strongly associated with tau than with amyloid beta pathology. AD neuropathology was associated with a distinct pattern of atrophy most pronounced in - but not restricted to - the MTL, differing from patterns seen in normal ageing. These results support the use of aggregate indices of AD-related atrophy over single-region morphometric characteristics for sample enrichment or as secondary outcomes in clinical trials.},
}

@article {pmid41785998,
year = {2026},
author = {Park, S and Gi, Y and Lim, H and Kim, BJ and Baek, SH and Kim, JH and Yoon, M},
title = {Dual-path mixture of experts for Alzheimer's diagnosis using volume and entropy MRI features.},
journal = {Journal of neuroscience methods},
volume = {},
number = {},
pages = {110728},
doi = {10.1016/j.jneumeth.2026.110728},
pmid = {41785998},
issn = {1872-678X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by brain atrophy, observable via MRI. Volumetric measures like hippocampal volume are widely used but often miss early microstructural changes. Texture features such as intensity entropy capture tissue heterogeneity and may improve early diagnosis. Combining these orthogonal modalities could yield better biomarkers.

NEW METHOD: We propose a Dual-Path Mixture of Experts (DP-MoE) model that integrates volumetric and entropy-based MRI features through two expert subnetworks and a self-attention gating mechanism. A residual fusion branch preserves raw input distributions, enhancing flexibility and expressiveness. The code is available at https://github.com/syoonni/DP-MOE.

RESULTS: The model was evaluated on three binary classification tasks (CN vs. AD, CN vs. MCI, MCI vs. AD) using T1-weighted and entropy-derived MRI. For CN vs. AD, it achieved an accuracy of 93.02% (0.9302 ± 0.0109) and an AUC of 0.975 ± 0.004, outperforming both the baseline MoE and logistic fusion models. Ablation studies confirmed the importance of both attention and residual components.

Prior methods used concatenation or fixed weighting, neglecting modality-specific characteristics. Volume and entropy provide orthogonal, complementary information. While Mixture of Experts is common in other fields, it remains underused in AD imaging. Our adaptive fusion approach improved both interpretability and accuracy, especially in early-stage discrimination.

CONCLUSIONS: DP-MoE offers an effective, interpretable framework for fusing heterogeneous MRI biomarkers and holds promise for deployment in early Alzheimer's diagnosis workflows.},
}

@article {pmid41785939,
year = {2026},
author = {Niño, SA and Barrios-Camus, O and Silva-Pavez, E and Cárdenas, JC and González-Billault, C},
title = {Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {168211},
doi = {10.1016/j.bbadis.2026.168211},
pmid = {41785939},
issn = {1879-260X},
abstract = {The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (sAD), yet its cell-autonomous effects remain poorly understood. While young, asymptomatic APOE4 carriers exhibit abnormal brain metabolism, the mechanistic link between mitochondrial dysfunction and lysosomal-autophagic failure remains unclear. In this study, we conducted a comprehensive analysis of primary human fibroblasts from APOE3 controls, APOE4, and sAD donors to assess mitochondrial bioenergetics, oxidative stress, autophagy, and lysosomal function. APOE4 fibroblasts displayed increased mitochondrial content-associated markers (PGC1α, mtDNA) accompanied by reduced respiratory capacity, elevated proton leak, and excessive mitochondrial ROS. In parallel, APOE4 fibroblasts showed impaired autophagic flux and reduced LC3-TOMM20 colocalization, indicating defective mitophagy. Lysosomal proteolytic activity, assessed using DQ-BSA, was significantly reduced and remained unresponsive under to starvation, in contrast to the partial recovery observed in sAD cells. Pharmacological targeting of mitochondrial ROS with site-specific inhibitors revealed that complex III-derived ROS is the predominant driver of redox stress in APOE4 fibroblasts, while complex I contributes primarily in sAD. Notably, selective inhibition of complex III-derived ROS with S3QEL restored lysosomal degradation, autophagic flux, and mitochondrial respiration in APOE4 cells. Together, these findings demonstrate that mitochondrial oxidative stress disrupts the mitochondria-lysosome axis in an APOE4-specific manner, revealing early and mechanistically distinct vulnerabilities that may precede neurodegeneration. Our results challenge the notion that APOE4 merely amplifies AD pathology and instead identity site-specific redox signaling as a promising target for allele-informed interventions.},
}

@article {pmid41785850,
year = {2026},
author = {Teng, F and Liu, J and Cui, T and Tan, X and Liu, K and Hou, Z and Zhou, L and Xie, Y and Li, R and Li, D and Li, B and Wang, D and Zhou, Q and Hu, B and Li, W},
title = {Efficient amyloid-β degradation in Alzheimer's disease using SPYTACs.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2026.01.034},
pmid = {41785850},
issn = {1097-4172},
abstract = {Clearance of aberrant cerebral amyloid-β (Aβ) deposits represents a promising therapeutic strategy for Alzheimer's disease (AD), yet current anti-Aβ immunotherapy raises safety concerns due to frequent adverse effects. Extracellular targeted protein degradation (eTPD) offers an approach for safe and efficient clearance of disease-causing proteins. Here, we develop a next-generation eTPD platform, synthetic peptide-programmed lysosome-targeting chimeras (SPYTACs), using entirely synthesized bispecific peptides. Leveraging low-density lipoprotein receptor-related protein 1 (LRP1), SPYTACs effectively facilitate targeted degradation of extracellular proteins and enable transcytosis across the blood-brain barrier. In vivo administration of SPYTACs effectively reduces peripheral and cerebral Aβ burden, attenuates synapse loss, and improves cognitive function in 5×FAD mice at both prodromal and symptomatic stages. Notably, SPYTAC treatment shows fewer side effects, including intracerebral hemorrhage and inflammation, compared with conventional immunotherapies. The high modularity and genetic encodability enable SPYTACs to target customized disease-causing proteins, underscoring their therapeutic versatility and translational promise across diverse diseases driven by pathogenic proteins.},
}

@article {pmid41785844,
year = {2026},
author = {Hansen, DV and Karch, CM and Mainali, D and Piccio, L},
title = {MS4A4A and MS4A6A: New targets to enhance microglia protective function in Alzheimer's disease.},
journal = {Neuron},
volume = {114},
number = {5},
pages = {791-794},
doi = {10.1016/j.neuron.2026.02.005},
pmid = {41785844},
issn = {1097-4199},
abstract = {MS4A4A and MS4A6A are microglia-expressed genes linked to Alzheimer's disease risk. In this issue of Neuron, Rosner et al.[1] show that these proteins cooperatively restrain TREM2 signaling, dampening protective microglial responses and highlighting MS4A inhibition as a potential strategy to rejuvenate the brain's innate immune system in Alzheimer's disease.},
}

@article {pmid41785827,
year = {2026},
author = {Abdelrahman, KS and Soltan, OM and Abo Mansour, HE and Nofal, AE and Eissa, EA and Salem, HR and Mahfouz, MM and El-Adawy, SA and Ewies, GSA and Hamdi, A and Elbadawi, MM and Abusabaa, AHA and El-Rashedy, AA and Konno, H and Bass, AKA},
title = {Design and development of 1,5-diarylpyrazole-based multitarget-directed ligands as dual COX-2/HDAC6 inhibitors for Alzheimer's disease therapy: Molecular dynamics and experimental insights.},
journal = {European journal of medicinal chemistry},
volume = {309},
number = {},
pages = {118738},
doi = {10.1016/j.ejmech.2026.118738},
pmid = {41785827},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, requiring multitarget-directed ligands capable of modulating interconnected pathological pathways. Here, a pharmacophore-hybridization strategy combining COX-2-selective 1,5-diarylpyrazole scaffolds with a zinc-binding group was used to design dual COX-2/HDAC6 inhibitors. Twenty hybrids were synthesized and evaluated, identifying 10a and 11e as the most potent compounds, with IC50 values of 0.18 and 0.66 μM for COX-2, and 0.15, 0.12 μM for HDAC6, respectively. Molecular dynamics simulations confirmed stable binding of 11e to both enzymes, with persistent hydrogen bonding, minimal RMSD fluctuations, and favorable binding free energies (ΔG_bind = -29.3 and -51.5 kcal/mol for HDAC6 and COX-2, respectively). Compound 11e exhibited potent neuroprotective activity by markedly enhancing α-tubulin acetylation, suppressing the expression of pro-inflammatory mediators (COX-2, IL-1β, IL-6, and TNF-α), promoting amyloid-β clearance, restoring memory-related gene expression, and significantly reducing Tau hyperphosphorylation. Histopathological analyses confirmed decreased phosphorylated STAT3 and Tau levels, preserved neuronal morphology via MAP2 stabilization, and protection of synaptic integrity through synaptophysin regulation. Behavioral studies in a scopolamine-induced AD mouse model demonstrated substantial improvements in learning and memory. These findings establish 11e as a potent dual COX-2/HDAC6 inhibitor and a promising multitarget scaffold for developing disease-modifying therapies for AD and related neurodegenerative disorders.},
}

@article {pmid41785736,
year = {2026},
author = {García-Yagüe, ÁJ and Carnicero-Senabre, D and Núñez, Á and Cipriani, R and Capetillo-Zarate, E and Escoll, M and Okunishi, I and Rojo, AI and Cuadrado, A},
title = {Hexaraphane as a potential therapeutic strategy for tauopathies.},
journal = {Redox biology},
volume = {92},
number = {},
pages = {104107},
doi = {10.1016/j.redox.2026.104107},
pmid = {41785736},
issn = {2213-2317},
abstract = {Alzheimer's disease (AD) is characterized by pathological hyperphosphorylation of TAU protein, leading to neurofibrillary tangle formation, synaptic dysfunction, neuroinflammation, and neuronal loss. Hexaraphane (6-(methylsulfinyl) hexyl isothiocyanate; HXN), a bioactive compound derived from Wasabia japonica, exhibits neuroprotective and anti-inflammatory properties, yet its potential role in tauopathies remains unknown. Here, we investigated whether HXN modulates pathological TAU phosphorylation and explored the underlying mechanisms in vitro and in vivo. Using primary neurons from APP/TAU transgenic mice with either NRF2 wild-type or knockout backgrounds, combined with complementary genetic and pharmacological approaches, we found that HXN markedly reduced pathological phospho-TAU epitopes (AT8 and PHF1). Notably, this effect occurred independently of NRF2 signaling. Mechanistically, HXN did not suppress GSK-3β activity or alter upstream PI3K/AKT or MAPK pathways. Instead, pharmacological inhibition experiments and phosphatase assays demonstrated that HXN promotes PP2A-dependent TAU dephosphorylation, identifying phosphatase activation as a central mechanism of action. Chronic oral administration of HXN in APP/TAU mice led to significant reductions in brain phospho-TAU levels across multiple regions and decreased blood circulating TAU-pThr[217] concentrations. These molecular changes were accompanied by attenuation of neuroinflammatory markers, preservation of neuronal integrity, restoration of synaptic plasticity, and improvements in cognitive and motor performance. Collectively, our findings identify HXN as a potent modulator of pathological TAU phosphorylation. These results support the development of HXN as a promising disease-modifying therapeutic strategy for AD and other TAU-driven neurodegenerative disorders.},
}

@article {pmid41785435,
year = {2026},
author = {Ross, D and Split, M and Kunicki, Z and Keszycki, R and Prieto, S and De Vito, AN and Manoochehri, M and Huey, ED and Barker, MS},
title = {Neuropsychiatric Symptoms in Patients With Pathologically Confirmed Comorbid Alzheimer Disease and Frontotemporal Lobar Degeneration.},
journal = {Neurology},
volume = {106},
number = {7},
pages = {e214750},
doi = {10.1212/WNL.0000000000214750},
pmid = {41785435},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Little is known about the clinical presentation in patients with comorbid Alzheimer disease neuropathologic change (ADNC) and frontotemporal lobar degeneration (FTLD) neuropathology, despite frequent comorbidity of neurodegenerative diseases on autopsy. In other neurodegenerative conditions, multiple pathologies alter the presentation of neuropsychiatric symptoms, complicating clinical care. We examined whether neuropsychiatric symptoms differ in patients with comorbid ADNC/FTLD compared with patients with each pathology alone.

METHODS: This was a retrospective examination of data from 29 US Alzheimer's Disease Research Centers, obtained through the National Alzheimer's Coordinating Center September 2024 data freeze. Patients with intermediate-to-high ADNC and/or FTLD neuropathology on autopsy were included. Neuropsychiatric symptoms were apathy, depressed mood, visual/auditory hallucinations, delusions, disinhibition, irritability, agitation, personality change, REM sleep behavior disorder, and anxiety, identified by clinicians at patients' final visit. Logistic regression models examined the odds of the comorbid vs single pathology groups expressing each neuropsychiatric symptom, controlling for age, sex, race, ethnicity, education, and interval between first visit and death.

RESULTS: Data from 919 patients (mean age 81 years [SD 12 years], 49% female) were analyzed. Ninety-four patients (mean age 84 years [SD 10 years], 46% female) had comorbid ADNC/FTLD pathology, 590 had ADNC only, and 235 had FTLD only. Compared with the FTLD-only group, patients in the comorbid ADNC/FTLD group were more likely to present with anxiety (odds ratio [OR] 3.11, 95% CI 1.38-6.98, p = 0.007), delusions (OR 2.59, 95% CI 1.15-5.79, p = 0.02), and irritability (OR 1.87, 95% CI 1.07-3.25, p = 0.03). Conversely, compared with the ADNC-only group, patients in the comorbid ADNC and FTLD group were more likely to present with personality change (OR 3.17, 95% CI 1.70-5.90, p < 0.001) and disinhibition (OR 2.00, 95% CI 1.14-3.53, p = 0.02).

DISCUSSION: Comorbid presence of ADNC and FTLD neuropathology, compared with each pathology alone, was associated with a greater likelihood of presenting with known neuropsychiatric symptoms of the other disease, irrespective of patients' clinical syndrome. Findings highlight the potential clinical diagnostic value of antemortem behavioral symptoms in identifying patients with comorbid pathology, although conclusions are limited by the cross-sectional nature of the neuropsychiatric data.},
}

@article {pmid41785366,
year = {2026},
author = {Boles, J and Gate, D},
title = {Astrocytes engineered to fight Alzheimer's plaques.},
journal = {Science (New York, N.Y.)},
volume = {391},
number = {6789},
pages = {990-991},
doi = {10.1126/science.aef8451},
pmid = {41785366},
issn = {1095-9203},
abstract = {Genetically altered astrocytes reduce a cardinal pathological feature of Alzheimer's disease.},
}

@article {pmid41785364,
year = {2026},
author = {Chen, Y and Liu, Y and Nguyen, K and Wu, J and Song, S and Lin, K and Rodrigues, PF and Du, S and Zhou, C and Xiong, K and Bosch, M and Lin, PB and Khantakova, D and Wu, S and Wu, M and Yuede, C and Holtzman, DM and Colonna, M},
title = {Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy.},
journal = {Science (New York, N.Y.)},
volume = {391},
number = {6789},
pages = {eads3972},
doi = {10.1126/science.ads3972},
pmid = {41785364},
issn = {1095-9203},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and is characterized by progressive amyloid accumulation followed by tau-mediated neurodegeneration. Despite advances in anti-amyloid immunotherapies, important limitations remain, highlighting the need for new therapeutic strategies. Here, we introduce anti-amyloid chimeric antigen receptors expressed in astrocytes (CAR-A) and validate their function in vitro. We show that two CAR-A designs reduce amyloid and associated pathology after plaque formation and prevent early plaque deposition in vivo. Single-nucleus RNA sequencing shows that CAR-A treatment induces a distinct glial response to amyloid pathology involving coordinated activity of astrocytes and microglia. Each construct additionally elicits distinctive, receptor-specific effects in astrocytes or microglia. Together, these findings support the therapeutic potential of CAR-A as a disease-modifying strategy for AD.},
}

@article {pmid41785267,
year = {2026},
author = {El Fadili, M and Er-Rajy, M and Mujwar, S and Samadi, A and Chtita, S and Elhallaoui, M},
title = {Computational modeling for rational design of novel phenoxy tacrine derivatives targeting Alzheimer's disease.},
journal = {PloS one},
volume = {21},
number = {3},
pages = {e0343723},
doi = {10.1371/journal.pone.0343723},
pmid = {41785267},
issn = {1932-6203},
abstract = {Alzheimer's is the leading factor behind dementia, producing steady impairments in memory, cognitive reasoning, behavioral, and social interactions. This scientific study investigates thirty-two phenoxy tacrine (PhO-THA) derivatives through an integrated computational modeling to identify potential therapeutic candidates. 3D-QSAR models were developed using comparative molecular similarity indices analysis and comparative molecular field analysis, which were subjected to rigorous internal and external validation to establish a robust quantitative relationship between molecular interaction fields and cytotoxic activities. Based on these validated structural insights, fourteen new compounds (D1-D14) were designed. Comprehensive molecular docking and molecular dynamics (MD) simulations, coupled with ADME-Tox profiling, were used to evaluate their pharmacological potential. Our results highlight four specific compounds (D9-D12) that exhibit favorable pharmacokinetic properties and a high safety profile, making them promising candidates for future drug development. D9 was selected for MD simulations due to its lower cytotoxic activity (pIC50 of 3.50), which is comparable to the reference THA drug (pIC50 of 3.52). The results demonstrated exceptional thermodynamic stability for D9 upon complexation with the NMDA receptor (PDB ID: 5EWJ) over a 100 ns simulation time.},
}

@article {pmid41785035,
year = {2026},
author = {Tang, M and Teng, S and Peng, Y and Kim, AY and Her, YR and Canoll, P and Bruce, JN and Faust, PL and Adhikari, K and De Vivo, DC and Monani, UR},
title = {A therapeutic role for a regulatory glucose transporter1 (GLUT1)-associated lncRNA in GLUT1-deficient mice.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI193519},
pmid = {41785035},
issn = {1558-8238},
abstract = {The mammalian brain relies primarily on glucose for its energy needs. Delivery of this nutrient to the brain is mediated by the glucose transporter-1 (GLUT1) protein. Low GLUT1 thwarts glucose entry into the brain, causing an energy crisis and, triggering, in one instance, the debilitating neurodevelopmental condition - GLUT1 deficiency syndrome (GLUT1DS). Current treatments for GLUT1DS are sub-optimal, as none address the root cause - low GLUT1 - of the condition. Levels of this transporter must respond rapidly to the brain's changing energy requirements. This necessitates fine-tuning its expression. Here we describe a long-noncoding RNA (lncRNA) antisense to GLUT1 (SLC2A1) and show that it is involved in such regulation. Raising levels of the lncRNA had a concordant effect on GLUT1 in cultured human cells and transgenic mice; reducing levels elicited the opposite effect. Delivering the lncRNA to GLUT1DS model mice via viral vectors induced GLUT1 expression, enhancing brain glucose levels to mitigate disease. Direct delivery of such a lncRNA to combat disease has not been reported previously and constitutes, to our knowledge, a unique therapeutic paradigm. Moreover, considering the importance of maintaining homeostatic GLUT1 levels, calibrating transporter expression via the lncRNA could become broadly relevant to myriad conditions, including Alzheimer's disease, wherein GLUT1 is perturbed.},
}

@article {pmid41789260,
year = {2024},
author = {Sanborn, V and Davis, JD and Korthauer, LE},
title = {Health Behavior Change to Mitigate Dementia Risk: An Updated Review.},
journal = {Current geriatrics reports},
volume = {13},
number = {3},
pages = {162-171},
pmid = {41789260},
issn = {2196-7865},
abstract = {Over the past two decades, we have become increasingly aware of the impact of health behaviors on risk for dementia and, more specifically, Alzheimer's disease. This concept was stressed in the 2020 Report of the Lancet Commission, which demonstrated that up to 40% of dementia cases could be mitigated by behavior change alone. Though there are several psychosocial and health factors associated with increased risk for Alzheimer's disease, health behaviors that appear particularly worthwhile for reducing risk include adherence to healthy diet, remaining physically active, and engaging in cognitively stimulating endeavors. The present review provides a general summary of what has been learned from observational and controlled studies examining the roles of these behaviors on cognitive outcomes, including risk for Alzheimer's disease. Though this line of research has largely confirmed the importance of integrating health behaviors to promote cognitive outcomes, some constraints inherent to intervention research (i.e., time restrictions, variable adherence, reduced generalizability) have limited conclusions. As such, many questions regarding the impact of health behaviors on Alzheimer's disease risk remain. Future research on these topics should integrate tailored interventions that consider individual factors that appear to impact the effectiveness of health behavior change on dementia risk (i.e., age, sex, culture, access to resources) and influence engagement in health behaviors during and after interventions (i.e., health beliefs).},
}

@article {pmid41784914,
year = {2026},
author = {Neha, and Mandal, S and Sharma, V and Dhindsa, J and Aran, KR},
title = {PAR-1 in Alzheimer's Disease: Pathophysiological Insights and Mechanistic Perspectives.},
journal = {Current medical science},
volume = {},
number = {},
pages = {},
pmid = {41784914},
issn = {2523-899X},
abstract = {The G protein-coupled receptor (GPCR) known as protease-activated receptor-1 (PAR-1) is triggered by thrombin and plays a multifaceted role in the onset and progression of Alzheimer's disease (AD). AD is an irreversible neurodegenerative disease characterized by amyloid-β (Aβ) accumulation, neuroinflammation, tau hyperphosphorylation, and synaptic dysfunction. Thrombin activates PAR-1, which plays multiple roles in the brain. It exacerbates neuroinflammation and Aβ pathology but also protects synaptic plasticity. In a preclinical model, PAR-1 inhibition rescues cognitive deficits and decreases Aβ accumulation, suggesting therapeutic potential. However, PAR-1 activation promotes Tau hyperphosphorylation and neurofibrillary tangle formation, contributing to synaptic loss and cognitive decline. PAR-1 increases the permeability of the blood‒brain barrier (BBB), facilitating the entry of toxic substances into the brain and increasing neurodegeneration. Although strong preclinical evidence exists, no clinical trials have yet directly targeted PAR-1 in AD. This review summarizes current understanding of the PAR-1 mechanism in AD and highlights its roles in Aβ deposition, neuroinflammation, and tau pathology. It also discusses the challenges and opportunities for translating PAR-1 modulation into clinical therapies, including repurposing existing PAR-1 inhibitors. By addressing the dual role of PAR-1 function, researchers may develop novel multitarget strategies to combat the multifactorial pathophysiology of AD.},
}

@article {pmid41784832,
year = {2026},
author = {El-Baga, SE and Hassan, MH and Awadalla, EA and Abd El-Kader, AEM},
title = {Crocin Mitigates Glutamate Excitotoxicity and Tau Hyperphosphorylation by Modulating EAAT2 and Akt/Tau Pathway in a Scopolamine-induced Rat Model of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41784832},
issn = {1573-6903},
abstract = {Alzheimer's disease (AD) is characterized by glutamatergic dysregulation and excitotoxicity, largely associated with impaired activity of the excitatory amino acid transporter 2 (EAAT2). Downregulation of EAAT2 results in glutamate accumulation, N-Methyl-D-Aspartate (NMDA) receptor overactivation, and neuronal injury. Crocin (Cr), a carotenoid compound extracted from saffron (Crocus sativus), exhibits potent antioxidant and neuroprotective properties, particularly in experimental models of neurodegeneration. Forty-eight adult male rats were divided into six groups: control (saline), crocin (50 mg/kg), scopolamine (3 mg/kg for 7 days), scopolamine followed by memantine (M) (20 mg/kg), scopolamine followed by crocin, and scopolamine followed by both memantine and crocin. This study aimed to evaluate the therapeutic potential of crocin, alone and in combination with memantine, in a scopolamine-induced rat model of Alzheimer's disease, with a focus on EAAT2 modulation. Scopolamine administration significantly elevated glutamate, NMDAR and p-tau levels while reducing p-Akt, GABA and EAAT2 levels, accompanied by marked hippocampal neurodegeneration. In contrast, crocin treatment, either alone or in combination with memantine, restored neurotransmitter balance, downregulated NMDAR, upregulated EAAT2, increased p-Akt expression level and reduced tau phosphorylation. Histological analysis further confirmed notable structural recovery of hippocampal neurons.},
}

@article {pmid41784652,
year = {2026},
author = {Chen, Y and Wang, Z and Chen, H and Cui, H and Li, S and , },
title = {Plasma p-tau217 assays effectively predict amyloid status but lack precision for tau staging in Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {3},
pages = {},
pmid = {41784652},
issn = {1432-1459},
support = {82471199//National Natural Science Foundation of China/ ; 82171582//National Natural Science Foundation of China/ ; },
abstract = {Blood-based biomarkers for Alzheimer's disease (AD) have demonstrated high performance in identifying amyloid-β (Aβ) pathology. However, the diagnostic accuracy of commercial plasma biomarker assays in predicting PET-defined AD stages-particularly late-stage tau accumulation-requires further evaluation. We included 229 participants from the Alzheimer's Disease Neuroimaging Initiative, all of whom underwent amyloid and tau PET imaging and testing with plasma assays. Among the plasma biomarkers, p-tau217 showed the strongest linear and non-linear associations with amyloid and tau PET. When distinguishing A + from A - T - participants, p-tau217 assays achieved the highest accuracy (AUC range: 0.85-0.91), outperforming other plasma biomarkers (AUC range: 0.66-0.81). However, the accuracy of plasma biomarkers, including p-tau217 assays, significantly decreased when differentiating A + T + from A + T - stages (AUC for p-tau217 assays: 0.69-0.77; AUC for other plasma biomarkers: 0.53-0.67; P < 0.05). These findings were replicated in an independent cohort (n = 334). Our study found that among currently available commercial plasma assays, including p-tau217 assays, they demonstrate high accuracy in classifying Aβ status but are less accurate in assessing tau pathology severity in Aβ positive individuals.},
}

@article {pmid41784383,
year = {2026},
author = {Suhandynata, RT and Bevins, EA and Metushi, IG},
title = {Endogenous Lithium Levels and Alzheimer Disease.},
journal = {Clinical chemistry},
volume = {72},
number = {3},
pages = {424-425},
doi = {10.1093/clinchem/hvaf174},
pmid = {41784383},
issn = {1530-8561},
}

@article {pmid41784299,
year = {2026},
author = {Luo, L and He, J and Liu, X and Zhuang, S and Xiao, Q},
title = {Association between anemia and cognitive dysfunction in the hypertensive older adults: a cross-sectional study.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/13607863.2026.2635536},
pmid = {41784299},
issn = {1364-6915},
abstract = {OBJECTIVES: Using 2011-2014 National Health and Nutrition Examination Survey (NHANES) data, the research aims to explore the association of anemia and cognitive dysfunction in older patients with hypertension.

METHOD: The study included 2005 older participants aged ≥60 years. Cognitive performance was evaluated by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning subtest, the Animal Fluency Test (AFT) and the Digit Symbol Substitution Test (DSST). Multivariate logistic regression analysis and a weighted restricted cubic spline (RCS) curve were employed to examine the potential association between hemoglobin levels and cognitive dysfunction.

RESULTS: Anemia was associated with higher odds of cognitive dysfunction in hypertensive older adults (OR = 1.663, 95% CI: 1.082-2.557, p = 0.022). Higher level of hemoglobin was associated with reduced odds of cognitive dysfunction (OR = 0.880, 95% CI: 0.782-0.991, p = 0.036). Hemoglobin levels below 13.67 g/dL were significantly associated with increased odds of cognitive impairment.

CONCLUSION: This study indicates the existence of an association between anemia and cognitive dysfunction among hypertensive older adults. Hemoglobin levels may serve as a predictor of cognitive decline, with 13.67g/dL as a potential threshold for intensive cognitive monitoring in high-risk older populations with hypertension.},
}

@article {pmid41784271,
year = {2026},
author = {Wang, RM and Wang, ZQ},
title = {lncRNAs: key player in Aβ deposition.},
journal = {RNA biology},
volume = {23},
number = {1},
pages = {1-16},
doi = {10.1080/15476286.2026.2639017},
pmid = {41784271},
issn = {1555-8584},
abstract = {Alzheimer's disease (AD) is a typical neurodegenerative disorder, characterized by the deposition of β-amyloid (Aβ) plaques. β- and γ-secretases generate Aβ by cleaving amyloid precursor protein. The imbalance between its production and clearance leads to Aβ accumulation, causing neuronal damage through mechanisms such as inducing oxidative stress and inflammatory responses. Long non-coding RNAs (LncRNAs), composed of more than 200 nucleotides, usually do not encode proteins and are involved in processes such as gene expression regulation, chromatin remodelling, and cell cycle control. Studies have shown that LncRNAs play a key role in brain development and the maintenance of neuronal function, especially by influencing Aβ deposition to affect the progression of AD. This review summarizes the pathways by which LncRNAs affect Aβ deposition, classifies them according to their modes of action, discusses the existing problems in current research, and summarizes and prospects their role in the treatment of AD.},
}

@article {pmid41783892,
year = {2026},
author = {Zhang, J and Han, J and Liu, Q},
title = {Transfer RNA-derived small RNAs (tsRNAs) in Alzheimer's disease: emerging mechanisms and diagnostic potential.},
journal = {Medical review (2021)},
volume = {6},
number = {1},
pages = {87-90},
doi = {10.1515/mr-2025-0078},
pmid = {41783892},
issn = {2749-9642},
abstract = {Transfer RNA-derived small RNAs (tsRNAs), a class of non-coding RNAs derived from precursor or mature tRNAs, are now recognized as critical regulators in response to cellular stress. tsRNAs exhibit differential expression during brain aging and in age-related neurodegenerative disorders such as Alzheimer's disease (AD), suggesting their involvement in the molecular processes underlying neuronal aging and degeneration. This article summarizes recent advances in our understanding of tsRNA biogenesis, classification, and function, emphasizing their regulatory role in brain aging and AD pathology. We also highlight the diagnostic and therapeutic implications of tsRNAs and discuss future directions for exploring their mechanistic and clinical relevance.},
}

@article {pmid41783833,
year = {2026},
author = {Liu, L and Yu, L and Petyuk, VA and Kapasi, A and Yoo, HB and Saba, A and Yang, HS and Chhatwal, JP and Bennett, DA},
title = {Association of Aβ monomers with cerebral amyloid angiopathy in brains without parenchymal Aβ deposition.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag051},
doi = {10.1093/braincomms/fcag051},
pmid = {41783833},
issn = {2632-1297},
abstract = {β-Amyloid (Aβ) deposition is a hallmark of both Alzheimer's disease and cerebral amyloid angiopathy. Whilst insoluble Aβ aggregates have been extensively studied, the role of soluble Aβ monomers in vascular amyloid pathology-and their association with cognitive decline-remains unclear in plaque-free brains. This study examined whether soluble cortical Aβ species are associated with cognitive outcomes and amyloid-related pathologies, including cerebral amyloid angiopathy, in the absence of parenchymal Aβ deposition. We examined post-mortem cortical tissue from nearly 200 individuals without parenchymal Aβ deposition, drawn from two longitudinal community-based cohorts. Soluble Aβ37, Aβ40 and Aβ42 were quantified by immunoassays, and total Aβ levels were measured using selected reaction monitoring proteomics. Associations with semiquantitative cerebral amyloid angiopathy burden and longitudinal cognitive trajectories were assessed using regression models adjusting for age, sex and education. Higher levels of soluble Aβ-particularly longer species such as Aβ42, reflected by elevated Aβ42/40 and reduced Aβ37/42 ratios-were significantly associated with greater cerebral amyloid angiopathy severity. Whilst immunoassay based total Aβ and Aβ ratio measures showed limited associations with cognitive outcomes, total Aβ levels quantified by selected reaction monitoring remained significantly associated with global cognitive decline. These findings support a pathogenic role for certain soluble Aβ monomers in vascular amyloid deposition. In contrast, cognitive impairment may be driven by other amyloid species such as oligomeric or extended Aβ forms. Aβ ratios may serve as specific markers for cerebral amyloid angiopathy and provide insights into early therapeutic strategies targeting vascular amyloid pathology.},
}

@article {pmid41783585,
year = {2026},
author = {Cheng, H and Kang, L and Xu, Y and Tanzi, RE and Zhang, C and Wang, C},
title = {Innovation breakthrough in the Alzheimer's disease pharmaceutical industry.},
journal = {NPJ drug discovery},
volume = {3},
number = {1},
pages = {9},
doi = {10.1038/s44386-026-00044-7},
pmid = {41783585},
issn = {3005-1452},
abstract = {Alzheimer's disease (AD) drug development has undergone cycles, driven initially by amyloid-β-based hypotheses and later setbacks by clinical failures. Recent advances in biotechnology, improved understanding of AD pathogenesis, and unmet medical needs have revitalized the field. This new wave is exemplified by lecanemab, the first fully FDA-approved disease-modifying therapy in two decades. We review approved and clinical-stage AD therapeutics using data from Cortellis and the FDA.},
}

@article {pmid41783572,
year = {2026},
author = {Liu, W and Xue, Y and Cao, C and Yang, L and Zhang, L},
title = {Copper Homeostasis and Cuproptosis in Neurological Disorders.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {580005},
doi = {10.2147/DDDT.S580005},
pmid = {41783572},
issn = {1177-8881},
abstract = {Neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose a serious global public health threat, with complex etiologies involving genetic, environmental, and metabolic factors. Current data indicate that the prevalence of these disorders is rapidly increasing with the aging population, resulting in a growing economic and healthcare burden worldwide. In recent years, the imbalance of copper homeostasis has been increasingly implicated in the pathogenesis of neurological diseases. Copper overload can aggravate neuronal injury by inducing oxidative stress (OS), mitochondrial dysfunction, and protein misfolding, while copper deficiency disrupts the function of copper-dependent enzymes and leads to metabolic abnormalities. The mechanism of cuproptosis, proposed in 2022, describes a novel form of programmed cell death characterized by lipoylated protein aggregation and the loss of Fe-S cluster proteins, offering new insights into copper-related diseases. Multiple studies have demonstrated the crucial role of copper homeostasis and cuproptosis in the onset, progression, and treatment of neurological diseases. This narrative review summarizes the molecular mechanisms involved in copper homeostasis regulation and, on that basis, discusses the role of copper metabolism abnormalities in AD, PD, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Wilson's disease (WD), Menkes disease (MD), and stroke. Additionally, we highlight the mechanisms of existing copper-regulating drugs and their therapeutic potential in neurological disorders, while pointing out the limitations of current drug development.},
}

@article {pmid41783522,
year = {2026},
author = {Ali, S and Kreshpa, W and Rosso, N and Piana, M and Roccatagliata, L and Cirone, A and Luigi, L and Campi, C and Pardini, M and Garbarino, S},
title = {A systematic study on the integration of MRI connectivity metrics for Alzheimer's diagnosis, staging, and cognitive decline prediction.},
journal = {Frontiers in neuroimaging},
volume = {5},
number = {},
pages = {1746464},
doi = {10.3389/fnimg.2026.1746464},
pmid = {41783522},
issn = {2813-1193},
abstract = {Alzheimer's disease (AD) is a degenerative neurological disorder marked by cognitive decline and functional disability. Despite the extensive use of magnetic resonance imaging (MRI) in machine learning (ML)-based AD studies, the relative and combined contributions of MRI-derived morphometric (MO), microstructural (MS), and graph-theoretical (GT) features are still not well explored in a unified, comparative framework. It remains unclear whether adding multimodal MRI-derived features consistently improves the predictive performance of ML-based approaches for AD diagnosis and cognitive decline. Addressing this gap, this study systematically analyzed the individual (MO, MS, GT) and combined (MO+MS, MO+GT, MS+GT, MO+MS+GT) utility of MRI-based feature sets. We developed an ensemble-based ML framework with a nested cross-validation module for two key tasks: (i) Alzheimer's disease cognitive stage classification (DSC) and (ii) longitudinal cognitive decline prediction (LCDP) in terms of mini-mental state examination (MMSE) score. In this study, we conducted feature ablation and statistical analysis to evaluate performance improvements resulting from the incremental addition of feature sets. The results of the study indicated that the proposed ensemble-based ML approach achieved the best predictive performance (balanced accuracy [BACC]: 0.898 ± 0.051) using a combination of MO and MS feature sets for cognitively normal (CN) vs. AD dementia (CN-ADD). In contrast, the best results for mild cognitive impairment (MCI) vs. ADD (MCI-ADD) and CN-MCI were achieved using the MO feature set alone, with BACC of 0.769 ± 0.116 and 0.652 ± 0.044, respectively. Likewise, for the LCDP task, the MO-based ensemble learner achieved an R[2] of 0.212 ± 0.177. These results demonstrate that MO features capture the most robust disease-related information, while multimodal integration offers task-specific and limited benefits. In addition, these findings demonstrate the potential of integrated MRI-derived features in ML frameworks for enhancing ADD diagnosis and cognitive decline prediction and underscore the importance of feature selection based on task complexity.},
}