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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

@article {pmid41576576,
year = {2026},
author = {Fiske, S and Cody, JL and Shen, M and Choi, J},
title = {AI conversational agents in older adults with chronic disease: A scoping review.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {68},
number = {},
pages = {103856},
doi = {10.1016/j.gerinurse.2026.103856},
pmid = {41576576},
issn = {1528-3984},
mesh = {Humans ; Chronic Disease/psychology/therapy ; Aged ; *Artificial Intelligence ; *Communication ; },
abstract = {To examine the relationship between artificial intelligence (AI) and older adults with chronic diseases a scoping review methodology was used. Using four electronic databases, data was managed in accordance with the PRISMA-ScR, analyzed and presented in a Matrix. Findings from 12 studies show AI conversational agents (CA) can improve chronic outcomes but factors affecting effectiveness on real-life situations in older adults limits usability and clinical relevance. Older adults with neurocognitive disorders (e.g., Alzheimer's dementia) and a general lack of research examining AI use in older adults with chronic diseases is dearth. Current research fails to recognize critical end-user differences (e.g., age variations, chronic disease severity, demographics) as multifarious technological features and privacy issues widen barriers including health outcomes, usability, trust and AI satisfaction in health decision making practices. Stakeholder perspectives to ensure human-patient and disease centered care approaches and age-disease variations are a critical technology integration point to improve relevance.},
}

Humans
Chronic Disease/psychology/therapy
Aged
*Artificial Intelligence
*Communication

@article {pmid41704086,
year = {2025},
author = {Mehrabadi, S},
title = {Uncovering the Healing Power of Stem Cells: Harnessing Regenerative Therapies for Alzheimer's Disease.},
journal = {Current aging science},
volume = {18},
number = {3},
pages = {175-184},
pmid = {41704086},
issn = {1874-6128},
mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology/pathology/metabolism/surgery ; *Regenerative Medicine/methods ; Animals ; Neurogenesis ; *Stem Cell Transplantation ; *Neural Stem Cells/transplantation/metabolism ; *Brain/metabolism/pathology/physiopathology ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cell Transplantation ; Apoptosis ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder with no known treatment. Recent advances in regenerative medicine, including stem cell therapies, hold promise for treating Alzheimer's disease and slowing its progression. This review explores the various types of stem cells, such as neural and mesenchymal stem cells, and how they can be harnessed for Alzheimer's treatment. It also discusses the potential mechanisms of action, including neurogenesis, anti-inflammatory and anti-apoptotic effects, and the secretion of various biologically active molecules by stem cells.},
}

Humans
*Alzheimer Disease/therapy/physiopathology/pathology/metabolism/surgery
*Regenerative Medicine/methods
Animals
Neurogenesis
*Stem Cell Transplantation
*Neural Stem Cells/transplantation/metabolism
*Brain/metabolism/pathology/physiopathology
Mesenchymal Stem Cells/metabolism
Mesenchymal Stem Cell Transplantation
Apoptosis

@article {pmid41703264,
year = {2026},
author = {Ma, Y and Li, Y and Wu, G and Liu, L and Tian, M and Han, X and Chen, X and Xuan, X and Zheng, T and Gao, X and Xia, Q and Li, F and Wang, D},
title = {Protective mutations associated with APOE in Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41703264},
issn = {1476-5578},
abstract = {Alzheimer' s disease (AD) is a progressive neurodegenerative disorder characterized by a spectrum of cognitive impairments, ranging from mild memory loss to severe cognitive decline and, ultimately, death. The global incidence of AD is projected to increase significantly, with late-onset AD being predominantly sporadic in nature. Over the past three decades, the Apolipoprotein E (APOE) gene has been recognized as the most important single genetic determinant of sporadic AD risk. The APOE4 allele is a major risk factor for AD and is known to exacerbate the pathological process for AD. Identifying protective variants that may reduce the risk or delay the onset of AD is of great significance for the development of effective treatments. This review comprehensively examines the protective effects of APOE and its related protective mutations. It also explores the impact of these unique protective variants at the cellular level during the pathological progression of AD. Furthermore, the review compiles new insights for AD treatment offered by these protective mutations, exploring the potential applications of APOE and its related protective variants in advanced therapeutic strategies, including gene editing, RNA editing, and stem cell therapy.},
}

@article {pmid41703146,
year = {2026},
author = {Yuste, MT and Badillo, E and Galecio, JS and Marín, P},
title = {Selective oestrogen receptor modulators and Alzheimer´s disease: a real-world pharmacovigilance study.},
journal = {European journal of clinical pharmacology},
volume = {82},
number = {3},
pages = {81},
pmid = {41703146},
issn = {1432-1041},
}

@article {pmid41702724,
year = {2026},
author = {Groshkov, AA and Kolotyeva, NA and Tregub, PP and Zhdankina, VI and Komleva, YK and Salmina, AB and Illarioshkin, SN},
title = {Diagnostics of Synucleinopathies by Protein Amplification Methods: Methodological and Bibliometric Analysis.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {1},
pages = {1-16},
doi = {10.1134/S000629792560214X},
pmid = {41702724},
issn = {1608-3040},
mesh = {Humans ; Bibliometrics ; *Synucleinopathies/diagnosis/metabolism ; *alpha-Synuclein/metabolism/analysis ; },
abstract = {Early preclinical diagnostics of neurodegenerative diseases (synucleinopathies, Alzheimer's disease, etc.) can be achieved through the detection of pathological amyloid aggregates in biological fluids. Protein amplification methods (PMCA, RT-QuIC) have become promising diagnostic tools by offering high sensitivity and specificity for detecting α-synuclein oligomers at the early disease stages and studying the fibril formation kinetics and mechanisms of amyloid aggregation. However, these methods have several significant limitations, as they are technically complex and time-consuming and lack standardized protocols, control samples, and substrates. Despite these challenges, protein amplification methods hold potential as the most productive, accessible, and standardizable diagnostic approaches in synucleinopathies. This review presents the results of bibliometric analysis of publications on the use of protein amplification methods in the diagnostics of synucleinopathies. We also provide a comparative analysis of common RT-QuIC protocols, with special focus on the method principles, approaches for its optimization, types of biological materials, key factors influencing the sensitivity and specificity of this technique, and areas for its improvement.},
}

Humans
Bibliometrics
*Synucleinopathies/diagnosis/metabolism
*alpha-Synuclein/metabolism/analysis

@article {pmid41702720,
year = {2026},
author = {Blankenship, HE and Higgs, MH and Harold, KM and Humphries, KM and Beckstead, MJ},
title = {Alzheimer's pathology enhances excitatory synaptic input and integration in VTA dopamine neurons.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.2085-25.2026},
pmid = {41702720},
issn = {1529-2401},
abstract = {In Alzheimer's disease (AD) models, ventral tegmental area (VTA) dopamine neurons are intrinsically hyperexcitable, yet release less dopamine and exhibit dysfunctional downstream signaling. Synaptic transmission is broadly disrupted in AD, but it is not known to what extent excitatory and inhibitory inputs to the VTA are altered. Here we describe enhanced synaptic excitation in dopamine neurons from male and female 3xTg-AD mice (an amyloid + tau-driven model). AMPAR-mediated excitatory input was enhanced in a subset of connections, while GABAAR-mediated inhibition decreased as a function of dendritic atrophy. Protein phosphorylation analysis and pharmacology suggested that strengthened excitation depends on both presynaptic protein kinase C activity and postsynaptic enhancement of perisomatic AMPA receptor currents. Biophysical modeling predicted that enhanced excitatory synaptic input in 3xTg-AD dopamine neurons, combined with altered dendritic morphology and intrinsic hypersensitivity, produces increased firing and a steeper input-output relationship. These results suggest that AD pathology is associated with increased sensitivity of single dopamine neurons, which may serve to maintain phasic dopamine signaling in early stages of degeneration.Significance Statement While recent studies describe a suspected role for VTA dopamine neurons in Alzheimer's disease, the influence of excitatory and inhibitory input as well as single neuron morphology is not known. Using single-cell patch-clamp electrophysiology we find that 3xTg-AD dopamine neurons receive enhanced glutamatergic synaptic input and reduced inhibitory GABA input, thus tipping the balance further toward excitation. By combining this with morphological reconstructions, multicompartmental biophysical modeling, and past findings of intrinsic hypersensitivity, we predict that synaptic changes drive increased burst firing and convey a steeper input-output relationship in 3xTg neurons. These modifications likely alter downstream signaling or serve as a compensatory protective mechanism in the face of degenerative pathology in AD.},
}

@article {pmid41702711,
year = {2026},
author = {Michalon, R and Planche, V and Lemoine, M and Keuck, L and Villain, N},
title = {Defining Alzheimer's disease: stipulations and the ethics of diagnostic change.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-337832},
pmid = {41702711},
issn = {1468-330X},
}

@article {pmid41702507,
year = {2026},
author = {Yan, C and Kong, Z and Pan, Y and Fu, Z and Han, K and Zhao, X and Zhang, J and Bo, L and Sun, W and Gao, J and Dong, X and Zheng, Z and Yue, X and Sun, P and Jiang, X and Chen, C},
title = {Anti-CLEC7A nanobody in situ engineering promotes amyloid-β oligomers clearance by CAR-microglia to alleviate Alzheimer's disease pathology in mice.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114710},
doi = {10.1016/j.jconrel.2026.114710},
pmid = {41702507},
issn = {1873-4995},
abstract = {Chimeric antigen receptor microglia (CAR-M)-mediated amyloid-β oligomers (AβO) phagocytosis shows great promise in Alzheimer's disease (AD) treatment, however, the limited AβO degradation of CAR-M compromises their anti-AβO potency. This work here reports an in situ engineered agonistic anti-C-type lectin domain containing 7 A (CLEC7A) nanobody to accelerate AβO degradation of CAR-M, augmenting their anti-AβO efficacy. Specifically, with the intranasal-delivered microglia-targeting lipid nanoparticles (LNP), this work generates an AβO-specific degradation-potentiated CAR-M by introducing dual mRNAs encoding AβO-specific CAR and anti-CLEC7A nanobody into the cerebral microglia. These data show that these engineered CAR-M exhibited superior phagocytic function and promoted intracellular AβO degradation via activating CLEC7A-spleen tyrosine kinase (SYK) signaling pathway through the local secretion of anti-CLEC7A nanobody. In the APP/PS1 mouse model of AD, these in situ reprogrammed CAR-M significantly reduced cerebral Aβ levels, suppressed neuroinflammation, and restored cognitive function. In sum, these findings demonstrate that potentiating AβO degradation within CAR-M effectively alleviates AD pathology, providing a promising therapeutic strategy for AD with broad application in other neurodegenerative diseases.},
}

@article {pmid41702369,
year = {2026},
author = {Travers-Lesage, V and Crouzier, L and Antonijevic, M and Wang, A and Toublet, FX and Davis, A and Modeste, F and Brazzolotto, X and Nachon, F and Since, M and Maurice, T and Rochais, C and Dallemagne, P},
title = {Access to novel potent pleiotropic prodrugs, targeting both butyrylcholinesterase and serotonin reuptake, with anti-amnesic activities in Alzheimer's disease model.},
journal = {European journal of medicinal chemistry},
volume = {307},
number = {},
pages = {118670},
doi = {10.1016/j.ejmech.2026.118670},
pmid = {41702369},
issn = {1768-3254},
abstract = {The treatment of Alzheimer's disease should undoubtedly be multifactorial and require a polypharmacological approach to be effective. Pleiotropic prodrugs can release, upon inhibition of a primary target, a drug that targets a second protein of therapeutic interest. Here, we describe the design of prodrugs that release a potent serotonin reuptake inhibitor, 7-hydroxysertraline, upon the inhibition of butyrylcholinesterase. Indeed, 7-hydroxysertraline is not only a ligand of the serotonin transporter but also possesses the structural requirements to yield carbamates, able to bind to the catalytic site of butyrylcholinesterase and undergo its carbamylation. This behavior could result in a pseudo-irreversible inhibition of butyrylcholinesterase, followed by release of the serotonin reuptake inhibitor. Several carbamates of 7-hydroxysertraline were synthesized and evaluated in vitro for their acetyl- and butyrylcholinesterase inhibitory activities and their affinity for the serotonin transporter. Structure-activity relationships were then established based on a molecular modelling study. Investigations into cholinesterase inhibition kinetics have been conducted, resulting in the selection of two prodrugs for in vivo evaluation in an Alzheimer's disease mouse model. One of these, compound 8e, provided complete protection against short- and long-term memory deficits induced by intracerebroventricular administration of β-amyloid oligomers. This makes compound 8e a promising candidate for preclinical development as a possible treatment for Alzheimer's disease.},
}

@article {pmid41702332,
year = {2026},
author = {Messak, M and Abdelmageed, A and Khattab, YA and Altalab, G and Mandour, Y and Shaker, O},
title = {α-synuclein monoclonal antibodies in Parkinson's disease: A failed promise or unmet potential?.},
journal = {Journal of the neurological sciences},
volume = {482},
number = {},
pages = {125806},
doi = {10.1016/j.jns.2026.125806},
pmid = {41702332},
issn = {1878-5883},
abstract = {BACKGROUND: Monoclonal antibodies (mAbs) have shown disappointing results in targeting α-synuclein (α-Syn) aggregates in PD, leading us to question whether this therapeutic approach is fundamentally flawed or unrealized potential awaiting better application. This review aims to assess the current evidence, identify key challenges hindering this therapeutic approach, and highlight priorities for future research.

METHODS: A narrative review of the literature was conducted focusing on available evidence with respect to safety, efficacy, pharmacokinetics, CNS exposure, peripheral and central target engagement, emerging biomarkers and PET scan imaging tracers, and lessons from immunotherapy development in Alzheimer's disease.

FINDINGS: Five RCTs, three phase-I and two phase-II trials, testing three different forms of mAb (n = 786) were identified. All studies showed that mAbs were generally safe. They demonstrated low but measurable CSF mAb concentration (CSF:Serum = 0.2-0.5%) with limited evidence regarding central target engagement. Phase-II trials failed to meet their primary efficacy endpoints and showed no significant slowing of disease progression (Cinpanemab 250 mg P-value = 0.7, 1250 mg P-value = 0.78, 3500 mg P-value = 0.7; Prasinezumab 1500 mg P-value = 0.24, 4500 mg P-value = 0.72). These disappointing results are attributed to several factors, including late timing of intervention, poor BBB permeability, heterogeneity in α-Syn pathology, not using sensitive tools to detect central target engagement and Delayed PET scan tracers' development.

CONCLUSION: Although there is strong preclinical evidence supporting the efficacy of mAb in PD, several limitations prevent this from translating into tangible clinical benefit. These limitations do not necessarily indicate a fundamental flaw in the therapeutic concept, but they do highlight the urgent need for future research to prioritize addressing these limitations.},
}

@article {pmid41702051,
year = {2026},
author = {Bartley, MM and St Sauver, JL and Schroeder, DR and Khera, N and Griffin, JM},
title = {Social Determinants of Health and Research Participation Among People Living With Mild Cognitive Impairment and Dementia.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261425294},
doi = {10.1177/07334648261425294},
pmid = {41702051},
issn = {1552-4523},
abstract = {IntroductionPeople most likely to be affected by Alzheimer's disease and related dementias (ADRD) are underrepresented in clinical research. Identifying and addressing factors which may influence their research participation is important to advance science and promote diversity. We examined the influence of social determinants of health (SDOH) on research participation among people living with ADRD.MethodsWe included those age 55 years and older living with ADRD, followed in our community practice in Rochester, Minnesota, who completed a questionnaire assessing SDOH and had at least one clinic visit between June 1, 2019 and June 1, 2020. Demographic and SDOH factors were examined by research participation.ResultsAmong 3273 people included, research participation was low overall (265/3273; 8.1%). People participating in research were more likely to be socially integrated and of higher educational attainment (p < 0.05).ConclusionPromoting social interaction is a potential area for focus to increase research participation in at risk populations.},
}

@article {pmid41701880,
year = {2026},
author = {Zhang, L and Li, L and Wang, X and Ma, L and Yan, L and Xiang, Q and Cui, Y and Liu, Z},
title = {Neuroinflammation and Cellular Senescence in Brain Aging and Neurodegeneration.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1538},
pmid = {41701880},
issn = {2152-5250},
abstract = {Against the backdrop of a rapidly aging global population, the incidence of neurodegenerative diseases such as Alzheimer's and Parkinson's continues to rise, imposing a severe socioeconomic burden. Neuroinflammation is recognized as the core mechanism linking physiological brain aging to pathological cognitive decline. This paper aims to systematically elucidate the multi-level activation mechanisms of neuroinflammation during aging and comprehensively evaluate drug intervention strategies targeting this process. Research reveals that the chronicity of neuroinflammation is driven by multiple cellular and molecular events. At the cellular level, aging and dysfunction in microglia and astrocytes lead to their respective transitions toward pro-inflammatory M1 and neurotoxic A1 phenotypes. These changes interact synergistically with blood-brain barrier dysfunction, peripheral immune cell infiltration, and abnormal aggregation of pathological proteins like Aβ and α-synuclein, forming a vicious cycle. At the molecular level, signaling pathways including NLRP3 inflammasome, NF-κB, and JAK/STAT are persistently activated, while epigenetic modifications play crucial regulatory roles. Addressing these mechanisms, this review systematically examines six major intervention strategies: modulating neuroimmune cell function, inhibiting core inflammatory pathways, targeting inflammatory mediators like cytokines, employing senolytics to clear senescent cells, enhancing endogenous anti-inflammatory defenses, and exploring multi-target natural products and drug repurposing. Research indicates that targeting neuroinflammation offers a highly promising new avenue for delaying brain aging and related diseases. However, this field still faces numerous challenges, including target specificity, blood-brain barrier delivery, individual heterogeneity, and difficulties in clinical translation. Future breakthroughs will depend on more precise drug design, innovative delivery technologies, biomarker development, and interdisciplinary collaborative research.},
}

@article {pmid41701875,
year = {2026},
author = {Li, M and Wang, H and Tang, Z and Yang, S and Lin, L},
title = {Dysregulated Lipid Metabolism and Neurovascular Unit Dysfunction: Novel Mechanisms Linking Alzheimer's Disease and Vascular Dementia.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1464},
pmid = {41701875},
issn = {2152-5250},
abstract = {The neurovascular unit (NVU) represents a multicellular functional ensemble pivotal to the preservation of cerebral homeostasis, encompassing endothelial cells, pericytes, glial cells (astrocytes, microglia, oligodendrocytes), and neurons. This complex orchestrates the regulation of blood-brain barrier (BBB) integrity, cerebral blood flow (CBF), and the metabolic microenvironment requisite for neuronal viability and functional competence. Accumulating lines of evidence have underscored that NVU dysfunction constitutes a critical early pathological event in neurodegenerative disorders, including Alzheimer's disease (AD) and vascular dementia (VaD). The present review summarizes the structural composition and core physiological functionalities of the NVU, with particular emphasis on the emerging role of lipid metabolism dysregulation in mediating NVU impairment-an aberrant process encompassing lipid droplets, apolipoprotein E (APOE), ATPase phospholipid transporting 11B (ATP11B), triggering receptor expressed on myeloid cells 2 (TREM2), and ATP-binding cassette (ABC) transporters. We further delineate the mechanisms by which disrupted lipid homeostasis elicits neuroinflammation, amplifies oxidative stress, impairs amyloid-β (Aβ) clearance, and precipitates BBB breakdown, ultimately culminating in cognitive decline. Simultaneously, this review examines controversies within the field, such as the specific role of apolipoprotein E ε4 allele (APOE4) in disease and highlights the significant pathophysiological differences between preclinical animal models and human diseases. Therapeutic strategies targeting lipid metabolism or the blood-brain barrier still face considerable challenges in clinical translation. Meanwhile, emerging tools such as lipidomics contribute to systematically analyzing the associated dysregulated lipid networks, thereby aiding in the identification of novel therapeutic targets.},
}

@article {pmid41701873,
year = {2026},
author = {Hong, J and Liu, Y and Peng, Q and Mei, Z and Wang, G},
title = {Cuproptosis and Aging: Molecular Mechanisms and Therapeutic Implications.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1305},
pmid = {41701873},
issn = {2152-5250},
abstract = {With the accelerated pace of global population aging, the number of people suffering from age-related diseases is increasing, posing a serious threat to human health and well-being. Age-related diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), hypertension, atherosclerosis, type 2 diabetes (T2DM), and osteoporosis (OP), are often characterized by physiological function decline and metabolic disorders caused by aging, among which dysregulation of metal ion homeostasis, especially copper homeostasis imbalance, has emerged as a major factor. Copper is an essential enzymatic cofactor whose homeostasis is tightly regulated at systemic, cellular, and subcellular levels. However, during the aging process, the balance between copper uptake and efflux becomes compromised, alongside a reduction in cellular copper-buffering capacity. These alterations may lead to the loss of copper homeostasis and induce cuproptosis, which is a recently elucidated form of regulated cell death (RCD) triggered by copper overload and disrupts mitochondrial metabolism by promoting the aggregation of lipoylated proteins in the tricarboxylic acid cycle (TCA) and destabilizing respiratory chain complexes. Copper homeostasis imbalance and the resulting cuproptosis accelerate the aging process by promoting molecular mechanisms, including telomere attrition, mitochondrial dysfunction, oxidative stress, proteostasis imbalance, epigenetic changes, and chronic inflammation. This review focuses on the reciprocal interactions between aging and copper homeostasis: it elucidates how aging impairs copper homeostatic regulation, and how dysregulated copper metabolism and subsequent cuproptosis accelerate aging and exacerbate age-related diseases. Furthermore, it explores potential therapeutic strategies targeting copper homeostasis and cuproptosis to treat age-related diseases.},
}

@article {pmid41701839,
year = {2026},
author = {Chen, J and Xu, M and Liu, Y and Hadi, F and Xue, S and Chien, S and Zhong, S},
title = {RNA-binding activity of PHGDH drives amyloid-beta production in a human brain organoid model of sporadic Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {8},
pages = {e2532234123},
doi = {10.1073/pnas.2532234123},
pmid = {41701839},
issn = {1091-6490},
support = {DP1DK126138//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; R01GM138852//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01HD107206//HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; F32AG094189//HHS | NIH | National Institute on Aging (NIA)/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Amyloid beta-Peptides/metabolism/biosynthesis ; *Organoids/metabolism/pathology ; Animals ; *Brain/metabolism/pathology ; Mice ; Amyloid Precursor Protein Secretases/metabolism/genetics ; *Phosphoglycerate Dehydrogenase/metabolism/genetics ; Aspartic Acid Endopeptidases/metabolism/genetics ; eIF-2 Kinase/metabolism/genetics ; Neurons/metabolism ; 3' Untranslated Regions ; Disease Models, Animal ; Eukaryotic Initiation Factor-2/metabolism/genetics ; *RNA-Binding Proteins/metabolism ; Phosphorylation ; Astrocytes/metabolism ; },
abstract = {Pathological progression in sporadic Alzheimer's disease (sAD) initiates with an early rise in soluble amyloid-β (Aβ), preceding plaque formation and neurodegeneration. However, the molecular event triggering this initial accumulation remains unknown. We report that phosphoglycerate dehydrogenase (PHGDH), a consistent biomarker of prodromal sAD, drives Aβ production through a previously unrecognized RNA-binding function. Specifically, PHGDH binds the 3'UTR of EIF2AK1 mRNA, enabling the physical interaction between PHGDH and the EIF2AK1 protein. By facilitating the recruitment of EIF2AK1 to its substrate EIF2α, this complex drives EIF2α phosphorylation, thereby selectively promoting the translation of BACE1, the rate-limiting enzyme for Aβ generation. We demonstrate that PHGDH overexpression elevates BACE1 protein and intracellular Aβ in neurons and astrocytes across mouse models and human brain organoids, independent of its canonical enzymatic or transcriptional roles. Mechanistically, this process requires a specific RNA-binding surface within PHGDH and the EIF2AK1 3'UTR. These findings define a PHGDH-EIF2AK1-EIF2α-BACE1 axis as a key driver of the earliest amyloid pathology in sAD.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Humans
*Amyloid beta-Peptides/metabolism/biosynthesis
*Organoids/metabolism/pathology
Animals
*Brain/metabolism/pathology
Mice
Amyloid Precursor Protein Secretases/metabolism/genetics
*Phosphoglycerate Dehydrogenase/metabolism/genetics
Aspartic Acid Endopeptidases/metabolism/genetics
eIF-2 Kinase/metabolism/genetics
Neurons/metabolism
3' Untranslated Regions
Disease Models, Animal
Eukaryotic Initiation Factor-2/metabolism/genetics
*RNA-Binding Proteins/metabolism
Phosphorylation
Astrocytes/metabolism

@article {pmid41701791,
year = {2026},
author = {Kittle, KR and Cicero, EC and Pelkmans, J and Flatt, JD and Anderson, JG},
title = {Health of Bi+ Dementia Caregivers: Moderation Effects of Minority and Caregiving Stress.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175251415106},
doi = {10.1177/15333175251415106},
pmid = {41701791},
issn = {1938-2731},
mesh = {Humans ; *Caregivers/psychology/statistics & numerical data ; Male ; Female ; *Stress, Psychological/psychology ; *Dementia/nursing ; Cross-Sectional Studies ; Middle Aged ; *Sexual and Gender Minorities/psychology/statistics & numerical data ; *Quality of Life/psychology ; Aged ; *Health Status ; Adult ; },
abstract = {Despite comprising the largest segment of the sexual minority population and experiencing unique stressors and health disparities, bi+ dementia caregivers remain underrepresented in health and caregiving research. This secondary analysis of cross-sectional survey data from LGBTQ+ dementia caregivers (bi+, n = 125; gay[g]/lesbian[l], n = 161) examined whether associations between minority and caregiving stressors and global health differed by caregiver group. Bi+ caregivers reported significantly higher minority stress and lower family quality of life but better health than g/l caregivers. Moderation analyses revealed: higher perceived stress predicted worse health for bi+ but better health for g/l; higher family quality of life predicted better health for both groups, with a stronger effect among bi+ caregivers; and more lifetime discrimination predicted worse health for both groups, with a stronger effect among bi+ caregivers. Results underscore the need for inclusive, affirming research and interventions addressing bi+ caregiver stress experiences.},
}

Humans
*Caregivers/psychology/statistics & numerical data
Male
Female
*Stress, Psychological/psychology
*Dementia/nursing
Cross-Sectional Studies
Middle Aged
*Sexual and Gender Minorities/psychology/statistics & numerical data
*Quality of Life/psychology
Aged
*Health Status
Adult

@article {pmid41701728,
year = {2026},
author = {Morita, K and Ihashi, S and Okamura, E and Goto, K and Yoshihara, T and Honda, A and Ema, M and Asano, M},
title = {Highly efficient production of transgenic rats with long DNA insertions using piggyBac transposase mRNA and piezo-assisted microinjection.},
journal = {PloS one},
volume = {21},
number = {2},
pages = {e0339406},
doi = {10.1371/journal.pone.0339406},
pmid = {41701728},
issn = {1932-6203},
mesh = {Animals ; *Microinjections/methods ; *Transposases/genetics/metabolism ; Rats ; Rats, Transgenic ; *RNA, Messenger/genetics ; Female ; Zygote/metabolism ; Male ; Transgenes ; *DNA/genetics ; },
abstract = {In the conventional method of producing transgenic (Tg) animals, donor DNA is microinjected into the pronuclei of zygotes using a sharp glass needle. However, this approach is generally inefficient as it requires highly skilled microinjection techniques to ensure zygote survival and the transgene is incorporated into only a small proportion of the offspring. In contrast, methods based on piggyBac transposase (PBase) enables more efficient insertion of DNA into the genome and generation of Tg animals. The use of piggyBac transposase have also been examined in rats→ However, this method has not yet been fully optimized or properly characterized. In this study, we examined the microinjection of PBase mRNA and donor plasmid DNA into the pronuclei of rat zygotes using piezo-assisted microinjection. This approach resulted in high survival rates and enabled the efficient generation of Tg rats, even with long donor DNA. When the zygotes were microinjected using Piezo, over 70% were viable, and after embryo transfer, over 80% of the pups carried the transgene. Furthermore, we confirmed germline transmission to the F1 and F2 generations. We also attempted to generate a rat model of Alzheimer's using this method→ However, the protein was not detected despite mRNA expression, and the phenotype was not observed in behavioral tests. Although the generation of Alzheimer's disease model remains a challenge, our findings show that piggyBac transposase mRNA combined with piezo-assisted microinjection represents a simple and efficient method for producing Tg rats, even with long donor DNA.},
}

Animals
*Microinjections/methods
*Transposases/genetics/metabolism
Rats
Rats, Transgenic
*RNA, Messenger/genetics
Female
Zygote/metabolism
Male
Transgenes
*DNA/genetics

@article {pmid41701723,
year = {2026},
author = {Li, R and Jiang, S and Pi, Z and Chen, G},
title = {Early diagnosis of Alzheimer's Disease: Graph theoretical analysis of cerebellar network features based on 18F-AV45 PET.},
journal = {PloS one},
volume = {21},
number = {2},
pages = {e0342738},
doi = {10.1371/journal.pone.0342738},
pmid = {41701723},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/diagnosis ; *Positron-Emission Tomography/methods ; Male ; Aged ; Female ; *Cerebellum/diagnostic imaging/pathology ; Early Diagnosis ; Cognitive Dysfunction/diagnostic imaging ; *Ethylene Glycols ; Aged, 80 and over ; Aniline Compounds ; Plaque, Amyloid/diagnostic imaging/pathology ; Machine Learning ; },
abstract = {Pathological and neuroimaging changes in the cerebellum of Alzheimer's disease (AD) patients have been well documented. However, the changes in cerebellar amyloid plaque deposition connectivity networks during AD progression based on positron emission tomography (PET) imaging remain unclear. We selected 18F-florbetapir PET (18F-AV45 PET) imaging data from the Alzheimer's disease neuroimaging initiative (ADNI) dataset (n = 612) and employed graph theoretical analysis to examine amyloid plaque deposition connectivity, comparing the connectivity differences across cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD groups. In addition, we combined graph theoretical features with the standardized uptake value ratio (SUVR) of regions of interest and applied them to machine learning models for the early diagnosis of AD. As cognitive decline progressed, significant changes in cerebellar network connectivity were observed across groups. Regarding local connectivity, changes in betweenness centrality were evident in multiple cerebellar regions at different cognitive stages. Cerebellar amyloid networks revealed early changes in amyloid plaque deposition connectivity. The machine learning model achieved an area under the curve (AUC) of 0.950 for distinguishing AD from CN, 0.995 for CN vs. EMCI, 0.964 for EMCI vs. LMCI and 0.632 for LMCI vs. AD. These findings provide new insights into the cerebellar pathological features of AD and highlight the potential of this approach for early identification and prediction of AD progression.},
}

Humans
*Alzheimer Disease/diagnostic imaging/diagnosis
*Positron-Emission Tomography/methods
Male
Aged
Female
*Cerebellum/diagnostic imaging/pathology
Early Diagnosis
Cognitive Dysfunction/diagnostic imaging
*Ethylene Glycols
Aged, 80 and over
Aniline Compounds
Plaque, Amyloid/diagnostic imaging/pathology
Machine Learning

@article {pmid41701678,
year = {2026},
author = {Deng, Y and Liu, Y and Hao, H and Xu, K and Zhu, Q and Li, H and Ma, T and Steenland, K},
title = {The role of comorbidities in the associations between air pollution and Alzheimer's disease: A national cohort study in the American Medicare population.},
journal = {PLoS medicine},
volume = {23},
number = {2},
pages = {e1004912},
doi = {10.1371/journal.pmed.1004912},
pmid = {41701678},
issn = {1549-1676},
mesh = {Humans ; *Alzheimer Disease/epidemiology/etiology/diagnosis ; United States/epidemiology ; Aged ; Medicare ; *Air Pollution/adverse effects ; Female ; Male ; *Particulate Matter/adverse effects ; Comorbidity ; Aged, 80 and over ; Cohort Studies ; Risk Factors ; *Environmental Exposure/adverse effects ; Incidence ; Air Pollutants/adverse effects ; },
abstract = {BACKGROUND: Air pollution and several common comorbidities-such as hypertension, stroke, and depression-are established risk factors for Alzheimer's disease (AD). However, whether these comorbidities mediate or amplify the effects of fine particulate matter (PM2.5) on AD remains unclear. We aimed to investigate whether these conditions modify or mediate the association between PM2.5 exposure and incident AD.

METHODS AND FINDINGS: We conducted a nationwide cohort study including 27.8 million US Medicare beneficiaries aged 65 years and older from 2000 to 2018. Exposure to PM2.5 was assessed using high-resolution air pollution datasets. Cox proportional hazards models were applied to estimate the associations between exposure to PM2.5, incident AD, and comorbidities. The potential for comorbidities to modify and mediate the association between PM2.5 and AD was evaluated by stratified analyses and mediation analysis. We identified approximately 3.0 million incident AD cases. PM2.5 exposure (5-year moving average prior to AD onset) was associated with increased risk of AD in the overall population (hazard ratio [HR]) per interquartile range [IQR, 3.8 µg/m3] increase: 1.085 (95% CI: 1.078, 1.091]. This association was slightly stronger in individuals with stroke (HR per IQR increase: 1.105; 95% CI: 1.096, 1.114), but there was little effect modification for hypertension and depression. PM2.5 exposure was also significantly associated with higher risks of hypertension, depression, and stroke, all of which were also linked to increased AD risk. However, mediation effects were minimal, with 1.6% of the association between PM2.5 and incident AD mediated by hypertension, 4.2% by stroke, and 2.1% by depression. Study limitations include use of administrative claims data and potential exposure misclassification from area-level PM2.5 estimates.

CONCLUSIONS: Our findings suggest that PM2.5 exposure was associated with increased AD risk, primarily through direct rather than comorbidity-mediated pathways. Stroke may modestly increase susceptibility. These findings highlight the need for air quality interventions as part of dementia prevention strategies in aging populations, especially those facing overlapping environmental and clinical vulnerabilities.},
}

Humans
*Alzheimer Disease/epidemiology/etiology/diagnosis
United States/epidemiology
Aged
Medicare
*Air Pollution/adverse effects
Female
Male
*Particulate Matter/adverse effects
Comorbidity
Aged, 80 and over
Cohort Studies
Risk Factors
*Environmental Exposure/adverse effects
Incidence
Air Pollutants/adverse effects

@article {pmid41701639,
year = {2026},
author = {Macomber, A and Zouridakis, A and Lubbat, V and Minogue, G and Kawles, A and Keszycki, R and Nelson, C and Gill, N and Gutstein, D and Castellani, R and Jamshidi, P and Grant, R and Mesulam, MM and Geula, C and Gefen, T},
title = {Vulnerability of anterior cingulate Von Economo neurons to FTLD-tauopathies in behavioral variant frontotemporal dementia.},
journal = {Cerebral cortex (New York, N.Y. : 1991)},
volume = {36},
number = {2},
pages = {},
doi = {10.1093/cercor/bhag011},
pmid = {41701639},
issn = {1460-2199},
support = {P30AG013854/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; R01 AG062566/AG/NIA NIH HHS/United States ; F31AG076318/AG/NIA NIH HHS/United States ; T32AG020506/AG/NIA NIH HHS/United States ; R01 NS085770/NS/NINDS NIH HHS/United States ; T32 NS047987/NS/NINDS NIH HHS/United States ; DGE-1842165//National Science Foundation's Graduate Research Fellowship/ ; //Karen Toffler Charitable Trust/ ; },
mesh = {Humans ; *Gyrus Cinguli/pathology ; Male ; Female ; Aged ; *Frontotemporal Dementia/pathology ; *Neurons/pathology ; Middle Aged ; *Tauopathies/pathology ; Aged, 80 and over ; tau Proteins/metabolism ; },
abstract = {Von Economo neurons (VENs) are unique spindle-shaped neurons that primarily reside in the anterior cingulate (ACC) and fronto-insular (FI) cortices. They are more numerous in species with affiliative behaviors and may support social-emotional functions. VENs are reduced in the ACC and FI of individuals with behavioral variant frontotemporal dementia (bvFTD), marked by personality changes and socially inappropriate behavior. Neuropathologies underlying bvFTD include frontotemporal lobar degenerations (FTLD) with tauopathy (FTLD-tau) or TDP-43 (FTLD-TDP). This study examined VEN density across three FTLD-tau subtypes: the 4R tauopathies of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), and the 3R tauopathy known as Pick's disease (PiD). Twenty-six right-handed bvFTD-FTLD-tau cases were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (PiD n = 9; CBD n = 11; PSP n = 6). Paraffin sections were cresyl violet-stained to visualize VENs in the ACC and analyzed using unbiased stereology. Wilcoxon rank-sum tests showed significantly lower VEN density in PiD than CBD (P < 0.05). No significant differences were found between PiD and PSP or CBD and PSP. Across isoforms, VEN density was over fourfold higher in 4R than 3R cases (P < 0.01). Overall, stereology indicates VENs are more vulnerable to 3R PiD than 4R CBD, both causes of bvFTD. The clinical implications of this differential vulnerability warrant further study.},
}

Humans
*Gyrus Cinguli/pathology
Male
Female
Aged
*Frontotemporal Dementia/pathology
*Neurons/pathology
Middle Aged
*Tauopathies/pathology
Aged, 80 and over
tau Proteins/metabolism

@article {pmid41701587,
year = {2026},
author = {Zhang, H and Wang, L and Zhao, Y and Xie, J and Fang, T and Song, R and Zhang, W},
title = {Heterophily-Aware Spectral GCN for Population-Level Brain Disorder Prediction.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3665521},
pmid = {41701587},
issn = {2168-2208},
abstract = {Integrating resting-state functional magnetic resonance imaging (rs-fMRI) and phenotypic data is a promising way to build a comprehensive population graph for the prediction of brain disorders using graph neural networks (GNNs). However, existing GNN-based methods face two limitations: the complexity of relationships between subjects poses challenges in constructing a well-defined population graph, and the inherent node heterophily within the population graph is often overlooked. To address them, we propose a population graph with a phenotypic encoder, which leverages rs-fMRI and phenotypic data to model complex relationships between subjects and enables GNN to learn population-level features. We also design a heterophily-aware spectral graph convolution network that incorporates local similarity-based learning to assess node homophily and addresses the heterophily issue. Experiments demonstrate that our method performs well in classifying both Alzheimer's Disease and Autism Spectrum Disorder. In addition, it can distinguish between progressive and stable mild cognitive impairment, facilitating timely interventions for the diseases.},
}

@article {pmid41701517,
year = {2026},
author = {Ejiofor, T and Oluwafunmilayo J, O and Kala, A and Ephraim, AD and Apochi, OO},
title = {Structural Brain Correlates With Appetite and Eating Disturbances Across the Alzheimer Disease Spectrum.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000719},
pmid = {41701517},
issn = {1546-4156},
abstract = {INTRODUCTION: Neuropsychiatric symptoms are integral features of Alzheimer disease (AD) and may precede cognitive impairment. Appetite and eating disturbances are common across the AD spectrum.

METHODS: We analyzed 7223 participants from the National Alzheimer's Coordinating Center with Uniform Data Set assessments and MRI. Appetite and eating disturbances were assessed using the Neuropsychiatric Inventory Questionnaire. Cross-sectional associations with brain volumes were examined using multivariable regression. Longitudinal analyses among participants without baseline appetite disturbance used discrete-time survival models.

RESULTS: Appetite disturbances were present in 9.4% of participants and were associated with greater neuropsychiatric burden and disease severity. Cross-sectionally, lower global gray matter volume showed the most robust association, while regional effects were attenuated after neuropsychiatric adjustment. Longitudinally, baseline brain structure predicted incident appetite disturbance only among cognitively normal participants (OR per SD decrease=0.87).

DISCUSSION: Appetite disturbances may reflect diffuse neurodegenerative vulnerability and represent early behavioral markers of Alzheimer-related brain aging.},
}

@article {pmid41701420,
year = {2026},
author = {Koundal, A and Chodhary, N and Kumar, H and Vashisht, K and Ashawat, MS and Kushawaha, SK},
title = {Ganaxolone as a promising therapeutic agent for Alzheimer's disease: signaling pathways and mechanistic insights-a narrative review.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41701420},
issn = {1568-5608},
}

@article {pmid41701395,
year = {2026},
author = {Nisar, A and Akhter, N and Chauhdary, Z and Anjum, F and Saleem, F and Sana, S and Rafiq, I and Mustafa, A},
title = {Investigating the Neuroprotective Effects of Saw Palmetto Fruit Extract Against D-Galactose and Aluminum Chloride Induced Alzheimer's Disease: In Vivo Study.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {76},
pmid = {41701395},
issn = {1573-6903},
}

@article {pmid41701084,
year = {2026},
author = {Shir, D and Lachner, C},
title = {Alzheimer's disease: a clinical update on diagnosis and treatment.},
journal = {Neurologia i neurochirurgia polska},
volume = {},
number = {},
pages = {},
doi = {10.5603/pjnns.109190},
pmid = {41701084},
issn = {0028-3843},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive cognitive and functional decline. As the population ages, the prevalence of AD is expected to increase significantly, imposing a growing burden on patients, caregivers, and healthcare systems. Advances in our understanding of AD pathophysiology and biomarker-based diagnosis have redefined clinical practice, introducing challenges in early detection, accurate diagnosis, and effective treatment.

STATE OF THE ART: Current AD diagnostic frameworks incorporate clinical assessment alongside biomarkers of amyloid and tau pathology, cerebrovascular contributions, and neurodegeneration. Imaging modalities and fluid biomarker analyses enable more precise diagnosis, although accessibility remains limited in many settings. Recent therapeutic advancements in the form of anti-amyloid monoclonal antibodies offer disease-modifying potential but are accompanied by implementation challenges, such as patient selection, monitoring for adverse events, and cost considerations.

CLINICAL IMPLICATIONS: Integrating biomarker testing into routine clinical practice requires a careful review of individual risks and benefits for each patient, balancing diagnostic accuracy with practical considerations like testing consequences, test availability, pretest probability, and patient preferences. Shared decision-making is pivotal when discussing treatment options, weighing potential clinical benefits against risks and the overall burden of care.

FUTURE DIRECTIONS: Enhancing the delivery of anti-amyloid antibodies and advancing research into tau-targeted therapies represent promising therapeutic avenues. Incorporating scalable, non-invasive biomarkers, e.g., plasma-based biomarkers, into clinical practice has the potential to transform diagnostic workflows, provided they are applied in appropriate clinical contexts. Bridging the gap between research innovations and real-world implementation will require coordinated, multidisciplinary collaboration across healthcare systems.},
}

@article {pmid41700962,
year = {2026},
author = {Hanson, HG and Arias, JJ and Wurtz, HM and Manchester, M and Scipion, C and Federman, AD},
title = {Primary Care Physician Perspectives on Artificial Intelligence for Dementia Screening: A Qualitative Study.},
journal = {AJOB empirical bioethics},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/23294515.2026.2632089},
pmid = {41700962},
issn = {2329-4523},
abstract = {BACKGROUND: Automated approaches to cognitive impairment screening may soon achieve sufficient levels of accuracy for clinical implementation but they present potentially serious ethical challenges. Overcoming such challenges for successful implementation of automated screening may depend on the perspective of the clinicians who are its intended users.

METHODS: We conducted a qualitative study of internal medicine, geriatrics and family medicine physicians recruited from ambulatory practices in New York City, NY to identify ethical challenges of implementing automated CI screening (n = 22). In four focus groups, we explored attitudes and beliefs about routine manual screening for cognitive impairment and automated screening based in machine learning models of data from electronic medical records (EMR) or patient audio recordings, using hypothetical scenarios. Focus group recordings were transcribed and analyzed using grounded theory.

RESULTS: Participants reported routine screening for cognitive impairment only in the context of the Medicare annual wellness visit and generally avoided routine screening because of limited treatment options to support patients, such as poor access to geriatrics/neuropsychiatric services. Thematic analysis revealed several perceived benefits: enhanced clinical efficiency, engagement in cognitive healthcare of their patients, and expanded access to cognitive care. They identified several potential challenges with ethics implications: concerns about accuracy of the technology, bias, difficulty communicating the technology and results to patients and caregivers that could impact their ability to provide informed consent, and risks to patients (privacy, stigmatization and insurability). They noted that without more health system infrastructure to support patients with dementia, the benefits of automated screening would be limited.

CONCLUSIONS: Physicians identified several critical ethical challenges to automated CI screening. Health systems will need to address these challenges to ensure benefit for and the safety, autonomy and privacy of patients and ultimately, the successful implementation of such technology.},
}

@article {pmid41700920,
year = {2026},
author = {Zhong, Y and Wei, L and Xue, R},
title = {GSK126 mitigates oxidative stress in Alzheimer disease models via an enhancer of Zeste homolog 2-H3 lysine 27 trimethylation-superoxide dismutase 1 axis.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag008},
pmid = {41700920},
issn = {1554-6578},
support = {2022ZD02//Key Research Project of Xi'an International Medical Center Hospital/ ; },
abstract = {Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss and with limited effective therapies. Oxidative stress, driven by disrupted redox balance and excessive reactive oxygen species (ROS), is believed to be a key pathogenic driver. This study aimed to explore the role and mechanism of the selective enhancer of Zeste homolog 2 (EZH2) methyltransferase inhibitor GSK126 in alleviating AD-related OS in AD models. Using Aβ1-42-induced AD model rats, we conducted Morris water maze tests, histologic and immunohistochemical staining, CCK-8/Annexin V-PI assays, Western blot, quantitative Reverse Transcription PCR (qRT-PCR), and Chromatin Immunoprecipitation quantitative Real-Time PCR (ChIP-qPCR). GSK126 shortened escape latency, reduced hippocampal pathology/apoptosis, upregulated Superoxide dismutase 1 (SOD1), and lowered ROS/malondialdehyde/protein carbonyls, thereby increasing antioxidant capacity in the AD model rats. In okadaic acid-treated SH-SY5Y cells, GSK126 enhanced viability, reduced apoptosis by downregulating Bax/c-Cas3 and upregulating Bcl-2 and upregulated SOD1 by inhibiting EZH2-mediated H3 lysine 27 trimethylation (H3K27me3) enrichment at the SOD1 promoter. SOD1 overexpression antagonized EZH2-induced damage. These results suggest that GSK126 could alleviate AD-related pathologic alterations in these models via the EZH2-H3K27me3-SOD1 axis, thereby suggesting a potential therapeutic target for AD.},
}

@article {pmid41700788,
year = {2026},
author = {Bafail, DA},
title = {The cognitive neutrality of common antidiabetic medications in older adults: A propensity score-matched cohort analysis from the National Alzheimer's Coordinating Center database.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410210},
doi = {10.1177/13872877251410210},
pmid = {41700788},
issn = {1875-8908},
abstract = {BackgroundType 2 diabetes mellitus (T2DM) affects about 25% of adults aged 65 years and older in the United States. It is linked to faster cognitive decline and nearly double the risk of dementia. However, the long-term cognitive effects of different diabetes medications are not well understood, as observational studies are often impacted by various biases.ObjectiveThis study aims to compare cognitive changes over time among older adults with T2DM who are taking different diabetes medications.MethodsWe examined data from 54,631 participants (204,031 observations) in the National Alzheimer's Coordinating Center (NACC) database from 2005 to 2019. We applied propensity score matching to reduce bias and create balanced groups for medication comparisons. We used linear mixed-effects models to assess rates of cognitive decline in 18 areas, including overall cognition, memory, executive function, language, and daily functioning. We also ran sensitivity, mediation, and moderation analyses, applying corrections for multiple testing using the domain-specific false discovery rate (FDR).ResultsOut of 86 comparisons between medication and cognitive outcomes, 96.5% (83 out of 86) found no meaningful differences in rates of cognitive decline. The only exception was a sharper decline in functional abilities (CDR judgment, community affairs, home/hobbies) for insulin-sulfonylurea combinations compared to insulin-metformin combinations (p < 0.05; Cohen's d = 0.52-0.59; NNT = 23-32). Metformin did not show any cognitive benefit compared to no medication, sulfonylurea, or insulin alone. The length of time a person has had diabetes turned out to be a stronger predictor of cognitive decline than any specific medication (p < 0.001). These results were consistent through additional analyses and corrections for multiple testing.ConclusionsThe choice of diabetes medication has little effect on cognitive changes in older adults with T2DM, as 96.5% of comparisons showed no significant differences. The duration of the disease, rather than the type of medication chosen, has a bigger impact on cognitive outcomes. This suggests that starting and maintaining good blood sugar control is more important than the specific cognitive effects of different medications.},
}

@article {pmid41700444,
year = {2026},
author = {Khan, B and Kong, Y and Luo, XQ and Ahmad, K and Iqbal, MK and Lu, JC and Huang, YL and Li, QF and Zhao, YF and Shi, QD and Supratik, K and Wang, YZ and Chi, XD and Sui, AR and Li, S},
title = {A low dose of the γ-secretase inhibitor DAPT improves learning and memory by regulating the NaV1.6/Notch axis in C57BL/6 male mice.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70369},
pmid = {41700444},
issn = {1476-5381},
support = {2023ZD0507100//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; 82401823//National Natural Science Foundation of China/ ; 82471464//National Natural Science Foundation of China/ ; LJ222510161002//Leading Talent Team Project of the Education Department of Liaoning Province/ ; },
abstract = {BACKGROUND AND PURPOSE: Cognitive impairment poses a major challenge in neurodegenerative diseases and inflammatory brain disorders due to limited treatment options. The voltage-gated sodium channel NaV1.6 is associated with synaptic plasticity and cognitive decline in APP/PS1 mice. DAPT, a γ-secretase inhibitor that blocks Notch signalling, has variable cognitive effects depending on dosage. This study investigates the dose-dependent effects of DAPT on cognition in C57BL/6 male mice, elucidating its mechanisms through NaV1.6 channels, Notch signalling, synaptic plasticity, and neurogenesis.

EXPERIMENTAL APPROACH: Mice received unilateral stereotactic injections in the right hemisphere of low-dose DAPT (1 μg·μl[-1]), high-dose DAPT (2 μg·μl[-1]), or DMSO (control). Cognitive abilities were evaluated using the Morris Water Maze and Y-maze, western blots, immunofluorescence, and RT-qPCR analysed NaV1.6, synaptic proteins, NMDA/AMPA receptors, and neuroinflammatory markers. Neurogenesis was assessed via Nissl and doublecortin (DCX) staining. Primary neuron experiments examined DAPT effects on NaV1.6 interactions.

KEY RESULTS: Low-dose DAPT significantly improved cognition, suppressed Notch pathway genes, reduced NaV1.6, and up-regulated synaptic proteins, NMDA/AMPA receptors, and neuronal markers in vivo/in vitro. In primary culture neurons, DAPT reduced Notch-1/NICD with TTX but not ATX-II. Inflammatory markers/cytokines were unchanged. In vitro, 5-μM DAPT decreased NaV 1.6, increased Notch receptors and reduced Notch-1/HES-1 mRNA. Low-dose DAPT enhanced neurogenesis (increased dentate gyrus DCX[+] cells). Molecular docking confirmed favourable DAPT- NaV 1.6 interactions.

CONCLUSION AND IMPLICATIONS: Low-dose DAPT improved cognitive function in C57BL/6 male mice, by modulating the NaV 1.6/Notch axis and enhancing neurogenesis, indicating its potential as a therapeutic strategy for Alzheimer's-related cognitive decline.},
}

@article {pmid41700389,
year = {2026},
author = {Fariñas Lucas, IDM and Al-Hilaly, YK and Lutter, L and Xue, WF and Serpell, LC},
title = {The supramolecular architecture of amyloid fibrils formed by a human tau-derived hexapeptide VQIVYK.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5nr04317d},
pmid = {41700389},
issn = {2040-3372},
abstract = {The sequence 306VQIVYK311 is an aggregation-prone region of the tau protein implicated in driving the assembly of tau into paired helical filaments. These filaments accumulate as intraneuronal neurofibrillary tangles in Alzheimer's disease and a range of tauopathies. Prolonged incubation of VQIVYK results in highly ordered fibrillar structures that give rise to unusually detailed and highly oriented X-ray fibre diffraction patterns. These mature fibrils provided the opportunity to use a novel integrative approach that combined X-ray fibre diffraction analysis with 3D contact point reconstruction atomic force microscopy (CPR-AFM) of individual filaments to determine molecular and supramolecular details. X-ray diffraction analysis resulted in a molecular model consistent with an X-ray crystallography structure, which could be further optimised to give rise to a highly twisted filamentous protofilament architecture. Analysis of individual fibril envelopes by CPR-AFM revealed a diverse polymorphous population with a major fibril morphology of apparently smooth, cylindrical fibrils, and morphological subpopulations of fibrils with clear left-handed twisting patterns, while X-ray diffraction suggests that the protofilament core structure remains consistent between the polymorphs. Here, we reveal that VQIVYK amyloid fibrils form a polymorphous amyloid population by assembly of highly ordered protofilaments. The combined approach provides novel molecular and supramolecular information regarding the structure of highly twisted amyloid fibrils.},
}

@article {pmid41700307,
year = {2026},
author = {Benussi, A and Cantoni, V and Palacino, F and Altomare, D and Moretti, DV and Manganotti, P and Borroni, B},
title = {EEG network reorganization across Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70275},
pmid = {41700307},
issn = {2352-8729},
abstract = {INTRODUCTION: Electroencephalography (EEG) provides a temporally precise index of neural dysfunction, capturing changes in oscillatory activity, connectivity, and network organization. While spectral slowing is well documented in Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB), less is known about how these alterations extend to large-scale networks.

METHODS: We studied 173 participants: 56 AD, 59 FTD, 26 DLB, and 32 healthy controls (HC). Resting-state EEG was analyzed to quantify spectral power and amplitude-envelope correlation-based connectivity across frequency bands.

RESULTS: AD showed canonical slowing with delta/theta increases and posterior alpha loss. FTD exhibited preserved alpha but frontal beta reductions, while DLB displayed delta/theta excess, posterior alpha attenuation, and uniquely reduced gamma. Connectivity analyses revealed syndrome-specific patterns of network reorganization with distinct frequency-dependent signatures.

DISCUSSION: EEG network metrics capture distinct disease signatures and may inform mechanistic models of dementia.},
}

@article {pmid41700306,
year = {2026},
author = {Giacomucci, G and Tabbì, SMR and Ingannato, A and Bagnoli, S and Padiglioni, S and Crucitti, C and Sensi, C and Sanesi, S and Moschini, V and Morinelli, C and Galdo, G and Berti, V and Nacmias, B and Bessi, V},
title = {Refining Alzheimer's disease biological diagnosis with plasma biomarkers: Resolving p-tau217 "gray zone" with p-tau181 integration.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70285},
pmid = {41700306},
issn = {2352-8729},
abstract = {BACKGROUND: Blood-based biomarkers offer a less invasive and more scalable alternative to cerebrospinal fluid (CSF) analysis and amyloid-positron emission tomography (PET) for the biological diagnosis of Alzheimer's disease (AD). Among blood-based biomarkers (BBMs), plasma phosphorylated tau217 (p-tau217) has shown the highest accuracy, although intermediate ("gray zone") values remain challenging to interpret.

METHODS: In this study, 401 individuals across the Alzheimer's Disease (AD) continuum (Subjective Cognitive Decline, Mild Cognitive Impairment, and AD dementia) underwent clinical and biomarker assessment. Plasma p-tau217, p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured. Core1 status was defined through CSF or amyloid-PET.

RESULTS: Plasma p-tau217 demonstrated the strongest discrimination of Core1 positivity (area under the curve [AUC] = 0.95) and showed the steepest increase with disease progression. A two-cutoff strategy improved diagnostic accuracy (94%), though 18% of patients fell into the gray zone. Within this subgroup, p-tau181 was the only predictor of Core1 status and correctly reclassified 77.4% of indeterminate cases.

DISCUSSION: These findings support a sequential plasma biomarkers approach for reliable AD detection.},
}

@article {pmid41700142,
year = {2026},
author = {Ackley, SF and Flanders, MD and Murchland, A and Chen, R and Wang, J and Shah, SJ and Huey, ED and Glymour, MM},
title = {Evaluation of amyloid change as a surrogate for cognitive decline: demonstration in individual-level data from the A4 study of solanezumab.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70205},
pmid = {41700142},
issn = {2352-8737},
abstract = {BACKGROUND: Differential amyloid change has served as a surrogate outcome in Alzheimer's disease trials, allowing accelerated approval of aducanumab and lecanemab. Individual-level data from the A4 study support the demonstration of novel methods to evaluate amyloid's validity as a surrogate for cognitive decline.

METHODS: In 812 participants, cognitive change was measured using the Clinical Dementia Rating Sum of Boxes (CDR-SB) score. Instrumental-variable analysis estimated the effect of amyloid change; mediation analysis quantified proportion of cognitive effects mediated by amyloid change.

RESULTS: Each 10-Centiloid reduction in amyloid due to randomization to treatment was associated with a 0.026 higher CDR-SB score (95% confidence interval [CI]: -0.013, 0.065). Amyloid reduction mediated 14.6% of solanezumab's effect on cognition (95% CI: -122%, 208%).

DISCUSSION: Near-zero effect estimates for amyloid change on cognitive decline in the A4 study suggest minimal impact of limited amyloid change reduction in populations with little disease progression. The broader question of validity of amyloid as a surrogate outcome cannot be conclusively answered in data from the A4 study due to study-intrinsic limitations. Replication in anti-amyloid trials with larger treatment effects will evaluate whether amyloid is an appropriate surrogate outcome.

HIGHLIGHTS: This study evaluated amyloid change's validity as a surrogate for cognitive and functional decline in AD drug trials.Newly available individual-level trial data from the A4 study enabled the application of epidemiologic and econometric methods to assess amyloid's impact on cognition.IV and causal mediation analyses estimated the effect of amyloid change on cognitive outcomes.Amyloid change mediated 15% of solanezumab's cognitive effect, though estimates were imprecise due to limited disease progression in the sample and solanezumab's minimal amyloid removal.Applying the same methods to data from trials of more effective anti-amyloid drugs could validate amyloid as a surrogate outcome, guide related regulatory decisions, and influence treatment strategy.},
}

@article {pmid41700119,
year = {2026},
author = {Kim, HK and Lee, JH and Chun, JH and Kim, YJ and Park, M and West, T and Kirmess, KM and Verghese, PB and Connell, D and Braunstein, JB and Ryu, YH and Cho, H and Lyoo, CH},
title = {Plasma p-tau217 predicts PET-based pathological staging for precision Alzheimer disease assessment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71199},
doi = {10.1002/alz.71199},
pmid = {41700119},
issn = {1552-5279},
support = {RS-2025-18362970//Ministry of Science and ICT, South Korea/ ; RS-2020-KH106683//Korea Health Industry Development Institute/Republic of Korea ; RS-2023-00247986//Ministry of Education/ ; 6-2024-0109//Yonsei University College of Medicine/ ; },
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/pathology/diagnostic imaging/blood/diagnosis ; *Positron-Emission Tomography ; Female ; Male ; Biomarkers/blood ; Aged ; Amyloid beta-Peptides/blood ; Aged, 80 and over ; Phosphorylation ; Brain/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: While positron emission tomography (PET) is the standard for pathological staging, its limited availability necessitates accessible alternatives. We evaluated plasma biomarkers for detecting PET-based stages using single-axis (Thal/Braak) and integrated A/T composite models.

METHODS: We enrolled 237 AD spectrum participants undergoing multimodal assessments including amyloid/tau PET and plasma biomarker analysis (phosphorylated tau [p-tau] 217, %p-tau217, and amyloid beta [Aβ] 42/40 ratio). Detecting and discriminative performance was assessed using receiver operating characteristics (ROC) analysis and probability-based stage prediction.

RESULTS: Plasma p-tau217-based biomarkers showed excellent detecting performance for early amyloid (Thal I-II; area under the curve values > 0.96) and intermediate tau (Braak III-IV; area under the curve values > 0.92). Probability-based prediction identified therapeutic window thresholds of 1.895-5.077 pg/mL. Notably, integrated A/T composite staging yielded highly consistent thresholds (< 3% variance).

DISCUSSION: Plasma p-tau217-based biomarkers accurately reflect PET-based staging across frameworks. The convergent therapeutic window thresholds demonstrate robust biological transitions, enabling accessible identification of optimal candidates for disease-modifying therapies.},
}

Humans
*tau Proteins/blood
*Alzheimer Disease/pathology/diagnostic imaging/blood/diagnosis
*Positron-Emission Tomography
Female
Male
Biomarkers/blood
Aged
Amyloid beta-Peptides/blood
Aged, 80 and over
Phosphorylation
Brain/pathology/diagnostic imaging

@article {pmid41700075,
year = {2026},
author = {Benejam, B and McCarron, M and Carmona-Iragui, M and Dunne, P and Maure-Blesa, L and Altuna, M and Arranz, J and Barroeta, I and Bejanin, A and Soriano, LDH and Fernández, S and Giménez, S and Lleó, A and Lynch, L and McCallion, P and Mulryan, N and Pertierra, L and Rebillat, AS and Rodríguez-Baz, Í and Hernández, AS and Vaqué-Alcázar, L and Videla, L and Wormald, A and Fortea, J and McGlinchey, E},
title = {Factors impacting survival in individuals with Down syndrome-associated Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71156},
doi = {10.1002/alz.71156},
pmid = {41700075},
issn = {1552-5279},
support = {//Instituto de Salud Carlos III through the Río Hortega Fellowship "CM23/00291" and co-funded by the European Union./ ; CP24/00112//Universidad Carlos III de Madrid/ ; 2326 - GRT-2024A//Fondation Jérôme Lejeune/ ; GBHI_ALZ-18-543740//Global Brain Health Institute/ ; //Ajuntament de Barcelona, in collaboration with Fundació La Caixa/ ; AACSF-25-1486364/ALZ/Alzheimer's Association/United States ; //Fondo de Investigaciones Sanitario/ ; //Instituto de Salud Carlos III and co-funded by the European Union through the Miguel Servet grant/ ; IIBSP-DOW-2020-151//Fundación Tatiana Pérez de Guzmán el Bueno/ ; SLT006/17/00119//Departament de Salut, Generalitat de Catalunya/ ; 1R01AG056850-01A1/NH/NIH HHS/United States ; R21AG056974/NH/NIH HHS/United States ; R01AG061566/NH/NIH HHS/United States ; 1R01AG081394-01/NH/NIH HHS/United States ; 1R61AG066543-01 to J.F./NH/NIH HHS/United States ; Program 1//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; CD23/00235 Sara Borrell postdoctoral fellowship//Instituto de Salud Carlos III/ ; IDS-TILDA-2021-001/HRBI_/Health Research Board/Ireland ; IDS-TILDA 2018-001/HRBI_/Health Research Board/Ireland ; },
mesh = {Humans ; *Down Syndrome/mortality/complications ; *Alzheimer Disease/mortality ; Female ; Male ; Ireland/epidemiology ; Middle Aged ; Spain/epidemiology ; Aged ; Adult ; Epilepsies, Myoclonic/epidemiology/mortality ; Kaplan-Meier Estimate ; },
abstract = {INTRODUCTION: Adults with Down syndrome (DS) are at high risk for Alzheimer's disease (AD), the leading cause of death in this population. Survival in DS after AD diagnosis appears shorter than in sporadic AD; however, the factors influencing survival remain poorly understood.

METHODS: We analyzed 157 adults with DS from Spain and Ireland who died of AD between 2012 and 2024. Clinical, genetic, and care predictors were examined using Kaplan-Meier curves and Cox regression.

RESULTS: Mean survival after AD diagnosis was 4.8 years (SD 3.5). Those in specialist intellectual disability dementia care had a longer survival time (mean 9.5 years) than other settings (mean 3.4 to 4.1 years; p < 0.001). Late-onset myoclonic epilepsy in DS (LOMEDS) was linked to a threefold higher risk of death after onset (p < 0.001).

DISCUSSION: Specialist care settings and LOMEDS timing significantly shape survival in DS-associated AD, highlighting the importance of tailored services and proactive epilepsy treatment.},
}

Humans
*Down Syndrome/mortality/complications
*Alzheimer Disease/mortality
Female
Male
Ireland/epidemiology
Middle Aged
Spain/epidemiology
Aged
Adult
Epilepsies, Myoclonic/epidemiology/mortality
Kaplan-Meier Estimate

@article {pmid41700069,
year = {2026},
author = {Yamane, T},
title = {[PET in Neurology: Imaging Pathology, Metabolism, and Disease Progression].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {2},
pages = {147-155},
doi = {10.11477/mf.188160960780020147},
pmid = {41700069},
issn = {1881-6096},
mesh = {Humans ; *Positron-Emission Tomography/methods ; Disease Progression ; *Nervous System Diseases/diagnostic imaging/metabolism/pathology ; Neurology ; Alzheimer Disease/diagnostic imaging ; },
abstract = {Anti-amyloid-β therapies for Alzheimer's disease-lecanemab (Leqembi approved in September 2023) and donanemab (Kisunla®; approved in September 2024)-have been authorized in Japan and are now in clinical use. In parallel, amyloid positron emission tomography (PET) is now reimbursed by the national health insurance for determining treatment eligibility and three amyloid PET radiopharmaceuticals are currently approved. Amyloid PET images interpretation relies primarily on visual reads, which require dedicated training, and clinicians with limited PET imaging experience may find some cases challenging. Although quantitative approaches (e.g., standardized uptake value ratio and Centiloid metrics) are available, their accurate application likewise necessitates appropriate training. Moreover, the availability of tau PET, which images cerebral tau deposition, is also expanding. Additional PET relevant to neurological diseases include those assessing glucose metabolism, oxygen metabolism, amino acid transport, and dopaminergic systems. When used appropriately, these modalities enable a noninvasive, multidimensional assessment of the pathology, metabolism, and disease burden, thereby allowing for a more refined characterization of neurological disorders.},
}

Humans
*Positron-Emission Tomography/methods
Disease Progression
*Nervous System Diseases/diagnostic imaging/metabolism/pathology
Neurology
Alzheimer Disease/diagnostic imaging

@article {pmid41700061,
year = {2026},
author = {Cao, H and Zheng, Z and Zhou, X and Kikuchi, M and Wong, HY and Cheng, EYL and Wong, BWY and Lo, RMN and Shoai, M and Chong, JR and Chan, ALT and Chen, C and Lam, LCW and Mok, VCT and Kwok, TCY and , and , and Chen, Y and Ip, FCF and Mok, KY and Miyashita, A and Ikeuchi, T and Hardy, J and Fu, AKY and Ip, NY},
title = {Ethnic-specific effects of the LILRB2-LILRB5 locus and newly identified risk loci for Alzheimer's disease in the East Asian population.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71219},
doi = {10.1002/alz.71219},
pmid = {41700061},
issn = {1552-5279},
support = {FIF20RD01//Fidelity Foundation/ ; C6027-19GF//Research Grants Council of Hong Kong Collaborative Research Fund/ ; T13-605/18W//Research Grants Council of Hong Kong Theme-Based Research Scheme/ ; HKUST16103122//Research Grants Council of Hong Kong General Research Fund/ ; HKUST16104624//Research Grants Council of Hong Kong General Research Fund/ ; HKUST16102824//Research Grants Council of Hong Kong General Research Fund/ ; AoE/M-604/16//Areas of Excellence Scheme of the University Grants Committee/ ; //InnoHK Initiative of the Innovation and Technology Commission of the HKSAR Government/ ; ITCPD/17-9//Innovation and Technology Fund for State Key Laboratory/ ; JLFS/M-604/24//SIAT-HKUST Joint Laboratory for Brain Science/ ; 2023B1212120004//Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders/ ; 2019B1515130004//Guangdong Provincial Fund for Basic and Applied Basic Research/ ; MOH-000707-00//National Medical Research Council Singapore Translational Research Investigator Award/ ; JP25dk0207060//AMED/ ; 25K02262//JSPS Grant-in-Aid for Scientific Research/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/ethnology ; *Genetic Predisposition to Disease/genetics ; *Receptors, Immunologic/genetics ; Genome-Wide Association Study ; *Asian People/genetics ; Male ; Female ; Polymorphism, Single Nucleotide/genetics ; *Membrane Glycoproteins/genetics ; Aged ; White People/genetics ; Genetic Loci ; East Asian People ; },
abstract = {INTRODUCTION: Genome-wide association studies have identified numerous Alzheimer's disease (AD) susceptibility loci in European populations. However, the genetic architecture of AD in non-European populations remains underinvestigated.

METHODS: We performed a genetic association study in East Asians (N = 8514) to validate known AD loci and identify new susceptibility loci.

RESULTS: We identified LILRB2-LILRB5 as an AD susceptibility locus with ethnic-specific effects between Europeans and East Asians. The lead variant, rs587709-T, was associated with decreased AD risk and increased LILRB5 expression in Europeans. Conversely, in East Asians, the same allele was associated with increased AD risk and increased LILRB2 expression. Furthermore, genome-wide analysis identified TTC3 and FAM135A as candidate susceptibility loci for AD or cognition.

DISCUSSION: The results establish LILRB2-LILRB5 as a cross-ancestry AD-associated locus with ethnic-specific genetic mechanisms and reveal new susceptibility loci, extending the understanding of the genetic etiology of AD.},
}

Humans
*Alzheimer Disease/genetics/ethnology
*Genetic Predisposition to Disease/genetics
*Receptors, Immunologic/genetics
Genome-Wide Association Study
*Asian People/genetics
Male
Female
Polymorphism, Single Nucleotide/genetics
*Membrane Glycoproteins/genetics
Aged
White People/genetics
Genetic Loci
East Asian People

@article {pmid41700028,
year = {2026},
author = {Zhang, X and Bao, H and Hu, J and Ren, W and He, Z and Yu-Taeger, L and Wu, A and Li, J},
title = {Neuropeptide-GPCR Regulation of the Neuroimmune Axis in Neurodegeneration: Mechanisms and Translation.},
journal = {Bioconjugate chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.bioconjchem.5c00637},
pmid = {41700028},
issn = {1520-4812},
abstract = {Chronic neuroinflammation and dysfunction of the neuro-glial-vascular unit (NGVU) are central mechanisms driving the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Neuropeptides, as key regulatory signaling molecules in the central nervous system (CNS), bind to specific G protein-coupled receptors (GPCRs) on the surfaces of microglia, astrocytes, oligodendrocytes, and cerebrovascular elements. Through cell type-specific biased signaling, they precisely regulate the threshold for inflammatory activation, coordinate phagocytosis and autophagy, maintain metabolic homeostasis, and support the function of the blood-brain barrier. This review systematically analyzes the immune-regulatory roles of key neuropeptides, including neuropeptide Y (NPY), vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide (VIP/PACAP), substance P (SP), and calcitonin gene-related peptide (CGRP). We focus on how these systems contribute to CNS homeostasis and disease-relevant processes, including myelin repair and neuroinflammatory regulation. Integrating evidence from preclinical models and human samples, it clarifies the pathological mechanisms linking these neuropeptides to disease progression. The review also outlines a translational research pathway focused on ligand structure engineering, targeted delivery, and biomarker-guided patient stratification, emphasizing receptor subtype selectivity and CNS permeability for precise therapy. By integrating the neuropeptide-mediated neuro-immune network, this work offers new insights into immune pathology in neurodegenerative diseases and provides a foundation for next-generation immune regulation.},
}

@article {pmid41699945,
year = {2026},
author = {Majuri, T and Silvan, J and Tolppanen, AM and Hartikainen, S and Huotari, T and Rautio, N and Miettunen, J and Nordström, T and Jääskeläinen, E and Haapea, M},
title = {Characteristics and predictors of antipsychotic medication off-label use among community-dwelling older people.},
journal = {Nordic journal of psychiatry},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/08039488.2026.2631597},
pmid = {41699945},
issn = {1502-4725},
abstract = {BACKGROUND: Concerns have been raised regarding the common off-label use of antipsychotic (AP) medications among older adults. However, comprehensive knowledge of the determinants of AP off-label use in this population remains limited.

METHODS: We examined characteristics and predictors of AP off-label use in a nationwide Finnish cohort of community-dwelling older adults with psychiatric morbidity-but without Alzheimer's disease-using longitudinal register data on sociodemographic and illness-related factors. The sample comprised four groups: those prescribed APs off-label (n = 20,563), those with non-psychotic mental disorders without off-label APs (CG1, n = 22,891), those with psychosis or bipolar disorder with APs (CG2, n = 8,966), and those with psychosis or bipolar disorder without APs (CG3, n = 4,585). Sociodemographic and illness-related factors were compared between the off-label and the comparison groups using logistic regression.

RESULTS: Compared to comparison groups, individuals with off-label use more frequently had cardiovascular diseases and strokes. Compared to CG1 and CG3, individuals with AP off-label use were more often female, had a lower prevalence of asthma/chronic obstructive pulmonary disease, and a higher use of psychotropic medications and opioids. Compared to CG2, individuals with off-label use were more often male and had a lower prevalence of diabetes, epilepsy, as well as a lower use of psychotropic medications and a higher use of opioids. Risperidone (43%) and quetiapine (39%) were the most used APs off-label.

CONCLUSION: Alternative treatments are needed to curb off-label AP use among community-dwelling older adults, given the high prevalence of cardiovascular disease and stroke. Monitoring guidelines are needed to promote safer prescribing practices.},
}

@article {pmid41699900,
year = {2026},
author = {Mulhall, S and Gibson, D and Longley, WA and D'Cunha, NM},
title = {Improving Access to Cognitive Interventions for People With Dementia in Australian Community-Based Settings.},
journal = {Australasian journal on ageing},
volume = {45},
number = {1},
pages = {e70140},
doi = {10.1111/ajag.70140},
pmid = {41699900},
issn = {1741-6612},
mesh = {Humans ; *Dementia/psychology/therapy/diagnosis/rehabilitation/physiopathology ; Australia ; *Health Services Accessibility/organization & administration ; *Cognition ; *Community Health Services/organization & administration ; Quality of Life ; *Cognitive Behavioral Therapy ; *Health Services for the Aged/organization & administration ; Treatment Outcome ; },
abstract = {Cognitive interventions, including cognitive stimulation therapy, cognitive rehabilitation and cognitive training, are increasingly recommended as key components of non-pharmacological post-diagnostic support for people with dementia. Cognitive interventions may help delay cognitive decline, enhance goal-directed functional abilities and improve quality of life. Despite inclusion in clinical guidelines and recommendations, guidance on the delivery of these interventions within Australian community settings remains limited and is underutilised. This article addresses a critical translation gap in cognitive interventions for people with dementia, synthesises the evidence through an Australian practice and policy lens, examines current uptake in community settings and identifies barriers, enablers and delivery models to inform implementation strategies. Community settings are defined as memory clinics, primary care, hospital outpatient services, allied health providers, community aged care and non-government providers. Current evidence indicates cognitive interventions have varying benefits across different outcomes, including cognitive function, social engagement, everyday functioning, quality of life and goal attainment. International practices related to implementation are explored, along with future directions for expanding access through technology, flexible delivery models, group-based approaches and integrating these interventions into existing care structures. Addressing the gap between recommendations and current practices requires building community awareness, improving access to professional education and training, and careful resource allocation. Cognitive interventions should be part of comprehensive rehabilitation and can be personalised to individual needs and goals. Expanding access and improving the availability of a range of cognitive interventions in community settings is crucial to ensure people with dementia receive best practice post-diagnostic support.},
}

Humans
*Dementia/psychology/therapy/diagnosis/rehabilitation/physiopathology
Australia
*Health Services Accessibility/organization & administration
*Cognition
*Community Health Services/organization & administration
Quality of Life
*Cognitive Behavioral Therapy
*Health Services for the Aged/organization & administration
Treatment Outcome

@article {pmid41699754,
year = {2026},
author = {Kanda, A and Mazumder, A and Das, S and Singh, A and Prabhakar, V},
title = {Bioactive-Guided Isolation and Optimization of Luffa Acutangula Nanoemulsion for In vitro, In vivo, and In silico Cholinesterase Inhibition for Alzheimer's Disease Management.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {2},
pages = {e02600},
doi = {10.1002/cbdv.202502600},
pmid = {41699754},
issn = {1612-1880},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Cholinesterase Inhibitors/chemistry/isolation & purification/pharmacology ; Emulsions/chemistry/pharmacology ; Mice ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism ; Particle Size ; Male ; Scopolamine ; *Plant Extracts/chemistry/isolation & purification/pharmacology ; *Neuroprotective Agents/isolation & purification/chemistry/pharmacology ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) progressively impairs memory and cognition. Luffa acutangula (LA), rich in triterpenoids, fatty acids, and iridoid glycosides, exerts anti-Alzheimer's effects by inhibiting acetylcholinesterase (AChE). This study aims to isolate bioactive compounds from LA fruits, formulate and optimize a nanoemulsion to improve brain targeting, and assess its anti-Alzheimer efficacy through in vitro, in vivo, and in silico approaches. LA was extracted using a 1:1 hydro-ethanol mixture and subsequently underwent chromatographic isolation to yield four major constituents: oleanolic acid, stearic acid, cucurbitacin H, and acutoside C. A multiple nanoemulsion (containing a mixture of isolated constituents) was formulated using Box-Behnken design and characterized for particle size, viscosity, entrapment efficiency, and FTIR compatibility. In vivo studies were conducted in scopolamine-induced memory-impaired mice using Hebb-William's Maze (HWM) and Cook's pole climbing tests. AChE activity was biochemically assessed, followed by histopathological brain analysis. Molecular docking was used to predict ligand-AChE binding affinities. The optimized L. acutangula loaded multiple nanoemulsion (LAMN) exhibited an average particle size of 142.1 nm, viscosity of 60 cP, and entrapment efficiency (EE) of 96.8 %. It decreased learning scores in the HWM and shortened latency time in Cook's pole-climbing test in memory-impaired mice. AChE levels were significantly reduced in LAMN-treated groups, correlating with histological evidence of hippocampal protection. Molecular docking revealed strong AChE binding, particularly by oleanolic acid (-10.5 kcal/mol), comparable to donepezil (-10.7 kcal/mol). LAMN offers a promising phytopharmaceutical intervention for AD, with multitargeted neuroprotective effects mediated through AChE inhibition and improved drug delivery across the blood-brain barrier. The findings support further clinical development of LA-based nanoformulations for AD management.},
}

*Alzheimer Disease/drug therapy/metabolism
Animals
*Cholinesterase Inhibitors/chemistry/isolation & purification/pharmacology
Emulsions/chemistry/pharmacology
Mice
Molecular Docking Simulation
Acetylcholinesterase/metabolism
Particle Size
Male
Scopolamine
*Plant Extracts/chemistry/isolation & purification/pharmacology
*Neuroprotective Agents/isolation & purification/chemistry/pharmacology
Maze Learning/drug effects

@article {pmid41699702,
year = {2026},
author = {Chung, TD and Liang, L and Wang, L and Kim, EG and Gupta, S and Pandey, I and Searson, PC},
title = {Mutations associated with Alzheimer's disease and aged serum synergistically elicit blood-brain barrier dysfunction in a tissue-engineered model.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00773-x},
pmid = {41699702},
issn = {2045-8118},
support = {R33HL154252/GF/NIH HHS/United States ; },
}

@article {pmid41699650,
year = {2026},
author = {Tang, PA and Ruiz-Pastor, MJ and Lewis, AE and Fladmark, KE and Kobro-Flatmoen, A and Halskau, Ø and Lal, P},
title = {Cetoleic acid and other long-chain unsaturated fatty acids as neuroprotective nutraceuticals.},
journal = {Lipids in health and disease},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12944-026-02876-8},
pmid = {41699650},
issn = {1476-511X},
abstract = {Long-chain monounsaturated fatty acids such as erucic acid, cetoleic acid and gondoic acid, are 20-22-carbon fatty acids with a double bond in their ω-9, ω-11 and ω-9 positions, respectively. Recent experimental research suggests that these lipids may provide benefits related to cardiovascular, but also brain health. Research on cetoleic acid using cell lines suggests that this fatty acid may positively affect neurological health. Also, in limited doses, erucic acid and gondoic acid have been reported to have a neuroprotective effect through action on peroxisome proliferator-activated receptors, and monounsaturated fatty acids generally are able to influence these receptors. Herein, we review the current state of knowledge of monounsaturated fatty acids effect on health, with an emphasis on erucic acid and cetoleic acid and their possible neuroprotective effects. Research has not progressed far regarding the direct neuroprotective effects of cetoleic acid, and mechanisms underlying such effects. However, both erucic and cetoleic acid influence the availabilities of docosahexaenoic and eicosapentaenoic acids, that do confer several health benefits, including neuroprotective effects. We highlight knowledge gaps related to metabolism, putative neuroprotective mechanisms, and briefly review animal model systems suitable for investigating these gaps.},
}

@article {pmid41699609,
year = {2026},
author = {Zhu, T and Zhou, C and Zhou, H and Shen, F and Wang, S and Zhou, Y and Jin, G and Zu, J and Yang, X and Shi, H and Cui, G and Hua, F},
title = {Overexpression of PGRMC2 in astrocytes improved cognitive function in a mouse model of Alzheimer's disease by modulating neuroinflammation.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-07862-3},
pmid = {41699609},
issn = {1479-5876},
support = {82171420//National Natural Science Foundation of China/ ; },
}

@article {pmid41699585,
year = {2026},
author = {Zhang, R and Chen, D and Qin, Y and Han, H and Yu, H},
title = {Longitudinal multi-modal data prediction model for mild cognitive impairment by deep survival analysis.},
journal = {BMC medical informatics and decision making},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12911-026-03387-3},
pmid = {41699585},
issn = {1472-6947},
}

@article {pmid41699438,
year = {2026},
author = {Yamazaki, A and Mishina, M and Sakamoto, Y and Suda, S},
title = {Time From Initial Community-Based Dementia Consultation to Confirmed Diagnosis: A Retrospective Analysis.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {2},
pages = {e70148},
doi = {10.1111/psyg.70148},
pmid = {41699438},
issn = {1479-8301},
mesh = {Humans ; Female ; Retrospective Studies ; Male ; Aged ; Japan ; *Referral and Consultation/statistics & numerical data ; *Dementia/diagnosis ; *Delayed Diagnosis/statistics & numerical data ; Aged, 80 and over ; *Cognitive Dysfunction/diagnosis ; Time Factors ; *Alzheimer Disease/diagnosis ; },
abstract = {BACKGROUND: With the launch of anti-amyloid beta antibody drugs, physicians face the need to quickly diagnose dementia. In prehospital consultation services in Japan, the duration from memory-related consultations to confirmed diagnosis has not been sufficiently investigated. Therefore, this study investigated the duration from initial community-based dementia consultation to confirmed diagnosis and the factors associated with diagnostic delays across dementia subtypes.

METHODS: This retrospective observational study included patients who consulted the Community Consultation Center for Citizens with Mild Cognitive Impairment and Dementia (CCCCMD) and subsequently received a confirmed dementia diagnosis at Nippon Medical School Musashi Kosugi Hospital between 2010 and 2024. Time to diagnosis was defined as the number of days from the initial CCCCMD consultation to diagnostic confirmation. We classified those who were diagnosed with dementia during outpatient visits amongst the consultees as Alzheimer disease (AD) or non-Alzheimer disease (non-AD). Diagnostic delay was further divided into pre-hospital interval and in-hospital phase. Group comparisons and multivariable Cox proportional hazards and logistic regression analyses were performed to identify factors associated with diagnostic delay.

RESULTS: A total of 739 patients were included: 504 with AD and 235 with non-AD dementias. Time to diagnosis was shorter in the AD group than in the non-AD group. This difference was primarily attributable to prolonged delays during the pre-hospital interval amongst patients with non-AD; however, delays during the in-hospital diagnostic process were small and largely overlapping between the groups. Diagnosis of AD, older age, and the presence of a primary care physician were associated with a shorter time to diagnosis, whereas higher cognitive scores at the initial community consultation were associated with longer diagnostic delays.

CONCLUSION: Diagnostic delay differed substantially by dementia subtype. These findings highlight the importance of community-based consultation pathways as key targets for reducing diagnostic delays, particularly for patients with non-AD dementias.},
}

Humans
Female
Retrospective Studies
Male
Aged
Japan
*Referral and Consultation/statistics & numerical data
*Dementia/diagnosis
*Delayed Diagnosis/statistics & numerical data
Aged, 80 and over
*Cognitive Dysfunction/diagnosis
Time Factors
*Alzheimer Disease/diagnosis

@article {pmid41699413,
year = {2026},
author = {Shaldam, MA and Carradori, S and Balaha, M and Guglielmi, P and Diomede, F and D'Agostino, I and Tawfik, HO},
title = {Patents involving monoamine oxidase (MAO): a comprehensive update (2022-2025) on its inhibitors and applications.},
journal = {Expert opinion on therapeutic patents},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543776.2026.2633345},
pmid = {41699413},
issn = {1744-7674},
abstract = {INTRODUCTION: Monoamine oxidases (MAOs) A and B are key enzymes for the oxidative deamination of monoamine neurotransmitters, including dopamine, serotonin, norepinephrine, and tyramine. Selective MAO-B inhibitors are clinically employed as adjuvant therapies for neurodegenerative disorders, whereas selective MAO-A inhibitors are mainly considered third-line options in the treatment of depression. However, due to their function in regulating synaptic activity and exogenous monoamine metabolism, research in this field is continually expanding.

AREAS COVERED: This review summarizes patents on MAO inhibitors between 2022 and 2025. For the most investigated chemotypes (14 synthetic cores along with compounds from natural sources), biological activities were analyzed. The compounds are divided into two main categories, naturally occurring molecules and newly synthesized derivatives, with a total of 114 compounds discussed. To provide a more comprehensive perspective on the therapeutic potential of these inhibitors, additional treatment alternatives are also outlined.

EXPERT OPINION: Recently patented MAO inhibitors show notable properties, including significant isoform selectivity and therapeutic potential toward other diseases, such as fibromyalgia, CDKL5-deficient disorder, neuropathic pain, and Alzheimer's disease.},
}

@article {pmid41699353,
year = {2026},
author = {Casciati, A and Colantoni, E and Camera, F and Fratini, E and Casula, EP and Mencarelli, L and Di Lorenzo, F and Bonnì, S and Koch, G and Tanno, B and Merla, C},
title = {Deregulation of Synaptic Plasticity-Related MicroRNAs After Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {442},
pmid = {41699353},
issn = {1559-1182},
support = {Regione Lazio POR FESR Lazio 2014-2020 n. A0375-2020-36546//Regione Lazio/ ; },
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is an emerging non-invasive therapeutic approach to slow down cognitive and functional decline in Alzheimer's disease (AD), potentially through plasticity-related mechanisms. MicroRNAs (miRNAs) play a crucial role in synaptic plasticity, and their deregulation contributes to AD-related cognitive impairment. In the present study, we first used a dosimetric model to translate rTMS field applied in AD patients to an in vitro system, identifying miRNAs as potential biomarkers responsive to rTMS. We found that rTMS induced in vitro deregulation of miR-26b, miR-125b, miR-181c, and miR-146a. Then, we investigated the effects of rTMS over precuneus during a 3-week, randomized, sham-controlled trial in AD patients. In patient serum, miR-26b, miR-30b, and miR-125b were significantly modulated in AD patients compared to healthy controls, though no significant modulation emerged between sham and rTMS groups before or after stimulation. Subsequently, the correlation analyses, which incorporated patients' cognitive scores, revealed that reduced miR-25 levels were significantly associated with cognitive improvement. However, no significant differences emerged between Real- and sham-rTMS correlation coefficients, likely due to the limited sample size, indicating that miR-25 may represent a general prognostic marker rather than a treatment-specific indicator. Furthermore, the ability of this miRNA to discriminate responders from non-responders, shown by ROC analysis, highlights its potential as a promising predictor of rTMS treatment efficacy to be validated in a larger patient cohort. Altogether, our findings suggest, for the first time, that rTMS may modulate specific miRNAs in AD patients, with miR-25 representing a pivotal key target for future validation studies.},
}

@article {pmid41699331,
year = {2026},
author = {Ercin, N and Besli, N and Beker, M and Celik, U},
title = {Non-canonical cell death in neurodegeneration: emerging mechanisms and therapeutic Frontiers.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {3},
pages = {72},
pmid = {41699331},
issn = {1573-675X},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism/genetics ; *Cell Death/drug effects ; Animals ; Necroptosis/drug effects ; Ferroptosis/drug effects ; Neuroprotective Agents/therapeutic use/pharmacology ; Pyroptosis/drug effects ; Oxidative Stress ; },
abstract = {Neurodegenerative diseases, specifically Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are defined by progressively increased neuronal loss that lacks curative therapies. Increasing evidence supports that non-canonical regulated cell death pathways including ferroptosis, necroptosis, pyroptosis, and parthanatos, are implicated in pathological mechanisms of neuroinflammation, and oxidative stress, and mitochondrial dysfunction, likely impacting neurodegenerative pathologies. In this review, we summarize the existing literature on the molecular pathways and potential pathogenic implications of these cell death pathways in neurodegenerative diseases, highlighting their upstream triggers, regulatory proteins, and downstream effectors. We also briefly describe representative pharmacological agents, including ferrostatin-1, necrostatin-1, MCC950 and PARP-inhibitors, that have shown neuroprotective effects in experimental studies. Experimental studies provide valuable information, but translation to clinical treatments presents barriers including overlapping regulated cell death mechanisms, constraints of bloodbrain barrier penetrance and concern for safety. Future development may come through concepts such as biomarker-based patient stratification strategies, multivalent interventions, and improved translational models. Identifying these new regulated cell death pathways may eventually provide new avenues to slow the progression of neurodegeneration and develop more targeted therapies.},
}

Humans
*Neurodegenerative Diseases/drug therapy/pathology/metabolism/genetics
*Cell Death/drug effects
Animals
Necroptosis/drug effects
Ferroptosis/drug effects
Neuroprotective Agents/therapeutic use/pharmacology
Pyroptosis/drug effects
Oxidative Stress