@article {pmid41186720,
year = {2025},
author = {Aijaz, M and Ahmad, M and Ahmad, S and Afzal, M and Kothiyal, P},
title = {The gut-brain axis: role of gut microbiota in neurological disease pathogenesis and pharmacotherapeutics.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41186720},
issn = {1432-1912},
abstract = {The gut-brain axis is a highly complex, bidirectional communication link between the gut and the central nervous system (CNS), mainly through neural, endocrine, immunological, and metabolic pathways. This review outlines the growing contribution of gut microbiota in the remediation of neurological health and also emphasizes the controlling role of gut microbiota on the synthesis of neurotransmitters. Emerging evidence indicates that dysbiosis of the gut is related to a variety of neurodegenerative and neuropsychiatric diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), autism spectrum disorders (ASD), depression, and glioblastoma. Mechanistic understandings show that gut microbes critically contribute to neuroimmune and blood-brain barrier (BBB) signaling. The peripheral association of gut microflora, networked with inflammasome activation, nuclear factor kappa B (NF-κB), and type-I IFN pathways highlights their role in CNS inflammation. Microbiota-targeted interventions with probiotics, prebiotics, synbiotics, antibiotics, dietary modifications, and fecal microbiota transplantation are examined for their therapeutic potential. These strategies appear to be promising to reinstate microbial balance, enhance neuroplastic responses, and ameliorate the disease symptoms. The review highlights personalized microbiome-based algorithms, underpinned by integrated multi-omics technologies and machine-learning-driven diagnostics. Future research should address underlying microbial mechanisms and perform large, randomized controlled trials in order to establish microbiota-based therapies for neurological disorders.},
}

@article {pmid41186623,
year = {2025},
author = {Li, H and Deng, B and Lin, M and Lai, L and Zhao, J and Li, Y},
title = {HDAC3 Epigenetic Suppression by Electroacupuncture Restores AMPA Receptor Function and Synaptic Plasticity in Alzheimer's Disease Models.},
journal = {Neuromolecular medicine},
volume = {27},
number = {1},
pages = {72},
pmid = {41186623},
issn = {1559-1174},
support = {20251289//The Guangdong Provincial Administration of Traditional Chinese Medicine/ ; 20252A011015//The Guangzhou Science and Technology Project for Traditional Chinese Medicine and Integrated Chinese and Western Medicine/ ; },
mesh = {Animals ; *Histone Deacetylases/physiology/genetics/biosynthesis ; *Alzheimer Disease/therapy/genetics/physiopathology ; *Receptors, AMPA/physiology/genetics/biosynthesis ; *Epigenesis, Genetic ; Mice ; Mice, Transgenic ; *Neuronal Plasticity/physiology/genetics ; Long-Term Potentiation ; *Electroacupuncture ; Disease Models, Animal ; Hippocampus/metabolism ; Amyloid beta-Protein Precursor/genetics ; Male ; Histones/metabolism ; Acetylation ; Mice, Inbred C57BL ; Humans ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by continuous cognitive deterioration, primarily resulting from the accumulation of amyloid-β (Aβ) plaques and tau-induced neurofibrillary tangles (NFTs). Recent studies have also highlighted histone deacetylase 3 (HDAC3) as a critical suppressor of synaptic plasticity. Although pharmacological inhibition of HDAC3 has been shown to facilitate long-term potentiation (LTP), the precise relationship between HDAC3 activity and AMPA receptor signaling, key components in LTP induction and maintenance, remains insufficiently understood. Electroacupuncture (EA), known to modulate epigenetic markers like H3K9/H3K27 acetylation and HDAC3/4 activity, may offer therapeutic potential by targeting these pathways. Here, we investigated EA's effects on AD-related pathology in APP/PS1 transgenic mice, focusing on HDAC3-AMPA receptor interactions in synaptic plasticity. Behavioral assays (Morris water maze) and electrophysiological recordings revealed that EA improved spatial learning ability and reinstated LTP in APP/PS1 transgenic mice. Mechanistically, EA reduced hippocampal HDAC3 expression while upregulating GluR1/GluR2 subunits and increasing acetylated H3K9K14/H3 levels, suggesting HDAC3-mediated transcriptional regulation of AMPA receptor genes. Co-immunoprecipitation assays further supported HDAC3's physical interaction with AMPA receptor components. Crucially, conditional knockout of HDAC3 in neurons rescued both LTP impairments and memory deficits, reinforcing its pivotal role in synaptic dysfunction. Our findings unveil a novel epigenetic mechanism whereby EA mitigates AD-associated synaptic damage by suppressing HDAC3 and enhancing AMPA receptor-dependent plasticity, highlighting HDAC3 as a promising therapeutic target for AD intervention.},
}

Animals
*Histone Deacetylases/physiology/genetics/biosynthesis
*Alzheimer Disease/therapy/genetics/physiopathology
*Receptors, AMPA/physiology/genetics/biosynthesis
*Epigenesis, Genetic
Mice
Mice, Transgenic
*Neuronal Plasticity/physiology/genetics
Long-Term Potentiation
*Electroacupuncture
Disease Models, Animal
Hippocampus/metabolism
Amyloid beta-Protein Precursor/genetics
Male
Histones/metabolism
Acetylation
Mice, Inbred C57BL
Humans

@article {pmid41186427,
year = {2025},
author = {Hsu, CH and Wang, CH and Huang, CC and Yeh, TC},
title = {Brexpiprazole-Induced Rhabdomyolysis and Extrapyramidal Symptoms in an Alzheimer Dementia Patient on Rivastigmine.},
journal = {American journal of therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1097/MJT.0000000000001949},
pmid = {41186427},
issn = {1536-3686},
}

@article {pmid41186287,
year = {2025},
author = {Huang, ML and Suzuki, Y and Sasaguri, H and Saito, T and Saido, TC and Imayoshi, I},
title = {Misclassification in memory modification in App[NL-G-F] knock-in mouse model of Alzheimer's disease.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.105347},
pmid = {41186287},
issn = {2050-084X},
support = {19K16292//Japan Society for the Promotion of Science/ ; 21H02485//Japan Society for the Promotion of Science/ ; 10.52926/jpmjcr1752//Japan Science and Technology Agency/ ; 21bm0704060h0001//Japan Agency for Medical Research and Development/ ; 24bm1123049h0001//Japan Agency for Medical Research and Development/ ; 10.52926/jpmjcr1921//Japan Science and Technology Agency/ ; 21dm0207090h0003//Japan Agency for Medical Research and Development/ ; JP22zf0127007//Japan Agency for Medical Research and Development/ ; },
mesh = {Animals ; *Alzheimer Disease/physiopathology/genetics/psychology ; Disease Models, Animal ; Mice ; *Memory ; Fear ; Mice, Transgenic ; *Amyloid beta-Protein Precursor/genetics ; Gene Knock-In Techniques ; Male ; Conditioning, Classical ; },
abstract = {Alzheimer's disease (AD), the leading cause of dementia, could potentially be mitigated through early detection and interventions. However, it remains challenging to assess subtle cognitive changes in the early AD continuum. Computational modeling is a promising approach to explain a generative process underlying subtle behavioral changes with a number of putative variables. Nonetheless, internal models of the patient remain underexplored in AD. Determining the states of an internal model between measurable pathological states and behavioral phenotypes would advance explanations about the generative process in earlier disease stages beyond assessing behavior alone. Previously, Gershman et al., 2017b proposed the latent cause model, which provides a normative account of memory modification phenomena in Pavlovian fear conditioning. Here, we assumed the latent cause model as an internal model and estimated internal states defined by the model parameters being in conjunction with measurable behavioral phenotypes. The 6- and 12-month-old App[NL-G-F] knock-in AD model mice and the age-matched control mice underwent memory modification learning, which consisted of classical fear conditioning, extinction, and reinstatement. The results showed that App[NL-G-F] mice exhibited a lower extent of reinstatement of fear memory. Computational modeling revealed that the deficit in the App[NL-G-F] mice would be due to their internal states being biased toward overgeneralization or overdifferentiation of their observations, and consequently, the competing memories were not retained. This deficit was replicated in another type of memory modification learning in the reversal Barnes maze task. Following reversal learning, App[NL-G-F] mice, given spatial cues, failed to infer coexisting memories for two goal locations during the trial. We concluded that the altered internal states of App[NL-G-F] mice illustrated their misclassification in the memory modification process. This novel approach highlights the potential of investigating internal states to precisely assess cognitive changes in early AD and multidimensionally evaluate how early interventions may work.},
}

Animals
*Alzheimer Disease/physiopathology/genetics/psychology
Disease Models, Animal
Mice
*Memory
Fear
Mice, Transgenic
*Amyloid beta-Protein Precursor/genetics
Gene Knock-In Techniques
Male
Conditioning, Classical

@article {pmid41186105,
year = {2025},
author = {Li, Y and Long, G and Zhang, X and Chen, K and Li, X and Zhang, Z},
title = {Shannon Entropy of Gray Matter Eigenmodes: A Novel Biomarker for Alzheimer's Disease and Heterogeneous MCI Trajectories.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e11614},
doi = {10.1002/advs.202511614},
pmid = {41186105},
issn = {2198-3844},
support = {2022ZD0211600//STI2030-Major Projects/ ; 32171085//National Natural Science Foundation of China/ ; 12405062//National Natural Science Foundation of China/ ; 82130118//State Key Program of National Natural Science of China/ ; ZZ13-YQ-073 Z0601//Fundamental Research Funds for the Central Public welfare research institution/ ; },
abstract = {Current Alzheimer's disease (AD) diagnostics rely on late-stage cognitive assessments or invasive biomarkers. Neuroimaging offers non-invasive alternatives, but single-modality approaches (structural atrophy or functional connectivity) face limitations in sensitivity and specificity for early detection. Entropy and temperature, novel structure-function coupling (SFC) biomarkers based on gray matter eigenmodes, are introduced to quantify cortical disorganization in early AD. Using multimodal MRI and amyloid-PET data from two cohorts (BABRI: N = 135; ADNI: N = 275), including cognitively normal (CN), mild cognitive impairment (MCI), and AD individuals, entropy is computed by projecting fMRI onto structural eigenmodes and temperature via eigenmode-based functional connectivity reconstruction. These indices are tested for diagnostic classification, Aβ prediction, and MCI subtype stratification (reversed/stable/progressed). Entropy is significantly higher in AD than CN and MCI (Δ = 8-21%, p < 0.001) in both cohorts. Left-hemisphere entropy yielded optimal diagnostic accuracy (AUC = 0.901 for CN vs MCI), while right/global entropy predicted Aβ burden (error reduction: 38.7-42.1%, p < 0.01). Entropy also distinguished MCI subtypes and captured biphasic changes in progressors. Temperature indices showed no significant group differences. Entropy from gray matter eigenmodes is a sensitive, non-invasive biomarker for AD diagnosis and pathology prediction, revealing hemispheric asymmetries and nonlinear progression in MCI.},
}

@article {pmid41185915,
year = {2025},
author = {Rodriguez, FS and Ziegert, N and Ross, SD},
title = {Non-Medical Activities in Dementia Care in Germany: Use and Experienced Effects.},
journal = {Journal of primary care & community health},
volume = {16},
number = {},
pages = {21501319251390081},
doi = {10.1177/21501319251390081},
pmid = {41185915},
issn = {2150-1327},
mesh = {Humans ; *Dementia/therapy ; Germany ; Male ; Female ; Middle Aged ; Aged ; Caregivers/psychology ; Leisure Activities ; Interviews as Topic ; Surveys and Questionnaires ; },
abstract = {Previous studies have shown benefits through non-pharmacological interventions for people with dementia. Non-medical activities (i.e., activities outside the medical sector) may have similar effect. As little is known about the use and perceived effects of non-medical activities in dementia care, this study's aim was to obtain population-based descriptive information. A survey in the form of structured interviews was conducted with n = 134 stakeholders. Participants used on average 17.7 non-medical activities (i.e., social, leisure, and household activities). They reported perceiving effects for, on average, 85.1% of the activities, which were mostly effects on improvements in wellbeing, activation, and social health. Overall, a higher use of non-medical activities was significantly associated with perceiving more effects, especially on cognition and preserving abilities, and perceiving not knowing an activity as a barrier. However, this differed by stakeholder group: Perceiving effects on cognition was only significant for caregiving professionals. Further, for this group, feeling sufficiently trained for dealing with dementia and self-organizing/ self-financing activities was associated with a higher use. Overall, the results indicate that non-medical activities are an important component of dementia care that seem to come with important benefits.},
}

Humans
*Dementia/therapy
Germany
Male
Female
Middle Aged
Aged
Caregivers/psychology
Leisure Activities
Interviews as Topic
Surveys and Questionnaires

@article {pmid41185813,
year = {2025},
author = {S, H and Rather, HJ and Dwivedi, A and Bala, S and Velladurai, P and Anantharaman, S},
title = {The Neuropsychology of Chronic Neurological Disorders: A Review of Cognitive and Emotional Impairments.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e93642},
pmid = {41185813},
issn = {2168-8184},
abstract = {Chronic neurological disorders (CNDs) represent a broad spectrum of conditions, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, stroke, and traumatic brain injury that significantly impair cognitive and emotional functioning. These neuropsychological deficits are not merely ancillary to neurological deterioration but are core features that profoundly affect daily living and long-term outcomes. This review synthesizes current evidence on the cognitive domains most commonly affected, such as memory, attention, executive function, and language, and the spectrum of emotional disturbances, including depression, anxiety, apathy, and mood dysregulation. By examining disorder-specific profiles, neurobiological underpinnings, and brain-behavior relationships, the review underscores the interdependence between cognitive and emotional processes. Further, it evaluates standard and emerging neuropsychological assessment tools, including neuroimaging and digital platforms, and outlines intervention strategies ranging from cognitive rehabilitation and psychotherapy to pharmacological and integrative care models. Limitations in cultural adaptation, technological implementation, and longitudinal tracking are discussed alongside future research directions emphasizing AI, genomics, and personalized medicine. The findings advocate for a multidisciplinary and patient-centered approach to neuropsychological care, which is essential for enhancing quality of life in individuals affected by CNDs.},
}

@article {pmid41185525,
year = {2025},
author = {Liu, Q and Feng, E and Li, S and Zhu, Y and He, X and Xu, X and Zheng, T and Tian, Y},
title = {High-Efficient Raman Enhancement on Organic Semiconductor-Stabilized Perovskite Heterostructures for Guiding Early Theranostics of Alzheimer's Disease.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e18319},
doi = {10.1002/anie.202518319},
pmid = {41185525},
issn = {1521-3773},
support = {2024YFC3406405//National Key Research and Development Program of China/ ; 22222405//National Natural Science Foundation of China/ ; 22393930//National Natural Science Foundation of China/ ; },
abstract = {Perovskites have recently emerged as attractive optoelectronic semiconductors due to tunable bandgap, large absorption coefficient, and long carrier lifetime, making it ideal as a kind of chemical-mechanism based surface-enhanced Raman scattering (SERS) substrates. However, perovskites generally demonstrate poor stability at ambient conditions, limiting their applications for SERS bioanalysis. Herein, we created a perovskite-based heterostructure through effectively passivating defects at the interface with hydrophobic organic semiconductors, which simultaneously enhanced the stability and efficiency of perovskite SERS substrate. The significant enhancement factor of 10[7] was mainly stemmed from the resonance Raman effect and the highly-efficient charge transfer process driven by a novel light-induced hot electron transfer mechanism in plasmon-free substrates previously never reported. This system was subsequently developed as an integrated theranostic SERS platform for miR-146a monitoring with a detection limit down to 0.2 fM, successfully guiding the early theranostics to enhance the therapeutic efficiency for Alzheimer's disease (AD). This work brings new light into the design of efficient and stable semiconductor SERS substrate and opens novel diagnosis and treatment options for AD.},
}

@article {pmid41185502,
year = {2025},
author = {Goyal, A and Kumari, A and Verma, A and Kumar, R and Thakur, M and Gopika, S},
title = {From Nature to Neuroscience: Exploring Carvacrol's Therapeutic Potential in Brain Health.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249387846251006093402},
pmid = {41185502},
issn = {1875-6166},
abstract = {Carvacrol is a major active compound present in the essential oils of various aromatic plants. Research strongly indicates that carvacrol holds considerable promise for use in the development of new pharmaceutical drugs and dietary supplements. Due to its broad spectrum of bioactive properties, carvacrol shows potential therapeutic applications for several complex and challenging brain-related disorders. Its actions are multifaceted; it mitigates neuroinflammation and exerts antioxidant properties as well as other neuroprotective effects that shield neural structures from degeneration. Additionally, carvacrol influences important neural systems, including the cholinergic and dopaminergic pathways, helping to regulate neurotransmitter levels and activity in ways that could mitigate neurological symptoms. Furthermore, its anti-apoptotic effects suggest that it can help prevent programmed cell death, a common factor in neurodegenerative diseases. Collectively, these biological properties make carvacrol an attractive option for use as an adjunctive or supportive therapy in managing a range of brain illnesses, including epilepsy, anxiety, depression, stroke, Parkinson's disease, and Alzheimer's disease. This study presents an extensive review of in vitro as well as in vivo research studies on carvacrol's protective effects across different brain disorders. By examining these studies, this review offers a comprehensive and up-to-date assessment of the biological activities and molecular mechanisms of carvacrol, emphasizing its potential role in therapeutic strategies aimed at supporting brain health and treating complex neurological conditions.},
}

@article {pmid41185432,
year = {2025},
author = {Beschorner, N and Xu, Y and Jucker, M and Ruiz-Riquelme, A},
title = {Amyloid-β Seeds in Alzheimer's Disease: Research Challenges and Implications.},
journal = {Journal of neurochemistry},
volume = {169},
number = {11},
pages = {e70267},
doi = {10.1111/jnc.70267},
pmid = {41185432},
issn = {1471-4159},
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Amyloid beta-Peptides/metabolism ; Animals ; },
abstract = {The amyloid cascade hypothesis, proposed over 30 years ago, places amyloid-β (Aβ) at the center of Alzheimer's disease (AD) pathogenesis. Though controversial, recent clinical successes with Aβ-targeting therapies have reinforced its importance. However, these treatments have shown only modest clinical benefits in line with a two-stage AD progression: an early phase driven by Aβ-seed and a later phase that progresses at least partly independently of Aβ. Evidence of Aβ seed transmission in humans raises both therapeutic potential and biosafety concerns. This review explores current understanding of Aβ seeds, including challenges in studying such seeds, model systems to study Aβ seeds, and biosafety issues when working with Aβ seeds.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Amyloid beta-Peptides/metabolism
Animals

@article {pmid41185093,
year = {2025},
author = {Song, Z and Bhandari, K and Hou, T and Ding, F},
title = {APOE Genotype Difference in the Biphasic Modulation of Amyloid-β Aggregation by Direct Binding and Lowering the Nucleation Barrier.},
journal = {Biomacromolecules},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biomac.5c01323},
pmid = {41185093},
issn = {1526-4602},
abstract = {Amyloid-β (Aβ) aggregation is a hallmark of Alzheimer's disease (AD), while the apoE4 isoform (C112R) represents the strongest genetic risk factor. We combined binding-site mapping and discrete molecular dynamics (DMD) simulations to elucidate isoform-specific apoE-Aβ interactions. Computational peptide-array analysis identified Aβ-binding hotspots in the apoE4 N-terminal domain (NTD) around R112, conferring greater Aβ-binding propensity than apoE3. DMD simulations showed that apoE4 NTD is less stable and more solvent-exposed, resulting in stronger Aβ binding, especially near the mutation site. Upon binding apoE NTDs, Aβ exhibited an increased β-sheet content, suggesting a lowered fibril nucleation barrier. Incorporating these insights into a recently established thermodynamic-kinetic framework of amyloid aggregation rationalizes apoE's biphasic effect on Aβ aggregation: apoE retards Aβ fibrillization at low Aβ-concentrations via monomer sequestration but accelerates the process at high concentrations by facilitating nucleation. Our findings offer mechanistic insight into the APOE genotype-dependent modulation of Aβ aggregation and may inform genotype-specific therapeutic strategies for AD.},
}

@article {pmid41185066,
year = {2025},
author = {Sekiya, H and Matsubara, T and DeTure, MA and Dickson, DW},
title = {Neuropathology of Lewy body dementia: Lewy-related pathology, α-synuclein oligomers, and comorbid pathologies.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {117},
pmid = {41185066},
issn = {1750-1326},
mesh = {Humans ; *Lewy Body Disease/pathology/metabolism ; *alpha-Synuclein/metabolism ; *Lewy Bodies/pathology/metabolism ; Parkinson Disease/pathology/metabolism ; },
abstract = {Lewy body dementia is the second most common form of neurodegenerative dementia, following Alzheimer's disease. This umbrella term encompasses dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The distinction between these two conditions lies in the timing of the onset of cognitive impairment relative to motor symptoms. In DLB, cognitive impairment precedes or coincides with motor symptoms within the first year, whereas in PDD, cognitive decline occurs more than a year after the onset of motor symptoms. Clinically, in addition to cognitive decline, patients with Lewy body dementia have parkinsonism, visual hallucinations, and fluctuations of cognitive status. The pathological hallmark of this condition is the presence of Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology. This is identical to Parkinson's disease, where dementia is not observed. The principal component of Lewy-related pathology is α-synuclein, which classifies this disorder as an α-synucleinopathy. While Lewy-related pathology represents a later stage of α-synuclein aggregation, earlier stages involve α-synuclein oligomers. Emerging evidence suggests α-synuclein oligomers may be more toxic than Lewy-related pathology. In addition to α-synuclein pathology, previous studies frequently observed comorbid pathological conditions, including Alzheimer's disease neuropathologic change, TAR DNA-binding protein 43 (TDP-43) pathology, and cerebral small vessel disease among others. In this review, we provide a comprehensive overview of the underlying pathologies for Lewy body dementia and their molecular mechanisms and clinical implications. We also discuss concepts including the prion-like propagation hypothesis of α-synuclein, α-synuclein strain hypothesis, and recent advances in machine learning algorithms for analyzing propagation patterns. The purpose of this manuscript is to elucidate these complex pathological conditions, advance our understanding of the disease, and improve diagnostic strategies.},
}

Humans
*Lewy Body Disease/pathology/metabolism
*alpha-Synuclein/metabolism
*Lewy Bodies/pathology/metabolism
Parkinson Disease/pathology/metabolism

@article {pmid41185063,
year = {2025},
author = {Li, R and Liu, L and Yang, J and Chai, W and Zhang, M and Wei, M and Wei, Y and Wang, X and Zhang, S and Wang, J and Guo, T and Han, Y},
title = {Longitudinal characteristics of plasma biomarkers in Chinese older adults with Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {239},
pmid = {41185063},
issn = {1758-9193},
support = {2023T160439//China Postdoctoral Science Foundation/ ; 82422027, U24A20340//National Natural Science Foundation of China/ ; 82327809, 82020108013//National Natural Science Foundation of China/ ; 2023B1515020113//Guangdong Basic and Applied Basic Science Foundation for Distinguished Young Scholars/ ; 2022ZD0211800//STI2030-Major Projects/ ; CNLZD2101, CNLZD2303//Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning/ ; },
}

@article {pmid41185054,
year = {2025},
author = {Leung, LY and Tam, HL and Asiamah, N and Ho, JK},
title = {Effect of melatonin on cognitive function in adults with cognitive impairment: a multi-dimensional meta-analysis of randomized trials.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {238},
pmid = {41185054},
issn = {1758-9193},
mesh = {Humans ; *Melatonin/therapeutic use/pharmacology ; *Cognitive Dysfunction/drug therapy/psychology ; Randomized Controlled Trials as Topic ; *Cognition/drug effects ; },
abstract = {BACKGROUND: Cognitive impairment leads to poor daily social and occupational functions and sleep disturbances. Approximately two-thirds of all individuals with mild cognitive impairment (MCI) experience sleep problems that further reduce cognitive function. Melatonin, a hormone secreted by the pineal gland, has proven effective in mitigating sleep problems and cognitive function in individuals with MCI. The current review investigated the efficacy of melatonin in improving cognitive function in adults with cognitive impairment.

METHODS: Seven databases were systematically searched for relevant randomized controlled trials published (in English or Chinese) until April 2025. Two reviewers independently selected studies, assessed quality (using the Physiotherapy Evidence Database scale), and extracted data.

RESULTS: In total, 394 potentially eligible articles were identified. Finally, 8 studies (518 participants) were included. Five, one, and two studies had good, excellent, and low quality, respectively. Pooled results indicated that melatonin significantly improved cognitive function in adults with cognitive impairment (mean difference [MD]: 1.08; p < 0.0001). Subgroup analyses by treatment duration, administration time, and cognitive impairment level revealed that the effects of melatonin were significant when it was administered for 13-24 weeks (MD: 2.04; p < 0.00001), between the times of 20:30 and 21:00 (MD: 2.2; p < 0.00001), and to individuals with MCI (MD: 2.63; p < 0.000001).

CONCLUSIONS: Our findings suggest that melatonin is relatively safe for individuals with cognitive impairment. Thus, we recommend it for adults with MCI. It should be administered between 20:30 and 21:00 for 13-24 weeks.},
}

Humans
*Melatonin/therapeutic use/pharmacology
*Cognitive Dysfunction/drug therapy/psychology
Randomized Controlled Trials as Topic
*Cognition/drug effects

@article {pmid41184966,
year = {2025},
author = {Shukla, S and Kadam, AA and Goyani, S and Jaiswal, N and Samantaray, K and Kashyap, S and Tomar, D and Jadiya, P},
title = {Cell-type-specific dysregulation of mitochondrial calcium signaling in Alzheimer's disease.},
journal = {Cell communication and signaling : CCS},
volume = {23},
number = {1},
pages = {472},
pmid = {41184966},
issn = {1478-811X},
support = {25POST1378440//American Heart Association/ ; 25POST1371847//American Heart Association/ ; 25CDA1454954//American Heart Association/ ; 24IPA1273195//American Heart Association/ ; R00DK120876/NH/NIH HHS/United States ; R00AG065445/NH/NIH HHS/United States ; AARG-NTF-23-1144888/ALZ/Alzheimer's Association/United States ; 24AARG-D-1191292/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Mitochondria/metabolism ; *Calcium Signaling ; Calcium/metabolism ; Calcium Channels/metabolism ; Microglia/metabolism ; Cell Line, Tumor ; Astrocytes/metabolism ; Cell Line ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid plaques, tau tangles, and synaptic dysfunction. Despite decades of research, effective disease-modifying therapies remain elusive, highlighting the need for alternative therapeutic targets. While neurons have traditionally been the focus of AD studies, increasing evidence underscores critical roles for glial cells particularly microglia and astrocytes in disease progression. Mitochondrial calcium (mCa[2+]) dysregulation has emerged as a key contributor to neurodegeneration, yet how mCa[2][+] signaling varies across brain cell types and contributes to AD pathology remains poorly understood.

METHODS: We developed stable human SH-SY5Y (neuroblastoma-derived cells), HMC3 (microglial-like cells), and SVGp12 (astrocytic-like cells) immortalized cell lines expressing APP mutations (Swedish, Florida, and London; APPswe/F/L). We assessed mitochondrial calcium uniporter (mtCU) expression, mCa[2+] flux using ratiometric calcium (Ca[2+]) indicators, and evaluated calcium retention capacity (mito-CRC) as a readout of mitochondrial permeability transition pore opening. Bioenergetic parameters including ATP, NADH, membrane potential, and oxygen consumption rate (OCR) were measured alongside structural mitochondrial changes, ROS levels, and cell death using imaging and biochemical assays.

RESULTS: APPswe/F/L expression induced mitochondrial dysfunction across all brain immortalized cell types, with neuroblastoma-derived cells exhibiting the highest susceptibility to mCa[2+] overload, energy failure, and cell death. Compared to neuroblastoma-derived cells, glial-like cells (astrocytic-like and microglial-like cells) showed higher expression of mtCU components, elevated mCa[2+] uptake at high Ca²⁺ concentrations, and greater mito-CRC. Conversely, neuroblastoma-derived cells displayed faster mCa[2+] uptake at low Ca[2+] levels, indicating distinct regulatory thresholds. Glial-like cells exhibited more elaborate mitochondrial networks and enhanced metabolic capacity, yet all cell types showed impaired mitochondrial structure, reduced membrane potential and respiration, and increased ROS under mutant APP expression.

CONCLUSIONS: This study reveals cell-type-specific differences in mCa[2+] signaling and mitochondrial function in AD, uncovering unique vulnerabilities in neuroblastoma-derived and glial-like cells. These findings highlight the need for cell-targeted strategies to restore mCa[2+] homeostasis and mitochondrial function in AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Mitochondria/metabolism
*Calcium Signaling
Calcium/metabolism
Calcium Channels/metabolism
Microglia/metabolism
Cell Line, Tumor
Astrocytes/metabolism
Cell Line

@article {pmid41184639,
year = {2025},
author = {Janelidze, S},
title = {A new blood biomarker for Alzheimer's disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41591-025-04028-4},
pmid = {41184639},
issn = {1546-170X},
}

@article {pmid41184638,
year = {2025},
author = {Yau, WW and Kirn, DR and Rabin, JS and Properzi, MJ and Schultz, AP and Shirzadi, Z and Palmgren, K and Matos, P and Maa, C and Pruzin, JJ and Schultz, SA and Buckley, RF and Rentz, DM and Johnson, KA and Sperling, RA and Chhatwal, JP},
title = {Physical activity as a modifiable risk factor in preclinical Alzheimer's disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41184638},
issn = {1546-170X},
support = {R01 AG062667/AG/NIA NIH HHS/United States ; R01 AG071865/AG/NIA NIH HHS/United States ; K23 AG084868/AG/NIA NIH HHS/United States ; K01 AG084816/AG/NIA NIH HHS/United States ; P01 AG036694/AG/NIA NIH HHS/United States ; P01 AG036694/AG/NIA NIH HHS/United States ; K24 AG035007/AG/NIA NIH HHS/United States ; Clinical Scientist Development Award//Doris Duke Charitable Foundation (DDCF)/ ; },
abstract = {Physical inactivity is a recognized modifiable risk factor for Alzheimer's disease (AD), yet its relationship with progression of AD pathology in humans remains unclear, limiting the effective translation into prevention trials. Using pedometer-measured step counts in cognitively unimpaired older adults, we demonstrated an association between higher physical activity and slower cognitive and functional decline in individuals with elevated baseline amyloid. Importantly, this beneficial association was not related to lower amyloid burden at baseline or longitudinally. Instead, higher physical activity was associated with slower amyloid-related inferior temporal tau accumulation, which significantly mediated the association with slower cognitive decline. Dose-response analyses further revealed a curvilinear relationship, where the associations with slower tau accumulation and cognitive decline reached a plateau at a moderate level of physical activity (5,001-7,500 steps per day), potentially offering a more approachable goal for older sedentary individuals. Collectively, our findings support targeting physical inactivity as an intervention to modify the trajectory of preclinical AD in future prevention trials, and further suggest that preferentially enrolling sedentary individuals with elevated amyloid may maximize the likelihood of demonstrating a protective effect of physical activity on tau accumulation and cognitive and functional decline in early AD.},
}

@article {pmid41184619,
year = {2025},
author = {Choe, K and Ali, J and Park, HY and Jang, SH and Choi, EY and Kang, MH and Park, TJ and Kim, MO},
title = {The mGluR2/3 agonist xanthurenic acid improves memory, attention, and synaptic deficits by modulating glutamate release in Alzheimer's disease model.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41184619},
issn = {1745-7254},
abstract = {Amyloid-beta (Aβ) aggregation is the key component of neuritic plaques that drives Alzheimer's disease (AD) progression and cognitive decline. Although synaptic dysfunction strongly correlates with cognitive impairment, its underlying mechanisms remain unclear. Recently, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key contributor to AD pathology, and xanthurenic acid (XA), a naturally occurring end-product of the KP, has been implicated in neuroprotection. In this study, we investigated the neuroprotective effects of intranasally administered XA in an Aβ-induced AD mouse model. AD-like pathology was induced in mice by intracerebroventricular injection of Aβ1-42. The mice received daily intranasal instillation of XA (0.5 μg/5 μL per nostril) for 6 weeks. After XA treatment was completed, the cognitive performance was assessed in behavioral tests, then the mice were euthanized, and the brain were collected for molecular and biochemical analyses. We showed that XA treatment significantly improved the cognitive function of AD mice, and reduced AD-related pathological markers such as APP, Aβ and BACE-1 in the cortex, hippocampus and olfactory bulb. XA treatment also attenuated Aβ-induced oxidative stress through upregulation of the Nrf2/HO-1/SOD1 and key enzymatic antioxidants (GSH, GST, CAT, SOD), while concurrently reducing lipid peroxidation. Furthermore, XA treatment preserved synaptic integrity, evidenced by restoring both pre- and postsynaptic markers (SNAP-25, SYP, SNAP-23, PSD-95) and enhancing signaling via the cAMP-PKA-CREB pathway. Notably, XA differentially modulated metabotropic glutamate receptors, decreasing mGluR2 and increasing mGluR3 expression. In vitro experiments were conducted in APPswe/ind-transfected SH-SY5Y neuroblastoma cells. XA (3-100 µM) dose-dependently improved the cell viability while reducing cytotoxicity and apoptosis. Overall, these results demonstrate that XA confers multifaceted neuroprotection by modulating Aβ pathology, oxidative stress, synaptic function, and glutamatergic signaling, suggesting its potential as a novel therapeutic strategy to mitigate cognitive decline and pathological progression in AD.},
}

@article {pmid41184576,
year = {2025},
author = {Lenharo, M},
title = {Alzheimer's decline slows with just a few thousand steps a day.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41184576},
issn = {1476-4687},
}

@article {pmid41184455,
year = {2025},
author = {Llibre-Guerra, JJ and McDade, EM and Schindler, SE and Clifford, DB and Supnet, C and Atri, A and Bateman, RJ},
title = {Towards pharmacological prevention of Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {41184455},
issn = {1759-4766},
abstract = {Prevention of Alzheimer disease (AD) is a medical challenge owing to its complex pathogenesis, which involves amyloid-β (Aβ) and tau aggregation, neuroinflammation and progressive neurodegeneration. Development of disease-specific biomarkers has transformed our ability to detect AD pathology early, enabling more accurate diagnosis, monitoring and the development of targeted disease-modifying therapies. Consequently, primary and secondary prevention of AD have become feasible goals. In this Perspective, we examine current and emerging pharmacological strategies for the prevention of AD, particularly the use of existing anti-Aβ therapies and emerging anti-tau approaches, among people at risk of AD or in the earliest, presymptomatic stages of the disease. We highlight the key challenges in implementing prevention trials, discuss ongoing prevention trials and their implications, and consider the potential and challenges of translation into clinical practice. Implementation of preventative strategies, supported by biomarker-guided patient selection and innovative trial designs, has the potential to substantially delay or prevent the cognitive decline caused by AD. Success would fundamentally transform the AD therapeutic landscape, reducing the socioeconomic burden of dementia and preserving cognitive function in ageing populations worldwide.},
}

@article {pmid41184442,
year = {2025},
author = {Garnier-Crussard, A and Landeau, B and Mezenge, F and Gonneaud, J and Roquet, D and Cotton, F and Chetelat, G},
title = {Heterogeneity of white matter hyperintensities in Alzheimer's disease captured by multimodal neuroimaging.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38433},
pmid = {41184442},
issn = {2045-2322},
support = {667696//European Union's Horizon 2020 Research and Innovation Program/ ; 667696//European Union's Horizon 2020 Research and Innovation Program/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *White Matter/diagnostic imaging/pathology/metabolism ; Aged ; Male ; Female ; *Neuroimaging/methods ; *Multimodal Imaging/methods ; Positron-Emission Tomography ; Aged, 80 and over ; Magnetic Resonance Imaging ; Fluorodeoxyglucose F18 ; },
abstract = {White matter hyperintensities (WMH) are common in older adults and are associated with cognitive disorders. They typically arise from small vessel disease, leading to demyelination and axonal loss. WMH are thus considered markers of cerebrovascular changes. However, other pathophysiological processes can lead to WMH, particularly in Alzheimer's disease (AD). Understanding the diverse origins of WMH could enhance the diagnosis and treatment of AD patients. We hypothesize that multimodal neuroimaging could help understand the heterogeneity of WMH and pinpoint their specific origin. We included 142 older adults from the community and memory clinic (with an emphasis on patients within the Alzheimer's continuum), and tested if multimodal neuroimaging signal within regional WMH (including T1w, T2w, [18]F-florbetapir [AV45] and [18]F-fluorodeoxyglucose [FDG] PET), is associated with amyloid load and cognition. We showed that intra-WMH T1w and T2w signal in the parietal and frontal lobes were linked to amyloid status; intra-WMH T2w signal in all regions negatively correlated with amyloid load, while intra-WMH T1w signals in the parietal lobe positively correlated with amyloid load; finally, intra-WMH T1w signal negatively correlated with cognition while T2w and marginally AV45 signals positively correlated with cognition. This study demonstrates the potential of multimodal neuroimaging to unravel the heterogeneity of WMH, which could enhance their interpretation and improve clinical decision-making.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
*White Matter/diagnostic imaging/pathology/metabolism
Aged
Male
Female
*Neuroimaging/methods
*Multimodal Imaging/methods
Positron-Emission Tomography
Aged, 80 and over
Magnetic Resonance Imaging
Fluorodeoxyglucose F18

@article {pmid41184419,
year = {2025},
author = {Wei, Y and Shan, Y and Fan, W and Huang, X and Ding, J and Mao, M and Liu, Q and Tian, M and Li, X and Lu, J and Chang, H and Dong, Y and Du, Y and Qiu, C and Han, X and Wang, Y},
title = {Heart rate response and recovery during exercise and dementia risk: a prospective UK biobank study.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38362},
pmid = {41184419},
issn = {2045-2322},
mesh = {Humans ; Male ; Female ; *Heart Rate/physiology ; *Exercise/physiology ; United Kingdom/epidemiology ; Aged ; Biological Specimen Banks ; Middle Aged ; Prospective Studies ; *Dementia/physiopathology/epidemiology ; Exercise Test ; Risk Factors ; Alzheimer Disease/physiopathology/epidemiology ; Electrocardiography ; Dementia, Vascular/physiopathology/epidemiology ; UK Biobank ; },
abstract = {The heart rate response/recovery (HRR) index, a common indicator for cardiovascular health during exercise, has been linked with neurocognitive disorders and mortality. However, the relationship between HRR index and dementia remains unknown. Electrocardiogram data from 46,348 middle-aged and older adults from the UK Biobank were analyzed following a standardized submaximal exercise stress test (15-second baseline, 6-minute exercise, and 1-minute recovery). The HRR index was calculated as the product of heart rate responses ratio during exercise (peak/resting heart rate) and recovery ratio (peak/recovery heart rate). We found that 519 participants were ascertained with dementia, including 232 with Alzheimer's disease (AD) and 85 with vascular dementia (VaD) during a median follow-up period of 12.62 years. Higher HRR index and recovery ratio were significantly associated with a reduced risk of all-cause dementia (HR: 0.72, 95% CI: 0.54-0.94, P = 0.017; HR: 0.75, 95% CI: 0.57-0.99, P = 0.018), but not with incident AD or VaD, respectively. In addition, higher HRR index was significantly correlated with slower cognitive decline in processing speed, reasoning, and memory (β:2.39, 95% CI: 0.28-4.49, P = 0.027; β: 2.12, 95% CI: 0.26-4.00, P = 0.027; β: 0.03, 95% CI: 0.02-0.05, P < 0.001), while the recovery ratio was significantly correlated with slower cognitive decline in reasoning and memory (β: 1.91, 95% CI: 0.04-3.79, P = 0.045; β: 0.03, 95% CI: 0.01-0.04, P < 0.001). Higher HRR index and recovery ratios are associated with a decreased risk of incident dementia and appear to have beneficial effects on delaying cognitive decline. The possible mechanisms for this may involve autonomic function and neurovascular health.},
}

Humans
Male
Female
*Heart Rate/physiology
*Exercise/physiology
United Kingdom/epidemiology
Aged
Biological Specimen Banks
Middle Aged
Prospective Studies
*Dementia/physiopathology/epidemiology
Exercise Test
Risk Factors
Alzheimer Disease/physiopathology/epidemiology
Electrocardiography
Dementia, Vascular/physiopathology/epidemiology
UK Biobank

@article {pmid41184364,
year = {2025},
author = {Xiao, B and Zeng, Y and Oros Klein, K and Granato, B and Blanchette, M and Shao, X and Greenwood, CMT},
title = {A multivariate approach to identify association between peripheral blood DNA methylation and cerebrospinal fluid biomarkers of Alzheimer disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38289},
pmid = {41184364},
issn = {2045-2322},
support = {Aging in Place Challenge program (AiP-009)//National Research Council Canada/ ; Canadian Institutes of Health Research Project grant PJT-148620//Fonds de recherche du Québec - Nature et technologies/ ; },
mesh = {*Alzheimer Disease/cerebrospinal fluid/blood/genetics ; Humans ; *DNA Methylation ; *Biomarkers/cerebrospinal fluid/blood ; tau Proteins/cerebrospinal fluid ; Aged ; Female ; Male ; Amyloid beta-Peptides/cerebrospinal fluid ; Multivariate Analysis ; Aged, 80 and over ; },
abstract = {DNA methylation has been shown to play a crucial role in many diseases, including Alzheimer's disease (AD). Although many studies have correlated DNA methylation in blood samples with risk of clinical AD diagnosis, few have examined links with AD neuropathology. Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, we investigate the associations between peripheral blood DNA methylation and three AD-associated biomarkers in cerebrospinal fluid: amyloid-β, phosphorylated tau-181, and total tau using an innovative multivariate approach. In our approach, we first adjusted the methylation values for covariates that have known wide-spread effects on methylation. We then developed and implemented a multivariate penalized model to find associations, jointly, between CSF biomarkers and sets of methylation residuals defined by regions around each gene. These penalized models then selected probes showing associations with one or more CSF biomarkers. We demonstrate, using both simulations and actual data, that our proposed multivariate approach is beneficial for detecting weak signals. We also provide complementary validation using data from the Canadian Longitudinal Study on Aging. Our multivariate strategy has the potential to increase feature selection accuracy among correlated predictors in epigenetic studies.},
}

*Alzheimer Disease/cerebrospinal fluid/blood/genetics
Humans
*DNA Methylation
*Biomarkers/cerebrospinal fluid/blood
tau Proteins/cerebrospinal fluid
Aged
Female
Male
Amyloid beta-Peptides/cerebrospinal fluid
Multivariate Analysis
Aged, 80 and over

@article {pmid41184271,
year = {2025},
author = {Li, M and Chen, S and Guo, R and Wang, Y and Yang, M and Liu, Y and Zhang, Q and Zhu, S and Li, J and Chen, F and Wang, B and Li, M and He, Q},
title = {Microglia-derived nanovesicles synchronize macroautophagy and chaperone-mediated autophagy for Alzheimer's disease therapy.},
journal = {Signal transduction and targeted therapy},
volume = {10},
number = {1},
pages = {360},
pmid = {41184271},
issn = {2059-3635},
support = {NSFC-STINT 82311530116//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Animals ; *Alzheimer Disease/genetics/pathology/drug therapy/therapy/metabolism ; Mice ; *Microglia/metabolism/pathology ; *Chaperone-Mediated Autophagy/drug effects/genetics ; Humans ; Sirolimus/pharmacology ; Disease Models, Animal ; *Autophagy ; Amyloid beta-Peptides/genetics ; Blood-Brain Barrier/drug effects/metabolism ; },
abstract = {Dysregulated autophagy is a hallmark of Alzheimer's disease (AD), yet the extent of impairment in macroautophagy and chaperone-mediated autophagy (CMA) remains unclear. Here, we show that both pathways are disrupted in AD model mice, preceding β-amyloid accumulation and driving disease progression. However, therapeutic autophagy modulation is severely restricted by the blood-brain barrier (BBB). To overcome this, we developed Microglia-Liposome Fusion Extrusion (MiLi-FE), a method to engineer microglia-derived nanovesicles (AR@ENV) for the codelivery of AR7 (a CMA inducer) and rapamycin (a macroautophagy inducer). Leveraging its microglial membrane origin, AR@ENV effectively crosses the BBB and targets inflammatory sites in the AD brain, where it is internalized by neurons. Once inside, they synchronously activate both autophagy pathways: AR7 antagonizes retinoic acid receptor alpha (RARα) to enhance CMA, while rapamycin inhibits mTOR to promote macroautophagy. This coordinated activation enhances clearance of β-amyloid and other toxic aggregates, restores proteostasis, and provides robust neuroprotection. Furthermore, the strategy ameliorates neuroinflammation and significantly rescues cognitive deficits in two distinct AD mouse models. By integrating synchronized dual autophagy activation with targeted biomimetic delivery, AR@ENV represents a promising therapeutic candidate for AD. Moreover, the MiLi-FE platform offers a versatile and scalable approach for delivering diverse therapeutics to the central nervous system, extending its potential applicability to a range of neurological disorders.},
}

Animals
*Alzheimer Disease/genetics/pathology/drug therapy/therapy/metabolism
Mice
*Microglia/metabolism/pathology
*Chaperone-Mediated Autophagy/drug effects/genetics
Humans
Sirolimus/pharmacology
Disease Models, Animal
*Autophagy
Amyloid beta-Peptides/genetics
Blood-Brain Barrier/drug effects/metabolism

@article {pmid41184101,
year = {2025},
author = {Gauvrit, T and Benderradji, H and Pelletier, A and Carvalho, K and Aboulouard, S and Faivre, E and Chatelain, E and Cannafarina, H and Labous, L and Launay, A and Fourcot, M and Kwiatkowski, D and Chesnais, L and Vallez, E and Cardon, T and Deleau, A and Thiroux, B and Eddarkaoui, S and Bogdanova, A and Besegher, M and Delahaye, F and Annicotte, JS and Le Gras, S and Tailleux, A and Salzet, M and Marot, G and Buée, L and Blum, D and Vieau, D},
title = {Sex-dependent effects of maternal high-fat diet during lactation in the offspring of adult THY-Tau22 mice.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf417},
pmid = {41184101},
issn = {1460-2156},
abstract = {The perinatal environment has been suggested to participate in the development of tauopathies and Alzheimer's disease but the molecular and cellular mechanisms involved remain contradictory and under-investigated. Here, we evaluated the effects of a maternal high-fat diet (HFD) during lactation on the development of tauopathy in the THY-Tau22 mouse strain, a model of progressive tau pathology associated with cognitive decline. During lactation, dams were fed either a chow diet (13.6% of fat) or a HFD (58% of fat). At weaning, offspring were fed a chow diet until sacrifice at 4 months of age (the onset of tau pathology) or 7 months of age (the onset of cognitive impairment). During lactation, maternal HFD increased body weight gain in offspring. At 3 months of age, maternal HFD led to a mild glucose intolerance only in male offspring. Moreover, it impaired spatial memory in both male and female 6-month-old offspring, with males being more impacted. These cognitive deficits were associated with increased phosphorylation of hippocampal tau protein-observed at 4 months in males and at 7 months in females, highlighting a sex-specific temporal shift. Additionally, maternal HFD modified adult hippocampal neurogenesis (AHN), leading to an increase of mature neuronal cells number in females and of dendritic arborization length in males. Synaptic analysis further revealed that maternal HFD led to synaptic loss only in males. Finally, multi-omics approaches showed that maternal HFD has long-term consequences on both transcriptome, proteome and regulome, this effect being also sex-dependent with mitochondrial pathways, ribosomal activity, cilium and the extracellular matrix predominantly impacted in males, while gliogenesis, myelination and synaptic plasticity were primarily affected in females. Regulome analysis suggested that this sex-dependent phenotype was more related to a temporal shift rather than distinct sex-specific alterations. Collectively, our data suggest that maternal HFD accelerates the development of tauopathy in THY-Tau22 offspring, with sex-dependent effects, males being impacted earlier than females. These findings highlight that exposure to maternal HFD represents a critical window of vulnerability, and potentially of opportunity, for interventions aimed at preventing the development of neurodegenerative diseases.},
}

@article {pmid41183995,
year = {2025},
author = {Okamura, N and Nakayama-Naono, R and Harada, R},
title = {[In vivo imaging of Alzheimer's disease lesion].},
journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica},
volume = {160},
number = {6},
pages = {398-403},
doi = {10.1254/fpj.25055},
pmid = {41183995},
issn = {0015-5691},
mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; Animals ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; },
abstract = {In the development of Alzheimer's disease (AD) therapeutics, positron emission tomography (PET) imaging techniques play an important role in the selection of patients for administration and objective evaluation of treatment effects. The clinical implementation of amyloid-β (Aβ) and tau PET agents is progressing, with the aim of noninvasively visualizing brain lesions in AD. Furthermore, the development of PET agents for imaging neuroinflammation is advancing. Near-infrared fluorescence (NIRF) imaging has attracted attention as an alternative technology to nuclear imaging. Near-infrared light in the wavelength range of 650-900 nm, known as the optical window, is absorbed less by living tissue compared to visible light. Therefore, by using probes that emit NIRF, it is possible to noninvasively measure the distribution of probes within the body. Indocyanine green (ICG), a non-specific NIRF probe, is already being used in surgical procedures, but NIRF probes specifically for AD lesions are still in the developmental stage. The characteristics required for NIRF Aβ probe include high binding affinity and selectivity for Aβ, excitation and fluorescence wavelengths in the optical window, and blood-brain barrier permeability. Numerous NIRF probes for Aβ have been developed, reaching levels suitable for use in animal experiments. In recent years, research has also progressed on the development of multi-target fluorescence imaging probes that can identify multiple targets with a single probe by utilizing differences in fluorescence wavelengths according to the binding targets.},
}

*Alzheimer Disease/diagnostic imaging
Humans
Animals
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism

@article {pmid41183968,
year = {2025},
author = {Higaki, Y and Kobayashi, Y},
title = {A Retrospective Study of the Association between Low Vitamin B1 in the Blood and Cognitive Impairment in Patients with Alzheimer's Disease.},
journal = {Journal of nutritional science and vitaminology},
volume = {71},
number = {5},
pages = {421-426},
doi = {10.3177/jnsv.71.421},
pmid = {41183968},
issn = {1881-7742},
mesh = {Humans ; *Alzheimer Disease/blood/complications ; Retrospective Studies ; Male ; *Thiamine/blood ; Aged ; Female ; *Cognitive Dysfunction/blood/etiology ; Aged, 80 and over ; *Vitamin B Deficiency/blood/complications ; Japan ; Folic Acid/blood ; Mental Status and Dementia Tests ; Vitamin B 12/blood ; Cognition ; Cross-Sectional Studies ; Middle Aged ; },
abstract = {This retrospective observational study investigated the association between low vitamin B1 (VB1) levels and cognitive impairment in 77 Japanese patients with Alzheimer's disease (AD). Multivariable regression analysis identified a significant correlation between low VB1 levels (<2.6 μg/dL) and lower Mini-Mental State Examination (MMSE) scores. Fisher's exact test demonstrated a strong association between VB1 deficiency and cognitive impairment (p=0.001). Scatter plot analysis supported these findings, illustrating a dose-dependent trend: patients with severe VB1 deficiency consistently exhibited low cognitive function, while those with higher VB1 levels showed better MMSE scores. In contrast, VB12 and folate levels showed no clear association with cognitive function. These results, together with animal studies, suggest that VB1 deficiency may contribute to AD-related neurodegeneration. While benfotiamine, a lipid-soluble VB1 derivative, has been suggested to improve cognition, its causal effect remains uncertain due to the study's cross-sectional design. Selection bias and the lack of dietary data are also limitations. Further longitudinal research is needed to determine whether VB1 supplementation could help mitigate cognitive decline in AD patients.},
}

Humans
*Alzheimer Disease/blood/complications
Retrospective Studies
Male
*Thiamine/blood
Aged
Female
*Cognitive Dysfunction/blood/etiology
Aged, 80 and over
*Vitamin B Deficiency/blood/complications
Japan
Folic Acid/blood
Mental Status and Dementia Tests
Vitamin B 12/blood
Cognition
Cross-Sectional Studies
Middle Aged

@article {pmid41183918,
year = {2025},
author = {Deng, Y and Ma, YN and Yamauchi, K and Karako, K and Song, P},
title = {Dementia strategies in an aging society: Policies, care, and global insights from the Japanese experience.},
journal = {Bioscience trends},
volume = {},
number = {},
pages = {},
doi = {10.5582/bst.2025.01309},
pmid = {41183918},
issn = {1881-7823},
abstract = {Aging of the population has become a critical challenge globally. The proportion of individuals age 60 years and older is projected to increase from 12% in 2015 to 22% by 2050, representing more than 2.1 billion older adults globally. This demographic transition is advancing particularly rapidly in Japan, which has become the first nation to become a "super-aged society". Projections indicate that by 2060, the number of older adults living with dementia will reach approximately 6.45 million (more than 17% of the elderly population), making it one of the country's most urgent health and social care challenges. Japan has developed a comprehensive response system that integrates medical, community, and family-based care. Key initiatives include a national dementia strategy, mechanisms for early screening and diagnosis, the establishment of memory clinics, and the implementation of the community-based integrated care system, which emphasizes coordination between healthcare and long-term care services. These measures have alleviated part of the burden on patients and families while enhancing social awareness of dementia and inclusion of those with that condition. Nevertheless, Japan continues to face significant structural challenges, such as severe shortages of healthcare personnel and professional caregivers, increasing fiscal pressure on long-term care financing, insufficient dissemination of innovative therapies and digital diagnostic tools, and disparities in social support between urban and rural areas. Cross-national comparisons indicate that Japan's experience offers valuable lessons for other rapidly aging societies, particularly in policy design, the integration of community-based care, and the promotion of a dementia-inclusive society. Summarizing and adapting Japan's approaches may therefore provide globally applicable strategies to build sustainable and equitable systems for dementia prevention, management, and care.},
}

@article {pmid41183852,
year = {2025},
author = {Gupta, S and Kishore, A and Rishi, V and Aggarwal, A},
title = {Synaptic Vesicle Cycle: From Mechanistic Insights to Epigenetic Perspectives.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00684},
pmid = {41183852},
issn = {1948-7193},
abstract = {The synaptic vesicle cycle is a critical process that ensures efficient neurotransmission across synaptic junctions, facilitating proper communication within the neuronal circuits. This cycle comprises several tightly regulated steps, including vesicle biogenesis, fusion with the presynaptic membrane, recycling, and degradation, all of which are essential for maintaining synaptic function. Specialized proteins orchestrate the molecular machinery responsible for coordinating vesicle trafficking throughout each stage of the cycle. In recent years, research has highlighted the emerging role of epigenetic regulation in modulating the synaptic vesicle cycle. Epigenetic modifications, such as DNA methylation, histone acetylation, and microRNA expression, regulate vesicle dynamics by modulating key stages of the vesicle trafficking cycle, that in turn affects neurotransmitter release and synaptic plasticity. These regulatory mechanisms ensure synaptic health and proper neuronal communication, while their disruption has been linked to synaptopathies, including autism, schizophrenia, Parkinson's, and Alzheimer's diseases. By examining both molecular and epigenetic factors, this review provides valuable insights into how gene expression and protein function are intricately involved in the regulation of the synaptic vesicle cycle. It highlights the importance of key events in regulating the synaptic vesicle cycle, their potential epigenetic drivers, and their relevance to addressing synaptic dysfunctions in various neurological disorders.},
}

@article {pmid41183617,
year = {2025},
author = {Zhao, X and He, Z},
title = {Traumatic brain injury and Alzheimer's disease related neurodegenerative diseases: Insights from animal models.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {104979},
doi = {10.1016/j.neures.2025.104979},
pmid = {41183617},
issn = {1872-8111},
abstract = {Alzheimer's disease and related neurodegenerative diseases (ADRD) represent a major global public health challenge, with their disease mechanisms remain largely unknown, and few treatments are available. Increasing epidemiological evidence underscores the critical role of traumatic brain injury (TBI) in the initiation and progression of ADRD, suggesting shared pathogenic mechanisms between these conditions. While there are still lack of perfect AD models in the field, TBI models may serve as useful and alternative platforms for investigating ADRD. In this review we delineate the definition and epidemiological characteristics of TBI. We further briefly compare the major experimental TBI animal models, outlining their respective strengths and limitations in replicating human neuropathology. Finally, we provide our perspective on potential mechanistic links between TBI and ND, including axonal injury, calcium homeostasis dysregulation, mitochondrial dysfunction, chronic neuroinflammation, blood-brain barrier disruption, and genetic susceptibility. We believe advancing preclinical and translational research on TBI not only enhances our understanding of the pathogenesis in ADRD but also holds promise for developing interventions to mitigate long-term consequences and improving clinical outcomes for many neurodegenerative diseases.},
}

@article {pmid41183391,
year = {2025},
author = {Lin Aung, T and Aung, YW and Shi, X},
title = {Meta-analysis of mRNA dysregulation associated with Parkinson's disease and other neurological disorders.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae1a8a},
pmid = {41183391},
issn = {2057-1976},
abstract = {Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, characterized by both motor and non-motor symptoms. In this study, we conducted a meta-analysis of gene expression profiles from four GEO datasets (comprising 59 PD patients and 41 participants control) to identify consistently differentially expressed messenger ribonucleic acids (DEmRNAs). We identified 5,495 down-regulated and 9,850 up-regulated DEmRNAs, of which 64 and 25, respectively, were common across all datasets. Functional enrichment analysis revealed that down-regulated DEmRNAs were primarily enriched in pathways related to neurotransmitter transport, dopamine biosynthesis, and dopaminergic synapse function, while up-regulated DEmRNAs were linked to cell cycle regulation and PI3K-Akt signaling. Notably, dysregulation of key genes, including SNCA (encoding α-synuclein), SLC6A3, TUBB, TUBB3, TUBB4B, and NDUFA9, were associated with PD as well as other neurodegenerative disorders, such as Alzheimer's, Huntington's, and Prion diseases. These DEmRNAs and pathways may offer potential biomarkers and therapeutic targets for PD and related neurological disorders.},
}

@article {pmid41183252,
year = {2025},
author = {Rosenau, C and Neuffer, J and Köhler, S and Helmer, C and Le Grand, Q and Mishra, A and Debette, S and Trégouët, DA and Deckers, K and Samieri, C},
title = {Updated LIfestyle for BRAin health (LIBRA2) Score, Genetics, and Risk of Alzheimer Disease, Vascular Dementia, and Stroke in Older Adults.},
journal = {Neurology},
volume = {105},
number = {10},
pages = {e214312},
doi = {10.1212/WNL.0000000000214312},
pmid = {41183252},
issn = {1526-632X},
mesh = {Humans ; Aged ; Female ; Male ; *Stroke/genetics/epidemiology ; *Alzheimer Disease/genetics/epidemiology ; *Dementia, Vascular/genetics/epidemiology ; Genetic Predisposition to Disease ; Aged, 80 and over ; Risk Factors ; *Life Style ; Prospective Studies ; France/epidemiology ; Apolipoprotein E4/genetics ; },
abstract = {BACKGROUND AND OBJECTIVES: Dementia and stroke are major global causes of disability, with modifiable lifestyle factors playing a significant role in their development. The updated LIfestyle for BRAin health (LIBRA2) score integrates 15 modifiable risk and protective factors to quantify lifestyle-based dementia risk, but its relationship with stroke and dementia subtypes remains unexplored. We investigated LIBRA2's association with stroke and dementia subtypes while also assessing potential interactions with genetic susceptibility.

METHODS: Prospective data were used from the French multicenter Three-City (3C) Study, with participants aged 65 years and older followed for up to 17 years. Weighted LIBRA2 scores at baseline were constructed based on the presence of 15 modifiable risk and protective factors, with higher scores representing higher lifestyle-based dementia risk. Cox proportional hazards models were used to study the association of LIBRA2 with incident dementia (and subtypes) and stroke, adjudicated by expert neurologist panels. Genetic susceptibility to dementia and stroke was assessed using APOE ε4 carriership and disease-specific genetic risk scores.

RESULTS: Analyses included 4,731 participants for stroke (mean age 73.8 years, 60.1% female) and 4,737 participants for dementia (mean age 73.8 years, 59.9% female). One-point increases in LIBRA2 scores (theoretical range -6.1 to +25.7) were associated with increased dementia risk (hazard ratio [HR] 1.08; 1.06-1.11), with a stronger association for vascular and mixed dementia (HR 1.13; 1.08-1.18) compared with Alzheimer disease (AD) dementia (HR 1.06; 1.03-1.09). LIBRA2 was not significantly associated with incident stroke risk (HR 1.03; 0.99-1.07). No significant interaction was found between LIBRA2 and APOE ε4 carriership or disease-specific genetic risk scores in relation to dementia subtypes or stroke.

DISCUSSION: LIBRA2 serves as a valuable tool for assessing lifestyle-related dementia risk and its subtypes but showed no association with stroke, highlighting the potential for a stroke-specific risk reduction model. These associations were independent of genetic disease susceptibility, reinforcing the universal benefits of lifestyle modifications on dementia risk reduction. The stronger association between LIBRA2 (and some individual components) and vascular or mixed dementia, compared with AD dementia, highlights the pivotal role of vascular mechanisms in the relationship between lifestyle and brain health.},
}

Humans
Aged
Female
Male
*Stroke/genetics/epidemiology
*Alzheimer Disease/genetics/epidemiology
*Dementia, Vascular/genetics/epidemiology
Genetic Predisposition to Disease
Aged, 80 and over
Risk Factors
*Life Style
Prospective Studies
France/epidemiology
Apolipoprotein E4/genetics

@article {pmid41183202,
year = {2025},
author = {Yang, X and Lee, JY and Moghadam, F and Steiner, J and Kim, SK and Ganjur, N and de Almenara, AJ and Stoltz, BM and Loh, YP and Goddard, WA},
title = {Predicted molecules followed by experimental validation for protecting human neurons from oxidative stress-induced cytotoxicity.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {45},
pages = {e2505359122},
doi = {10.1073/pnas.2505359122},
pmid = {41183202},
issn = {1091-6490},
support = {no numbef//HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; R01HL155532 R35HL150807 and R35GM145239//HHS | NIH (NIH)/ ; CAP23011-200//National Research Council of Science and Technology (NST)/ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology/chemistry ; Animals ; },
abstract = {Alzheimer neurodegenerative disease (AD) has had a major impact worldwide, with no effective drugs for treatment. We discovered and reported earlier that neurotrophic factor-α1 (NF-α1)/carboxypeptidase E (CPE) reversed neurodegeneration and cognitive dysfunction in AD mouse models. We then predicted computationally and validated experimentally that CPE interacts with a pharmacophore of six residues on the 5-HT1E receptor (HTR1E) to activate the ERK-BCL2 signaling pathway leading to protection of human neurons against oxidative stress-induced cell death. We now report using this pharmacophore for in silico virtual screening of ~6 million small molecules to discover candidates with similar binding and neuroprotective properties as CPE. This in silico search identified a molecule (Z124) that was verified experimentally to bind to HTR1E with protective efficacy comparable to NF-α1/CPE but requiring a higher concentration. Next, we carried out R-group design optimization based on Z124 to identify 4 compounds predicted to have much better efficacy than Z124. These compounds were synthesized and tested for neuroprotective activity. All four compounds showed binding to HTLA-HTR1E cells comparable to CPE. We determined the Kd for two of these compounds: R9, 1.38 ± 0.2 nM, and R10, 2.1 ± 0.2 nM, to be over 15 times better than CPE. Furthermore, all four new compounds showed protective activity against oxidative stress-induced cytotoxicity in human HEK293 cells stably transfected with HTR1E, as well as human primary neurons. Mechanistically, R9 and R10 activated ERK phosphorylation and increased the mitochondria prosurvival protein, BCL2, making them excellent candidates for further development as a drug to treat neurodegenerative diseases.},
}

Humans
*Oxidative Stress/drug effects
*Neurons/drug effects/metabolism/pathology
*Neuroprotective Agents/pharmacology/chemistry
Animals

@article {pmid41183134,
year = {2025},
author = {Wallman-Jones, A and Noohi, F and Roy, ARK and Zhang, BY and Sible, IJ and Gerenza, AK and Martinez-Arroyo, AI and Rocha, S and Perry, DC and Kramer, JH and Miller, BL and Rabinovici, GD and LaJoie, R and Sturm, VE},
title = {Reward system atrophy relates to heightened feelings of physical closeness in Alzheimer's disease.},
journal = {Social cognitive and affective neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1093/scan/nsaf113},
pmid = {41183134},
issn = {1749-5024},
abstract = {The experience of interpersonal space may be altered in Alzheimer's disease (AD) due to atrophy in brain systems that support emotion and reward processing. Seventy participants (AD = 36, healthy controls=34) underwent structural neuroimaging and completed a modified stop-distance paradigm, an established interpersonal distance task, in which they indicated at which distance they preferred to have a conversation with the experimenter. After estimating the distance between themselves and the experimenter, participants rated their emotional experience. Feelings of physical closeness were calculated as the discrepancy between the perceived and actual distance between the participant and experimenter. Participants also estimated their distance from the wall, which served as a non-social control task. Unlike the healthy controls, the participants with AD felt physically closer to the experimenter than they were (despite no differences in objective interpersonal distance) and reported greater positive emotional experience. Voxel-based morphometry analyses revealed greater feelings of physical closeness related to smaller gray matter volume in the right ventral striatum and right medial orbitofrontal cortex (p FWE<.05). These results suggest that reward system atrophy influences how people with AD experience interpersonal space. Individuals with AD may feel physically closer to others than they are and find social proximity more enjoyable than healthy controls.},
}

@article {pmid41183099,
year = {2025},
author = {Liu, J and Zhang, ZZ and Yu, GR and Han, X},
title = {Quercetin Targets HSP90α and Regulates Keap1/Nrf2 Pathway to Inhibit Crosstalk between Apoptosis and Ferroptosis in Oxidatively Stressed Neurons.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {11},
pages = {e70583},
doi = {10.1002/jbt.70583},
pmid = {41183099},
issn = {1099-0461},
support = {//This study was supported by the National Key Research and Development Program of China (2022YFC3501400) and Jiangsu Province Graduate Practice and Innovation Program (SJCX25_0998)./ ; },
mesh = {*Quercetin/pharmacology ; *HSP90 Heat-Shock Proteins/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Ferroptosis/drug effects ; *Oxidative Stress/drug effects ; *Neurons/metabolism/pathology/drug effects ; *Apoptosis/drug effects ; *Signal Transduction/drug effects ; Humans ; Animals ; },
abstract = {The rising incidence and mortality rates associated with Alzheimer's disease (AD) have garnered significant attention. The interplay between ferroptosis and apoptosis, both of which are driven by oxidative stress, contributes to neuronal death and accelerates the progression of AD. In this study, we observed that neuronal cells exhibited characteristics of both ferroptosis and apoptosis following exposure to a specific concentration of hydrogen peroxide; both processes could be effectively inhibited by quercetin. To further investigate the precise mechanisms, we conducted target enrichment analysis utilizing databases pertinent to quercetin, AD, oxidative stress, ferroptosis, and apoptosis. Our findings identified HSP90AA1 as a potential key target through which quercetin disrupts the interplay between ferroptosis and apoptosis. We subsequently focused on HSP90α, encoded by HSP90AA1, and validated its role in ferroptosis and apoptosis using HSP90α and Nrf2 inhibitors. Our results demonstrate that under oxidative stress conditions, quercetin induces the activation of HSP90α. This activated chaperone binds to kelch-like ECH-associated protein 1 (Keap1), which disrupts the Keap1-Nrf2 complex and facilitates the release of nuclear factor erythroid 2-related factor 2 (Nrf2). The liberated Nrf2 translocates to the nucleus, initiating the expression of cytoprotective genes. Once in the nucleus, Nrf2 activates the Glutathione peroxidase 4 (GPX4) pathway and the expression of B-cell lymphoma-2 (Bcl-2) family proteins to inhibit ferroptosis and apoptosis. This study elucidates the crosstalk mechanism by which quercetin modulates neuronal ferroptosis and apoptosis under oxidative stress, providing new insights and potential therapeutic targets for the prevention and treatment of AD.},
}

*Quercetin/pharmacology
*HSP90 Heat-Shock Proteins/metabolism
*NF-E2-Related Factor 2/metabolism
*Kelch-Like ECH-Associated Protein 1/metabolism
*Ferroptosis/drug effects
*Oxidative Stress/drug effects
*Neurons/metabolism/pathology/drug effects
*Apoptosis/drug effects
*Signal Transduction/drug effects
Humans
Animals

@article {pmid41182881,
year = {2025},
author = {Aoki, S and Onodera, W and Takashima, A and Kawasaki, K and Imadegawa, K and Kurahashi, H and Oishi, M and Asahi, T and Soeda, Y},
title = {E3 ligase Praja1 mediates ubiquitination and degradation of microtubule-associated protein tau.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70303},
pmid = {41182881},
issn = {1742-4658},
support = {JPMXS0440500024//Agency for Cultural Affairs, Government of Japan/ ; //OPTORUN Co., Ltd./ ; //Global Consolidated Research Institute for Science, Wisdom, Waseda University/ ; },
abstract = {The RING-H2 type E3 ligase Praja family is composed of E3 ubiquitin-protein ligases Praja1 and Praja2, which promote the degradation of substrates through the ubiquitin-proteasome system. Both paralogs contribute to neuronal maturation and differentiation, indicating a significant role in the nervous system. Aggregation-prone proteins associated with neurodegenerative diseases, including TAR DNA-binding protein 43 (TDP-43) and α-synuclein, are degraded and/or suppressed by Praja1. Furthermore, the expression level of the microtubule-associated protein tau (MAPT) gene, which is frequently mutated in Alzheimer's disease, is regulated by Praja2. Although the Praja family has been shown to recognize various aggregation-prone proteins as substrates, it has not been determined whether tau, a key protein that aggregates in tauopathies, is also recognized by Praja proteins. In this study, we show that Praja1, but not Praja2, recognizes tau as a candidate substrate. We observed that the tau protein level in human neuroblastoma SH-SY5Y cells decreased depending on the E3 ligase activity of Praja1. Furthermore, the in vivo/in vitro ubiquitination assay showed that Praja1 ubiquitinates tau, indicating that it is a target substrate. Next, by combining ancestral sequence reconstruction and mutational analysis, we revealed that the Praja1-tau interaction began just after the duplication of the Praja family in the common ancestor of placentals. Lastly, to test whether this interaction is disrupted under pathological conditions, P301L tau was introduced, resulting in a degradation similar to that of wild-type tau. These results reveal an unidentified mechanism of tau proteostasis by Praja1 and may provide insight into the pathogenesis of neurodegenerative diseases, including tauopathy.},
}

@article {pmid41182837,
year = {2025},
author = {Rani, S and Kaur, M and Pothal, P and Rajput, K and Khera, A and Sharma, A and Thombare, V and Sethi, A and Paul, B and Gartia, J and Yadav, VK and Patil, NA and Ranawat, P and Suresh Babu, AR and Singh, G and Barnwal, RP},
title = {Identifying Novel Spiro-Indenoquinoxaline-Pyrrolidine-Based Amyloid Beta Inhibitors in Alzheimer's Disease from In Silico to In Vitro.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00728},
pmid = {41182837},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by memory loss and other cognitive functions. The key hallmarks of AD include extracellular beta-amyloid clumps and intracellular neurofibrillary tau tangles in the neurons. Cholinesterase inhibitors and NMDA-receptor antagonists and their combination are already approved treatments; however, these only give short-term symptom relief. Therefore, new therapeutic techniques and novel drugs are required to combat the century-old AD. This study includes the screening of nine novel small compounds (spiro-indenoquinoxaline-pyrrolidines) via in silico approaches; these compounds have been scrutinized to explore their potential as antiamyloidogenic drugs. Computational tools, including ADMET analysis, molecular docking, and molecular dynamics (MD) simulations, have been used for screening the selected compounds against monomeric peptides of Aβ (Aβ1-40 and Aβ1-42) and their oligomeric counterparts, i.e., 6Aβ9-40 and 6Aβ1-42. Among the nine molecules screened for this study, ADPR-d reflected the best drug-likeness and negligible toxicity. Further, ADPR-d has the highest binding affinity for all the peptides selected for this study. Additionally, MD simulations of Aβ peptide-ADPR-d complexes confirmed a stable complex formation. In vitro aggregation assay and cell culture studies for Aβ1-42 also support our in silico findings. The positive findings of the presented study highlight that the ADPR-d molecule may prove to be a potential therapeutic molecule against AD. However, these results would require further in vitro and in vivo analysis before proceeding to clinical settings with these compounds against AD.},
}

@article {pmid41182777,
year = {2025},
author = {Thomas, ML and Edland, SD and Duehring, J},
title = {The MMSE can yield biased and imprecise estimates of change: A novel IRT analysis of latent change scores from the A4 clinical trial.},
journal = {Psychological assessment},
volume = {},
number = {},
pages = {},
doi = {10.1037/pas0001426},
pmid = {41182777},
issn = {1939-134X},
support = {//National Institutes of Health; National Institute of Mental Health/ ; },
abstract = {The measurement precision of change scores has previously been investigated from the perspective of classical test theory. However, the measurement precision of change scores has not been thoroughly explored from an item response theory (IRT) perspective. In this study, we provide, to our knowledge, one of the first direct investigations of change score precision within an IRT framework. Specifically, using archival data from the antiamyloid treatment in asymptomatic Alzheimer's trial, we examined standard error of estimate for change scores on the mini-mental state examination, one component of the preclinical Alzheimer cognitive composite used to measure change between intervention arms. Multidimensional two-parameter IRT models were fitted to the mini-mental state examination item data with one latent dimension reflecting baseline ability and a second reflecting change in ability over time (i.e., latent change scores). Results showed that standard error depended on change magnitude and that change scores were expected to be biased toward zero when baseline performance scores were near ceiling. The results demonstrate why measures with pronounced ceiling effects should not be used to assess change in clinical trials or other longitudinal studies, and should be used cautiously in clinical settings. This study also demonstrates how IRT can be used to evaluate change score precision. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid41182424,
year = {2025},
author = {Wang, X and Zhang, L and Gao, X and Zhang, L and Yu, J and Liu, Y and Fang, M and Yan, Y and Chen, L and Du, J and Guan, H and Huang, C and Fan, S},
title = {Liu Jun Zi Decoction extends lifespan and healthspan through p16/p21 signaling in Caenorhabditis elegans.},
journal = {Biogerontology},
volume = {26},
number = {6},
pages = {201},
pmid = {41182424},
issn = {1573-6768},
support = {82073951//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism ; *Longevity/drug effects ; *Drugs, Chinese Herbal/pharmacology ; Signal Transduction/drug effects ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Aging/drug effects ; },
abstract = {Age-related functional decline has emerged as a major challenge to human health and societal development. Safe and effective anti-aging interventions, particularly those involving natural products, offer promising strategies to delay aging and promote healthy longevity. In this study, we used Caenorhabditis elegans (C. elegans) models to investigate the anti-aging effects and underlying mechanisms of Liu Jun Zi Decoction (LJZD), a traditional Chinese herbal formula. The results showed that LJZD extended lifespan and enhanced stress resistance and locomotion in C. elegans. Serum pharmacochemistry, network pharmacology, and molecular docking identified key bioactive compounds that target the IIS/mTOR and p16/p21 pathways. Furthermore, we found that LJZD promoted longevity by improving mitochondrial function via the IIS-mTOR axis. Notably, LJZD also conferred neuroprotection in Aβ-/tau-expressing models. These findings provide mechanistic insights into multi-target herbal interventions for aging and neurodegeneration.},
}

Animals
*Caenorhabditis elegans/drug effects/metabolism
*Longevity/drug effects
*Drugs, Chinese Herbal/pharmacology
Signal Transduction/drug effects
*Caenorhabditis elegans Proteins/metabolism/genetics
Aging/drug effects

@article {pmid41182353,
year = {2025},
author = {Cai, Y and Huang, S and Dong, Y and Li, S and Jin, X},
title = {PIWI-Interacting RNAs in brain health and disease: biogenesis, mechanisms, and therapeutic horizons.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41182353},
issn = {1432-2072},
support = {81971083//National Natural Science Foundation of China/ ; 25JCLZJC00190//Tianjin Natural Science Foundation Project/ ; },
abstract = {PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs originally identified for their role in transposon silencing in germ cells, have recently been recognized as pivotal regulators of gene expression in the central nervous system. Beyond their canonical functions in genome defense, emerging evidence highlights piRNAs as key modulators of neuronal development, synaptic plasticity, axonal regeneration, and neuroimmune interactions-processes central to brain function and dysfunction. This review provides a comprehensive overview of piRNA biogenesis, molecular mechanisms, and regulatory pathways relevant to neurobiology. We focus on the growing body of evidence implicating piRNA dysregulation in major neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, glioma, autism spectrum disorder, and schizophrenia. Importantly, we discuss the neuropharmacological implications of piRNA pathways as novel targets for therapeutic intervention and their potential utility as biomarkers for early diagnosis and treatment stratification. By integrating mechanistic insights with emerging translational evidence, this review highlights piRNAs as promising molecular targets in the development of next-generation neurotherapeutics aimed at modifying disease progression and improving brain health.},
}

@article {pmid41181807,
year = {2025},
author = {Richardson, DL and Whitney, E},
title = {Deep Brain Stimulation: Overview and Applications in the Context of Neuropsychiatric Conditions.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e93661},
pmid = {41181807},
issn = {2168-8184},
abstract = {Deep brain stimulation (DBS) is a neuromodulatory therapy involving the implantation of electrodes into brain structures in order to help normalize brain activity in a variety of neurological disorders. The mechanisms of DBS operate at micro-, meso-, and macroscale levels to influence neuronal signaling, synaptic reorganization, and network-wide connectivity between brain regions. Recent advances in connectomics and sensing technologies have allowed for more precise and adaptive stimulation strategies, increasing the potential to target complex, heterogeneous neuropsychiatric conditions. DBS has already been well-explored as a treatment for obsessive-compulsive disorder. Emerging research has explored the use of DBS for other neuropsychiatric conditions as well, including autism spectrum disorder (ASD), treatment-refractory depression (TRD), and dementia associated with Alzheimer's disease (AD). DBS for ASD shows promise in reducing self-injurious behaviors and aggression by targeting the nucleus accumbens (NAc), amygdala, and posteromedial hypothalamus. In TRD, DBS to the subcallosal cingulate gyrus (SCG), medial forebrain bundle (MFB), and ventral capsule/ventral striatum (VC/VS) has demonstrated significant antidepressant effects. For dementia and AD, DBS targeting the fornix and nucleus basalis of Meynert (NBM) has shown promise in slowing cognitive decline. Despite the variety of targets, connectomic analyses reveal overlapping cortical-subcortical network dysfunctions across these disorders. These findings offer insight into shared neurobiological mechanisms of these disorders, as well as guide refinement of therapeutic targets for future study. Overall, DBS for neuropsychiatric conditions remains in its early stages, hindered by disorder heterogeneity and challenges in identifying optimal brain targets. Advances in functional neuroimaging, closed-loop stimulation, and machine learning-driven connectomic approaches can aid in target selection as well as better understanding the neuroanatomy and physiology underlying these complex conditions, which, in turn, lead to improved patient outcomes. Further research is necessary to establish standardized protocols and expand the therapeutic applications of DBS in neuropsychiatry.},
}

@article {pmid41181790,
year = {2025},
author = {Iyer, PJ and Soni, A and Waheed, N and Abboud, E and Deesawala, A and Clementina, R and Hazir, M and Chunawala, P and Jatin, CP and Vejju, S and K, V and Gedda, H and Vats, B and Devella, SG and Reddy, Y and Khan, U},
title = {Exploring Alzheimer's Awareness: A Content Quality and Reliability Assessment.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e93705},
pmid = {41181790},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with significant public health implications. Social media platforms like Instagram have emerged as influential tools for health communication, yet the quality and reliability of content remain variable. This study aimed to systematically evaluate the nature, accuracy, reliability, and overall educational quality of AD-related content disseminated on Instagram, to determine whether the information provided is evidence-based, appropriately sourced, and suitable for public health education. A cross-sectional observational study was conducted over 20 days in January 2025, analyzing posts from six popular Alzheimer's-related hashtags. A total of 600 posts were screened, of which 288 met the inclusion criteria. Posts were assessed for type, uploader category, content category, factual accuracy, Global Quality Score (GQS), and Reliability Score. Statistical comparisons were made between two groups of posts based on content accuracy and quality. Among the 288 posts analyzed, 162 (56.25%) were images and 126 (43.75%) were videos. Doctors (90, 30.94%) and researchers (82, 28.47%) were the most common uploaders. The majority of posts focused on etiology (66, 22.19%), prevention (60, 20.88%), and symptoms (60, 20.88%). Only 120 (51.9%) posts in Group A were factually accurate, compared to 22 (38.59%) in Group B (P < 0.000001). The mean GQS and Reliability Score were significantly higher in Group A (2.28 ± 1.04 and 2.29 ± 1.21) than in Group B (1.93 ± 1.10 and 1.72 ± 1.09), indicating better quality and trustworthiness of content. Instagram serves as a widely used platform for disseminating Alzheimer's-related information. However, the overall quality and reliability of content are suboptimal, with less than half of the posts being factually accurate. Healthcare professionals and researchers tend to produce more credible content, while posts from patients and non-medical users are less reliable. There is a pressing need to promote the creation and amplification of evidence-based, high-quality content to enhance public understanding and support for AD.},
}

@article {pmid41181519,
year = {2025},
author = {Shou, Q and Cen, S and Chen, NK and Ringman, JM and Kim, H and Jack, CR and Borowski, BJ and Senjem, ML and Arani, A and Wang, DJJ and , },
title = {Generative diffusion model enables quantification of calibration-free arterial spin labeling perfusion magnetic resonance imaging data in an Alzheimer's disease cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70214},
pmid = {41181519},
issn = {2352-8729},
abstract = {INTRODUCTION: M0 images were missing in Siemens ASL data in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, prohibiting cerebral blood flow (CBF) quantification.

METHODS: A conditional latent diffusion model was trained and evaluated on in-house datasets, then applied to the Siemens data in ADNI-3. Regional CBF differences by Alzheimer's disease (AD) stages, their accuracy for AD classification, and CBF trajectory slopes were compared between generated data (Siemens) and acquired data (General Electric).

RESULTS: The diffusion model generated M0 images with high fidelity (SSIM = 0.918 ± 0.023, PSNR = 31.361 ± 2.537) and minimal CBF bias (mean difference is 0.21 ± 1.58 mL/100 g/min). Both generated and acquired CBF showed similar spatial patterns and decreasing trends with AD progression in specific AD-related regions. Generated CBF also improved accuracy in classifying AD stages compared to qualitative perfusion images.

CONCLUSION: This study shows the potential of diffusion models for imputing missing modalities in large-scale studies exploring the use of ASL as a biomarker of AD.

HIGHLIGHTS: Using latent diffusion model, we can generate M0 image from control image in arterial spin labeling (ASL) with high fidelity.The generated M0 can be used for cerebral blood flow (CBF) quantification in Alzheimer's Disease Neuroimaging Initiative dataset.The performance of classification between Alzheimer's disease (AD) patients and cognitive normal people is better when using generated CBF maps than using non-quantitative perfusion images.ASL CBF decreases with AD progression in key AD-related brain regions.},
}

@article {pmid41181030,
year = {2025},
author = {Gray, AJ and Robinson, RE and Berghol, SA and Rosene, DL and Moore, TL and Bigio, IJ},
title = {Birefringence microscopy enables rapid, label-free quantification of myelin debris following induced cortical injury.},
journal = {Neurophotonics},
volume = {12},
number = {4},
pages = {045006},
pmid = {41181030},
issn = {2329-423X},
abstract = {SIGNIFICANCE: Myelin breakdown is prevalent in a range of neurodegenerative diseases, aging, and following various forms of trauma. Yet, current imaging techniques have limited capacity for large-scale study of myelin structural damage. A high-throughput, quantitative imaging method would greatly enhance our understanding of myelin degradation in different contexts.

AIM: We aim to establish birefringence microscopy (BRM) as a high-throughput, label-free imaging technique for large-scale, quantitative assessment of myelin pathology in post-mortem brain tissue. BRM has the capacity to provide rapid myelin imaging, which will provide information complementary to other myelin imaging techniques.

APPROACH: BRM enables label-free structural imaging of myelin with high spatial resolution. We leverage the high-throughput imaging capability of BRM to characterize the distribution of myelin pathology in a rhesus monkey model of cortical injury across the corpus callosum. This framework is applied at two different post-injury survival times (6 and 12 weeks).

RESULTS: We validate BRM for label-free structural imaging of myelin pathology across large regions of tissue (within the corpus callosum) using a fluorescent myelin stain and several immunohistochemical labels. Next, we train and validate a deep learning-based object detection network for automated identification of myelin pathology, using BRM, in the corpus callosum of monkeys with an induced cortical lesion. BRM, paired with deep learning, revealed significantly higher myelin damage through the corpus callosum, resulting from the lesion, in 6-week recovery monkeys compared with 12-week recovery and age-matched controls (P < 0.01). There was no significant difference between 12-week recovery monkeys and age-matched controls.

CONCLUSIONS: BRM enables large-scale assessment of myelin structural alterations in post-mortem brain tissue. When combined with deep-learning object detection, BRM enables rapid quantification of myelin damage in the corpus callosum after cortical injury. With proper training, this can be extended to study structural changes in other diseases and regions such as Alzheimer's disease and chronic traumatic encephalopathy as well as normal aging.},
}

@article {pmid41181014,
year = {2025},
author = {Srivastava, S and Ali, A and Kanika, and Samadder, P and Kumar, B and Mishra, AK and Khan, MR and Ali, N and Son, YO and Khan, R},
title = {Green synthesis of coconut coir-based carbon dots for efficient detection of ferric ions.},
journal = {RSC advances},
volume = {15},
number = {49},
pages = {41537-41545},
pmid = {41181014},
issn = {2046-2069},
abstract = {Iron (Fe) is an essential micronutrient for metabolic and physiological processes. Its dysregulation is associated with disorders such as Alzheimer's and hemochromatosis. Therefore, the development of cost-effective and selective probes for Fe(iii) detection is of significant clinical importance. In this study, fluorescent carbon dots derived from coconut coir (CCDs) were synthesized via a single-step hydrothermal method. The CCDs exhibited strong blue emission at 450 nm under 350 nm excitation and demonstrated selective fluorescence quenching in the presence of Fe(iii) ions, with a detection limit of 223.2 μM. HR-TEM revealed the particle size of CCDs ranged between 5.64 to 10 nm. XRD confirmed the crystalline nature. FTIR spectra indicated presence of hydroxyl and carboxyl groups contributing to dispersibility and surface passivation. Raman spectroscopy showed distinct D (1354 cm[-1]) and G (1582.61 cm[-1]) bands, characteristic of low-dimensional carbon nanostructures. Bioimaging and cytocompatibility studies in L929 fibroblast cells confirmed biocompatibility up to 500 μg mL[-1]. Collectively, these findings highlight the potential of CCDs as an effective fluorescent probe for Fe(iii) sensing and bioimaging applications in medical diagnostics. The CCDs were cytocompatible at concentrations up to 500 μg mL[-1].},
}

@article {pmid41180962,
year = {2025},
author = {Alkam, T and Tarshizi, E and Van Benschoten, AH},
title = {Red-flagging multimorbidity clusters for Alzheimer's disease risk using explainable machine learning: Evidence from a national emergency department sample.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251392474},
pmid = {41180962},
issn = {2542-4823},
abstract = {BACKGROUND: Emergency-department (ED) visits capture diagnostic data that could flag patients at heightened risk for Alzheimer's disease (AD) long before cognitive symptoms are formally recognized.

OBJECTIVE: To examine how age and multimorbidity interact to predict AD and to test whether explainable machine learning enhances risk stratification using national ED data.

METHODS: We analyzed 554,985 ED visits (2010-2014 National Emergency Department Sample) from adults ≥ 60 y. ICD-9-CM codes identified AD and 17 chronic conditions. Logistic regression estimated odds ratios (ORs) for single and combined comorbidities across five age bands. Predictive performance of logistic regression, decision tree, random forest and XGBoost was compared; Shapley Additive exPlanations (SHAP) interpreted model output.

RESULTS: Urinary-tract infection (UTI; OR = 2.74), depression (1.93), hypothyroidism (1.68) and anemia (1.57) independently increased AD odds. Possessing all four "red-flag" conditions tripled risk (OR = 3.31), and each additional red-flag raised risk by 74%. Age showed a steep gradient: relative to 60-65 y, ORs climbed from 2.58 (66-70 y) to 25.8 (86-90 y; all p < 0.001). XGBoost performed best (AUC = 0.782; recall = 0.821), and SHAP confirmed age and red-flag multimorbidity as dominant predictors.

CONCLUSIONS: Routine ED codes reveal an age-dependent, dose-response relationship between specific multimorbidity clusters and AD. An interpretable XGBoost model accurately identifies high-risk patients, outlining a practical pathway for real-time cognitive-risk alerts in acute-care settings.},
}

@article {pmid41180961,
year = {2025},
author = {Wang, H and Mao, X and Liu, S and Zhang, J and Li, E and Song, Y and Li, H and Chang, L and Wu, Y},
title = {Effects of sleep deprivation on cognition and synaptic associated proteins in rodents: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251391704},
pmid = {41180961},
issn = {2542-4823},
abstract = {BACKGROUND: Sleep disorders are a significant risk factor for cognitive decline and Alzheimer's disease (AD). However, preclinical studies investigating the effects of sleep deprivation (SD) on cognition and synaptic proteins have produced inconsistent findings, hindering translational progress.

OBJECTIVE: This systematic review and meta-analysis identify key factors moderating the effects of SD on cognition and synaptic proteins in rodent models.

METHODS: Following PRISMA guidelines, we analyzed 21 eligible studies using meta-analysis, subgroup, meta-regression, and multilevel analyses to identify sources of experimental heterogeneity.

RESULTS: SD significantly reduced synaptic proteins overall. While the global effect on cognition was not significant, subgroup analyses revealed robust cognitive impairment in Wistar rats undergoing fragmented sleep, particularly when assessed by Morris water maze or novel object recognition tests. Key synaptic proteins (PSD-95, synaptophysin) were consistently reduced in the hippocampus and prefrontal cortex.

CONCLUSIONS: Our comprehensive review synthesizes diverse studies, concluding that methodological choices are the primary drivers of heterogeneity in preclinical SD research. We provide evidence-based guidance for selecting appropriate rodent models, behavioral paradigms, and biochemical indicators to investigate the molecular mechanisms linking sleep disorders and cognitive decline. This work offers a significant framework to standardize and enhance the reliability of preclinical studies. By validating models that directly connect fragmented sleep-a condition common in AD patients-to synaptic pathology in vulnerable brain regions, our research strengthens the mechanistic link between sleep disturbance and cognitive impairment in AD and encourages a greater focus on this critical relationship for the readers of the Journal of Alzheimer's Disease Reports and AD researchers.},
}

@article {pmid41180960,
year = {2025},
author = {Morales, AL and Andrade, LD and Bronberg, R and Ramallo, V and Figueroa, MI and Dipierri, JE},
title = {Geospatial and temporal disparities in Alzheimer's disease deaths in Argentina.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251391705},
pmid = {41180960},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) and other dementias are currently among the leading causes of morbidity and mortality worldwide.

OBJECTIVE: To analyze the spatial and temporal behavior of AD mortality in Argentina.

METHODS: This is a retrospective eco-epidemiological study based on the Death Certificate between 1997-2017 provided by the Ministry of Health. The specific death rates (SDRs) related to AD were calculated per 1000 deaths (AD*1000) by gender and age at departmental, provincial, and regional levels for the entire period. The Join Point method was applied to analyze the temporal trend, and SaTScan software was used to establish geospatial disparities.

RESULTS: The highest SDRs were recorded in the departments, provinces, and regions located in the center of the country. At all administrative levels, female SDRs were almost twice as high as male SDRs. A positive secular trend in SDR was observed in all regions, with a significant increase between 1997-2002 and a less pronounced increase between 2003-2017. Clusters with the highest relative risks of AD death were located in the center of the country.

CONCLUSIONS: Following the global pattern, Argentina and all its regions show an increasing trend of AD deaths, with higher rates among women and older age groups. However, notable geospatial disparities attributed to population dynamics, migrations, and regional socioeconomic characteristics were identified.},
}

@article {pmid41180959,
year = {2025},
author = {He, L and Rao, Y and Wang, J and Yang, F},
title = {Association between self-reported sensory impairments and low cognitive performance in older adults: A cross-sectional study based on National Health and Nutrition Examination Survey (NHANES).},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251392551},
pmid = {41180959},
issn = {2542-4823},
abstract = {BACKGROUND: Early identification of risk factors is vital for the control of cognitive degenerative diseases, and sensory impairments could be potential candidate indicators.

OBJECTIVE: To determine whether self-reported hearing loss (HL), olfactory dysfunction (OD), and gustatory dysfunction (GD) are associated with low cognitive performance.

METHODS: Cross-sectional data from the 2011-2012 National Health and Nutrition Examination Survey (NHANES) were used. Data on participants' subjective hearing ability, olfactory and gustatory status were obtained from corresponding questionnaire datasets. Cognitive function was measured by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). The lowest quartile score of the four tests was used as the cutoff value to indicate low cognitive performance. Univariate and multivariate logistic regression analyses were conducted to investigate the association between sensory impairments and cognitive decline.

RESULTS: The data of 1416 adults aged ≥60 years were included. Univariate logistic regression analyses showed that the association between self-reported HL, OD, GD, and low cognitive performance was significant across all four cognition tests. Multiple models of multivariate logistic regression adjusted by covariate factors were established and showed significant association between self-reported HL, OD, GD, and low cognitive performance.

CONCLUSIONS: Self-reported hearing loss, olfactory and gustatory dysfunction demonstrated significant associations with impaired cognitive performance in older adults. Multiple sensory impairments may lead to progressively worse cognitive performance.},
}

@article {pmid41180958,
year = {2025},
author = {Libard, S and Alafuzoff, I},
title = {Tar DNA binding protein 43, a proteinopathy with preference for olfactory structures in COVID-19 subjects.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251386016},
pmid = {41180958},
issn = {2542-4823},
abstract = {BACKGROUND: Olfactory impairment (OI) is an early symptom of neurodegenerative diseases (ND) and COVID-19 infection. Proteinopathies associated with ND include amyloid-β (Aβ), hyperphosphorylated τ (HPτ), α-synuclein (α-syn), and Tar DNA binding protein 43 (TDP43). It is unclear whether COVID-19 infection influences the listed proteinopathies in the olfactory bulb and tract (OB/OT) aggravating the OI.

OBJECTIVE: To study proteinopathies associated with ND in the brain and OB/OT in 32 subjects with COVID-19 infection and 10 age- and gender-matched controls.

METHODS: Postmortem brain tissue was assessed for various proteinopathies and the OB/OT for proteinopathies, inflammatory markers and a marker for severe acute respiratory syndrome coronavirus 2 spike protein.

RESULTS: Twenty percent of control and 16% of COVID-19 subjects lacked proteinopathies in their OB/OT. HPτ was detected in OB/OT in 80% of controls and 81% of COVID-19 subjects, Aβ in 30% of controls and 16% of COVID-19 subjects. All controls lacked TDP43 in OB/OT, 40% displayed TDP43 in their brain. TDP43 was seen in the OB/OT in 38% of COVID-19 subjects, of whom 42% lacked TDP43 in the brain. Sixty percent of controls displayed α-syn in OB/OT and the brain, whereas 34% of COVID-19 subjects displayed α-syn in the OB/OT, of whom 36% lacked it in the brain.

CONCLUSIONS: All proteinopathies associated with ND were detected in OB/OT in COVID-19 patients whereas TDP43 was lacking in controls. Our results suggest that there might be an association between COVID-19 and TDP43 and α-syn in the OB/OT, which may explain the chronic OI.},
}

@article {pmid41180957,
year = {2025},
author = {Pulukuri, SV and Spurlock, EE and Tuz-Zahra, F and Tripodis, Y and Sampani, K and Nicks, R and Meng, G and Alvarez, VE and McKee, AC and Xia, W and Mordes, DA and Subramanian, ML and Stein, TD},
title = {Vitreous STMN2 levels reflect TDP-43-associated neurodegeneration in postmortem eyes and brains.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251392553},
pmid = {41180957},
issn = {2542-4823},
abstract = {Stathmin-2 (STMN2) levels decline in brains with transactive response DNA binding protein-43 (TDP-43) inclusions. TDP-43-related changes could extend to ocular structures, although vitreous STMN2 levels remain uncharacterized. This exploratory study analyzed 72 post-mortem brains and eyes depending on the presence or absence of TDP-43 inclusions in the brain and across neuropathological diagnostic groups (Alzheimer's disease [AD], chronic traumatic encephalopathy [CTE], AD and CTE, or neither). Results showed decreased vitreous STMN2 levels in TDP-43-positive cases but no association with diagnostic groups. Vitreous STMN2 was correlated with vitreous neurofilament light chain. Diminished vitreous STMN2 levels might indicate TDP-43-associated neurodegeneration.},
}

@article {pmid41180956,
year = {2025},
author = {Marmor, A and Meiner, Z and Kahana Merhavi, S and Vakil, E},
title = {Cognitive reserve as a predictor of cognitive decline, but not age of diagnosis in patients with possible young-onset Alzheimer's disease: An underexplored population.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251383903},
pmid = {41180956},
issn = {2542-4823},
abstract = {BACKGROUND: The cognitive reserve (CR) theory aims to explain the disparity often observed between brain damage and its clinical manifestation.

OBJECTIVE: To explore the CR theory in young-onset Alzheimer's disease (YOAD), a population not previously investigated in this context. The goal is to assess whether, similar to late-onset Alzheimer's disease (LOAD), a high CR delays diagnosis but may accelerate cognitive decline.

METHODS: This is a retrospective study including 72 patients (ages: 46-64) who were diagnosed with possible YOAD. They were followed up for three years, using the Mini-Mental State Examination.

RESULTS: Unlike the findings with LOAD, age of diagnosis of the YOAD did not correlate significantly with CR variables, years of education or family size. However, years of education predicted greater cognitive decline in the first year, and women showed increased deterioration. Family size showed inconsistent associations, highlighting its limitations.

CONCLUSIONS: In contrast to studies among LOAD, there was no significant correlation between age of diagnosis and CR among YOAD, suggesting that other mechanisms might be more influential than CR parameters in younger individuals. However, similar to LOAD, YOAD patients with higher education experienced faster disease progression, implying that diagnoses are frequently made when brain pathology is already severe. These findings reinforce the growing perspective that YOAD and LOAD may constitute distinct forms of AD, each with unique clinical and pathological features. They also underscore the urgent need for early detection tools and cognitive interventions to ease the challenges faced by these young patients.},
}

@article {pmid41180953,
year = {2025},
author = {Nabizadeh, F},
title = {Apolipoprotein E gene allele 4 and amyloid-beta mediate tau-related network breakdown.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf404},
pmid = {41180953},
issn = {2632-1297},
abstract = {There have been reports of altered functional connectivity in Alzheimer's disease, which is associated with the buildup of pathogenic proteins in the brain, including neurofibrillary tau tangles and amyloid-beta plaques. It is believed that the tau aggregates are the main driver of functional disconnection and resulted in cognitive decline in Alzheimer's disease. Tau propagates through connected neurons, a phenomenon often described as the 'prion-like' properties of tau, which can locally result in functional connectivity disruption. Apolipoprotein E gene allele 4 status and amyloid-beta are accelerating factors for tau-related pathological changes in Alzheimer's disease. However, the potential role of apolipoprotein E gene allele 4 and amyloid-beta in mediating the tau-related functional disconnection is not clear. I aimed to investigate the mediating effect of apolipoprotein E gene allele 4 and amyloid-beta on the local association of tau spreading on functional connections. I analysed follow-up resting-state functional MRI (fMRI) (non-baseline visit) and longitudinal tau-PET data from 211 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and 138 healthy elderly individuals from the Harvard Aging Brain Study (HABS). The follow-up resting-state fMRI (non-baseline visit) was studied in order to study the time needed effect of tau pathology. The top 10 regions with the highest probability-weighted SUVR values using Gaussian mixture models were selected as individual-level tau-PET epicentres. I looked at how the relationship between functional connectivity to epicentres and individualized connectivity-related tau spreading was mediated by amyloid-beta status and the apolipoprotein E gene allele 4 genotype. Higher rates of tau aggregation accumulation were seen in areas with stronger connectedness (shorter distance-based connectivity) to the baseline-defined tau epicentres. Moreover, the association between functional connectivity to epicentres and tau spreading through functional connections was mediated by apolipoprotein E gene allele 4 and amyloid-beta status in both dataset's participants. Tau aggregates spread through functional connections and locally disrupt connectivity between tau epicentre and non-epicentre regions, which is mediated in apolipoprotein E gene allele 4 carriers and amyloid-beta-positive participants. These findings have implications for trial designs, proposing that apolipoprotein E gene allele 4 carriers and amyloid-beta-positive participants might need earlier intervention to attenuate tau spreading and tau relative functional disconnection.},
}

@article {pmid41180952,
year = {2025},
author = {Zammit, M and Price, J and Christian, B and Rafii, M and , },
title = {A comparison of multiple amyloid PET radiotracers for Down syndrome clinical trials.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf406},
pmid = {41180952},
issn = {2632-1297},
abstract = {Adults with Down syndrome carry high risk of developing Alzheimer's disease and efforts to include this population in clinical trials remain limited. A barrier to recruitment for anti-amyloid trials includes the availability of the same amyloid PET radiotracer to multiple treatment centres. The objective of the study is to compare longitudinal rates of change between different amyloid PET radiotracers, particularly Pittsburgh compound B and florbetapir, in Down syndrome and to compare the estimated age at amyloid-positivity derived from these radiotracers. Two hundred thirty-seven adults with Down syndrome from the Trial Ready Cohort-Down syndrome and Alzheimer's Biomarker Consortium-Down syndrome studies were imaged using T1-weighted MRI and using PET images of Pittsburgh compound B, florbetapir, NAV4694 or flutemetamol to screen for amyloid plaque burden. Currently, Pittsburgh compound B and florbetapir have longitudinal data from these cohorts, while NAV4694 has one individual with longitudinal scans and flutemetamol has no available longitudinal data. Pittsburgh compound B displayed a greater effect size to measure amyloid change compared to florbetapir. NAV4694 and Pittsburgh compound B, which are structurally similar compounds, displayed similar sensitivity to measure longitudinal amyloid increase. The estimated age at amyloid onset showed no significant difference between Pittsburgh compound B, florbetapir, NAV4694 or flutemetamol. The findings suggest that different amyloid PET radiotracers provide consistent estimates of amyloid onset age for adults with Down syndrome. Multicentre studies of Alzheimer's disease therapeutics can utilize multiple amyloid PET radiotracers to facilitate recruitment; however, these radiotracers have different sensitivity to detect longitudinal change.},
}

@article {pmid41180905,
year = {2025},
author = {Omar, H and Yetman, L and Tranchant, CC and Gallibois, M and Haché, JC and Faig, K and Handrigan, G and McGibbon, C and Jarrett, P},
title = {"It's About Connections": A Grounded Theory of Older Adults' Engagement in Remotely Delivered Home-Based Physical and Cognitive Exercise Interventions Aiming to Reduce the Risk of Dementia.},
journal = {Journal of patient experience},
volume = {12},
number = {},
pages = {23743735251392324},
pmid = {41180905},
issn = {2374-3735},
abstract = {Physical exercise and cognitive training have the potential to enhance cognitive function and mobility in older adults at risk of dementia. However, little is known about the experience of receiving such interventions in the home settings of older adults. Fifteen participants (mean age 70.8 years) who completed the 16-week interventions of SYNERGIC@Home feasibility trial were interviewed to understand participants' engagement in home-based physical and cognitive exercise interventions delivered one-on-one through videoconferencing. Grounded theory data analysis was completed collaboratively by qualitative researchers. Results show that participants' engagement was driven by personal connection to dementia and mediated by relationships fostered largely with individual exercise trainers. Participants were also invested in the greater good (wanting their participation to make a difference to dementia research), their own outcomes, or their family's and society at large. Overall, they reflected on their participation as a rich learning experience. We propose that the quality of interpersonal connections and personalized support are of primary importance for older adults to stay engaged in physical exercise and cognitive training programs delivered remotely. SYNERGIC@Home trial registration number: NCT04997681, https://clinicaltrials.gov/study/NCT04997681.},
}

@article {pmid41180843,
year = {2025},
author = {Ceccarelli, MC and Lai, L and Carmignani, A and Battaglini, M and Ciofani, G},
title = {Polydopamine nanoparticles as immunomodulators: inhibition of M1 microglial polarization.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {13},
number = {},
pages = {1672520},
pmid = {41180843},
issn = {2296-4185},
abstract = {Neuroinflammation is a central feature of numerous neurodegenerative diseases, including Alzheimer's and Parkinson's disease, where excessive activation of microglia can contribute to neuronal damage. The pro-inflammatory M1 phenotype of microglia is characterized by increased production of reactive oxygen species (ROS), overexpression of surface markers such as CD40 and CD86, and secretion of cytokines like IL-6, IL-8, and TNF-α, all of which exacerbate oxidative stress and neurodegeneration. The development of strategies to control and tune microglial pro-inflammatory activation is therefore critical for reducing the progression of these conditions. In this study, the potential of polydopamine nanoparticles (PDNPs) as novel immunomodulatory agents for attenuating M1 microglial polarization was investigated. PDNPs were synthesized via a simple and reproducible protocol and thoroughly characterized in terms of size, morphology, hydrodynamic diameter, and surface charge, confirming their uniformity and stability. Biocompatibility assays showed that PDNPs are well tolerated by human microglial clone 3 (HMC3) cells, with minimal cytotoxicity even at relatively high concentrations. Confocal microscopy and flow cytometry analyses demonstrated efficient internalization of PDNPs by microglia, with preferential accumulation in lysosomal compartments and negligible mitochondrial localization. To mimic neuroinflammatory conditions, HMC3 cells were stimulated with interferon-gamma (IFN-γ), which significantly increased intracellular ROS levels, surface expression of CD40 and CD86, and secretion of pro-inflammatory cytokines. The co-treatment with PDNPs effectively mitigated these effects by reducing oxidative stress, suppressing the upregulation of M1 markers, and decreasing cytokine release, thereby preventing the shift toward a pro-inflammatory state. The results of this work demonstrate that PDNPs not only exhibit excellent biocompatibility and cellular uptake but also provide a robust means of counteracting IFN-induced microglial activation. These results establish PDNPs as promising nanoplatforms for modulating neuroinflammation and microglial activation. This study highlights the potential of PDNPs for future applications in the treatment of neurodegenerative diseases.},
}

@article {pmid41180815,
year = {2025},
author = {Gephine, L and Corvaisier, S and Bernay, B and Freret, T and Leger, M},
title = {LOU/c/jall rat as a model of resilience in the context of streptozotocin-induced cognitive impairment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1666397},
pmid = {41180815},
issn = {1663-4365},
abstract = {INTRODUCTION: The concept of cognitive resilience (CR) has emerged to explain the lack of correlation between the extent of brain lesions and the severity of cognitive symptoms in Alzheimer's disease (AD), but the underlying mechanisms remain poorly understood.

METHODS: To investigate this, we developed a preclinical model of CR using a sporadic model of AD in a specific rat strain named LOU/c/jall described as a successful aging model. LOU/c/jall and Wistar control rats were bilaterally injected with streptozotocin (STZ; 3 mg/kg) or a vehicle solution into the cerebral ventricles. Cognitive performance and neuropathological examinations were evaluated 1 month after surgery.

RESULTS: Our results showed that STZ-injected Wistar exhibited greater cognitive deficits than LOU/c/jall, despite similar brain alterations, revealing for the first time CR in the LOU/c/jall strain. Proteomic analysis identified differentially expressed proteins involved in the AD pathway between the two strains.

DISCUSSION: Understanding the role of these proteins in AD could improve our understanding of the brain mechanisms underlying CR and guide the development of more targeted therapeutic strategies.},
}

@article {pmid41180813,
year = {2025},
author = {Zhu, Y and Tu, Y and Ren, C and Ke, Y and Guo, Q},
title = {Elevated gonadotropins and risk of dementia in Chinese adults aged over 80: a cross-sectional study.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1651723},
pmid = {41180813},
issn = {1663-4365},
abstract = {INTRODUCTION: Age-related elevation of gonadotropins may contribute to cognitive decline, while apolipoprotein E epsilon 4 (APOE ε4) is an established risk factor for Alzheimer's disease (AD). This study investigated the associations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels with global cognition and dementia in adults aged over 80.

METHODS: A total of 509 adults (440 males and 69 females) were included in this cross-sectional analysis, comprising 337 with normal cognition (NC), 97 with Alzheimer's disease-related dementia (AD-D), and 75 with vascular dementia (VD). Cognitive status was assessed using Mini-Mental State Examination (MMSE). Plasma gonadotropins and sex hormones were measured by chemiluminescence. Multivariable linear and logistic regression models, adjusted for potential confounders, were employed.

RESULTS: Follicle-stimulating hormone concentrations were significantly elevated in males with dementia and females with VD compared to NC. LH concentrations were significantly elevated in VD across sexes compared with NC. Neither estradiol nor total testosterone differed across groups. Continuous LH, rather than FSH, was significantly associated with MMSE scores in the total cohort and males after adjusting covariates (both p < 0.05). When dichotomized by median (19.9 IU/L for males; 67.1 IU/L for females), FSH was significantly associated with MMSE after further adjusting for LH (both p < 0.05). A significant interaction between high FSH and APOE ε4 carrier status on cognitive impairment was observed (p < 0.05). After multivariate adjustment including LH, elevated FSH was independently associated with higher AD-D risk both when defined by median split (total sample: OR = 3.109; males: OR = 3.597) and as a continuous variable (total: OR = 1.033; males: OR = 1.048). In contrast, higher continuous LH was linked to lower AD-D risk in the total cohort and males, regardless of FSH adjustment. Neither FSH nor LH concentrations were associated with VD risk after adjusting for covariates. The area under the receiver operating characteristic curve for FSH in predicting AD-D in males was 0.600, with an optimal cutoff value of 28.4 IU/L.

CONCLUSION: Elevated FSH and reduced LH may be associated with poorer cognition and an increased risk of AD-D in very old Chinese adults, particularly in males.},
}

@article {pmid41180709,
year = {2025},
author = {Khan, A and Asghar, T and Yumn, L and Ishtiaq, S and Saeed, M and Ansari, RA and Fatima, M and Antar, M and Haider, MZ and Laghari, MA},
title = {Trends in hypertensive heart disease-related mortality among population with Alzheimer's in the United States: a 22-year nationwide analysis.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {11},
pages = {7325-7333},
pmid = {41180709},
issn = {2049-0801},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, while hypertensive heart disease (HHD) is a major cardiovascular condition linked to chronic hypertension (HTN). HTN is common among patients with AD, significantly impacting mortality. This study explores trends in HHD-related mortality among patients with AD in the US from 1999 to 2020, utilizing the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database.

METHODS: Data from the CDC WONDER database were used to extract mortality information for individuals aged ≥65 years, with AD and HHD as the underlying or contributing causes of death. Mortality rates were analyzed by age, sex, race/ethnicity, urban-rural classification, and region. Both crude- and age-adjusted mortality rates (AAMRs) were calculated. Joinpoint regression was employed to identify significant trends and changes in mortality over time.

RESULTS: HHD-associated mortality among patients with AD showed a significant upward trend, with deaths rising from 710 in 1999 to 3263 in 2020. The AAMR increased from 2.08 per 100 000 in 1999 to 6.26 per 100 000 in 2020, a threefold increase. Female patients had higher mortality rates than males throughout the study period. The highest mortality rates were observed in the age group of 85+ years, with notable regional disparities, particularly in the South and Midwest. The COVID-19 pandemic in 2020 contributed to a marked spike in mortality.

CONCLUSION: A concerning rise in HHD-related mortality among patients with AD, particularly in the last decade is observed. Significant disparities exist across demographic groups and regions. These findings highlight the need for public health interventions and policies to address the dual burden of AD and HHD.},
}

@article {pmid41180593,
year = {2025},
author = {Civita, E and Nicolella, V and Fiorenza, M and Cosimato, V and Castaldo, G and Morra, VB and Moccia, M and Terracciano, D},
title = {Advancing Clinical Use of Neurofilament Light Chain: Translational Insights From Research to Routine Practice.},
journal = {Biomarker insights},
volume = {20},
number = {},
pages = {11772719251364018},
pmid = {41180593},
issn = {1177-2719},
abstract = {Neurofilament Light Chain (NfL) has emerged as a promising biomarker for neurological diseases. NfL, a structural component of axons, is released into cerebrospinal fluid (CSF) and blood following neuro-axonal damage. Highly sensitive immunometric assays have enabled its reliable quantification in blood, facilitating non-invasive monitoring. Several studies demonstrated strong correlations between NfL levels and the risk of developing different neurological diseases and, in individuals already living with a neurological disease, with the risk of worsening. However, interpretation is affected by factors like age, BMI, renal function, and comorbidities. NfL is already utilized as a diagnostic and prognostic biomarker in clinical practice, particularly in specialized centers and research settings, although no FDA-cleared assay is currently available for routine use. Recent research has highlighted that NfL may represent the first of a new generation of neurological biomarkers, with many more ready to come, such as glial fibrillary acidic protein (GFAP), further improving diagnostic and prognostic accuracy. Despite its promising role in the landscape of biomarkers, challenges remain to implement NfL in daily clinical practice, including standardization of assays, defining reference values, and ensuring methodological consistency. Addressing these limitations will be essential for integrating NfL into routine clinical practice, ultimately advancing precision medicine in neurology.},
}

@article {pmid41180536,
year = {2025},
author = {Zhang, S and Wu, H and Ma, L and Li, R and Zhang, L and Liu, L and He, X and Zhao, T},
title = {The exploration of using plasma biomarkers of p-tau217 and p-tau181 for screening Alzheimer's disease in very elderly people.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1668512},
pmid = {41180536},
issn = {1664-2295},
abstract = {INTRODUCTION: Blood-based biomarkers for Alzheimer's disease (AD), such as phosphorylated tau (p-tau181, p-tau217) and amyloid beta (Aβ), have the potential to serve as screening tools for probable AD in the elderly population.

METHODS: AD screening [Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA)] was conducted among very elderly individuals residing in a nursing community and a geriatric hospital. Based on cognitive evaluation, participants were categorized into two groups: cognitively normal (n = 62) and probable AD (n = 78). Plasma concentrations of Aβ42, Aβ40, p-tau181, p-tau217, and glial fibrillary acidic protein (GFAP) were measured using the single molecule array (Simoa) platform. Group comparisons of plasma biomarker levels were performed, and receiver operating characteristic (ROC) curve analyses were conducted for each biomarker relative to AD diagnosis.

RESULTS: Significant differences were observed in plasma p-tau181, p-tau217, and GFAP levels between the cognitively normal and probable AD groups (p < 0.01). In contrast, Aβ42, Aβ40, and the Aβ42/Aβ40 ratio showed no significant differences (p > 0.01). The area under the ROC curve (AUC) was 0.886 for p-tau181, 0.655 for p-tau217, and 0.869 for GFAP.

DISCUSSION: Plasma biomarkers p-tau181, p-tau217, and GFAP demonstrate clinical utility in distinguishing AD from normal cognition, suggesting that blood-based testing may serve as a feasible screening tool for early identification of AD in very elderly populations.},
}

@article {pmid41180528,
year = {2025},
author = {Koike, T and Morita, A and Sekine, T and Sakai, T and Tsuchiya, T and Takenobu, A and Teraoka, A},
title = {SynthSR-generated 3D T1-weighted MRI from routine 2D clinical images: Validation for VSRAD analysis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1645891},
pmid = {41180528},
issn = {1664-2295},
abstract = {BACKGROUND: The Voxel-based Specific Regional Analysis System for Alzheimer's Disease (VSRAD), a voxel-based morphometry tool quantifying medial temporal lobe atrophy as region-specific Z-scores, is widely used in clinical practice for detection of Alzheimer's disease (AD). However, it typically require high-resolution 3D T1-weighted MRI, which is often difficult to acquire in elderly or cognitively impaired patients. This study aimed to evaluate whether 3D volumes generated by SynthSR from 2D T1-weighted MRI can yield volumetric and VSRAD-derived indices that are comparable to those from standard 3D images, by assessing agreement, rank consistency, and diagnostic performance.

METHODS: In this retrospective single-center study, MRI data from 75 patients were analyzed using both standard 3D T1-weighted images and SynthSR-generated 3D volumes reconstructed from 2D T1-weighted sequences. Regional brain volumes and four key Z-score indices from VSRAD were compared using Wilcoxon signed-rank tests with Bonferroni correction, robust Bland-Altman analysis, Spearman's rank correlation, and receiver operating characteristic (ROC) curve analysis focusing on Score 1 "Severity."

RESULTS: All Z-score indices and segmented volumes showed significant absolute differences between the two methods (p < 0.0071), with SynthSR-based data generally yielding larger volume estimates. Despite these differences, Spearman's ρ remained consistently high (ρ > 0.7) for brain volume and Score 3 "Ratio," and other clinically relevant indices also demonstrated moderate correlations. ROC analysis demonstrated high value of the area under the curve (AUC) values for both standard 3D volumes (0.90) and SynthSR-generated 3D volumes (0.96), with no statistically significant difference between the two methods (Z = 0.009, p = 0.99, DeLong's test).

CONCLUSION: Although SynthSR-based images produced systematically different absolute values, they preserved rank-order correlations and maintained diagnostic performance comparable to that of standard 3D volumes in VSRAD analysis. Considering that conventional 3D acquisitions are often difficult to obtain in elderly patients undergoing dementia screening, SynthSR-based reconstruction may represent a practical alternative in routine clinical practice, particularly for Score 1 "Severity," the most clinically relevant marker of hippocampal atrophy.},
}

@article {pmid41180498,
year = {2025},
author = {Shamsi, A and Alrouji, M and AlOmeir, O and Tasqeruddin, S and Dinislam, K and Zuberi, A},
title = {CRISPR-Cas9: bridging the gap between aging mechanisms and therapeutic advances in neurodegenerative disorders.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1681891},
pmid = {41180498},
issn = {1662-5102},
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, ALS, and spinocerebellar ataxia are becoming more prevalent as populations age, posing major global health challenges. Despite decades of research, effective treatments that halt or reverse these conditions remain elusive. Aging is the most significant risk factor in the development of these diseases, intertwining with molecular processes like DNA damage, mitochondrial dysfunction, and protein aggregation. Recent advances in gene-editing technologies, particularly CRISPR-Cas9, are beginning to shift the therapeutic landscape. This revolutionary tool allows for precise correction of genetic mutations associated with neurodegeneration, offering the potential for disease modification rather than symptom management alone. In this review, we explore how CRISPR-Cas9 is being leveraged to target key genes implicated in various neurodegenerative conditions and how it may overcome barriers posed by aging biology. We also examine the delivery systems and safety challenges that must be addressed before clinical application. With continued progress, CRISPR-Cas9 could mark a turning point in our ability to treat or even prevent age-related neurological decline.},
}

@article {pmid41180422,
year = {2025},
author = {Gu, SC and Sun, QY and Liu, HQ and Shen, CY and Su, H and Xie, F and Ye, Q},
title = {Omics-derived biological modules reflect tau positron emission tomography in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70172},
pmid = {41180422},
issn = {2352-8737},
abstract = {BACKGROUND: Tau neurofibrillary pathology is a hallmark of Alzheimer's disease (AD) and can be quantified in vivo using tau-selective positron emission tomography (tau PET). Tau PET signal closely correlates with cognitive decline and disease stage, yet the molecular networks underpinning tau accumulation remain incompletely defined.

METHODS: We performed multi-omics integration of proteomics, transcriptomics, and tau PET standardized uptake value ratios (SUVRs), and clinical assessments data from cognitively normal and cognitively impaired individuals. Using Light Gradient Boosting Machine (LightGBM), two-way orthogonal partial least squares, and network-based approaches, we explored key tau-associated proteomic signatures and constructed protein-protein interaction (PPI) modules. Module activities were quantified by gene set variation analysis and related to tau PET and cognition.

RESULTS: Among 60 regions, 15 tau PET imaging biomarkers were selected based on group differences, LightGBM importance, and cognitive relevance. Fifty key tau-associated proteins were identified and organized into four functional modules. PPI modules 1 (metabolic-cytoskeletal) and 3 (adhesion-nutrient sensing) exhibited strong associations with elevated tau PET uptake across selected cortical and limbic regions, as well as with cognitive impairment.

CONCLUSION: Distinct modules reflected regional tau PET burden and cognitive outcomes in AD, highlighting convergent disruptions in energy metabolism, cytoskeletal stability, and intercellular signaling.

HIGHLIGHTS: Integration of proteomics, transcriptomics, tau positron emission tomography (PET) imaging, and cognition in Alzheimer's disease.Fifteen key tau PET imaging biomarkers were prioritized.Fifty key tau-associated proteins were identified.Four distinct molecular networks contribute to regional tau pathology and cognition.Modules 1 (metabolic-cytoskeletal) and 3 (adhesion-nutrient sensing) strongly associated with tau PET burden and cognitive impairment.},
}

@article {pmid41179804,
year = {2025},
author = {Yang, L and Yu, H and Chai, GS},
title = {Aβ and tau clearance through aerobic exercise: unveiling the β2-adrenergic receptor's role in regulating autophagy-lysosomal pathways.},
journal = {Autophagy reports},
volume = {4},
number = {1},
pages = {2572512},
pmid = {41179804},
issn = {2769-4127},
abstract = {The systematic dissection of molecular mechanisms through which aerobic exercise (AE) mitigates neurodegenerative pathologies remains a significant challenge. Alzheimer's disease (AD) is characterized by impaired autophagy-lysosomal flux and the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. We recently identified the β2-adrenergic receptor (β2-AR) as a key mediator of exercise-induced bene = d sought to dissect its role in regulating distinct proteostatic pathways. We revealed that AE activates β2-AR signaling to promote lysosomal acidification via upregulation of VMA21, an essential assembly factor for the vacuolar ATPase (V-ATPase) proton pump, thereby facilitating Aβ clearance. Concurrently, AE enhanced autophagosome-lysosome fusion through the β2-AR - retinoid X receptor alpha (RXRα) - charged multivesicular body protein 4B (CHMP4B) axis, promoting tau degradation. Critically, pharmacological inhibition of β2-AR fully abolished these effects. Here, we propose an integrated mechanism through which β2-AR activation by AE could coordinate dual autophagy-lysosomal recovery processes and suggest that targeting this pathway offers a promising therapeutic strategy for AD and related proteostatic disorders.},
}

@article {pmid41179212,
year = {2025},
author = {Yuan, C and Lv, S and Han, Y and Li, Y and Xian, Z and Liu, G and Xiao, S},
title = {Quercetagitrin Ameliorates Alzheimer-Like Pathologies Associated with TNFα/NFκB Pathway in APP/PS1 Mice.},
journal = {ACS omega},
volume = {10},
number = {42},
pages = {49816-49827},
pmid = {41179212},
issn = {2470-1343},
abstract = {Background: Alzheimer's disease (AD) is a neurodegenerative disease with two pathological features in the brain: amyloid β (Aβ) plaques and tau tangles. Neuroinflammation plays an important role in the development of AD, closely related to both Aβ and tau pathologies. Tumor necrosis factor α (TNFα) and nuclear factor-κB (NFκB) behave as key regulators of neuroinflammation in AD. It is pressing to develop effective AD drugs. Objective: This study aimed to explore the effects and mechanisms of quercetagitrin in AD using a combination of network pharmacology analyses and in vivo experiments. Methods: The potential target of quercetagitrin in AD was predicted by network pharmacology. The interaction between the compound and the target protein was measured by molecular docking. The in vivo effects were performed in APP/PS1 mice via mouse behavior tests, Western blotting, ThS staining, immunohistochemical staining, and immunofluorescence staining. Results: First, network pharmacology analyses were conducted to predict the primary target of the compound, which is TNFα. Then, molecular docking showed that quercetagitrin interacts with TNFα with a high affinity. Finally, the level of TNFα was reduced, and the activation of NFκB signaling was inhibited by quercetagitrin in APP/PS1 mice. Meanwhile, quercetagitrin treatment ameliorated Aβ pathology, cognitive impairments, and neuroinflammation in the AD mice. Conclusions: These findings demonstrate quercetagitrin as a potential therapeutic drug for AD.},
}

@article {pmid41179172,
year = {2025},
author = {da Silva, LRG and de Sá, CB and do Amaral, BS and Romeiro, NC and Cass, QB and Valverde, AL},
title = {Affinity Selection-Mass Spectrometry for the Identification of Ligands of Acetylcholinesterase from Topsentia ophiraphidites and Docking Studies for the Dereplicated Ligands.},
journal = {ACS omega},
volume = {10},
number = {42},
pages = {50275-50284},
pmid = {41179172},
issn = {2470-1343},
abstract = {Acetylcholinesterase (AChE) inhibition has been successful for the treatment of Alzheimer's disease and still stands as an important target in the search for novel ligands. In this context, affinity selection-mass spectrometry (AS-MS) has been acknowledged as a high-throughput screening (HTS) technique for large molecular libraries in drug discovery programs and natural product investigations. In this work, an AS-MS assay with AChE immobilized onto magnetic beads (AChE-MB) has been used to search for ligands in samples of the sponge Topsentia ophiraphidites collected in the archipelago of Fernando de Noronha, Brazil. Ligand dereplication disclosed 6-desmethyl-6-ethyl-9,10-dihydrospongosoritin A, 3,5-dibromo-O-methyltyrosine, 3-bromo-5-iodo-O-methyltyrosine, and 3,5-di-iodo-O-methyltyrosine as AChE ligands, which showed affinity ratios of 1.84, 1.34, 1.26, and 1.20, respectively, in the AS-MS assay. As a complementary approach, molecular docking analysis with human AChE has been carried out for the disclosed dereplicated ligands, in which the (R, R) stereoisomer of 6-desmethyl-6-ethyl-9,10-dihydrospongosoritin A stood out, performing important intermolecular interactions with the active sites of AChE, especially with the peripheral anionic site, at the entrance of the gorge. The results stimulate further investigations of these ligands in other pharmacological assays in order to better understand their mechanisms of action.},
}

@article {pmid41178992,
year = {2025},
author = {Chen, B and Wang, Q and Wang, Y and Liu, Q and Chen, W and Mao, H and Li, J and Liu, Q and Zhou, X},
title = {Mitochondrial quality control in neurodegenerative diseases: from molecular mechanisms to natural product therapies.},
journal = {Frontiers in physiology},
volume = {16},
number = {},
pages = {1695681},
pmid = {41178992},
issn = {1664-042X},
abstract = {BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, etc., are a group of complex and heterogeneous disorders characterized by progressive synaptic loss and pathological protein alterations. Mitochondria are the main source of energy produced by neurons and support the high energy consumption of the nervous system. Mitochondrial quality control, involving processes like mitophagy and mitochondrial biogenesis, is crucial for mitochondrial homeostasis, and mitochondrial dysfunction is closely related to neurodegenerative diseases pathogenesis, making targeting mitochondrial quality control a potential therapeutic strategy. Natural products offer benefits such as cost-effectiveness, fewer side effects, and other positive qualities, making them suitable choices as supplements or alternatives to traditional drugs for treating neurodegenerative diseases.

METHODS: A thorough search was conducted on many databases including Web of Science, PubMed, EMBASE, and MEDLINE to investigate the role of mitochondria in neurodegenerative diseases and the therapeutic effects of natural products.

RESULTS: By searching the relevant studies on neurodegenerative diseases and mitochondria in recent years, we observed a rise in the number of studies examining the functional characteristics and biological events of mitochondrial quality control systems in neurodegenerative diseases pathogenesis and the potential for natural products regulating mitochondrial quality control to improve neurodegenerative diseases.

CONCLUSION: This review summarizes the functional characteristics and biological events of mitochondrial quality control systems in neurodegenerative diseases pathogenesis, and comprehensively analyzes the pharmacological mechanisms by which natural products regulate mitochondrial quality control to improve neurodegenerative diseases, aiming to provide a scientific basis for further research and new clinical drug development.},
}

@article {pmid41178976,
year = {2025},
author = {Bae, HJ and Kim, SI and Kim, SY and Cho, YE and Sung, S and Lim, S and Cho, K and Park, SJ and Lim, S},
title = {Lacticaseibacillus rhamnosus CBT LR5 with skim milk alleviates scopolamine-induced cognitive impairment in mice.},
journal = {Frontiers in microbiology},
volume = {16},
number = {},
pages = {1672153},
pmid = {41178976},
issn = {1664-302X},
abstract = {INTRODUCTION: Emerging evidence highlights the gut-brain axis as a pivotal pathway linking gastrointestinal health with cognitive function, particularly in neurodegenerative conditions such as Alzheimer's disease (AD).

METHODS: This study investigated the cognitive-enhancing effects of the probiotic strain Lacticaseibacillus rhamnosus CBT LR5 (LR5), alone or in combination with skim milk, in a mouse model of scopolamine-induced cognitive impairment. The cognitive functions were evaluated using the novel object recognition test (NOR) and the passive avoidance test (PAT).

RESULTS: The results demonstrated that the oral administration of LR5, especially when combined with skim milk, significantly ameliorated scopolamine-induced cognitive deficits. Mechanistically, treatment with LR5 combined with skim milk restored the diversity and composition of the gut microbiota increased the abundance of beneficial genera, such as Muribaculaceae and enhanced intestinal barrier integrity by increasing the expression of tight junction proteins, including claudin-1, occludin, and zonula occludens-1. Additionally, this combination reduced systemic inflammation by lowering serum TNF-α and PGE2 levels and promoted increased expression of BDNF by activating the CREB-BDNF-TrkB signaling pathway in hippocampal and cortical tissues. Furthermore, correlation analyses revealed significant associations between specific gut bacterial genera, such as Lacticaseibacillus, Turicibacter, Cryptobacteroides, Ruminococcus, and Muribaculaceae, and cognitive or inflammatory biomarkers.

DISCUSSION: Collectively, these findings suggest that the synergistic effects of L. rhamnosus CBT LR5 combined with skim milk may represent an effective dietary intervention for cognitive enhancement, potentially through gut microbiota modulation, improved barrier integrity, reduced inflammation, and enhanced neurotrophic signaling.},
}

@article {pmid41178777,
year = {2025},
author = {Yigitturk, G and Cavusoglu, T},
title = {A Review of The Place of Adipose-Derived Stem Cells among Stem Cell Applications in Neurodegenerative Diseases.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266363649250620113954},
pmid = {41178777},
issn = {1873-4294},
abstract = {Treatment of neurodegenerative diseases aims to slow disease progression, alleviate symptoms, and improve life quality. Adipose-Derived Stem Cells (ADSCs) have emerged as a promising treatment for neurodegenerative diseases that can be easily obtained from adipose tissues. Their abundance, accessibility, and potential for multilinear differentiation make them an attractive candidate for regenerative medicine. ADSCs can release neurotrophic factors, modulate neuroinflammation, and potentially differentiate into neurons, giving hope for neuronal repair and replacement. Preclinical studies have shown the efficacy of several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and spinal cord injuries. ADSC has demonstrated the potential to improve functional results, promote neurogenesis, induce tissue integrity, and reduce neuron loss. Clinical trials are still underway, but evidence of the effectiveness of ADSC in neurodegeneration is still being developed. The first clinical studies focused on safety and feasibility and achieved promising results. Optimizing cell transmission, controlling tumor growth, standardizing treatment protocols and such challenges remain. Current research is aimed at addressing these obstacles and transforming ADSC therapy into a widespread clinical practice. This review focuses on the characteristics, problems, and future approaches of ADSC in the context of neurodegenerative diseases and therapeutic processes.},
}

@article {pmid41178766,
year = {2025},
author = {Wang, Y and Hu, J and Zhu, Q and Wang, S and Yu, S},
title = {Emerging Potential of Ras-proximate-1 (Rap1) in Mediating Neurodegenerative Diseases.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X440842251020104840},
pmid = {41178766},
issn = {1875-6190},
abstract = {Neurodegenerative diseases have posed a rising global threat to the aging population, presenting structural and functional impairments in the central nervous system. These progressive disorders, which affect the brain and spinal cord, develop due to the continuous loss of neurons and myelin sheaths. Such specific pathophysiological changes lead to neurological dysfunction in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, resulting in typical motor dysfunctions and cognitive disorders, as well as symptoms like behavioral abnormalities and personality changes. To date, despite various treatments attempting to manage these symptoms, patients' quality of life remains severely deteriorated. A few effective therapeutics are available to mitigate the progression of neurodegenerative injuries. Increasing attention is now focused on molecular regulatory mechanisms, particularly the association between immune regulation and the neurovascular unit. A critical component in this process is Ras-proximate-1 (Rap1), a small Guanosine Triphosphatase (GTPase). Rap1 is determined to regulate glia-mediated immunoinflammatory responses, vascular endothelial function, and neuronal activity. It also modulates synaptic plasticity and mitochondrial function via autophagy-dependent modulation, which are significantly impacted during neuronal degeneration. Additionally, signaling pathways, including PI3K/Akt and ERK, are identified as its downstream effectors. Furthermore, by mediating the permeability of the blood-brain barrier, Rap1 probably influences neuroimmune-vascular modulation throughout the development of neurological disorders. In this review, we investigate recent studies to explore the emerging therapeutic potential of Rap1 in the inflammation-related regulation within neurodegenerative diseases. We also discuss novel treatments and possible targets, including natural medicines and genetic modulation, to enhance therapeutic effects and improve prognosis.},
}

@article {pmid41178759,
year = {2025},
author = {Paitel, ER and Pettigrew, C and Callow, DD and Moghekar, A and Miller, MI and Faria, AV and Oishi, K and Albert, M and Soldan, A},
title = {Cerebellar White Matter Microstructure Is Associated With Age, Cerebrospinal Fluid Amyloid Beta Levels, and Cognition in Cognitively Unimpaired Older Adults.},
journal = {Human brain mapping},
volume = {46},
number = {16},
pages = {e70398},
doi = {10.1002/hbm.70398},
pmid = {41178759},
issn = {1097-0193},
support = {P30-AG066507/AG/NIA NIH HHS/United States ; T32-AG027668/AG/NIA NIH HHS/United States ; U19-AG033655/AG/NIA NIH HHS/United States ; U19-AG065169/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; Male ; Female ; *White Matter/diagnostic imaging/pathology/anatomy & histology ; Middle Aged ; Aged, 80 and over ; *Cerebellum/diagnostic imaging/pathology ; *Aging/pathology/physiology ; Magnetic Resonance Imaging ; tau Proteins/cerebrospinal fluid ; Adult ; *Cognition/physiology ; Executive Function/physiology ; Peptide Fragments/cerebrospinal fluid ; Gray Matter/diagnostic imaging/pathology ; Biomarkers/cerebrospinal fluid ; },
abstract = {Structural changes in the cerebellum contribute to cognitive decline due to aging and Alzheimer's disease (AD). However, it is unclear whether age and AD pathology are associated with structural alterations in the cerebellum among cognitively unimpaired individuals and how these alterations relate to cognition. This study examined the association of age and cerebrospinal fluid (CSF) AD biomarkers (amyloid beta [Aβ42/Aβ40], phosphorylated tau [p-tau181]) with cerebellar gray matter (GM) and white matter (WM) volumes and cerebellar WM microstructure, measured via magnetic resonance imaging (MRI) among 176 cognitively unimpaired middle-aged and older adults (mean age = 66.70, range = 34-89). Cognition was measured with executive function and visuospatial composite scores. Older age was associated with lower cerebellar GM and WM volumes (ps < 0.01) and greater mean diffusivity (MD) in the cerebellar peduncles (p < 0.01). In contrast, more abnormal Aβ levels were associated with lower MD in three regions of interest, including the middle cerebellar peduncle (MCP, p < 0.01), a composite of superior, middle, and inferior peduncles (p < 0.05), and within-cerebellar WM (p < 0.05). Patterns were similar when comparing biomarker positive versus negative groups, particularly for the MCP. Further, lower MD in the peduncles and cerebellar WM was associated with better executive function and visuospatial composite scores (ps < 0.05), whereas cerebellar volumetric measures were not related to cognition. Results suggest that older age is associated with microstructural and volumetric cerebellar GM and WM alterations. In contrast, Aβ levels are associated with WM microstructural properties in cognitively unimpaired individuals. These findings highlight the importance of cerebellar WM microstructure to cognition and are consistent with, and expand on, previous reports that have linked more abnormal amyloid levels to WM microstructure in cerebral tracts. They also suggest that cerebellar WM alterations may be markers of preclinical AD.},
}

Humans
Aged
*Amyloid beta-Peptides/cerebrospinal fluid
Male
Female
*White Matter/diagnostic imaging/pathology/anatomy & histology
Middle Aged
Aged, 80 and over
*Cerebellum/diagnostic imaging/pathology
*Aging/pathology/physiology
Magnetic Resonance Imaging
tau Proteins/cerebrospinal fluid
Adult
*Cognition/physiology
Executive Function/physiology
Peptide Fragments/cerebrospinal fluid
Gray Matter/diagnostic imaging/pathology
Biomarkers/cerebrospinal fluid

@article {pmid41178698,
year = {2025},
author = {Bangs, MC and Gadhavi, J and Carter, EK and Ping, L and Duong, DM and Dammer, EB and Wu, F and Shantaraman, A and Fox, EJ and Johnson, ECB and Lah, JJ and Levey, AI and Seyfried, NT},
title = {Proteomic subtyping of Alzheimer's disease CSF links blood-brain barrier dysfunction to reduced levels of tau and synaptic biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70830},
doi = {10.1002/alz.70830},
pmid = {41178698},
issn = {1552-5279},
support = {U01AG061357/AG/NIA NIH HHS/United States ; R01AG070937/AG/NIA NIH HHS/United States ; P30AG066511/AG/NIA NIH HHS/United States ; T32AG087922/AG/NIA NIH HHS/United States ; //Foundation for the National Institutes of Health/ ; A2024029F//BrightFocus Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/classification ; *tau Proteins/cerebrospinal fluid ; *Proteomics ; Biomarkers/cerebrospinal fluid ; Male ; Female ; *Blood-Brain Barrier/physiopathology/metabolism ; Aged ; Black or African American ; Middle Aged ; Aged, 80 and over ; Synapses/metabolism ; White ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) shows clinical and molecular heterogeneity shaped by demographic and genetic factors.

METHODS: To resolve this heterogeneity, we performed a network-based proteomic analysis of cerebrospinal fluid (CSF) from 431 individuals, including 111 African Americans, to identify protein co-expression modules and define AD subtypes.

RESULTS: Ten co-expression modules reflecting diverse pathways and cell types were identified, many linked to demographics and AD biomarkers. One subtype, enriched in African Americans and males, showed low CSF tau, elevated plasma proteins, and reduced synaptic proteins, features consistent with blood-brain barrier (BBB) dysfunction. This subtype also showed the highest levels of thrombin activity, capable of cleaving tau. Introducing plasma into CSF ex vivo recapitulated the BBB subtype signature, supporting a causal role for plasma proteases in tau and synaptic protein depletion.

CONCLUSION: These findings link BBB dysfunction and plasma proteases to CSF tau loss and highlight the need for diversity in AD-biomarker research.

HIGHLIGHTS: Race and sex correlate with key AD proteomic network modules. We identify six proteomic subtypes with distinct demographic and AD biomarker profiles. Subtype 3 demonstrates an A+/T- phenotype and a profile suggestive of BBB dysfunction. Low CSF tau and neuronal proteins may stem from infiltrating plasma protease cleavage. Plasma spike-in experiments show decreased endogenous CSF tau and neuronal proteins.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/classification
*tau Proteins/cerebrospinal fluid
*Proteomics
Biomarkers/cerebrospinal fluid
Male
Female
*Blood-Brain Barrier/physiopathology/metabolism
Aged
Black or African American
Middle Aged
Aged, 80 and over
Synapses/metabolism
White

@article {pmid41178581,
year = {2025},
author = {Şen, İ and Yeşildal, TK and Abdulqadir, AH and Yaman, İ and Tosun, SN and Zengin, G and Cakmak, YS},
title = {Comprehensive evaluation of Onosma rostellatum: antioxidant, enzyme inhibitory and anticancer properties of root and leaf extracts.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70284},
pmid = {41178581},
issn = {1097-0010},
support = {//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; },
abstract = {BACKGROUND: The incidence and mortality of diseases such as cancer, Alzheimer's, and diabetes have increased in recent years. Along with limited treatment success, severe side effects of synthetic drugs are a major concern. Therefore, natural bioactive compounds are gaining attention as alternative therapeutic agents due to their efficacy and lower toxicity. This study investigated the protective and therapeutic potential of extracts of different parts of Onosma rostellatum, a plant used in traditional medicine, in terms of their antioxidant, enzyme inhibitory and anticancer activities.

RESULTS: Antioxidant, enzyme inhibition, anticancer activities and phenolic composition of the extracts were evaluated. Methanol leaf extract showed the strongest activity in antioxidant assays, with the highest 2,2-diphenyl-1-picrylhydrazyl (46.59 ± 0.03 g Trolox equivalents (TE) kg[-1]) and ferric reducing antioxidant power (90.74 ± 0.59 g TE kg[-1]) activities, while the root methanol extract exhibited the strongest 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical scavenging activity (453.86 ± 2.20 g TE kg[-1]) and the highest cupric reducing antioxidant capacity value (243.64 ± 0.49 g TE kg[-1]). The aqueous leaf extract demonstrated superior metal-chelating ability (32.59 ± 0.13 g ethylenediaminetetraacetic acid kg[-1]). Leaf extracts displayed the highest copper ion reducing capacity (94.64 ± 0.23 g TE kg[-1]). Ethyl acetate leaf extracts showed the most significant inhibition against α-amylase and α-glucosidase. High-performance liquid chromatographic analysis revealed rosmarinic acid and quercetin as major phenolic constituents. In cell culture experiments, the ethyl acetate leaf extract demonstrated the most potent anticancer effect, with an IC50 value of 167.2 ± 0.32 μg mL[-1] after 72 h.

CONCLUSION: Onosma rostellatum extracts possess strong antioxidant, enzyme inhibitory and anticancer activities, largely associated with their phenolic components. These findings highlight the potential of this plant as a natural source of therapeutic agents. © 2025 Society of Chemical Industry.},
}

@article {pmid41178353,
year = {2025},
author = {Raket, LL and Pichet Binette, A and Mattsson-Carlgren, N and Janelidze, S and Zetterberg, H and Ashton, NJ and Blennow, K and Stomrud, E and Palmqvist, S and Hansson, O},
title = {Estimating the time course of biomarker changes in Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf413},
pmid = {41178353},
issn = {1460-2156},
abstract = {Recent advancements in biomarkers have transformed Alzheimer's disease (AD) diagnosis from being purely symptom-based to include biological criteria. With new treatments targeting AD's core biology, understanding the timeline of biological changes is crucial as the disease progresses over decades. Longitudinal data from amyloid-beta (Aβ) PET and cognitive tests (MMSE and ADAS-cog) from the Alzheimer's Disease Neuroimaging Initiative (n=1,448) and BioFINDER (n=2,088) were used to stage patients against an estimated continuous disease timeline (predicted time since Aβ-PET positivity). The estimated timeline was validated by comparing correlations with unseen biomarkers and cognitive measures against alternative staging approaches. Trajectories for plasma, CSF, MRI, and PET biomarkers, measuring Aβ, tau, and neurodegeneration, were mapped along this AD continuum. The proposed staging approach was found to produce stronger correlations with unseen cognitive measures and biomarkers compared to alternative staging methods, including amyloid and tau PET clocks (all pairwise p<0.05). Findings related to biomarker trajectories were highly consistent across cohorts. The period from Aβ-PET positivity to end-stage AD dementia (MMSE = 0) was estimated at 20-25 years, with a presymptomatic phase of 7-11 years. CSF Aβ42/40 became abnormal about a year before Aβ-PET positivity, CSF p-tau231, p-tau217, and plasma p/np-tau217 1-3 years after, and tau-PET about 8 years after. Neurodegenerative biomarkers, such as hippocampal volume, became clearly abnormal in early dementia stages, 14-16 years after Aβ-PET positivity. The progression from initial biomarker abnormality to severe AD spans two decades. Disease progression modeling elucidates the evolution of AD biomarkers and cognition, highlighting the relative timing of biomarker abnormalities. These models can determine disease stages, aiding prognosis and evaluation for disease-modifying treatments.},
}

@article {pmid41178220,
year = {2025},
author = {Jang, YJ and Kim, H and Jung, JH and Han, K and Jeon, HJ},
title = {Changes in Smoking Status in Depressed Patients and the Risk of Dementia.},
journal = {The Journal of nervous and mental disease},
volume = {},
number = {},
pages = {},
doi = {10.1097/NMD.0000000000001849},
pmid = {41178220},
issn = {1539-736X},
support = {SMO1161491//Samsung Medical Center/ ; },
abstract = {INTRODUCTION: Smoking is a known risk factor for dementia, but the effects of changes in smoking behavior after a depression diagnosis remain unclear.

METHODS: We conducted a nationwide cohort study of 1,290,530 individuals newly diagnosed with depression in South Korea between 2009 and 2012. Participants were categorized by smoking status before and after diagnosis. Incident dementia, including Alzheimer disease (AD) and vascular dementia (VD), was tracked through 2018. Adjusted hazard ratios (HRs) were estimated using Cox models.

RESULTS: Continued smoking showed the highest dementia risk (HR 1.338 for all-cause; 1.323 for AD; and 1.524 for VD). Quitting reduced risk but remained higher than in persistent non-smokers. Middle age was a key risk period for AD. For VD, men had consistently higher risk, while women had increased risk only in the cessation group.

CONCLUSIONS: Changes in smoking behavior after depression diagnosis influence dementia risk, underscoring the need for cessation strategies.},
}

@article {pmid41178159,
year = {2025},
author = {Mosna, S and Dormann, D},
title = {TDP-43 Phosphorylation: Pathological Modification or Protective Factor Antagonizing TDP-43 Aggregation in Neurodegenerative Diseases?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e70084},
doi = {10.1002/bies.70084},
pmid = {41178159},
issn = {1521-1878},
support = {//Deutsche Forschungsgemeinschaft (DFG)/ ; //VERUM Foundation/ ; },
abstract = {TDP-43 is a ubiquitously expressed RNA-binding protein that aggregates in the brains of patients suffering from neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease. Aggregated TDP-43 in these diseases is hyperphosphorylated in its C-terminal intrinsically disordered region, while physiological TDP-43 is normally unphosphorylated. Whether TDP-43 phosphorylation is a pathological driver, or rather a protective antagonist of TDP-43 aggregation and consequently neurodegeneration, is still debated and a matter of ongoing research. Here, we review current knowledge about TDP-43 phosphorylation in disease and the kinases and phosphatases that regulate this post-translational modification. We discuss how TDP-43 phosphorylation is thought to shape TDP-43's phase separation, aggregation and toxicity in neurodegenerative diseases. We highlight recent research that provides evidence that hyperphosphorylation antagonizes TDP-43 phase separation and aggregation, and speculate about a potential role of condensates in TDP-43 phosphorylation.},
}

@article {pmid41178110,
year = {2025},
author = {Polk, S and Rassaeikashuk, M and Thilagavathi, R and Selvam, C},
title = {Targeting Poly (ADP-Ribose) Polymerase-1 for the Treatment of Neurodegenerative Diseases.},
journal = {Chemical biology & drug design},
volume = {106},
number = {5},
pages = {e70189},
doi = {10.1111/cbdd.70189},
pmid = {41178110},
issn = {1747-0285},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology/enzymology ; *Poly (ADP-Ribose) Polymerase-1/metabolism/antagonists & inhibitors ; alpha-Synuclein/metabolism ; Animals ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/chemistry/pharmacology ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Poly (ADP-ribose) Polymerase 1 (PARP1) has many functions that intertwine with the pathology of many diseases. Because of PARP1's function in DNA repair and cell death, neurodegeneration research is another pathology that PARP1 included. By PARylation, PARP1 acts as a direct and indirect modulator of amyloid β, α-Synuclein (α-syn), tau protein, and other proteins indicated in neurodegenerative diseases. PARylation influences the function, activation, and localization of these proteins. This review paper overviews neurodegeneration and the significant diseases resulting from neurodegeneration and compiles mechanisms and functions Poly (ADP-ribose) Polymerase-1 has in neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism/pathology/enzymology
*Poly (ADP-Ribose) Polymerase-1/metabolism/antagonists & inhibitors
alpha-Synuclein/metabolism
Animals
*Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/chemistry/pharmacology
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid41177994,
year = {2025},
author = {Hyde, Z and Flicker, L and Douglas, R and Rind, S and Rind, N and LoGiudice, D and Smith, K},
title = {Development of a Memory Clinic at an Aboriginal Community-Controlled Health Service: Profile of the First Patients.},
journal = {Australasian journal on ageing},
volume = {44},
number = {4},
pages = {e70106},
doi = {10.1111/ajag.70106},
pmid = {41177994},
issn = {1741-6612},
support = {//National Health and Medical Research Council/ ; //Medical Research Future Fund/ ; },
mesh = {Humans ; Female ; Male ; Aged ; Middle Aged ; Aged, 80 and over ; Adult ; *Health Services, Indigenous/organization & administration ; Western Australia/epidemiology ; *Cognitive Dysfunction/diagnosis/ethnology/therapy/psychology ; *Dementia/diagnosis/ethnology/therapy/psychology ; *Community Health Services/organization & administration ; *Memory ; },
abstract = {OBJECTIVES: Dementia is the leading cause of burden of disease in older Australians. Older Aboriginal and Torres Strait Islander people experience an increased risk of cognitive impairment and dementia. This article describes the clinical profile of the first patients seen at a memory clinic established in an Aboriginal community-controlled health service (ACCHS) in metropolitan Perth, Western Australia.

METHODS: This was an audit of 64 patients attending a memory clinic between March 2020 and February 2023 (inclusive).

RESULTS: The median age of patients was 67.7 years (range 35-95 years; interquartile range [IQR] 13.4 years) and 34 (53%) were female. The majority (94%) were living independently. Thirty-four patients (53%; 95% confidence interval 41%-65%) were diagnosed with cognitive impairment. A further six (9%) were diagnosed with depression without cognitive impairment. The most common diagnoses in cognitively impaired patients were cognitive impairment not dementia (CIND; 27%); mild neurocognitive disorder (21%); dementia due to Alzheimer's disease (15%); Alzheimer's disease dementia, mixed type (9%); and other mixed dementias (9%). Women were slightly more likely than men to have cognitive impairment (56% vs. 52%), although this was not statistically significant (p = 0.74). The number of Aboriginal people seen in the clinic's first 3 years of operation was over 12 times that seen at a nearby hospital-based service during the same period.

CONCLUSIONS: A memory clinic located within an ACCHS was well-attended and fulfilled a need not met by mainstream services. The successful model described in this article could be adopted by other Aboriginal health services.},
}

Humans
Female
Male
Aged
Middle Aged
Aged, 80 and over
Adult
*Health Services, Indigenous/organization & administration
Western Australia/epidemiology
*Cognitive Dysfunction/diagnosis/ethnology/therapy/psychology
*Dementia/diagnosis/ethnology/therapy/psychology
*Community Health Services/organization & administration
*Memory

@article {pmid41177895,
year = {2025},
author = {Au, R and Bose, N and Imam, F and Kolachalama, VB},
title = {Technological advances enabling an enhanced understanding of early Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70883},
doi = {10.1002/alz.70883},
pmid = {41177895},
issn = {1552-5279},
support = {RDADB-202104-2021750//Alzheimer's Drug Discovery Foundation/ ; 20SFRN35360180//American Heart Association/ ; AG083735/AG/NIA NIH HHS/United States ; AG072654/AG/NIA NIH HHS/United States ; AG062109/AG/NIA NIH HHS/United States ; AG083735/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Early Diagnosis ; Brain ; Precision Medicine ; },
abstract = {The aspirations of Alzheimer's disease (AD) precision medicine and precision brain health are not fully realized despite significant advances in early pathological detection. Hampering progress is the difficult challenge of the accurate detection of behavioral symptoms that can help differentiate those at high risk specific to AD versus those with more AD and related dementias (ADRD), who may have AD along with other types of dementia, as well as those who will and will not progress to clinically expressed disease. Technological advances in hardware, software, and analytics are paving the way to opportunities to overcome these long-standing barriers to early clinical symptom detection, when recent and emerging interventions might be most effective. It is important to note that these innovations must not exist in isolation. Integration of data from both AD/ADRD related studies and non-AD related studies is needed whenever brain-related measures are collected to fully realize the scientific opportunities. We envision a near future of harmonized participant data sharing, encompassing standardized multimodal data alongside emerging digital streams, to deliver an invaluable resource for the global research community. HIGHLIGHTS: Technology is overcoming barriers to accurate early detection of behavioral symptoms of AD/ADRD. The National Alzheimer's Coordinating Center is paving the way for the integration of technological advances into AD/ADRD research. A technologically-enabled framework provides a solution for open science on a global scale.},
}

Humans
*Alzheimer Disease/diagnosis
*Early Diagnosis
Brain
Precision Medicine

@article {pmid41177791,
year = {2025},
author = {Bolshakova, OI and Golomidov, IM and Latypova, EM and Ryabova, EV and Sarantseva, SV},
title = {Role of Oxidative Stress in Human Neurodegenerative Pathologies: Lessons from the Drosophila Model.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266356916250729040245},
pmid = {41177791},
issn = {1873-4294},
abstract = {Oxidative stress plays a critical role in many diseases, making it essential to study its impact on disease progression. However, clinical trials have many limitations and, in some cases, may not be possible at all. In this case, the development of in vivo models is highly anticipated. This is especially relevant for neurodegenerative diseases. Drosophila melanogaster models have a number of advantages over many other animal models, including the availability and costeffectiveness of breeding, the accumulated knowledge of the Drosophila genome, and the ability to manipulate a large number of individuals. The latter allows for rapid screening and in-depth studies of potential therapeutic agents, including natural compounds with antioxidant activity. This review describes genetic models of such pathologies as Parkinson's disease, Huntington's disease, Alzheimer's disease and hereditary spastic paraplegia created on Drosophila melanogaster. Studies conducted on such models are presented with an emphasis on the role of oxidative stress analysis. Oxidative stress is proven to be a link between neurodegenerative and metabolic diseases. In addition, studies on Drosophila melanogaster have been analyzed, in which the prospects of natural compounds as therapeutic agents for neurodegenerative and metabolic diseases have been demonstrated.},
}

@article {pmid41177743,
year = {2025},
author = {Pereira da Silva, AM and de Deus, O and Ribeiro, FV and Tudella, GCN and Cabeça, LS and Silva, LL and Han, ML and Franco, JO and Costa, JGP and Santos do Nascimento, MDV and Andrade Fernandes, JV and Franco, ES and de Sousa Maia, MB},
title = {Efficacy and Safety of Lithium for Behavioral and Cognitive Symptoms in Alzheimer's Disease Dementia: A Systematic Review With Frequentist and Bayesian Meta-Analysis.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.10.001},
pmid = {41177743},
issn = {1545-7214},
abstract = {BACKGROUND: Alzheimer's disease (AD) dementia is the leading cause of cognitive decline in late life, yet treatment options remain limited. Lithium, widely used in bipolar disorder, has been suggested to exert neuroprotective effects through inhibition of GSK-3β and modulation of amyloid and tau pathology. We aimed to evaluate the efficacy and safety of lithium in AD dementia.

METHODS: This systematic review and meta-analysis was prospectively registered in PROSPERO and conducted following PRISMA guidelines. We searched PubMed, Embase, and Cochrane Library through April 2025 for randomized controlled trials (RCTs) comparing lithium with placebo or standard therapy in patients with AD dementia or amnestic mild cognitive impairment. Outcomes included cognition (MMSE, ADAS-Cog, memory tasks), function (CDR-SB, conversion to AD), neuropsychiatric symptoms (NPI), CSF biomarkers, and safety (adverse events [AEs], serious AEs [SAEs]). Random-effects meta-analyses were complemented by Bayesian methods and trial sequential analyses.

RESULTS: Six RCTs involving 394 participants (196 lithium, 198 placebo) met inclusion criteria. Lithium did not significantly improve global cognition (MMSE: MD -1.61, 95% CI -4.11 to 0.88; ADAS-Cog: MD -1.82, -3.05 to -0.60; both with high heterogeneity). Memory outcomes were mixed, with possible benefit for figure recall but not delayed verbal recall. No consistent benefits were observed for episodic memory, functional outcomes (CDR-SB), neuropsychiatric symptoms, or CSF biomarkers. Safety analyses showed no increased risk of SAEs; drug-related AEs were more frequent but heterogeneous across trials.

CONCLUSIONS: Lithium demonstrated an acceptable safety profile within the dosing regimens studied. However, current evidence does not support consistent cognitive or functional benefits in AD dementia. Larger, well-designed RCTs are warranted to clarify its potential therapeutic role.},
}

@article {pmid41177554,
year = {2025},
author = {Novau-Ferré, N and Mateu-Fabregat, J and Papagiannopoulos, CK and Chalitsios, CV and Panisello, L and Markozannes, G and Tsilidis, KK and Bulló, M and Papandreou, C},
title = {Glycemic index, glycemic load, and risk of dementia: a prospective analysis within the UK Biobank cohort.},
journal = {International journal of epidemiology},
volume = {54},
number = {6},
pages = {},
doi = {10.1093/ije/dyaf182},
pmid = {41177554},
issn = {1464-3685},
support = {/ALZ/Alzheimer's Association/United States ; //Spanish Ministry of Health/ ; PI19/00854//European Union/ ; PI22/001139//European Union/ ; },
mesh = {Humans ; Male ; Female ; Prospective Studies ; United Kingdom/epidemiology ; *Glycemic Index ; Aged ; *Dementia/epidemiology ; *Glycemic Load ; Middle Aged ; Proportional Hazards Models ; Risk Factors ; Biological Specimen Banks ; Incidence ; Diet ; Alzheimer Disease/epidemiology ; Dementia, Vascular/epidemiology ; *Dietary Carbohydrates ; UK Biobank ; },
abstract = {BACKGROUND: Dementia risk is influenced by metabolic and lifestyle factors, including hyperinsulinemia, chronic inflammation, and type 2 diabetes. Glycemic index (GI) and glycemic load (GL) reflect the quality and quantity of dietary carbohydrates and their impact on glucose metabolism and systemic health. However, their associations with the risk of dementia subtypes remain unclear. This study examined the associations between dietary GI and GL and the risk of all-cause and different dementia subtypes, such as Alzheimer's disease (AD), vascular dementia (VD), and frontotemporal dementia.

METHODS: A prospective analysis was conducted by using data from 202 302 dementia-free participants in the UK Biobank cohort. Dietary GI and GL were estimated by using the Oxford WebQ 24-hour web-based dietary questionnaire. Cox proportional hazards regressions with restricted cubic splines were used to evaluate nonlinear relationships. Two-piece Cox models were used to identify inflection points, which served as reference values to estimate hazard ratios (HRs).

RESULTS: Dementia incidence was 0.89 per 1000 person-years. GI (mean±SD: 48.71 ± 7.68) showed an inverse J-shaped association with dementia risk, while GL (121.49 ± 39.00) showed a J-shaped pattern, with inflection points at 49.30 and 111.01, respectively. After adjusting for potential confounders, GI values of <49.30 were inversely associated with dementia risk [HR, 0.838; 95% confidence interval (CI), 0.758-0.926], while GL values of >111.01 were associated with higher dementia risk (HR, 1.145; 95% CI, 1.048-1.251). Similar findings were observed for AD and VD.

CONCLUSION: Low-GI diets may offer protective effects against all-cause dementia, AD, and VD, whereas high-GL diets may increase the risk. These findings underscore the importance of considering both carbohydrate quality and quantity in dementia prevention and management strategies.},
}

Humans
Male
Female
Prospective Studies
United Kingdom/epidemiology
*Glycemic Index
Aged
*Dementia/epidemiology
*Glycemic Load
Middle Aged
Proportional Hazards Models
Risk Factors
Biological Specimen Banks
Incidence
Diet
Alzheimer Disease/epidemiology
Dementia, Vascular/epidemiology
*Dietary Carbohydrates
UK Biobank

@article {pmid41177416,
year = {2025},
author = {Bashir, B and Gulati, M and Vishwas, S and Hussain, MS and Gupta, G and Kumar, P and Negi, P and Mittal, N and Dua, K and Singh, SK},
title = {Bridging the gap in the management of Alzheimer's disease using fecal microbiota transplantation.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104052},
doi = {10.1016/j.mcn.2025.104052},
pmid = {41177416},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that greatly impairs the health status of human beings and creates significant burdens on individuals, families, and society. AD is characterized by the buildup of pathological proteins and glial cell dysregulated activity. Additional hallmark features include oxidative stress, neuroinflammation, impaired autophagy, cellular senescence, mitochondrial dysfunction, epigenetic alterations, reduced neurogenesis, increased blood-brain barrier permeability, and age-inappropriate intestinal dysbiosis. There is significant evidence that shows that microbiota in the gut affects the development and progression of AD. As a result, gut microbiota modulation has been identified as a new method of clinical management of AD, and more and more efforts have been devoted to identifying new methodologies for its prevention and treatment. This paper will discuss the role of gut microbiome in the etiopathogenesis of AD and consider the possibilities of fecal microbiota extract (FME) supplementation, commonly referred to as fecal microbiota transplantation (FMT). It is both a prophylactic and curative approach. The FMT therapy is grounded on the premise that anti-inflammatory effects, modifications of amyloid β, improved synaptic plasticity, short-chain fatty acids, and histone acetylation are the principles behind the enhancement of AD. The current review will present an overview of the linkage between FMT and AD as well. It further examines and evaluates the effects of FMT on aging-based mechanisms that support the development of AD. It also provides a broad description of the recent clinical and preclinical evidence on the application of FMT to AD.},
}

@article {pmid41177383,
year = {2025},
author = {Gu, T and Ma, S and Liu, W and Wang, L},
title = {Pregnane X receptor activation regulate amyloid transport to improve cognition functions in Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {1007},
number = {},
pages = {178310},
doi = {10.1016/j.ejphar.2025.178310},
pmid = {41177383},
issn = {1879-0712},
abstract = {OBJECTIVES: To explore the concept about nuclear receptor pregnane X receptor (PXR) activation could be beneficial for the Alzheimer's disease (AD) treatment, as well as the underlying mechanism.

METHODS: For in vitro experiments, human brain microvascular endothelial cells (hCMEC/D3) were exposed to Aβ42 and hyperforin (HPF), a human PXR agonist followed by measurement of P-glycoprotein(P-gp)and low-density lipoprotein receptor-related protein 1 (LRP1) expression. Further, 7 months old 5 × FAD mice were used for in vivo experiments. Due to the species-difference characteristics of PXR, these mice were treated with pregnenolone carbonitrile (PCN, a rodent PXR agonist) rather than hPXR agonist, or corn oil for 28 days. Meanwhile, untreated C57BL/6 mice were used as the control group. The improvements of animal behavior were evaluated by Morris water maze and novel arm exploration test. The pathological profiles were assessed by immunohistochemistry and transmission electron microscopy. The cerebral blood flow (CBF) and Aβ transporters were analyzed by speckle contrast imaging and Western blot respectively.

RESULTS: In vitro experiments showed that the P-gp and LRP1 levels in hCMEC/D3 were reduced due to exposure of Aβ42, while HPF can restore their expression levels. 5 × FAD mice treated with the PCN improved cognitive functions and cerebral blood flow. These functional improvements were associated with a reduction in amyloid plaques, cerebral amyloid angiopathy, neuroinflammation and a recovery of blood-brain barrier transport function. The underlying mechanisms could be that PXR activation up-regulates the expression of P-gp and LRP1 and inhibits inflammation via STAT3, and increases the clearance of Aβ42 in the brain.

CONCLUSIONS: These results demonstrate the beneficial impact of PXR activation on cognitive functions, parenchymal amyloid plagues and cerebral angiopathy, and highlights the therapeutic potential of PXR agonists for treatment of AD patients.},
}

@article {pmid41177382,
year = {2025},
author = {Maisto, N and Dashtiani, S and Forte, J and Ammendolia, MG and Triaca, V and Rinaldi, F and Mango, D},
title = {Ellagic acid-loaded nanovesicles rescue LTP impairment and neuroinflammation in an AD ex-vivo model.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178317},
doi = {10.1016/j.ejphar.2025.178317},
pmid = {41177382},
issn = {1879-0712},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), cause progressive neurological decline and major healthcare challenges. AD is marked by deterioration in learning, memory, and cognition, leading to dementia. Early-stage AD brains show accumulation of amyloid-beta (Aβ) protofibrils and plaques, particularly in the hippocampus, associated with chronic neuroinflammation and impaired synaptic plasticity that drive cognitive decline. Current AD treatments primarily relieve symptoms without slowing disease progression, and existing monoclonal antibodies targeting Aβ plaques have controversial side effects. This has driven interest in natural compounds like polyphenols for their broad biological activities. Ellagic acid (EA), a natural polyphenol, exhibits antioxidant, anti-inflammatory, and neuroprotective properties. Experimental models of neurodegenerative diseases have shown EA's potential to improve memory and cognition by modulating synaptic plasticity. This study has evaluated EA's impact on hippocampal synaptic plasticity and its neuroprotective effects against Aβ1-42-mediated impairments using electrophysiological recordings and immunofluorescence analysis, evaluating microglial morphological normalization as well as interleukins expression. It has been found that, in ex vivo brain slices, EA modulated synaptic plasticity at high concentration, while at the dose that per se does not alter neurotransmission it rescued LTP and basal neurotransmission impairment Aβ1-42 mediated, and normalized neuroinflammation by reducing interleukins expression released by activated microglia. However, EA's poor water solubility and extensive first-pass metabolism limit its clinical use. Here, EA has been encapsulated in non-ionic surfactant vesicles (NSVs), and the formulation (EA-NSVs) has demonstrated a neuroprotective effect at a lower dose compared to free EA, effectively rescuing synaptic impairment induced by Aβ1-42.},
}

@article {pmid41176993,
year = {2025},
author = {Xue, P and Yu, H and Zhu, Y and Liu, F},
title = {Quantitative perfusion assessment with arterial spin labeling magnetic resonance imaging for predicting cognitive decline in Alzheimer's disease: A systematic review and meta-analysis.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {143},
number = {},
pages = {111711},
doi = {10.1016/j.jocn.2025.111711},
pmid = {41176993},
issn = {1532-2653},
abstract = {BACKGROUND: Arterial spin labeling (ASL) magnetic resonance imaging (MRI) is a potential tool for diagnosis and prediction of Alzheimer's disease (AD). This study evaluates effectiveness of ASL in differentiating AD patients or individuals with mild cognitive impairment (MCI) from healthy individuals with normal cognition (HC).

METHODS: After conducting literature search in electronic databases (Google Scholar, PubMed, and Science Direct), studies were selected by following precise eligibility criteria. Meta-analyses of standardized mean difference (SMDs) were performed to examine differences in cerebral blood flow (CBF) between individuals with AD, MCI, and HC. Meta-analyses of correlation coefficients were performed to achieve pooled correlation between CBF and cognitive performance measures.

RESULTS: Fifteen studies (671 HC, 539 MCI, and 463 CE individuals) were included. The ages of these individuals were: 70.6 [95 %CI: 66.6, 74.7], 71.9 [95 %CI: 67.8, 76.1], and 73.2 [95 %CI: 69.2, 77.3] years for HC, MCI, and AD individuals respectively. The percentages of women in HC, MCI and AD groups in these studies were 58 % [95 %CI: 52, 63], 54 % [95 %CI: 49, 60], and 54 % [95 %CI: 48, 61]. As a composite measure for multiple brain regions, CBF was significantly lower in AD patients compared to HC (SMD - 0.70 [95 %CI: -0.92, -0.49]; I[2] = 0 %; p < 0.0001) or individuals with MCI (SMD - 0.62 [95 %CI: -0.86, -0.37]; I[2] = 0 %; p < 0.0001). However, composite CBF was not significantly lower in individuals with MCI in comparison with HC (SMD - 0.17 [95 %CI: -0.42, 0.08]; I[2] = 11.7 %; p = 0.190). In various parts of the brain including the cerebellum, cingulate, deep gray matter, limbic system, and cortices, CBF was significantly lower in AD patients in comparison with HC or MCI individuals. However, CBF was not significantly different in individuals with MCI in comparison with HC in some parts including deep gray matter, limbic system, and frontal lobe. Pooled correlation coefficients between CBF and any cognitive assessment test score were - 0.005 [95 %CI: -0.066, 0.057] (p = 0.878) for HC, -0.114 [95 %CI: -0.236, 0.009] (p = 0.070) for MCI, and 0.297 [95 %CI: 0.213, 0.381] (p < 0.0001) for AD groups.

CONCLUSIONS: ASL is a promising MRI method that can provide an alternative to nuclear methods for the diagnosis of AD. However, more studies are required to evaluate its detecting and predicting role in individuals with MCI.},
}

@article {pmid41176929,
year = {2025},
author = {Akan, T and Akan, S and Alp, S and Ledbetter, CR and Tafti, AP and Arevalo, O and Bhuiyan, MAN},
title = {Deep Learning in neuroimaging for neurodegenerative diseases: State-of-the art, Challenges, and Opportunities.},
journal = {Journal of the neurological sciences},
volume = {478},
number = {},
pages = {123735},
doi = {10.1016/j.jns.2025.123735},
pmid = {41176929},
issn = {1878-5883},
abstract = {Neuroimaging is commonly used to diagnose neurodegenerative diseases (NDDs), providing crucial insights into brain changes before clinical symptoms manifest. Deep learning (DL) for neuroimaging can improve early diagnosis and disease monitoring. Clinical implementation of DL faces challenges in accurately representing real-world data. Recent models, particularly those focused on diagnostic categorization, have achieved high accuracy, but their applicability to patients is limited. Conflicting inferences have been reported, with findings from small cohorts generalizing conclusions without considering inter-scanner, intra- and inter-site variations. A theoretically feasible method involves gathering a comprehensive dataset that encompasses all patient demographics, but this presents practical challenges including harmonization, data incompleteness, class imbalance, and substantial costs. Existing research has also mostly focused on common NDDs like Alzheimer's Disease (AD) and Parkinson's Disease (PD). This contribution expands the literature by looking at a wider range of NDDs, exploring the latest advancements in applying deep learning algorithms to neuroimaging analysis for the diagnosis and monitoring of NDDs, including AD, Frontotemporal Dementia (FTD), Lewy Body Dementia, PD, Huntington's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. We emphasize how these approaches are handling spatial/temporal information available in brain volume imaging data. We conclude by discussing the challenges associated with the use of voxel-based, patch-based, ROI-based, and slice-based approaches in brain volume imaging. These challenges are further compounded by issues such as inter-site and inter-scanner variability, class imbalances in medical datasets, and the scarcity of accurately annotated data, all of which impact the performance and generalizability of deep learning models.},
}

@article {pmid41176545,
year = {2025},
author = {El Hajj, W and Pujo-Menjouet, L and Tine, LM and Volpert, V},
title = {Modelling of anti-inflammatory treatment in the Alzheimer disease: optimal regimen and outcome.},
journal = {Bulletin of mathematical biology},
volume = {87},
number = {12},
pages = {171},
pmid = {41176545},
issn = {1522-9602},
support = {Project-ANR-21-CE15-0011//PrionDiff/ ; },
mesh = {*Alzheimer Disease/drug therapy/immunology ; Humans ; *Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/therapeutic use ; Mathematical Concepts ; Cytokines/metabolism ; *Models, Biological ; Treatment Outcome ; Computer Simulation ; Microglia/drug effects ; Disease Progression ; Inflammation Mediators/metabolism/antagonists & inhibitors ; },
abstract = {The application of non-steroidal anti-inflammatory drugs (NSAIDs) for Alzheimer's disease is considered to be a promising therapeutic approach. Epidemiological studies suggest potential benefits of NSAIDs; however, these findings are not consistently supported by clinical trials. This long-standing discrepancy has persisted for decades and remains a significant barrier to developing effective treatment strategies. To assess the efficacy of NSAIDs in Alzheimer's disease, we have developed a mathematical model based on a system of ordinary differential equations. The model captures the dynamics of key players in disease progression, including A β -monomers, oligomers, pro-inflammatory mediators (M1 microglial cells and pro-inflammatory cytokines), and anti-inflammatory mediators (M2 microglial cells and anti-inflammatory cytokines). The effects of NSAIDs are modeled through a reduction in the production rate of inflammatory cytokines (IC). While a single NSAID administration temporarily reduces IC levels, their concentration eventually returns to baseline due to drug elimination. The return time depends on the drug dose, resulting in a patient-specific return time function. By analyzing this function, we propose an optimal treatment regimen and identify conditions under which NSAID treatment is most effective in reducing IC levels. Our results suggest that NSAID efficacy in Alzheimer's disease is influenced by the stage of the disease (with earlier intervention being more effective), patient-specific parameters, and the treatment regimen. The approach developed here can also be generalized to evaluate the efficacy of anti-inflammatory treatments for other diseases.},
}

*Alzheimer Disease/drug therapy/immunology
Humans
*Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/therapeutic use
Mathematical Concepts
Cytokines/metabolism
*Models, Biological
Treatment Outcome
Computer Simulation
Microglia/drug effects
Disease Progression
Inflammation Mediators/metabolism/antagonists & inhibitors

@article {pmid41176298,
year = {2025},
author = {Pishgahzadeh, E and Bozorgchami, N and Talebi, M and Masoudifar, R and Ahmadi, M and Ghorbani-Bidkorpeh, F},
title = {Different strategies to make biobetters: physicochemical, pharmacodynamics, and pharmacokinetic aspects came into focus.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {126319},
doi = {10.1016/j.ijpharm.2025.126319},
pmid = {41176298},
issn = {1873-3476},
abstract = {Technological advancements in the discovery/development of biological products have led to significant improvements in both products and processes, resulting in more effective medications. Biological medications, or biopharmaceuticals, whose patents have expired, present a substantial opportunity for the development of biosimilars, biobetters, and subsequent iterations of biological drugs. Interest in biological drugs has surged, primarily because of their potential to address diseases that conventional synthetic drugs inadequately manage. These pathological conditions includecancer, diabetes, ophthalmic disorders, arthritis, Alzheimer's disease, hemophilia, and diseases related to the immune system. Biobetters represent a new category of biopharmaceutical molecules developed through modifications to their molecular profiles. These modifications can be achieved through molecular, chemical, or functional changes. As a result, these enhanced biologics can exhibit significant ameliorations, such as extended half-life, reduced toxicity and adverse effects, mitigated immunogenetic responses, and improved pharmacodynamic properties. The Quality by Design (QbD) approach plays a crucial role in developing biobetters and improved versions of existing protein-based therapeutics. By employing QbD principles, the design of biobetters can be optimized to enhance characteristics such as target epitope affinity, selectivity, and stability against degradation. Given the importance of this topic, this comprehensive review article aims to provide an in-depth examination of various approaches for developing biobetters, with a primary focus on pharmacodynamics and pharmacokinetics. The article begins by clarifying the concepts of biologics, biosimilars, and biobetters before delving into the diverse strategies used in creating biobetters.},
}

@article {pmid41176285,
year = {2025},
author = {Glaubitz, E and Wang, XH and Xi, K and Feiz, F and Pahlajani, S and Maloney, T and Tanzi, E and Hojjati, H and Zhou, L and Glodzik, L and Chiang, G and Li, Y and Razlighi, R and de Leon, M and Butler, T},
title = {PET-measured tau deposition in emotion-related brain regions is differentially associated with depressive symptoms in individuals with versus without Alzheimer's disease pathology.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115889},
doi = {10.1016/j.bbr.2025.115889},
pmid = {41176285},
issn = {1872-7549},
abstract = {Depressive symptoms are common in patients diagnosed with Alzheimer's Disease (AD) and can also precede AD as a risk factor and/or prodrome. Brain deposition of hyper-phosphorylated tau is a hallmark pathology of AD. Tau deposition in brain regions involved in emotional processing is likely to be pathophysiologically relevant to these links between AD and depression. We used 18F-MK6240 PET to measure tau in amygdala, hippocampus, and nucleus accumbens-regions implicated in depression-in 141 participants with and without AD. In addition to tau PET, participants underwent amyloid-beta (Aβ) PET, MRI, and cognitive evaluation. Depressive symptoms were assessed with the Beck Depression Inventory (BDI). Multiple regression analyzed contributions of tau and Aβ status (positive vs. negative), depression (BDI > 13), cognition (impaired vs. normal), age and sex to tau burden in the three regions. A significant interaction between tau status and depression prompted subgroup analyses of tau-positive (n=34) and tau-negative (n=107) participants. Among tau-positive participants, depression was associated with greater tau in the nucleus accumbens, a region critical for reward processing and motivation. This finding suggests that tau-mediated accumbens dysfunction may contribute to anhedonia, a key symptom of depression that is particularly common in AD-related depression. In tau-negative participants, greater depression was associated with less tau in the medial temporal lobe. This unexpected finding requires confirmation through further research, but could reflect impaired neurogenesis in depression without AD pathology.},
}

@article {pmid41176079,
year = {2025},
author = {Wnuk, HK and Van Orden, KA and Wang, KH},
title = {Bridging Social Isolation, Loneliness, and Brain Aging: A Narrative Review of Mechanisms and Translational Interventions.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106451},
doi = {10.1016/j.neubiorev.2025.106451},
pmid = {41176079},
issn = {1873-7528},
abstract = {Social isolation and loneliness (SIL) are increasingly recognized as potent determinants of cognitive decline in aging and Alzheimer's disease-related dementias (ADRD). Yet, despite their prevalence, the neurobiological pathways through which SIL accelerates brain aging remain incompletely understood, and effective interventions are scarce. This narrative review synthesizes human and animal research to present a translational framework linking SIL to brain aging across cognitive-affective, socio-behavioral, physiological, and neural domains. Converging evidence indicates that SIL and cognitive impairment constitute a self-reinforcing loop: isolation amplifies age-related deficits in cognitive control, emotional regulation, and stress resilience, while these impairments heighten social threat sensitivity and blunt social reward, perpetuating isolation. Cross-species findings implicate interconnected neural networks, including the prefrontal and insular cortices, hippocampus, and associated reward and stress-regulatory systems, as critical hubs mediating this loop. Large-scale human neuroimaging consortia reveal convergent neural signatures of SIL within these networks, supported by mechanistic findings from animal models that identify shared molecular cascades involving neuroinflammation, glucocorticoid imbalance, myelin disruption, and dysregulated oxytocin and dopaminergic signaling. Importantly, evidence from animal resocialization paradigms and human multimodal interventions demonstrates that SIL-related neural and behavioral alterations are partially reversible, highlighting enduring plasticity in the aging brain. Together, these findings define SIL and cognitive decline as a dynamic, mutually reinforcing cycle that accelerates brain aging through convergent molecular and circuit mechanisms. Targeting these pathways, by enhancing cognitive control, modulating reward systems, reducing stress reactivity, and strengthening social connectedness, offers a promising translational route to preserve resilience and cognitive vitality across the lifespan.},
}

@article {pmid41175989,
year = {2025},
author = {Andraini, T and Fauré, L and Mouledous, L and Gauzin, S and Ghasemi, Z and Lejards, C and Florian, C and Belenguer, P and Miquel, MC and Rampon, C},
title = {Targeting adult-born neurons to correct early deficits in pattern separation in the Tg2576 mouse model of Alzheimer's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107158},
doi = {10.1016/j.nbd.2025.107158},
pmid = {41175989},
issn = {1095-953X},
abstract = {Hippocampal adult neurogenesis in mammals generates a unique population of immature granule neurons that play a crucial role in memory, learning and spatial processing. In both Alzheimer's disease (AD) patients and mouse models, this neurogenic capacity of the dentate gyrus is reduced. Mouse models of AD have shown that hippocampal adult neurogenesis is altered early in the course of the disease, contributing to hippocampal-dependent memory impairments. Early stages of AD are also associated with mitochondrial dysfunction in adult-born neurons. While mitochondria have emerged as key regulators of adult neurogenesis, they have been found to be dysfunctional in AD context and to contribute to neurodegenerative diseases. In this study, we investigated the timing and nature of memory deficits in Tg2576 mice, a model of AD, focusing on tasks that depend on hippocampal neurons born in adulthood. We found that Tg2576 mice exhibit early deficits in pattern separation tasks. Notably, adult-born neurons in Tg2576 mice show reduced connectivity and mitochondrial content along with the first memory deficits. To mitigate these defects, we used NeuroD1, a potent neuronal transcription factor, to enhance the development of adult-born neurons in Tg2576 mice. Overexpression of NeuroD1 restored both mitochondrial content and spine density in these neurons to levels comparable to those in control mice. In addition, this intervention restored pattern separation performance in Tg2576 mice, highlighting the potential of strategies targeting mitochondria to correct adult neurogenesis-related memory deficits in the early stages of AD.},
}

@article {pmid41175945,
year = {2025},
author = {Fujii, K and Takeuchi, T and Fujino, Y and Tanaka, N and Fujino, N and Takeda, A and Minakawa, EN and Nagai, Y},
title = {Oral administration of arginine suppresses Aβ pathology in animal models of Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {191},
number = {},
pages = {106082},
doi = {10.1016/j.neuint.2025.106082},
pmid = {41175945},
issn = {1872-9754},
abstract = {Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain. In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an App[NL-G-F] knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated App[NL-G-F] knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes. These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.},
}

@article {pmid41175916,
year = {2025},
author = {Vanya, and Kumari, S and Bagri, K and Deshmukh, R},
title = {Tangles and Plaques: A deep dive into the pathological hallmarks of Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.10.050},
pmid = {41175916},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. In AD, there is a gradual impairment of memory and cognitive function that interferes with daily living. The pathophysiology of AD revolves around complex interactions between amyloid-β (Aβ) overproduction and accumulation, followed by tau hyperphosphorylation, which together promote a cascade of neuronal dysfunction and degeneration. AD has two forms, sporadic and familial, with genetic variants such as triggering receptor expressed on myeloid cells-2 (TREM2). Various other variants also lead to impaired amyloid clearance and altered immune responses. Along with these genetic factors, aging remains the primary risk factor, and environmental as well as lifestyle factors can act synergistically to accelerate disease onset and progression. Although significant advances have been made in the last five decades, there has been only limited progress in the treatment because of a poor understanding of the molecular basis of AD. This makes current treatments largely focus on symptomatic management. This narrative review provides an updated synthesis of Alzheimer's disease pathophysiology, focusing on Aβ and tau pathology, glial activation, neuroinflammatory cascades, disrupted neurogenesis, and blood-brain barrier dysfunction. A focus and deeper understanding can help to develop new strategies that might work beyond the present conventional treatment. Due to the increasing global prevalence of AD, it is important to continue research into these mechanisms for the development of more effective interventions and improved patient outcomes.},
}

@article {pmid41175892,
year = {2025},
author = {Prajapati, P and Desai, A and Shah, P and Pulusu, V and Haque, A and Kalam, MA and Shah, S},
title = {Comparative in-vivo and in-vitro characterization of Donepezil loaded Lactoferrin linked PEG coated and uncoated nanocarriers as intranasal drug delivery system.},
journal = {Journal of liposome research},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/08982104.2025.2573681},
pmid = {41175892},
issn = {1532-2394},
abstract = {Alzheimer's disease treatment faces challenges with conventional oral formulations of donepezil (DNP). This study aims to develop and characterize DNP-loaded Lactoferrin (LCF)-linked PEG-coated nano-carriers for intranasal delivery. The formulation was developed using a Quality by Design (QbD) approach integrated with molecular docking. A novel micelle-enhanced spectrofluorimetric method was developed and validated for in-vitro and in-vivo characterization of the nano-carriers. The method was optimized using Analytical Quality by Design (AQbD) principles. In-vivo pharmacokinetic and bio-distribution studies were conducted in rats to compare the developed formulation with uncoated NLCs and conventional dosage forms. The LCF-PEG-coated NLCs showed improved brain targeting efficiency compared to uncoated NLCs and conventional formulations. The spectrofluorimetric method demonstrated high sensitivity and reliability for both in-vitro and in-vivo analyses. The developed DNP-loaded LCF-PEG-coated NLCs show promise as an effective intranasal delivery system for Alzheimer's disease treatment. The novel spectrofluorimetric method offers a sustainable and efficient alternative to conventional LC-MS/MS techniques for characterizing DNP formulations.},
}

@article {pmid41175871,
year = {2025},
author = {Zhu, B and Wangzhou, A and Yu, D and Li, T and Schmidt, R and De Florencio, SL and Chao, L and Thurber, AL and Zhou, M and Msheik, Z and Perez, Y and Grinberg, LT and Spina, S and Ransohoff, RM and Kriegstein, AR and Seeley, WW and Nowakowski, T and Piao, X},
title = {G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2025.10.029},
pmid = {41175871},
issn = {1097-4199},
}

@article {pmid41175793,
year = {2025},
author = {Torrealba-Acosta, G and Yang, S and Calvo-Marín, J and Moghekar, AR and Kamalian, A and Lutz, MW and , },
title = {Identifying a proteomics signature of cognitive impairment and dementia in blood and cerebrospinal fluid through a mediation analysis framework.},
journal = {Neurobiology of aging},
volume = {157},
number = {},
pages = {79-88},
doi = {10.1016/j.neurobiolaging.2025.10.004},
pmid = {41175793},
issn = {1558-1497},
abstract = {This study aimed to identify CSF and plasma proteins that mediate the association between age and mild cognitive impairment (MCI) and Alzheimer's disease using mediation analysis. By focusing on proteins significantly associated in both CSF and plasma, we sought to identify biomarkers accessible for clinical applications. Proteomic measurements were obtained from CSF and plasma from a cohort of cognitively normal and MCI patients at the Johns Hopkins Alzheimer's Disease Research Center using Olink Proximity Extension Assay technology. Mediation effects were estimated using single- and multiple-mediator models and validated in three independent datasets: Duke (CSF), ADNI (CSF), and UK Biobank (plasma). Over 3000 proteins in 86 patients were analyzed. Three candidates, leiomodin-1 (LMOD1), glial fibrillary acidic protein (GFAP), and elastin (ELN), met the criteria for mediation in both CSF and plasma. Multiple mediator models demonstrated a significant combined mediation effect on MCI in CSF (OR: 1.122, 95 % CI: 1.026-1.439) and plasma (OR: 1.142, 95 % CI: 1.058-1.410). Across validation cohorts, GFAP consistently showed significant mediation effects (Duke CSF: OR: 1.114, 95 % CI: 1.069-1.206; ADNI: OR: 1.004, 95 % CI: 1.000-1.009; UK Biobank: OR: 1.030, 95 % CI: 1.026-1.034). In contrast, ELN and LMOD1 demonstrated mediation effects in the discovery dataset but were not consistently reproduced in external cohorts. Our findings highlight GFAP as a robust mediator of age-related risk of cognitive impairment across CSF and plasma, supporting its utility as a practical biomarker. ELN and LMOD1 may represent exploratory candidates reflecting extracellular matrix and vascular processes requiring further validation.},
}

@article {pmid41175714,
year = {2025},
author = {Kovac, D and Novakova, L and Mekyska, J and Novotny, K and Brabenec, L and Klobusiakova, P and Rektorova, I},
title = {Digital speech biomarkers for assessing cognitive decline across neurodegenerative conditions.},
journal = {Computers in biology and medicine},
volume = {198},
number = {Pt B},
pages = {111251},
doi = {10.1016/j.compbiomed.2025.111251},
pmid = {41175714},
issn = {1879-0534},
abstract = {This study investigates speech impairments in individuals with mild cognitive impairment due to Alzheimer's disease (MCI-AD), mild cognitive impairment with Lewy bodies (MCI-LB), and Parkinson's disease with mild cognitive impairment (PD-MCI), compared to healthy controls (HC), aiming to identify linguistic and acoustic digital biomarkers that differentiate these groups. Monologue recordings were collected from 68 HC, 42 MCI-AD, 50 MCI-LB, and 47 PD-MCI participants (ON state). Participants were instructed to speak spontaneously for one and a half minutes. Speech was automatically transcribed, manually corrected, and analyzed using natural language processing to extract eight linguistic (lexical/syntactic) and four acoustic (prosodic) biomarkers. Group differences were assessed using the Mann-Whitney U test, with Spearman's correlation used to examine associations with clinical and MRI measures (FDR-corrected). Machine learning models (XGBoost) were applied to evaluate the classificatory and predictive potential of speech features. Distinct speech patterns were observed across groups: MCI-AD participants exhibited reduced use of function words, resulting in increased content density, PD-MCI participants used shorter sentences and fewer coordinating conjunctions with longer pauses, and MCI-LB participants exhibited greater lexical repetition than MCI-AD. Altered speech features correlated with structural brain changes but not with global cognition (MoCA) or depressive symptoms (GDS). Sentence structure and pausing features showed strong interrelationships. Machine learning models showed that adding speech biomarkers improved classification performance compared to using clinical scores alone. In regression analyses, the models predicted MoCA with a normalized error of 10%, performing similarly on automatic and manually corrected transcripts. These findings suggest that speech biomarkers and traditional clinical assessments may offer complementary information about cognitive status and brain health, supporting their use in scalable, non-invasive cognitive monitoring.},
}

@article {pmid41175671,
year = {2025},
author = {Träuble, J and Hiscox, LV and Johnson, CL and Aviles-Rivero, A and Schönlieb, CB and Kaminski Schierle, GS},
title = {Brain age prediction and early neurodegeneration detection using contrastive learning on brain biomechanics: a retrospective, multicentre study.},
journal = {EBioMedicine},
volume = {121},
number = {},
pages = {105996},
doi = {10.1016/j.ebiom.2025.105996},
pmid = {41175671},
issn = {2352-3964},
abstract = {BACKGROUND: One of the main reasons why drugs for neurodegenerative diseases often fail is that treatment typically begins only after symptoms have appeared-by which point significant, and possibly irreversible, damage may have already occurred. Non-invasive imaging techniques, such as Magnetic Resonance Imaging (MRI), have previously been explored for presymptomatic diagnosis, but with limited success. More recently, Magnetic Resonance Elastography (MRE)-a technique capable of mapping the brain's biomechanical properties, including stiffness and damping ratio-has shown promise in detecting early changes. However, current studies have been limited by small sample sizes, and a lack of robust algorithms capable of accurately interpreting data under such constraints.

METHODS: We developed a self-supervised contrastive regression framework trained on 3D MRE-derived stiffness and damping ratio maps from 311 healthy individuals (aged 14-90) and evaluated its performance against structural 3D T1-weighted MRI. Brain age predictions were used to compute brain age gaps (BAGs), quantifying deviations from normative ageing trajectories. We applied the models to Alzheimer's disease (AD, n = 11) and mild cognitive impairment (MCI, n = 20) cohorts, and analysed whole-brain and region-specific predictions using occlusion-based saliency maps and subcortical segmentation.

FINDINGS: Self-supervised models using MRE achieved a mean absolute error (MAE) of 3.51 years in brain age prediction-significantly outperforming MRI (MAE: 4.79 years, p < 0.05) under matched conditions. The greater age sensitivity of MRE translated into improved differentiation of Alzheimer's disease (AD) and mild cognitive impairment (MCI) from healthy individuals. Stiffness was the dominant ageing biomarker in AD (BAG increase: +9.2 years, p < 0.05), whereas damping ratio revealed early MCI-related changes (BAG increase: +6.3 years, p < 0.05). Region-wise analysis identified the caudate (stiffness) and thalamus (damping ratio) as key markers for AD and MCI, respectively. Notably, some cognitively normal individuals exhibited biomechanical profiles resembling patients with MCI or AD, suggesting that these individuals may share some biomechanical characteristics with clinical populations.

INTERPRETATION: In our controlled experimental setting, MRE combined with contrastive learning provides a sensitive, non-invasive biomarker of brain ageing and neurodegeneration, outperforming MRI and differentiating disease stage-specific biomechanical signatures. Regional BAG profiling may have the potential to identify at-risk, cognitively normal individuals, which could facilitate timely intervention trials in the future, pending longitudinal validation.

FUNDING: Gates Cambridge Trust; Cambridge Centre for Data-Driven Discovery (Schmidt Sciences); Wellcome Trust; NIH (R01-AG058853, U01-NS112120); UK EPSRC; UK MRC; Alzheimer's Research UK; Michael J. Fox Foundation; Infinitus China Ltd.},
}