@article {pmid41240919,
year = {2025},
author = {Kaila, LV and Ikeda, M and Sultana, J and Chouliaras, L and O'Brien, JT and Taylor, JP},
title = {The evolving therapeutic landscape of dementia with Lewy bodies.},
journal = {The Lancet. Neurology},
volume = {24},
number = {12},
pages = {1038-1052},
doi = {10.1016/S1474-4422(25)00323-0},
pmid = {41240919},
issn = {1474-4465},
mesh = {Humans ; *Lewy Body Disease/therapy/diagnosis ; },
abstract = {Dementia with Lewy bodies has a complex clinical presentation, with symptoms spanning cognitive, neuropsychiatric, motor, autonomic, and sleep domains. The disorder causes high morbidity, is associated with high caregiver burden, and can result in considerable health-care costs. Although symptomatic treatments remain scarce, emerging evidence supports a multipronged approach that integrates pharmacological and non-pharmacological interventions that target different signs and symptoms. Novel frameworks, such as the DIAMOND Lewy toolkit, provide structured management guidance. Beyond symptom control, research is at a turning point, with increasing focus on disease-modifying therapies. Ongoing clinical trials are exploring many therapeutic targets, including α-synuclein aggregation and neuroinflammation. Other potential targets in the treatment of dementia with Lewy bodies include amyloid β, given that the presence of Alzheimer's disease copathology is common in patients with this disease.},
}

Humans
*Lewy Body Disease/therapy/diagnosis

@article {pmid41240918,
year = {2025},
author = {Scholz, SW and Okubadejo, NU and Prakash, P and Liddelow, SA and Ryten, M and Halliday, GM},
title = {Advances in the genetics and pathology of Lewy body dementia.},
journal = {The Lancet. Neurology},
volume = {24},
number = {12},
pages = {1026-1037},
doi = {10.1016/S1474-4422(25)00363-1},
pmid = {41240918},
issn = {1474-4465},
mesh = {Humans ; *Lewy Body Disease/genetics/pathology ; alpha-Synuclein/genetics/metabolism ; Lewy Bodies/pathology ; Alzheimer Disease/genetics/pathology ; },
abstract = {Lewy body dementia is a heterogeneous disease that is underdiagnosed and poorly understood. Pathologically, Lewy body dementia is characterised by the accumulation of intraneuronal aggregates of misfolded α-synuclein, known as Lewy bodies and Lewy neurites. The genetic architecture of Lewy body dementia is complex, involving both common genetic variants with small risk effects and rare genetic variants with large effects. Alzheimer's disease pathology frequently coexists with Lewy body pathology and influences the clinical presentation. A deeper understanding of the pathophysiological pathways, including mitochondrial dysfunction, lysosomal dysfunction, and neuroinflammation, can enhance disease modelling, and this knowledge will ultimately facilitate the development of therapeutic interventions. The biological relationships that Lewy body dementia shares with other neurodegenerative and psychiatric disorders might also be crucial for the development of therapeutic strategies.},
}

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

@article {pmid41240917,
year = {2025},
author = {Jack, CR and Hu, M and Wiste, HJ and Knopman, DS and Vemuri, P and Graff-Radford, J and Lowe, VJ and Vassilaki, M and Cogswell, PM and Schwarz, CG and Algeciras-Schimnich, A and Petersen, RC and Therneau, TM},
title = {Lifetime and 10-year absolute risk of cognitive impairment in relation to amyloid PET severity: a retrospective, longitudinal cohort study.},
journal = {The Lancet. Neurology},
volume = {24},
number = {12},
pages = {1016-1025},
doi = {10.1016/S1474-4422(25)00350-3},
pmid = {41240917},
issn = {1474-4465},
mesh = {Humans ; Male ; *Cognitive Dysfunction/diagnostic imaging/epidemiology/metabolism/genetics ; Female ; Aged ; Longitudinal Studies ; Retrospective Studies ; *Positron-Emission Tomography ; Middle Aged ; Aged, 80 and over ; Apolipoprotein E4/genetics ; Alzheimer Disease/diagnostic imaging/epidemiology ; Severity of Illness Index ; },
abstract = {BACKGROUND: A key knowledge gap concerns the lifetime risk of developing cognitive impairment among individuals who are cognitively unimpaired with abnormal Alzheimer's disease biomarkers. Our aim was to compute lifetime and 10-year absolute risk of cognitive impairment as a function of continuous amyloid PET.

METHODS: In this retrospective, longitudinal cohort study of data from participants of the population-based Mayo Clinic Study of Aging (Olmsted County, MN, USA), we computed lifetime and 10-year absolute risk of cognitive impairment in participants who were cognitively unimpaired and aged 50 years or older at enrolment. The primary predictor of interest was biological Alzheimer's disease severity, based on amyloid PET centiloid value. Starting age, sex, and APOE ε4 carriership status were also predictors. Outcomes were incident mild cognitive impairment (MCI), dementia, and death, which were ascertained or estimated via multistate hidden Markov modelling both in study and out of study.

FINDINGS: Between Nov 29, 2004, and Dec 2, 2024, 5158 participants (2623 [51%] women and 2535 [49%] men) who are cognitively unimpaired and 700 (307 [44%] women and 393 [56%] men) with MCI were included for analysis. Lifetime risk of MCI and dementia increased monotonically with increasing centiloid value (p<0·0001), which was the predictor with the largest effect. Lifetime risk of MCI for male APOE ε4 carriers who are cognitively unimpaired at a starting age of 75 years was 56·2% (95% CI 50·5-61·9) for centiloid 5, 60·2% (54·9-65·6) for centiloid 25, 71·0% (65·2-76·7) for centiloid 50, 75·2% (69·1-81·2) for centiloid 75, and 76·5% (70·5-82·4) for centiloid 100. Lifetime risk of MCI for female APOE ε4 carriers who are cognitively unimpaired at a starting age of 75 years was 68·9% (63·7-74·1) for centiloid 5, 71·3% (66·6-76·0) for centiloid 25, 77·6% (72·5-82·7) for centiloid 50, 81·2% (76·7-85·7) for centiloid 75, and 83·8% (78·5-89·1) for centiloid 100. Within each centiloid group, and for both men and women, lifetime and 10-year absolute risk for MCI and dementia was greater for APOE ε4 carriers than for non-carriers (p<0·0001). Biological severity of Alzheimer's disease was a predictor of 10-year absolute risk of MCI and dementia (p<0·0001); however, starting age (p<0·0001) had a more prominent effect. The rate of incident dementia was two times greater among individuals who had previously left the study than those who remained in the study.

INTERPRETATION: Lifetime and 10-year absolute risk for MCI and dementia among individuals who are currently cognitively unimpaired increase with increasing biological severity of Alzheimer's disease. This information should be important for risk-benefit evaluation of therapeutic interventions in the future. The high lifetime risk in participants with higher centiloid values addresses academic controversies concerning risk of future impairment associated with biomarkers of Alzheimer's disease among individuals who are cognitively unimpaired. Ascertainment and modelling of out-of-study outcomes are necessary for accurate lifetime risk estimates.

FUNDING: US National Institutes of Health, GHR Foundation, and the Alexander Family.},
}

Humans
Male
*Cognitive Dysfunction/diagnostic imaging/epidemiology/metabolism/genetics
Female
Aged
Longitudinal Studies
Retrospective Studies
*Positron-Emission Tomography
Middle Aged
Aged, 80 and over
Apolipoprotein E4/genetics
Alzheimer Disease/diagnostic imaging/epidemiology
Severity of Illness Index

@article {pmid41240899,
year = {2025},
author = {Xu, F and Carro, E},
title = {Early screening for Alzheimer's disease: A scientific, ethical, and value-based framework for targeted screening in at-risk individuals.},
journal = {Med (New York, N.Y.)},
volume = {6},
number = {11},
pages = {100919},
doi = {10.1016/j.medj.2025.100919},
pmid = {41240899},
issn = {2666-6340},
mesh = {*Alzheimer Disease/diagnosis ; Humans ; *Early Diagnosis ; *Mass Screening/ethics/methods ; Biomarkers ; },
abstract = {Although curative therapies for Alzheimer's disease (AD) remain elusive, recent approval of disease-modifying treatments and advances of less- or non-invasive biomarkers have shifted the paradigm toward earlier detection, including in asymptomatic individuals. Here, we propose a multidisciplinary framework, integrating scientific evidence, ethical principles, and value-based health care, to guide the responsible development and deployment of early detection programs for AD.},
}

*Alzheimer Disease/diagnosis
Humans
*Early Diagnosis
*Mass Screening/ethics/methods
Biomarkers

@article {pmid41240853,
year = {2025},
author = {Dang, K and Zheng, Q and Zhou, T and Wang, Y and Pan, D and Du, L and Suo, S and Dang, Y and Ma, L and Gao, X},
title = {Enhancing cognitive function with biopeptides from porcine brain hydrolysates via key targets: Keap1, p38α, AChE, and BACE1.},
journal = {Food chemistry},
volume = {497},
number = {},
pages = {147028},
doi = {10.1016/j.foodchem.2025.147028},
pmid = {41240853},
issn = {1873-7072},
abstract = {Previous research has reported the efficacy of porcine brain hydrolysate (PBH) in improving Alzheimer's disease (AD). Nevertheless, the identification and screening of peptides with memory-enhancing effects within PBH remains ambiguous. The memory-enhancing effect of PBH was evaluated through animal and human experiments. Peptides with potential memory-enhancement effects were screened using molecular docking based on key target proteins (Keap1, BACE1, AChE, and p38α), and confirmed through cellular experiments. Results showed a significant reduction in behavioral errors of mice and marked improvements in the memory scores of humans. Five peptides with potential memory-enhancing effects were identified and screened. Cell experiments demonstrated that the cell activities were increased to 89.83 % and 78.14 % respectively for FPLHP and WGQKPW. Furthermore, the two peptides could reduce the contents of the four target proteins, thereby exhibiting the potential of memory enhancement. These findings offer a novel strategy for the discovery of peptides, which contribute to the development of memory-enhancing.},
}

@article {pmid41240623,
year = {2025},
author = {Raghuvanshi, R and Wakudkar, SC and Manda, S and Bharate, SB},
title = {Design, synthesis, and biological evaluation of kenpaullone derivatives as potential dual inhibitors of cholinesterases and glycogen synthase kinase-3β.},
journal = {Bioorganic chemistry},
volume = {167},
number = {},
pages = {109232},
doi = {10.1016/j.bioorg.2025.109232},
pmid = {41240623},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder that demands therapeutic approaches targeting multiple pathological pathways. Among these, the cholinergic deficit, amyloid-β (Aβ) aggregation, and tau hyperphosphorylation are recognized as key contributors to disease progression. This study aimed to develop multitarget-directed ligands (MTDLs) by rationally modifying the potent but poorly soluble glycogen synthase kinase 3β (GSK-3β) inhibitor, kenpaullone 17b, to simultaneously inhibit cholinesterases (ChEs) and GSK-3β while improving physicochemical properties. Initial substitution of the C9-bromo group in 17b with a sulfonamide moiety produced compound 17m, which retained strong GSK-3β inhibition (IC50 = 0.35 μM) and acquired modest acetylcholinesterase (AChE) inhibitory activity (IC50 = 20 μM). Further elongation of the C9 substituent with a cyclohexylaminopropyl chain yielded compound 18o, exhibiting balanced dual inhibition of AChE (IC50 = 1.7 μM), butyrylcholinesterase (BChE) (IC50 = 5.3 μM), and GSK-3β (IC50 = 5.7 μM). Compound 18o also inhibited Aβ1-42 self-aggregation by 21 % at 10 μM and demonstrated blood-brain barrier (BBB) permeability with a 100-fold improvement in aqueous solubility compared with 17b. Molecular docking and molecular dynamics simulations revealed stable dual binding conformations within the AChE and GSK-3β active sites, supported by key hydrogen bonds and hydrophobic interactions. Overall, the structurally flexible analog 18o represents a promising dual ChE/GSK-3β inhibitor with improved drug-like characteristics, warranting further preclinical evaluation as a potential therapeutic lead for AD.},
}

@article {pmid41240614,
year = {2025},
author = {Khan, U and Ahmad, M and Tuba, M and Naaz, R and Qayum, F and Khatoon, S and Sanobar, and Ahamad, S and Saquib, M and Hussain, MK},
title = {Natural alkaloids with therapeutic potential against Alzheimer's disease through cholinesterase inhibition.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 2},
pages = {118371},
doi = {10.1016/j.ejmech.2025.118371},
pmid = {41240614},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which the decline of cholinergic neurotransmission plays a central role in cognitive impairment. Cholinesterase inhibition remains an established therapeutic approach to enhance acetylcholine levels and provide symptomatic relief. Natural alkaloids have long served as an important source of cholinesterase inhibitors, offering diverse molecular scaffolds, stereochemical complexity, and strong biological relevance. This review provides a comprehensive overview of natural alkaloids reported as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, highlighting their structural diversity, mechanisms of inhibition, and structure-activity relationships. In addition, the review presents a brief analysis on the emerging pseudo-natural product (PNP) framework as a complementary strategy for designing new alkaloid-inspired potential inhibitors that combine nature-derived functionality with synthetic innovation. Overall, the manuscript underscores the enduring significance of alkaloids in cholinesterase inhibitor discovery and their potential in developing next-generation therapeutics for AD.},
}

@article {pmid41240472,
year = {2025},
author = {Nada, H and Yuan, S and El Gaamouch, F and Cho, S and Kuncewicz, K and Calvo-Barreiro, L and Gabr, MT},
title = {TREM2 activation by first-in-class direct small molecule agonists: DEL screening, optimization, biophysical validation, and functional characterization.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 3},
pages = {118358},
doi = {10.1016/j.ejmech.2025.118358},
pmid = {41240472},
issn = {1768-3254},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial function, and its loss-of-function variants are linked to Alzheimer's disease (AD) and neurodegenerative disorders. While TREM2 activation is a promising therapeutic strategy, no small molecule agonists acting via direct TREM2 binding have been reported to date. Here, we describe the discovery of first-in-class, direct small molecule TREM2 agonists identified through DNA-encoded library (DEL) screening. The DEL hit (4a) demonstrated TREM2 binding affinity, as validated by three biophysical screening platforms (TRIC, MST, and SPR), induced Syk phosphorylation, luciferase assay and enhanced microglial phagocytosis. Pre-liminary optimization yielded 4i, which maintained TREM2 engagement with improved selectivity over TREM1 and no cytotoxicity. Molecular dynamics simulations predicted that 4a stabilizes a transient binding pocket on TREM2, indicating the possibility of a novel mechanism for receptor activation. These findings provide the first proof-of-concept for direct pharmacological TREM2 agonism, offering a foundation for developing therapeutics against AD and related disorders.},
}

@article {pmid41240389,
year = {2025},
author = {Jahanmehr, D and Ahmadi, A and Fadaei, M and Sangi Nasab Lahijan, A and Shafiee Sabet, M and Kalantari Dehaghi, H and Asadi-Golshan, R},
title = {The Ketogenic Diet: A Possible Intervention for Improving Hippocampal Function in Neurological Disorders.},
journal = {Nutrition reviews},
volume = {},
number = {},
pages = {},
doi = {10.1093/nutrit/nuaf210},
pmid = {41240389},
issn = {1753-4887},
abstract = {With a focus on the hippocampus, in this review we examined the emerging role of the ketogenic diet (KD) in treating neurological disorders. There are multiple pathways through which various versions of the KD influence the hippocampus: energy metabolism shifts, neurotransmitter modulation, neuroinflammation control, and synaptic plasticity and epigenetic regulation modifications. Both animal studies and clinical research, with emphasis on epilepsy and Alzheimer disease, have revealed the therapeutic potential of KDs. By modifying energy metabolism and lowering neuroinflammation, KDs may have therapeutic uses such as treatment of epilepsy and Alzheimer disease. In addition, ketones may stabilize hippocampal neuronal networks and reduce amyloid-beta toxicity. Individualized factors and the duration and timing of KD intervention play critical roles in achieving optimal outcomes, such as enhanced hippocampal function and neuroprotection. While preclinical studies have demonstrated enhanced hippocampal synaptic plasticity and neuroprotection, the long-term neurological and metabolic effects of KDs require further clinical validation. There are still a number of important research gaps, especially with regard to the application of animal findings to humans. Future studies should concentrate on long-term human trials using standardized designs to investigate how KDs can affect the nervous system.},
}

@article {pmid41240365,
year = {2025},
author = {Zammit, MD and Bruzzone, H and Cody, KA and Morse, J and Wilson, R and Bettcher, BT and McLachlan, MJ and McVea, AK and DiFilippo, AH and Carey, FJ and Janelidze, S and Hansson, O and Price, JC and Laymon, CM and Minhas, DS and Luo, W and Rosas, HD and Lai, F and Lee, JH and Lao, PJ and Ances, BM and Krinsky-McHale, SJ and Hom, CL and Hartley, SL and Zaman, SH and Johnson, SC and Cohen, AD and Head, E and Mapstone, ME and Handen, BL and Christian, BT and Tudorascu, DL and Langhough, RE and Betthauser, TJ and , },
title = {The tau biomarker cascade is condensed in Down syndrome compared to sporadic Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf428},
pmid = {41240365},
issn = {1460-2156},
abstract = {Characterizing the timing and progression of Alzheimer's disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer's disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium - Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer's Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analyzed on Lilly MSD were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modeling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help identify optimal treatment windows for these individuals.},
}

@article {pmid41240282,
year = {2025},
author = {Tatara, Y and Yamamoto, H and Terai, K and Matsuta, R and Kasai, S and Tamada, Y and Mikami, T and Murashita, K and Itoh, K},
title = {Multi-marker discovery for mild cognitive impairment in metabolomics using machine learning with a global surrogate model via partial least squares.},
journal = {Metabolomics : Official journal of the Metabolomic Society},
volume = {21},
number = {6},
pages = {164},
pmid = {41240282},
issn = {1573-3890},
support = {JPMJCE1302//Center of Innovation Program from the Japan Science and Technology Agency (JST, COI)/ ; JPMJPF2210//Center of Innovation Program from the Japan Science and Technology Agency (JST, COI-NEXT)/ ; },
mesh = {*Cognitive Dysfunction/metabolism/diagnosis/blood ; *Metabolomics/methods ; *Biomarkers/blood/metabolism ; Least-Squares Analysis ; Humans ; *Machine Learning ; Male ; Aged ; Female ; Principal Component Analysis ; Aged, 80 and over ; Algorithms ; },
abstract = {INTRODUCTION: Dementia can be prevented through early intervention; hence, there is an urgent need for biomarkers to help diagnose mild cognitive impairment (MCI).

OBJECTIVES: We aimed to develop a multi-marker panel composed of plasma metabolites to aid in the diagnosis of MCI.

METHODS: We performed an analysis of a multi-marker panel of MCI metabolites using a random forest algorithm with variable selection methods and a global surrogate with principal component analysis and partial least squares (PLS).

RESULTS: By incorporating variable selection methods, we constructed a predictive model that demonstrated robust performance, with an AUC of approximately 0.85 in both cross-validation and test evaluations, using only five metabolites (methionine, quinic acid, hypoxanthine, O-acetylcarnitine, and 2-oxoglutaric acid). However, owing to the limited number of selected metabolites, it was challenging to infer the biological meaning of this multi-marker panel. To interpret this multi-marker panel biologically, we constructed a global surrogate model using PLS. By examining the PLS loadings corresponding to the scores with intergroup differences, we identified a relationship between 14 metabolites involved in neuronal energy metabolism and neurotransmission. This suggests that the multi-marker panel constructed in this study is related to abnormalities in energy metabolism and neurotransmission in patients with MCI.

CONCLUSION: The method used in this study may be broadly applicable for analyzing multi-marker panels of metabolites and their biological interpretation. This study included an independent validation, and further larger-scale studies using additional external cohorts are warranted to confirm the generalizability of this approach.},
}

*Cognitive Dysfunction/metabolism/diagnosis/blood
*Metabolomics/methods
*Biomarkers/blood/metabolism
Least-Squares Analysis
Humans
*Machine Learning
Male
Aged
Female
Principal Component Analysis
Aged, 80 and over
Algorithms

@article {pmid41240244,
year = {2025},
author = {Jayathilaka, NS and Weththasinghe, AV and Amarasekara, CI and Amasha, EADH and Wijekoon, KJ and Firdous, SM},
title = {Targeting the Gut-Brain Axis Through Insulin-like Growth Factors: Therapeutic Implications and Future Directions.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {4},
pages = {150},
pmid = {41240244},
issn = {1559-1166},
mesh = {Humans ; Animals ; *Brain/metabolism ; Gastrointestinal Microbiome ; *Somatomedins/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy/therapy ; *Insulin-Like Growth Factor I/metabolism ; *Brain-Gut Axis ; *Gastrointestinal Tract/metabolism ; Insulin-Like Peptides ; },
abstract = {The gut-brain axis represents a sophisticated bidirectional communication network connecting the gastrointestinal tract and central nervous system through neural, endocrine, and immune pathways. Insulin-like growth factors (IGFs), particularly IGF-1 and IGF-2, function as pivotal mediators within this communication framework. These polypeptide growth factors regulate intestinal barrier integrity, microbiota homeostasis, neurogenesis, and synaptic plasticity mechanisms. Clinical evidence from 1989 to 2024 demonstrates that gut microbiota-derived short-chain fatty acids enhance IGF-1 production through novel molecular mechanisms. This narrative review examines IGF roles in gut-brain communication and evaluates therapeutic potential for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and depression, as well as inflammatory bowel disorders. Current clinical trials investigating IGF-based interventions show preliminary promising results, though studies remain limited in scope and patient numbers. Key therapeutic challenges include delivery mechanisms across biological barriers, oncogenic safety concerns related to cell proliferation, and substantial individual variability in treatment responses. Future directions emphasize development of tissue-specific IGF modulators, microbiome-targeted interventions, and precision medicine approaches utilizing advanced biomarkers. Understanding IGF-mediated gut-brain communication presents therapeutic opportunities for complex pathological conditions simultaneously affecting gastrointestinal and neurological systems.},
}

Humans
Animals
*Brain/metabolism
Gastrointestinal Microbiome
*Somatomedins/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy/therapy
*Insulin-Like Growth Factor I/metabolism
*Brain-Gut Axis
*Gastrointestinal Tract/metabolism
Insulin-Like Peptides

@article {pmid41240183,
year = {2025},
author = {García-Castro, P and Conejo, NM and González-Pardo, H},
title = {Transcranial photobiomodulation therapy in older women regarding cognitive functions: a systematic review.},
journal = {Lasers in medical science},
volume = {40},
number = {1},
pages = {480},
pmid = {41240183},
issn = {1435-604X},
mesh = {Humans ; *Low-Level Light Therapy/methods ; Female ; *Cognition/radiation effects ; Aged ; *Cognitive Dysfunction/therapy ; Animals ; Alzheimer Disease/therapy ; },
abstract = {Transcranial photobiomodulation therapy (tPBM) is a promising non-invasive treatment that uses red or near-infrared light to modulate biological functions and elicit therapeutic effects. This systematic review aimed to summarise the evidence on the effectiveness of tPBM in improving cognitive function in older women, in experimental animal models and in humans, by analyzing the optimal tPBM parameters and behavioral and neurobiological outcomes. tPBM offers advantages specific to older women as a non-invasive brain stimulation technique, applied to a sensitive population with increased risk of ageing-related brain dysfunction due to increased life expectancy. A comprehensive literature search was conducted in PubMed, Scopus, and PsycINFO databases, and only seven articles on older women were included in the review. Studies have shown that tPBM significantly improves cognitive impairment in Alzheimer's disease and related dementias, stroke, cognition and Parkinson's disease in older women. Despite the heterogeneity in the application parameters and limited number of studies, tPBM therapy was preliminarily found to be a safe, feasible, and effective non-pharmacological therapy for several neurological and mental health conditions in older women. Further research is required to establish standardized protocols for optimal therapeutic applications.},
}

Humans
*Low-Level Light Therapy/methods
Female
*Cognition/radiation effects
Aged
*Cognitive Dysfunction/therapy
Animals
Alzheimer Disease/therapy

@article {pmid41239890,
year = {2025},
author = {Pokorny, R and Ryan, JM and Abd-Elaziz, K and van den Berg, F and Rabiner, E and Searle, GE and Schneider, M and Wiessner, C and Stallaert, JF and Permanne, B and Quattropani, A and Beher, D},
title = {Safety, Tolerability, Pharmacokinetics, and Brain Target Occupancy of the OGA Inhibitor ASN90 in Healthy Participants.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70104},
pmid = {41239890},
issn = {1531-8257},
abstract = {BACKGROUND: The OGA inhibitor ASN90/FNP-223 has the potential for disease modification in neurodegenerative diseases. A phase 1 clinical program in healthy participants was performed to determine its suitability for subsequent studies in movement disorders and Alzheimer's disease (AD) patients.

METHODS: Clinical Study 1: A randomized, double-blind, placebo-controlled, first-in-human study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of single and multiple doses of orally administered ASN90 in healthy adult and elderly participants. Clinical Study 2: A phase 1, open-label, positron emission tomography (PET) study in healthy participants to determine the relationship between plasma concentration and brain target occupancy of ASN90 following a single oral dose.

OBJECTIVES: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and central nervous system (CNS) target engagement of ASN90 in healthy participants.

RESULTS: ASN90 was considered safe and well tolerated with dose-proportional pharmacokinetics at steady-state up to oral doses of 500 mg twice daily. Cerebrospinal fluid-to-plasma ratios for mean peak and mean systemic exposures were in the range of 2.5%-4.6%. Investigation of CNS occupancy using a PET ligand demonstrated that target occupancy of greater than 98% in the brain of healthy participants can be achieved at doses that are clinically well tolerated.

CONCLUSIONS: The phase 1 results of ASN90 in healthy participants provide strong support for its further development in progressive supranuclear palsy (PSP) and AD. Currently, Ferrer Internacional, S.A. is conducting a phase 2 study, known as PROSPER (ClinicalTrials.gov ID: NCT06355531), to evaluate the efficacy, safety, and pharmacokinetics of ASN90 in slowing the progression of PSP. © 2025 International Parkinson and Movement Disorder Society.},
}

@article {pmid41239821,
year = {2025},
author = {Kronvold, C and Sperling, S and Möller, S and Grauslund, J and Stokholm, L},
title = {Primary open-angle glaucoma as a marker of upcoming Alzheimer's disease: A 20-year Danish National Registry-Based Study.},
journal = {Acta ophthalmologica},
volume = {},
number = {},
pages = {},
doi = {10.1111/aos.70039},
pmid = {41239821},
issn = {1755-3768},
support = {2410//P. Carl Petersen Foundation/ ; 24030032//Synoptik Foundation/ ; },
abstract = {PURPOSE: To investigate whether primary open-angle glaucoma (POAG) is associated with an increased long-term risk of developing Alzheimer's disease, given its shared neurodegenerative features.

METHODS: A 20-year longitudinal, registry-based matched cohort study was conducted using Danish national health registries from 1998 to 2018. Individuals aged 65 years or older with POAG identified by registration with the diagnostic code (ICD-10 = H40.1*) or at least four redeemed glaucoma prescriptions (ATC = S01E*) within 1 year entered the cohort. Each individual with POAG was randomly matched with five controls of the same sex and birth year. The outcome of Alzheimer's disease was defined by registration with the diagnostic code (ICD-10 = G30*, F00*). A Cox regression model adjusting for age, sex and systemic comorbidities estimated the hazard ratio (HR) for Alzheimer's disease and a Fine-Grey competing-risk model accounted for death as a competing event.

RESULTS: The study included 61 829 individuals with POAG and 306 794 matched controls (42.63% males, 57.37% females; median age 75.22 years, IQR: 70.35-80.63). Alzheimer's disease developed in 1.61% of individuals with POAG and 1.59% of controls. POAG did not appear to increase the risk of Alzheimer's disease (adjusted HR 0.98, 95% CI: 0.93-1.03). Competing risk analyses found a slightly increased risk of Alzheimer's disease observed among men with POAG (sHR 1.12, 95% CI: 1.03-1.21), whereas no association was found among women (sHR 1.00, 95% CI: 0.94-1.07).

CONCLUSION: In this nationwide matched cohort study, POAG was not clearly associated with an overall increased risk of developing Alzheimer's disease over 20 years.},
}

@article {pmid41239797,
year = {2025},
author = {Garg, N and Dhankhar, S and Dhariya, A and Parkash, C and Chauhan, S and Singh, TG},
title = {Role of Liposomes in the Treatment of Neurodegenerative Disorders: A Comprehensive Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {25},
number = {4},
pages = {496-512},
pmid = {41239797},
issn = {1875-6166},
mesh = {Humans ; *Liposomes/metabolism/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Drug Delivery Systems/methods ; *Neuroprotective Agents/administration & dosage/therapeutic use ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {The complex etiology and limited therapy options of neurodegenerative illnesses pose daunting challenges to modern medicine. Nonetheless, novel treatment approaches have exciting new possibilities because of developments in nanotechnology. Liposomes have garnered a lot of interest as a potential treatment for neurological illnesses due to the fact that they are able to adapt to their role as nanocarriers. This review article discusses various uses of liposomes, including their ability to help treat neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as their diagnostic and neuroprotective uses. Liposomes allow for the targeted delivery of medicines to specific brain areas with minimal systemic side effects since they encapsulate and carry therapeutic molecules across the blood-brain barrier. Due to the fact that they are biocompatible, have surface features that can be adjusted, and have the ability to co-deliver many drugs, liposomes are excellent candidates for combination therapy and personalized medicine procedures. In spite of this, there is a growing body of research that suggests liposomes could serve as a versatile platform for the improvement of neurodegenerative disease treatment. This is a positive sign for the future results of patients and their quality of life.},
}

Humans
*Liposomes/metabolism/chemistry
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
*Drug Delivery Systems/methods
*Neuroprotective Agents/administration & dosage/therapeutic use
Blood-Brain Barrier/metabolism/drug effects

@article {pmid41239791,
year = {2025},
author = {Bassi, P and Rana, S and Sapra, V and Raina, A and Kumar, P and Devi, S},
title = {Exploring Novel Therapeutic Avenues: Drug Repurposing for Neurodegenerative Movement Disorders.},
journal = {Current drug research reviews},
volume = {17},
number = {3},
pages = {375-393},
pmid = {41239791},
issn = {2589-9783},
mesh = {Humans ; *Drug Repositioning/methods ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Movement Disorders/drug therapy ; },
abstract = {Neurodegenerative movement disorders, encompassing conditions such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a significant burden on individuals, families, and healthcare systems globally. Traditional drug discovery approaches for these disorders have encountered challenges, including high costs and lengthy timelines. Drug repurposing has emerged in recent years as a promising approach to expedite the discovery of new treatments by leveraging existing drugs approved for other indications. This review explores the landscape of drug repurposed for neurodegenerative movement disorders, highlighting promising candidates, underlying mechanisms, and clinical implications. The rationale behind repurposing, including the advantages of utilizing existing pharmacological agents with established safety profiles and known pharmacokinetics, along with techniques utilized for repurposing (computational and experimental), have been elaborated. Several studies on the potential of pre-existing drugs such as isradipine, tetracycline, ambroxol, metformin, deferiprone, simvastatin, etc., which have been repurposed for neurodegenerative movement disorders, including Parkinson's disease, Huntington's disease, Alzheimer's disease, Multiple Sclerosis, etc. have been discussed. Further, the current scenario and future prospective of drug repurposing have also been touched upon.},
}

Humans
*Drug Repositioning/methods
*Neurodegenerative Diseases/drug therapy
Animals
*Movement Disorders/drug therapy

@article {pmid41239670,
year = {2025},
author = {He, L and Xing, C and Yang, X and Wang, S and Tian, B and Cheng, J and Yao, Y and Sui, B},
title = {Association between visceral adiposity index and cognitive dysfunction in US participants derived from NHANES data: A cross-sectional analysis.},
journal = {Medicine},
volume = {104},
number = {46},
pages = {e45814},
doi = {10.1097/MD.0000000000045814},
pmid = {41239670},
issn = {1536-5964},
mesh = {Humans ; Cross-Sectional Studies ; Male ; Female ; Nutrition Surveys ; *Cognitive Dysfunction/epidemiology/etiology ; Aged ; Middle Aged ; United States/epidemiology ; *Intra-Abdominal Fat ; *Obesity, Abdominal/epidemiology/complications ; Neuropsychological Tests ; Risk Factors ; },
abstract = {This study examines the cross-sectional association between the Visceral Adiposity Index (VAI) and domain-specific cognitive performance in US older adults. We analyzed data from 1323 participants aged ≥ 60 years in the National Health and Nutrition Examination Survey (NHANES) 2011 to 2014. Cognitive function was assessed with CERAD Word‑List Learning (memory/learning), Animal Fluency Test (semantic fluency/executive function), and the Digit Symbol Substitution Test (DSST; processing speed/attention). We fitted a sequence of multiple linear regression models: model 1 (crude), model 2 (adjusted for demographic covariates), model 3 (further adjusted for lifestyle factors), and model 4 (additionally adjusted for clinical comorbidities). Effect estimates are presented as β coefficients with 95% confidence intervals and P-values. VAI showed no significant link with composite cognition in age‑ and sex-unadjusted analyses (Model 1), while DSST approached significance (β = -0.16, 95% CI - 0.31 to - 0.02, P = .027). After adjusting for demographics (Model 2) DSST remained significant (β = -0.15, 95% CI - 0.29 to - 0.01, P = .031). Adding lifestyle factors (Model 3) gave a similar DSST effect (β = -0.15, P = .017) and also negative associations for immediate recall (β = -0.14, P = .039) and animal fluency (β = -0.18, P = .012). Full adjustment for sociodemographic and clinical comorbidities (Model 4) rendered these associations non‑significant (all P >.05), with Delayed Recall borderline (β = 0.15, P = .054). Sensitivity tests excluding clinical covariates partly restored the intermediate‑model effects, and removing the dyslipidemia covariate partly reversed attenuation, suggesting cardiometabolic comorbidities and overlap between VAI and lipid measures drive much of the attenuation. Age- and lifestyle-adjusted analyses showed inverse, domain‑specific links between higher VAI and cognition (most notably processing speed), but these weakened after full sociodemographic and clinical adjustment, suggesting measured sociodemographic and cardiometabolic factors largely explain the crude associations. Intermediate-model findings are hypothesis‑generating. Longitudinal studies with repeated measures, direct visceral-fat imaging, and mechanistic biomarkers are needed to separate confounding from mediation and to determine whether VAI or its metabolic components independently predict cognitive decline.},
}

Humans
Cross-Sectional Studies
Male
Female
Nutrition Surveys
*Cognitive Dysfunction/epidemiology/etiology
Aged
Middle Aged
United States/epidemiology
*Intra-Abdominal Fat
*Obesity, Abdominal/epidemiology/complications
Neuropsychological Tests
Risk Factors

@article {pmid41239587,
year = {2025},
author = {Chang, H},
title = {Epidemiological trends, attributable risks, decomposition analysis, and forecasts of Alzheimer's disease and other dementias burden in China, 1990 to 2036: A population-based observational study.},
journal = {Medicine},
volume = {104},
number = {46},
pages = {e45880},
doi = {10.1097/MD.0000000000045880},
pmid = {41239587},
issn = {1536-5964},
mesh = {Humans ; China/epidemiology ; *Alzheimer Disease/epidemiology/mortality ; Male ; Female ; Aged ; Risk Factors ; Incidence ; Middle Aged ; Aged, 80 and over ; Disability-Adjusted Life Years ; *Dementia/epidemiology ; Forecasting ; Global Burden of Disease/trends ; Cost of Illness ; Adult ; },
abstract = {This study analyzes the burden of Alzheimer disease and other dementias (ADOD) in China using Global Burden of Disease 2021 data. The data on ADOD in China from 1990 to 2021 was collected from the Global Burden of Disease 2021. The incidence rate, mortality and the number of disability adjusted life years (DALYs), and age-standardized rates of ADOD were analyzed. Use Joinpoint analysis to evaluate trends. Analyze the attribution ratio of risk factors such as smoking, high body mass index, and high fasting blood glucose (FPG) to the burden of ADOD disease. Evaluate the relative contributions of epidemiological changes, population growth, and population aging through decomposition analysis. Autoregressive Integrated Moving Average model is used to evaluate future trends. Age-standardized incidence rose from 121.11 (95% confidence interval: 105.5-137.99) to 151.47 (131.22-173.34) per 100,000, with an estimated annual percentage change (APC) of 0.41% (0.34-0.49%). Age-standardized mortality declined from 31.39 (7.6-83.63) to 30.82 (7.88-82.43) per 100,000, yet deaths increased by 3.92% annually (estimated APC: 3.79-4.04%). disability adjusted life years (DALYs) surged to 10.07 (4.95-22.22) million, with age-standardized DALY rate reaching 562.39 (271.16-1238.81) per 100,000. Joinpoint regression confirmed upward trends for age-standardized incidence (average APC = 0.60%, 0.46-0.74%) and age-standardized DALY rate (average APC = 0.10%, -0.01 to 0.22%). The incidence rate, mortality, and DALYs of ADOD in men and women mostly occur in the age group over 75 years old. FPG was the leading risk factor, attributing to 10.5% of DALYs, followed by smoking (8.0%) and high body mass index (0.2%). Decomposition analysis identified epidemiological changes as the primary driver of mortality increases (679,000 deaths, 45.6% contribution), exceeding aging (595,000 deaths) and population growth (214,000 deaths). Projections to 2036 indicate dramatic growth: cases rising to 7.46 (5.73-9.20) million, deaths to 1.12 (0.93-1.31) million, and DALYs to 23.76 (19.10-28.43) million. The ADOD burden in China has significantly increased, especially among women and the elderly population. It is worth noting that FPG is the primary risk factor for ADOD. The disease ADOD burden will continue to rise. Attention should be paid to the issue of population aging, and interventions targeting ADOD risk factors should be emphasized.},
}

Humans
China/epidemiology
*Alzheimer Disease/epidemiology/mortality
Male
Female
Aged
Risk Factors
Incidence
Middle Aged
Aged, 80 and over
Disability-Adjusted Life Years
*Dementia/epidemiology
Forecasting
Global Burden of Disease/trends
Cost of Illness
Adult

@article {pmid41239516,
year = {2025},
author = {Shi, Y and Li, Y and Ci, R and Yan, S and Tian, T and Zheng, N and Zhu, W and Qin, Y},
title = {Dynamic functional connectivity and transcriptomic signatures reveal stage-dependent brain network dysfunction in Alzheimer's disease spectrum.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {247},
pmid = {41239516},
issn = {1758-9193},
support = {2022YFC2406903//National Key Research and Development Program of China/ ; 81873890//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/genetics/diagnostic imaging ; Male ; Female ; Magnetic Resonance Imaging ; Cross-Sectional Studies ; Aged ; *Cognitive Dysfunction/physiopathology/diagnostic imaging/genetics ; *Brain/physiopathology/diagnostic imaging/metabolism ; *Transcriptome ; *Nerve Net/physiopathology/diagnostic imaging ; Middle Aged ; Neuropsychological Tests ; Disease Progression ; },
abstract = {BACKGROUND: Alzheimer's Disease Spectrum (ADS) progresses from preclinical stages to dementia, with dynamic functional connectivity (dFC) changes emerging early. This study aimed to investigate the dynamic changes in brain networks across different stages of ADS and their underlying molecular mechanisms.

METHODS: This cross-sectional study included 239 participants: 69 Healthy Controls (HC), 83 with Subjective Cognitive Decline (SCD), 56 with Mild Cognitive Impairment (MCI), and 31 with Alzheimer's disease (AD). All participants underwent neuropsychological testing and resting-state functional magnetic resonance imaging (rs-fMRI). Leading Eigenvector Dynamics Analysis (LEiDA), a data-driven method that captures time-resolved whole-brain dFC, was applied to identify transient brain states and calculated their occupancy rate, dwell time, and transition probabilities. Group differences in these dynamic metrics were assessed using a General Linear Model (GLM), and their correlations with cognitive performance were examined. To explore the molecular basis of significant dFC alterations, we performed gene-category enrichment analysis. This analysis integrated the spatial maps of altered brain states with regional gene expression data from the Allen Human Brain Atlas (AHBA), using spin permutations to ensure statistical robustness.

RESULTS: We identified ten recurring brain states and characterized how their transition patterns, stability, and frequency differed as a function of disease severity. Specifically, early disruptions appeared as altered transition probabilities between states, while later stages showed pronounced changes in the dwell time and occurrence rates of specific states, closely associated with cognitive decline. Notably, one brain state marked by synchronized activity in attention, salience, and default mode networks emerged as a critical hub linked to both cognitive deterioration and excitatory-inhibitory imbalance. Genes associated with this state were enriched in glycine-mediated synaptic pathways and expressed in both excitatory and inhibitory neurons, showing spatial and temporal patterns that extended from early development into late disease stages.

CONCLUSIONS: Our study uncovered the stage-dependent dFC changes and their molecular underpinnings of brain network dysfunction across the ADS.},
}

Humans
*Alzheimer Disease/physiopathology/genetics/diagnostic imaging
Male
Female
Magnetic Resonance Imaging
Cross-Sectional Studies
Aged
*Cognitive Dysfunction/physiopathology/diagnostic imaging/genetics
*Brain/physiopathology/diagnostic imaging/metabolism
*Transcriptome
*Nerve Net/physiopathology/diagnostic imaging
Middle Aged
Neuropsychological Tests
Disease Progression

@article {pmid41239142,
year = {2025},
author = {Eva, TA and Shenoy, A and Gupta, VB and Palanivel, V and Salkar, A and Nasab, SN and Chitranshi, N and Mirzaei, M and You, Y and Graham, SL and Basavarajappa, D and Gupta, V},
title = {The Dynamic Roles of Repressor Element 1-Silencing Transcription Factor (REST): A Double-Edged Sword in Neural Health and Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {46},
pmid = {41239142},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Repressor Proteins/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; *Neurons/metabolism/pathology ; *Health ; },
abstract = {The repressor element 1-silencing transcription factor (REST), or neuron-restrictive silencer factor (NRSF), is crucial for gene regulation since it binds to chromatin and recruits chromatin-modifying enzymes. Acting as a regulatory hub, REST orchestrates neurogenesis, neuronal differentiation, and the preservation of neuronal identity by regulating a broad network of target genes across stem cells, non-neuronal cells, and neurons. These targets influence critical processes such as axonal growth, vesicular transport, neurotransmitter release, and ion conductance. An important feature of normal aging in cortical and hippocampal neurons is REST induction, where it contributes to extended longevity by repressing genes linked to neuronal excitability and stress vulnerability. However, REST's role in neurodegenerative diseases remains complex and context dependent. Variations in its expression and subcellular localization, including cytoplasmic translocation or loss, have been implicated in the pathology of disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and epilepsy. Given its broad regulatory functions, REST has emerged as an attractive therapeutic target. Strategies such as microRNA modulation, small molecule inhibitors, and complex-disrupting compounds have been explored, each offering unique opportunities and challenges. Understanding REST's molecular mechanisms and disease-specific functions is critical for identifying novel therapeutic interventions. This review provides a comprehensive analysis of REST's role in aging and neurodegeneration, highlighting its regulatory networks, disease relevance, and recent therapeutic strategies targeting REST, with an emphasis on their potential for clinical translation.},
}

Humans
Animals
*Repressor Proteins/metabolism/genetics
*Neurodegenerative Diseases/metabolism/pathology/genetics
*Neurons/metabolism/pathology
*Health

@article {pmid41239092,
year = {2025},
author = {Kong, W and Miao, X and Dang, R and Jiang, P and Feng, L},
title = {Mechanisms and Clinical Significance of Endosomal Toll-Like Receptors in Neurological Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {54},
pmid = {41239092},
issn = {1559-1182},
support = {82373585//National Natural Science Foundation of China/ ; 2023M741364//the China Postdoctoral Science Foundation/ ; ZR2022MH007//the Natural Science Foundation of Shandong Province/ ; 2022YXNS124//the Jining Key R&D Projects/ ; 2022YXNS137//the Jining Key R&D Projects/ ; 202304040457//the Medical and Health Science and Technology Development Project of Shandong Province/ ; },
mesh = {Humans ; *Toll-Like Receptors/metabolism ; *Endosomes/metabolism ; Animals ; *Nervous System Diseases/metabolism ; Signal Transduction ; Clinical Relevance ; },
abstract = {Neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and epilepsy constitute a major global public health burden, affecting millions of patients. Recent studies have shown that the complex interactions between the immune system and the nervous system play a significant role in these diseases, especially Toll-like receptors (TLRs), among which endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) are crucial in neuroinflammation and disease progression. This review systematically elaborates on the biological characteristics of endosomal TLRs, their distribution, and signaling pathways within the central nervous system, with a particular focus on their "double-edged sword" effect in specific disease contexts: on the one hand, they may provide neuroprotection, while on the other hand, they can exacerbate neural injury and neurodegeneration during immune dysregulation. Furthermore, this article evaluates the potential and challenges of utilizing endosomal TLRs as early diagnostic biomarkers. It summarizes research progress in targeted regulatory strategies as emerging therapeutic approaches, along with the encountered bottlenecks in clinical translation. The review aims to systematically integrate fundamental mechanistic research with clinical application prospects, emphasizing the critical importance of in-depth elucidation of the mechanistic roles of endosomal TLRs in neurological disorders and their translational value in diagnosis and treatment. Clinical trial number: not applicable.},
}

Humans
*Toll-Like Receptors/metabolism
*Endosomes/metabolism
Animals
*Nervous System Diseases/metabolism
Signal Transduction
Clinical Relevance

@article {pmid41239049,
year = {2025},
author = {Ma, H and Cong, C},
title = {Insights and advances of theranostic nanoscale metal-organic frameworks.},
journal = {Mikrochimica acta},
volume = {192},
number = {12},
pages = {809},
pmid = {41239049},
issn = {1436-5073},
mesh = {*Metal-Organic Frameworks/chemistry ; Humans ; *Theranostic Nanomedicine/methods ; Contrast Media/chemistry ; Animals ; },
abstract = {As one class of multifunctional materials, metal-organic frameworks (MOFs) with virtues like large surface area, high porosity, and tailorability have been found in many applications. Particularly, the investigation on health is rapidly growing. Accurate diagnosis and efficient treatment of diseases are increasingly important but challenging. Nanoplatforms based on MOFs are receiving much attention, which has made significant progress in imaging and drug delivery during the past few years. This review article will summarize and discuss the latest development of nanoscale MOFs in the following topics: contrast agents for magnetic resonance imaging (MRI); X-ray computed tomography imaging (CT); optical imaging (OI); photoacoustic imaging (PAI); photothermal imaging (PTI); positron emission tomography (PET); single-photon emission computed tomography (SPECT); and multimodal imaging (MI). In addition, targeting drug delivery by MOFs to treat diseases will be categorized into the followings: cancers; lung diseases; bone diseases; diabetes; infections; wound healing; bowel diseases; Alzheimer's disease; ocular diseases; and atherosclerosis.},
}

*Metal-Organic Frameworks/chemistry
Humans
*Theranostic Nanomedicine/methods
Contrast Media/chemistry
Animals

@article {pmid41238997,
year = {2025},
author = {Chen, Y and Wang, Z and Chen, H and Xu, J and Li, H and Li, S and , },
title = {CSF Glucose-6-Phosphate Isomerase Is a Tau-Related Biomarker Associated with Neurodegeneration and Cognitive Impairment in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {47},
pmid = {41238997},
issn = {1559-1182},
support = {82471199//the National Natural Science Foundation of China/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/cerebrospinal fluid/complications/pathology ; *tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Aged ; Male ; *Cognitive Dysfunction/cerebrospinal fluid/complications ; *Glucose-6-Phosphate Isomerase/cerebrospinal fluid ; *Nerve Degeneration/cerebrospinal fluid ; Cross-Sectional Studies ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; Magnetic Resonance Imaging ; Cohort Studies ; },
abstract = {Skeletal diseases are closely linked to Alzheimer's disease (AD) in terms of epidemiology and pathogenesis. Glucose-6-phosphate isomerase (GPI), a critical enzyme in the glycolytic pathway that participates in various skeletal disorders, has unclear effects on AD pathological progression in humans. This cross-sectional study included 601 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) [260 (43.3%) women; 288 (47.9%) APOE ε4 carriers]. The cohort comprised 151 cognitively normal (CN) participants [mean age 74.7 (5.9) years] and 450 cognitively impaired (CI) participants [mean age 72.8 (7.8) years]. We assessed CSF GPI levels, AD biomarkers (CSF β-amyloid [Aβ]42, phosphorylated Tau [p-Tau]181), magnetic resonance imaging-based neurodegenerative changes, and cognitive function. Associations between CSF GPI levels and AD pathology, neurodegeneration, and cognition were evaluated using linear regression models. Mediation models were employed to investigate the potential mechanism of how CSF GPI affects AD pathology. Findings were validated in two independent external cohorts using autopsy-confirmed Braak staging (n = 419; mean age 84.1 [6.6] years; 195 [46.5%] women) and cross-platform validation (n = 36). Among the total cohort (N = 601), CSF GPI levels were significantly elevated among participants with tau pathology (T+ group), regardless of Aβ status, and correlated positively with CSF p-Tau181 but not with Aβ42. Higher CSF GPI levels were also associated with downstream events of tau pathology, including reduced hippocampal volume and worse cognitive performance. Mediation analyses revealed that CSF GPI partially mediated tau pathology's effects on hippocampal volume reduction and cognitive impairment. Moreover, CSF GPI exhibited excellent diagnostic accuracy in distinguishing tau-positive/negative (T+/-) participants (area under the curve [AUC] = 0.833), with even higher accuracy when combined with demographic indicators (AUC = 0.862). In the external cohort, we used Braak staging of neuropathologies found at autopsy to indicate tau pathology and validated its positive association with CSF GPI levels (p < 0.001), with cross-platform validation demonstrating strong concordance of GPI measurements between different analytical methods (r = 0.817, p < 0.001). CSF GPI shows associations with tau pathology independent of amyloid status and may partially mediate relationships between tau pathological changes and neurodegeneration. These findings indicate that CSF GPI may serve as a potential biomarker reflecting tau-related pathological processes. However, further validation studies are required to establish its utility for clinical diagnostic evaluation or therapeutic monitoring.},
}

Humans
Female
*Alzheimer Disease/cerebrospinal fluid/complications/pathology
*tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Aged
Male
*Cognitive Dysfunction/cerebrospinal fluid/complications
*Glucose-6-Phosphate Isomerase/cerebrospinal fluid
*Nerve Degeneration/cerebrospinal fluid
Cross-Sectional Studies
Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
Magnetic Resonance Imaging
Cohort Studies

@article {pmid41238954,
year = {2025},
author = {Augusto-Oliveira, M and Arrifano, GP and Leal-Nazaré, CG and Soares-Silva, I and Lopes-Araujo, A and Santos-Sacramento, L and Crespo-Lopez, ME},
title = {Lifestyle Drives Astroglial Plasticity Toward Cognitive Improvement: Roles of Physical Exercise, Environmental Enrichment, Diet, and Sleep.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {42},
pmid = {41238954},
issn = {1559-1182},
support = {444791/2023-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 427784/2018-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
mesh = {Humans ; *Neuronal Plasticity/physiology ; *Astrocytes/physiology ; *Cognition/physiology ; Animals ; *Sleep/physiology ; *Exercise/physiology ; *Life Style ; *Diet ; *Environment ; },
abstract = {Lifestyle, including physical exercise, diet, intellectual and social engagement, and sleep, represents a powerful nonpharmacological alternative to improve cognitive performance or mitigate cognitive decline associated with ageing or neuropathological conditions. Among brain cells, astrocytes, the most abundant glial cell, are involved in virtually all brain functions, from neurogenesis and synaptogenesis to brain homeostasis, defence, and cognition. Recent studies demonstrate that astrocytes are very sensitive to lifestyle changes, undergoing morphological, molecular, and functional remodelling. These adaptations include enhanced astrocyte complexity, increased synaptic coverage, modulation of inflammatory pathways, and changes in gene expression. Such modifications, accompanied by cognitive improvements, are observed in models of Alzheimer's and Parkinson's, depression, and cerebral ischaemia, as well as in sleep quality and dietary patterns-making astrocytes key elements in lifestyle-induced neural plasticity driving brain health and cognitive improvements. Here, we discuss astroglial roles in translating lifestyle benefits into cognitive improvements; such mechanisms may represent a therapeutic target to prevent or even mitigate cognitive dysfunction associated with ageing or neurological conditions, ultimately contributing to quality of life.},
}

Humans
*Neuronal Plasticity/physiology
*Astrocytes/physiology
*Cognition/physiology
Animals
*Sleep/physiology
*Exercise/physiology
*Life Style
*Diet
*Environment

@article {pmid41238774,
year = {2025},
author = {Cerman, J and Škorvagová, A and Vyhnálek, M and Veverová, K and Dvořák, K and Kozák, Š and Kavka, A and Hort, J},
title = {Concordance between amyloid PET and CSF biomarkers in clinical setting: a cross-platform comparison and in-depth analysis of discordant cases.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39963},
pmid = {41238774},
issn = {2045-2322},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis/metabolism ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Female ; *Positron-Emission Tomography/methods ; Aged ; tau Proteins/cerebrospinal fluid ; Middle Aged ; Peptide Fragments/cerebrospinal fluid ; *Amyloid/metabolism ; Aged, 80 and over ; Enzyme-Linked Immunosorbent Assay ; Apolipoprotein E4/genetics ; },
abstract = {Reliable detection of amyloid pathology is essential for Alzheimer's disease (AD) diagnosis and treatment. We directly compared routine ELISA assays and the automated Lumipulse platform against quantitative amyloid PET in a real-world memory clinic cohort. In 153 participants, flutemetamol amyloid PET and CSF biomarkers were assessed across platforms. Concordance with PET and predictors of discordance were evaluated. PET visual reads and Centiloids showed near-perfect agreement (AUC = 0.99). The p-tau181/Aβ42 ratio achieved the highest concordance with PET (OPA 87% ELISA, 92% Lumipulse), while the Lumipulse Aβ42/40 ratio reached 93%. About 6% of participants showed consistent discordance between CSF and PET, associated with APOE ε4 and mixed or non-AD pathologies. Automated CSF assays align strongly with amyloid PET and support biomarker standardization. Persistent discrepancies between CSF and PET likely reflect underlying biological heterogeneity such as mixed or non-AD pathologies and APOE ε4 carriage.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis/metabolism
Male
*Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Female
*Positron-Emission Tomography/methods
Aged
tau Proteins/cerebrospinal fluid
Middle Aged
Peptide Fragments/cerebrospinal fluid
*Amyloid/metabolism
Aged, 80 and over
Enzyme-Linked Immunosorbent Assay
Apolipoprotein E4/genetics

@article {pmid41238639,
year = {2025},
author = {Esteve, M and Martinez-Gracia, A and Rodríguez-Sala, JJ and Brotons-Mas, JR and Falcó, A},
title = {A novel approach integrating topological deep learning from EEG Data in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39942},
pmid = {41238639},
issn = {2045-2322},
support = {TED2021-129347B-C22//Ministerio de Ciencia e Innovación/ ; TED2021-129347B-C22//Ministerio de Ciencia e Innovación/ ; TED2021-129347B-C22//Ministerio de Ciencia e Innovación/ ; TED2021-129347B-C22//Ministerio de Ciencia e Innovación/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology ; *Electroencephalography/methods ; *Deep Learning ; Male ; Female ; Aged ; Neural Networks, Computer ; Support Vector Machine ; Middle Aged ; Frontotemporal Dementia/diagnosis/physiopathology ; },
abstract = {High-throughput analysis of EEG data has significantly contributed to understanding neural dynamics in Alzheimer's disease diagnosis. However, the complexity and high dimensionality of EEG signals pose challenges for traditional classification methods, which often fail to capture intricate patterns. To address this, we propose a hybrid approach integrating Topological Deep Learning (TDL) with machine learning models-including Support Vector Machines (SVM), Random Forest (RF), Neural Networks (NN), and Logistic Regression (LR)-for Alzheimer's disease classification. By leveraging TDL, our method extracts topological and neural features from EEG data, enhancing the identification of disease-specific patterns that conventional models may overlook. The dataset consists of EEG recordings from 88 individuals, categorized into AD patients, FTD patients, and CN, providing a robust foundation for model evaluation. Our findings demonstrate that NN augmented by TDL achieve the highest classification accuracy, reaching up to 90% in distinguishing AD, FTD, and CN cases. These results highlight the potential of TDL-enhanced deep learning models in clinical applications, offering a more accurate and detailed tool for Alzheimer's disease diagnosis and differentiation from other neurodegenerative conditions. This work is presented as a proof-of-concept demonstrating that persistence-based topological descriptors can enhance EEG classification; multicenter validation on larger, diverse cohorts will be required to confirm generalizability.},
}

Humans
*Alzheimer Disease/diagnosis/physiopathology
*Electroencephalography/methods
*Deep Learning
Male
Female
Aged
Neural Networks, Computer
Support Vector Machine
Middle Aged
Frontotemporal Dementia/diagnosis/physiopathology

@article {pmid41238601,
year = {2025},
author = {Alzarea, SI},
title = {Identification of novel neuraminidase 1 modulators as potential therapeutics for Alzheimer's disease using virtual screening and molecular dynamics simulations.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39901},
pmid = {41238601},
issn = {2045-2322},
support = {KSRG-2024-340//King Salman Center for Disability Research/ ; },
mesh = {*Neuraminidase/antagonists & inhibitors/metabolism/chemistry ; *Alzheimer Disease/drug therapy/enzymology/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Humans ; *Enzyme Inhibitors/pharmacology/chemistry ; Drug Evaluation, Preclinical ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder caused by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, resulting in neuronal dysfunction and cognitive decline. The neuraminidase isoenzyme NEU1 is a most ubiquitous mammalian enzyme, involved in various cellular mechanisms. The deficiency of NEU1 has been implicated in the pathophysiology of AD, significantly in amyloid precursor protein (APP) metabolism and Aβ clearance. Despite extensive research, no potent NEU1 modulator has been developed to regulate its activity for therapeutic intervention in AD. The present work aims to identify potential NEU1 modulators from a library of seaweed Metabolites Database through molecular docking, ADMET analysis, and molecular dynamics (MD) simulations. A library of 1,077 seaweed metabolites was screened, identifying 20 active compounds, of which 4 met Lipinski's Rule of Five criteria. ADMET profiling revealed favorable pharmacokinetic properties for BE003, BS032, and RG007, with good blood-brain barrier permeability and bioavailability. Molecular docking demonstrates that BE003, BS032, RG007, and BD039 metabolites exhibited the highest binding affinities for the NEU1 active site. Additionally, MD simulation and MM-GBSA validated the stability of the metabolite-protein complex, with BE003 demonstrating the most stable interactions. Comparative docking against a natural substrate (Neu5Ac) and a NEU1 inhibitor (17f) revealed that BE003 shares significant interaction, RMSD stability profiles with the substrate and loop conformational dynamics while differing from the inhibitor. Our findings emphasize the potential of this modulator as a novel therapeutic target against NEU1 in AD treatment. Further experimental validation and preclinical studies are needed to confirm its efficacy in modulating NEU1 activity.},
}

*Neuraminidase/antagonists & inhibitors/metabolism/chemistry
*Alzheimer Disease/drug therapy/enzymology/metabolism
Molecular Dynamics Simulation
Molecular Docking Simulation
Humans
*Enzyme Inhibitors/pharmacology/chemistry
Drug Evaluation, Preclinical

@article {pmid41238324,
year = {2025},
author = {Soulier, T and Burgos, N and Hassanaly, R and Pitombeira, M and Solal, M and Roy, H and Hamzaoui, M and Yazdan-Panah, A and de Paula Faria, D and Louapre, C and Bodini, B and Bottlaender, M and Ayache, N and Colliot, O and Stankoff, B},
title = {Artificial intelligence in presymptomatic neurological diseases: Bridging normal variation and prodromal signatures.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {944-950},
doi = {10.1016/j.neurol.2025.07.011},
pmid = {41238324},
issn = {0035-3787},
mesh = {Humans ; *Prodromal Symptoms ; *Artificial Intelligence/trends ; *Nervous System Diseases/diagnosis ; Early Diagnosis ; Deep Learning ; Machine Learning ; Cognitive Dysfunction/diagnosis ; },
abstract = {Presymptomatic neurological diseases are marked by early pathological changes that occur before overt clinical symptoms. These stages, which include prodromes such as REM sleep behavior disorder in Parkinson's or mild cognitive impairment in Alzheimer's, offer critical opportunities for early intervention. However, their detection remains challenging due to the subtlety of changes and the overlap with normal interindividual variability. Artificial intelligence (AI), especially machine learning (ML) and deep learning (DL), offers new tools to uncover hidden signatures in complex biomedical data. First, we explore how supervised ML models can detect known prodromal patterns across diverse modalities, including EEG, cognitive scores, and structural imaging. Depending on the input, various model types - such as tree-based algorithms for structured data and convolutional or transformer networks for images and signals - can extract predictive features of early neurodegeneration. These approaches have demonstrated success in identifying at-risk individuals before clinical thresholds are reached. Yet, detecting only known patterns limits the scope of early intervention. Many individuals who will go on to develop neurological disease may not yet exhibit any recognized prodromal syndrome. Bridging this gap requires moving beyond predefined labels toward models capable of identifying subtle, unknown anomalies in individuals still considered healthy. Second, we address the detection of latent anomalies among individuals not yet considered at risk without identifiable known prodromal patterns. By mining clinical records, free-text medical notes, and population-level health databases (e.g., UK Biobank, EDS-AP-HP), and by analyzing sensor data from smartphones or wearables, AI can flag deviations from healthy patterns long before symptom onset or formal diagnosis. This approach holds promise for scalable, low-burden, ecological screening. Finally, we introduce the concept of pseudo-healthy twins - synthetic, personalized baselines generated from structural data such as MRI, to improve anomaly detection. These models predict a patient's expected healthy signal in another modality, such as PET, enabling the subtraction of normal anatomical and physiological variability to isolate disease-specific effects. Generative models like GANs and VAEs have shown promise in producing these cross-modal references, enhancing early anomaly detection in diseases like Alzheimer's and multiple sclerosis. Together, these approaches show how AI can bridge the gap between normal variation and early pathology, enabling more sensitive, personalized, and population-scalable detection of presymptomatic neurological disease.},
}

Humans
*Prodromal Symptoms
*Artificial Intelligence/trends
*Nervous System Diseases/diagnosis
Early Diagnosis
Deep Learning
Machine Learning
Cognitive Dysfunction/diagnosis

@article {pmid41238323,
year = {2025},
author = {Cohen, M},
title = {Digital health in presymptomatic diseases.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {937-943},
doi = {10.1016/j.neurol.2025.06.017},
pmid = {41238323},
issn = {0035-3787},
mesh = {Humans ; *Nervous System Diseases/diagnosis ; Telemedicine/trends ; Early Diagnosis ; Parkinson Disease/diagnosis ; *Asymptomatic Diseases/therapy ; *Prodromal Symptoms ; Digital Health ; },
abstract = {Most of widely available consumer devices like smartphones and tablets are equipped with various sensors that allow for detection of subtle and undetectable neurological impairment of various neurological functions like motricity, coordination, cognition, visual function or eye movements. This opens the perspective of earlier diagnosis of neurological diseases, even at the preclinical stage, which could allow for earlier therapeutic intervention and improved long term outcomes. In this article, we review how technology can enhance the clinician's examination skills and the current level of evidence in the field of preclinical diseases detection, in diseases like Parkinson's disease, Alzheimer's disease or multiple sclerosis. Many studies reported subtle impairment regarding fine motricity, eye movements, cognition, voice features and speech. We will also discuss current limitations regarding scientific evidence and practical implementation in the daily practice, as well as future perspectives.},
}

Humans
*Nervous System Diseases/diagnosis
Telemedicine/trends
Early Diagnosis
Parkinson Disease/diagnosis
*Asymptomatic Diseases/therapy
*Prodromal Symptoms
Digital Health

@article {pmid41238322,
year = {2025},
author = {Dupont, S},
title = {Late-onset epilepsy as a prodromal symptom.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {929-936},
doi = {10.1016/j.neurol.2025.07.007},
pmid = {41238322},
issn = {0035-3787},
mesh = {Humans ; *Prodromal Symptoms ; *Epilepsy/diagnosis/epidemiology/etiology ; Age of Onset ; Alzheimer Disease/diagnosis/complications/epidemiology ; Risk Factors ; Stroke/diagnosis/complications ; Aged ; },
abstract = {Late-onset epilepsy (LOE) of unknown etiology accounts for 15-30% of all LOE cases. A critical question is whether these unexplained seizures represent a prodromal manifestation of an underlying neurological disorder - most notably, stroke or Alzheimer's disease (AD). Growing evidence suggests that seizures may be an early sign of subclinical cerebrovascular disease, serving as a warning signal for future stroke, or an early symptom of a neurodegenerative disorder, particularly AD, reflecting initial pathological changes such as amyloid-β and tau deposition. An alternative hypothesis proposes that shared risk factors - especially cardiovascular ones - underlie all three conditions: LOE, stroke, and AD. As a result, it is recommended that patients with LOE of unknown etiology undergo comprehensive cardiovascular evaluation and receive appropriate management of any identified risk factors. However, it remains unclear whether this approach is sufficient to prevent future strokes. Cognitive assessment is also essential in these patients. In this context, prodromal seizures may provide an opportunity to identify individuals suitable for early, targeted interventions aimed at slowing neurodegeneration.},
}

Humans
*Prodromal Symptoms
*Epilepsy/diagnosis/epidemiology/etiology
Age of Onset
Alzheimer Disease/diagnosis/complications/epidemiology
Risk Factors
Stroke/diagnosis/complications
Aged

@article {pmid41238317,
year = {2025},
author = {Wallon, D and Garnier-Crussard, A},
title = {The challenging concept of preclinical Alzheimer's disease.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {881-892},
doi = {10.1016/j.neurol.2025.07.016},
pmid = {41238317},
issn = {0035-3787},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/pathology ; *Prodromal Symptoms ; Biomarkers/analysis ; Prognosis ; tau Proteins ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a decades-long process that begins before any first cognitive symptoms. Neuropathology and in vivo biomarker studies have revealed a silent preclinical phase. However, its precise definition and boundaries remain debated. Elucidating the biological events and temporal sequence that characterize this stage is essential, while researchers try to identify the optimal window to prevent or postpone cognitive decline. At the same time, "preclinical AD" raises unresolved challenges in diagnosis, prognosis, therapeutic intervention and ethics. This narrative review synthesizes the current evidence, from clinical characterization to prevention trials and societal considerations, with an emphasis on original findings for amyloid, tau and neurodegeneration biomarkers. We critically contrast the two principal research frameworks that structure the field and examine how each shapes patient classification and trial design. By integrating these lines of evidence, we explore persistent gaps in prognostic modeling and in the clinical efficacy of disease-modifying strategies. The review aims to provide a concise but comprehensive overview of the preclinical concept for clinicians and researchers developing the next generation of preventive interventions for AD.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/pathology
*Prodromal Symptoms
Biomarkers/analysis
Prognosis
tau Proteins

@article {pmid41238313,
year = {2025},
author = {Rival, M and Thouvenot, E},
title = {Tracing Neurological Diseases in the presymptomatic phase: moving forward a detection panel.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {821-828},
doi = {10.1016/j.neurol.2025.08.004},
pmid = {41238313},
issn = {0035-3787},
mesh = {Humans ; Biomarkers/analysis ; *Nervous System Diseases/diagnosis ; Neurodegenerative Diseases/diagnosis ; Early Diagnosis ; Disease Progression ; *Prodromal Symptoms ; Asymptomatic Diseases ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) often exhibit a prolonged presymptomatic phase during which neuropathological changes silently progress. Recent advances in biomarker research have revealed molecular and imaging signatures that precede clinical onset by years, offering a critical window for early intervention. This review synthesizes current knowledge on the most promising presymptomatic biomarkers across these conditions, highlighting their biological origins, diagnostic performance, and clinical utility. Particular emphasis is placed on the development and validation of biomarker panels, which combine multiple markers to enhance diagnostic sensitivity and specificity, enabling more accurate detection of disease in its earliest stages. Minimally invasive approaches, such as blood-based assays, are also discussed for their potential to facilitate widespread screening and longitudinal monitoring. As these biomarkers begin to integrate into clinical workflows, particularly in AD and MS, international collaboration will be essential to standardize methodologies and ensure equitable implementation. Ultimately, presymptomatic biomarkers hold transformative potential for shifting neurology toward a proactive and precision-based paradigm.},
}

Humans
Biomarkers/analysis
*Nervous System Diseases/diagnosis
Neurodegenerative Diseases/diagnosis
Early Diagnosis
Disease Progression
*Prodromal Symptoms
Asymptomatic Diseases

@article {pmid41238191,
year = {2025},
author = {Yang, Y and Wang, Q and Wang, Z and Wang, Y and Liu, B and Zhang, Y and Mao, X and Sun, H},
title = {The Role of Fatty Acids in Neurodegenerative Diseases: Mechanistic Insights and Therapeutic Strategies.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {100944},
doi = {10.1016/j.jlr.2025.100944},
pmid = {41238191},
issn = {1539-7262},
abstract = {Fatty acids (FAs) play multifaceted roles in neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review systematically summarizes current understanding of fatty acid metabolism and its diverse implications in NDD pathology. Short-chain fatty acids (SCFAs), primarily generated by gut microbiota, regulate neuroinflammation, gut-brain communication, and blood-brain barrier (BBB) integrity via epigenetic modifications and immune modulation. Medium-chain fatty acids (MCFAs) exhibit therapeutic potential by improving energy metabolism and neuromuscular function, particularly in ALS models. Long-chain polyunsaturated fatty acids (PUFAs), notably docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), contribute to neuronal membrane integrity, synaptic plasticity, and antioxidant defense, mitigating oxidative stress and neuroinflammation. Conversely, saturated and certain n-6 fatty acids may exacerbate neurodegeneration through pro-inflammatory and oxidative pathways. Emerging evidence highlights fatty acid involvement in key pathological processes such as lipid peroxidation, mitochondrial dysfunction, ferroptosis, and BBB disruption. Therapeutically, targeted supplementation, dietary modification, microbiome manipulation, and advanced nanotechnology-based delivery systems are promising strategies. Nevertheless, precise therapeutic efficacy depends critically on disease stage, dosage, genetic background, and individual metabolic context. Integrating personalized medicine with precision nutritional strategies and novel drug-delivery platforms offers promising avenues to translate fatty acid-based interventions into clinical practice, potentially improving patient outcomes in the aging global population.},
}

@article {pmid41238157,
year = {2025},
author = {Wang, Z and Sun, C and Hu, K and Zang, Y and Cheng, Y and Xu, H and Xu, R},
title = {Effects of whole-body vibration on animal models of neurodegenerative diseases: A systematic review.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115555},
doi = {10.1016/j.expneurol.2025.115555},
pmid = {41238157},
issn = {1090-2430},
abstract = {BACKGROUND: The incidence of neurodegenerative diseases (NDs) is gradually increasing with the aging. Non-pharmacological treatments have positive effects on delaying the progression of NDs. While regular exercise is known to benefit patients, the therapeutic potential of whole-body vibration (WBV) remains understudied.

PURPOSE: This systematic review aims to synthesize evidence from animal models to evaluate WBV's efficacy in improving ND-related outcomes and to explore the relationships between WBV parameters (frequency, amplitude, duration) and functional improvements.

METHODS: PubMed and Web of Science were searched from 1983 to 24 February 2025 for animal studies that reported the improvement of brain function or performance after WBV exposure. Based on 11 original publications of good scientific standard, according to the PRISMA statement, we analyzed information on study design, animal characteristics and exposure and outcome variables.

RESULTS: According to the risk of bias assessment results obtained using the SYRCLE risk of bias tool, none of the included studies fully meet all methodological criteria, which may lead to potential bias. These selected studies have demonstrated WBV has potential therapeutic benefits in animal models of NDs, including motor performance, cognitive function and emotional regulation. In addition, system analysis reveals relationships between specific vibration parameters (frequency, amplitude, duration) and their interactions with different outcomes.

CONCLUSION: WBV holds significant potential as a non-invasive adjunct therapy for NDs, particularly Alzheimer's Disease (AD). Future research should prioritize protocol standardization and translational trials to validate efficacy in human ND populations.},
}

@article {pmid41238155,
year = {2025},
author = {Heath, AM and Mojabi, FS and Kraybill, EP and Beard, C and Venkataramanan, V and Cuéllar, V and Piekarski, D and McNerney, MW},
title = {Comparison of treatment schedules on cognitive effects of rTMS in the 3xTg-AD model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115551},
doi = {10.1016/j.expneurol.2025.115551},
pmid = {41238155},
issn = {1090-2430},
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a promising non-invasive therapy for improving cognition in Alzheimer's disease (AD), but the optimal treatment parameters have yet to be elucidated. One important parameter is the treatment schedule. In this study, we used an established rodent low intensity rTMS stimulation protocol to compare cognitive and biochemical effects of a intensive treatment protocol (daily for 12 days) to a distributed protocol (twice a week for six weeks) in 12-month-old 3xTg-AD mice and B6 controls. We found that both protocols improved object place memory function, but only the distributed protocol improved working memory as measured with the Y-Maze. We did not find any effect of either rTMS protocol on BDNF or amyloid pathology, although these measures correlated well with activity and cognitive performance, suggesting rTMS improvement was independent of these mechanisms. Intensive rTMS increased choline acetyltransferase-positive neurons in the anterior bed nucleus of the stria terminalis (BNST), which may be due to the function of this region in mediating cognitive and limbic circuitry. These results indicate that while both treatment protocols can improve specific aspects of recognition memory, only distributed rTMS improves working memory function, possibly due to causing less cognitive fatigue and physiological stress. Future studies should examine region specific changes relating working memory function and stress related signaling to further understand the mechanisms behind this important rTMS treatment parameter.},
}

@article {pmid41238102,
year = {2025},
author = {Long, J and Liu, S and Shi, Y and Zhang, C and Qin, L and Ai, Q},
title = {Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical.},
journal = {Metabolism: clinical and experimental},
volume = {},
number = {},
pages = {156436},
doi = {10.1016/j.metabol.2025.156436},
pmid = {41238102},
issn = {1532-8600},
abstract = {The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases-including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)-are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.},
}

@article {pmid41238077,
year = {2025},
author = {Ancy, PM and Sumithra, M},
title = {Development and optimization of flavonoid-enriched solid lipid nanoparticles of Peperomia Pellucida for enhanced brain delivery in Alzheimer's disease: A Quality by Design approach.},
journal = {Annales pharmaceutiques francaises},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.pharma.2025.11.003},
pmid = {41238077},
issn = {2772-803X},
abstract = {OBJECTIVES: The Peperomia pellucida plant exhibits notable neuroprotective potential but has low oral bioavailability in the brain. Herein, we aimed to enhance the oral bioavailability and brain distribution of Peperomia Pellucida, by formulating its flavonoid-enriched fraction into solid lipid nanoparticles as a potential therapeutic approach for Alzheimer' disease.

MATERIALS AND METHODS: Flavonoid-enriched solid lipid nanoparticles of Peperomia pellucida were formulated using an ultrasonication method. A Box-Behnken design was utilized to optimize particle size, entrapment efficiency, and burst release. The optimized formulation was identified via numerical and graphical optimization, and validated through reproducibility studies. Further characterization included scanning electron microscopy and in vivo drug release studies in rats.

RESULTS: Glycerol tripalmitate-based solid lipid nanoparticles exhibited superior entrapment efficiency and reduced burst release. The mean particle size of the solid lipid nanoparticles ranged 110-884 nm, with entrapment efficiency ranging 55-94%. Oral administration of the optimized formulation significantly improved bioavailability in rats and enhanced drug distribution in the cortex and hippocampus of the brain.

CONCLUSION: The results highlight the potential of solid lipid nanoparticles as an effective delivery system for the flavonoid-enriched fraction of Peperomia Pellucida, enhancing its therapeutic impact in the treatment of Alzheimer's disease.},
}

@article {pmid41238044,
year = {2025},
author = {Yang, W and Yong, S and Zhang, W and Zhou, Q and Tan, X and Xu, Y},
title = {Exploring the toxicological impact of di(2-ethylhexyl) phthalate exposure on Alzheimer's disease via network toxicology and integrative bioinformatics analysis.},
journal = {Brain research bulletin},
volume = {233},
number = {},
pages = {111635},
doi = {10.1016/j.brainresbull.2025.111635},
pmid = {41238044},
issn = {1873-2747},
abstract = {This study investigates the potential involvement of the environmental contaminant di(2-ethylhexyl)phthalate (DEHP) in the etiology and progression of Alzheimer's disease (AD). Available data indicates that DEHP, a prevalent plasticizer capable of traversing the blood-brain barrier, can induce oxidative stress and other neurotoxic effects, potentially aggravating the etiology of Alzheimer's disease. The multi-target molecular pathways remain inadequately comprehended, and the existing research exhibits methodological deficiencies. We employed a comprehensive computational biology strategy that incorporated network toxicology, machine learning, and molecular docking techniques to systematically elucidate the neurotoxic pathways of DEHP. This approach aims to elucidate the theoretical foundations for environmental risk assessment and Alzheimer's disease biomarker identification by examining how DEHP may expedite the advancement of Alzheimer's disease through disruption of mitochondrial homeostasis and neuronal structural integrity.},
}

@article {pmid41237903,
year = {2025},
author = {Mulet, M and Sánchez Milán, JA and Lorca, C and Fernández-Rhodes, M and Adrados-Planell, A and Bejarano Castillo, MC and Saiz, L and Mateos-Moreno, MV and Hase, Y and Mira, A and Rábano, A and Ser, TD and Kalaria, RN and Lagunas, A and Mir, M and Crespo, A and Samitier, J and Gallart-Palau, X and Serra, A},
title = {Oral microbiome-derived proteins in brain extracellular vesicles circulate and tie to specific dysbiotic and neuropathological profiles in age-related dementias.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101464},
doi = {10.1016/j.mcpro.2025.101464},
pmid = {41237903},
issn = {1535-9484},
abstract = {The involvement of the oral microbiome (OM) in the pathophysiology of Alzheimer's disease (AD) and vascular dementia (VaD) has been recognized epidemiologically, but the molecular mechanisms remain elusive. In this study, we uncovered the presence of oral microbiome-derived proteins (OMdPs) in brain extracellular vesicles (bEVs) from post-mortem AD and VaD subjects using unbiased metaproteomics. OMdPs circulation in blood extracellular vesicles was also confirmed in an independent cohort. Our findings also reveal that specific OMdPs are present in bEVs, with their levels varying with disease progression. Peptidome-wide correlation analyses further explored their exchange dynamics and composition within bEVs. Additionally, we validated the ability of OM-derived EVs (OM-EVs) to cross the blood-brain barrier (BBB) using a BBB-on-a-chip model, confirming a potential route for bacterial-derived molecules to reach the CNS. Bioinformatics-driven interaction analyses indicated that OMdPs engage with key neuropathological proteins, including amyloid-beta and tau, suggesting a novel mechanism linking dysbiotic OM to dementia. These results provide new insights into the role of the OM in neurodegeneration and highlight OMdPs as potential biomarkers and therapeutic targets.},
}

@article {pmid41237676,
year = {2025},
author = {Aumont, E and Hall, BJ and Chan, T and Trudel, L and Bezgin, G and Hosseini, SA and Therriault, J and Macedo, AC and Fernández Arias, J and Rahmouni, N and Servaes, S and Vitali, P and Stevenson, J and Fonov, V and Montembeault, M and Klostranec, J and Iturria-Medina, Y and Gauthier, S and Rosa-Neto, P and , },
title = {Optimized atlas for early tau-PET staging via native space segmentations.},
journal = {Neurobiology of aging},
volume = {158},
number = {},
pages = {1-10},
doi = {10.1016/j.neurobiolaging.2025.11.002},
pmid = {41237676},
issn = {1558-1497},
abstract = {Positron Emission Tomography (PET) early Braak staging might be susceptible to anatomical variability and atrophy in the medial temporal lobe (MTL) structures. These factors should be accounted for in an optimized atlas to improve staging accuracy. This study aimed to compare the accuracy of early tau detection using traditional standard space methods versus using a native space MTL segmentations. Twelve native space MTL structures were used as regions of interest (ROI) for [[18]F]MK6240 tau-PET images and compared with standard space Braak stage ROIs for 333 participants aged over 55. We used the Rey Auditory Verbal Learning Test (RAVLT) to assess memory function. Native and standard space tau-PET stage ROIs were compared, then combined with anatomical constraints into an optimized standard space MTL atlas. The native space MTL tau-PET staging identified 34 participants with significantly more advanced tau accumulation. Of these, 14 had significant entorhinal and transentorhinal tau despite being classified as Braak stage I when using the original standard space method (here called pre-I stage). In addition, 19 were classified as Braak stage III despite being at Braak stage II using standard space methods (here called pre-III stage). These pre-III participants displayed a significant memory impairment. We found that a standard space spatial smoothing to 6 mm at FWHM best allowed to replicate native space results, resulting in the optimized atlas identifying 29 of these 33 more advanced cases. Therefore, standard space approaches can be improved to better capture early AD tau pathology and be more sensitive to cognitive impairment.},
}

@article {pmid41237536,
year = {2025},
author = {Platero, C and Bengoa, J},
title = {Benchmarking parametric models of disease progression for early detection of cognitive decline.},
journal = {Computer methods and programs in biomedicine},
volume = {274},
number = {},
pages = {109162},
doi = {10.1016/j.cmpb.2025.109162},
pmid = {41237536},
issn = {1872-7565},
abstract = {BACKGROUND AND OBJECTIVE: Disease progression models (DPMs) are valuable tools for characterizing early cognitive decline in Alzheimer's Disease (AD) and supporting clinical decision-making. This study aimed to (1) evaluate the diagnostic and prognostic performance of parametric DPMs, (2) identify optimal subsets of neuropsychological markers for DPM construction, and (3) benchmark three parametric DPM frameworks in early detection tasks.

METHODS: We analyzed longitudinal neuropsychological data from 1163 participants classified as cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Three DPM approaches (Leaspy, RPDPM, and GRACE) were trained on selected marker subsets and evaluated using metrics related to diagnostic accuracy, time to conversion estimation, and robustness to missing data. Model performance was assessed via detection rates, area under the curve (AUC), mean absolute error (MAE), and Pearson correlation between estimated/observed onset ages.

RESULTS: Leaspy achieved the highest diagnostic accuracy with an AUC of 0.96 and strong correlation with observed conversion time (r = 0.78). RPDPM showed superior robustness to missing data and maintained accurate predictions even with up to 40% data loss. GRACE offered the best trajectory fit (lowest error) but lower sensitivity to clinical transitions. A compact combination of neuropsychological tests, particularly CDRSB, ADAS13, and MMSE, was sufficient for reliable model training. Prognostic evaluation demonstrated that Leaspy provided the most consistent identification of individuals who converted to mild cognitive impairment within five years.

CONCLUSIONS: Parametric DPMs based solely on neuropsychological measures can effectively support early detection and prognosis of cognitive decline. Leaspy showed the best overall performance, while RPDPM proved more resilient to missing data. These models enable individualized disease timelines and can inform clinical decision-making and patient stratification. All code and data used are publicly available, facilitating reproducibility and clinical translation.},
}

@article {pmid41237466,
year = {2025},
author = {Peng, TR and Lin, HH and Tseng, TL and Wu, TW},
title = {Effectiveness of probiotic supplements on cognitive function in mild cognitive impairment and Alzheimer's disease: A meta-analysis of randomized controlled trials.},
journal = {General hospital psychiatry},
volume = {97},
number = {},
pages = {284-293},
doi = {10.1016/j.genhosppsych.2025.11.004},
pmid = {41237466},
issn = {1873-7714},
abstract = {BACKGROUND: Cognitive impairment, encompassing mild cognitive impairment (MCI) and Alzheimer's disease (AD), poses a significant public health challenge worldwide. Emerging evidences suggest that probiotics, through modulation of the gut-brain axis, may improve cognitive function. However, their efficacy in individuals with cognitive impairment remains unclear.

METHODS: This meta-analysis adhered to PRISMA guidelines, systematically reviewing randomized controlled trials (RCTs) investigating the effects of probiotics for individuals with cognitive impairment. Data were extracted from the PubMed, Embase, and Cochrane databases. Subgroup analyses were conducted based on different measurement scales (MMSE, MoCA, and RBANS), population types (cognitive impairment vs. no cognitive impairment), multiple or single strain and intervention duration. Effect sizes were expressed as standardized mean differences (SMDs) using random-effects models.

RESULTS: Fifteen RCTs involving 994 participants were included. Probiotic supplementation significantly improved cognitive function compared to placebo (SMD = 0.57; 95 % CI, 0.19-0.94; P = 0.003). Subgroup analyses revealed that both single-strain and multi-strain probiotics were effective; however, multi-strain probiotics demonstrated greater heterogeneity and variability in efficacy. Cognitive improvements were most pronounced with supplementation durations of at least 12 weeks (SMD = 0.73; 95 % CI, 0.30-1.16; P = 0.0009) and higher probiotic doses (>1 × 10[9] CFU/g; SMD = 0.93; 95 % CI, 0.36-1.49; P < 0.01).

CONCLUSION: Probiotic supplementations significantly enhance cognitive function in individuals with cognitive impairment, particularly with single-strain formulations, higher doses, and a minimum duration of 12 weeks.},
}

@article {pmid41237463,
year = {2025},
author = {Cho, E and Yi, JH and Jeon, SJ and Kim, DH and Kwon, H and Jeon, J and Kwon, KJ and Jang, DP and Moon, M and Shin, CY and Kim, DH},
title = {Increases in brain catecholamine levels counteract memory deficits and reduces Aβ deposition in 5XFAD male mice.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118764},
doi = {10.1016/j.biopha.2025.118764},
pmid = {41237463},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a degenerative brain disease that presents with neurological symptoms and memory loss, with no clear treatment. Catecholamines, including dopamine, epinephrine, and norepinephrine, can inhibit or degrade the abnormal aggregation of proteins that cause diseases; however, developing these catecholamines as medication is difficult. This study aimed to demonstrate that increasing the levels of catecholamines in the brain may help improve symptoms of AD. We tested whether an increase in catecholamines by bupropion, a dopamine and norepinephrine re-uptake inhibitor, improves the symptoms of AD. Dopamine and norepinephrine showed similar effects in inhibiting amyloid β (Aβ) aggregation and the decomposition of Aβ aggregates as curcumin, a positive control. Dopamine and norepinephrine blocked Aβ aggregates-induced abnormal hippocampal long-term potentiation. The intraperitoneal administration of bupropion increased the concentrations of dopamine and norepinephrine in the hippocampus from 1 to 6 h after administration. In the Aβ-induced memory decline model, bupropion showed a dose-dependent improvement in learning and memory. In 5XFAD mice administered bupropion for 2 months, significant improvements in memory and Aβ deposition were also found compared to vehicle-treated 5XFAD mice. These results suggest that the symptoms of AD can be improved or delayed by increasing the amount of dopamine and norepinephrine using bupropion.},
}

@article {pmid41237410,
year = {2025},
author = {Wenzheng, H and Agyemang, EF and Srivastav, S and Shaffer, J and Kakraba, S},
title = {AI-Enhanced Multi-Algorithm R Shiny App for Predictive Modeling and Analytics: A Case study of Alzheimer's Disease Diagnostics.},
journal = {JMIR aging},
volume = {},
number = {},
pages = {},
doi = {10.2196/70272},
pmid = {41237410},
issn = {2561-7605},
abstract = {BACKGROUND: AI has demonstrated superior diagnostic accuracy compared to medical practitioners, highlighting its growing importance in healthcare. SMART-Pred (Shiny Multi-Algorithm R Tool for Predictive Modeling) is an innovative AI-based application for Alzheimer's disease (AD) prediction using handwriting analysis.

OBJECTIVE: To develop and evaluate a non-invasive, cost-effective AI tool for early AD detection, addressing the need for accessible and accurate screening methods.

METHODS: The study employed Principal Component Analysis (PCA) for dimensionality reduction of handwriting data, followed by training and evaluation of ten diverse AI models, including logistic regression, Naïve Bayes, random forest, AdaBoost, Support Vector Machine (SVM), and neural network. Model performance was assessed using accuracy, sensitivity, specificity, F1-score, and ROC-AUC metrics. The DARWIN dataset, comprising handwriting samples from 174 participants (89 AD patients, 85 healthy controls) was used for validation.

RESULTS: The Neural Network classifier achieved an accuracy of 91% with a 95% CI ranging from 0.79-0.97 and an AUC of 94%, on the test set after identifying the most significant features for AD prediction. These results surpass current clinical diagnostic tools, which typically achieve around 81% accuracy. SMART-Pred's performance aligns with recent AI advancements in AD prediction, such as the Cambridge scientists' AI tool achieving 82% accuracy in identifying AD progression within three years using cognitive tests and MRI scans. The variables "air_time" and "paper_time" consistently emerged as critical predictors for AD across all ten AI models, highlighting their potential importance in early detection and risk assessment. To augment transparency and interpretability, we incorporated the principles of explainable AI, specifically using SHapley Additive exPlanations (SHAP) values, a state-of-the-art method to emphasize the features responsible for our model's efficacy.

CONCLUSIONS: SMART-Pred offers non-invasive, cost-effective, and efficient AD prediction, demonstrating the transformative potential of AI in healthcare. While clinical validation is necessary to confirm the practical applicability of the identified key variables, this study contributes to the growing body of research on AI-assisted AD diagnosis and may lead to improved patient outcomes through early detection and intervention.},
}

@article {pmid41237058,
year = {2025},
author = {Xu, F and Wang, J and Gao, P and Li, D and Liu, X},
title = {Neuroprotective Effects of Triterpenoids From Rosa laevigata Root: Identification, Molecular Docking, and In Vitro Evaluation for Alzheimer's Disease Treatment.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e02742},
doi = {10.1002/cbdv.202502742},
pmid = {41237058},
issn = {1612-1880},
abstract = {This study investigates the neuroprotective effects of triterpenoid compounds from Rosa laevigata Michx. roots against Alzheimer's disease (AD). A total of 62 compounds were identified using ultra-performance liquid chromatography-Orbitrap-tandem mass spectrometry analysis, which included 55 triterpenoids and seven flavonoids. Among 15 isolated compounds, compound 13 demonstrated the strongest acetylcholinesterase (AChE) inhibitory activity, with an IC50 of 3.38 µmol/L, and a maximum inhibition rate of 87.20%. Compound 13 exhibited favorable and stable binding with AChE in molecular docking studies, whilst demonstrating mixed-type inhibition in enzyme kinetics. In the H2O2-induced SH-SY5Y cell model, compound 13 exhibited 84.45% viability at 25 µmol/L, surpassing Trolox's 74.16%. Research indicates that R. laevigata Michx. root triterpenes exert neuroprotective effects through AChE inhibition and antioxidant activity, with compound 13 potentially serving as a multi-target lead compound for treating AD.},
}

@article {pmid41236865,
year = {2025},
author = {Hanyu, H and Koyama, Y and Momose, T and Watanabe, S},
title = {Patient With Mild Alzheimer's Disease Homozygous for ApoE ε4 Showing Improved Cognition, No Brain Volume Loss, and Complete Amyloid Clearance After Lecanemab Treatment.},
journal = {Geriatrics & gerontology international},
volume = {},
number = {},
pages = {},
doi = {10.1111/ggi.70251},
pmid = {41236865},
issn = {1447-0594},
}

@article {pmid41236724,
year = {2025},
author = {Eissman, JM and Qiao, M and Kalia, V and Zerlin-Esteves, M and Reyes-Dumeyer, D and Piriz, A and Dubey, S and Nandakumar, R and Lee, AJ and Lantigua, RA and Medrano, M and Mejia, DR and Honig, LS and Dalgard, CL and Miller, GW and Mayeux, R and Vardarajan, BN},
title = {Genetic regulation of the metabolome differs by sex, Alzheimer's disease stage, and plasma biomarker status.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70898},
doi = {10.1002/alz.70898},
pmid = {41236724},
issn = {1552-5279},
support = {R56AG063908/AG/NIA NIH HHS/United States ; R01AG067501/AG/NIA NIH HHS/United States ; RF1AG015473/AG/NIA NIH HHS/United States ; 5UL1TR001873/AG/NIA NIH HHS/United States ; /TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood/metabolism ; Male ; Female ; Biomarkers/blood ; *Metabolome/genetics ; Quantitative Trait Loci/genetics ; Aged ; Polymorphism, Single Nucleotide/genetics ; Sex Factors ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-supported Alzheimer's disease (AD).

METHODS: We computed metabolite quantitative trait loci (QTL) with whole-genome sequencing (WGS) and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components.

RESULTS: We identified 72 SNP-metabolite associations spanning 66 genes and 12 metabolite classes, including PYROXD2/N6-methyllysine, FAAH/myristoylglycine, and FADS2/arachidonic acid. Additionally, we found differences in genetic regulation of metabolites among individuals with clinically-defined AD compared to biomarker-defined AD based on a published plasma P-tau181 cutoff. We also found more SNP-metabolite associations among males compared to females.

DISCUSSION: In summary, we identified sex- and disease-specific genetic regulators of plasma metabolites, revealing unique biological mechanisms of genetic perturbations in AD.

HIGHLIGHTS: Genetic regulators of the metabolome spanned 66 genes and 12 metabolite classes. Clinically versus biomarker-defined Alzheimer's disease (AD) affects genetic regulators of the metabolome. Most metabolite quantitative trait loci (QTLs) are not shared between males and females.},
}

Humans
*Alzheimer Disease/genetics/blood/metabolism
Male
Female
Biomarkers/blood
*Metabolome/genetics
Quantitative Trait Loci/genetics
Aged
Polymorphism, Single Nucleotide/genetics
Sex Factors
Aged, 80 and over

@article {pmid41236559,
year = {2025},
author = {Liu, X and Valencak, TG and Guo, B and Ren, D},
title = {Effects of Osteopontin Combined with Milk Fat Globule Membrane Proteins on Scopolamine-Induced Learning and Memory Impairment in Mice.},
journal = {Neurochemical research},
volume = {50},
number = {6},
pages = {359},
pmid = {41236559},
issn = {1573-6903},
support = {2024AC38038//Guangxi Science and Technology Base and Talent Program/ ; 2024AC38038//Guangxi Science and Technology Base and Talent Program/ ; },
mesh = {Animals ; *Scopolamine/toxicity ; *Osteopontin/therapeutic use/pharmacology/administration & dosage ; Mice ; *Memory Disorders/chemically induced/drug therapy/metabolism ; Male ; Hippocampus/drug effects/metabolism ; *Glycoproteins/therapeutic use/pharmacology/administration & dosage ; *Glycolipids/therapeutic use/pharmacology/administration & dosage ; Lipid Droplets ; Maze Learning/drug effects ; Acetylcholinesterase/metabolism ; Superoxide Dismutase/metabolism ; Malondialdehyde/metabolism ; },
abstract = {This study investigated the effects of osteopontin (OPN) combined with milk fat globule membrane (MFGM) proteins on scopolamine-induced learning and memory impairment in mice. A dementia model was established through intraperitoneal injection of scopolamine, followed by random allocation into seven experimental groups: blank control, model control, OPN alone, MFGM alone, and three combination groups (low-, intermediate-, and high-dosage OPN + MFGM). Cognitive performance was evaluated using the Morris water maze test, accompanied by quantification of hippocampal acetylcholinesterase (AChE) activity, antioxidant enzyme activities (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px]), malondialdehyde (MDA)) from both hippocampal tissue and serum. We found significant cognitive improvements in the intermediate- and high-dosage combination group to the model group, which had reduced escape latency, increased platform crossings, and prolonged target quadrant duration in the water maze test. Biochemical results suggest that these combination treatments significantly suppressed AChE activity in hippocampal tissue while they enhanced antioxidant capacity through elevated SOD and GSH-Px activities, accompanied by reduced MDA levels in both brain and serum. Our study demonstrates that the combination of OPN and MFGM administration improved learning and memory in mice with scopolamine-induced dementia through dose-dependent effects on the central cholinergic nervous and antioxidant system.},
}

Animals
*Scopolamine/toxicity
*Osteopontin/therapeutic use/pharmacology/administration & dosage
Mice
*Memory Disorders/chemically induced/drug therapy/metabolism
Male
Hippocampus/drug effects/metabolism
*Glycoproteins/therapeutic use/pharmacology/administration & dosage
*Glycolipids/therapeutic use/pharmacology/administration & dosage
Lipid Droplets
Maze Learning/drug effects
Acetylcholinesterase/metabolism
Superoxide Dismutase/metabolism
Malondialdehyde/metabolism

@article {pmid41236362,
year = {2025},
author = {Zide, BS and Barker, MS and Silverman, HE and Manoochehri, M and Fremont, R and Stein, C and Kunicki, ZJ and Lee, S and Devanand, DP and Huey, ED},
title = {Feasibility and tolerability of low-dose lithium for the treatment of agitation and abnormal motor behaviors in Frontotemporal Dementia.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/09540261.2025.2572365},
pmid = {41236362},
issn = {1369-1627},
abstract = {Agitation and abnormal motor behaviors are common, distressing symptoms of Frontotemporal Dementia (FTD). While these symptoms currently lack efficacious and safe pharmacological treatments, case reports in FTD and a clinical trial in Alzheimer's disease suggest that patients may benefit from lithium treatment. We designed a randomized, double-blind, placebo-controlled, 12-week clinical trial to evaluate low-dose lithium for the treatment of agitation and abnormal motor behaviors in FTD. However, the trial did not meet its recruitment target (n = 60). This report assesses the trial's feasibility and tolerability using recruitment, study completion, and safety metrics. Sixteen adults with FTD (median age 59.5 years; 69% female) were enrolled from 2017 to 2021. Fourteen participants (88%) completed the trial. The majority of participants on lithium were taking the maximum daily dose by Week 12 (600 mg), had median (interquartile range) final serum lithium levels of 0.42 (0.37-0.57), and reported minimal side effects, including drowsiness, diarrhea, constipation and insomnia. Preliminary data from intended efficacy outcomes showed no median pre-post changes between treatment groups. Low-dose lithium is feasible and well-tolerated in an FTD population. Further systematic study of lithium and its efficacy to treat agitation and abnormal motor behaviors in FTD is warranted.},
}

@article {pmid41236360,
year = {2025},
author = {Zhang, Y and Wang, Y and Zhao, Y and Xin, Y and Zhang, L and Shan, P and Zhu, Y},
title = {Associations Between Malignant Tumors and Alzheimer's Disease: A Cross-Sectional Study.},
journal = {Brain and behavior},
volume = {15},
number = {11},
pages = {e71066},
doi = {10.1002/brb3.71066},
pmid = {41236360},
issn = {2162-3279},
support = {QDFYQN2023226//Youth Research Fund of Qingdao University/ ; 202418000774//Shandong Provincial Medical and Health Science and Technology Guidance Project/ ; },
mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; *Alzheimer Disease/epidemiology ; Middle Aged ; Aged ; *Neoplasms/epidemiology ; Nutrition Surveys ; Adult ; Neurofilament Proteins ; Risk Factors ; United States/epidemiology ; COVID-19/epidemiology ; },
abstract = {INTRODUCTION: Although there is potential overlap in the pathological and physiological mechanisms underlying malignant tumors and Alzheimer's disease (AD), a significant gap remains in the epidemiological evidence supporting their association. We used data from the National Health and Nutrition Examination Survey (NHANES) to elucidate the epidemiological relationship between malignant tumors and AD.

METHODS: We analyzed data from NHANES from 2013 to March 2020, prior to the COVID-19 pandemic, including 9274 participants aged ≥ 20 years. Multivariate logistic regression was used to explore the link among malignant tumors, tumor types, and AD risk. Sensitivity analyses were performed to evaluate the robustness of the association with neurofilament light chain levels, composite cognitive function scores, and different analytic populations. Additionally, subgroup analyses were performed to explore the association between malignancy and AD risk in specific subpopulations.

RESULTS: Among the 9274 participants included in the study, 1432 were identified as having malignant tumors. There was a significant association between malignant tumors and AD [adjusted odds ratio (aOR): 1.55; 95% confidence interval (CI): 1.27-1.89; p < 0.001]. The risk of AD was higher in patients with colorectal and prostate cancer compared to those with other malignancies. Sensitivity analysis of neurofilament light chain levels suggested that malignant tumors may contribute to the development of mild cognitive impairment (aOR: 1.52; 95% CI: 1.01-2.27; p = 0.044). Subgroup analysis revealed that AD risk following a malignant tumor diagnosis was higher in people < 65 years old and those with medium-high incomes.

CONCLUSIONS: Malignant tumors may be significantly associated with increased AD risk, particularly in patients with colorectal and prostate cancer. Moreover, individuals < 65 years old and those with middle-high income had increased risk of developing AD following a malignancy. These findings underscore the significance of early AD detection and prevention in patients with a history of malignant tumors.},
}

Humans
Male
Female
Cross-Sectional Studies
*Alzheimer Disease/epidemiology
Middle Aged
Aged
*Neoplasms/epidemiology
Nutrition Surveys
Adult
Neurofilament Proteins
Risk Factors
United States/epidemiology
COVID-19/epidemiology

@article {pmid41236085,
year = {2025},
author = {Zhu, H and Yi, X and He, M and Wu, S and Li, M and Gao, S},
title = {Childhood Obesity and Age-Related Diseases: A Systematic Review and Meta-Analysis of Mendelian Randomization Evidence.},
journal = {Pediatric obesity},
volume = {},
number = {},
pages = {e70071},
doi = {10.1111/ijpo.70071},
pmid = {41236085},
issn = {2047-6310},
support = {82270924//National Natural Science Foundation of China/ ; 81970732//National Natural Science Foundation of China/ ; 2021-I2M-1-016//the CAMS Innovation Fund for Medical Sciences (CIFMS)/ ; 2022-PUMCH-C-014//the National High Level Hospital Clinical Research Funding/ ; 2025-PUMCH-C-041//the National High Level Hospital Clinical Research Funding/ ; },
abstract = {BACKGROUND: Childhood obesity poses a global health threat, with emerging evidence suggesting distinct adipocyte senescence patterns compared to adult-onset obesity. We systematically explored whether childhood obesity may be causally associated with age-related diseases through a meta-analysis of Mendelian randomization (MR) evidence.

METHODS: We screened six databases (MEDLINE, PubMed, EMBASE, Web of Science, Cochrane Library and CNKI) and identified 45 MR articles examining paediatric adiposity and major age-related diseases. For each disease, we performed a meta-analysis using results from published MR studies and conducted de novo analyses based on genetic data from UK Biobank (n = 453 169), FinnGen (n > 200 000) and other large consortiums.

RESULTS: The meta-analysis examined 44 diseases across 9 systems, revealing suggestive associations between genetically determined childhood obesity and increased risk of 16 age-related diseases, including hypertension, atrial fibrillation, coronary artery disease, stroke and myocardial infarction; colorectal, endometrial and pancreatic cancers; nonalcoholic fatty liver disease, type 2 diabetes, diabetic nephropathy; multiple sclerosis and gout; Alzheimer's disease; depression and asthma. Three of these associations were marginal (p = 0.03-0.05). Paradoxical inverse associations emerged for breast cancer and ulcerative colitis.

CONCLUSION: The findings from this meta-analysis underscore associations between childhood adiposity and multisystem age-related pathologies, underscoring the imperative for early obesity prevention.},
}

@article {pmid41236074,
year = {2025},
author = {Wu, J and Ge, YH and Zhang, XZ and Li, Y and Luo, MQ and Fang, X and Zhang, W and Wang, YK and Ding, XP and Zhu, YC and Gao, F and Shen, Y and Zhang, W},
title = {Association of plasma p-tau217 levels with cerebral small vessel disease burden: Cross-sectional insights from the Hefei Aging Study.},
journal = {Brain research bulletin},
volume = {232},
number = {},
pages = {111602},
doi = {10.1016/j.brainresbull.2025.111602},
pmid = {41236074},
issn = {1873-2747},
mesh = {Humans ; *Cerebral Small Vessel Diseases/blood/pathology/diagnostic imaging ; *tau Proteins/blood ; Female ; Cross-Sectional Studies ; Male ; Aged ; Aged, 80 and over ; Magnetic Resonance Imaging ; *Aging/blood/pathology ; Biomarkers/blood ; Phosphorylation ; },
abstract = {BACKGROUND: Phosphorylated tau (p-tau217) is a well-established and recognized biomarker for Alzheimer's disease (AD), however, its relationship with cerebral small vessel disease (CSVD) remains inadequately explored. This study examines the association between plasma p-tau217 levels and CSVD burden within a community-based cohort.

METHODS: We conducted a cross-sectional analysis of data from 515 participants aged years and older enrolled in the Hefei Aging Study (HAS). CSVD burden was quantified using magnetic resonance imaging (MRI) markers, including white matter hyperintensities (WMH), lacunar infarcts, cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS). Associations were evaluated using logistic regression and generalized linear models, adjusting for relevant covariates.

RESULTS: Individuals with CSVD (score ≥1, n = 145) had significantly higher median p-tau217 levels compared to those without CSVD (0.245 vs. 0.227 pg/mL, p = 0.010). Elevated p-tau217 was independently associated with WMH (odds ratio [OR] =1.462, p = 0.006) and CMBs (OR =1.290, p = 0.033) after adjusting for covariates. Stratified analyses indicated stronger associations in APOE ε4-negative individuals (OR=1.244, p = 0.027). A linear relationship was observed between log-transformed p-tau217 and CSVD burden (β =0.113, p < 0.001), although the effect sizes were modest (adjusted R² =0.025).

CONCLUSION: Plasma p-tau217 levels are associated with CSVD burden, particularly WMH and CMBs, suggesting a role for tau pathology in vascular injury. The APOE ε4 genotype appears to modulate this relationship, highlighting distinct pathways in amyloid- and tau-mediated vascular damage.},
}

Humans
*Cerebral Small Vessel Diseases/blood/pathology/diagnostic imaging
*tau Proteins/blood
Female
Cross-Sectional Studies
Male
Aged
Aged, 80 and over
Magnetic Resonance Imaging
*Aging/blood/pathology
Biomarkers/blood
Phosphorylation

@article {pmid41235867,
year = {2025},
author = {Ladurner, G and Harper, DJ and May, L and Worm, S and Patel, Y and Varaka, M and Prokesch, M and Garhöfer, G and Merkle, C and Baumann, B},
title = {Comparative Investigation of the Retinal Phenotype of Three Mouse Models of Alzheimer's Disease With Optical Coherence Tomography.},
journal = {Investigative ophthalmology & visual science},
volume = {66},
number = {14},
pages = {35},
doi = {10.1167/iovs.66.14.35},
pmid = {41235867},
issn = {1552-5783},
mesh = {Animals ; *Tomography, Optical Coherence/methods ; *Alzheimer Disease/pathology ; Disease Models, Animal ; Mice ; Mice, Transgenic ; *Retina/pathology ; Phenotype ; Mice, Inbred C57BL ; Male ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {PURPOSE: Mouse models of Alzheimer's disease (AD) are designed to replicate a multitude of pathologies. However, a direct comparison between models is virtually impossible due to vastly differing data acquisition and image processing protocols. Based on the hypothesis that a well-defined experimental framework is key to determining subtle differences in their retinal phenotype, we use a standardized anesthesia protocol, the same optical coherence tomography (OCT) system and image processing pipeline to compare commercially available AD mouse models.

METHODS: Two models of amyloidosis (5xFAD and APP/PS1) and one of tau pathology (PS19) were investigated (age = 42.5 ± 6.5 weeks). A high-resolution OCT prototype was used to image the retina of animals under isoflurane anesthesia. Retinal OCT parameters were mapped and compared.

RESULTS: Total retinal thickness was comparable for the amyloidosis models (transgenic [tg] and non-transgenic [ntg] APP/PS1 = 209.3 µm and 210.7 µm, and tg and ntg 5xFAD = 212.1 µm and 211.2 µm), but, on average, approximately 17% thicker for the tg and ntg PS19 mice (256.4 µm and 236.8 µm). APP/PS1 mice had approximately 10 µm thicker outer retinal layers (ORL) in tg and ntg models and 10 µm thinner inner retinal layers (IRL) in comparison to 5xFAD mice. PS19 mice had between 10 and 20 µm thicker IRL and ORL than the amyloidosis models. The vascular density in superficial vascular, intermediate, and deep capillary plexuses differed significantly for 5xFAD mice.

CONCLUSIONS: Despite standardized conditions, the retinal parameters were not constant across different mouse models of AD, indicating fundamental phenotypical differences.},
}

Animals
*Tomography, Optical Coherence/methods
*Alzheimer Disease/pathology
Disease Models, Animal
Mice
Mice, Transgenic
*Retina/pathology
Phenotype
Mice, Inbred C57BL
Male
Amyloid beta-Protein Precursor/genetics

@article {pmid41235769,
year = {2025},
author = {Wang, J and Li, Y and Yang, Y and Liang, Z and Xie, P and Li, X and Guo, Y and Li, S and Chen, X},
title = {Lateralization Disruption and Dynamic Balance Alterations in Alzheimer's Disease: Impacts on Hemispheric Interaction and Cognitive Performance.},
journal = {Human brain mapping},
volume = {46},
number = {16},
pages = {e70411},
doi = {10.1002/hbm.70411},
pmid = {41235769},
issn = {1097-0193},
support = {F2022203081//Natural Science Foundation of Hebei Province/ ; 62103354//National Natural Science Foundation of China/ ; 62271341//National Natural Science Foundation of China/ ; 62371416//National Natural Science Foundation of China/ ; 62471428//National Natural Science Foundation of China/ ; C20220337//Funding Project for the Introduced Overseas Students of Hebei Province/ ; 22567619H//Hebei Innovation Capability Improvement Plan Project/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging/complications ; Male ; Female ; *Functional Laterality/physiology ; Aged ; Magnetic Resonance Imaging ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; *Default Mode Network/diagnostic imaging/physiopathology ; *Cognitive Dysfunction/physiopathology/diagnostic imaging/etiology ; *Cerebral Cortex/diagnostic imaging/physiopathology ; },
abstract = {Brain lateralization is considered evolutionarily adaptive. Impaired functional specialization is thought to cause abnormal lateralization in neurological disorders. However, the dynamic changes in brain laterality in Alzheimer's disease (AD) remain unclear. In this study, resting-state fMRI data and neuropsychological assessments from 109 participants (49 AD patients and 60 healthy controls [HC]) were used. Dynamic laterality time series were constructed by extracting the dynamic laterality index (DLI) within each sliding window. We assessed two key features: laterality reversal (LR), reflecting intra-hemispheric processing efficiency, and laterality fluctuation (LF), indicating inter-hemispheric communication. Group differences in dynamic laterality characteristics were analyzed using statistically rigorous methods, regressing out gender, age, years of education, and head movements. Spearman correlation analyses examined the relationship between laterality characteristics and cognitive performance. Our results showed that AD patients exhibited a more pronounced loss of left lateralization as well as stronger right lateralization, especially in the somatomotor network (SMN) and default mode network (DMN). Additionally, we observed decreased LR as well as increased LF with global trends in AD. These divergent changes disrupted the dynamical balance between intra- and inter-hemispheric information interaction. Notably, this imbalance depended on the degree of lateralization, and the higher order cognitive networks with high-level lateralization were more vulnerable. Importantly, the observed abnormal lateralization metrics were associated with worse cognitive impairment. Our study highlights a disruption of dynamic lateralization balance in higher order cortical networks in AD patients and reveals its potential role in the disease's pathophysiology.},
}

Humans
*Alzheimer Disease/physiopathology/diagnostic imaging/complications
Male
Female
*Functional Laterality/physiology
Aged
Magnetic Resonance Imaging
Middle Aged
*Nerve Net/diagnostic imaging/physiopathology
*Default Mode Network/diagnostic imaging/physiopathology
*Cognitive Dysfunction/physiopathology/diagnostic imaging/etiology
*Cerebral Cortex/diagnostic imaging/physiopathology

@article {pmid41235755,
year = {2025},
author = {Ramirez, P and Sun, W and Dehkordi, SK and Zare, H and Pascarella, G and Carninci, P and Fongang, B and Bieniek, KF and Frost, B},
title = {Long-read sequencing reveals genomic and epigenomic variation in the dark genome of human Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70852},
doi = {10.1002/alz.70852},
pmid = {41235755},
issn = {1552-5279},
support = {//BrightFocus Foundation/ ; R25 GM095480/GM/NIGMS NIH HHS/United States ; RF1 NS112391/NS/NINDS NIH HHS/United States ; R01AG078964/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; DNA Methylation/genetics ; Aged ; Male ; Female ; Epigenomics ; Brain/metabolism/pathology ; *Epigenesis, Genetic/genetics ; Aged, 80 and over ; Genome, Human ; Retroelements/genetics ; Genomics ; Genetic Variation ; },
abstract = {INTRODUCTION: Faulty DNA repair and epigenetic regulation contribute to neurodegeneration in Alzheimer's disease. Long-read sequencing enables analysis of "dark regions" that are difficult to study via traditional sequencing methodologies.

METHODS: Using nanopore whole-genome DNA sequencing of post mortem brain from early- and late- stage Alzheimer's disease cases and controls, we analyzed retrotransposition, non-allelic homologous recombination (NAHR), structural variation, and DNA methylation within repetitive regions.

RESULTS: Retrotransposon insertions and NAHR were enriched in centromeric/pericentromeric and ribosomal DNA (rDNA) in the aged brain. Putatively somatic AluY retrotransposon insertions trended upward in late-stage disease. Enrichment of NAHR between repetitive regions and DNA demethylation were detected in early disease. Differential methylation of dark regions within specific Alzheimer's disease risk genes and repetitive elements occurred across disease stage.

DISCUSSION: This study provides the first long-read analysis of repetitive elements in the aged human brain and identifies these regions as hotspots for genomic variation in Alzheimer's disease.

HIGHLIGHTS: Long-read sequencing enables analysis of "dark" regions Alzheimer's disease brains Somatic AluY retrotransposon insertions may be elevated in late-stage disease Retrotransposon-associated non-allelic homologous recombination (NAHR) is enriched in repetitive regions in early disease DNA demethylation within the centro/pericentromere and ribosomal DNA (rDNA) occur across disease stage Dark regions of risk genes are differentially methylated across disease stage.},
}

Humans
*Alzheimer Disease/genetics/pathology
DNA Methylation/genetics
Aged
Male
Female
Epigenomics
Brain/metabolism/pathology
*Epigenesis, Genetic/genetics
Aged, 80 and over
Genome, Human
Retroelements/genetics
Genomics
Genetic Variation

@article {pmid41235368,
year = {2025},
author = {Arellano, A and Palma-Florez, S and Cabrera, P and Cortés-Adasme, E and Bolaños, K and Celis, F and Araya-Vergara, AJ and Pérez, M and Crespo, A and Matus, MH and Araya, E and Aldunate, R and Kogan, MJ and Samitier, J and Lagunas, A and Mir, M and Hassan, N},
title = {Attenuation of blood-brain barrier dysfunction by functionalized gold nanoparticles against amyloid-β peptide in an Alzheimer's disease-on-a-chip model.},
journal = {Materials today. Bio},
volume = {35},
number = {},
pages = {102453},
pmid = {41235368},
issn = {2590-0064},
abstract = {Gold nanoparticles (GNP) are highly valuable in nanotechnology due to their biocompatibility and unique physicochemical properties, which make them attractive as nanocarriers for targeted drug delivery. In the context of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), GNP hold promise for reducing the toxicity of Amyloid-β peptide (Aβ) aggregates. However, a major challenge in developing new therapies for NDDs lies in the limited reliance on animal models and the difficulty of crossing the blood-brain barrier (BBB). This study investigates the effects of GNP on Aβ toxicity using a human-based BBB-organ-on-a-chip model (BBB-oC), mimicking the 3D cellular architecture of the BBB under both normal and pathological conditions. We rationally designed a novel nanosystem functionalized with the peptide D3, which functions both as a selective Aβ toxicity inhibitor and a BBB-targeting agent. The results show that GNP can cross the BBB, reduce the Aβ-induced cytotoxicity, and promote the maintenance of the BBB integrity. Moreover, controlling the shape of GNP further enhanced their protective effect. Overall, this work highlights the feasibility of rationally designed GNP as a promising therapeutic strategy for AD, evaluated through a more reliable and predictive human-relevant model.},
}

@article {pmid41235285,
year = {2025},
author = {Manzoor, H},
title = {A Neuroimaging Audit of Patients Referred to an Old-Age Community Mental Health Team From Memory Assessment Service: Compliance With the Royal College of Radiologists Guidance.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e96682},
pmid = {41235285},
issn = {2168-8184},
abstract = {Background Neuroimaging is a crucial component in the assessment of patients with suspected dementia, aiding in diagnostic confirmation, subtype differentiation, and the exclusion of reversible causes. The Royal College of Radiologists (RCR) provides standards to guide the structured and comprehensive reporting of imaging scans, aiding in diagnostic accuracy and clinical decision-making. Local compliance with RCR standards may vary, which could influence the clinical utility of the scans. This audit was undertaken to evaluate local compliance with RCR reporting standards and identify areas for improvement. Methodology A total of 50 referrals from the Memory Assessment Service to the Old Age Community Mental Health Team (April 2024-September 2025) were reviewed. Radiology reports were analyzed for compliance with RCR standards, focusing on documentation of atrophy pattern, vascular pathology, reversible causes, use of rating scales, and inclusion of diagnostic conclusions. Data were also organized by imaging modality and indication to assess reporting consistency and completeness. Results Of the 50 referrals, nine (18%) patients were diagnosed with dementia without neuroimaging, consistent with clinical guidelines. Among 41 imaged patients, 33 had CT and four had MRI scans. Cerebral atrophy was described in 85% of reports, increasing to 100% for cognitive impairment cases; however, standardized scoring systems were infrequently used (Medial Temporal Atrophy score 7/22). Vascular pathology was mentioned in most reports with severity markers, but Fazekas scoring was used in 3/22 scans. Reversible causes were more comprehensively covered in scans done for indications other than cognitive impairment. Overall, 15/22 (68%) cognitive impairment reports included a diagnostic conclusion. Conclusions Local neuroimaging reports for dementia patients showed comprehensive recognition of atrophy and vascular changes but inconsistent use of standardized scoring, documentation of reversible causes, and diagnostic conclusions. Structured reporting templates and multidisciplinary feedback could improve adherence to RCR standards and enhance clinical utility.},
}

@article {pmid41235150,
year = {2025},
author = {Nigdelioglu Dolanbay, S},
title = {Monoterpene-rich essential oil from Artemisia santonicum L. exerts neuroprotective effects in Aβ-induced SH-SY5Y cells: Modulation of tau pathology, neuroinflammation, oxidative stress, and synaptic-metabolic pathways.},
journal = {Toxicology research},
volume = {14},
number = {6},
pages = {tfaf155},
pmid = {41235150},
issn = {2045-452X},
abstract = {Understanding the complex biological mechanisms of ad requires innovative treatment approaches for this disease. In this context, natural compounds, especially monoterpenes, attract attention with their potential for biological activity. In this study, the therapeutic potential of monoterpene rich essential oil obtained from Artemisia santonicum L. for the treatment of ad was comprehensively evaluated. GC-MS analysis showed that the major monoterpenes were limonene, camphor, pinene, terpineol, and carvone in essential oil obtained from A. santonicum L. Possible common targets of monoterpenes with ad were predicted and their PPI networks were analyzed. Furthermore, gene set enrichment analysis was applied to understand the functional roles of these possible common targets and their relationships with biological pathways. Molecular docking studies revealed the binding affinities and interaction abilities of monoterpenes with the predicted possible common targets. The monoterpene rich essential oil obtained from A. santonicum L. used in our study provides a neuroprotective effect by targeting the pathological mechanisms of ad. We designed in vitro experiments to elucidate the mechanism of the mentioned neuroprotective effect. Within the scope of the study, neuroprotective effect analyses were performed to evaluate cell viability rates and in vitro AChE enzyme activity, while the ELISA method was used to determine phosphorylated tau levels and to assess neuroinflammatory responses. In addition, apoptosis levels, MMP changes and intracellular ROS accumulation were examined by flow cytometry analyses. These comprehensive analyses aimed to reveal the molecular mechanisms of the neuroprotective effect of monoterpene rich essential oil obtained from A. santonicum L. and to shed light on its potential therapeutic applications in ad.},
}

@article {pmid41235132,
year = {2025},
author = {Chatterjee, A and Cavaillès, C and Davies, NM and Yaffe, K and Andrews, SJ},
title = {Disentangling the Causal Effects of Education and Participation Bias on Alzheimer Disease Using Mendelian Randomization.},
journal = {Neurology. Genetics},
volume = {11},
number = {6},
pages = {e200307},
pmid = {41235132},
issn = {2376-7839},
abstract = {BACKGROUND AND OBJECTIVES: People with university degrees have a lower incidence of Alzheimer disease (AD). However, the relationship between education and AD could be due to selection, collider, or ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. In this study, we use 2-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD.

METHODS: We used genome-wide association study summary statistics for educational attainment, 3 measures of participation, AD (clinically diagnosed AD), and AD/ADRD (AD and related dementia; includes clinical diagnosis and family history). Independent genome-wide significant single-nucleotide variations (SNVs) were extracted from the exposure data sets and harmonized with the outcome SNPs. Fixed-effects inverse variance-weighted meta-analysis was the primary MR method; Cochran Q statistic and MR Egger intercept were used to test for heterogeneity and pleiotropy, and radial MR was used to identify outliers. Sensitivity analyses included MR Egger, weighted median, and mode. Bidirectional analyses were used to test whether AD pathology affects participation, and multivariable MR (MVMR) assessed independent exposure-outcome effects.

RESULTS: Educational attainment reduced the risk of AD (ORIVW 95% CI 0.70 [0.63-0.79], p = 8e-10), and the results were robust based on sensitivity analyses. However, education increased the risk of AD/ADRD, although the results were not robust in sensitivity analyses (ORIVW 95% CI 1.09 [1.02-1.15], p = 0.006). Participation in the mental health questionnaire reduced the odds of AD (ORIVW 95% CI 0.325 [0.128-0.326], p = 0.01). When adjusting for participation in MVMR, education remained associated with a reduced risk of AD (ORIVW 95% CI 0.76 [0.62-0.92], p = 0.006).

DISCUSSION: Univariable MR analyses indicated that education and participation reduced the risk of AD. However, MR also suggested that education increased the risk of AD/ADRD, highlighting the inconsistencies between clinical and proxy diagnoses of AD, as proxy-AD may be affected by selection, collider, or ascertainment bias. MVMR suggested that education remained associated with reduced AD risk after adjusting for participation and the protective effect of education may be due to other biological mechanisms, such as cognitive reserve.},
}

@article {pmid41235113,
year = {2025},
author = {Zampieri, TT and Higa, GSV and Borges, FS and Viana, FJC and Cruvinel, E and Bentivoglio, LE and Lugao, AB and Ulrich, H and Britto, LR and Katti, KV and Chesne, AM and de Pasquale, R},
title = {Exposure to β-hydroxybutyrate reduces the operating set point and increases excitability in hippocampal circuitry of healthy mice.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1557612},
pmid = {41235113},
issn = {1663-9812},
abstract = {The ketogenic diet is a therapeutic strategy applied to reduce brain hyperexcitability in conditions such as epilepsy, Parkinson's and Alzheimer's disease, migraines, and autism. This diet reduces circulating glucose levels and increases ketone bodies, with β-hydroxybutyrate (BHB) being one of the leading promoters of the beneficial effects. BHB was previously reported as a mediator of cognitive restoration and memory formation. Herein, we investigate the effect of exogenous BHB on hippocampal neuronal excitability and synaptic plasticity mechanisms, regardless of the pathological or neurodegenerative conditions. Electrophysiological experiments were conducted to explore both passive and active neuronal properties, including action potential firing and spontaneous and evoked postsynaptic responses. Electrical stimulation along the CA3-CA1 pathway enabled the assessment of both short- and long-term synaptic plasticity, as well as the mechanisms mediated by AMPA and NMDA receptors. Experiments were conducted in hippocampal slices treated with 3-β-hydroxybutyrate glycerides (DHB) and niacin (HCAR2 agonist). Although DHB incubation did not alter passive membrane properties, it significantly increased neuronal excitability, reflected in an elevated firing rate upon depolarizing stimulation and enhanced spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons, which were dependent on synaptic inputs. DHB treatment led to a reduction in long-term potentiation (LTP) in CA1 neurons, suggesting a metaplastic effect independent of NMDA receptor activation. Importantly, these DHB-induced neuronal alterations were found to be independent of HCAR2 receptor activation, supporting the involvement of distinct intracellular pathways and long-term modulatory mechanisms. Our findings indicate that DHB exerts a modulatory effect on hippocampal neural activity by enhancing excitability and concurrently promoting a compensatory reduction in LTP, suggesting a homeostatic balancing mechanism.},
}

@article {pmid41235101,
year = {2025},
author = {Chen, XQ},
title = {APP Gene-based Strategies to Combat Alzheimer's Disease in Down Syndrome.},
journal = {Current genomics},
volume = {26},
number = {4},
pages = {245-248},
pmid = {41235101},
issn = {1389-2029},
}

@article {pmid41235013,
year = {2025},
author = {Nenezic, N and Dragicevic Jeremic, J and Rancic, N and Dejanovic, B and Kostic, D and Nenezic, D and Safiye, T and Alexopoulos, C and Kostic, S},
title = {The Link Between Serum Levels of Dehydroepiandrosterone and Alzheimer's Disease: A Pilot Study in the Serbian Population.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e94489},
pmid = {41235013},
issn = {2168-8184},
abstract = {Background and aim Alzheimer's disease (AD) is the most prevalent type of dementia and a major health concern among the elderly population. Considering the role of neurosteroids in neurodegenerative processes, this pilot study aimed to investigate the association between serum dehydroepiandrosterone sulfate (DHEA-S) and cortisol concentrations, as well as their ratio, in patients with AD compared with cognitively intact individuals. Methods An observational case-control study was conducted involving 45 patients with clinically probable AD, diagnosed according to the 2011 National Institute on Aging-Alzheimer's Association criteria, and 40 healthy control participants matched for age and sex. Fasting morning serum concentrations of DHEA-S and cortisol were measured after a 12-hour overnight fast in all participants, and the cortisol/DHEA-S ratio was calculated. Cognitive status was assessed using the Montreal Cognitive Assessment and Clinical Dementia Rating scales. Results No statistically significant difference in serum DHEA-S concentrations was found between patients with AD and controls. However, patients with AD had significantly higher cortisol levels (398.85 vs. 337.40 nmol/L; p = 0.026) and a higher cortisol/DHEA-S ratio, showing a trend toward statistical significance (p = 0.078). Among participants aged 65-75 years, the cortisol/DHEA-S ratio was significantly higher in patients with AD than in controls (p = 0.031). In the control group, males had significantly higher DHEA-S levels than females (p = 0.020), whereas no sex difference was observed in the AD group. Conclusions The findings of this pilot study suggest that elevated cortisol levels and an imbalance in the cortisol/DHEA-S ratio may contribute to AD pathophysiology. DHEA-S alone did not show a significant association with disease presence, but the observed age- and sex-related differences indicate that this neurosteroid may play a differential role in the development and progression of AD.},
}

@article {pmid41234939,
year = {2025},
author = {Wang, R and Peng, S and Zhu, J and Xu, Y and Wang, M and Zhang, L and Qiu, Y and Hou, D and Wang, Q and Liu, R},
title = {Innovations in Alzheimer's disease diagnostic technologies: clinical prospects of novel biomarkers, multimodal integration, and non-invasive detection.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1651708},
pmid = {41234939},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) plaques and the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, ultimately leading to cognitive decline and neuronal loss. Current diagnostic methods, including clinical evaluations, neuroimaging examinations, and cerebrospinal fluid biomarker testing, face challenges such as insufficient sensitivity and specificity, as well as operational complexity. In recent years, significant advancements have been made in diagnostic technologies, with the emergence of new biomarkers and detection methods, including blood-based Aβ and tau protein detection, ocular biomarker testing, and non-invasive screening through urine or breath analysis. These innovative developments, combined with multimodal diagnostic technologies that integrate imaging, genomics, and proteomics, have opened new possibilities for the early diagnosis and precise staging of Alzheimer's disease. Furthermore, advancements in microfluidic chips and biosensor technologies have enhanced the capability for rapid, efficient, and cost-effective diagnosis. As research continues to evolve, the gradual application of these advanced technologies in clinical practice is expected to revolutionize the management of Alzheimer's disease, facilitating early intervention and the formulation of individualized treatment strategies.},
}

@article {pmid41234527,
year = {2025},
author = {Akbarian, B and Hett, K and Phan, T and Lee, JJ and Eaton, J and Donahue, MJ and Darby, RR},
title = {Microstructural grey matter alterations in patients with behavioural variant frontotemporal dementia.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf427},
pmid = {41234527},
issn = {2632-1297},
abstract = {Behavioural variant frontotemporal dementia is characterized by progressive changes to personality and behaviour, yet early detection and disease staging remain challenging. Current clinical neuroimaging relies on visual assessment of atrophy patterns, which may overlook subtle structural changes. While volumetric analysis has improved the ability to detect neurodegeneration and track disease progression, it may lack the sensitivity to identify microstructural alterations that precede frank atrophy. Texture analysis, a quantitative approach that evaluates the spatial regularity of grey matter density, has demonstrated promise in detecting early microstructural changes in Alzheimer's disease and distinguishing frontotemporal dementia subtypes. However, its potential as a biomarker for early behavioural variant frontotemporal dementia detection and disease staging remain unexplored. This study evaluates the potential of autocorrelation-based texture features as biomarkers for detecting early-stage behavioural variant frontotemporal dementia and tracking disease progression, comparing their sensitivity and specificity to regional brain volume. We analysed structural MRI scans from behavioural variant frontotemporal dementia patients with mild (n = 21, 61.5 ± 8.5 years, 4.7% female) and moderate dementia (n = 11, 64.4 ± 9.3, 18.1% female) alongside healthy controls (n = 33, 63.1 ± 7.9 years; 36.3% female). Texture and volumetric measures were extracted from frontotemporal regions implicated in behavioural variant frontotemporal dementia pathology. First, we compared these features between healthy controls and patients with mild dementia to identify regions relevant for early diagnosis. Second, we compared patients with mild versus moderate dementia to identify regions linked to disease stage. Analyses were performed both within a composite frontotemporal region of interest and within 160 frontotemporal subregions. We applied false discovery rate correction for multiple comparisons. Microstructural abnormalities captured by texture analysis and volumetric reductions were significantly lower in patients with mild dementia compared to healthy controls within the composite frontotemporal and many subregions (PFDR < 0.05). In moderate dementia, texture features detected alterations in composite frontotemporal (PFDR < 0.05) and subregions, including the anterior cingulate, insula and orbitofrontal cortices (PFDR < 0.05) even when volumetric differences were absent. This study demonstrates that texture-based MRI metrics provide a sensitive measure of microstructural alterations in behavioural variant frontotemporal dementia, detecting some disease-related changes even in regions without detectable volumetric reductions. While volumetric measures are effective for identifying individuals with early-stage disease, texture analysis may offer increased sensitivity for tracking disease progression. Longitudinal studies are needed to validate the predictive value of texture features for clinical decline in behavioural variant frontotemporal dementia.},
}

@article {pmid41234424,
year = {2025},
author = {Hosseini, AA and Shao, B and Lee, AR and Dhillon, P and Junaid, K and Gran, B and Sellars, P and Sargisson, H and Jung, J and Mukaetova-Ladinska, EB},
title = {The Cognitive and Neuroimaging for Neurodegenerative Disorders Study (CogNID): design and initial findings from real-world clinical practice.},
journal = {Frontiers in psychiatry},
volume = {16},
number = {},
pages = {1630082},
pmid = {41234424},
issn = {1664-0640},
abstract = {INTRODUCTION: Dementia presents with significant heterogeneity across age groups, particularly in early-onset cognitive decline (EOCD), which poses diagnostic and management challenges. The Cognitive and Neuroimaging for Neurodegenerative Disorders (CogNID) study aims to characterise clinical, cognitive, neuroimaging, and biomarker features across a diverse cohort of individuals with cognitive impairment, with a focus on diagnostic complexity, biomarker utility, and mortality.

METHODS: Out of 680 study participants within this prospective cohort enrolled from the real-world clinics within the National Health Service, who consented to take part in the study, we analysed data from 429. Individuals were recruited between December 2018 and November 2024 from the Memory Clinics, including the early-onset dementia service and associated services. Participants underwent structured cognitive assessments, neuroimaging (MRI/CT), and Cerebrospinal fluid (CSF) biomarker evaluation, where available. Diagnoses were made by multidisciplinary consensus. Group comparisons were conducted between early-onset (EOCD, <65 years) and late-onset cognitive decline (LOCD, ≥65 years).

RESULTS: Of the 429 participants, 349 (81.4%) had EOCD and 80 (18.6%) had LOCD. The mean age was 60.05 years, with no significant difference in sex or ethnicity across groups. Depression and anxiety were common (29.6%), as were cardiovascular risk factors. Lumbar punctures were more frequently performed in EOCD (p = 0.03), with 36.4% of tested participants demonstrating biomarker profiles consistent with Alzheimer's disease (A+T+). Functional cognitive disorder (FCD) was more common in EOCD (22.3% vs. 5.0%, p < 0.001). Subgroup analysis revealed significantly lower ACE-III scores and higher pathological CSF findings in Alzheimer's disease versus FCD. Mortality was higher in the LOCD group (11.3% vs. 4.6%, p = 0.03).

CONCLUSION: The CogNID study highlights the clinical and diagnostic heterogeneity of individuals with cognitive impairment, particularly in younger adults. Incorporating neuroimaging and CSF biomarkers into routine clinical pathways enhances diagnostic precision and reveals distinct phenotypic profiles between EOCD and LOCD. These findings underscore the need for harmonised diagnostic protocols, broader biomarker accessibility, and inclusive recruitment strategies in dementia research and clinical services.},
}

@article {pmid41234238,
year = {2025},
author = {Song, K and Choi, J and Jeong, D and Shin, D and Ah, YM and Lee, KY and Choi, KH},
title = {Comparative effects of SGLT2 inhibitors and incretin-based therapies on dementia risk in type 2 diabetes: a systematic review and meta-analysis.},
journal = {Frontiers in endocrinology},
volume = {16},
number = {},
pages = {1695075},
pmid = {41234238},
issn = {1664-2392},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/complications ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; *Incretins/therapeutic use ; *Dementia/prevention & control/epidemiology/etiology ; *Hypoglycemic Agents/therapeutic use ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; },
abstract = {BACKGROUND: Antidiabetic drugs lower blood glucose levels and may also have neuroprotective and vascular protection effects. In particular, sodium-glucose cotransporter 2 inhibitors (SGLT2is) and incretin mimetics have demonstrated dementia-reducing effects. We evaluated whether SGLT2is reduce dementia risk compared with incretin mimetics in patients with type 2 diabetes (T2D).

METHODS: Systematic review and meta-analysis were performed by searching the PubMed, Embase, and Cochrane Library databases through February 2025. Both randomized trials and cohort studies were identified and qualitatively assessed, but only cohort studies were included in the quantitative meta-analysis. We also compared the effects of SGLT2is with those of dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1RA) on dementia incidence.

RESULTS: Nine studies were identified for analysis. Compared with incretin mimetics, SGLT2is significantly reduced the overall dementia risk [hazard ratio (HR) 0.82, 95% CI: 0.73-0.91], and SGLT2is had stronger effects than DPP-4i (HR 0.67, 95% CI: 0.59-0.77) and GLP-1RA (HR 0.93, 95% CI: 0.86-1.00). SGLT2i also reduced the risks of vascular dementia and Alzheimer's disease (HR 0.49, 95% CI: 0.35-0.70 vs. HR 0.68, 95% CI: 0.52-0.88, respectively). The results of subgroup analyses revealed increased benefits for patients aged older than 65 years. Empagliflozin was the most consistently protective among the SGLT2i agents.

CONCLUSION: SGLT2is may provide neuroprotective benefits beyond glycemic control in patients with T2D, particularly in older populations at higher risk of cognitive decline. These findings support consideration of SGLT2is as a preferred therapeutic option for patients with T2D at increased risk of dementia, although randomized controlled trials would further strengthen this evidence base.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024567890 identifier PROSPERO (CRD420251037959).},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy/complications
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
*Incretins/therapeutic use
*Dementia/prevention & control/epidemiology/etiology
*Hypoglycemic Agents/therapeutic use
Dipeptidyl-Peptidase IV Inhibitors/therapeutic use

@article {pmid41234220,
year = {2025},
author = {Fujishiro, H and Kawakami, I and Oshima, K and Torii, Y and Arafuka, S and Iritani, S and Ikeda, K},
title = {Systematized delusions in a patient with covert hepatic encephalopathy: A clinicopathological insight into prodromal dementia with Lewy bodies.},
journal = {PCN reports : psychiatry and clinical neurosciences},
volume = {4},
number = {4},
pages = {e70247},
pmid = {41234220},
issn = {2769-2558},
abstract = {BACKGROUND: Late-onset psychosis is an early clinical manifestation of psychiatric-onset prodromal dementia with Lewy bodies (DLB); however, its underlying neuropathology remains poorly understood. Clinicopathological correlations are often limited by the gap between symptom onset and the autopsy.

CASE PRESENTATION: A 66-year-old man with autopsy-confirmed DLB presented with persistent systematized delusions. After treatment for liver cirrhosis during hospitalization, the patient's physical symptoms improved; however, persecutory delusions developed. The patient was clinically diagnosed with covert hepatic encephalopathy (HE). The delusions were atypical for covert HE, suspecting delusional disorder. His systematized delusions persisted for 3 months until his death, without the development of cognitive decline or Parkinsonism during his lifetime. An autopsy revealed an early transitional type of Lewy body disease with minimal Alzheimer's type II astrocytes indicative of HE. Severe neuronal loss was observed in the locus coeruleus (LC), while the substantia nigra (SN) and nucleus basalis of Meynert (nbM) were preserved. Abundant alpha-synuclein-positive structures were identified in the LC, periaqueductal gray matter, nbM, amygdala, and thalamus, with sparse involvement of the SN, neocortex, peripheral autonomic nervous system, including the heart and gastrointestinal tract.

CONCLUSION: Selective Lewy body involvement, sparing the SN and neocortex, may explain the isolated psychiatric symptoms in the absence of Parkinsonism or dementia. Systemic conditions such as covert HE may have contributed to the emergence of persistent delusions. This case highlights the need for multidisciplinary approaches that integrate psychosomatic assessments with neuropathological investigations to evaluate late-onset psychosis.},
}

@article {pmid41234138,
year = {2025},
author = {},
title = {Correction to: Polygenic Risk Scores for Alzheimer's Disease and General Cognitive Function Are Associated With Measures of Cognition in Older South Asians.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {80},
number = {12},
pages = {},
doi = {10.1093/gerona/glaf220},
pmid = {41234138},
issn = {1758-535X},
}

@article {pmid41234025,
year = {2025},
author = {Oomens, JE and Vos, SJ and Maserejian, NN and Boada, M and Didic, M and Engelborghs, S and Fladby, T and van der Flier, WM and Frisoni, GB and Fröhlich, L and Gill, KD and Grimmer, T and Hort, J and Itoh, Y and Iwatsubo, T and Klimkowicz-Mrowiec, A and Landau, SM and Lee, DY and Lleó, A and Martinez-Lage, P and de Mendonça, A and Meyer, PT and Parchi, P and Pardini, M and Parnetti, L and Popp, J and Rami, L and Reiman, EM and Rinne, JO and Rodrigue, KM and Sánchez-Juan, P and Santana, I and Scarmeas, N and Scheltens, P and Skoog, I and Sperling, RA and Stern, Y and Villeneuve, S and Waldemar, G and Wiltfang, J and Zetterberg, H and Alcolea, D and Allegri, RF and Altomare, D and Bateman, RJ and Baiardi, S and Baldeiras, I and Blennow, K and Braber, AD and van Buchem, MA and Byun, MS and Cerman, J and Chen, K and Chipi, E and Day, GS and Drzezga, A and Ekblad, LL and Förster, S and Fortea, J and Freund-Levi, Y and Frings, L and Guedj, E and Habeck, CG and Handels, R and Hausner, L and Hellwig, S and Jiménez-Bonilla, JF and Juaristi, AI and Kandimalla, R and Kern, S and Bordewick Kirsebom, BS and Kornhuber, J and Legdeur, N and Levin, J and Maier, W and Marquié, M and Minatani, S and Morbelli, SD and Mroczko, B and Ntanasi, E and de Oliveira, CR and Orellana, A and Peters, O and Prabhakar, S and Ramakers, IH and Rodríguez-Rodriguez, E and Ruiz, A and Rüther, E and Sakhardande, J and Selnes, P and Silva, D and Soininen, H and Spiru, L and Takeda, A and Teunissen, CE and Tijms, BM and Vermunt, L and Wallin, ÅK and Wiels, W and Yannakoulia, M and Yi, D and Zettergren, A and , and , and , and , and , and , and Ossenkoppele, R and Verhey, FR and Visser, PJ and Jansen, WJ},
title = {Associations of lifestyle factors with amyloid pathology in persons without dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251379083},
doi = {10.1177/13872877251379083},
pmid = {41234025},
issn = {1875-8908},
abstract = {BackgroundThe association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood.ObjectiveThe aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology.MethodsFor this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology.ResultsWe included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66-0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73-0.99, p = 0.029; OR = 0.62, 95%CI 0.45-0.86, p = 0.004).ConclusionsIn NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.},
}

@article {pmid41233906,
year = {2025},
author = {Kaloss, AM and Browning, JL and Li, J and Pan, Y and Watsen, S and Sontheimer, H and Theus, MH and Olsen, ML},
title = {Meningeal vascular Aβ deposition associates with cerebral hypoperfusion and compensatory collateral remodeling.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {245},
pmid = {41233906},
issn = {1758-9193},
support = {R01 AG065836/AG/NIA NIH HHS/United States ; R01 AG065836/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Male ; Female ; *Cerebrovascular Circulation/physiology ; *Amyloid beta-Peptides/metabolism ; Mice ; *Alzheimer Disease/pathology/metabolism ; *Meninges/metabolism/blood supply/pathology ; Mice, Transgenic ; Disease Models, Animal ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; *Collateral Circulation/physiology ; },
abstract = {BACKGROUND: Global reductions in cerebral blood flow (CBF) are among the earliest and most consistent abnormalities observed in Alzheimer's disease (AD), preceding both cortical plaque formation and cognitive decline. While the pial arterial network-a critical supplier of intracortical perfusion-has been overlooked in this context, it may play a pivotal role in early vascular pathology. Here, we report extensive cerebral amyloid angiopathy (CAA) within the pial artery and arteriole network in the J20 (PDGF-APPSw, Ind) mouse model of AD.

METHODS: Using premortem delivery of Methoxy-XO4 to label Aβ, and arterial vascular labeling, we assessed Aβ burden on the pial artery/arteriole network and cerebral blood flow in aged male and female WT and J20 AD mice.

RESULTS: We show that 12-month-old J20 mice exhibit significant Aβ deposition across major leptomeningeal arteries (ACA, MCA) and pial collaterals, with ~ 40% vessel coverage in males and ~ 20% in females-substantially exceeding Aβ levels in cortical or hippocampal vessels. This vascular Aβ burden was accompanied by compensatory enlargement and increased tortuosity of pial collateral vessels. Yet, despite this apparent remodeling, CBF was reduced by ~ 15% in J20 mice, and this decline was significantly associated with leptomeningeal CAA burden.

CONCLUSIONS: This is the first study to comprehensively characterize meningeal arterial Aβ accumulation in a preclinical model of vascular AD, mirroring recent observations in early-stage human disease. Our findings implicate meningeal CAA as a potential driver of early CBF disruption and suggest that pial collateral remodeling may reflect a compensatory response to vascular insufficiency. Moreover, we identify robust sex differences in CAA burden, paralleling sex-specific patterns of parenchymal Aβ pathology in humans. These results highlight the leptomeningeal vasculature as a novel and understudied locus for early AD pathology and a potential therapeutic target to preserve cerebrovascular integrity.},
}

Animals
Male
Female
*Cerebrovascular Circulation/physiology
*Amyloid beta-Peptides/metabolism
Mice
*Alzheimer Disease/pathology/metabolism
*Meninges/metabolism/blood supply/pathology
Mice, Transgenic
Disease Models, Animal
*Cerebral Amyloid Angiopathy/pathology/metabolism
*Collateral Circulation/physiology

@article {pmid41233833,
year = {2025},
author = {Yu, C and Li, M and Shen, F and Gao, S and Wang, J and He, C and Wang, L and Wu, Y and Du, Y},
title = {Electroacupuncture alleviates cognitive impairments in APP/PS1 mice via gastric vagal afferent-mediated activation of the nucleus tractus solitarius‒locus coeruleus noradrenergic circuit.},
journal = {Chinese medicine},
volume = {20},
number = {1},
pages = {188},
pmid = {41233833},
issn = {1749-8546},
support = {No. 82205271//National Natural Science Foundation of China/ ; No. 82505777//National Natural Science Foundation of China/ ; No. 82074566//National Natural Science Foundation of China/ ; No. ZY2025L183//Chinese Medicine Research Project supported by the Hubei Administration of Traditional Chinese Medicine, China/ ; No. ZY2025Q034//Chinese Medicine Research Project supported by the Hubei Administration of Traditional Chinese Medicine, China/ ; 2023AFD113//Key Chinese Medicine Project supported by Hubei Provincial Natural Science Foundation/ ; },
abstract = {OBJECTIVE: Neuroinflammatory cascades mediated by the locus coeruleus-norepinephrine (LC-NE) system emerge as critical pathophysiological determinants governing the etiology and advancement of neurodegenerative disorders, including Alzheimer's disease (AD). Therapeutic modulation of neuroinflammatory processes may mitigate AD-associated cognitive decline. Electroacupuncture (EA) targeting the Foot Yangming of Stomach Meridian acupoints demonstrates efficacy in ameliorating AD-related cognitive dysfunction through dual peripheral and central anti-inflammatory actions, though the precise neural circuitry linking peripheral interventions to central effects remains undefined.

METHODS: In this study, APP/PS1 transgenic mice were administrated with EA stimulation at ST36 and ST37. Cognitive function was assessed via the Morris water maze and novel object recognition tests. Spatial learning capacities and episodic memory retention were quantified through Morris water maze paradigm and object novelty discrimination assays, respectively. Retrograde neural tracing was employed to validate the nucleus tractus solitarius (NTS)-LC noradrenergic projection. Multimodal approaches integrating chemogenetic manipulation, immunofluorescence microscopy, Western blotting, Golgi-Cox neuronal morphology analysis, and Nissl histochemistry elucidated the gastrointestinal vagal afferent fiber (GVAF)-NTS-LC circuit's role in EA-mediated neuroinflammatory regulation. Circuit-specific functional validation was conducted through selective GVAF blockade.

RESULTS: EA at ST36 and ST37 attenuated hippocampal synaptic ultrastructural degeneration via NTS-LC noradrenergic circuit activation. This intervention suppressed proinflammatory cytokines expression (IL-6, IL-1β, TNF-α) and microglial hyperactivation through ADRB2/PKA/CREB pathway modulation, effectively rescuing cognitive deficits in AD models. GVAF ablation reversed EA-induced neuroinflammatory suppression, confirming the circuit dependence.

CONCLUSIONS: EA at ST36/ST37 alleviates AD-related cognitive impairment through sequential GVAF-NTS-LC circuit activation and downstream ADRB2/PKA/CREB-mediated neuroinflammatory resolution. This work identifies a previously unrecognized peripheral-central neural circuit mechanism underlying EA's therapeutic efficacy in AD pathogenesis.},
}

@article {pmid41233412,
year = {2025},
author = {Christova, P and James, LM and Georgopoulos, AP},
title = {Brain volumes discriminate clinical dementia rating scale categories.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39852},
pmid = {41233412},
issn = {2045-2322},
mesh = {Humans ; Male ; Female ; Aged ; *Dementia/pathology/diagnosis/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Organ Size ; Gray Matter/pathology ; Aged, 80 and over ; Middle Aged ; Severity of Illness Index ; Atrophy ; Alzheimer Disease/pathology ; },
abstract = {Brain atrophy is well documented in various kinds of dementia, particularly in Alzheimer's disease. Here, we evaluated gray matter volume of 87 cortical and subcortical areas in 460 individuals characterized according to the Clinical Dementia Rating (CDR) as cognitively unimpaired (n = 352), undetermined (n = 72), or mild dementia (n = 36). We found a highly significant correspondence between increased dementia severity and reduced brain volume, particularly for the amygdala and temporal cortical areas, including the hippocampus, middle temporal gyrus, and inferior temporal gyrus. The negative correlation between brain volumes and dementia severity was significantly stronger in men than women, and in apolipoprotein E4 carriers than non-carriers. Brain volumes discriminated between cognitively unimpaired and mild dementia cases with high accuracy; application of those classification functions to the undetermined group resulted in two distinct groups, one resembling the cognitively unimpaired Control group and another resembling the Dementia group. These findings highlight the correspondence between clinical dementia stages and objective brain volume measures, and point to the potential clinical utility of adjunctive structural brain measures to identify individuals with memory complaints who may be at risk of dementia.},
}

Humans
Male
Female
Aged
*Dementia/pathology/diagnosis/diagnostic imaging
*Brain/pathology/diagnostic imaging
Magnetic Resonance Imaging
Organ Size
Gray Matter/pathology
Aged, 80 and over
Middle Aged
Severity of Illness Index
Atrophy
Alzheimer Disease/pathology

@article {pmid41233409,
year = {2025},
author = {Lai, Y and Zhao, H},
title = {Therapeutic efficacy of rehmannioside A on 5×FAD mice in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39825},
pmid = {41233409},
issn = {2045-2322},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; Oxidative Stress/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism/pathology ; Male ; *Saponins/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; Memory/drug effects ; Mice, Transgenic ; Plaque, Amyloid/drug therapy/pathology ; Drugs, Chinese Herbal ; },
abstract = {Alzheimer's disease (AD), characterized by Aβ plaques and cognitive decline, remains a significant therapeutic challenge due to limited efficacy of current pharmacotherapies, while Rehmannioside A (ReA) has shown promising neuroprotective effects against neurodegenerative diseases. This research focuses on investigating the therapeutic effects of ReA on 5×FAD mice, emphasizing its potential application in AD treatment. The 5×FAD mice were divided into experimental groups and treated with ReA at varied dosages or donepezil for a twelve-week continuous treatment period. A series of evaluation methods, including behavioral tests, histopathological analysis, Western blotting, and measurement of oxidative and inflammatory markers, were implemented. The findings demonstrated that optimal ReA doses significantly improved learning, memory, and cognitive functions in 5×FAD mice, reduced Aβ plaque accumulation in the hippocampus, decreased microglial cell counts, increased PSD 95 and synapsin-1 protein expression, mitigated oxidative stress and inflammation, and showed no harmful effects on liver or kidney function. ReA's diverse biological activities suggest its potential in reducing neural damage. More extensive studies are needed to fully understand its molecular mechanisms in AD, which could lead to the development of innovative and effective treatments for this severe neurodegenerative condition.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
Mice
Oxidative Stress/drug effects
Disease Models, Animal
*Neuroprotective Agents/pharmacology/therapeutic use
Hippocampus/drug effects/metabolism/pathology
Male
*Saponins/pharmacology/therapeutic use
Amyloid beta-Peptides/metabolism
Memory/drug effects
Mice, Transgenic
Plaque, Amyloid/drug therapy/pathology
Drugs, Chinese Herbal

@article {pmid41233403,
year = {2025},
author = {Kovač, V and Huntosova, V and Fedorova, V and Georgiou, N and Lai, JZ and Chien, FC and Chen, SJ and Dolenec, F and Siposova, K},
title = {Unraveling the structure-activity relationships of organometallic ferrocene-pyrazole and ferrocene-pyrimidine curcumin analogues in amyloid-β aggregation and glioblastoma treatment.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39867},
pmid = {41233403},
issn = {2045-2322},
support = {HRZZ-IP-2020-02-9162//Hrvatska Zaklada za Znanost/ ; No. 09-I02-03-V01-00021//NextGenerationEU/ ; SAS-NSTC-JRP-2024-03_SUPRA-SIGHT//Slovenská Akadémia Vied/ ; 2/0034/22//Vedecká Grantová Agentúra MŠVVaŠ SR a SAV/ ; No.101007642; PhytoApp//European Union's Horizon 2020 Research and Innovation programme/ ; },
mesh = {Humans ; *Ferrous Compounds/chemistry/pharmacology ; *Glioblastoma/drug therapy/metabolism/pathology ; *Metallocenes/chemistry/pharmacology ; *Curcumin/pharmacology/chemistry/analogs & derivatives ; *Amyloid beta-Peptides/metabolism/chemistry ; *Pyrazoles/chemistry/pharmacology ; *Pyrimidines/chemistry/pharmacology ; Structure-Activity Relationship ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Apoptosis/drug effects ; Protein Aggregates/drug effects ; Cell Survival/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; },
abstract = {Neurodegenerative and oncological disorders, such as Alzheimer's disease (AD) and glioblastoma (GBM), are major global health challenges. Recent evidence indicates shared molecular mechanisms between these diseases, including dysregulated oxidative stress, mitochondrial dysfunction, and protein aggregation. We hypothesized that ferrocene-containing curcumin derivatives could exert dual-functional effects by simultaneously modulating amyloid-β (Aβ) aggregation and inhibiting glioblastoma cell proliferation. This study explores organometallic ferrocene compounds linked to four pyrazole and two pyrimidine analogues of curcumin with different substituents for their effects on amyloid-β-peptide (Aβ) aggregation and glioblastoma. To test this, pyrazole (FcPy-Cur-H, FcPy-Cur-COPh, FcPy-Cur-COFc, FcPy-Cur-Me) and pyrimidine (FcPyn-Cur-O, FcPyn-Cur-S) analogues were synthesized and evaluated. Thioflavin T fluorescence, atomic force microscopy, and single-molecule localization microscopy revealed structure-dependent inhibition of Aβ fibrillogenesis, with FcPyn-Cur-O, FcPyn-Cur-S, and FcPy-Cur-H showing the strongest anti-amyloidogenic activity. Concurrently, these derivatives reduced U87MG glioblastoma cell viability in a dose-dependent manner, inducing apoptotic features, mitochondrial disruption, and α-tubulin destabilization. Our results demonstrate that specific structural modifications of ferrocene-curcumin analogues enhance their dual anti-amyloidogenic and anticancer activities, highlighting the therapeutic potential of multifunctional compounds. This study provides a conceptual advance by combining neurodegenerative and oncological targets within a single chemical framework, offering a promising strategy for the development of multitargeted therapeutics for complex brain disorders.},
}

Humans
*Ferrous Compounds/chemistry/pharmacology
*Glioblastoma/drug therapy/metabolism/pathology
*Metallocenes/chemistry/pharmacology
*Curcumin/pharmacology/chemistry/analogs & derivatives
*Amyloid beta-Peptides/metabolism/chemistry
*Pyrazoles/chemistry/pharmacology
*Pyrimidines/chemistry/pharmacology
Structure-Activity Relationship
Cell Line, Tumor
Cell Proliferation/drug effects
Apoptosis/drug effects
Protein Aggregates/drug effects
Cell Survival/drug effects
*Protein Aggregation, Pathological/drug therapy/metabolism

@article {pmid41233387,
year = {2025},
author = {Park, JS and Kim, S and Jeong, D and Choi, JP and Jeong, H and Park, AJ and Kim, YS and Lee, J and Kim, SH},
title = {Dementia in older adults with schizophrenia: a 12-year analysis of prevalence, incidence, and treatment patterns in South Korea.},
journal = {Schizophrenia (Heidelberg, Germany)},
volume = {11},
number = {1},
pages = {134},
pmid = {41233387},
issn = {2754-6993},
abstract = {Older adults with schizophrenia face a significantly elevated risk of dementia. However, recent trends remain unclear within South Korea's rapidly aging schizophrenia population. This study aimed to quantify the burden of dementia in older schizophrenia patients by examining prevalence, incidence, dementia subtypes, pharmacologic treatment, and healthcare utilization. Using nationwide Health Insurance Review and Assessment (HIRA) data from 2010 to 2021, we identified 220,378 individuals aged ≥50 with schizophrenia. Dementia was diagnosed in 14.6% of patients, with 20.7% of cases occurring before age 60. Patients with dementia were more likely to be female and to have a higher comorbidity burden. Age-standardized all-cause dementia prevalence rose from 11.8% (2010) to 15.8% (2021) in those aged ≥50, and from 24.2% to 32.8% in those aged ≥65-exceeding estimates in the general population. In contrast, incidence declined from 3.4% to 1.7% over the same period. Alzheimer's disease (AD) was the most prevalent subtype (12.2%), followed by vascular dementia (VD, 2.4%), and frontotemporal dementia (0.5%). A lower AD/VD prevalence ratio in schizophrenia (5.3 vs. 8.6 in the general population) suggests a relatively higher burden of vascular pathology. Cognitive enhancer prescriptions increased from 62% to 77% in patients with dementia, compared to 4% to 10% in those without dementia. In 2021, those with dementia were more likely to live in nursing homes (68% vs. 56%) and had greater annual increases in psychiatric hospitalization duration (+2.30 vs. +1.11 days/year). These findings underscore growing care demands and need for integrated treatment strategies for aging schizophrenia patients with dementia.},
}

@article {pmid41233270,
year = {2025},
author = {Li, D and He, J and Liu, B and Zhu, L and Yang, Y and Peng, Y and Wang, R},
title = {Iron Dysregulation and Neuronal Volume Loss in Alzheimer's Disease: Insights from Hippocampal Subregional Analysis.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2025.10.038},
pmid = {41233270},
issn = {1878-4046},
abstract = {RATIONALE AND OBJECTIVES: Disruption of iron homeostasis and ferroptosis has been implicated in Alzheimer's disease (AD), yet their effects on brain volume across hippocampal subregions remain unclear. This study aimed to examine the relationship between iron deposition and brain atrophy across hippocampal subregions, and to identify potential imaging biomarkers for early diagnosis and disease monitoring.

MATERIALS AND METHODS: Fifty-four AD patients and 48 age- and gender-matched cognitively normal controls underwent quantitative susceptibility mapping (QSM) and 3D T1-weighted MRI to assess magnetic susceptibility and volume across 24 hippocampal subregions. Associations among imaging metrics, demographic data, and cognitive scores were analyzed. An AD prediction model was established through multivariate logistic regression of QSM indicators.

RESULTS: Several subregions exhibited significant alterations in both QSM and volume in AD (p < 0.05), with iron deposition and atrophy in specific regions correlating with cognitive impairment. Notably, five AD-specific subregions (left CA4, GC_ML_DG, Fimbria; right CA4, Fimbria) showed significant inverse correlations between susceptibility values and neuronal volume (p < 0.05). A multivariate diagnostic model incorporating QSM features demonstrated strong discriminatory power (AUC = 0.914, 95% CI: 0.861-0.967).

CONCLUSION: Alzheimer's disease exhibits spatially heterogeneous iron accumulation and atrophy, whose interconnections underscore the disease's complex pathology. Subregional QSM indicators exhibit early diagnostic potential, warranting further validation as a prospective biomarker.},
}

@article {pmid41233182,
year = {2025},
author = {Nakayama, H},
title = {[Brain Pathology of Cognitive Dysfunction in Aged Non-human Animals].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1241-1247},
doi = {10.11477/mf.188160960770111241},
pmid = {41233182},
issn = {1881-6096},
mesh = {Animals ; *Cognitive Dysfunction/pathology ; *Brain/pathology/metabolism ; *Aging/pathology ; Humans ; Alzheimer Disease/pathology ; Cats ; Amyloid beta-Peptides/metabolism ; },
abstract = {Cognitive dysfunction, characterized by the deposition of amyloid β (Aβ), such as senile plaque (SP) and cerebral amyloid angiopathy (CAA), and phosphorylated tau are observed in several animal species, including primates, dogs, and cats, suggesting that these disorders are universal age-related phenomena in vertebrates. Additionally, argyrophilic neurofibrillary tangles positive for phosphorylated tau have been observed in primates, marine mammals, and felines. Recent findings regarding the pathology of cognitive dysfunction in aged non-human animals provide valuable information from a comparative perspective for advancing research on the pathogenesis, diagnosis, and treatment of Alzheimer's disease.},
}

Animals
*Cognitive Dysfunction/pathology
*Brain/pathology/metabolism
*Aging/pathology
Humans
Alzheimer Disease/pathology
Cats
Amyloid beta-Peptides/metabolism

@article {pmid41233181,
year = {2025},
author = {Yoshiyama, K},
title = {[Agitation].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1231-1240},
doi = {10.11477/mf.188160960770111231},
pmid = {41233181},
issn = {1881-6096},
mesh = {Humans ; *Dementia/therapy/complications ; *Psychomotor Agitation/therapy/etiology ; },
abstract = {Agitation is a behavioral and psychological symptom of dementia (BPSD); however, until recently, there has been no consensus-based definition. When initiating therapeutic interventions, the type of dementia that is the cause of the BPSD must be considered and treatment must be tailored accordingly. As with other types of BPSD, non-pharmacological interventions are considered the first-line treatment for agitation, unless the symptoms present an exceptional level of urgency. Person-centered care is effective as a non-pharmacological intervention for agitation. Other examples include music therapy, animal-assisted therapy, and aromatherapy; however, these are not very effective for agitation. Useful information on non-pharmacological interventions for agitation can be obtained from the website "Ninchisho Chienowa-net," which is a web-based system that collects information on the coping strategies of caregivers for BPSD. If non-pharmacological interventions are ineffective or the symptoms are urgent, pharmacological treatment should be considered. Brexpiprazole has been approved as effective for agitation in Alzheimer's disease. For the treatment of agitation, medications other than brexpiprazole are frequently used in clinical settings and may offer some degree of efficacy.},
}

Humans
*Dementia/therapy/complications
*Psychomotor Agitation/therapy/etiology

@article {pmid41232837,
year = {2025},
author = {Čater, M and Šimon, M and Morton, NM and Kunej, T and Horvat, S},
title = {PLA2G4E in health and disease: Insights from omics and functional analyses.},
journal = {Progress in lipid research},
volume = {},
number = {},
pages = {101359},
doi = {10.1016/j.plipres.2025.101359},
pmid = {41232837},
issn = {1873-2194},
abstract = {The phospholipase A2 (PLA2) enzyme superfamily has been extensively studied, but comprehensive reviews on cytosolic phospholipase A2 group IVE (PLA2G4E) remain scarce, limiting our understanding of its role in lipid metabolism and disease. Our review synthesizes current findings on the human PLA2G4E gene and its murine ortholog Pla2g4e, drawing from multi-omics analyses and a range of functional studies. Pla2g4e exhibits distinct expression patterns across tissues, suggesting potential tissue-specific roles. In addition to its phospholipase activity, PLA2G4E exhibits N-acyltransferase activity and responds to calcium influx. Emerging evidence suggests possible involvement in metabolic disorders such as obesity and diabetes, particularly through effects on glucose uptake and insulin sensitivity. PLA2G4E has been implicated in the synthesis of N-acylethanolamines with potential effects on energy homeostasis, stress adaptation, neuronal signaling, pain perception, cognition, and motor coordination. Genomic and preliminary functional evidence further point to possible roles in immune regulation and neurobiology, with some associations reported in neurodegenerative diseases such as Alzheimer's disease. Comprehensive insights into the biological roles of PLA2G4E are essential for clarifying its enzymatic functions and potential involvement in disease mechanisms; however, further experimental and clinical studies are needed to substantiate these emerging associations and assess its therapeutic potential.},
}

@article {pmid41232786,
year = {2025},
author = {Shen, B and Zhang, Y and Travison, TG and Shardell, M and McCoy, RG and Saegusa, T and Falvey, J and Chen, C},
title = {A joint learning framework for analyzing data from national geriatric centralized networks: A new toolbox deciphering real-world complexity.},
journal = {Journal of biomedical informatics},
volume = {},
number = {},
pages = {104954},
doi = {10.1016/j.jbi.2025.104954},
pmid = {41232786},
issn = {1532-0480},
abstract = {OBJECTIVE: We propose JLNet, along with a companion R software package, as a systematic joint learning framework for analyzing data from national geriatric centralized networks, such as Medicare Claims. JLNet addresses key challenges in real-world, large-scale healthcare datasets, including hospital-level clustering and heterogeneity, patient-level variability from high-dimensional covariates, and losses to follow-up, while promoting easy implementation to ultimately support decision-making.

METHODS: JLNet proceeds in three steps: (1) fit a dynamic propensity score model to handle patient loss to follow-up; (2) fit a projection-based regularized regression to identify predictive patient-level features while adjusting for hospital-level confounding; and (3) perform hospital-level clustering using transformed residuals, enabling downstream analyses without sharing raw data. We applied JLNet to Medicare claims data to study post-fracture recovery among older adults with Alzheimer's disease and related dementias (ADRD) following a hip fracture (2010-2018), and evaluated its performance via numerical experiments.

RESULTS: JLNet identified clinically meaningful patient-level variables (e.g., age, weight loss, peripheral vascular disease, etc.) and distinct hospital clusters associated with variation in post-discharge recovery, measured by days at home, among patients with ADRD. Numerical experiments showed that JLNet outperformed existing approaches in variable selection and hospital clustering in the setting involving high-dimensional covariates and unmeasured hospital-level confounding.

DISCUSSION AND CONCLUSION: JLNet is a scalable, interpretable framework for analyzing centralized health data. It enhances identification of high-risk subcohorts and hospital clusters, supporting more precise resource allocation and personalized care strategies for high-risk older adults. Findings also inform the design of tailored interventions in real-world settings.},
}

@article {pmid41232727,
year = {2025},
author = {Zhang, Q and Long, S and Zhang, N and Sun, G and Zhao, L and Zhong, R},
title = {Shared and divergent neurotoxic mechanisms of Bisphenol A and Di(2-ethylhexyl) phthalate with implication for Alzheimer's disease: Insights from network toxicology and in vitro validation.},
journal = {Toxicology and applied pharmacology},
volume = {506},
number = {},
pages = {117637},
doi = {10.1016/j.taap.2025.117637},
pmid = {41232727},
issn = {1096-0333},
abstract = {Bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) are widely recognized environmental neurotoxicants implicated in Alzheimer's disease (AD). However, the shared and divergent mechanisms by which BPA and DEHP induce neurotoxicity in AD remain largely unexplored. In this study, we conducted the first systematic comparative analysis of overlapping and distinct neurotoxic pathways of BPA and DEHP by integrating network toxicology and in vitro experimental validation. Five shared core targets (MMP9, PPARG, MAPK14, BCL2, and BCL2L1) were identified from multiple databases. Experimental validation confirmed that BPA and DEHP significantly upregulated MMP9, PPARG, and phosphorylated MAPK14, while downregulating BCL2 and BCL2L1 at both transcriptional and protein levels. KEGG pathway enrichment revealed both shared and divergent pathways, with the lipid and atherosclerosis pathway emerging as a common AD-relevant pathway, whereas BPA and DEHP showed compound-specific involvement in PI3K-Akt, MAPK, and other signaling cascades. Molecular docking analysis further demonstrated favorable binding of both BPA and DEHP to the shared core targets. Collectively, this study provides novel mechanistic insights into both overlapping and distinct neurotoxic effects of BPA and DEHP in AD, offering a theoretical basis for future mechanistic research and environmental risk assessment.},
}

@article {pmid41232717,
year = {2025},
author = {Castellano Candalija, A and Díez Porres, L and Notario Leo, H and Roca Martiartu, A and Mayoral Canalejas, N and Alonso Babarro, A},
title = {Prevalence and decision-making in advanced dementia.},
journal = {Revista clinica espanola},
volume = {},
number = {},
pages = {502388},
doi = {10.1016/j.rceng.2025.502388},
pmid = {41232717},
issn = {2254-8874},
abstract = {INTRODUCTION: Dementia is a chronic neurodegenerative disease with a high prevalence and economic cost. Our objective was to evaluate the prevalence of advanced dementia (AD) in patients hospitalized in the Internal Medicine service; to analyze the therapeutic and diagnostic measures implemented, the degree of adequacy of the therapeutic effort and the information of the family.

METHODOLOGY: Descriptive study that included a retrospective analysis of medical records and a telephone interview with family. Patients with GDS 6-7 dementia admitted to Internal Medicine were included, for 3 weeks in 3 different months.

RESULTS: 194 (22%) patients with dementia were included. The prevalence of admissions with AD was 11%. The median age was 87.5 years (QR 81.75-93), 65% women. 45% came from residence for the elderly. The most frequent etiology was Alzheimer's (48%). The most frequent cause of admission was infection (72%). 37% died. Regarding the measures implemented: 100% were treatment intravenous; 89% received anticoagulation; 26% received artificial nutrition; 81% received pharmacological restraint and 63% physical restraint; and 48% underwent invasive diagnostic tests. Regarding adequacy: lipid-lowering treatment was withdrawn in 19%, antidementia drugs in 23%, anticoagulation in 21%; cardiopulmonary resuscitation was not performed in 30%, adequacy of care in 34%, and 13% were assessed by Palliative Care. A telephone interview was conducted with 55 patients. 42% were not aware of any complications. Care planning was carried out in 2 patients.

CONCLUSIONS: The prevalence of admission to AD is high, and almost half of the patients come from residence for the elderly. Associated mortality is high and therapeutic adequacy and planning are very scarce.},
}

@article {pmid41232709,
year = {2025},
author = {Zhou, W and Qu, R and Luo, W and Zhang, H and Gong, L and , },
title = {Identification of cognitive brain diseases using a dual-branch siamese network on structural magnetic resonance imaging data.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.011},
pmid = {41232709},
issn = {1873-7544},
abstract = {Early diagnosis of Alzheimer's Disease is crucial for optimizing treatment efficacy, as delayed detection often limits therapeutic outcomes. Traditional diagnostic approaches, such as cognitive assessments, PET scans, and lumbar punctures, are often invasive, costly, and less accessible. To address these limitations, we propose a Dual-Branch Siamese Network aimed at enhancing the classification accuracy of Alzheimer's Disease, Mild Cognitive Impairment, and Cognitively Normal individuals using structural MRI data. Our model integrates neuroimaging features from both Subcortical Segmentation and Cortical Parcellation, leveraging their complementary strengths to improve diagnostic precision. Experimental evaluations demonstrate that our model achieves a classification accuracy of 93% on the original dataset. To further validate the model's generalizability, we tested the trained model on a separate independent test set from the new ADNI4 database (N=191). On this independent cohort, the model achieved a robust classification accuracy of 88.48%, demonstrating its potential for real-world application. Additionally, by implementing network pruning, we reduced the model's complexity by 60% without sacrificing accuracy, thereby enhancing its feasibility for clinical use. Compared to other methods, such as convolutional neural networks and ensemble learning systems, our model demonstrates superior accuracy in multi-class classification and remains competitive in binary classification tasks. Notably, our pruned model balances accuracy with efficiency, outperforming other models in terms of computational feasibility without compromising diagnostic precision. These findings highlight the potential of our approach to facilitate early diagnosis and intervention for neurodegenerative diseases like Alzheimer's Disease.},
}

@article {pmid41232530,
year = {2025},
author = {Wang, D and Gazzara, MR and Jewell, S and Wales-McGrath, BD and Yang, K and Brown, CD and Choi, PS and Barash, Y},
title = {A deep dive into statistical modeling of RNA splicing QTLs reveals variants that explain neurodegenerative disease.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2025.10.012},
pmid = {41232530},
issn = {1537-6605},
abstract = {Genome-wide association studies (GWASs) have identified thousands of putative disease-causing variants with unknown regulatory effects. Efforts to connect these variants with splicing quantitative trait loci (sQTLs) have provided functional insights, yet sQTLs reported by existing methods cannot explain many GWAS signals. We show that current sQTL modeling approaches can be improved by considering alternative splicing representation, model calibration, and covariate integration. We then introduce MAJIQTL, a pipeline for sQTL discovery. MAJIQTL includes two statistical methods: a weighted multiple-testing approach for sGene discovery and a model for sQTL effect-size inference to improve variant prioritization. By applying MAJIQTL to GTEx, we find significantly more sGenes harboring sQTLs with functional significance. Notably, our analysis implicates the variant rs528823 in Alzheimer disease. Using antisense oligonucleotides, we test this variant's effect by blocking the implicated YBX3 binding site, leading to exon skipping in MS4A3.},
}

@article {pmid41232397,
year = {2025},
author = {Zuo, Y and Ding, X and Sun, Y and Wang, L and Song, Y and Zhao, Z and Liu, C},
title = {Critical nodes in precision diagnosis and treatment of Alzheimer's disease: exploration of multidimensional biomarkers and prospects for targeted intervention.},
journal = {Journal of the neurological sciences},
volume = {479},
number = {},
pages = {123734},
doi = {10.1016/j.jns.2025.123734},
pmid = {41232397},
issn = {1878-5883},
abstract = {Alzheimer' s disease (AD), characterized by cognitive decline and progressive neurodegeneration, remains a major clinical and scientific challenge due to its complex pathophysiology and marked heterogeneity. Important signs of the disease, like the buildup of β-amyloid, changes in Tau proteins, inflammation in the brain, and problems with mitochondria, form the basis for developing targeted treatments. This review summarizes recent advances in the identification of therapeutic targets and multi-dimensional biomarkers, such as liquid, imaging, and multi-omics-based markers. These biomarkers hold potential for early diagnosis, disease subtyping, and therapeutic response monitoring. We suggest that combining biomarkers and treatment targets could be a key approach to improving personalized care for AD.},
}

@article {pmid41232357,
year = {2025},
author = {Castillo-Moral, Á and Tchoumtchoua, J and Leonard, K and Del Bas, JM and Ortega, N and Escoté, X and Teichenné, J},
title = {Neuroprotective effects of polyphenol-rich extracts obtained from agricultural by-products in an induced cognitive decline model of zebrafish larvae and in human neurons.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118776},
doi = {10.1016/j.biopha.2025.118776},
pmid = {41232357},
issn = {1950-6007},
abstract = {Neurodegenerative diseases are closely associated with chronic neuroinflammation and oxidative stress, which contribute to progressive neuronal dysfunction and cell death. Due to their antioxidant and anti-inflammatory properties, polyphenols have gained attention as potential neuroprotective agents. Agricultural by-products represent a promising and sustainable source of polyphenols, yet their neuroprotective value remains underexplored. In this study, we evaluated four polyphenol-rich extracts derived from red onion peels (ROPE), olive pruning (OPE), vineyard pruning (VPE) and chicory leaves (CLE), obtained by subcritical water extraction. Their effects were tested in two complementary models of neurodegeneration: in vitro human neurons (SH-SY5Y cells) exposed to D-galactose and a basic cognitive decline model of zebrafish larvae exposed to aluminium chloride (AlCl3). All extracts exhibited anti-inflammatory effects in vitro, significantly reducing IL-1β and IL-8 mRNA expression, at doses ranging 12.5-50 μg/mL in cell medium. In the zebrafish model, treatment with 100 μg/mL ROPE or VPE in medium restored the normal sensorimotor pattern in the Dark-Light-Dark test, while ROPE treatment additionally rescued basal startle responses and enhanced habituation indexes, even surpassing healthy control larvae. Overall, these results highlight the potential of polyphenol-rich agri-food extracts, particularly ROPE, as neuroprotective and cognitive-enhancing compounds and support their further investigation as natural and sustainable interventions to slow or prevent neurodegenerative processes.},
}

@article {pmid41232325,
year = {2025},
author = {Guo, X and Tang, P and He, J and Li, R},
title = {Dissecting the effect of blood colony-stimulating factors and receptors on Alzheimer's disease: the role of myeloid traits and inflammation.},
journal = {Cytokine},
volume = {197},
number = {},
pages = {157072},
doi = {10.1016/j.cyto.2025.157072},
pmid = {41232325},
issn = {1096-0023},
abstract = {BACKGROUND: Research has suggested a potential link between colony-stimulating factors (CSFs) and Alzheimer's disease (AD), but the findings have been inconsistent, and the causal relationship remains uncertain.

METHODS: We performed a Mendelian Randomization (MR) analysis to explore the association between blood levels of CSFs and their receptors with AD and its biomarkers. The study utilized summary-level data on blood levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and their receptors from deCODE. Data on AD were sourced from the International Genomics of Alzheimer's Project (IGAP), UK Biobank (UKB), and FinnGen, while cerebrospinal fluid p-Tau and β-amyloid levels were from the largest GWAS currently available. Additional summary-level data on amyloid PET imaging and AD progression from ADNI and the Knight-ADRC were also included.

RESULTS: Genetically predicted one standard deviation increase in blood G-CSF was associated with a higher risk of AD across three datasets (IGAP: OR = 1.35, 95 %CI = 1.15-1.57, P < 0.001; IGAP+UKB: OR = 1.27, 95 %CI = 1.12-1.43, P < 0.001; FinnGen: OR = 1.43, 95 %CI = 1.26-1.61, P < 0.001), but not AD progression. Elevated blood G-CSF levels were inversely related to β-amyloid levels (β = -0.14, 95 %CI = -0.19 to -0.09, P < 0.001) and positively associated with p-Tau levels (β = 0.08, 95 %CI = 0.03 to 0.14, P = 0.001) in cerebrospinal fluid. Furthermore, genetically predicted blood G-CSF levels were positively associated with amyloid PET imaging in the brain (β = 0.10, 95 % CI: 0.06 to 0.14, P < 0.001). However, no significant associations were found between blood levels of other CSFs, and their receptors and AD risk. In contrast, there was little evidence supporting the impact of AD on CSFs levels. The multivariable MR analysis showed that the association between G-CSF and AD, along with its biomarkers, disappeared after adjusting for C-reactive protein levels, but not for neutrophil count.

CONCLUSION: These findings indicate a harmful role of G-CSF in the development of AD, primarily driven by inflammatory responses rather than neutrophil counts. Therefore, interventions targeting AD through CSFs, especially G-CSF, should be cautiously approached.},
}

@article {pmid41231963,
year = {2025},
author = {Zhang, T and Zhu, H},
title = {Library size-stabilized metacells construction enhances co-expression network analysis in single-cell data.},
journal = {PLoS computational biology},
volume = {21},
number = {11},
pages = {e1013697},
doi = {10.1371/journal.pcbi.1013697},
pmid = {41231963},
issn = {1553-7358},
abstract = {Single-cell RNA sequencing (scRNA-seq) deciphers cell type-specific co-expression networks to resolve biological functions but remains constrained by data sparsity and compositional biases. Conventional metacells construction strategies mitigate sparsity by aggregating transcriptionally similar cells but often neglect systematic biases introduced by compositional data. This problem leads to spurious co-expression correlations and obscuring biologically meaningful interactions. Through mathematical modeling and simulations, we demonstrate that uncontrolled library size variance in traditional metacells inflates false-positive correlations and distorts co-expression networks. Here, we present LSMetacell (Library Size-stabilized Metacells), a computational framework that explicitly stabilizes library sizes across metacells to reduce compositional noise while preserving cellular heterogeneity. LSMetacell addresses this by stabilizing library sizes during metacells aggregation, thereby enhancing the accuracy of downstream analyses such as Weighted Gene Co-expression Network Analysis (WGCNA). Applied to a postmortem Alzheimer's disease brain scRNA-seq dataset, LSMetacell revealed robust, cell type-specific co-expression modules enriched for disease-relevant pathways, outperforming the conventional metacells approach. Our work establishes a principled strategy for resolving compositional biases in scRNA-seq data, advancing the reliability of co-expression network inference in studying complex biological systems. This framework provides a generalizable solution for improving transcriptional analyses in single-cell studies.},
}

@article {pmid41231728,
year = {2025},
author = {Luan, Y and Huang, Q and Wang, J and Guan, Y and Li, B and Franzmeier, N and Xie, F and Ewers, M},
title = {Synaptic density and tau pathology in Alzheimer's disease: a dual role in susceptibility and degeneration.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf425},
pmid = {41231728},
issn = {1460-2156},
abstract = {Fibrillar tau is a defining hallmark of Alzheimer's disease, gradually accumulating and spreading throughout the brain. The synapse plays a key role in this process-both by facilitating the spread of tau between neurons and by serving as a direct target of tau-induced neurotoxicity. However, few studies in humans have explored synaptic density both as a facilitating factor and as a target of tau pathology. In this dual PET tracer study, we used 18F-SynVesT-1 synaptic vesicle glycoprotein 2A (SV2A) PET to assess synaptic density and 18F-MK6240 tau-PET to assess fibrillar tau in 59 amyloid-PET-positive patients and 25 amyloid-PET-negative cognitively normal individuals from the Chinese Preclinical Alzheimer's Disease Study (CPAS). Spatial correlation analyses revealed that brain regions with higher SV2A tracer uptake in cognitively normal individuals exhibited higher 18F-MK6240 uptake in Alzheimer's disease. These findings were independently replicated in the Alzheimer's Disease Neuroimaging Initiative (ADNI), where normal SV2A-PET maps from CPAS were correlated with tau-PET data from 372 Aβ+ participants, including longitudinal follow-up in 204 cases. In both cohorts, regions with higher normal synaptic density showed greater tau burden, and in ADNI, higher synaptic density in normal brain also predicted faster tau accumulation over time. Gene-set enrichment analyses of transcriptomic data mapped onto regional tau-PET uptake further showed that areas of high 18F-MK6240 uptake were enriched in genes encoding synapse-related proteins. Together, these findings suggest that synapse-rich regions are especially prone to tau accumulation. We also investigated the downstream impact of tau on synaptic integrity. Notably, regions with higher 18F-MK6240 uptake showed reduced SV2A tracer uptake, indicating synaptic loss, not only in the same regions but also in areas connected to those with high tau. Stronger loss of SV2A tracer uptake was observed in the regions with stronger resting-state functional connectivity to epicenters of high 18F-MK6240 uptake in the Alzheimer's disease group. The connectivity-dependent synaptic loss could not be fully explained by tau levels in the connected target regions but was found to be partially mediated by them. These findings suggest that tau pathology contributes to synaptic loss both locally and in distant, connected brain regions. Overall, our results highlight the central importance of the synapse in Alzheimer's disease: synapses appear to both facilitate fibrillar tau accumulation and become impaired through its toxic effects. Understanding the synapse's role in tau pathology may open new avenues for therapeutic interventions aimed at slowing down tau progression and neurodegeneration.},
}

@article {pmid41231717,
year = {2025},
author = {Al-Nasser, M and Al-Nasser, A},
title = {The second victim's satisfaction index model.},
journal = {International journal of health care quality assurance},
volume = {},
number = {},
pages = {1-17},
doi = {10.1108/IJHCQA-05-2025-0071},
pmid = {41231717},
issn = {1758-6542},
abstract = {PURPOSE: This article proposes a new customer satisfaction model. The purpose of the proposed model is to identify the key factors that influence the second victim's (SV's) satisfaction level. In a medical context, the SV refers to caregivers who provide all kinds of daily support to a close relative who is living with chronic and irreversible conditions, such as Alzheimer's patients.

DESIGN/METHODOLOGY/APPROACH: The model is simulated from the American customer satisfaction model, but with different latent variables. Based on literature and theoretical considerations, four predictors of caregiver satisfaction were identified: knowledge, empathy, memory and lifestyle. To evaluate the research model, this study employed the partial least squares structural equation modeling technique.

FINDINGS: Data were collected from a sample of 154 Alzheimer's caregivers over a period of three months using convenience and network sampling techniques. The analysis revealed several key findings. Both knowledge and memory had a significant and positive influence on caregivers' satisfaction, indicating the importance of cognitive resources and caregiving competence. In addition, memory and lifestyle influence empathy, suggesting that both personal reflection and healthy routines may enhance emotional attunement toward care recipients.

The main limitation we faced in this study is the difficulty in collecting a large sample size; the study relies on a sample of 154 caregivers.

PRACTICAL IMPLICATIONS: This study offers valuable models that shape SV's satisfaction. By identifying and validating the roles of knowledge, memory, empathy and lifestyle, the model offers a robust framework for developing targeted interventions to support and empower caregivers.

SOCIAL IMPLICATIONS: The insights gained from this research can contribute to greater family caregivers' awareness, especially on caregiver knowledge and memory to improve the lifestyle and increase their satisfaction level when they are dealing with Alzheimer's patients.

ORIGINALITY/VALUE: The originality of this study lies in its optimal model results, which show the main significant factors of the SVs, which advances understanding and opens new avenues for future research.},
}

@article {pmid41231696,
year = {2025},
author = {Zheng, C and El-Sappagh, S and Abuhmed, T},
title = {4DfCF: 4D fMRI CrossFormer Vision Transformer.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3631655},
pmid = {41231696},
issn = {2168-2208},
abstract = {Investigating the spatiotemporal dynamics of the human brain is a complex challenge due to the intricate nature of brain networks, and the limitations of current analytical methods. Herein, we introduce the 4D functional Magnetic Resonance Imaging (fMRI) CrossFormer (4DfCF), a novel vision transformer architecture designed to process high-dimensional 4D fMRI data. This model integrates temporal and spatial dimensions to effectively learn and predict cognitive and clinical outcomes. We further evaluated the 4DfCF on three benchmark datasets: Attention Deficit Hyperactivity Disorder-200 (ADHD-200), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Autism Brain Imaging Data Exchange (ABIDE). The results showed that our model consistently outperforms state-of-the-art baseline models, achieving an accuracy improvement of 5-10%, a precision increase of 4-8%, a recall enhancement of 6-9%, and an F1-score boost of 7-11%. Additionally, the 4D fMRI CrossFormer-Tiny variant demonstrated greater efficiency than existing methods, using 20% fewer computational resources and achieving 30% faster training times. Pre-training experiments further reveal that models pre-trained on one dataset and fine-tuned on another achieved faster convergence and higher accuracy, with the Autism Brain Imaging Data Exchange (ABIDE) pre-trained models showing the best performance. Additionally, we employed an explainable AI method to identify the brain regions associated with disease diagnosis. Overall, our findings highlight the potential of the 4DfCF to advance precision neuroscience through efficient and scalable analysis of complex fMRI data.},
}

@article {pmid41225397,
year = {2025},
author = {Melendo-Azuela, EM and Lladó, A and Vela, E and Mariscal, S and Cleries, M and Piñol-Ripoll, G and Santaeugènia, SJ},
title = {Epidemiological evolution and healthcare services utilization in elderly dementia patients of Catalonia.},
journal = {BMC public health},
volume = {25},
number = {1},
pages = {3919},
pmid = {41225397},
issn = {1471-2458},
support = {SLT008/18/00061//PERIS 2019/ ; SLT008/18/00050//PERIS 2019/ ; },
abstract = {BACKGROUND: Assessing the dynamics and burden of dementia is necessary to improve healthcare plans. This study aimed to describe the epidemiology and characteristics of dementia diagnoses in Catalonia (North-East of Spain) and evaluate healthcare services utilization and associated expenditures in people with dementia compared with people without.

METHODS: Retrospective study including all the dementia population (2013–2020) using data from an administrative database, the Catalan Health Surveillance System, covering a 7.5–7.7-million population. Data included demographic, clinical, healthcare services utilization, and morbidity-associated risk variables, and was analyzed according to dementia type, including Alzheimer’s disease (AD), vascular dementia (VD), frontotemporal dementia (FTD), dementia with Lewy bodies (LBD), and unspecified dementia (UD). We compared comorbidities and morbidity-associated risk, healthcare services utilization and associated expenditures, and mortality rates between people with dementia and the population without dementia adjusted for age, sex, and income level.

RESULTS: During the study period, dementia prevalence remained stable, and incidence modestly decreased. AD and VD incidence rates decreased, whereas UD modestly increased, being the highest in 2019. Patients with dementia had a higher prevalence of comorbidities, morbidity-associated risk, healthcare services utilization, specially admissions in nursing homes and intermediate care, healthcare-associated expenditures, and mortality than people without dementia adjusted by age, sex, and income level in 2019. An expenditure €1311.7 per person per year was attributable to dementia, representing an increase of 44.1% of total healthcare costs. Compared to other dementia types, AD and VD had increased admissions, and VD had the highest expenditures. The use of antidepressants and benzodiazepines progressively decreased.

CONCLUSIONS: Using a population dataset, this study showed that dementia is associated with a high burden and healthcare needs, providing useful information to design improved healthcare plans.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-025-24341-4.},
}

@article {pmid41231544,
year = {2025},
author = {Benedet, AL and Arslan, B and Tan, K and Huber, H and Pola, I and Di Molfetta, G and Kvartsberg, H and Dolado, AO and Janelidze, S and Blennow, K and Zetterberg, H and Hansson, O and Rosa-Neto, P and Ashton, NJ},
title = {Diagnostic Value of Serum p-tau217 in Alzheimer Disease: Equal to Plasma in Levels and Clinical Utility?.},
journal = {Clinical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1093/clinchem/hvaf162},
pmid = {41231544},
issn = {1530-8561},
support = {//University of Gothenburg/ ; //Weston Brain Institute/ ; MOP-11-51-31/CAPMC/CIHR/Canada ; RFN 152985/CAPMC/CIHR/Canada ; 159815/CAPMC/CIHR/Canada ; 162303/CAPMC/CIHR/Canada ; MOP-11-51-31//Canadian Consortium of Neurodegeneration and Aging/ ; NIRG-12-92090/ALZ/Alzheimer's Association/United States ; NIRP-12-259245/ALZ/Alzheimer's Association/United States ; //Brain Canada Foundation/ ; 2020-VICO-279314//Fonds de Recherche du Québec-Santé/ ; 2024-VICO-356138//Fonds de Recherche du Québec-Santé/ ; AF-940262//Swedish Alzheimer Foundation/ ; //Stiftelsen för Gamla Tjänarinnor/ ; AARFD-22-974564//Alzheimer's Association Research Fellowship/ ; 2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer Drug Discovery Foundation/ ; ADSF-21-831376-C//AD Strategic Fund/ ; ADSF-21-831381-C//AD Strategic Fund/ ; ADSF-21-831377-C//AD Strategic Fund/ ; ADSF-24-1284328-C//AD Strategic Fund/ ; 22HLT07//AD Strategic Fund/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; //Familjen Rönströms Stiftelse/ ; FO2022-0270//Hjärnfonden, Sweden/ ; //Marie Skłodowska-Curie grant/ ; JPND2021-00694//European Union Joint Programme-Neurodegenerative Disease Research/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute/ ; 2017-00915//UK Dementia Research Institute/ ; 2022-00732//UK Dementia Research Institute/ ; AF-930351//UK Dementia Research Institute/ ; AF-939721//UK Dementia Research Institute/ ; AF-968270//UK Dementia Research Institute/ ; FO2017-0243//UK Dementia Research Institute/ ; ALZ2022-0006//UK Dementia Research Institute/ ; ALFGBG-715986//UK Dementia Research Institute/ ; ALFGBG-965240//UK Dementia Research Institute/ ; JPND2019-466-236//UK Dementia Research Institute/ ; SG-23-1038904//UK Dementia Research Institute/ ; ZEN24-1069572//UK Dementia Research Institute/ ; SG-23-1061717//UK Dementia Research Institute/ ; 2022-00775//GHR Foundation/ ; 2022-0231//Knut and Alice Wallenberg Foundation/ ; AF-980907//Lund University/ ; FO2021-0293//Swedish Brain Foundation/ ; 1412/22//Parkinson Foundation of Sweden/ ; //Rönström Family Foundation/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; 2020-O000028//Skåne University Hospital Foundation/ ; 2022-1259//Regionalt Forskningsstöd/ ; 2022-Projekt0080//Swedish Federal Government/ ; },
abstract = {BACKGROUND: Phosphorylated tau 217 (p-tau217) has emerged as a leading blood-based biomarker for Alzheimer disease (AD). While typically measured in plasma, serum is a widely used matrix in clinical laboratories, yet few p-tau217 assays have been validated for serum. Evaluating serum p-tau217 performance is essential for expanding its use in clinical and research settings, particularly for cohorts with only serum samples available.

METHODS: We quantified p-tau217 in plasma and serum from individuals within the AD continuum (n = 100; mean age 72.5 ± 5.0 years; 54% female) using 6 assays across 4 platforms. Spearman correlation, Passing-Bablok regression, and receiver operating characteristics analysis were used to assess intermatrix agreement and diagnostic performance. Specific validation parameters (e.g., precision, parallelism, dilution linearity, stability) were evaluated in both matrices.

RESULTS: High correlations between plasma and serum were observed for most assays (ρ > 0.8), though plasma often yielded higher concentrations. Notably, the Lumipulse assay showed near-perfect correlation (ρ = 0.98) and minimal bias. Fold changes in p-tau217 levels across the AD continuum were comparable between matrices, though cutoffs for detecting AD pathology differed. Applying plasma-derived cutoffs to serum resulted in misclassification rates ranging from 16% to 47%, except for Lumipulse (10% in serum vs 5% in plasma). Not all assays performed equally in serum, as reflected in validation metrics.

CONCLUSIONS: Serum p-tau217, across multiple platforms, shows strong correlations with plasma p-tau217 and reflected comparable patterns across the AD continuum. However, absolute concentrations differed for most assays, thus requiring differing disease specific cutoffs. Most of the evaluated platforms demonstrated reliable quantification of p-tau217 in serum, yielding satisfactory validation performance. These findings support serum as a viable alternative to plasma for p-tau217 quantification in both research and clinical settings, provided matrix-specific validation is ensured.},
}

@article {pmid41231438,
year = {2025},
author = {Constantino, NJ and Ashley, CC and Macauley, SL},
title = {The Energetic Collapse of the Alzheimer's Brain: Metabolic Inflexibility Across Cells and Networks.},
journal = {Journal of neurochemistry},
volume = {169},
number = {11},
pages = {e70294},
doi = {10.1111/jnc.70294},
pmid = {41231438},
issn = {1471-4159},
support = {//Coins for Alzheimer's Research Trust/ ; A20201775S//BrightFocus Foundation/ ; P20GM148326/GM/NIGMS NIH HHS/United States ; P30AG072946/AG/NIA NIH HHS/United States ; R01AG068330/AG/NIA NIH HHS/United States ; R01AG093847/AG/NIA NIH HHS/United States ; T32NS115704/NS/NINDS NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Energy Metabolism/physiology ; *Brain/metabolism/pathology ; Animals ; *Neurons/metabolism/pathology ; *Nerve Net/metabolism ; },
abstract = {Alzheimer's disease (AD) is more than just amyloid and tau. While often described as a disease of metabolic dysfunction, AD can more accurately be described as a disorder of metabolic inflexibility that leads to bioenergetic failure. In the healthy brain, neurons, glia, and vascular cells dynamically share and switch between different fuel sources (e.g., glucose, lactate, ketones, and fatty acids) to match functional demand. In AD, this adaptability is progressively lost because cellular metabolism is actively reprogrammed to support neuroinflammatory and disease-associated processes at the cost of neuronal function. Microglia, in particular, upregulate glycolytic metabolism, alter lipid handling, and prioritize immune functions, which actively depletes the brain's energy supply. These adaptations are initially compensatory but ultimately trap the brain in a rigid metabolic program that deprioritizes neuronal support. This metabolic shift unfolds along a biphasic trajectory: early, glia-driven hypermetabolism aligned with inflammation, followed by late-stage brain hypometabolism and energy collapse that leads to neuronal dysfunction. System-level consequences include altered excitability, decreased network connectivity, sleep disruption, and cognitive decline. Critically, these changes feed forward to accelerate AD pathogenesis: glycolytically biased microglia and stressed neurons promote amyloid-β production, tau release, and protein aggregation, adding to metabolic rigidity. Evidence from human neuroimaging studies, brain/cerebral spinal fluid (CSF) multi-omic studies, and preclinical studies demonstrate that shifts in glycolytic flux, tricarboxylic acid cycle (TCA) intermediates, and lipid metabolism parallel amyloid and tau pathology and cognition decline. We hypothesize that these metabolic programs, while initially protective, are chronically maladaptive yet reversible. We propose that restoring metabolic flexibility can mitigate amyloid and tau pathology, neuronal loss, and functional decline. Ongoing preclinical studies and clinical trials are actively exploring metabolism as a therapeutic target in AD. Collectively, these findings define AD as a disorder of metabolic inflexibility, where adaptive shifts in cellular metabolism become pathologically rigid and drive disease progression, while offering a promising target for therapeutic intervention in AD.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Energy Metabolism/physiology
*Brain/metabolism/pathology
Animals
*Neurons/metabolism/pathology
*Nerve Net/metabolism

@article {pmid41231363,
year = {2025},
author = {Prufer Q C Araujo, I and Ellingson, T and Schwartz, NU and Dietz, CD and Tammewar, G and Deniz, K and Eslami-Amirabadi, M and Breithaupt, AG and Rosenberg, M and Bui, NM and Gonzalez, Y and La Joie, R and Ljubenkov, PA and Possin, KL and Rojas, JC and Soleimani-Meigooni, DN and Wang, Y and Staffaroni, AM and Stephens, ML and Tsoy, E and Windon, CC and Boxer, AL and Rabinovici, GD and Miller, BL and VandeVrede, L},
title = {Blood-based Alzheimer's disease biomarkers in a behavioral neurology clinic: Real-world implementation, clinical utility, and diagnostic performance.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70891},
doi = {10.1002/alz.70891},
pmid = {41231363},
issn = {1552-5279},
support = {K23AG073514/NH/NIH HHS/United States ; P30AG062422/NH/NIH HHS/United States ; P01AG038791/NH/NIH HHS/United States ; R01AG019724/NH/NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //Shenandoah Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Biomarkers/blood ; *tau Proteins/blood ; Retrospective Studies ; Female ; Male ; Aged ; Aged, 80 and over ; Middle Aged ; },
abstract = {INTRODUCTION: Blood-based biomarkers (BBMs) for Alzheimer's disease (AD), including plasma phosphorylated tau (p-tau), are increasingly used in clinical practice, but "real-world" implementation patterns, context-of-use (COU), clinical utility, and diagnostic performance are incompletely understood.

METHODS: A retrospective analysis of the first year of BBM use in a tertiary level cognitive neurology subspecialty clinic was conducted, including review of COU, impact on diagnostic certainty, prescription of AD-related medications, and additional AD-biomarker testing.

RESULTS: P-tau181 was ordered frequently to detect AD in a diverse cohort, across a wide spectrum of COU, including typical, early-onset, and atypical AD presentations; mixed etiology; AD co-pathology; and borderline symptoms. P-tau181 impacted diagnostic confidence, AD-related medication prescription, and follow-on testing. Renal impairment was a common confounder.

CONCLUSIONS: Implementation of BBMs was feasible and impactful in a memory clinic, especially in a diagnostically complex and diverse patient population, underscoring the need for additional data from real-world settings.

HIGHLIGHTS: Blood-based biomarkers (BBMs) were quickly adopted and accelerated precision diagnosis in a large memory clinic. BBM use cases were diverse and included all stages/types of AD and non-AD syndromes. Plasma p-tau has the potential to impact diagnostic certainty and clinical decision making. Diagnostic performance of p-tau is reasonable, though renal function impacts overall accuracy.},
}

Humans
*Alzheimer Disease/diagnosis/blood
*Biomarkers/blood
*tau Proteins/blood
Retrospective Studies
Female
Male
Aged
Aged, 80 and over
Middle Aged

@article {pmid41231278,
year = {2025},
author = {Kechko, OI and Mukhina, KA and Yanvarev, DV and Eremina, SY and Katkova-Zhukotskaya, OA and Chaprov, KD and Drutskaya, MS and Kozin, SA and Makarov, AA and Mitkevich, VA},
title = {Therapeutic Potential of HAEEPGP Peptide Against β-Amyloid Induced Neuropathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {36},
pmid = {41231278},
issn = {1559-1182},
support = {19-74-30007//Russian Science Foundation/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/toxicity/metabolism ; Mice, Transgenic ; Humans ; Caenorhabditis elegans/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; *Oligopeptides/pharmacology/pharmacokinetics/therapeutic use ; Brain/pathology/metabolism/drug effects ; Microglia/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; Astrocytes/drug effects/metabolism/pathology ; },
abstract = {The development of effective therapies for Alzheimer's disease remains a critical challenge in modern medicine. While monoclonal antibodies targeting beta-amyloid (Aβ) have shown the most significant clinical efficacy, their use is limited by poor blood-brain barrier permeability and side effects, which are occasionally severe. We previously devised ion-complementary to Aβ tetrapeptide HAEE, that was able to suppress amyloidogenesis in vivo. In this study, we modified HAEE by adding PGP amino acid residues to its C-terminus to improve its pharmacological properties. Pharmacokinetic analysis revealed that the [125]I-HAEEPGP half-life in mouse plasma was twice that of [125]I-HAEE and C-terminus modification of HAEE significantly increased its brain tissue penetration. Isothermal titration calorimetry experiments revealed that HAEEPGP formed a stable complex with Aβ and, besides, exhibited higher affinity for pathogenic isomerized Aβ than for the native peptide. [125]I-HAEEPGP showed enhanced accumulation in the brain of 5xFAD transgenic mice compared to wild-type controls. Furthermore, using western blotting, ELISA, and flow cytometry, we demonstrated that HAEEPGP considerably reduced Aβ-induced astrocyte and microglia activation, prevented synaptic degeneration in 5xFAD mice, and restored lifespan of Caenorhabditis elegans overexpressing human Aβ. These features of HAEEPGP have positioned it as a promising therapeutic candidate for Aβ-related neuropathology.},
}

Animals
*Amyloid beta-Peptides/toxicity/metabolism
Mice, Transgenic
Humans
Caenorhabditis elegans/metabolism
*Alzheimer Disease/drug therapy/pathology/metabolism
Mice
*Oligopeptides/pharmacology/pharmacokinetics/therapeutic use
Brain/pathology/metabolism/drug effects
Microglia/drug effects/metabolism/pathology
Mice, Inbred C57BL
Astrocytes/drug effects/metabolism/pathology

@article {pmid41231253,
year = {2025},
author = {Yu, Y and Sun, Y and Zhao, T},
title = {The roles of glycerophospholipids in the aging retina and age-related macular degeneration.},
journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie},
volume = {},
number = {},
pages = {},
pmid = {41231253},
issn = {1435-702X},
support = {No. 2023SK2032//Key Research and Development Program of Hunan Province of China/ ; No. kq2502054//the Changsha Municipal Natural Science Foundation/ ; No. 2025JGB161//Project Program of central south university graduate education teaching reform/ ; },
abstract = {Glycerophospholipids (GPs) are integral constituents of cellular membranes, and play a crucial role in the regulation of lipid metabolism homeostasis and physiological conditions. However, pathological alterations associated with aging, such as variations in plasma GP concentrations, disruptions in intercellular GP transport, and local accumulation of excessive GPs, have been observed. These changes induce irreversible cellular degeneration, ultimately leading to tissue damage in organs such as the brain and retina. A growing body of evidences has demonstrated that GPs play significant roles in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Similarly, GPs have been implicated in the pathogenesis and progression of age-related macular degeneration (AMD), a degenerative condition affecting the choroid and retinal layers of the eye. Understanding the homeostasis of GP metabolism in the aging retina and in AMD is essential for elucidating the pathogenic processes involved in AMD. In this review, we present a comprehensive overview of the mechanisms of GPs in the aging retina and their correlation with degenerative processes associated with AMD. KEY MESSAGES: What is known Metabolic dysregulation of glycerophospholipids (GPs) plays vital roles in age-related macular degeneration (AMD) and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Patients with age-related neurological disorders exhibit a significantly higher risk of developing AMD compared to healthy individuals, potentially due to shared pathological mechanisms, including mitochondrial metabolic disturbance, chronic inflammation and autophagy dysfunction. What is new The interconnection between multiple GP species and their metabolites has been established to delineate complex pathogenic mechanisms underlying the aging retina and AMD, including cell senescence, autophagy and apoptosis, oxidative stress, inflammation, vascular abnormalities. GPs may serve as potential therapeutic targets to prevent or delay the progression of AMD.},
}

@article {pmid41231230,
year = {2025},
author = {Venkatesh, R and Cardone, KM and Bradford, Y and Moore, AK and Kumar, R and Moore, JH and Shen, L and Kim, D and Ritchie, MD},
title = {Integrative multi-omics approaches identify molecular pathways and improve Alzheimer's disease risk prediction.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70886},
doi = {10.1002/alz.70886},
pmid = {41231230},
issn = {1552-5279},
support = {R01HL169458,U01AG066833,P30AG073105//the National Institutes of Health/ ; T32HG000046/HG/NHGRI NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; P30AG073105/AG/NIA NIH HHS/United States ; HL-169458//NHLBI Division of extramural Research/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Genome-Wide Association Study ; Male ; Female ; Multifactorial Inheritance/genetics ; Transcriptome/genetics ; Aged ; Genetic Predisposition to Disease ; Risk Assessment ; Risk Factors ; Multiomics ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder with heterogeneous genetic and molecular underpinnings. Polygenic scores (PGS) capture little of this complexity.

METHODS: We conducted genome-, transcriptome-, and proteome-wide association studies (G/T/PWAS) on 15,480 individuals from the Alzheimer's Disease Sequencing Project R4 (ADSP) to identify AD-associated signals, followed by pathway enrichment analysis. Integrative risk models (IRMs) were developed using genetically regulated components of gene and protein expression and clinical covariates. Elastic-net logistic regression and random forest classifiers were evaluated using standard metrics and compared against baseline PGS.

RESULTS: Known and novel signals were identified via G/T/PWAS. Enrichment analyses highlighted cholesterol and immune signaling pathways. The best-performing IRM, random forest with transcriptomic and covariate features, achieved area under the receiver operating characteristic (AUROC) of 0.703 and area under the precision-recall curve (AUPRC) of 0.622, significantly outperforming PGS and baseline models.

DISCUSSION: Integrating univariate discovery approaches with multivariate modeling enhances AD risk prediction and offers novel insights into underlying biological processes.

HIGHLIGHTS: Identified novel contributions to Alzheimer's disease (AD) from a multi-omics perspective. Integrated genome-wide association studies (GWAS), transcriptome-wide association studies (TWAS), and proteome-wide association studies (PWAS) in a unified association study framework. Developed a method for predicting heritable risk of late-onset AD. Demonstrated that ancestry-aware modeling improves AD risk prediction accuracy.},
}

Humans
*Alzheimer Disease/genetics
Genome-Wide Association Study
Male
Female
Multifactorial Inheritance/genetics
Transcriptome/genetics
Aged
Genetic Predisposition to Disease
Risk Assessment
Risk Factors
Multiomics

@article {pmid41231229,
year = {2025},
author = {Rousset, RZ and Dolan, CV and Wilson, DH and In 't Veld, L and Ligthart, L and Teunissen, CE and de Geus, EJC and den Braber, A},
title = {Genetic and environmental contributions to variation in plasma phosphorylated tau 217.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70906},
doi = {10.1002/alz.70906},
pmid = {41231229},
issn = {1552-5279},
support = {904-61-090//Netherlands Organization for Scientific Research (NWO)/ ; 985-10-002//Netherlands Organization for Scientific Research (NWO)/ ; 904-61-193//Netherlands Organization for Scientific Research (NWO)/ ; 480-04-004//Netherlands Organization for Scientific Research (NWO)/ ; 400-05-717//Netherlands Organization for Scientific Research (NWO)/ ; Addiction-31160008//Netherlands Organization for Scientific Research (NWO)/ ; 016-115-035//Netherlands Organization for Scientific Research (NWO)/ ; 400-07-080//Netherlands Organization for Scientific Research (NWO)/ ; NWO-Groot 480-15-001/674//Netherlands Organization for Scientific Research (NWO)/ ; Middelgroot-911-09-032//Netherlands Organisation for Health Research and Development (ZonMW)/ ; 73305095007//Netherlands Organisation for Health Research and Development (ZonMW)/ ; 10510032120003//Netherlands Organisation for Health Research and Development (ZonMW)/ ; 01254 (GenomEUtwin)//European Commission/ ; 01413 (ENGAGE)//European Commission/ ; 860197 (MIRIADE)//European Commission/ ; 381434 (Horizon 2020)//European Commission/ ; 101034344 (EPND)//European Commission/ ; //Alzheimer Drug Discovery Foundation/ ; //National Multiple Sclerosis Society/ ; /ALZ/Alzheimer's Association/United States ; LSHM20106//Health Holland, Topsector Life Sciences & Health/ ; //The Selfridges Group Foundation/ ; //Alzheimer Netherlands/ ; },
mesh = {Humans ; *tau Proteins/blood/genetics ; Male ; Female ; Phosphorylation ; Amyloid beta-Peptides/blood ; Aged ; Biomarkers/blood ; Neurofilament Proteins/blood ; Middle Aged ; Alzheimer Disease/genetics/blood ; Glial Fibrillary Acidic Protein/blood ; Peptide Fragments/blood ; Aged, 80 and over ; *Gene-Environment Interaction ; },
abstract = {INTRODUCTION: Plasma phosphorylated tau 217 (p-au217) is a promising Alzheimer's disease (AD) biomarker. Little is known about the causes of variance in p-tau217 concentrations in cognitively unimpaired populations.

METHODS: The present sample included cognitively healthy twins and their family members (n = 6495). Biometric twin models were used to determine relative genetic and environmental contributions to variance in p-tau217, and genetic and environmental correlations between p-tau217 and neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid beta 42/40 (Aβ42/40).

RESULTS: Genetic contributions accounted for 42% (males) and 41% (females) of variance in p-tau217. Half of the genetic effects were sex specific. Genetic and environmental contributions to p-tau217 were partially shared with NfL, GFAP, and Aβ42/40, but different patterns were found in males and females.

DISCUSSION: P-tau217 concentrations are moderately heritable. Sex-specific genetic influences are found to act on p-tau217. In cognitively unimpaired participants, p-tau217 and Aβ42/40 reflect different biological processes.

HIGHLIGHTS: Phosphorylated tau (p-tau)217 concentrations are substantially heritable (> 41%). Genetic contributions to variation in plasma p-tau217 were found to be sex specific. Genetic and environmental correlations were found between p-tau217 and Alzheimer's disease biomarkers. P-tau217 reflects different processes in cognitively unimpaired males and females.},
}

Humans
*tau Proteins/blood/genetics
Male
Female
Phosphorylation
Amyloid beta-Peptides/blood
Aged
Biomarkers/blood
Neurofilament Proteins/blood
Middle Aged
Alzheimer Disease/genetics/blood
Glial Fibrillary Acidic Protein/blood
Peptide Fragments/blood
Aged, 80 and over
*Gene-Environment Interaction