@article {pmid40603917,
year = {2025},
author = {Roshanfekr, A and Moeini, Z and Golmohammadi, F and Balalaie, S and Seyedarabi, A},
title = {Antioxidative effects of phytoaromatic compounds on the cysteine of the SKCGS peptide as a critical aggregation domain of tau.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23206},
pmid = {40603917},
issn = {2045-2322},
abstract = {Cysteine residues play a crucial role in maintaining the structural and functional integrity of proteins, but they are highly susceptible to oxidative modifications. These modifications can contribute to disorders such as Alzheimer's disease (AD). In tau protein, the SKCGS sequence, especially the cysteine residue at position C-322, is particularly vulnerable to oxidative stress (OS). This vulnerability promotes tau fibrillation and aggregation, both in vitro and in vivo. This study evaluated the antioxidative effects of cinnamaldehyde (Cin), phenylethyl alcohol (PEA), and the common crude spices (cinnamon, rose, saffron, and cardamom) on the SKCGS peptide of the tau protein (in solution and aroma forms), with a focus on their ability to prevent oxidative damage. We adopted a novel approach using aromatherapy that utilizes the aromatic and volatile properties of natural compounds. By combining biochemical assessments with molecular docking studies, we aimed to provide a comprehensive understanding of the protective mechanisms of the natural phytoaromatic compounds used in this study. The antioxidative potential of these compounds was assessed using the DPPH assay; thiol levels measured via DTNB and mBBr assays; and binding interactions evaluated through molecular docking. The DPPH assay confirmed the antioxidative activity of all tested compounds. DTNB and mBBr assays showed that the phytoaromatic compounds significantly preserved free thiol content in the SKCGS peptide under oxidative conditions (p < 0.05). Molecular docking predicted favorable binding interactions between the phytoaromatic compounds and the cysteine residue in the SKCGS sequence, suggesting a protective mechanism against OS. The data presented provided strong evidence supporting the idea that phytoaromatic compounds could be promising candidates for developing innovative treatment approaches for AD. The encouraging results from this study justify further exploration of phytoaromatic compounds as therapeutic agents for AD. This research opens up new avenues for creating effective treatments to address one of the most significant challenges in neurodegenerative medicine.},
}

@article {pmid40603911,
year = {2025},
author = {Zhou, J and Wei, Y and Li, X and Zhou, W and Tao, R and Hua, Y and Liu, H},
title = {A deep learning model for early diagnosis of alzheimer's disease combined with 3D CNN and video Swin transformer.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23311},
pmid = {40603911},
issn = {2045-2322},
support = {20232BAB202025//Natural Science Foundation of Jiangxi Province/ ; },
abstract = {Alzheimer's disease (AD) constitutes a neurodegenerative disorder predominantly observed in the geriatric population. If AD can be diagnosed early, both in terms of prevention and treatment, it is very beneficial to patients. Therefore, our team proposed a novel deep learning model named 3D-CNN-VSwinFormer. The model consists of two components: the first part is a 3D CNN equipped with a 3D Convolutional Block Attention Module (3D CBAM) module, and the second part involves a fine-tuned Video Swin Transformer. Our investigation extracts features from subject-level 3D Magnetic resonance imaging (MRI) data, retaining only a single 3D MRI image per participant. This method circumvents data leakage and addresses the issue of 2D slices failing to capture global spatial information. We utilized the ADNI dataset to validate our proposed model. In differentiating between AD patients and cognitively normal (CN) individuals, we achieved accuracy and AUC values of 92.92% and 0.9660, respectively. Compared to other studies on AD and CN recognition, our model yielded superior results, enhancing the efficiency of AD diagnosis.},
}

@article {pmid40603729,
year = {2025},
author = {Colonna, M and Holtzman, DM},
title = {Rethinking TREM2 as a target for Alzheimer's disease after the INVOKE-2 trial failure.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {40603729},
issn = {1546-170X},
}

@article {pmid40603554,
year = {2025},
author = {Xu, QH and Huang, YJ},
title = {Rethinking the link between gestational diabetes and dementia risk.},
journal = {Diabetologia},
volume = {},
number = {},
pages = {},
pmid = {40603554},
issn = {1432-0428},
}

@article {pmid40603530,
year = {2025},
author = {Jeon, HL and Choo, E and Jeong, SH and Yun, J and Jeong, CW and Lee, H},
title = {Risk of Alzheimer's disease and Parkinson's disease following androgen deprivation therapy in a real world nationwide cohort.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23490},
pmid = {40603530},
issn = {2045-2322},
support = {2023//Korea Institute of Drug Safety and Risk Management/ ; },
mesh = {Humans ; Male ; *Alzheimer Disease/epidemiology/etiology/chemically induced ; Aged ; *Parkinson Disease/epidemiology/etiology ; *Androgen Antagonists/adverse effects/therapeutic use ; Republic of Korea/epidemiology ; *Prostatic Neoplasms/drug therapy ; Cohort Studies ; Middle Aged ; Risk Factors ; Aged, 80 and over ; Proportional Hazards Models ; Propensity Score ; Dementia, Vascular/epidemiology ; },
abstract = {The association between androgen deprivation therapy (ADT) and dementia including Alzheimer's disease remains debatable. Moreover, the evidence regarding the risk of vascular dementia and Parkinson's disease associated with ADT is limited. A population-based cohort study was conducted using the national health insurance data (2012-2022) from South Korea. Eligible patients newly diagnosed with prostate cancer who underwent ADT were compared with those who did not receive ADT. We applied propensity score matching and performed Cox proportional hazards regression analysis to calculate the adjusted hazard ratios (aHR) and 95% confidence intervals (CI). Of 163,723 patients with prostate cancer between 2013 and 2017, 24,456 were eligible. After 1:1 propensity score matching, 10,168 patients were included in each group. The risk of overall dementia was not significantly higher in ADT users compared with that of non-users (aHR = 1.07; 95% CI: 0.97-1.19); however, the elevated risk of Alzheimer's disease was observed (aHR = 1.39; 95% CI: 1.21-1.59). ADT was not associated with the risk of vascular dementia (aHR = 1.14; 95% CI: 0.70-1.94) and Parkinson's disease (aHR = 1.01; 95% CI: 0.75-1.35). Our updated evidence reinforces previous findings, indicating a positive association between ADT and the risk of Alzheimer's disease. However, it is unlikely that ADT increases the risk of vascular dementia and Parkinson's disease.},
}

Humans
Male
*Alzheimer Disease/epidemiology/etiology/chemically induced
Aged
*Parkinson Disease/epidemiology/etiology
*Androgen Antagonists/adverse effects/therapeutic use
Republic of Korea/epidemiology
*Prostatic Neoplasms/drug therapy
Cohort Studies
Middle Aged
Risk Factors
Aged, 80 and over
Proportional Hazards Models
Propensity Score
Dementia, Vascular/epidemiology

@article {pmid40603418,
year = {2025},
author = {Nikanfar, M and Nouri, M and Hassanpour, M and Rezaei, J and Nourazarian, A},
title = {Elevated miRNA-21, miRNA-155, and miRNA-182 levels correlate with cytokine dysregulation in neurological disorders and indicate potential for biomarker and therapy development.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23523},
pmid = {40603418},
issn = {2045-2322},
support = {IR.TBZMED.REC.1399.765//Tabriz University of Medical Sciences/ ; },
mesh = {Humans ; *MicroRNAs/cerebrospinal fluid/genetics ; Female ; Biomarkers/cerebrospinal fluid ; Male ; *Cytokines/cerebrospinal fluid/metabolism ; Middle Aged ; Aged ; Alzheimer Disease/cerebrospinal fluid/genetics ; *Nervous System Diseases/cerebrospinal fluid/genetics ; Parkinson Disease/cerebrospinal fluid/genetics ; Multiple Sclerosis/cerebrospinal fluid/genetics ; Adult ; Case-Control Studies ; },
abstract = {Cytokines and microRNAs (miRNAs) play a crucial function in neurological disorders. The purpose of this study was to investigate the interactions between cytokine networks and miRNA-21, miRNA-155, and miRNA-182 in the cerebrospinal fluid (CSF) of individuals with Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis. Twenty patients diagnosed with MS, AD, and PD had CSF samples taken, while twenty healthy individuals served as controls. Cytokine levels (IL-6, TNF-α, IL-10, and CCL2) and miRNA expression were determined using an enzyme-linked immunosorbent test (ELISA) and qRT-PCR, respectively. The aim of this study was to identify the correlation between miRNA expression and cytokine levels.Compared with the control group, patients with MS and AD had significantly higher levels of miRNA-21, miRNA-155, and miRNA-182. The disease groups showed increased cytokine levels, particularly in AD and MS. Strong and statistically significant positive correlations were observed between miRNA-21 and IL-6 (r = 0.72, p < 0.001), miRNA-155 and TNF-α (r = 0.68, p < 0.001), and miRNA-182 and CCL2 (r = 0.75, p < 0.001) in all groups. This study provides new insights into the consistent patterns of miRNA expression and cytokine levels in the cerebrospinal fluid of individuals with neurological disorders. The significant correlations between certain miRNAs and cytokines suggest potential regulatory connections, offering valuable information on the pathogenesis of various diseases and identifying potential therapeutic targets.},
}

Humans
*MicroRNAs/cerebrospinal fluid/genetics
Female
Biomarkers/cerebrospinal fluid
Male
*Cytokines/cerebrospinal fluid/metabolism
Middle Aged
Aged
Alzheimer Disease/cerebrospinal fluid/genetics
*Nervous System Diseases/cerebrospinal fluid/genetics
Parkinson Disease/cerebrospinal fluid/genetics
Multiple Sclerosis/cerebrospinal fluid/genetics
Adult
Case-Control Studies

@article {pmid40603372,
year = {2025},
author = {Abbasi, MM and Khandae, S and Shahabi, M and Attarzadeh, M and Karimi, M and Saghafi, H and Razeghi, S and Khamseh, F and Rashidkhani, B},
title = {Association between the DASH diet and Alzheimer's disease in a case-control study.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23312},
pmid = {40603372},
issn = {2045-2322},
support = {IR.SBMU.NNFTRI.REC.1402.027//National Nutrition and Food Technology Research Institute/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology ; Male ; Female ; Case-Control Studies ; *Dietary Approaches To Stop Hypertension ; Aged ; Middle Aged ; Iran/epidemiology ; Risk Factors ; },
abstract = {The findings on the connection between Alzheimer's disease and the dietary approaches to stop hypertension (DASH) are inconsistent. Additionally, the relationship between Alzheimer's and the DASH diet has not been explored in the Middle East region. This case-control study aimed to evaluate the association between adherence to DASH diet and the risk of Alzheimer's disease. The study included 212 participants (106 cases and 106 controls). Cases were recruited among people in the early stages of the disease who had been diagnosed with Alzheimer's disease within the past six months. Controls were selected from health centers across Tehran. Dietary intake was assessed using a validated 168-item food frequency questionnaire. Four DASH diet indices (Dixon, Mellen, Fung, and Günther) were used to evaluate the adherence. After adjusting for potential confounders, higher adherence to Günther's, Mellen's, and Fung's DASH diet indices were significantly associated with a reduced risk of Alzheimer's disease (Mellen's OR: 0.29; 95% CI: 0.10-0.83; Fung's OR: 0.22; 95% CI: 0.08-0.65; Günther's OR: 0.36; 95% CI: 0.13-1.00). Adherence to DASH dietary pattern might be associated with a decreased risk of Alzheimer's disease. Future studies should aim to investigate the association in a prospective design in the Middle East.},
}

Humans
*Alzheimer Disease/epidemiology
Male
Female
Case-Control Studies
*Dietary Approaches To Stop Hypertension
Aged
Middle Aged
Iran/epidemiology
Risk Factors

@article {pmid40603145,
year = {2025},
author = {Chandler, JM and Lansdall, CJ and Ye, W and McDougall, F and Belger, M and Toth, B and Mi, X and Sink, KM and Atkins, AS},
title = {The Alzheimer's Disease Cooperative Study - Activities of Daily Living dependence score: revision and validation of an algorithm evaluating patient dependence across the spectrum of AD severity.},
journal = {The journal of prevention of Alzheimer's disease..},
volume = {},
number = {},
pages = {100261},
doi = {10.1016/j.tjpad.2025.100261},
pmid = {40603145},
issn = {2426-0266},
abstract = {BACKGROUND: Increasing dependence on informal and formal caregivers in Alzheimer's disease (AD) contributes to high societal cost. Treatments that delay time to increased dependence/care needs would be clinically meaningful, but these outcomes are rarely collected in early AD clinical trials. The 2015 ADCS-ADL dependence algorithm was created to estimate level of dependence in AD.

OBJECTIVES: To revise the original dependence algorithm to improve accuracy of dependence scores (DS) across AD severity, including early symptomatic AD.

DESIGN: Secondary data analysis SETTING: Community cohort; randomized clinical trial PARTICIPANTS: 14,000 participants enrolled across GERAS-EU observational study and 12 AD clinical trials.

MEASUREMENTS: Three-phase algorithm revision: 1) reassess ADCS-ADL items to identify those appropriate for assessing dependence; 2) (a) assign individual item responses to degrees of assistance and (b) to operationalize assignment of DS based on extent of total assistance needed; and 3) validate revised algorithm in multiple datasets across AD severity from mild cognitive impairment due to AD to moderate-severe AD.

RESULTS: The revised DS (0-6) algorithm classified most participants with early symptomatic AD as independent or moderately independent (DS<3) at baseline. With disease progression over time, the proportion of participants who were mildly to fully dependent (DS≥3) increased across AD severity. Increased DS was associated with incremental worsening of clinical outcomes.

CONCLUSIONS: The revised ADCS-ADL DS algorithm provides a supplementary approach to evaluate the impact of emerging treatments on independence/care needs in AD and may be useful in clinical trials where the ADCS-ADL has been collected.

EXPEDITION 1 NCT00905372; EXPEDITION 2 NCT00904683; EXPEDITION 3 NCT01900665; AMARANTH NCT02245737; TRAILBLAZER-ALZ NCT03367403; TRAILBLAZER-ALZ 2 NCT04437511; GRADUATE I NCT03444870; GRADUATE II NCT03443973; CREAD NCT02670083; CREAD 2, NCT03114657; TAURIEL NCT03289143; LAURIET NCT03828747.},
}

@article {pmid40603012,
year = {2025},
author = {Kato, D},
title = {Impact of Sex Differences in Oligodendrocytes and Their Progenitor Cells on the Pathophysiology of Neuropsychiatric Disorders.},
journal = {Journal of Nippon Medical School = Nippon Ika Daigaku zasshi},
volume = {92},
number = {3},
pages = {226-233},
doi = {10.1272/jnms.JNMS.2025_92-306},
pmid = {40603012},
issn = {1347-3409},
mesh = {Humans ; *Oligodendroglia/pathology/physiology/metabolism ; *Sex Characteristics ; Female ; Male ; Animals ; Cell Differentiation/genetics ; *Mental Disorders/physiopathology/pathology/etiology ; Cell Proliferation/genetics ; *Oligodendrocyte Precursor Cells/pathology/physiology/metabolism ; Myelin Sheath/metabolism ; Multiple Sclerosis/physiopathology/pathology ; Autism Spectrum Disorder/physiopathology ; Alzheimer Disease/physiopathology/pathology ; Cell Movement ; Gene Expression ; },
abstract = {Neuropsychiatric disorders such as multiple sclerosis, Alzheimer's disease, and autism spectrum disorder exhibit significant sex differences in prevalence, progression, and response to treatment. Emerging evidence suggests that oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs) play pivotal roles in these pathologies via mechanisms involving neuroinflammation, energy metabolism, and hormonal modulation, resulting in distinct functional outcomes. Specifically, female OPCs display higher proliferative and migratory capacities, whereas male OPCs are more prone to differentiation and myelination, thus contributing to robust myelin integrity. Dysregulation of these cells disrupts myelination and exacerbates disease progression. Addressing sex-specific gene expression in OPCs and OLs is therefore considered crucial for the development of targeted therapeutic strategies. This review highlights the significance of sex differences in the proliferation and differentiation of OPCs, as well as gene expression changes in OPCs and OLs, and emphasizes their contribution to the pathophysiology of neuropsychiatric disorders. Improved understanding of these differences is vital for advancing personalized sex-specific treatments and improving the clinical outcomes of neuropsychiatric disorders.},
}

Humans
*Oligodendroglia/pathology/physiology/metabolism
*Sex Characteristics
Female
Male
Animals
Cell Differentiation/genetics
*Mental Disorders/physiopathology/pathology/etiology
Cell Proliferation/genetics
*Oligodendrocyte Precursor Cells/pathology/physiology/metabolism
Myelin Sheath/metabolism
Multiple Sclerosis/physiopathology/pathology
Autism Spectrum Disorder/physiopathology
Alzheimer Disease/physiopathology/pathology
Cell Movement
Gene Expression

@article {pmid40603003,
year = {2025},
author = {Afraz, ES and Hoseinikhah, SA and Moradikor, N},
title = {Recent Advances in Aging-Related Diseases: Accelerated Aging, Molecular Mechanisms, Interventions, and Therapies.},
journal = {Aging and disease},
volume = {16},
number = {4},
pages = {1785-1792},
doi = {10.14336/AD.2025.10618},
pmid = {40603003},
issn = {2152-5250},
mesh = {Humans ; *Aging/physiology/genetics ; Oxidative Stress ; Sarcopenia/therapy ; Biomarkers/metabolism ; },
abstract = {Aging is a multifaceted biological process influenced by cellular stress, mitochondrial dysfunction, and immune system alterations. This editorial commentary categorizes recent findings of Aging and Disease into three main areas: the acceleration of aging, prediction of age-related decline, and emerging therapeutic strategies. Research indicates that factors such as oxidative stress, chronic inflammation, and genetic predispositions contribute to premature cellular aging and the onset of age-related diseases. Recent advances in biomarkers and machine learning have improved our ability to predict biological age and associated risks, including sarcopenia and cardiovascular decline. Promising therapeutic interventions such as mitochondrial transplantation, immune system modulation, and targeted gene therapies show efficacy in decelerating aging processes and treating conditions such as Alzheimer's disease and tissue fibrosis. A deeper understanding of these interconnected mechanisms lays the groundwork for developing personalized interventions that promote healthy aging.},
}

Humans
*Aging/physiology/genetics
Oxidative Stress
Sarcopenia/therapy
Biomarkers/metabolism

@article {pmid40602844,
year = {2025},
author = {McGillivray, IL and Chen, A and Normandin, PA},
title = {Case Report: Care of the Agitated Emergency Department Patient With Alzheimer's Disease.},
journal = {Journal of emergency nursing},
volume = {51},
number = {4},
pages = {553-569},
doi = {10.1016/j.jen.2025.04.002},
pmid = {40602844},
issn = {1527-2966},
mesh = {Humans ; *Alzheimer Disease/nursing/complications/psychology ; *Psychomotor Agitation/nursing/etiology ; Female ; *Emergency Service, Hospital ; *Emergency Nursing/methods ; },
abstract = {Global estimates of persons in various stages of Alzheimer's disease, a form of dementia, were estimated to be at 416 million. It is estimated that 22% of people who are 50 years of age or older have Alzheimer's disease. According to the National Institute on Aging, millions of families took care of loved ones at home who had serious chronic diseases, which included Alzheimer's disease. It is important that these statistics are understood by emergency nurses because their assigned emergency patient may be in any stage of Alzheimer's disease. This case report is about a patient with advanced Alzheimer's disease being cared for at home by her daughter, an experienced emergency nurse. The patient developed uncontrollable agitation owing to Alzheimer's disease dementia that necessitated multiple emergency department visits. A gap in emergency nurses' knowledge of available resources to help family members navigate home care of loved ones with Alzheimer's disease was identified. Tools that empower emergency nurses during care of patients with uncontrolled Alzheimer's disease agitation are provided. Palliative and hospice services available for loved ones with Alzheimer's disease are discussed. Emergency nurses are encouraged to share information with families to facilitate dignity during a loved one's end of life.},
}

Humans
*Alzheimer Disease/nursing/complications/psychology
*Psychomotor Agitation/nursing/etiology
Female
*Emergency Service, Hospital
*Emergency Nursing/methods

@article {pmid40602789,
year = {2025},
author = {Graham, NSN and Zimmerman, KA and Hain, J and Rooney, E and Lee, Y and Del Giovane, M and Parker, T and Wilson, MG and Malhotra, P and David, MCB and Kolanko, M and Patel, M and Veleva, E and Swann, O and Heslegrave, A and Zetterberg, H and Friedland, D and Sylvester, R and Sharp, DJ},
title = {Biomarker evidence of neurodegeneration in mid-life former rugby players.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf152},
pmid = {40602789},
issn = {1460-2156},
support = {//NIHR Academic Clinical Lectureships/ ; //NIHR Imperial Biomedical Research Centre/ ; MR/W016095/1/MRC_/Medical Research Council/United Kingdom ; /ALZS_/Alzheimer's Society/United Kingdom ; #2023-00356//Swedish Research Council/ ; #2022-01018//Swedish Research Council/ ; #2019-02397//Swedish Research Council/ ; 101053962//Swedish Research Council/ ; #ALFGBG-71320//Swedish Research Council/ ; #201809-2016862//Alzheimer's Drug Discovery Foundation/ ; #ADSF-21-831376-C//Alzheimer's Drug Discovery Foundation/ ; #ADSF-21-831381-C//Alzheimer's Drug Discovery Foundation/ ; #ADSF-21-831377-C//Alzheimer's Drug Discovery Foundation/ ; #ADSF-24-1284328-C//Alzheimer's Drug Discovery Foundation/ ; #22HLT07//European Partnership on Metrology/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Stiftelsen/ ; //Erling-Persson Family Foundation/ ; #FO2022-0270//Stiftelsen för Gamla Tjänarinnor/ ; 860197//H2020 Marie Skłodowska-Curie Actions/ ; JPND2021-00694//H2020 Marie Skłodowska-Curie Actions/ ; //University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute/ ; },
abstract = {Repetitive head impacts and traumatic brain injuries in contact sports, such as rugby union, are associated with increased risk of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. Advances in fluid and imaging biomarkers are transforming dementia diagnosis but have not been systematically applied to individuals previously exposed to head impacts during rugby participation. We used biomarkers, including those with sensitivity and specificity for early Alzheimer's pathology to explore neurodegenerative risk in mid-life elite retired rugby players with significant repetitive head impact exposure. Plasma neurofilament light, glial fibrillary acid protein, amyloid-β (Aβ)42, Aβ40 and phospho-tau217 were quantified using ultrasensitive single molecule array digital enzyme-linked immunosorbent assay (SiMoA) in former elite rugby players as well as age/sex-matched unexposed controls. 3 T MRI and neuropsychology assessments were performed, with National Institute for Neurological Disorders and Stroke criteria used to ascertain the presence of traumatic encephalopathy syndrome. Regression models were used to relate plasma/imaging biomarkers to clinical phenotype. Individual-levels analyses were performed for fluid and imaging metrics, based on control biomarker distributions. Biomarker data from two aligned un-exposed Alzheimer's cohorts were included to contextualize our findings. Two hundred ex-rugby players (median age 44 years, 90% males) and 33 unexposed controls were assessed. Twenty-four (12%) ex-players fulfilled criteria for traumatic encephalopathy syndrome but none had dementia. Plasma phospho-tau217 concentrations were 17.6% higher in ex-rugby players than controls (95% confidence interval 3.7-33.3, P = 0.047). A total of 46 (23.1%) ex-players had elevated phospho-tau217 at the individual level; as did 18 (9.0%) players in relation to raised plasma neurofilament light. Ex-players' concentrations were lower than in unexposed adults with late onset Alzheimer's disease (n = 69). Ex-players also showed significantly reduced volumes in the frontal/cingulate cortex on voxel-based morphometry at the group level; with reduced white matter and lower hippocampal volume associated with longer career durations within ex-players. Trauma-associated white matter changes measured with diffusion tensor imaging were uncommon in ex-players (4.6%). Traumatic encephalopathy syndrome was significantly more common in ex-players with elevated phospho-tau217, while those with raised plasma neurofilament light had significantly more anxiety and depressive symptoms. Frontal brain volumes correlated negatively with neurofilament light (r = -0.21, P = 0.010), and hippocampal volumes correlated negatively with phospho-tau217 (r = -0.19, P = 0.024). Elite rugby participation is associated with abnormal fluid and neuroimaging neurodegeneration biomarkers in mid-life. These include elevated phospho-tau217, which may indicate amyloid-dependent tau pathology. The results provide support for using state-of-the-art neurodegenerative biomarkers in the evaluation of long-term effects of sports head impact exposure.},
}

@article {pmid40602729,
year = {2025},
author = {Krick, KE and Weekman, EM and Johnson, SN and Sudduth, TL and Rogers, CB and Nicolayson, EJ and Kleinhenz, MT and Wilcock, DM},
title = {Age-related cerebral amyloid angiopathy accumulation in the APPSw mouse model is associated with perivascular inflammation and brain-wide vascular and inflammatory gene and protein changes.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107013},
doi = {10.1016/j.nbd.2025.107013},
pmid = {40602729},
issn = {1095-953X},
abstract = {Cerebral amyloid angiopathy (CAA) is an extremely common pathology of Alzheimer's disease (AD) included under vascular contributions to cognitive impairment and dementia (VCID). CAA has been reported in 78-98 % of AD cases and has clinical significance when considering side effects that arise when using amyloid targeting immunotherapies. Despite its prevalence, studies addressing CAA mechanisms have been scarce and there are clear gaps in our understanding of how CAA progresses. This study uses Tg2576 mice, who develop CAA over time, to establish a time course of CAA progression at 8-, 14-, and 20-months of age. We identify changes in transcriptomic signatures of glial cells using NanoString nCounter and targeted protein changes using NanoString Digital Spatial Profiling. Meso Scale Discovery and immunohistochemistry are used to establish disease progression. In this study, we saw many changes primarily associated with inflammatory response, with some changes being transient (Tnf, Lsr; VEGF) and others remaining chronically altered (Osmr, Ccl3; CTSD). Overarchingly, many of these changes relate to the perpetuation of inflammation or recruiting additional immune support, which we see in across our timepoints. Further, we identified differences in abundance of proteins (CD45, GFAP, CD31) based on presence of CAA positive vessels within a brain region. We also identified sex-specific differences in CAA burden, as well as how glial reactivity and vessel density change during disease progression. This data represents a comprehensive analysis of CAA progression and differential responses to parenchymal and vascular amyloid that could inform future basic and clinical studies.},
}

@article {pmid40602675,
year = {2025},
author = {Markowicz-Piasecka, M and Laitinen, T and Huttunen, KM},
title = {Optimizing the Structure of Repurposed Metformin Can Improve Anti-cholinesterase and Anti-amyloidogenic Effects.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177886},
doi = {10.1016/j.ejphar.2025.177886},
pmid = {40602675},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) and diabetes mellitus (DM) share common pathological features, including insulin resistance, oxidative stress, and inflammation, suggesting AD may be considered a brain-specific form of DM. Metformin, a widely used antidiabetic drug, has shown neuroprotective effects potentially beneficial in AD by modulating insulin signaling, reducing inflammation, and inhibiting beta-amyloid (Aβ) aggregation. However, its hydrophilic nature limits brain permeability, prompting the synthesis of metformin derivatives to enhance pharmacokinetic properties. This study investigates a series of sulfonamide derivatives of metformin for their cholinesterase (ChE) inhibition using human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), anti-Aβ aggregation using thioflavin T fluorescence assay in vitro, and antioxidative properties in human umbilical endothelial cells (HUVEC) and astrocytes. In vitro assays revealed that studied derivatives exhibit selective inhibitory activity against BChE over AChE. Additionally, certain derivatives demonstrated a synergistic effect with donepezil in AChE inhibition. The derivatives effectively inhibited also Aβ aggregation at both early and late stages, which may reduce Aβ plaque formation. Furthermore, the antioxidative properties of these derivatives were validated in cell-based assays, showing protective effects against oxidative stress in HUVEC and astrocytes. Thus, these findings suggest that metformin derivatives could serve as a dual-action therapy for AD by targeting both cholinergic and amyloidogenic pathways while providing antioxidative support. Future studies may focus on refining these compounds to optimize therapeutic potential in AD treatment, presenting a promising approach for repurposing antidiabetic drugs to address neurodegenerative disease mechanisms.},
}

@article {pmid40602590,
year = {2025},
author = {French, AR and Christian-Hinman, CA},
title = {Aromatase inhibition modulates intrinsic properties and excitability of hippocampal CA1 pyramidal cells in the APP/PS1 mouse model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115365},
doi = {10.1016/j.expneurol.2025.115365},
pmid = {40602590},
issn = {1090-2430},
abstract = {Changes in the hippocampus stemming from heightened neuronal excitability contribute to memory loss in AD. In this context the role of estradiol, the primary estrogen in the brain, is mixed as it generally supports cognition but is also pro-convulsive. In addition to circulating ovarian estradiol in females, neurons in both males and females, including many of those in the hippocampus, express the enzyme aromatase, which converts testosterone to estradiol. Previous studies suggest that aromatase inhibition modulates hippocampal function and excitability, demonstrating actions of local neuroestradiol. However, it's unknown how the role of estradiol in regulating hippocampal excitability changes in the context of AD. Here we investigated whether inhibition of aromatase modifies hippocampal CA1 pyramidal cell intrinsic excitability in the APP/PS1 mouse model of AD, which is prone to hyperexcitability and seizures. Mice at 11-14 weeks old received daily injections of the aromatase inhibitor letrozole or vehicle for 7 days. 24 h after the final injection, acute slices through the dorsal hippocampus were prepared and the response function of CA1 pyramidal cells to injected current was measured using whole-cell patch-clamp electrophysiology. CA1 pyramidal cells in vehicle-treated gonad-intact APP/PS1 mice showed increased excitability compared to those in wild-type counterparts, and this difference was reversed by letrozole. Furthermore, the effects of APP/PS1 genotype and of letrozole in females were abolished after ovariectomy. Overall, these results suggest that estradiol plays a complex role in regulating hippocampal excitability in AD.},
}

@article {pmid40602528,
year = {2025},
author = {Scalia, E and Calligaris, M and Lo Pinto, M and Castelbuono, S and Iemmolo, M and Lo Re, V and Bivona, G and Piccoli, T and Ghersi, G and Scilabra, SD},
title = {Proteome profiling of cerebrospinal fluid and machine learning reveal protein classifiers of two forms of Alzheimer's disease characterized by increased or not altered levels of tau.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101025},
doi = {10.1016/j.mcpro.2025.101025},
pmid = {40602528},
issn = {1535-9484},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that presents with heterogeneous clinical and pathological features, necessitating improved biomarkers for accurate diagnosis and patient stratification. In this study, we applied a data-independent acquisition (DIA)-based proteomics workflow to cerebrospinal fluid (CSF) samples from 138 individuals, including AD patients with high (Aβ+/tau+) or normal (Aβ+/tau-) CSF tau levels, and non-AD controls. Analysis using an Astral mass spectrometer enabled unprecedented proteome depth, identifying 2661 proteins with high data completeness. Comparative proteomic profiling revealed distinct protein signatures for Aβ+/tau+ and Aβ+/tau- subtypes. These findings were validated using an independent internal cohort and further corroborated with publicly available datasets from larger external AD cohorts, demonstrating the robustness and reproducibility of our results. Using machine learning, we identified a panel of 15 protein classifiers that accurately distinguished the two AD subtypes and controls across datasets. Notably, several of these proteins were elevated in the preclinical stage, underscoring their potential utility for early diagnosis and stratification. Together, our results demonstrate the power of DIA proteomics on the Astral platform, combined with machine learning, to uncover subtype-specific biomarkers of AD and support the development of personalized diagnostic strategies.},
}

@article {pmid40602523,
year = {2025},
author = {Thompson, J and Vasefi, M},
title = {Increased risk of dementia and its subtypes following various forms of acquired brain injury: a meta-analysis and systematic review.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.06.064},
pmid = {40602523},
issn = {1873-7544},
abstract = {In recent years, acquired brain injuries (ABIs) have been implicated in the development and pathogenesis of dementia; however, existing data is conflicting and often lacks precise classifications or comprehensive analyses. This review sought to synthesize available evidence to assess the association between four major ABI types-traumatic brain injury (TBI), cerebral atherosclerosis (AS), intracranial hemorrhage, and ischemic stroke-and risk of subsequent all-cause dementia (ACD) and dementia subtypes, including Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal lobar degeneration (FTLD), and dementia with Lewy bodies (DLB). A comprehensive literature review was conducted across public databases, assessing studies published until February 2025, and garnering 107 studies that met inclusion criteria. Meta-analysis of pooled odds ratios (ORs) and 95% confidence intervals (CIs) indicated that TBI was associated with increased ACD, AD, VaD, and FTLD (OR: 1.79, CI: 1.66-1.92, OR: 1.60, CI: 1.44-1.77, OR: 2.03, CI: 1.79-2.30, and OR: 3.99, CI: 2.20-7.20, respectively); cerebral AS was linked to increased odds of ACD, VaD, and FTLD (OR: 1.29, CI: 1.14-1.45, OR: 2.77, CI: 1.72-4.44, and OR: 1.16, CI: 1.07-1.26, respectively); and both intracranial hemorrhage and ischemic stroke conferred increased risks for ACD, AD, and VaD (OR: 2.40, CI: 2.27-2.55, OR: 1.28, CI: 1.03-1.59, and OR: 5.75, CI: 4.73-6.99, as well as OR: 1.24, CI: 1.18-1.31, OR: 1.89, CI: 1.79-2.00, and OR: 2.01, CI: 1.80-2.25, respectively). This meta-analysis indicates a significant relationship between various ABIs and subsequent dementia with variation in subtype-specific associations, underscoring the importance of ABI prevention and post-injury monitoring to mitigate dementia risk.},
}

@article {pmid40602330,
year = {2025},
author = {Zhang, X and Han, C and Zhu, S and Tao, L and Chhetri, JK and Chan, P},
title = {Motoric cognitive risk syndrome and epigenetic aging in a cohort of the community-dwelling aging population.},
journal = {Maturitas},
volume = {199},
number = {},
pages = {108644},
doi = {10.1016/j.maturitas.2025.108644},
pmid = {40602330},
issn = {1873-4111},
abstract = {BACKGROUND: Preventing dementia is a global priority. Motoric cognitive risk (MCR) is a pre-dementia syndrome comprising age-related functional declines; however, there is little evidence of its association with accelerated aging.

OBJECTIVE: To investigate the cross-sectional association between MCR and epigenetic aging using 13 DNA methylation (DNAm) clocks.

METHODS: A total of 2949 participants from the Health and Retirement Study (HRS) cohort were included in this study. Of the 13 epigenetic clocks, nine were first-generation clocks and four were second-generation. The association between the prevalence of MCR and epigenetic aging clocks along with their accelerated aging (AccelAge) measures was calculated using logistic and linear regression models.

RESULTS: The prevalence of MCR was 1.90 %; those with the syndrome had a mean age of 69.7 years. MCR was associated with Horvath 2, YANG, and GrimAge DNAm clocks in both logistic and linear regression models. Individuals with MCR had a higher rate of accelerated aging according to Horvath 2 AccelAge (OR = 1.37, 95 % CI = 1.02-1.85, P = 0.035), YANG AccelAge (OR = 1.29, 95 % CI = 1.03-1.62, P = 0.024) and GrimAge AccelAge (OR = 1.47, 95 % CI = 1.07-2.04, P = 0.019) in the logistic regression model, and Horvath 2 AccelAge (β = 0.34, 95 % CI = 0.04-0.64, P = 0.027), YANG AccelAge (β = 0.41, 95 % CI = 0.13-0.68, P = 0.003) and GrimAge AccelAge (β = 0.28, 95 % CI = 0.03-0.52, P = 0.025) in the linear regression model. A linear dose-response relationship with relative risk of MCR was observed in the multivariable-adjusted restricted cubic splines curves.

CONCLUSION: MCR was found to be a state of accelerated aging according to Horvath 2, YANG, and GrimAge DNAm clocks. Individuals with accelerated aging as measured by GrimAge had the highest odds of MCR. Epigenetic aging could serve as a marker for dementia risk in older individuals.},
}

@article {pmid40602315,
year = {2025},
author = {Del Pup, F and Zanola, A and Tshimanga, LF and Bertoldo, A and Finos, L and Atzori, M},
title = {The role of data partitioning on the performance of EEG-based deep learning models in supervised cross-subject analysis: A preliminary study.},
journal = {Computers in biology and medicine},
volume = {196},
number = {Pt A},
pages = {110608},
doi = {10.1016/j.compbiomed.2025.110608},
pmid = {40602315},
issn = {1879-0534},
abstract = {Deep learning is significantly advancing the analysis of electroencephalography (EEG) data by effectively discovering highly nonlinear patterns within the signals. Data partitioning and cross-validation are crucial for assessing model performance and ensuring study comparability, as they can produce varied results and data leakage due to specific signal properties (e.g., biometric). Such variability in model evaluation leads to incomparable studies and, increasingly, overestimated performance claims, which are detrimental to the field. Nevertheless, no comprehensive guidelines for proper data partitioning and cross-validation exist in the domain, nor is there a quantitative evaluation of the impact of different approaches on model accuracy, reliability, and generalizability. To assist researchers in identifying optimal experimental strategies, this paper thoroughly investigates the role of data partitioning and cross-validation in evaluating EEG deep learning models. Five cross-validation settings are compared across three supervised cross-subject classification tasks (brain-computer interfaces, Parkinson's, and Alzheimer's disease classification) and four established architectures of increasing complexity (ShallowConvNet, EEGNet, DeepConvNet, and Temporal-based ResNet). The comparison of over 100,000 trained models underscores, first, the importance of using subject-based cross-validation strategies for evaluating EEG deep learning architectures, except when within-subject analyses are acceptable (e.g., BCI). Second, it highlights the greater reliability of nested approaches (e.g., N-LNSO) compared to non-nested counterparts, which are prone to data leakage and favor larger models overfitting to validation data. In conclusion, this work provides EEG deep learning researchers with an analysis of data partitioning and cross-validation and offers guidelines to avoid data leakage, currently undermining the domain with potentially overestimated performance claims.},
}

@article {pmid40602196,
year = {2025},
author = {Dugar, N and Kanhed, AM and Azam, MA and Jupudi, S},
title = {Computational insights, synthesis and cytotoxicity evaluation of phenothiazine derivatives as a dual inhibitors targeting MAO-B and AChE.},
journal = {Biophysical chemistry},
volume = {325},
number = {},
pages = {107486},
doi = {10.1016/j.bpc.2025.107486},
pmid = {40602196},
issn = {1873-4200},
abstract = {Alzheimer's disease is a paragon of neurodegenerative diseases with prominent vagueness of cognitive impairment due to dysregulation of cholinergic and monoaminergic systems. This research employed molecular mechanics and quantum Mechanics to evaluate the plausible role of designed phenothiazine-derivatives as dual MAO-B and Acetylcholinesterase inhibitors. Synthesis and Cytotoxicity studies were performed for the eloquent molecules. In-silico studies revealed that halogens may enhance the binding affinity of compounds towards the target. NJ3b-d exhibited moderate inhibition in the SH-SY5Y cell lines compared with memantine (IC5035.88 μg/ml). 150 ns MD studies revealed the stability of NJ3c (IC5048.06 μg/ml) in the catalytic pockets of enzymes. DFT, pKa, BDE, Fukui-function, Epik-state, and membrane-permeability studies were performed to analyze the chemical stability and permeability. The results of QM displayed the compound NJ3c as BBB-permeable and it has thermal and kinetic stability. Our findings suggested that NJ3c can be considered a potential candidate for dual targeting MAO-B and Acetylcholinesterase.},
}

@article {pmid40602043,
year = {2025},
author = {Gong, Y and Li, G and Meng, Y and Wei, J and Tang, Q and Huang, L and Zhang, K and Liao, X},
title = {Development of a CRISPR/Cas13a-based electrochemiluminescence biosensing strategy for sensitive detection of α-synuclein oligomers in neurodegenerative diseases.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {166},
number = {},
pages = {109038},
doi = {10.1016/j.bioelechem.2025.109038},
pmid = {40602043},
issn = {1878-562X},
abstract = {In this study, we report a highly sensitive CRISPR/Cas13a-based electrochemiluminescence (ECL) biosensor for detecting α-synuclein oligomers, early biomarkers for neurodegenerative diseases. The system integrates aptamer recognition, T7 transcription, CRISPR/Cas13a cleavage, and EXPAR amplification. α-Synuclein binding triggers the release of the T7 promoter, leading to RNA production that activates Cas13a, initiating collateral cleavage and EXPAR, generating double-stranded DNA that interacts with [Ru(phen)2dppz][2+] to produce a measurable ECL signal. The sensor achieved an ultralow detection limit of 1.025 aM with high specificity and stability. In serum samples, recovery ranged from 95.2 % to 99.8 %, demonstrating strong accuracy. No interference was observed from unrelated proteins. The biosensor showed excellent reproducibility (intra-day RSD = 0.78 %, inter-day RSD = 2.86 %) and stable performance over 14 days. Compared to other existing methods, this strategy offers superior sensitivity and comparable dynamic range, making it highly suitable for clinical use. Although the assay requires multiple steps and approximately two hours, the tradeoff is justified by its performance. This work highlights the potential of combining CRISPR/Cas13a with ECL for ultra-sensitive biomarker detection in complex samples, supporting early diagnosis and monitoring of Parkinson's and Alzheimer's disease.},
}

@article {pmid40602039,
year = {2025},
author = {Huang, J and Peng, XQ and Liu, RH and Wang, SB and Rao, WW},
title = {The twelve-month prevalence of mental disorders among Teochew adults in the Teoswa region of China: An epidemiological study.},
journal = {Asian journal of psychiatry},
volume = {110},
number = {},
pages = {104592},
doi = {10.1016/j.ajp.2025.104592},
pmid = {40602039},
issn = {1876-2026},
abstract = {The Teoswa region is a distinctive cultural area in the eastern coastal Guangdong Province, China. The trend of rapidly increasing burden of mental disorders in the Teoswa region highlights the necessity to grasp the latest prevalence of mental disorders among Teochew adults. A multistage stratified cluster random sampling method was implemented in the Teoswa region between September and December 2021. A two-phase diagnostic procedure was used: multiscale screening and the Mini International Neuropsychiatric Interviews (MINI) diagnosis. This study found that the 12-month prevalence of mental disorders was (7.05 %, 95 %CI: 5.91 %-8.38 %). Sleep disorders showed the highest prevalence rate (4.37 %, 95 %CI: 3.49 %-5.47 %), followed by anxiety disorders (3.19 %, 95 %CI: 2.43 %-4.18 %), mood disorders (1.81 %, 95 %CI: 1.27 %-2.57 %), Alzheimer's disease (0.34 %, 95 %CI: 0.16 %-0.72 %), schizophrenia (0.23 %, 95 %CI: 0.07 %-0.72 %), posttraumatic stress disorder (0.12 %, 95 %CI: 0.03 %-0.47 %). Facing the non-negligible epidemic of mental disorders in the Teoswa region, policymakers should prioritize evidence-based prevention and intervention measures to address this public health challenge.},
}

@article {pmid40601773,
year = {2025},
author = {Chafe, SC and Zhai, K and Aghaei, N and Miletic, P and Huang, Z and Brown, KR and Mobilio, D and Young, D and Suk, Y and Grewal, S and McKenna, D and Alizada, Z and Kieliszek, AM and Lam, FC and Escudero, L and Huang, Q and Huebner, A and Lu, J and Ang, P and Anand, A and Custers, S and Apel, E and Slassi, S and Brakel, B and Kim, J and Liu, JKC and Bassey-Archibong, BI and Abdo, R and Shargall, Y and Lu, JQ and Cutz, JC and Zhang, Q and Li, SS and Venugopal, C and Hynds, RE and Dufour, A and Moffat, J and Swanton, C and Bao, S and Singh, SK},
title = {A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis.},
journal = {Science translational medicine},
volume = {17},
number = {805},
pages = {eadu2459},
doi = {10.1126/scitranslmed.adu2459},
pmid = {40601773},
issn = {1946-6242},
mesh = {Humans ; *Brain Neoplasms/secondary/genetics ; *Lung Neoplasms/pathology/genetics ; *Amyloid Precursor Protein Secretases/metabolism/genetics ; *Aspartic Acid Endopeptidases/metabolism/genetics ; Animals ; *Carcinoma, Non-Small-Cell Lung/genetics/pathology ; Cell Line, Tumor ; *Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Mice ; ErbB Receptors/metabolism ; *CRISPR-Cas Systems/genetics ; Xenograft Model Antitumor Assays ; Gene Expression Regulation, Neoplastic ; },
abstract = {Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation screen to identify molecular drivers of brain metastasis from an orthotopic xenograft model derived from a patient with NSCLC. We found that activating expression of the Alzheimer's disease-associated beta-secretase 1 (BACE1) led to a substantial increase in brain metastases. Furthermore, genetic and pharmacological inhibition of BACE1 blocked NSCLC brain metastasis. Mechanistically, we identified that BACE1 acts through epidermal growth factor receptor to drive this metastatic phenotype. Together, our data highlight the power of in vivo CRISPR activation screening to unveil molecular drivers and potential therapeutic targets of NSCLC brain metastasis.},
}

Humans
*Brain Neoplasms/secondary/genetics
*Lung Neoplasms/pathology/genetics
*Amyloid Precursor Protein Secretases/metabolism/genetics
*Aspartic Acid Endopeptidases/metabolism/genetics
Animals
*Carcinoma, Non-Small-Cell Lung/genetics/pathology
Cell Line, Tumor
*Clustered Regularly Interspaced Short Palindromic Repeats/genetics
Mice
ErbB Receptors/metabolism
*CRISPR-Cas Systems/genetics
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic

@article {pmid40601581,
year = {2025},
author = {Tunç, T and Kılınç, N and Demirel, N and Alım, Z},
title = {Chiral Anthranilic Amides as Potential Cholinesterase Inhibitors: Synthesis, Bioactivity Assessment, and Molecular Modeling.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e00974},
doi = {10.1002/cbdv.202500974},
pmid = {40601581},
issn = {1612-1880},
support = {FEF.A3.24.006//Kırşehir Ahi Evran University/ ; MMF.A3.24.002//Kırşehir Ahi Evran University/ ; },
abstract = {Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are central therapeutic targets for Alzheimer's disease (AD). In this study, novel chiral anthranilic amide derivatives (5a-5d, 7a, and 7b) were synthesized from chiral amines and were characterized by [1]H, [13]C NMR, LC-MS, and IR, then inhibitory effect of 5a-5d, 7a, and 7b on AChE/BChE activity was investigated by in vitro inhibition and in silico studies. For AChE, IC50 values of 5a-5d, 7a, and 7b were found to be 70, 63.64, 53.85, 36.84, 17.07, and 17.5 nM, respectively. For BChE, IC50 values of 5a-5d, 7a, and 7b were found as 46.66 µM, 33.33 µM, 116.6 µM, 233.3 µM, 175 nM and, 116.6 nM, respectively. All compounds had better inhibition effects against AChE than BChE. The enantioselective inhibition was observed in the compounds 5a-5d. For AChE, the S-enantiomers exhibited stronger inhibition than the R-enantiomers. However, in the case of BChE, R-enantiomers had better inhibition effects. Although molecules 7a and 7b had a stronger inhibition effect than molecules 5a-5d for AChE and BChE, the enantioselectivity was decreased in these molecules. This result was attributed to the spacer group effect in 7a and 7b.},
}

@article {pmid40601547,
year = {2025},
author = {Fukasawa, K and Hoshi, H and Hirata, Y and Kobayashi, M and Shibamiya, K and Ichikawa, S and Shigihara, Y},
title = {Regular physical activity affects brain activities in old individuals: an observational study.},
journal = {PloS one},
volume = {20},
number = {7},
pages = {e0326163},
doi = {10.1371/journal.pone.0326163},
pmid = {40601547},
issn = {1932-6203},
mesh = {Humans ; Male ; Female ; *Exercise/physiology ; Aged ; *Brain/physiology/physiopathology ; Magnetoencephalography ; Aged, 80 and over ; Retrospective Studies ; Neuropsychological Tests ; Dementia/physiopathology ; Cognition/physiology ; },
abstract = {BACKGROUND: A healthy lifestyle, including regular physical activity, prevents cognitive decline and dementia. Evaluating the influence of regular physical activity on the brain is essential for properly assessing patients' conditions and designing effective therapeutic strategies. We aimed to investigate whether and how electrophysiological brain activity reflects the influence of regular physical activity.

METHODS AND FINDINGS: Clinical records from 327 patients who visited our outpatient department for dementia were analysed retrospectively. Patients were classified into two groups: 'Active' for those who engaged in regular physical activity and 'Nonactive' for patients who did not. Electrophysiological brain activity was recorded using magnetoencephalography and quantitatively evaluated using three spectral parameters: median frequency, individual alpha frequency, and Shannon's spectral entropy. Cognitive state was assessed using three neuropsychological assessments: the Japanese version of Mini-Mental State Examination (MMSE-J), Frontal Assessment Battery (FAB-J), and Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-J cog). The effects of group ('Active' or 'Nonactive') on the spectral parameters were examined using an analysis of covariance with one of the neuropsychological assessments as a covariate. The size of contribution was quantified in the unit of neuropsychological assessments using a regression model. A main effect of group was observed for all three spectral parameters. The size of contribution was equivalent to approximate changes of 3-11 points in MMSE-J, 3-7 points in FAB-J, and 10-14 points in ADAS-J cog scores. The main limitations of our study are: (1) this study was conducted in a single site; (2) possibility of reverse causality; and (3) some potential confounding factors, such as genetic factors, were not considered.

CONCLUSIONS: Electrophysiological brain activity reflects the influence of regular physical activity as well as current cognitive states. Such insights are valuable for physicians to design effective therapeutic strategies and provide clinical advice to patients with cognitive impairment and dementia.},
}

Humans
Male
Female
*Exercise/physiology
Aged
*Brain/physiology/physiopathology
Magnetoencephalography
Aged, 80 and over
Retrospective Studies
Neuropsychological Tests
Dementia/physiopathology
Cognition/physiology

@article {pmid40601463,
year = {2025},
author = {Gong, C and Qin, H and El-Yacoubi, MA},
title = {Hybrid Transformer for Early Alzheimer's Detection: Integration of Handwriting-Based 2D Images and 1D Signal Features.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3585379},
pmid = {40601463},
issn = {2168-2208},
abstract = {Alzheimer's Disease (AD) is a prevalent neurodegenerative condition where early detection is vital. Handwriting, often affected early in AD, offers a non-invasive and cost-effective way to capture subtle motor changes. State-of-the-art research on handwriting, mostly online, based AD detection has predominantly relied on manually extracted features, fed as input to shallow machine learning models. Some recent works have proposed deep learning (DL)-based models, either 1D-CNN or 2D-CNN architectures, with performance comparing favorably to handcrafted schemes. These approaches, however, overlook the intrinsic relationship between the 2D spatial patterns of handwriting strokes and their 1D dynamic characteristics, thus limiting their capacity to capture the multimodal nature of handwriting data. Moreover, the application of Transformer models remains basically unexplored. To address these limitations, we propose a novel approach for AD detection, consisting of a learnable multimodal hybrid attention model that integrates simultaneously 2D handwriting images with 1D dynamic handwriting signals. Our model leverages a gated mechanism to combine similarity and difference attention, blending the two modalities and learning robust features by incorporating information at different scales. Our model achieved state-of-the-art performance on the DARWIN dataset, with an F1-score of 90.32% and accuracy of 90.91% in Task 8 ('L' writing), surpassing the previous best by 4.61% and 6.06% respectively.},
}

@article {pmid40601428,
year = {2025},
author = {Giudici, KV and de Souto Barreto, P and Cantet, C and Zetterberg, H and Blennow, K and Vellas, B and , },
title = {Associations between intrinsic capacity, plasma p-tau181 and cognitive function over a 5-year follow-up among community-dwelling older adults: a secondary analysis of the MAPT Study.},
journal = {The Journal of frailty & aging..},
volume = {14},
number = {4},
pages = {100064},
doi = {10.1016/j.tjfa.2025.100064},
pmid = {40601428},
issn = {2260-1341},
abstract = {BACKGROUND: Intrinsic capacity (IC) is a recent key concept proposed by the World Health Organization (WHO) based on aspects of functional ability (both physical and mental) rather than the presence or absence of diseases, with a potential to predict several health outcomes.

OBJECTIVE: To explore associations between IC and cognitive function (prospectively), and between IC and plasma p-tau181 (cross-sectionally and prospectively) among community-dwelling older adults.

METHODS: Observational study with 491 subjects ≥70 years (67.4 % female, mean 75.3 years, SD=4.4), participants from the Multidomain Alzheimer Preventive Trial (MAPT). IC domains (locomotion, cognition, psychological, vitality) were combined into a 0-100 score. Alternative classification was based on the number of domains' abnormalities. Plasma p-tau181 was measured at baseline and 36 months of follow-up. A composite cognitive score (CCS) based on four tests was determined at baseline, 6, 12, 24, 36, 48 and 60 months.

RESULTS: Inverse cross-sectional associations were observed between baseline IC score and p-tau181 (unadjusted model: β=-0.08, 95 %CI -0.13 to -0.03; p = 0.0025). A significant mean difference in p-tau181 3-year changes was observed between participants with low and normal IC (based on IC score) (adjusted model: 1.71, 95 %CI 0.01 to 3.40; p = 0.0483). Prospective 5-year associations between IC and CCS were only observed in unadjusted analysis according to the alternative IC classification (-0.21, 95 %CI -0.38 to -0.04; p = 0.0156).

CONCLUSION: IC was associated with plasma p-tau181 and cognitive function, but findings varied according to the method of IC classification. Further research may help settle the role of IC as a predictor of neurodegenerative diseases such as AD. In this regard, multidomain interventions have potential to protect IC over the aging process and prevent cognitive impairment, and should also be encouraged.},
}

@article {pmid40601390,
year = {2025},
author = {Han, YY and Huang, XY and Su, Y and Ma, JJ and Wu, J},
title = {Chaperone-Mediated Autophagy: A Critical Regulator of Neuroinflammation and Neurodegeneration.},
journal = {Advanced biology},
volume = {},
number = {},
pages = {e00191},
doi = {10.1002/adbi.202500191},
pmid = {40601390},
issn = {2701-0198},
support = {32400789//National Natural Science Foundation of China/ ; BK20240436//Natural Science Foundation of Jiangsu Province/ ; 24QL200220//Suzhou Medical College-QiLu Medical Research Program of Soochow University/ ; （2024)09//Suzhou Industrial Park Healthcare Talent Support Initiative/ ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by hallmark pathological features such as the accumulation of misfolded proteins and neuroinflammation. Chaperone-mediated autophagy (CMA), a selective lysosomal pathway, facilitates the degradation of proteins containing KFERQ-like motifs via the receptor lysosome-associated membrane protein type 2A (LAMP2A). In the recent review, the pivotal role of CMA in regulating proteostasis and modulating inflammatory responses is highlighted. This commentary explores the multifaceted roles of CMA in neurodegenerative disease progression, emphasizing its involvement in age-related decline, feedback loops between CMA dysregulation and neurodegeneration, and potential as a therapeutic target. Emerging CMA activators and the challenges of modulating CMA for clinical use are also discussed.},
}

@article {pmid40601365,
year = {2025},
author = {Dibello, V and Solfrizzi, V and Lozupone, M and Vertucci, V and Santarcangelo, F and Pace, C and Dibello, A and Daniele, A and Panza, F},
title = {Targeting oral frailty indicators of late-life cognitive disorders and depression: a systematic review.},
journal = {Age and ageing},
volume = {54},
number = {7},
pages = {},
doi = {10.1093/ageing/afaf182},
pmid = {40601365},
issn = {1468-2834},
mesh = {Humans ; *Oral Health ; *Depression/diagnosis/epidemiology/psychology ; Aged ; *Frailty/diagnosis/psychology/physiopathology ; *Cognitive Dysfunction/psychology/diagnosis ; Geriatric Assessment ; *Cognition ; Aged, 80 and over ; },
abstract = {BACKGROUND: Oral frailty is an age-related gradual loss of oral function together with a cognitive and physical function decline. Previous systematic reviews and meta-analyses examined the association of some oral frailty indicators with late-life cognitive and late-life depression (LLD). However, none of these studies investigated a large series of possible indicators and outcomes.

OBJECTIVE: To clarify the impact of oral frailty indicators on late-life cognitive disorders and LLD.

DESIGN: Systematic review.

SUBJECTS: Sixty-three studies (56,520,662 subjects) with 11 oral frailty indicators in four categories: (i) oral health status deterioration, (ii) decline in oral motor skills, (iii) chewing, swallowing, and saliva disorders, and (iv) oral pain.

METHODS: From database inception to April 24, 2024, six different electronic databases were consulted by two independent researchers assessing the eligibility of 24,045 records against the inclusion criteria and found 63 studies fitting the eligibility requirements. The protocol was registered a priori with PROSPERO (CRD42021249428).

RESULTS: Four oral frailty indicators (number of remaining teeth, periodontal disease, difficulties in chewing, and difficulties in swallowing) were associated with late-life cognitive impairment/decline, mild cognitive impairment (MCI), dementia, and LLD. Among categories, oral health status deterioration and chewing, swallowing, and saliva disorders were associated with late-life cognitive impairment/decline, MCI, dementia, and LLD. Decline in oral motor skills was associated with late-life cognitive impairment/decline, while oral pain was related only to LLD.

CONCLUSION: Certain oral frailty indicators may contribute to the development of late-life cognitive disorders and LLD.},
}

Humans
*Oral Health
*Depression/diagnosis/epidemiology/psychology
Aged
*Frailty/diagnosis/psychology/physiopathology
*Cognitive Dysfunction/psychology/diagnosis
Geriatric Assessment
*Cognition
Aged, 80 and over

@article {pmid40601364,
year = {2025},
author = {Yang, WK and Shao, SC and Liu, CC and Chi, CC},
title = {Influenza vaccination and risk of dementia: a systematic review and meta-analysis.},
journal = {Age and ageing},
volume = {54},
number = {7},
pages = {},
doi = {10.1093/ageing/afaf169},
pmid = {40601364},
issn = {1468-2834},
mesh = {Humans ; *Dementia/epidemiology/prevention & control/diagnosis ; *Influenza Vaccines/administration & dosage ; *Influenza, Human/prevention & control/epidemiology ; *Vaccination ; Risk Factors ; Risk Assessment ; Incidence ; Aged ; },
abstract = {BACKGROUND: The association between influenza vaccination and a reduction in dementia was unclear with inconsistent evidence. We aimed to evaluate the association between influenza vaccination and dementia risk in the overall population and the high-risk populations for dementia, such as patients with chronic kidney syndrome (CKD), chronic obstruction pulmonary disease (COPD) and vascular disease.

METHODS: We performed a systematic review and searched PubMed, Embase and CENTRAL from inception to 6 April 2025. The risk of bias was assessed using the Newcastle-Ottawa Scale. A random-effects model meta-analysis was executed.

RESULTS: We included eight cohort studies with 9,938,696 subjects. Except for one study, the risk of bias of all other included studies was low. Influenza vaccination was associated with a reduced risk of incident dementia in high-risk populations for dementia, but not in the overall population (HR 0.93; 95% CI: 0.86-1.01). For high-risk populations, more than one dose of influenza vaccination showed an association with a lower risk of incident dementia (2-3 doses: HR 0.84; 95% CI: 0.76-0.92; ≥ 4 doses: HR 0.43; 95% CI: 0.38-0.48).

CONCLUSION: Influenza vaccination was associated with a decreasing risk of incident dementia in a dose-response manner.},
}

Humans
*Dementia/epidemiology/prevention & control/diagnosis
*Influenza Vaccines/administration & dosage
*Influenza, Human/prevention & control/epidemiology
*Vaccination
Risk Factors
Risk Assessment
Incidence
Aged

@article {pmid40601284,
year = {2025},
author = {Dharshini, LCP and Sakthivel, KM and Rex, KGR and Rasmi, RR},
title = {Targeting the redox neuroinflammatory nexus: insights into Alzheimer's and Parkinson's diseases.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40601284},
issn = {1568-5608},
abstract = {Neurodegenerative diseases, including Alzheimer's and Parkinson's, are characterized by the progressive deterioration of neuronal structure and function within the central and peripheral nervous systems. Among the multifactorial mechanisms implicated in their pathogenesis, oxidative stress and chronic neuroinflammation have emerged as pivotal contributors. An imbalance in redox homeostasis, marked by excessive generation of reactive oxygen species (ROS) and impaired antioxidant defenses, leads to sustained activation of inflammatory pathways and exacerbation of neuronal injury. This intricate interplay, known as the redox-neuroinflammatory nexus, constitutes a central axis in the onset and progression of neurodegeneration. This review underscores the critical role of redox imbalance in neurodegenerative processes and provides a comprehensive analysis of the oxidative stress and inflammation crosstalk in Alzheimer's and Parkinson's diseases, offering insights into potential therapeutic targets.},
}

@article {pmid40601218,
year = {2025},
author = {Singh, S and Kumar, U},
title = {G-Protein-Coupled Receptor-Microtubule Interactions Regulate Neurite Development and Protect Against β-Amyloid Neurotoxicity.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40601218},
issn = {1559-1182},
support = {MOP 74465/CAPMC/CIHR/Canada ; 402594-11 and 16-05171//Natural Sciences and Engineering Research Council of Canada/ ; },
abstract = {G-protein-coupled receptors (GPCRs) regulate multiple cellular functions, including neurite formation and maturation, processes often disrupted in neurodegenerative diseases. Like GPCRs, microtubule-associated proteins (MAPs, including MAP2 and Tuj1) and the synaptic vesicle protein synaptophysin are essential for neurite formation, maturation, and organization, which underpin brain development and cognitive function. Despite their importance, the functional crosstalk between GPCRs and MAPs, particularly in neurogenesis and pathological conditions such as Alzheimer's disease (AD), remains poorly understood. We show that somatostatin and dopamine receptors (SSTR and DR) are the structural anchors in developing neurites, enabling MAP recruitment and synaptic protein localization. Our findings reveal a cAMP-dependent interplay involving PTEN and ERK1/2, modulating neurite formation and MAPs organization. Notably, we show that β-amyloid (Aβ) disrupts the constitutive association of MAP2 and Tuj1, inducing an increase in intracellular cAMP levels, loss of neurite integrity, and impaired neuronal viability. The activation of SSTR and DR signaling restores neurite architecture and synaptic integrity via p-AKT activation and PTEN inhibition, highlighting a neuroprotective mechanism. Together, our results reveal a novel role of GPCRs in orchestrating interactions with MAPs to regulate neuronal maturation, neurite formation, and synaptic integrity. This study provides a new mechanistic rationale for therapeutic strategies aimed at preserving cognitive function in neurological disorders such as AD.},
}

@article {pmid40601155,
year = {2025},
author = {Lachén-Montes, M and Anaya-Cubero, E and Cartas-Cejudo, P and Extramiana, L and Fernández-Irigoyen, J and Santamaría, E},
title = {Combination of Antibody Arrays to Characterize the Effect of Neuropathological Stimulus in Human Olfactory Neuroepithelial Cells.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2929},
number = {},
pages = {227-238},
pmid = {40601155},
issn = {1940-6029},
mesh = {Humans ; *Neuroepithelial Cells/metabolism/pathology ; *Protein Array Analysis/methods ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; },
abstract = {It has been established that smell impairment is a common early feature of neurodegenerative diseases (NDs), being most prevalent in Alzheimer's disease patients. As well as in other brain regions, the deposition of pathological substrates such as amyloid peptides (Aβ) or the hyperphosphorylated form of tau has been suggested as a potential origin of olfactory deficits. Nevertheless, other trends of thought are now suggesting the detriment in the soluble forms of these proteins as potentially responsible of the neurodegenerative process. Either way, the molecular mechanisms triggered by the presence and aggregation of these pathological substrates are not fully understood. In this chapter, we describe a workflow combining the use of neuropathological substrates depicting a neurodegenerative environment in an olfactory-related context with the employment of protein arrays targeting both extracellular and intracellular proteins aiming to characterize the molecular mechanisms underlying the established role of neuropathological hallmarks.},
}

Humans
*Neuroepithelial Cells/metabolism/pathology
*Protein Array Analysis/methods
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Alzheimer Disease/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology

@article {pmid40600946,
year = {2025},
author = {},
title = {A blood test for Alzheimer's disease.},
journal = {The Medical letter on drugs and therapeutics},
volume = {67},
number = {1732},
pages = {109},
doi = {10.58347/tml.2025.1732b},
pmid = {40600946},
issn = {1523-2859},
}

@article {pmid40600814,
year = {2025},
author = {Foxe, D and Muggleton, J and Cheung, SC and Mueller, N and Ahmed, RM and Narasimhan, M and Burrell, JR and Hwang, YT and Cordato, NJ and Piguet, O},
title = {Survival rates in frontotemporal dementia and Alzheimer's disease.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/17582024.2025.2527553},
pmid = {40600814},
issn = {1758-2032},
abstract = {AIM: To evaluate the survival rates in well-characterized cohorts of frontotemporal dementia (FTD) subtypes - behavioral variant (bvFTD), progressive nonfluent aphasia (PNFA), and semantic dementia (SD) - and both typical (amnestic) and atypical (aphasic: logopenic progressive aphasia [LPA]) presentations of Alzheimer's disease (AD).

PATIENTS & METHODS: Three hundred and twenty-one participants (54 bvFTD, 26 PNFA, 22 SD, 20 LPA, 32 AD, 167 controls) were recruited. Patients underwent a comprehensive baseline assessment and annual reviews. Survival data were analyzed using Kaplan-Meier curves and Cox proportional hazard models.

RESULTS: Median survival from symptom onset was longest in SD (11.9 years) and shortest in LPA (7 years). Median survival for the bvFTD, PNFA, and AD groups was 8.7, 8.6, and 10 years, respectively. SD survival was significantly longer than PNFA and AD. Female sex was associated with shorter survival in LPA. Shorter symptom duration at baseline assessment was related to shorter survival in bvFTD, SD, LPA, and AD. Lower overall cognition in bvFTD, LPA, and AD, and worse functional outcomes in SD and AD at baseline were associated with shorter survival.

CONCLUSIONS: Our findings demonstrate distinct survival patterns across FTD and AD subtypes. Demographic and presenting clinical features provide valuable prognostic insights for survival.},
}

@article {pmid40600688,
year = {2025},
author = {Fortea, J and Ferrer-Picón, E},
title = {An overview of the rivastigmine 13.3 mg/24h transdermal patch as a treatment option for Alzheimer's disease.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737175.2025.2527211},
pmid = {40600688},
issn = {1744-8360},
abstract = {INTRODUCTION: Rivastigmine, a cholinesterase inhibitor, was first approved for the treatment of Alzheimer's disease (AD) dementia more than 20 years ago. Initially available as an oral formulation, a transdermal system was subsequently developed with the aim of improving tolerability while providing similar efficacy. Transdermal rivastigmine is approved for the treatment of severe AD as well as mild-to-moderate AD.

AREAS COVERED: Herein, the authors review randomized clinical trials, meta-analyses, and post-marketing observational studies involving the rivastigmine 13.3 mg/24 h patch for the treatment of patients with AD.

EXPERT OPINION: Cholinesterase inhibitors are a mainstay of the symptomatic treatment of patients with AD. Rivastigmine is available as oral and transdermal formulations, with the latter providing improved tolerability and convenience while maintaining efficacy. The high-dose 13.3 mg/24 h patch might offer benefits for some patients compared to the lower dose patch (4.6 mg/24 h) in patients with mild-to-moderate or severe AD, showing improvements in daily functioning and global clinical status on top of the cognitive benefits. The ability to titrate up to a dose of 13.3 mg/24 h provides an option for patients with severe AD or with an inadequate response to lower doses of rivastigmine.},
}

@article {pmid40600563,
year = {2025},
author = {Tripathi, S and Sharma, Y and Kumar, D},
title = {Harnessing Nature's Bounty: The Neuroprotective Potential of Phytoconstituents and Nanotechnology in Neurodegenerative Disease Therapeutics.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273370166250610152453},
pmid = {40600563},
issn = {1996-3181},
abstract = {Investigations into the bioactive components of plant-based natural products indicate promising therapeutic potential for neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The loss and dysfunction of neurons characterize these disorders. Effective therapeutic guidelines are still elusive despite advances in our comprehension of NDs, in part because of unanswered questions about the safety and efficacy of natural therapies. On the other hand, preclinical models have shown that natural products-such as fruits, vegetables, nuts, herbs, and phytoconstituents found in freshwater and marine flora-have neuroprotective effects. These substances have the ability to work through a variety of pathways, halting cell death and reinstating neuronal activity. According to recent research, adding these phytoconstituents to nanocarriers, such as nanoparticles, can improve their selectivity and stability, possibly boosting the effectiveness of treatment. By making these agents more specific to target sites, nanotechnology presents a promising treatment option for NDs. Clinical trials assessing the efficacy of these natural compounds in treating neurological conditions are becoming more common as research advances, underscoring their potential as neuroprotective drugs. This study primarily focuses on the therapeutic efficacy of specific natural compounds and their bioactive components, which exhibit neuroprotective benefits in conditions associated with undiagnosed depression. Several preclinical models have demonstrated better results when natural derivatives are used, which has led to an increase in the use of natural therapies for treating NDs. Overall, despite ongoing difficulties, natural products have a great deal of promise for treating and preventing NDs; however, more research is needed to determine safe and effective treatment modalities.},
}

@article {pmid40600562,
year = {2025},
author = {Ye, JX and Wu, JY and Zhu, M and Ai, L and Huang, Q},
title = {Elucidating the Role of Gardeniae Fructus and Scutellariae Radix Herb Pair in Alzheimer's Disease via Network Pharmacology: Emphasis on Oxidative Stress, and the PI3K/Akt Pathway.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892010326797250422095516},
pmid = {40600562},
issn = {1873-4316},
abstract = {BACKGROUND: The combination of Gardeniae Fructus (ZZ) and Scutellariae Radix (HQ) is a traditional Chinese medicine used for Alzheimer's disease (AD). However, the molecular mechanisms underlying its anti-dementia effects, particularly its multi-component synergy and pathway modulation, remain poorly understood.

OBJECTIVE: Our study employed an integrated systems pharmacology approach to mechanistically decode the anti-AD properties of ZZ-HQ, combining network pharmacology predictions, molecular docking simulations, and experimental validation to identify critical bioactive components, molecular targets, and therapeutic pathways.

METHODS: A comprehensive network pharmacology analysis was performed to identify bioactive compounds within the ZZ-HQ complex and their potential protein targets associated with AD. Molecular docking was utilized to predict and assess the binding interactions between key bioactive compounds and AD-related protein targets. Experimental validation focused on baicalin, a major active compound in the ZZ-HQ complex, evaluating its effects on cell viability, apoptosis regulation, oxidative stress reduction, and the activation of the PI3K/Akt signaling pathway.

RESULTS: Fifty-four bioactive compounds were identified in the ZZ-HQ complex, interacting with 258 AD-associated proteins. Key compounds, such as baicalein and norwogonin, demonstrated strong binding affinities with pivotal proteins, including SRC and PIK3R1. Experimental studies further confirmed that baicalin significantly improved cell viability by activating the PI3K/Akt pathway, reducing apoptosis, and alleviating oxidative stress.

CONCLUSION: Our study uncovered the therapeutic potential of the ZZ-HQ combination in addressing AD through multi-target mechanisms, particularly via modulation of the PI3K/Akt pathway and oxidative stress. These findings provide a scientific basis for the pharmacological effects of ZZ-HQ and offer valuable insights for further research on its potential application in AD treatment.},
}

@article {pmid40600553,
year = {2025},
author = {Zhu, Y and Jin, X and Liu, J},
title = {Investigating the Biomarkers for Alzheimer's Disease: Insights from Microarray Analysis, Mendelian Randomization, and Experimental Validation.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673366495250527055016},
pmid = {40600553},
issn = {1875-533X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with a steadily increasing prevalence. However, the mechanisms underlying AD remain unclear, and current treatments have only limited efficacy.

OBJECTIVE: This study aimed to identify potential biomarker genes for AD and to explore the underlying mechanisms by integrating microarray analysis, Mendelian randomization (MR), and experimental validation.

METHODS: AD-related microarray datasets were downloaded from the Gene Expression Omnibus database. Differential expression analysis identified differentially expressed genes (DEGs) between AD and control samples. Summary-level data from genomewide association studies on AD were integrated with expression quantitative trait loci data to identify genes with potential causal relationships with AD using MR. The intersections between DEGs and causal genes were identified as hub genes. Functional analysis was performed to explore underlying mechanisms. Quantitative real-time PCR was applied to validate the expression of hub genes in clinical samples.

RESULTS: Differential expression analysis identified 312 DEGs, whereas MR identified 202 genes with causal effects on AD. The intersection of these two sets identified four hub genes: FCRLB, MT2A, PFKFB3, and SRGN. Functional analysis indicated significant associations between AD and immune-related pathways. Correlation analysis revealed significant connections between hub genes and immune cells in AD. The expression of MT2A, PFKFB3, and SRGN was significantly upregulated, whereas FCRLB was downregulated in clinical AD samples compared with controls.

CONCLUSION: The integration of microarray analysis, MR, and experimental validation identified and validated four potential biomarker genes with causal effects on AD, namely FCRLB, MT2A, PFKFB3, and SRGN. Functional analysis indicated a pivotal role of the immune microenvironment in AD. These findings offer insights into the molecular mechanisms of AD and have implications for improving its diagnosis and treatment strategies.},
}

@article {pmid40600550,
year = {2025},
author = {Hasan, U and Jain, H and Ali, R},
title = {Advancing Amyloid Aggregation Research: A Focus on Innovative Therapies, Molecular Modeling and Nano-Delivery Systems in Alzheimer's Disease.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501388678250618070927},
pmid = {40600550},
issn = {1873-5592},
abstract = {INTRODUCTION: Alzheimer's disease (AD), the most common form of dementia, is a major global health issue. Its complex pathology, including amyloid-beta (Aβ) aggregation, leads to neuronal damage and cognitive decline. Since Aβ plays a major role in AD, therapies targeting its production, aggregation, and clearance are being actively explored. This review discusses recent advances in gene therapy, enzyme inhibitors, molecular modeling, and nano-delivery systems aimed at modifying AD progression, highlighting their potential and challenges.

METHODS: This review compiles findings on BACE1 and γ-secretase inhibitors, gene therapies that modify amyloid metabolism, and combination therapies. Studies have been selected based on their focus on Aβ regulation and their impact on disease progression, cognitive function, and breakthroughs in diagnostics, molecular modeling, and drug delivery for neurodegenerative conditions.

RESULTS: BACE1 inhibitors, such as verubecestat, and γ-secretase inhibitors, shows potential, however, they face significant challenges related to BBB penetration and adverse effects. Gene therapies using AAV vectors and CRISPR/Cas9 technologies are promising, particularly for individuals genetically predisposed to these diseases. Combination therapies targeting amyloid, tau, and neuro-inflammation have emerged as effective approaches. Advancements in PET, SPECT, MRI, small molecule probes, molecular modeling, and nano-particle-based drug delivery are improving diagnostic and treatment options.

DISCUSSION: The findings emphasize the multifactorial complexity of amyloid disorders and the limitations of mono-therapies. While certain agents demonstrated efficacy in early disease stages, most treatments have failed in advanced phases due to poor central nervous system (CNS) bioavailability, adverse effects, or insufficient target engagement. Novel delivery systems, combination therapies, and computational design approaches offer enhanced translational potential. However, challenges such as immune responses, delivery efficiency, and off-target effects continue to pose significant barriers.

CONCLUSION: Aβ-targeted therapies, including enzyme inhibitors and gene therapies, hold promise, though challenges such as BBB penetration and toxicity still remain. Combination therapies, along with advancements in diagnostics and drug delivery technology, are essential for finding effective treatments for Alzheimer's, Parkinson's, and other neurodegenerative diseases. Future research should prioritize overcoming the persistent barriers to BBB penetration, enhancing therapeutic selectivity, and refining drug delivery systems to enable more precise, targeted interventions, to ultimately reduce the progression of disease at the molecular level.},
}

@article {pmid40600549,
year = {2025},
author = {Guan, J and Chen, C and Wu, S and Zhu, H},
title = {The Role of PGE2 in Age-related Diseases.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501383329250616070727},
pmid = {40600549},
issn = {1873-5592},
abstract = {In the past several years, human life expectancy has increased dramatically, and the global aging process is accelerating at an unprecedented rate. Impaired organ functions and systemic inflammation increase the risk of aging-related diseases. It seriously affects the quality of life in older adults and places a heavy burden on the global economy and public health. Inflammation is the cornerstone of many age-related diseases, and among various inflammatory mediators, Prostaglandin E2 (PGE2) has emerged as a key player. For example, PGE2 could participate in the progression of Alzheimer's disease (AD) by modulating neuroinflammation. Plasma PGE2 is regarded as a potential and specific diagnostic biomarker, and higher initial PGE2 levels are positively correlated with longer survival in AD. PGE2 also mediates bone and muscle metabolism to affect age-related musculoskeletal diseases, including sarcopenia, osteoporosis, and osteoarthritis. It activates the EP4 receptor on sensory nerves to inhibit sympathetic nerve activity and modulate bone formation. Moreover, the PGE2/EP4 axis positively regulates muscle mass and strength. In diabetes, increased Cox-2 and m-PGES2 promote PGE2 production. The activated PGE2/EP3 axis exacerbates the progression of type 2 diabetes (T2D) by impairing glucose metabolism and accelerating β-cell senescence. Therefore, the role of PGE2 in age-related diseases deserves greater attention. Its involvement is driven by the dysregulation of its biosynthesis, metabolism, and receptor- mediated signaling. Regulating the concentration of PGE2 or modulating receptor activity represents a promising therapeutic strategy for managing age-related diseases.},
}

@article {pmid40600544,
year = {2025},
author = {El Elhaj, A and Onger, ME},
title = {Exploring Neurodegenerative Diseases: Bridging the Gap between in vitro and in vivo Models.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128374254250605070049},
pmid = {40600544},
issn = {1873-4286},
abstract = {Neurological disorders are brain conditions characterized by the loss of nerve cells, leading to a decline in function. Standard examples include dementia, tremors, involuntary movements, muscle weakness, and autoimmune attacks. The most common form of dementia is Alzheimer's, affecting over 5 million elderly individuals, while tremors, stiffness, and slow movement are caused by Parkinson's. Involuntary movements and emotional problems are caused by Huntington's, while muscle weakness and eventual demise are caused by Amyotrophic lateral sclerosis. Vision problems, fatigue, and difficulty walking are caused by Multiple sclerosis (MS), an autoimmune disease that attacks the myelin sheath. In vitro models provide cost and complexity reduction, environmental control, and high-through". Researchers employ both cell-based (in vitro) and animal- based (in vivo) models to investigate neurodegenerative illnesses and endeavor to formulate novel treatments for diverse conditions. In vitro models provide cost and complexity reduction, environment control, and high-throughput screening of potential therapeutic agents compared to in vivo models. Nevertheless, they possess constraints, including the absence of intricate interactions that transpire in the entire organism and the inability to reproduce the disease progression completely.},
}

@article {pmid40600526,
year = {2025},
author = {Li, J and Zhou, Y and Tao, L and He, C and Li, C and Wu, L and Yao, P and Qian, X and Liu, J},
title = {Identification of Shared Gene Signatures Associated with Alzheimer's Disease and COVID-19 through Bioinformatics Analysis.},
journal = {Combinatorial chemistry & high throughput screening},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113862073383437250528173103},
pmid = {40600526},
issn = {1875-5402},
abstract = {BACKGROUND: Some studies have shown a link between Alzheimer's disease (AD) and COVID-19. This includes a Mendelian randomization study, which suggests that Alzheimer's disease and COVID-19 may be causally linked in terms of pathogenic mechanisms. However, there are fewer studies related to the two in terms of common pathogenic genes and immune infiltration. We conducted this study to identify key genes in COVID-19 linked to Alzheimer's disease, assess their relevance to immune cell profiles, and explore potential novel biomarkers.

METHODS: The RNA datasets GSE157103 and GSE125583 for COVID-19 and Alzheimer's disease, respectively, were acquired via the GEO database and subsequently processed. Through the utilization of differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA), genes associated with Alzheimer's disease and COVID-19 were identified. The immune cell signatures were estimated using the xCell algorithm, and correlation analysis identified links between key genes and significantly different immune cell signatures. Finally, we conducted transcription factor (TF) analysis, mRNA analysis, and sensitivity drug analysis.

RESULTS: Differential analysis identified 3560 (2099 up-regulated and 1461 down-regulated) and 1456 (640 up-regulated and 816 down-regulated) differential genes for COVID-19 and AD compared to normal controls, respectively. WGCNA analysis revealed 254 key module genes for COVID-19 and 791 for AD. We combined the differential genes and WGCNA key module genes for each disease to obtain two gene sets. The intersection of these two gene sets was examined to obtain intersecting genes. Subsequently, PPI network analysis was conducted, leading to the identification of 12 hub genes. Then, 12 immune-related hub genes were further identified. Immune infiltration patterns and the correlation between 12 hub genes and 64 immune cell types were analyzed. The analysis revealed a significant positive correlation between the two diseases under study. The relationship network between Transcription Factors and mRNA, as well as the predictions of drugs, further illustrate the strong association between the two diseases. This provides valuable information for further target exploration and drug screening.

CONCLUSION: Our study suggests potential shared genes, signalling pathways, and common drug candidates that may be associated with COVID-19 and AD. This may provide insights for future studies of AD patients infected with SARS-CoV-2 and help improve diagnostic and therapeutic approaches.},
}

@article {pmid40600491,
year = {2025},
author = {Liaquat, M and Le Gall, G and Scholey, A and Pontifex, MG and Bastiaanssen, TFS and Muller, M and Minihane, AM and Vauzour, D},
title = {APOE4 genotype shapes the role of dietary fibers in cognitive health through gut microbiota changes.},
journal = {Gut microbes},
volume = {17},
number = {1},
pages = {2526133},
doi = {10.1080/19490976.2025.2526133},
pmid = {40600491},
issn = {1949-0984},
mesh = {Humans ; *Gastrointestinal Microbiome ; *Apolipoprotein E4/genetics/metabolism ; Male ; *Dietary Fiber/metabolism/administration & dosage ; Female ; Aged ; *Cognitive Dysfunction/microbiology/genetics/metabolism ; Cross-Sectional Studies ; Genotype ; Feces/chemistry/microbiology ; *Cognition ; Middle Aged ; Fatty Acids, Volatile/blood/metabolism ; Bacteria/classification/genetics/isolation & purification/metabolism ; },
abstract = {APOE4, a key risk factor for Alzheimer's disease, influences gut microbiota and microbial metabolites (e.g. amino acids and dietary fiber (DF) derived short-chain fatty acids (SCFAs)). However, its role in modulating microbiota-driven DF metabolism and its effect on cognitive status remains unclear. This cross-sectional study (n = 170) investigates the association between APOE4 genotype, DF consumption, and metabolism in individuals with subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) compared to healthy controls (HC). Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) and [1]H NMR metabolomic techniques were used to quantify SCFAs in serum and fecal samples, respectively. Gut microbiota speciation was carried out by 16S rRNA amplicon sequencing. We found that DF intake was significantly associated with APOE4 genotype and cognitive status, with lower consumption in APOE4 carriers (p < 0.05) and those with cognitive impairment (SCI and MCI) (p = 0.03). Differences (p < 0.05) in gut microbiota (both α- and β-diversity) and SCFAs were evident between APOE4 and non-APOE4 carriers, with stronger associations with DF consumption and cognitive status evident in non-APOE4 carriers. These findings suggest that targeting DF-induced changes in gut microbiota and serum SCFAs may be an effective strategy for mitigating cognitive impairment, but primarily in non-APOE4 carriers.},
}

Humans
*Gastrointestinal Microbiome
*Apolipoprotein E4/genetics/metabolism
Male
*Dietary Fiber/metabolism/administration & dosage
Female
Aged
*Cognitive Dysfunction/microbiology/genetics/metabolism
Cross-Sectional Studies
Genotype
Feces/chemistry/microbiology
*Cognition
Middle Aged
Fatty Acids, Volatile/blood/metabolism
Bacteria/classification/genetics/isolation & purification/metabolism

@article {pmid40600356,
year = {2025},
author = {Hardy, J},
title = {Milestone Review: The History of Molecular Genetics Analysis of Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {169},
number = {7},
pages = {e70148},
doi = {10.1111/jnc.70148},
pmid = {40600356},
issn = {1471-4159},
mesh = {*Alzheimer Disease/genetics/history ; Humans ; History, 20th Century ; History, 21st Century ; Amyloid beta-Protein Precursor/genetics ; *Molecular Biology/history ; Animals ; Mutation/genetics ; Genome-Wide Association Study ; Genetic Predisposition to Disease/genetics ; },
abstract = {Alzheimer research has been driven by genetic findings: from the 1990s until about 2005, by the identification of amyloid precursor protein (APP) and presenilin (PSEN) mutations, leading to the formulation of the amyloid hypothesis, and then from ~2007 by genome-wide studies which have led to the increasing appreciation of the importance of microglial insufficiency in the disease pathogenesis. These genome findings have led not only to key mechanistic insights but also to progress in the use of genetic data to predict those at high risk of the disease so that earlier treatment becomes more practical. In this review I will outline these developments and attempts to synthesise the findings into a coherent single view of the disease.},
}

*Alzheimer Disease/genetics/history
Humans
History, 20th Century
History, 21st Century
Amyloid beta-Protein Precursor/genetics
*Molecular Biology/history
Animals
Mutation/genetics
Genome-Wide Association Study
Genetic Predisposition to Disease/genetics

@article {pmid40600330,
year = {2025},
author = {Comert Onder, F and Ural, K and Onder, A and Ozpolat, B and Ay, M},
title = {New and potential boron-containing compounds for treatment of Alzheimer's disease and cancers.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/17568919.2025.2525065},
pmid = {40600330},
issn = {1756-8927},
abstract = {AIM: In this study, new boron-containing carbamate compounds were synthesized and evaluated as potential acetylcholinesterase (AChE) inhibitors by in vitro and in silico analyses.

MATERIALS & METHODS: The structures were characterized by spectroscopic analysis including [1]H NMR, [13]C NMR, [11]B NMR, and MS. The purities of the compounds were determined by HPLC analysis. In vitro and in silico analyses were performed.

RESULTS: Based on our findings, compounds (1-4) demonstrated more potent AChE inhibitory activity compared to tacrine, which is an FDA-approved AChE inhibitor. Compound 4 had the highest inhibitory activity with an IC50 of 37.87 ± 0.96 nM and was more effective than tacrine (74.23 ± 0.83 nM). Compounds 1, 2, and 3, respectively, showed 1.78-, 1.73-, and 1.58-fold more potent enzyme inhibition activity compared to tacrine. The strong interactions with critical residues in the binding pocket of AChE were identified between protein and the compounds. Furthermore, compound 4 exerted an antiproliferative activity against various human cancer cell lines (32.91 ± 4.92 µM in HT29 and 42.38 ± 2.73 µM in MCF-7).

CONCLUSION: Our study indicates the discovery of new boron-containing AChE inhibitors as potential candidates for the treatment of Alzheimer's disease and cancer.},
}

@article {pmid40600294,
year = {2025},
author = {Chen, Y and Albert, AL and Sehrawat, A and Farinas, MF and L Lopez, O and Zeng, X and Cohen, AD and Karikari, TK},
title = {Equivalence of Plasma and Serum for Clinical Measurement of p-tau217: Comparative Analyses of Four Blood-Based Assays.},
journal = {Journal of neurochemistry},
volume = {169},
number = {7},
pages = {e70114},
pmid = {40600294},
issn = {1471-4159},
support = {R01 AG083874/AG/NIA NIH HHS/United States ; U24AG082930//NIH/NIA/ ; P30 AG066468/AG/NIA NIH HHS/United States ; RF1 AG077474/AG/NIA NIH HHS/United States ; R01 AG083156/AG/NIA NIH HHS/United States ; R37 AG023651/AG/NIA NIH HHS/United States ; R01 AG025516/AG/NIA NIH HHS/United States ; R01 AG073267/AG/NIA NIH HHS/United States ; R01 AG075336/AG/NIA NIH HHS/United States ; R01 AG072641/AG/NIA NIH HHS/United States ; P01 AG025204/AG/NIA NIH HHS/United States ; U01 NS131740/NS/NINDS NIH HHS/United States ; U01 NS141777/NS/NINDS NIH HHS/United States ; R01 MH108509/MH/NIMH NIH HHS/United States ; DAF2255207//Aging Mind Foundation/ ; HT94252320064//DoD/ ; //Anbridge Charitable Fund/ ; //Department of Psychiatry, University of Pittsburgh/ ; },
mesh = {Humans ; *tau Proteins/blood ; Female ; Male ; Biomarkers/blood ; *Plasma/chemistry/metabolism ; Aged ; *Alzheimer Disease/blood/diagnosis ; Middle Aged ; Aged, 80 and over ; Phosphorylation ; Cohort Studies ; *Serum/chemistry ; },
abstract = {Phosphorylated tau (p-tau) 217 is a promising blood biomarker for Alzheimer's disease (AD). However, most p-tau217 assays have been validated solely in ethylenediaminetetraacetic acid (EDTA) plasma, leaving the clinical applicability of serum p-tau217 largely unexplored despite serum being a preferred matrix in many clinical laboratories. To address this gap, we compared p-tau217 concentrations and classification accuracies in matched plasma and serum samples in four research-use-only assays. Paired plasma and serum samples were processed from the same venipuncture collection and assessed with each of the four p-tau217 assays following manufacturer-recommended procedures in two research cohorts from the University of Pittsburgh Azheimer's Disease Research Center (Pitt-ADRC; n = 50) and the Human Connectome Project (n = 34). The four assays evaluated included three from commercial sources-Lumipulse (recently gained FDA approval), ALZpath, and NULISA-and another from the University of Pittsburgh (Pittsburgh plasma p-tau217). Plasma and serum p-tau217 levels varied across assays; the ALZpath, Pittsburgh, and NULISA methods showed significantly lower p-tau217 levels in serum compared with plasma (p < 0.0001) for both cohorts, while Lumipulse showed higher plasma levels in the Pitt-ADRC cohort but equivalent plasma and serum levels in the HCP cohort. Yet, strong correlations (rho > 0.8) were observed between plasma and serum p-tau217 pairs for all methods. Both plasma and serum p-tau217 demonstrated strong classification accuracies to differentiate clinical AD from normal controls, with high AUC (up to 0.963) for all methods. The exception was the Pittsburgh assay, where plasma p-tau217 had significantly superior AUC to serum p-tau217 (plasma: 0.912, serum: 0.844). The rest of the assays had equivalent accuracies in both matrices. Serum p-tau217 performs equivalently as plasma p-tau217 for most assessed assays. Serum can be used as a substitute for plasma in the use of most p-tau217 assays to evaluate Aβ pathology in AD for both research and clinical purposes.},
}

Humans
*tau Proteins/blood
Female
Male
Biomarkers/blood
*Plasma/chemistry/metabolism
Aged
*Alzheimer Disease/blood/diagnosis
Middle Aged
Aged, 80 and over
Phosphorylation
Cohort Studies
*Serum/chemistry

@article {pmid40600213,
year = {2025},
author = {Borrego-Ruiz, A and Borrego, JJ},
title = {Human oral microbiome and its influence on mental health and brain disorders.},
journal = {AIMS microbiology},
volume = {11},
number = {2},
pages = {242-294},
pmid = {40600213},
issn = {2471-1888},
abstract = {The human oral microbiome can affect brain functions directly through the trigeminal nerve and olfactory system and indirectly via the oral-gut-brain axis. However, the potential link between the oral microbiome and mental health remains an area that requires further investigation. Taking into consideration that gut microbiota dysbiosis plays a role in the onset and progression of several mental disorders, as well as the potential influence of the oral microbiome on mental health via direct pathways, the present narrative review explores the role of the human oral microbiome in health and disease, along with the factors that affect its composition, with a particular focus on its potential impact on mental health, including its involvement in a range of mental disorders and brain-related conditions, such as Alzheimer's disease, Parkinson's disease, autism spectrum disorder, anxiety, depression, stress, bipolar disorder, Down's syndrome, cerebral palsy, epilepsy, and schizophrenia. Chronic oral diseases can impair the oral mucosal barrier, allowing microorganisms and endotoxins to enter the bloodstream, triggering systemic inflammation, and affecting the blood-brain barrier. This pathway can lead to neuroinflammation and cognitive dysfunction and contribute to adverse mental health effects. Additionally, translocation of oral bacteria to the gut can drive persistent inflammation and thereby affect brain health. Multiple studies suggest a potential relationship between the oral microbiome and several mental disorders, but further research is needed to strengthen the evidence surrounding these associations and to fully clarify the underlying mechanisms linking the oral microbiome to these conditions. Given the promising implications, future research should focus on elucidating the biological mechanisms through which alterations in the oral microbiome influence the development and progression of determinate neurodegenerative and neuropsychiatric disorders. Additionally, identifying reliable biomarkers linked to the oral microbiome could enhance early detection, diagnosis, and monitoring of these conditions.},
}

@article {pmid40600183,
year = {2025},
author = {Fu, X and Cai, H and Quan, S and Ren, Z and Xu, Y and Jia, L},
title = {Immune cells in Alzheimer's disease: insights into pathogenesis and potential therapeutic targets.},
journal = {Medical review (2021)},
volume = {5},
number = {3},
pages = {179-202},
pmid = {40600183},
issn = {2749-9642},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder for which there are currently no effective treatment options. Increasing evidence suggests that AD is a systemic disease closely associated with the immune system, not merely a central nervous system (CNS) disorder. Immune cells play crucial roles in the onset and progression of AD. Microglia and astrocytes are the primary inflammatory cells in the brain that can sensitively detect changes in the internal environment and transform into different phenotypes to exert differing effects at various stages of AD. Peripheral immune cells, such as T cells, B cells, monocytes/macrophages, and neutrophils can also be recruited to the CNS to mediate the inflammatory response in AD. As such, investigating the role of immune cells in AD is particularly important for elucidating its specific pathogenesis. This review primarily discusses the roles of central innate immune cells, peripheral immune cells, and the interactions between central and peripheral immune cells in the development of neuroinflammation in AD. Furthermore, we listed clinical trials targeting AD-associated neuroinflammation, which may represent a promising direction for developing effective treatments for AD in the future.},
}

@article {pmid40600167,
year = {2025},
author = {Aremu, SA},
title = {Alternative splicing and the aging brain in AfrAbia: New frontiers in dementia research.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {101-109},
pmid = {40600167},
issn = {2667-2421},
abstract = {AfrAbia (Sub-Saharan Africa and Arab world), is undergoing a significant demographic shift characterized by increased longevity and rising dementia rates. Despite this, molecular insights into brain aging in these regions, especially in RNA processing pathways like alternative splicing (AS), are virtually absent. AS promotes transcriptomic and proteomic complexity and is pivotal for brain function, with its dysregulation connected to neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). However, current knowledge is overwhelmingly derived from Western populations, limiting global applicability. This perspective synthesizes the mechanisms and regulatory elements of AS, its role in aging and neurodegeneration, and emerging biomarkers and therapeutic strategies. Special attention is paid to ancestry-associated splicing variants and fluid biomarker development in AfrAbian cohorts. We argue for inclusive, population-specific molecular studies to bridge disparities in dementia diagnosis, treatment, and prevention.},
}

@article {pmid40600046,
year = {2025},
author = {Kishor Kumar Reddy, C and Ahmed, HI and Mohzary, M and Monika Singh, T and Shuaib, M and Alam, S and Alnami, HM},
title = {AlzheimerViT: harnessing lightweight vision transformer architecture for proactive Alzheimer's screening.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1568312},
pmid = {40600046},
issn = {2296-858X},
abstract = {BACKGROUND: Alzheimer's is a disease in the human brain characterized by gradual memory loss, confusion, and alterations in behavior. It is a complex and continuously degenerative disorder of the nervous system, which still has early detection and diagnosis as challenges to overcome. The disease causes significant damage in individuals suffering from the disorder as they progressively lose cognitive ability. Its diagnosis and management depend primarily on the ability to diagnose early to initiate proper intervention. Unfortunately, this remains a difficult feat, given the resemblance of early signs of the disease with symptoms associated with normal aging and other disorders involving cognition. While clinical tests have their limitations, brain imaging such as MRI can provide detailed insights into changes in the brain. Deep learning techniques, mainly when applied to MRI data, have proven helpful in the early detection of Alzheimer's Disease.

METHODS: In the proposed study, a lightweight, self-attention-based vision transformer (ViT) is employed to predict Alzheimer's disease using MRI images from the OASIS-3 dataset. Data pre-processing and augmentation techniques have been added to strengthen the model's generalization ability and enhance model performance, which is visualized using Grad-Cam.

RESULTS: The proposed model achieves exceptional results with an accuracy of 98.57%, approximate precision of 98.7%, Recall of about 98.47%, and specificity of 98.67%. It also achieves a Kappa Score of 97.2% and an AUC ROC Score of 99%.

CONCLUSION: This paper, along with comprehensive data pre-processing and augmentation, represents one of the major steps toward achieving more robust and clinically applicable models for Alzheimer's disease prediction. The proposed study indicates that deep learning models have the potential to enhance the diagnosis of Alzheimer's disease. By integrating Deep learning techniques with careful data processing, more reliable early detection models can be developed, which in turn leads to better treatment outcomes.},
}

@article {pmid40600033,
year = {2025},
author = {Pandey, P and Bhatia Khan, S and Pruthi, J and Albalawi, E and Algarni, A and Almusharraf, A},
title = {GAN-enhanced deep learning for improved Alzheimer's disease classification and longitudinal brain change analysis.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1587026},
pmid = {40600033},
issn = {2296-858X},
abstract = {Alzheimer's disease (AD) is commonly defined by a progressive decline in cognitive functions and memory. Early detection is crucial to mitigate the devastating impacts of AD, which can significantly impair a person's quality of life. Traditional methods for diagnosing AD, while still in use, often involve time-consuming processes that are prone to errors and inefficiencies. These manual techniques are limited in their ability to handle the vast amount of data associated with the disease, leading to slower diagnosis and potential misclassification. Advancements in artificial intelligence (AI), specifically machine learning (ML) and deep learning (DL), offer promising solutions to these challenges. AI techniques can process large datasets with high accuracy, significantly improving the speed and precision of AD detection. However, despite these advancements, issues such as limited accuracy, computational complexity, and the risk of overfitting still pose challenges in the field of AD classification. To address these challenges, the proposed study integrates deep learning architectures, particularly ResNet101 and long short-term memory (LSTM) networks, to enhance both feature extraction and classification of AD. The ResNet101 model is augmented with innovative layers such as the pattern descriptor parsing operation (PDPO) and the detection convolutional kernel layer (DCK), which are designed to extract the most relevant features from datasets such as ADNI and OASIS. These features are then processed through the LSTM model, which classifies individuals into categories such as cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD). Another key aspect of the research is the use of generative adversarial networks (GANs) to identify the progressive or non-progressive nature of AD. By employing both a generator and a discriminator, the GAN model detects whether the AD state is advancing. If the original and predicted classes align, AD is deemed non-progressive; if they differ, the disease is progressing. This innovative approach provides a nuanced view of AD, which could lead to more precise and personalized treatment plans. The numerical outcome obtained by the proposed model for ADNI dataset is 0.9931, and for OASIS dataset, the accuracy gained by the model is 0.9985. Ultimately, this research aims to offer significant contributions to the medical field, helping healthcare professionals diagnose AD more accurately and efficiently, thus improving patient outcomes. Furthermore, brain simulation models are integrated into this framework to provide deeper insights into the underlying neural mechanisms of AD. These brain simulation models help visualize and predict how AD may evolve in different regions of the brain, enhancing both diagnosis and treatment planning.},
}

@article {pmid40600022,
year = {2025},
author = {Blotenberg, I and Jeran, L and Rodriguez, FS and Michalowsky, B and Platen, M and Teipel, S and Hoffmann, W and Thyrian, JR},
title = {The Role of Social Support for Depressive Symptoms in Dementia: A Four-Year Longitudinal Study.},
journal = {Innovation in aging},
volume = {9},
number = {6},
pages = {igaf047},
pmid = {40600022},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: Depressive symptoms are common in people with dementia, significantly reducing well-being and potentially exacerbating dementia symptoms. The objective of the present study was to investigate the role of support from the social environment for depressive symptoms in people with dementia over a 4-year period.

RESEARCH DESIGN AND METHODS: We used data from a cohort of 334 community-dwelling people with dementia (M age = 80.2, 59.3% female) who were interviewed annually in their homes by specially qualified nurses. We used multilevel growth curve models with random intercepts and slopes to model depressive symptoms over time. We modeled both the role of between-person differences and the role of within-person changes in social support for depressive symptoms.

RESULTS: At the beginning of the study, 13.8% of people with dementia reported mild to severe depressive symptoms. People with more social support showed fewer depressive symptoms overall over the 4-year period (% change per point on a scale from 22 to 110: -1.2, 95% CI: -1.8, -0.4). In addition, a decline in a person's social support was associated with more depressive symptoms (% change: -0.9, 95% CI: -1.7, -0.2). These effects were stable even after controlling for sociodemographic (age, sex, education) and clinical factors (cognitive and functional status, comorbidities).

DISCUSSION AND IMPLICATIONS: The social environment plays an important role in depressive symptoms in people with dementia-beyond clinical factors like cognitive and functional abilities. Improving support from the social environment could be a lever for alleviating depressive symptoms. In the care of people with dementia, not only medical needs but also psychosocial needs should come to the forefront.},
}

@article {pmid40599906,
year = {2025},
author = {Nguyen, N and Gomar, JJ and Truong, JN and Barbero, J and Do, PP and Rommal, A and Oh, A and Eidelberg, D and Koppel, J and Vo, A},
title = {An artificial intelligence-derived metabolic network predicts psychosis in Alzheimer's disease.},
journal = {Brain communications},
volume = {7},
number = {3},
pages = {fcaf159},
pmid = {40599906},
issn = {2632-1297},
abstract = {The delusions and hallucinations that characterize Alzheimer's disease psychosis (AD + P) are associated with violence towards caregivers and an accelerated cognitive and functional decline whose management relies on the utilization of medications developed for young people with schizophrenia. The development of novel therapies requires biomarkers that distinguish AD + P from non-psychotic Alzheimer's disease. We investigated whether there might exist a brain metabolic network that distinguishes AD + P from non-psychotic Alzheimer's disease that could be used as a biomarker to predict and track the course of AD + P for use in clinical trials. Utilizing F-18 fluorodeoxyglucose positron emission tomography scans from cohorts of cognitively healthy elderly (N = 174), those with Alzheimer's disease without psychosis (N = 174) and those with AD + P (N = 88) participating in the Alzheimer's Disease Neuroimaging Initiative study, we employed a convolutional neural network to identify and validate the Alzheimer's Psychosis Network. We analysed network progression, clinical correlations and psychosis prediction using expression scores and network organization using graph theory. The Alzheimer's Psychosis Network accurately distinguishes AD + P from controls (97%), with increasing scores correlating with cognitive decline. The Alzheimer's Psychosis Network-based approach predicts psychosis in Alzheimer's disease with 77% accuracy and identifies specific brain regions and connections associated with psychosis. Alzheimer's Psychosis Network expression was found to be associated with increased cognitive and functional decline that characterizes AD + P. The increased metabolic connectivity between motor and language/social cognition regions in AD + P may drive delusions and agitated behaviour. Alzheimer's Psychosis Network holds promise as a biomarker for AD + P, aiding in treatment development and patient stratification.},
}

@article {pmid40599765,
year = {2025},
author = {Wei, X and Qin, W},
title = {Exploring causal links between brain functional networks and neurodegenerative disease risk using Mendelian randomization.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251348844},
pmid = {40599765},
issn = {2542-4823},
abstract = {BACKGROUND: Resting-state functional magnetic resonance imaging (rsfMRI) is pivotal for mapping alterations in brain functional networks associated with neurodegenerative diseases, particularly Alzheimer's disease (AD). However, the causal mechanisms linking such network dysfunction to disease pathogenesis remain unresolved.

OBJECTIVE: This study aimed to elucidate bidirectional causal relationships between 191 resting-state fMRI phenotypes (derived from 34,691 individuals) and six neurodegenerative diseases, specifically AD, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), dementia with Lewy bodies (DLB), and Parkinson's disease (PD), using disease-specific GWAS data from European-ancestry cohorts.

METHODS: Bidirectional two-sample Mendelian randomization (MR) was performed using rsfMRI phenotypes from Zhao et al. (2022) and GWAS summary statistics (AD: ieu-b-5067/ebi-a-GCST90027158, ALS: ebi-a-GCST90027164, FTD: ieu-b-43, MS: ieu-b-18, DLB: ebi-a-GCST90001390, PD: ieu-b-7). Instrumental variables were filtered for significance (p < 5 × 10^-8), with sensitivity analyses (MR-PRESSO, Cochran's Q, MR-Egger) to ensure robustness.

RESULTS: Forward MR identified 26 rsfMRI phenotypes causally linked to neurodegenerative diseases. AD risk was associated with reduced cerebellum-subcortical connectivity (OR = 0.957, p = 0.004), while heightened cerebellar activity increased DLB risk (OR = 2.58, p = 0.0063). Reverse MR revealed 64 disease-to-network effects: AD altered default mode network connectivity (OR = 0.965, p = 0.034), and PD disrupted salience-central executive network interactions (OR = 0.950, p = 0.00011).

CONCLUSIONS: This study establishes robust bidirectional causal pathways between brain functional networks and neurodegenerative diseases, with AD showing unique vulnerability in cerebellar-subcortical and default mode circuits. These findings highlight network-specific therapeutic targets for AD and related disorders.},
}

@article {pmid40599654,
year = {2025},
author = {Mohamadi, MH and Bavafa, A and Salehi, S and Abedi, M and Shahabi, F and Jafarlou, S and Kolivand, P and Sahab-Negah, S},
title = {Cognitive Effect of Levetiracetam in Patients with Alzheimer's Disease or Mild Cognitive Impairment: A Systematic Review.},
journal = {Current therapeutic research, clinical and experimental},
volume = {103},
number = {},
pages = {100798},
pmid = {40599654},
issn = {0011-393X},
abstract = {BACKGROUND: Various therapeutic interventions have been investigated for cognitive impairment, a common problem in Alzheimer's disease (AD). Levetiracetam (LEV), an antiepileptic drug, has been shown to alleviate cognitive impairment.

OBJECTIVE: The present systematic review aimed to evaluate the cognitive effects of LEV in patients with AD or mild cognitive impairment (MCI).

METHODS: We searched PubMed/MEDLINE, Scopus, Web of Sciences, and Embase databases for all studies on LEV and cognitive impairment. After multistep screening, we identified qualified interventional studies and performed further data extraction. We reviewed the methodological diversity across the studies and assessed the quality of each study using the critical appraisal of the Joanna Briggs Institute checklist (the risk of bias assessment).

RESULTS: Of the 1091 publications, only 5 articles were qualified for review. All studies enrolled patients with AD or MCI, and at least 1 arm of the trial involved LEV therapy. Four of 5 studies reported significant cognitive improvement in patients with AD or MCI after the LEV trials, whereas 1 study found no significant change in cognitive status. The risk of bias assessment revealed that 4 studies had a low risk of bias. Among them, 3 showed significant improvement, whereas 1 did not report a significant change in cognitive function.

CONCLUSIONS: The efficacy of LEV therapy for cognitive impairment varies across studies owing to different methodologies, dosages, treatment durations, and outcome assessment tools. This study suggests that LEV may exert a beneficial impact on cognitive function in patients with AD or MCI. However, a quantitative comparison or meta-analysis is essential to draw definitive conclusions about the cognitive effects of LEV in AD and MCI.},
}

@article {pmid40599507,
year = {2025},
author = {Jones, T and Shalom, M and Chalamgari, A and Gold, J and Zomalan, B and Patel, S and Munjal, V and Khan, MF and Mao, Y and Gendreau, JL and Abraham, ME},
title = {The Potential for Neuromodulation in the Treatment of Alzheimer's Disease: A Review of Clinical Trials.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e85156},
pmid = {40599507},
issn = {2168-8184},
abstract = {There is still no cure for Alzheimer's disease (AD), which remains the leading cause of dementia in Western countries. Neuromodulation, the use of electrical or chemical interventions to modify neuronal excitability, has shown promise in treating several neurological conditions and has become a topic of interest in the context of AD. We aim to review clinical trials related to neuromodulation in AD. Analysis of current clinical trials was conducted using ClinicalTrials.gov. The search term used was "Alzheimer's disease," and results were filtered for studies that included neuromodulation. One hundred and eleven clinical trials were found, and 82 trials remained after exclusion. All trials utilized some form of neuromodulation device as the primary intervention, with transcranial magnetic stimulation and transcranial direct current stimulation as the most common modalities. Thirty-six (43.9%) trials were completed, 20 (24.3%) were not yet recruiting, 23 (28.0%) were actively recruiting, and three (3.7%) were enrolling by invitation. Of the completed trials, only 11 (30.6%) had associated results, and of those 11, eight (22.2% of completed trials, 72.7% of trials with results) were associated with published articles in a peer-reviewed journal. All but one of the eight trials displayed some form of improvement in their metric of choice. Although the number of trials with published results is limited, there appears to be positive evidence of the efficacy of neuromodulation in treating AD. The medical community must continue to emphasize the need for additional clinical trials in this area.},
}

@article {pmid40599392,
year = {2025},
author = {Scharfman, HE and Kam, K and Duffy, ÁM and LaFrancois, JJ and Leary, P and Chartampila, E and Ginsberg, SD and Lisgaras, CP},
title = {Evidence that cholinergic mechanisms contribute to hyperexcitability at early stages in Alzheimer's disease.},
journal = {Frontiers in dementia},
volume = {4},
number = {},
pages = {1513144},
pmid = {40599392},
issn = {2813-3919},
abstract = {A long-standing theory for Alzheimer's disease (AD) has been that deterioration of synapses and depressed neuronal activity is a major contributing factor. We review the increasing evidence, in humans and in mouse models, that show that there is often neuronal hyperactivity at early stages rather than decreased activity. We discuss studies in mouse models showing that hyperexcitability can occur long before plaque deposition and memory impairment. In mouse models, a generator of the hyperactivity appears to be the dentate gyrus. We present evidence, based on mouse models, that inhibition of muscarinic cholinergic receptors or medial septal cholinergic neurons can prevent hyperactivity. Therefore, we hypothesize the novel idea that cholinergic neurons are overly active early in the disease, not depressed. In particular we suggest the medial septal cholinergic neurons are overly active and contribute to hyperexcitability. We further hypothesize that the high activity of cholinergic neurons at early ages ultimately leads to their decline in function later in the disease. We review the effects of a prenatal diet that increases choline, the precursor to acetylcholine and modulator of many other functions. In mouse models of AD, maternal choline supplementation (MCS) reduces medial septal cholinergic pathology, amyloid accumulation and hyperexcitability, especially in the dentate gyrus, and improves cognition.},
}

@article {pmid40599381,
year = {2025},
author = {Borges, KA and Lombardi, I and Sivilli, M and Aabye, J and Romano, I and Nasruddin, SA and Padalkar, MV and Moussouros, D and Savinova, OV},
title = {Brain microvascular calcification is increased in human donors with dementia compared to elderly controls: a pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1557625},
pmid = {40599381},
issn = {1663-4365},
abstract = {INTRODUCTION: Intracranial vascular calcification has been observed in the setting of both Alzheimer's disease (AD) and vascular dementia. Increased calcification in intracranial and extracranial arteries is associated with an increased risk of dementia; however, less is known about the prevalence and implications of microvascular calcification in AD and related dementias. In this study, we compared microvascular calcification in AD-relevant brain regions between human donors with vs. without dementia and/or late-onset AD diagnoses.

METHODS: Brain tissue was sampled bilaterally from basal ganglia, hippocampus, posterior cingulate cortex, substantia nigra, and subventricular zone, along with bilateral carotid arteries in a cohort of human donor cadavers with and without dementia at death (n = 23, 61% females, 86.4 ± 7.9 years of age). An additional cohort included postmortem posterior cingulate cortex samples from NIH NeuroBioBank donors with and without confirmed late-onset AD (n = 10, 40% females, 78.3 ± 2.1 years of age). All samples were scanned by micro-computed tomography. Vascular calcification was quantified as the sum of voxels at an intensity of ≥130 Hounsfield units in a standardized tissue volume. Findings were confirmed by histology.

RESULTS: Our findings indicate higher odds of dementia per one quartile increase in microvascular calcification volume in the hippocampus [OR 9.601 (CI 2.518, 86.803), p = 0.0091], posterior cingulate cortex [OR 2.894 (CI 1.222, 8.923), p = 0.0302], and subventricular zone [OR 2.851 (CI 1.153, 9.482), p = 0.0427]. Similarly, in posterior cingulate cortex samples from the NeuroBioBank, significantly higher microvascular calcification was observed in late-onset AD cases [median 0.0153 (IQR 0.0075, 0.0581), % by volume] compared to controls [median 0.0024 (IQR 0.0016, 0.0104), % by volume; p = 0.0265]. Internal carotid calcification was significantly associated with microvascular calcification in the basal ganglia [OR 1.699 (CI 1.156, 2.496), p = 0.0093], hippocampus [OR 1.580 (CI 1.056, 2.366), p = 0.0281], and posterior cingulate cortex [OR 1.524 (CI 1.009, 2.299), p = 0.0452].

DISCUSSION: Our findings indicate that microvascular calcification impacts brain regions relevant to morphologic changes (hippocampus) and hypoperfusion (posterior cingulate cortex) in AD. Our study expands on a recent report of increased brain calcification in the setting of AD, suggesting that microvascular calcification carries pathophysiological significance in the development and/or progression of AD and related dementias.},
}

@article {pmid40599380,
year = {2025},
author = {O'Niel, A and Parkins, CJ and Pederson, A and Saltonstall, E and Bunnell, E and Aggarwal, R and Sandholm, P and Kessler, K and Harrison, HF and Smith, JL and Hirsch, AJ and Raber, J},
title = {Effects of West Nile virus on behavioral and cognitive performance, cortical Aβ pathology, viral loads, and immune measures of middle-aged NL-G-F/E3 and NL-G-F/E4 mice.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1600119},
pmid = {40599380},
issn = {1663-4365},
abstract = {INTRODUCTION: West Nile Virus (WNV) can cause severe and long-lasting neurological disease and results in some neuropathology and neuroinflammation seen in Alzheimer's disease (AD). Exposure to WNV might impact AD-relevant behavioral and cognitive performance and neuropathology via AD-susceptibility genes (i.e., E4) and by inducing neuroinflammation (i.e., increases in TCR-α, IFN-γ, TNF-α, and CXCL- 10). There are three human apolipoprotein E (E) isoforms, which play a role in cholesterol metabolism: E2, E3, and E4. Compared to E3, E4 is an AD risk factor.

METHODS: We crossed knock-in (KI) mice expressing human amyloid precursor protein (APP) containing the dominant NL-G-F mutations with human apoE targeted replacement (TR) mice and used middle-aged NL-G-F/E3 and NL-G-F/E4 mice to assess the role of prior WNV (subtype Kunjin virus) (KUNV) exposure on hAPP/Aβ-induced behavioral alterations, cognitive injury, circadian body temperatures, viral loads, neuropathology, and transcript levels of four immune measures important in the detrimental effects of KUNV on brain function.

RESULTS: KUNV affected physiological, behavioral, cognitive, amyloid pathology, viral load, and immune measures in middle aged NL-G-F mice in an apoE isoform-dependent fashion. NL-G-F/E4 mice were more susceptible to KUNV induced cognitive injury and prolonged viral load in the cortex.

DISCUSSION: These results support an important apoE isoform-dependent role in modulating phenotypes in the NL-G-F AD mouse model following WNV exposure.},
}

@article {pmid40599376,
year = {2025},
author = {Hodsdon, ME and Abel, A and Chambers, A and Lu, M and Morris, A and Pontecorvo, MJ and Reiske, H and Burnham, SC and Collins, EC and Mintun, M and Schade, A and Beck, RC},
title = {Clinical validation of the Lilly SP-X P-tau217 assay: Performance in underrepresented cohorts.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70139},
pmid = {40599376},
issn = {2352-8729},
abstract = {INRODUCTION: Plasma phosphorylated tau217 (p-tau217) is a biomarker for the detection of amyloid pathology. We present performance characteristics of the Lilly SP-X P-tau217 assay in a clinical validation cohort, as a whole and divided into subpopulations from traditionally underrepresented groups.

METHODS: We measured p-tau217 levels in plasma samples from participants with mild cognitive impairment. Assay performance in predicting positivity for amyloid beta (Aβ) positron emission tomography was examined using two numerical cutoffs.

RESULTS: Two p-tau217 cutoffs were determined with an upper-level group with 95% positive predictive value for Aβ positivity and a lower-level group with 84% negative predictive value for Aβ negativity, with 91% sensitivity and 90% specificity. The remaining indeterminate group represented 18% of participant samples. Similar performance was observed across validation subgroups.

DISCUSSION: The validation data support the potential clinical utility of the SP-X p-tau217 assay in multiple subpopulations to aid in Alzheimer's disease diagnosis.

HIGHLIGHTS: The Lilly SP-X p-tau217 assay showed strong concordance with amyloid PET in total cohort and underrepresented groups.Assay performance is in line with guidance from the Global CEOi on AD Working Group.Data support the clinical utility of the assay in multiple cohorts to aid in AD diagnosis.},
}

@article {pmid40599314,
year = {2025},
author = {Ma, H and Yu, Z and Qiao, Q and Wang, W and Li, Z and Wang, P and Song, J and Zhang, X and Su, Y and Sun, Y and Xie, Z and Zhang, Z},
title = {Metabolomic and microbial insights: Kai-Xin-San's impact on Alzheimer's disease pathology.},
journal = {iScience},
volume = {28},
number = {7},
pages = {112817},
pmid = {40599314},
issn = {2589-0042},
abstract = {There has been increasing interest in the connection between AD, gut microbiota, and metabolites. Kai-Xin-San (KXS) has been commonly employed in ancient and modern Chinese clinical trials for the treatment of dementia; however, whether the protective effect of KXS in AD is related to the gut microbiota remains elusive. APP/PS1 mice were used as the model of AD. 43 key metabolites influenced by KXS were screened using untargeted metabolomics. At the genus level, Clostridium_IV, Eubacterium, Acetatifactor, etc., were identified to be impacted by KXS using 16S rRNA sequencing. Additionally, we identified 9 distinct intestinal floras at the genus level that were correlated with 13 pivotal differential metabolites related to cognitive impairment. KXS also inhibited the neuroinflammation, mostly via regulating the key metabolites. A potential relationship between gut microbiota, metabolites, and neuroinflammation is suggested as a protective mechanism of KXS in AD. These findings provide support for further development of KXS.},
}

@article {pmid40599204,
year = {2025},
author = {Tang, S and Luo, W and Cheng, C and Shen, L and Wu, X and Xiao, X},
title = {BDNF gene therapy rescues neuronal function via unique and common transcriptional responses in Aβ and tau-driven Alzheimer's disease mouse models.},
journal = {Biochemistry and biophysics reports},
volume = {43},
number = {},
pages = {102089},
pmid = {40599204},
issn = {2405-5808},
abstract = {Brain-derived neurotrophic factor (BDNF) protects neurons from degeneration, making it a promising therapeutic target for Alzheimer's disease (AD). However, the genetic regulation resulting from BDNF overexpression in the brain remains to be further illustrated. Using APP/PS1 and rTg4510 mouse models, we analyzed hippocampal transcriptomes after intrahippocampal AAVT42-BDNF injection. In APP/PS1 mice with Aβ accumulation, BDNF upregulated genes involved in neuronal signaling and downregulated neurodegenerative pathways. In rTg4510 mice with p-tau pathology, upregulated genes were associated with cell differentiation and neuronal development, while downregulated genes were related to metabolism and biosynthesis. A comparison of differentially expressed genes (DEGs) between the two strains identified eight commonly upregulated genes (Cecr2, Cdhr1, Dusp6, Pam, Rasd1, Dusp4, Htr5b, Tmem117) and two downregulated genes (Abhd14a, Pmel). Notably, three genes - Npy, Crh, Tac1-were upregulated in both models, suggesting shared neuroprotective mechanisms. These findings reveal distinct and common genetic responses to BDNF in Aβ and p-tau pathogenesis, supporting its potential as a therapeutic strategy for AD.},
}

@article {pmid40599166,
year = {2025},
author = {Arora, S and Critchley, G and Dekmak, AS and Miesenböck, G and Kempf, A and Ligoxygakis, P},
title = {Loss of the NF-κB negative regulator Pirk in Drosophila links brain and gut immunity to neurodegeneration.},
journal = {Brain communications},
volume = {7},
number = {2},
pages = {fcaf144},
pmid = {40599166},
issn = {2632-1297},
abstract = {A gut-brain axis influenced by host innate immunity and resident microbiota has been implicated in neurological conditions including Alzheimer's disease. However, the precise connection of innate immunity to Alzheimer's disease remains unclear. Using Pirk, a negative regulator of the IMD/NF-κB pathway in Drosophila, we studied the neurological phenotypes induced when genetically predisposing flies to chronically over-active immunity. Pirk mutants exhibited age-dependent neurological phenotypes such as reduced locomotion and altered sleep patterns coupled to an increased number of brain lesions. Gut-specific pirk-RNA interference led to earlier onset of the neurological phenotypes which, alongside changes in intestinal bacteria in pirk mutants, highlighted a potential early role for the intestinal ecosystem in the onset of neurodegeneration. In contrast, glia-specific RNA interference of pirk resulted in late onset of the relevant phenotypes suggesting a later contribution of the nervous system to the underlying neuropathology. Knockout of the antimicrobial peptide (AMP) gene AttacinD or rearing flies in axenic conditions recovered some of the neurological phenotypes, suggesting both chronic AMP gene expression as well as gut bacteria changes as mediators. Our results indicate an evolutionarily conserved path to neurodegeneration linked to dysregulated immunity. They also reveal that in this context, age-dependent neurodegeneration can happen in less complex non-vertebrate brains in the absence of beta-amyloid or tau aggregation.},
}

@article {pmid40599054,
year = {2025},
author = {Dregni, AJ and Hong, M},
title = {Impact of Lysine Acetylation Mutations on the Structure of Full-Length Tau Fibrils.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00149},
pmid = {40599054},
issn = {1948-7193},
abstract = {The tau protein aggregates into amyloid fibrils in Alzheimer's disease and other neurodegenerative diseases. In these tauopathies, tau is decorated with posttranslational modifications, including phosphorylation and acetylation, suggesting that these modifications may cause tau to aggregate into specific pathological structures. Here, we investigate how pseudoacetylation of three lysine residues, K311Q, K321Q, and K369Q, affects the fibrilization and fibril structure of full-length four-repeat tau. These acetyl mimics are in addition to four phospho-mimetic glutamate mutations at the PHF1 epitope (4E tau). The joint mutant 4E3Q tau formed well-ordered amyloid fibrils without anionic cofactors. The 4E3Q tau fibrils lack twists, preventing structure determination by cryoelectron microscopy and necessitating characterization by solid-state NMR. [13]C and [15]N chemical shifts indicate that pseudoacetylation caused the protein to adopt a distinct fold from the parent 4E tau fibrils: the rigid core contains β-strands between R2 and R4 repeats and near the end of the C-terminal domain. Importantly, the C-terminal half of the R3 repeat containing the K321Q mutation is disordered, in qualitative contrast with 4E tau. Chemical shifts indicate that these structural changes likely result from the disruption of salt bridges between lysine and aspartate residues. 4E3Q tau contains an immobilized R2, which differs from that of AD tau. These results provide insights into the impact of acetylation on tau fibrilization and fibril structure and suggest that acetylation of these three lysine residues in AD may occur after the formation of the paired-helical filament structure.},
}

@article {pmid40598949,
year = {2025},
author = {Zhang, P and Wu, N and Xue, Q and Li, J and Ouyang, Q and Yu, X and Yang, Y and Dong, Y and Li, F and Wang, T and Li, S and Pan, XF},
title = {Plasma leptin, resistin, tumor necrosis factor-alpha, and interleukin-6 with risk of dementia: A prospective population study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251352480},
doi = {10.1177/13872877251352480},
pmid = {40598949},
issn = {1875-8908},
abstract = {BackgroundAdipokines secreted from adipose tissue may contribute to dementia pathogenesis.Objective: Our study investigated the associations between plasma levels of leptin, resistin, TNF-α, and IL-6 and the risk of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD).MethodsPlasma protein levels were measured using the Olink Proximity Extension Assay, and dementia was ascertained from hospital admissions and death registries in the UK Biobank. Multivariable Cox proportional hazards models with stepwise covariate adjustments were used to assess associations. Subgroup analyses were conducted to examine whether the associations differed by sociodemographic characteristics, lifestyle factors, and major diseases.ResultsAmong 32,002 participants, 793 developed all-cause dementia, including 260 with AD and 96 with VaD. Plasma levels of resistin and IL-6 were positively associated with risks of all-cause dementia, with hazard ratios (95% confidence intervals) of 1.10 (1.03, 1.18) and 1.10 (1.04, 1.17), respectively. Leptin (0.98; 0.86, 1.12) and TNF-α levels (1.06; 0.98, 1.13) were not significantly associated with all-cause dementia. Resistin (1.28; 1.08, 1.53) and TNF-α levels (1.21; 1.04, 1.40) were associated with VaD risk. There was a lack of evidence for the associations between four adipokines and AD. Subgroup analyses showed stronger associations between resistin and all-cause dementia in those with high body mass index, diabetes, or stroke.ConclusionsPlasma levels of resistin and IL-6 were positively associated with risks of all-cause dementia, with resistin and TNF-α strongly linked to VaD. These findings support a potential role of adipokines in dementia pathogenesis, particularly for VaD.},
}

@article {pmid40598947,
year = {2025},
author = {Osawa, A and Maeshima, S and Kamiya, M and Ueda, I and Itoh, N and Kondo, I and Arai, H},
title = {Intervention Effects of the Holistic Physio-Cognitive Rehabilitation for Alzheimer Disease and Mild Cognitive Impairment.},
journal = {Annals of geriatric medicine and research},
volume = {29},
number = {2},
pages = {207-212},
pmid = {40598947},
issn = {2508-4909},
support = {21-37//National Center for Geriatrics and Gerontology/ ; },
mesh = {Humans ; *Cognitive Dysfunction/rehabilitation/psychology ; Male ; *Alzheimer Disease/rehabilitation/psychology ; Female ; Aged ; Retrospective Studies ; Activities of Daily Living ; Aged, 80 and over ; Japan ; *Exercise Therapy/methods ; Treatment Outcome ; Cognition ; Mental Status and Dementia Tests ; Cognitive Training ; },
abstract = {BACKGROUND: Cognitive decline in dementia often leads to impaired activities of daily living (ADL), which worsens as the condition progresses. Although a complex rehabilitation program that includes exercise, cognitive tasks, and family guidance improves physical ability in people with dementia and mild cognitive impairment (MCI), the effects on cognitive function and ADL remain unclear. We conducted this study to clarify this point.

METHODS: This retrospective observational study was conducted at the outpatient rehabilitation department of the National Center for Geriatrics and Gerontology, Japan. It analyzed 50 MCI and Alzheimer disease (AD) patients who participated in a holistic physico-cognitive rehabilitation (HPCR) program. The control group consisted of 50 patients matched by age, gender, disease, and Barthel Index (BI) from 963 MCI and AD patients who did not undergo HPCR. Cognitive function was assessed using the Mini-Mental State Examination, and ADL was evaluated with the BI.

RESULTS: Both groups showed a significant decline in MMSE scores after 1 year. However, the intervention group maintained its ADL function, while the control group experienced a significant reduction in BI scores.

CONCLUSION: HPCR, combining exercise therapy and cognitive training, may help maintain ADL in patients with MCI and AD despite cognitive decline. This study suggests that rehabilitation plays a crucial role in sustaining daily functioning in dementia care.},
}

Humans
*Cognitive Dysfunction/rehabilitation/psychology
Male
*Alzheimer Disease/rehabilitation/psychology
Female
Aged
Retrospective Studies
Activities of Daily Living
Aged, 80 and over
Japan
*Exercise Therapy/methods
Treatment Outcome
Cognition
Mental Status and Dementia Tests
Cognitive Training

@article {pmid40598878,
year = {2025},
author = {Morioka, D and Kobayashi, R and Sakamoto, K and Shirata, T and Kobayashi, T and Suzuki, A},
title = {Clinical Characteristics of Older Adults With Late-Onset Suicide Attempts: A Hospital-Based Retrospective Study.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {25},
number = {4},
pages = {e70063},
doi = {10.1111/psyg.70063},
pmid = {40598878},
issn = {1479-8301},
support = {23GB1003//Ministry of Health, Labour and Welfare/ ; },
mesh = {Humans ; Male ; Female ; Retrospective Studies ; Aged ; *Suicide, Attempted/statistics & numerical data/psychology ; *Depressive Disorder, Major/diagnosis/epidemiology/psychology ; Middle Aged ; Aged, 80 and over ; Hospitalization/statistics & numerical data ; *Dementia/diagnosis/epidemiology ; *Lewy Body Disease/diagnosis/epidemiology/psychology ; *Alzheimer Disease/diagnosis/epidemiology ; Age of Onset ; *Mental Disorders/epidemiology/diagnosis ; },
abstract = {BACKGROUND: No previous study has fully described older adults who make a first suicide attempt late in life. We retrospectively reviewed adults ≥ 60 years admitted to a university psychiatric ward after an attempt to (1) detail their demographic and clinical features; (2) compare admission and discharge diagnoses to measure diagnostic shifts-especially from major depressive disorder (MDD) to dementia; and (3) determine whether certain dementia subtypes, notably dementia with Lewy bodies (DLB), are over-represented.

METHODS: Medical charts of patients transported to the emergency department and hospitalised between April 2015 and March 2024 were screened. After excluding cases with psychiatric disorders before the age of 60 years, 63 late-onset attempters were analysed. Diagnoses were reassessed with DSM-5-TR and standard neurodegenerative criteria; discrepancies were resolved by two senior psychiatrists. Mini-Mental State Examination scores, suicide methods and demographics were compared across final diagnoses.

RESULTS: At discharge, psychiatric disorders predominated (65.1%), but dementia was present in 31.7%; DLB was the leading subtype (19.0%), followed by Alzheimer's disease (9.5%). Diagnostic revision was common: 17 patients (27.0%) changed diagnosis during hospitalisation, including 15 who shifted from MDD to dementia; 10 of these reclassifications were to DLB and six met criteria for psychiatric-onset DLB. Mini-Mental State Examination scores did not differ between MDD and DLB, although scores were lower in Alzheimer's disease. Suicide methods-most often drug overdose-showed no relation to diagnosis.

CONCLUSIONS: Almost one-third of older first-time attempters harboured unrecognised dementia, most frequently DLB and over one-quarter of initial MDD diagnoses converted to dementia after full assessment. Brief cognitive screens alone missed these cases. Routine post-attempt care for older adults should therefore include informant history, detailed neuropsychological testing and dementia-specific biomarkers to guide targeted prevention and treatment.},
}

Humans
Male
Female
Retrospective Studies
Aged
*Suicide, Attempted/statistics & numerical data/psychology
*Depressive Disorder, Major/diagnosis/epidemiology/psychology
Middle Aged
Aged, 80 and over
Hospitalization/statistics & numerical data
*Dementia/diagnosis/epidemiology
*Lewy Body Disease/diagnosis/epidemiology/psychology
*Alzheimer Disease/diagnosis/epidemiology
Age of Onset
*Mental Disorders/epidemiology/diagnosis

@article {pmid40598871,
year = {2025},
author = {Bose, C and Hindle, A and Smith, SC and Strickland, J and Zhang, C and Guzman, I and Baker, A and Ponomarev, I and Manczak, M and Shin, AC and Pal, R and Singh, SP and Lawrence, JJ},
title = {Low-dose dietary vorinostat increases brain histone acetylation levels and reduces oxidative stress in an Alzheimer's disease mouse model.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251352107},
doi = {10.1177/13872877251352107},
pmid = {40598871},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) disrupts histone acetylation/deacetylation homeostasis, blocking access of transcription factors to DNA, and compromising learning. Vorinostat (VOR), the only FDA-approved HDAC inhibitor that is orally bioavailable and brain penetrant, confers neuroprotection in AD models. We delivered VOR via diet in an AD mouse model, examining tolerability, accompanied by biochemical analyses.ObjectiveOur objective was to examine dietary delivery of vorinostat for tolerability, including changes to histone acetylation, amyloid-β (Aβ) production, oxidative stress (OS), mitochondrial health, and synaptic integrity.MethodsFood pellets containing control, 0.18 mg/g (low-dose) and 0.36 mg/g (high-dose) VOR were administered to hAβ-KI AD mice for 14 days. Brain acetyl-histone H3 (AH3), total H3 expression, and synaptic markers were measured via Western blot. Aβ, H2O2, antioxidant capacity, lipid peroxidation (via 4-hydroxynonenal (4-HNE)), adenosine triphosphate (ATP), and citrate synthase (CS) activity were measured in brain tissue.ResultsVOR inhibited brain HDAC enzyme activity and increased AH3 and H3 expression at both VOR doses. Aβ and synaptic proteins were not significantly affected; however, OS markers were improved at both doses. Both doses increased CS activity, while ATP was increased only at the low dose. Finally, low-dose VOR was tolerable over 2 months.ConclusionsWe established that low-dose VOR, delivered via diet, is tolerable in AD mice, successfully inhibiting brain HDAC activity while reducing OS and improving mitochondrial health. This study improves existing preclinical experimental designs by enabling noninvasive manipulation of histone acetylation through dietary intervention. This route of administration provides advantages for future preclinical animal studies.},
}

@article {pmid40598860,
year = {2025},
author = {Walczak, K and Kołodziejczyk, W and Pszczołowska, M and Kozłowska, M and Beszłej, JA and Leszek, J},
title = {Klotho protein in Alzheimer's disease: Diet leading to immortality?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251350125},
doi = {10.1177/13872877251350125},
pmid = {40598860},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, leading to progressive cognitive decline and premature death. Despite decades of research, the exact cause of AD remains unknown, and current treatments only slow disease progression without addressing its root cause. Recent studies suggest that endogenous factors such as the Klotho protein may have neuroprotective properties and influence AD progression. This review aims to explore the role of Klotho protein in AD, with a particular focus on its biological functions, expression, and potential therapeutic implications. Additionally, it examines the relationship between Klotho levels and dietary patterns. A literature review was conducted to analyze existing research on Klotho protein, its neuroprotective effects, and its correlation with different dietary factors in the context of AD. Evidence suggests that Klotho protein plays a crucial role in cellular metabolism and neuroprotection. Higher levels of Klotho have been linked to better cognitive function and reduced neurodegeneration. Emerging research also indicates that certain dietary patterns, particularly the Mediterranean diet, may positively influence Klotho expression. Klotho protein represents a promising therapeutic target in AD, potentially slowing disease progression through its neuroprotective effects. Further research is needed to better understand the mechanisms regulating Klotho levels, particularly the impact of diet, and how they can be leveraged for AD prevention and treatment.},
}

@article {pmid40598859,
year = {2025},
author = {Moreira, NCDS and Piassi, LO and Lima, JEBF and Passos, GA and Sakamoto-Hojo, ET},
title = {PTEN inhibition induces neuronal differentiation and neuritogenesis in SH-SY5Y cells via AKT signaling pathway.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251352194},
doi = {10.1177/13872877251352194},
pmid = {40598859},
issn = {1875-8908},
abstract = {BackgroundPTEN is a key regulator of neuronal differentiation and neurogenesis. Its role in modulating the PI3K/AKT pathway and oxidative stress responses in neuronal models remains an area of active investigation.ObjectiveThis study aimed to assess the effects of PTEN knockdown on neuronal differentiation, neuritic growth, and PI3K/AKT pathway activation in SH-SY5Y cells.MethodsSH-SY5Y cells were treated with PTEN siRNA to induce PTEN knockdown. The level of PTEN inhibition was confirmed, and assays were performed to evaluate neurogenesis and neuritogenesis at 3- and 7-days post-treatment. Protein expression analysis of key components in the AKT/GSK3-β/Tau pathway was conducted to assess their role in neurogenesis. Additionally, the PI3K inhibitor LY294002 was used to examine its impact on PTEN knockdown-induced neuronal differentiation.ResultsPTEN knockdown significantly increased neurite lengths and reduced cytoplasmic size, indicating neuronal differentiation. Protein analysis showed that PTEN inhibition modulated the expression of components in the AKT/GSK3-β/Tau pathway. The PI3K inhibitor LY294002 prevented neuronal differentiation, confirming the involvement of the PI3K/AKT pathway in mediating the effects of PTEN knockdown.ConclusionsOur findings demonstrate that PTEN plays a crucial role in regulating neuronal differentiation in SH-SY5Y cells. The PI3K/AKT pathway mediates the effects of PTEN knockdown, suggesting PTEN as a potential therapeutic target for neurodegenerative diseases where its dysregulation may contribute to disease progression.},
}

@article {pmid40598858,
year = {2025},
author = {Zeng, Y and Zhao, X and Sang, S and Yu, S and Zhong, C},
title = {Glucose-lipid metabolic index reflects cognitive impairment of non-diabetic elderly individuals.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251352548},
doi = {10.1177/13872877251352548},
pmid = {40598858},
issn = {1875-8908},
abstract = {BackgroundGlucose and lipid metabolic disorders are involved in the impairment of cognitive function. However, it remains unclear the link between a new indicator of glucose-lipid metabolism index (GLMI) and cognitive impairment.ObjectiveThis study investigates the relationship between GLMI and multidimensional cognitive function in adults aged ≥ 60 years.MethodsGLMI was derived from glucose and lipid metabolism parameters. Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning test, Animal Fluency Test (AFT) and Digit Symbol Substitution Test (DSST) were used to evaluate the cognitive abilities of participants. Linear regression, subgroup analyses, multivariable adjustments, and restricted cubic spline (RCS) models were employed to evaluate GLMI-cognition associations.ResultsAmong 787 participants from NHANES 2011-2014, diabetic individuals exhibited higher GLMI levels and more severe cognitive impairment than non-diabetic counterparts. In non-diabetic adults, GLMI showed linear correlations with CERAD and DSST assessed cognitive deficits. Subgroup analyses confirmed high GLMI as an independent risk factor for cognitive dysfunction in CERAD and DSST assessment. Multivariable regression revealed increased GLMI significantly elevated cognitive decline risk. ROC analysis identified 581.41 as the optimal GLMI cutoff (specificity: 86.0%) for predicting DSST impairment, outperforming traditional indices (TyG/HOMA-IR). RCS models demonstrated nonlinear GLMI-cognition associations, with a dose-dependent risk curve (200-800 range) and critical threshold at 545.ConclusionsThis study establishes that a high score of GLMI is associated with great severity of cognitive impairment in non-diabetic population.},
}

@article {pmid40598857,
year = {2025},
author = {Liu, SK and Cao, H and Yang, X and Zhou, X and Chen, Y and Fu, WY and Chan, SY and Ip, FC and Mok, KY and Mok, VC and Kwok, TC and Hardy, J and Fu, AK and Ip, NY},
title = {An ABCA1 missense variant decreases cholesterol efflux and confers Alzheimer's disease risk in the Chinese population.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251350722},
doi = {10.1177/13872877251350722},
pmid = {40598857},
issn = {1875-8908},
abstract = {BackgroundGenetic studies have revealed that single-nucleotide polymorphisms (SNPs) of ABCA1 are associated with Alzheimer's disease (AD) risk. However, their AD-related effects in non-European populations are not well studied. Moreover, the functional implications of these AD-associated SNPs remain unclear.ObjectiveWe examined the AD associations of ABCA1 SNPs in the Chinese population and investigated the underlying mechanisms whereby these SNPs modulate AD risk.MethodsWe conducted a genetic analysis in a Hong Kong Chinese AD cohort (n = 332 patients with AD, n = 316 normal controls). Specifically, we analyzed 6 independent ABCA1 SNPs reported to be associated with AD risk in populations of European descent. To investigate the effects of these SNPs on ABCA1 protein function and brain molecular phenotypes, we analyzed cholesterol efflux in human glioblastoma cells as well as the associations between the AD risk SNPs and brain transcriptomic profiles, respectively.ResultsThe ABCA1 coding SNP, rs2230806 (p.R219 K), was significantly associated with AD in the Chinese population, specifically in females (odds ratio [95% confidence interval] = 1.65 [1.16-2.33]). Notably, human glioblastoma cells expressing the ABCA1 R219 K showed a 17% cholesterol efflux reduction (p < 0.001). Moreover, ABCA1 rs2230806 was associated with changes in the expression of oligodendrocyte genes involved in myelination in the brain in females.ConclusionsWe identified a significant AD risk ABCA1 coding variant in the Chinese population and demonstrated its effects on cholesterol efflux and brain molecular phenotypes. These results shed light on the genetic basis whereby an ABCA1 genetic variant contributes to AD pathogenesis.},
}

@article {pmid40598757,
year = {2025},
author = {Wan, J and Luo, Y and Derreumaux, P and Wei, G and Li, H},
title = {pH-Dependent β-Strand Alignment of the Alzheimer's Amyloid-β (16-22) Peptide.},
journal = {Proteins},
volume = {},
number = {},
pages = {},
doi = {10.1002/prot.70012},
pmid = {40598757},
issn = {1097-0134},
abstract = {The extracellular amyloid plaques of amyloid-β (Aβ) peptides formed in the human brain are an important pathological hallmark of Alzheimer's disease. There is evidence that pH affects the morphologies of fibrils and the kinetics of amyloid fibril formation. However, the underlying molecular mechanism is not well understood. In this study, as a first step to understand pH-modulated Aβ fibril formation, we investigated the conformations of Aβ (16-22) octamers by performing extensive all-atom replica exchange molecular dynamics simulations at both neutral and acidic pH. Our simulations showed that the residues Phe20 and Ala21 in the C terminal have higher β-sheet probability (78.8%, 55.8%) at acidic pH than (62.3%, 43.6%) at neutral pH. Out-of-register antiparallel β-strand alignments of the Aβ (16-22) peptide are predominantly in the 1-, 2-, and 3-residue shifts at both pH conditions, which agrees well with solid-state NMR results on Aβ peptides. We also found that there are multiple in-register and out-of-register parallel β-strand alignments under both pH conditions. However, the pH conditions affect the probability of β-strand alignments for the Aβ (16-22) peptide, and the residue-residue interaction of bilayer β-sheet and β-barrel are different at different pH conditions. Our analysis showed that the electrostatic interactions among peptides are much stronger at neutral pH than at acidic pH, while the vdW interactions are slightly stronger at acidic pH than at neutral pH. These results provide atomistic insight into the early stage of aggregation of amyloid-β (Aβ) peptides at acidic and neutral pH conditions.},
}

@article {pmid40598720,
year = {2025},
author = {Kurkute, P and Sonawane, S and Pratyush, K and Dravyakar, B and Ansari, A and Bawane, P and Agrawal, YO and Khairnar, M and Mohd Siddique, MU},
title = {A Multiscale Computational Study for the Identification of Novel Inhibitors Targeting Tau-Tubulin Kinase 1 (TTBK1) in Alzheimer's Disease.},
journal = {Current computer-aided drug design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734099366145250526081959},
pmid = {40598720},
issn = {1875-6697},
abstract = {INTRODUCTION: Excessive phosphorylation of tau protein by the tau-tubulin kinase 1 (TTBK1) enzyme is implicated in the pathogenesis of several neurodegenerative diseases. Based on a comprehensive literature review and availability of the co-crystal structure of TTBK1 in complex inhibitor (pdb id 4BTK), we designed a multiscale computational approach to identify novel hits from the ZINC13 chemical library.

METHODS: The High-Throughput Virtual Screening (HTVS) of the ZINC13 database (containing 13,195,609 molecules) was carried out against TTBK1 protein (PDB id 4BTK). Top-scoring molecules and reference molecules were further subjected to MD simulations, PCA analysis, DCCM assay, binding free energies calculations, and in-silico ADME calculations.

RESULTS: From a preliminary HTVS study, six molecules were identified based on their docking scores: ZINC37289024, ZINC89755080, ZINC20993115, ZINC72445968, ZINC28247630, and ZINC16638515, with the docking score of -10.186, -09.229, -09.045, -09.021, -08.920 and -08.821, respectively. In subsequent MD simulations studies, the protein backbone RMSD values were observed to be 1.978, 1.8178, 2.2309, 1.7933, 1.8837, 1.9461, and 1.8711 Å, respectively. Similarly, the protein backbone RMSF values were 0.9511, 1.0172, 1.2023, 1.0591, 1.0029, 1.9755, and 0.9200 Å, respectively. PCA, DCCM, and MMGBSA analysis indicated that these complexes were quite stable throughout the 100 ns MD simulations. In-silico ADME predictions of identified top six hits suggested that these top six hits possess favorable drug-like properties, supporting their potential as the lead candidates for therapeutic development.

CONCLUSION: A multiscale molecular modelling approach was employed, and six top-scoring hits were identified as promising TTBK1 inhibitors. Analysis of the in-silico data suggested that ZINC37289024 would be the most promising clinical candidate for AD. However, further in-vitro and in-vivo experimental data would be needed for validation of these results.},
}

@article {pmid40598718,
year = {2025},
author = {Strijkert, F and Huitema, RB and van Munster, BC and Spikman, JM},
title = {Profile of impairments in social and non-social cognition in vascular dementia compared to Alzheimer's disease and behavioral variant frontotemporal dementia.},
journal = {Journal of the International Neuropsychological Society : JINS},
volume = {},
number = {},
pages = {1-7},
doi = {10.1017/S1355617725101045},
pmid = {40598718},
issn = {1469-7661},
abstract = {OBJECTIVE: Impairments in emotion recognition, a crucial component of social cognition, have been previously demonstrated in patients with behavioral variant frontotemporal dementia (bv-FTD) and Alzheimer's disease (AD). However, to date, it is unclear whether patients with early-stage vascular dementia (VaD) display deficient emotion recognition. We investigated profiles of impairments in emotion recognition and non-social cognitive functions, comparing VaD patients to bv-FTD and AD patients, and healthy control participants (HC).

METHOD: Eighty-one memory clinic patients with early-stage VaD (n = 30), bv-FTD (n = 21) and AD (n = 30), and 40 HCs were included and performed Ekman 60 Faces Test (EFT; emotion recognition), Auditory Verbal Learning Test (AVLT; memory - encoding and retrieval) and Trailmaking Test (TMT A, TMT B, TMT B/A; information processing speed, executive functions). Differences between groups were analyzed with analysis of variance (ANOVA), using age, education and sex adjusted norm Z scores.

RESULTS: All patient groups performed significantly worse than HCs on EFT (p < .001). Mean performance of VaD patients was in between bv-FTD and AD (only bv-FTD < AD, p < .01). All patient groups were also impaired on AVLT encoding, TMT-B and TMT B/A. Social and non-social neurocognitive functions differed between groups, with specific impairments in processing speed in VaD, emotion recognition in bv-FTD and memory retrieval in AD, and memory encoding and cognitive control impaired in all three groups.

CONCLUSIONS: We found significantly different profiles in VaD, bv-FTD and AD. Assessing emotion recognition has additive value in the distinction between patient groups, allowing for more timely and accurate diagnosis in clinical practice.},
}

@article {pmid40598606,
year = {2025},
author = {Conley, AC and Key, AP and Blackford, JU and Russell, JK and Albert, KM and Gong, X and Bubser, M and Rook, JM and Conn, PJ and Lindsley, CW and Jones, CK and Newhouse, PA},
title = {Safety, tolerability, pharmacokinetic and pharmacodynamic effects of the muscarinic M1 positive allosteric modulator VU0467319 for Alzheimer's disease: a single ascending-dose study in healthy participants.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {144},
pmid = {40598606},
issn = {1758-9193},
support = {PCTR-16-383171/ALZ/Alzheimer's Association/United States ; 21040501.03//Alzheimer's Drug Discovery Foundation/ ; },
mesh = {Humans ; Male ; Adult ; Female ; Middle Aged ; Young Adult ; *Receptor, Muscarinic M1/metabolism ; Adolescent ; Dose-Response Relationship, Drug ; *Alzheimer Disease/drug therapy ; Healthy Volunteers ; Evoked Potentials/drug effects ; Allosteric Regulation/drug effects ; Double-Blind Method ; Brain/drug effects ; Cognition/drug effects ; Electroencephalography ; Neuropsychological Tests ; *Nootropic Agents/pharmacokinetics/adverse effects/pharmacology ; },
abstract = {The development of cholinergic neurotransmitter based cognitive enhancers for Alzheimer's disease and other neuropsychiatric disorders have focused recently on allosteric modulation of specific muscarinic acetylcholine receptor (mAChR) subtypes to reduce dose-limiting side-effects that have been the hallmark of earlier orthosteric mAChR agonists. VU0467319 (VU319) is an investigational positive allosteric modulator of the M1 mAChR. A Phase 1 first-in-human study was conducted assessing safety and brain activity utilizing cognitive tasks and event-related potentials (ERPs) in single-ascending dose and food effect studies. VU319 was given orally to 52 healthy volunteers aged 18-55 years. The single ascending dose study tested 40 participants in five dose escalating cohorts (60, 120, 240, 400, 600 mg; 6 VU319/2 placebo per dose). The food effect study involved 12 participants, 10 VU319 (120 mg)/2 placebo. Exploratory cognitive and electrophysiological tasks were examined pre-dosing and at 5 h post-dose. Tolerability was good with no observed dose limiting side effects throughout the full dose range tested. In the single ascending dose study, there were 47 TEAEs reported across the 5 cohorts, 14 in the placebo group and 33 across the 5 active dose cohorts. In the food effect study, there were 20 TEAEs reported, 6 in the placebo group and 14 in the fed and fasted conditions. Drug exposure increased with dose in a less than dose-proportional manner with a half-life ranging from 30 to 55 h. Peak concentration was observed between 5 and 9.5 h across the dosage groups. Absorption was increased with food. Exploratory cognitive/ERP testing showed evidence for drug-induced CNS activity on higher doses of VU319 compared to placebo. Single dose VU319 across five ascending cohorts appeared to have a favorable safety profile and a PK profile consistent with once daily dosing. Target engagement results suggest stimulation of the cholinergic system functioning in healthy adults following a single dose of VU319. These results provide a strong foundation for further studies of positive allosteric modulators of muscarinic M1 receptors for potential cognitive or behavioral benefits.},
}

Humans
Male
Adult
Female
Middle Aged
Young Adult
*Receptor, Muscarinic M1/metabolism
Adolescent
Dose-Response Relationship, Drug
*Alzheimer Disease/drug therapy
Healthy Volunteers
Evoked Potentials/drug effects
Allosteric Regulation/drug effects
Double-Blind Method
Brain/drug effects
Cognition/drug effects
Electroencephalography
Neuropsychological Tests
*Nootropic Agents/pharmacokinetics/adverse effects/pharmacology

@article {pmid40598577,
year = {2025},
author = {Wang, Y and Wang, Z and Li, Y and Cao, M and Zhang, S and Ding, S and Chen, S and Jin, Y and Zhang, Y and Gao, J and Xiao, M},
title = {Arhgef7 as a key target for enriched environment rescuing spatial cognitive deficits and anxiety-like behaviors in a mouse model of Alzheimer's disease following early social isolation.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {143},
pmid = {40598577},
issn = {1758-9193},
support = {82304466//National Natural Science Foundation of China/ ; 82204365//National Natural Science Foundation of China,China/ ; BK20241869//Natural Science Foundation of Jiangsu Province/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/psychology/pathology/genetics/complications ; *Social Isolation/psychology ; Mice, Transgenic ; Disease Models, Animal ; Mice ; *Anxiety/metabolism/psychology ; *Cognitive Dysfunction/metabolism ; *Rho Guanine Nucleotide Exchange Factors/metabolism/genetics ; Prefrontal Cortex/metabolism/pathology ; Male ; *Environment ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Both social and physical environmental factors influence the progression of Alzheimer's disease (AD), but the underlying mechanisms are not yet fully understood. This study aims to investigate how an enriched environment (EE) alleviates the detrimental effects of early social isolation (SI) on AD-like pathophysiology.

METHODS: Four-week-old 5×FAD transgenic mice were randomly divided into group-housed and isolated groups. After 3 weeks, the mice were further raised in either a physical EE or a standard environment for an additional 3 weeks. Subsequently, these experimental subjects underwent a two-week of behavioral tests while maintaining their original housing conditions unchanged, followed by neuropathological analyses. A series of experiments were conducted on the medial prefrontal cortex (mPFC), including transcriptome sequencing, cellular localization, and knockdown and overexpression of a candidate gene, to identify the key molecules through which physical EE alleviates SI-induced AD-like alterations. The protective effects of the identified gene on cultured forebrain neurons exposed to β-amyloid stimulation, as well as its associated signaling pathways, were also investigated.

RESULTS: EE enhanced cognitive function and alleviated anxiety-like behavior in SI-5×FAD mice, partially reversing dendritic and synaptic loss and glial cell activation in the mPFC. However, it did not mitigate deficits in social and cooperative behaviors, hypomyelination, or β-amyloid deposition. Notably, group-housed 5×FAD mice raised in the EE exhibited alleviation of the aforementioned AD-like phenotypes. Transcriptomic and bioinformatic analyses pinpointed Rho guanine nucleotide exchange factor 7 (Arhgef7) as a pivotal mediator of the beneficial effects of physical EE. Arhgef7 overexpression in mPFC neurons enhanced dendritic and synaptic growth and alleviated spatial cognitive impairments and anxiety-like behavior in SI-5×FAD mice, but it did not correct hypomyelination or social behavior deficits. Consistently, knockdown of Arhgef7 in mPFC neurons of group-housed 5×FAD mice selectively impaired neuronal processes and spatial cognition, and increased anxiety-like behavior. Mechanistically, Arhgef7 protected cortical neurons from β-amyloid toxicity by activating the Wnt signaling pathway.

CONCLUSION: Arhgef7 in mPFC neurons is essential for the physical components of EE selectively alleviating spatial cognitive deficits and anxiety-like behaviors in early isolated AD model mice, serving as a potential target for the prevention and treatment of AD.},
}

Animals
*Alzheimer Disease/metabolism/psychology/pathology/genetics/complications
*Social Isolation/psychology
Mice, Transgenic
Disease Models, Animal
Mice
*Anxiety/metabolism/psychology
*Cognitive Dysfunction/metabolism
*Rho Guanine Nucleotide Exchange Factors/metabolism/genetics
Prefrontal Cortex/metabolism/pathology
Male
*Environment
Mice, Inbred C57BL

@article {pmid40598304,
year = {2025},
author = {Bregendahl, M and Kaya, ZB and Singer, W and McLean, PJ},
title = {Alpha-synuclein seeding amplification assays in Lewy body dementia: a brief review.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {77},
pmid = {40598304},
issn = {1750-1326},
mesh = {Humans ; *Lewy Body Disease/diagnosis/metabolism ; *alpha-Synuclein/metabolism/analysis ; Brain/metabolism/pathology ; },
abstract = {Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterized by cognitive decline, sleep disturbances, motor dysfunction, and other debilitating clinical symptoms. Neuropathologically, LBD is characterized by the progressive accumulation of alpha-synuclein (aSYN) in vulnerable cellular populations in the brain. Diagnosing LBD is challenging due to the overlap of clinical symptoms with Alzheimer's disease (AD) and other neurodegenerative disorders with current diagnostic tools, including clinical examinations by specialized neurologists and brain imaging, limited by accessibility. Taken together, LBD is often misdiagnosed, especially at early disease stages. Seed amplification assays to detect pathogenic aSYN (aSYN SAAs) are emerging as promising tools to detect aSYN pathology in biological specimens. These assays amplify trace amounts of misfolded aSYN, enabling their potential detection in brain, CSF, saliva, skin, and blood. This review compares the sensitivity and specificity of aSYN SAAs across different biological samples and explores the potential of the assay as a diagnostic in LBD. We also highlight challenges that will need to be addressed going forward if the aSYN SAA is to be widely adopted as a diagnostic test. Despite current limitations, aSYN SAAs hold promise for early and precise diagnosis, paving the way for targeted treatments that could significantly improve patient care and outcomes.},
}

Humans
*Lewy Body Disease/diagnosis/metabolism
*alpha-Synuclein/metabolism/analysis
Brain/metabolism/pathology

@article {pmid40598239,
year = {2025},
author = {Erskine, D and Taylor, JP},
title = {Current strategies in the management of dementia with lewy bodies and future directions based on disease pathophysiology.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {78},
pmid = {40598239},
issn = {1750-1326},
support = {ARUK-SRF2022A-006//Alzheimer's Research UK/ ; },
abstract = {Dementia with Lewy bodies (DLB) is thought to be the second most common form of dementia after Alzheimer’s disease, and is characterised by a combination of cognitive, neuropsychiatric and motor symptoms. The present review seeks to discuss current strategies for the management of DLB, and future directions for novel disease-modifying therapies. Current best practice for the clinical management of DLB is based upon therapies that target specific symptom domains due to the lack of disease-modifying therapies. Cholinesterase inhibitors are the frontline treatment for treating cognitive decline in DLB, whereas the treatment of motor symptoms remains challenging due to poor response to dopaminergic therapies and the potential for exacerbation of neuropsychiatric features. There is emerging evidence suggesting a range of further pharmacological and non-pharmacological therapies may be effective in treating specific symptom domains of DLB, but further evidence is warranted to demonstrate their efficacy. A key challenge in the treatment of DLB is incomplete understanding of disease pathophysiology, which has limited attempts to develop disease-modifying therapies. In the present article, we discuss the multi-faceted nature of DLB neuropathology, from Lewy body pathology to mitochondrial dysfunction, and discuss therapies in development that target particular aspects of DLB neuropathology. In particular, we highlight antibody-based therapies to attenuate protein aggregation, compounds that enhance the generation of cellular energy and autophagy-enhancing agents as particular areas of promise. Furthermore, we discuss how optimal strategies for disease modification will be centred on agents that treat DLB neuropathology more holistically, and will be underpinned by a more complete understanding of the pathogenic events that underlie the full spectrum of pathological changes observed in the DLB brain.},
}

@article {pmid40598011,
year = {2025},
author = {Zhao, W and Robbins, CB and Grewal, DS and Patel, H and Soundararajan, S and Liu, AJ and Johnson, KG and Agrawal, R and Petrella, JR and Stinnett, SS and Parker, D and Fekrat, S},
title = {Correlating retinal and choroidal vascular parameters with volumetric MRI in Alzheimer's disease and amnestic mild cognitive impairment.},
journal = {BMC ophthalmology},
volume = {25},
number = {1},
pages = {365},
pmid = {40598011},
issn = {1471-2415},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; Male ; Female ; *Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology ; Aged ; Tomography, Optical Coherence/methods ; *Choroid/blood supply/diagnostic imaging ; *Retinal Vessels/pathology/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Middle Aged ; Aged, 80 and over ; Fluorescein Angiography/methods ; *Amnesia ; },
abstract = {BACKGROUND: We assess the relationships between retinal and choroidal structural and microvascular parameters and brain volumetric magnetic resonance imaging (MRI) parameters in individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD).

METHODS: Participants underwent optical coherence tomography (OCT) and OCT angiography (OCTA) imaging using the Zeiss Cirrus HD-5000 AngioPlex (Carl Zeiss Meditec, Dublin, CA) and volumetric brain MRI imaging with NeuroQuant (CorTechs Labs, San Diego, CA) analysis. Retinal and choroidal structural and microvascular parameters were extracted from OCT and OCTA scans. Superficial capillary plexus perfusion density and vessel density in the 3 × 3 mm and 6 × 6 mm circles and rings centered on the fovea were determined. Hippocampal, superior lateral ventricle (SLV), and inferior lateral ventricle (ILV) volumes were determined. Correlations between OCT, OCTA, and volumetric MRI parameters in patients with aMCI and AD were explored using Spearman partial correlation analysis.

RESULTS: 68 eyes of 37 aMCI participants and 64 eyes of 33 AD participants were analyzed. In the eyes with aMCI, hippocampal volume negatively correlated with FAZ area and positively correlated with perfusion density and vessel density in the 3 mm OCTA scan. In the aMCI cohort, SLV and ILV volume inversely correlated with perfusion density in the 3 mm and 6 mm OCTA scans, respectively. In the eyes with AD, SLV and ILV volume inversely correlated with perfusion density and vessel density in the 3 mm and 6 mm OCTA scans. Central subfield thickness, ganglion cell-inner plexiform layer thickness, RNFL thickness, and choroidal vascularity index did not significantly correlate with SLV, ILV, or hippocampal volume in any cohorts (p > 0.05).

CONCLUSIONS: Decline in retinal microvascular parameters significantly correlated with hippocampal volume loss and ventricular expansion, suggesting that these parameters may mirror cerebral neurodegeneration in individuals with aMCI and AD.

TRIAL REGISTRATION: Clinical trial identifier: NCT03233646, registration date: July 20, 2017.},
}

Humans
*Cognitive Dysfunction/diagnosis/diagnostic imaging
Male
Female
*Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology
Aged
Tomography, Optical Coherence/methods
*Choroid/blood supply/diagnostic imaging
*Retinal Vessels/pathology/diagnostic imaging
*Magnetic Resonance Imaging/methods
Middle Aged
Aged, 80 and over
Fluorescein Angiography/methods
*Amnesia

@article {pmid40597958,
year = {2025},
author = {Vacher, M and Lee, S and Price, P and Ha, P and Waters, S and Laws, SM},
title = {Relationship between cytomegalovirus antibody levels and cognitive performance is dependent on age and genetic risk.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {270},
pmid = {40597958},
issn = {1471-2377},
mesh = {Humans ; Female ; Aged ; Male ; *Cytomegalovirus/immunology ; Middle Aged ; Aged, 80 and over ; *Antibodies, Viral/blood ; *Cytomegalovirus Infections/genetics/immunology ; *Aging/genetics ; *Tumor Necrosis Factor-alpha/genetics ; *Cognition/physiology ; Apolipoprotein E4/genetics ; *Genetic Predisposition to Disease ; Australia ; Amyloid beta-Peptides/metabolism ; Age Factors ; Genotype ; },
abstract = {Human cytomegalovirus (CMV) is endemic worldwide. It is often acquired in childhood and persists throughout adult life. CMV is linked with several diseases of aging, but associations with cognitive performance are not consistent. Here we address whether this may reflect a dependence on putative genetic determinants, Apolipoprotein E (APOE) ε4 and Tumour Necrosis Factor (TNF), and/or the age of the subjects tested. CMV-reactive antibodies were quantitated in 419 individuals aged 71.7 [53.2-89.1] years, drawn from the Australian Imaging, Biomarker & Lifestyle (AIBL) study. Cognitive composite scores, covering five domains, a global score of cognitive performance, brain amyloid-β (Aβ) burden and demographic data were available. APOE and TNF-308 (rs1800629) genotypes were extracted from genome-wide array data. Bivariate and multivariate analyses were applied. CMV antibody levels were negatively correlated with Aβ burden and correlated directly with cognition in participants carrying the minor allele of TNF-308, notably in those lacking the APOE ε4 allele. Cognitive performance exhibited a decrease with age, but CMV antibody levels were maintained. Regression analyses revealed significant interactions between TNF-308 genotype and CMV antibody levels in the overall cohort and in participants younger than 71.1 years (median split). No such interaction was observed in those older than 71.1 years. Overall, CMV antibodies may play a protective role in carriers of the minor allele of TNF-308. This was significant in younger individuals and could be eclipsed by advanced age or carriage of the APOE ε4. The interactions described may explain disagreements in the literature regarding the effects of CMV and TNF-308.},
}

Humans
Female
Aged
Male
*Cytomegalovirus/immunology
Middle Aged
Aged, 80 and over
*Antibodies, Viral/blood
*Cytomegalovirus Infections/genetics/immunology
*Aging/genetics
*Tumor Necrosis Factor-alpha/genetics
*Cognition/physiology
Apolipoprotein E4/genetics
*Genetic Predisposition to Disease
Australia
Amyloid beta-Peptides/metabolism
Age Factors
Genotype

@article {pmid40597607,
year = {2025},
author = {Paul, S and Pramanick, R and Das, N and Baczynska, E and Bedrood, Z and Chakraborti, T and Basu, S and Wlodarczyk, J},
title = {2dSpAn-Auto: an automated tool for analysis of two-dimensional dendritic spine images.},
journal = {BMC bioinformatics},
volume = {26},
number = {1},
pages = {162},
pmid = {40597607},
issn = {1471-2105},
support = {SUR/2022/00290//Science and Engineering Research Board/ ; },
mesh = {*Dendritic Spines ; *Software ; *Image Processing, Computer-Assisted/methods ; Animals ; Humans ; Algorithms ; },
abstract = {BACKGROUND: Quantitative analysis of dendritic spine morphology and density is crucial for understanding synaptic plasticity and its role in neuropsychiatric disorders, including Alzheimer's disease and schizophrenia. While both 3D and 2D approaches exist for spine analysis, 2D methods offer advantages in computational efficiency, rapid assessment, and more reasonable to use in case of limited z-resolution images acquired through confocal and previous generation super-resolution microscopy. In this work, we developed a modality-agnostic spine segmentation approach based on 2D skeletonization. Specifically, we implemented two analytical workflows, viz., 2dSpAn-Auto.b, that implements binary skeletonization alogrithm and 2dSpAn-Auto.f, that generates fuzzy skeletons directly from gray-scale images. Our developed method enables fast and automatic segmentation and morphological analysis of 2D maximum intensity projection images of dendritic spines. Expert users can fine-tune parameters when needed, though default settings prove robust across various imaging conditions. The developed 2dSpAn-Auto software tool is most suitable for automated batch processing while maintaining user flexibility through an intuitive graphical interface.

RESULTS: 2dSpAn-Auto is validated across multiple imaging modalities (in vitro, ex vivo, and in vivo) for automatic assessment of dendritic spine parameters including spine density, morphometry (spine area, spine length, head width, minimum and average neck width), and total dendrite length. Validation studies demonstrate high accuracy and reproducibility across varying imaging protocols and experimental conditions. Multiple images from similar experimental setups can be processed seamlessly in the batch mode.

CONCLUSIONS: 2dSpAn-Auto provides a robust, interpretable solution for fast analysis of dendritic spines, a critical need in neurological research and clinical assessment. The combination of automated processing with optional expert oversight makes it suitable for both routine analysis and specialized research applications. The software, complete with the source code and comprehensive documentation, is available to the research community for non-commercial use under GNU General Public License (GPL) v3.},
}

*Dendritic Spines
*Software
*Image Processing, Computer-Assisted/methods
Animals
Humans
Algorithms

@article {pmid40597402,
year = {2025},
author = {Li, J and Yu, K and Bu, F and Li, P and Hao, L},
title = {Exploring the impact of coffee consumption and caffeine intake on cognitive performance in older adults: a comprehensive analysis using NHANES data and gene correlation analysis.},
journal = {Nutrition journal},
volume = {24},
number = {1},
pages = {102},
pmid = {40597402},
issn = {1475-2891},
support = {201303069, 202201220//Inner Mongolia Health Commission scientific research project/ ; 2023LHMS08057//Inner Mongolia Natural Science Foundation project/ ; YCPY 2025049//Inner Mongolia Medical University Ying Cai Support Program/ ; 101322025026//Inner Mongolia Medical University Maker Incubation Program/ ; mnzl202022//the Bethune Urological Oncology Special Grant from the Beijing Bethune Charity Foundation/ ; NJZY22629//Inner Mongolia Higher Education Science and Technology Research Project/ ; YKD2024LH012//Inner Mongolia Medical University Scientific Research Project/ ; YDZJ202301ZYTS100//the Natural Science Foundation Project of Jilin Province/ ; 20200201315JC//Jilin Scientific and Technological Development Program/ ; 20210101272JC//the Science Foundation of Jilin Province/ ; J2023JKJ017//Jilin Province Tianhua Health Foundation/ ; },
mesh = {Humans ; *Caffeine/administration & dosage/pharmacology ; *Coffee ; Aged ; Male ; *Cognition/drug effects ; Female ; Nutrition Surveys ; Middle Aged ; Alkaline Phosphatase/blood ; Mendelian Randomization Analysis ; Aged, 80 and over ; },
abstract = {PURPOSE: To investigate the effects of coffee consumption and caffeine intake on cognitive performance in older adults, with a particular focus on the potential mediating role of alkaline phosphatase(ALP).

METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014, involving 2,254 participants aged 60 and older. Cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test, Animal Fluency test, and Digit Symbol Substitution Test (DSST). To establish causal relationships between coffee consumption, caffeine intake, ALP levels, and cognitive performance, we employed methodologies such as Mendelian randomization, protein quantitative trait locus analysis, and protein-protein interaction networks.

RESULTS: The NHANES study revealed significant findings regarding coffee consumption and cognitive performance. Compared to non-coffee consumers, individuals consuming ≥ 480 g/day of coffee had a significantly lower odds of low CERAD scores, with an adjusted OR of 0.58 (95% CI: 0.41-0.82) in the fully adjusted Model 4. Similarly, those consuming caffeinated coffee 477.9 g/day) had an OR of 0.56 (95% CI: 0.34-0.92). A comparison of the lowest quartile of ALP intake with the highest quartile showed an OR of 1.82 (95% CI: 1.16-2.85), indicating a negative correlation with cognitive performance. Mendelian Randomization (MR) studies suggested that increased coffee intake is associated with cognitive impairment progression, while coffee consumption may protect against Lewy body dementia (OR = 0.2365, 95% CI: 0.0582-0.9610). Additionally, coffee/caffeine intake affected serum ALP (OR = 0.86, 95% CI: 0.79-0.93) and cognitive ability (OR = 0.95, 95% CI: 0.92-0.98), both indicating protective effects. Finally, the IGFLR1 gene exhibited a moderate colocalization with ALP, suggesting potential therapeutic significance.

CONCLUSIONS: This study provides evidence of a positive correlation between coffee consumption, caffeine intake, and cognitive performance in older adults, with ALP potentially contributing to this relationship. These findings underscore the importance of considering dietary factors in cognitive health management for aging populations, highlighting the need for further research to clarify the specific mechanisms involved.

CLINICAL TRIAL NUMBER: Not applicable.},
}

Humans
*Caffeine/administration & dosage/pharmacology
*Coffee
Aged
Male
*Cognition/drug effects
Female
Nutrition Surveys
Middle Aged
Alkaline Phosphatase/blood
Mendelian Randomization Analysis
Aged, 80 and over

@article {pmid40597399,
year = {2025},
author = {Azargoonjahromi, A and Nasiri, H and , },
title = {CSF Amyloid-β42 associates with neuropsychiatric and cognitive outcomes via cerebral glucose metabolism.},
journal = {Molecular brain},
volume = {18},
number = {1},
pages = {55},
pmid = {40597399},
issn = {1756-6606},
mesh = {*Amyloid beta-Peptides/cerebrospinal fluid ; Humans ; *Glucose/metabolism ; Male ; *Peptide Fragments/cerebrospinal fluid ; Female ; *Cognition ; Cognitive Dysfunction/cerebrospinal fluid/metabolism ; Aged ; Positron-Emission Tomography ; Alzheimer Disease/metabolism/cerebrospinal fluid ; *Brain/metabolism ; Middle Aged ; },
abstract = {Amyloid-β42 (Aβ42) regulates synaptic plasticity and memory formation at physiological levels in the brain, but in Alzheimer's disease (AD), it can disrupt brain function and glucose metabolism. This disruption contributes to cognitive decline and neuropsychiatric symptoms, highlighting the need to better understand its complex effects. This study investigated the associations among cerebrospinal fluid (CSF) Aβ42 levels, cerebral glucose metabolism (assessed via FDG-PET), neuropsychiatric symptoms (evaluated using the NPI), and cognitive performance (measured by ADAS-Cog13 and MoCA) in individuals with AD, mild cognitive impairment (MCI), and cognitively normal (CN) participants. After adjusting for age, gender, education, and ApoE ɛ4 status, a significant positive relationship between CSF Aβ42 levels and cerebral glucose metabolism was observed in the MCI and AD groups, but not in the CN group. In the MCI group, higher cerebral glucose metabolism was associated with reductions in both neuropsychiatric and depressive symptoms, suggesting that higher glucose metabolism reflect higher activation state of investigated brain regions. In contrast, in the CN group, elevated CSF Aβ42 levels were directly linked to increased depressive symptoms, indicating that higher CSF Aβ42 may contribute to depression even in the absence of cognitive decline. Further analysis revealed that CSF Aβ42 levels were indirectly associated with reduced neuropsychiatric and depressive symptoms through enhanced cerebral glucose metabolism as mediator solely in the MCI group. Regarding cognitive performance, cerebral glucose metabolism showed a strong relationship with cognition in both the MCI and AD groups. Furthermore, higher CSF Aβ42 levels were positively associated with better cognitive performance in the MCI and AD groups, with cerebral glucose metabolism potentially mediating this relationship, while no effect was seen in the CN group. In short, CSF Aβ42 positively influenced cerebral glucose metabolism, which was linked to reduced neuropsychiatric and depressive symptoms as well as improved cognitive performance in MCI and AD groups.},
}

*Amyloid beta-Peptides/cerebrospinal fluid
Humans
*Glucose/metabolism
Male
*Peptide Fragments/cerebrospinal fluid
Female
*Cognition
Cognitive Dysfunction/cerebrospinal fluid/metabolism
Aged
Positron-Emission Tomography
Alzheimer Disease/metabolism/cerebrospinal fluid
*Brain/metabolism
Middle Aged

@article {pmid40597176,
year = {2025},
author = {Wang, Y and Song, Y and Zhang, C and Ren, J and Xue, P and Hou, Y and Chen, Z},
title = {A dynamic prediction model for predicting the time at which patients with MCI progress to AD based on time-dependent covariates.},
journal = {BMC medical informatics and decision making},
volume = {25},
number = {1},
pages = {226},
pmid = {40597176},
issn = {1472-6947},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; *Alzheimer Disease/diagnosis ; *Disease Progression ; Aged ; Male ; Female ; Aged, 80 and over ; Time Factors ; *Models, Statistical ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is an irreversible neurodegenerative disorder that imposes a significant burden on families and society. Timely intervention during the transitional stages from Mild Cognitive Impairment (MCI) to AD can help mitigate this issue. The MCI-to-AD conversion time would be helpful if it could be predicted. Most studies rely on Cox models, which possess certain limitations and do not intuitively forecast the duration until patients with MCI progress to AD. Thus we construct a new dynamic prediction model based on the conditional restricted mean survival time (cRMST) from a time-scale perspective to explore the factors influencing progression to AD in patients with MCI and predict the average time required MCI patients to progress to AD at different time points in the future.

METHODS: We construct a new two-stage dynamic prediction model (tRMST model) based on the conditional restricted mean survival time (cRMST) in combination with landmark method to apply in the analysis of the ADNI database.

RESULTS: The results of the ADNI analysis showed that four variables (Education, MMSE, ADAS-Cog13 and P-tau) have dynamic effects over time. The C-index and the mean prediction error of the cross validation are better than the static RMST model.

CONCLUSION: This study presents a time-scale dynamic prediction model that effectively leverages longitudinal data to identify the dynamic effects of the factors' impact on the outcome over time, thereby assisting physicians in personalizing treatment for patients.},
}

Humans
*Cognitive Dysfunction/diagnosis
*Alzheimer Disease/diagnosis
*Disease Progression
Aged
Male
Female
Aged, 80 and over
Time Factors
*Models, Statistical

@article {pmid40597083,
year = {2025},
author = {Hao, M and Chen, J},
title = {Trend analysis and future predictions of global burden of alzheimer's disease and other dementias: a study based on the global burden of disease database from 1990 to 2021.},
journal = {BMC medicine},
volume = {23},
number = {1},
pages = {378},
pmid = {40597083},
issn = {1741-7015},
support = {20240305084YY//Department of Science and Technology of Jilin Province/ ; },
mesh = {Humans ; *Global Burden of Disease/trends ; Male ; Female ; *Alzheimer Disease/epidemiology ; Aged ; Middle Aged ; Prevalence ; Aged, 80 and over ; Incidence ; *Dementia/epidemiology ; Disability-Adjusted Life Years ; Databases, Factual ; Global Health ; Pattern Analysis, Machine ; },
abstract = {BACKGROUND: As the global aging issue grows, dementia, particularly Alzheimer's disease (AD), has become a major public health challenge for everyone. This study utilizes the Global Burden of Disease (GBD) database to analyze trends in the epidemiology of AD and other dementias from 1990 to 2021 and to predict future burdens to 2040.

METHODS: We examined global, regional, and national data on AD and other dementias, focusing on incidence, prevalence, and Disability-Adjusted Life Years (DALYs). Joinpoint regression analysis was employed to identify significant changes in trends over time. The effects of age, period, and birth cohort on the risk of AD and other dementias were analyzed. Additionally, the impact of aging, population growth, and epidemiological changes on DALYs was assessed across different Socio-demographic Index (SDI) quintiles.

RESULTS: The global burden of AD and other dementias has significantly increased, with the highest incidence, prevalence, and DALYs observed in East Asia. A notable increase in prevalence was observed in females over 65 years compared to males. Joinpoint regression analysis revealed substantial changes in trends in 1995, 2005, 2011, and 2019, with a noticeable acceleration post-2011, especially after 2019. Age was a significant risk factor, with a sharp increase in risk after 60 years of age. Epidemiological changes had a minor impact globally but varied by region and gender. Bayesian age-period-cohort modeling predicts sustained growth through 2040, with age-standardized incidence and prevalence rates projected to reach 144.85 and 821.80 per 100,000 respectively, driven predominantly by aging populations in high SDI regions and demographic expansion in low SDI regions.

CONCLUSIONS: The global burden of AD and other dementias is escalating, with a pronounced increase expected by 2040. This study highlights the need for targeted interventions, particularly in regions with higher burdens and among older populations. The findings underscore the importance of considering SDI, age, and gender when planning public health strategies to address the growing challenge of AD and other dementias.},
}

Humans
*Global Burden of Disease/trends
Male
Female
*Alzheimer Disease/epidemiology
Aged
Middle Aged
Prevalence
Aged, 80 and over
Incidence
*Dementia/epidemiology
Disability-Adjusted Life Years
Databases, Factual
Global Health
Pattern Analysis, Machine

@article {pmid40597079,
year = {2025},
author = {Paduvilan, AK and Livingston, GAL and Kuppuchamy, SK and Dhanaraj, RK and Subramanian, M and Al-Rasheed, A and Getahun, M and Soufiene, BO},
title = {Attention-driven hybrid deep learning and SVM model for early Alzheimer's diagnosis using neuroimaging fusion.},
journal = {BMC medical informatics and decision making},
volume = {25},
number = {1},
pages = {219},
pmid = {40597079},
issn = {1472-6947},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Neuroimaging/methods ; *Support Vector Machine ; Early Diagnosis ; Aged ; },
abstract = {Alzheimer's Disease (AD) poses a significant global health challenge, necessitating early and accurate diagnosis to enable timely interventions. AD is a progressive neurodegenerative disorder that affects millions worldwide and is one of the leading causes of cognitive impairment in older adults. Early diagnosis is critical for enabling effective treatment strategies, slowing disease progression, and improving the quality of life for patients. Existing diagnostic methods often struggle with limited sensitivity, overfitting, and reduced reliability due to inadequate feature extraction, imbalanced datasets, and suboptimal model architectures. This study addresses these gaps by introducing an innovative methodology that combines SVM with Deep Learning (DL) to improve the classification performance of AD. Deep learning models extract high-level imaging features which are then concatenated with SVM kernels in a late-fusion ensemble. This hybrid design leverages deep representations for pattern recognition and SVM's robustness on small sample sets. This study provides a necessary tool for early-stage identification of possible cases, so enhancing the management and treatment options. This is attained by precisely classifying the disease from neuroimaging data. The approach integrates advanced data pre-processing, dynamic feature optimization, and attention-driven learning mechanisms to enhance interpretability and robustness. The research leverages a dataset of MRI and PET imaging, integrating novel fusion techniques to extract key biomarkers indicative of cognitive decline. Unlike prior approaches, this method effectively mitigates the challenges of data sparsity and dimensionality reduction while improving generalization across diverse datasets. Comparative analysis highlights a 15% improvement in accuracy, a 12% reduction in false positives, and a 10% increase in F1-score against state-of-the-art models such as HNC and MFNNC. The proposed method significantly outperforms existing techniques across metrics like accuracy, sensitivity, specificity, and computational efficiency, achieving an overall accuracy of 98.5%.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Deep Learning
*Neuroimaging/methods
*Support Vector Machine
Early Diagnosis
Aged

@article {pmid40597012,
year = {2025},
author = {Lv, S and Jiao, H and Zhong, X and Qu, Y and Zhang, M and Wang, R and Liu, D and Yan, X},
title = {Associations between serum lipid levels and cognitive impairment in hypertensive patients: a case-control study.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {272},
pmid = {40597012},
issn = {1471-2377},
mesh = {Humans ; Male ; Female ; *Hypertension/blood/complications ; Case-Control Studies ; Aged ; *Cognitive Dysfunction/blood/etiology ; Middle Aged ; *Lipids/blood ; Cholesterol, LDL/blood ; },
abstract = {OBJECTIVE: Previous studies have shown that lower serum lipid levels are associated with the development of cognitive impairment (CI), dementia, and Alzheimer's disease. However, the relationship between serum lipid levels and CI in hypertensive patients has not been determined. This case-control study aimed to investigate the relationship between serum lipid levels and CI in hypertensive patients.

METHODS: A total of 1840 hypertensive patients (age: 69.70 ± 6.07; sex: male: 908/49.35%) were enrolled in this study, including 460 hypertensive patients with CI and 1380 hypertensive patients with normal cognitive function matched 1:3 by age and sex. The cognitive function and sleep quality of hypertensive patients were assessed using the Mini-mental State Examination (MMSE) and Pittsburgh Sleep Quality Index (PSQI). The relationship between serum lipid levels and CI in hypertensive patients was analyzed using multifactorial logistic regression. Spearman's correlation coefficient was used to analyze the correlation of serum lipid levels with MMSE scores and PSQI total scores in hypertensive patients.

RESULTS: After adjusting for all factors, serum low-density lipoprotein cholesterol (LDL-C) levels were negatively correlated with CI in hypertensive patients (OR = 0.823, 95%CI: 0.729-0.928, P = 0.001), and this association remained significant in patients with at least a junior high school education (OR = 0.727, 95%CI: 0.592-0.894, P = 0.002). However, serum total cholesterol (TC) and triglyceride (TG) levels were not correlated with CI in patients with hypertension (P > 0.05). In addition, serum LDL-C levels were positively correlated with MMSE total score (r = 0.139, P < 0.001), orientation (r = 0.118, P < 0.001), memory (r = 0.057, P = 0.014), attention and numeracy (r = 0.091, P < 0.001), recall ability (r = 0.065, P = 0.005), and language ability (r = 0.107, P < 0.030); serum TG, TC, and LDL-C levels were negatively correlated with PSQI total score (r = - 0.051, P = 0.029; r = - 0.090, P < 0.001; r = - 0.082, P < 0.001).

CONCLUSION: Lower serum LDL-C levels are associated with CI in hypertensive patients. Although causality cannot be inferred, findings suggest that LDL-C may be a relevant biomarker in cognitive screening. Therefore, serum lipid levels should be reasonably controlled according to their individual conditions.},
}

Humans
Male
Female
*Hypertension/blood/complications
Case-Control Studies
Aged
*Cognitive Dysfunction/blood/etiology
Middle Aged
*Lipids/blood
Cholesterol, LDL/blood

@article {pmid40596977,
year = {2025},
author = {Long, Y and Liu, J and Guo, J and Jiang, J and Wang, X and Sun, R},
title = {Integrated genetic analysis of Alzheimer's disease and stroke subtypes: insights from LDSC, PLACO, and MR studies.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {260},
pmid = {40596977},
issn = {1471-2377},
support = {82001131 and 82002644//the National Natural Science Foundation of China/ ; 2024JQ22 and 2024JQ19//Outstanding Medical Fund for Young Scholar of the First Affiliated Hospital of Harbin Medical University/ ; HZKY20220315（202201826）//Chunhui Program-Cooperative Research Project of the Ministry of Education/ ; 2023CX04//Innovation Fund for Stem Cell Clinical Research Filing Institutions of the First Affiliated Hospital of Harbin Medical University/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Genome-Wide Association Study/methods ; *Stroke/genetics/classification ; Mendelian Randomization Analysis/methods ; Polymorphism, Single Nucleotide/genetics ; *Linkage Disequilibrium/genetics ; Genetic Predisposition to Disease/genetics ; },
abstract = {PURPOSE: This study aimed to evaluate the genetic relationship between Alzheimer's disease (AD) and stroke, including its subtypes.

METHODS: The Linkage Disequilibrium Score Regression (LDSC) for heritability and genetic correlations, Polygenic Likelihood Ratio under a Composite Null Hypothesis (PLACO) method for pleiotropic loci and locus, and Functional maps and annotations from genome-wide association studies (FUMA) for function analysis of multi-effect loci, multi-marker analysis of genoMic annotation (MAGMA) for gene tissue specificity, Mendelian Randomization (MR) analyses for causal relationships between AD and five stroke subtypes were performed through Single Nucleotide Polymorphism (SNP) heritability enrichments and causal associations were analyzed using comprehensive GWAS data.

RESULTS: Manhattan plots revealed pleiotropic SNPs mainly on chromosomes 11 and 19, with additional loci on chromosomes 1, 2, and 3 for specific subgroups. Key genes like DEDD, UFC1, USP21, affecting both AD and stroke subtypes, were enriched in brain tissues, highlighting shared mechanisms. Stratified LD score regression showed overlaps in brain regions such as substantia nigra and spinal cord. MR analysis indicated AD as a risk factor for LAS and AS but protective for cerebral embolism stroke (CES), supported by consistent causal effect estimates without publication bias. This study reveals that AD shares genetic factors with multiple stroke subtypes, notably in brain tissues, impacting their etiology and potential treatments.

CONCLUSION: Overall, our study revealed that AD shares genetic factors with multiple stroke subtypes, notably in brain tissues. MR analysis indicates AD is a risk factor for LAS and AS, but protective for CES.},
}

Humans
*Alzheimer Disease/genetics
Genome-Wide Association Study/methods
*Stroke/genetics/classification
Mendelian Randomization Analysis/methods
Polymorphism, Single Nucleotide/genetics
*Linkage Disequilibrium/genetics
Genetic Predisposition to Disease/genetics

@article {pmid40596742,
year = {2025},
author = {Leming, M and Im, H},
title = {Differential dementia detection from multimodal brain images in a real-world dataset.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70362},
doi = {10.1002/alz.70362},
pmid = {40596742},
issn = {1552-5279},
support = {R01GM138778/NH/NIH HHS/United States ; R01GM138778-04S1//NIH Office of the Director/ ; //MGH ECOR Fund for Medical Discovery Awards/ ; },
mesh = {Humans ; *Dementia/diagnostic imaging/diagnosis ; *Brain/diagnostic imaging ; Diagnosis, Differential ; Female ; Male ; Aged ; Electronic Health Records ; *Deep Learning ; *Artificial Intelligence ; *Multimodal Imaging ; *Neuroimaging/methods ; Databases, Factual ; Magnetic Resonance Imaging ; Alzheimer Disease/diagnostic imaging ; },
abstract = {INTRODUCTION: Artificial intelligence (AI) models have been applied to differential dementia detection tasks in brain images from curated, high-quality benchmark databases, but not real-world data in hospitals.

METHODS: We describe a deep learning model specially trained for disease detection in heterogeneous clinical images from electronic health records without focusing on confounding factors. It encodes up to 14 multimodal images, alongside age and demographics, and outputs the likelihood of vascular dementia, Alzheimer's, Lewy body dementia, Pick's disease, mild cognitive impairment, and unspecified dementia. We use data from Massachusetts General Hospital (183,018 images from 11,015 patients) for training and external data (125,493 images from 6,662 patients) for testing.

RESULTS: Performance ranged between 0.82 and 0.94 area under the curve (AUC) on data from 1003 sites.

DISCUSSION: Analysis shows that the model focused on subcortical brain structures as the basis for its decisions. By detecting biomarkers in real-world data, the presented techniques will help with clinical translation of disease detection AI.

HIGHLIGHTS: Our artificial intelligence (AI) model can detect neurodegenerative disorders in brain imaging electronic health record (EHR) data. It encodes up to 14 brain images and text information from a single patient's EHR. Attention maps show that the model focuses on subcortical brain structures. Performance ranged from 0.82 to 0.94 area under the curve (AUC) on data from 1003 external sites.},
}

Humans
*Dementia/diagnostic imaging/diagnosis
*Brain/diagnostic imaging
Diagnosis, Differential
Female
Male
Aged
Electronic Health Records
*Deep Learning
*Artificial Intelligence
*Multimodal Imaging
*Neuroimaging/methods
Databases, Factual
Magnetic Resonance Imaging
Alzheimer Disease/diagnostic imaging

@article {pmid40596736,
year = {2025},
author = {Kemna, RE and Kueck, PJ and Honea, R and Clark, Z and Rekowski, M and Weidling, I and Mayfield, H and John, CS and Burns, J and Wilkins, HM and Swerdlow, R and Morris, JK},
title = {Mitochondrial DNA affects tau phosphorylation in aging and Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70390},
doi = {10.1002/alz.70390},
pmid = {40596736},
issn = {1552-5279},
support = {T32 AG078114/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 CA168524/CA/NCI NIH HHS/United States ; P30 CA168524/CA/NCI NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; R00AG050490/AG/NIA NIH HHS/United States ; R01AG081304/AG/NIA NIH HHS/United States ; R01AG062548/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/genetics ; *tau Proteins/metabolism ; *DNA, Mitochondrial/metabolism/genetics ; Female ; Phosphorylation ; Aged ; *Cognitive Dysfunction/metabolism/pathology/genetics ; Male ; *Aging/metabolism ; Brain/pathology/metabolism ; Aged, 80 and over ; Mitochondria/metabolism ; },
abstract = {INTRODUCTION: Impaired mitochondrial function is seen in Alzheimer's disease (AD), but its role is unclear. Mitochondrial DNA (mtDNA) supports bioenergetic metabolism, but it is uncertain how it might influence AD neuropathology.

METHODS: We used cytoplasmic hybrid (cybrid) cell lines made from SH-SY5Y cells expressing mtDNA from cognitively healthy (CH), mild cognitive impairment (MCI), or AD individuals to investigate the impact of mtDNA-determined mitochondrial function on amyloid, tau, and neurodegeneration (ATN) markers. Cybrid measurements were correlated with cognition and brain morphometry.

RESULTS: Relative to cybrids expressing mtDNA from CH individuals, MCI and AD cybrids contained more phosphorylated tau-217 (p-tau217), p-tau181, and total tau. Cybrid p-tau217 correlated with plasma p-tau217 from the mtDNA donor (β = 0.605, p < 0.001). We observed negative relationships between cybrid p-tau217 and cognition and brain morphometry. MCI and AD cybrid proteomes showed mitochondrial dysfunction.

DISCUSSION: mtDNA-determined mitochondrial function affects cell physiology in AD-relevant ways. Our study suggests that mtDNA affects ATN status and clinical state.

HIGHLIGHTS: Mitochondrial DNA (mtDNA)-determined mitochondrial function drives Alzheimer's disease (AD) hallmarks. Cytoplasmic hybrid outcomes associate with mtDNA-donor clinical measures. Proteomic analyses indicate mitochondrial dysfunction in AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology/genetics
*tau Proteins/metabolism
*DNA, Mitochondrial/metabolism/genetics
Female
Phosphorylation
Aged
*Cognitive Dysfunction/metabolism/pathology/genetics
Male
*Aging/metabolism
Brain/pathology/metabolism
Aged, 80 and over
Mitochondria/metabolism

@article {pmid40596706,
year = {2025},
author = {Galgani, A and Mary, A and Lombardo, F and Martini, N and Scotto, M and Tognoni, G and Siciliano, G and Ceravolo, R and Giorgi, FS and Heneka, MT},
title = {Locus coeruleus integrity correlates with plasma soluble Axl levels in Alzheimer's disease patients.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70434},
doi = {10.1002/alz.70434},
pmid = {40596706},
issn = {1552-5279},
support = {PE2013-02359574//Ministero della Salute/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/pathology/diagnostic imaging ; Male ; Female ; *Locus Coeruleus/pathology/diagnostic imaging ; *Receptor Protein-Tyrosine Kinases/blood ; Axl Receptor Tyrosine Kinase ; *Proto-Oncogene Proteins/blood ; Aged ; Magnetic Resonance Imaging ; Biomarkers/blood ; Cohort Studies ; Middle Aged ; },
abstract = {INTRODUCTION: Locus coeruleus (LC) is one of the earliest structures altered in Alzheimer's disease (AD). Inflammation is also now considered critical in AD pathology, early stage included. However, no association between LC degeneration and the peripheral inflammation has been reported yet.

METHODS: A cohort of 102 patients was studied for which both magnetic resonance imaging (MRI) scans and blood samples were available. LC integrity was assessed by MRI, and plasma soluble TAMs (Tyro3, Axl, and MerTK) receptor levels were measured by enzyme-linked immunosorbent assay (ELISA).

RESULTS: We found that plasma levels of the soluble TAMs receptor Axl were correlated with LC rostral degeneration in the whole cohort (p = 0.007), as well as in the AD+ group (p = 0.017), but not in the AD- group.

DISCUSSION: These results uncover a new relationship between peripheric markers of inflammation and central early AD neurodegeneration.

HIGHLIGHTS: In Alzheimer's disease, no link between locus coeruleus degeneration and microglial activation was reported. Plasma Axl, Tyro3, and MerTK levels and locus coeruleus integrity were assessed in Alzheimer's disease patients. Locus coeruleus integrity positively correlates with plasma AXL, linked to microglia activation. Axl-noradrenergic signaling interplay deserves further larger longitudinal studies.},
}

Humans
*Alzheimer Disease/blood/pathology/diagnostic imaging
Male
Female
*Locus Coeruleus/pathology/diagnostic imaging
*Receptor Protein-Tyrosine Kinases/blood
Axl Receptor Tyrosine Kinase
*Proto-Oncogene Proteins/blood
Aged
Magnetic Resonance Imaging
Biomarkers/blood
Cohort Studies
Middle Aged

@article {pmid40596195,
year = {2025},
author = {Alasiry, A and Shinan, K and Alsadhan, AA and Alhazmi, HE and Alanazi, F and Ashraf, MU and Muhammad, T},
title = {A novel neuroimaging based early detection framework for alzheimer disease using deep learning.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23011},
pmid = {40596195},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Neuroimaging/methods ; Early Diagnosis ; Magnetic Resonance Imaging/methods ; Positron-Emission Tomography/methods ; Male ; Female ; Brain/diagnostic imaging ; Diagnosis, Computer-Assisted/methods ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that significantly impacts cognitive function, posing a major global health challenge. Despite its rising prevalence, particularly in low and middle-income countries, early diagnosis remains inadequate, with projections estimating over 55 million affected individuals by 2022, expected to triple by 2050. Accurate early detection is critical for effective intervention. This study presents Neuroimaging-based Early Detection of Alzheimer's Disease using Deep Learning (NEDA-DL), a novel computer-aided diagnostic (CAD) framework leveraging a hybrid ResNet-50 and AlexNet architecture optimized with CUDA-based parallel processing. The proposed deep learning model processes MRI and PET neuroimaging data, utilizing depthwise separable convolutions to enhance computational efficiency. Performance evaluation using key metrics including accuracy, sensitivity, specificity, and F1-score demonstrates state-of-the-art classification performance, with the Softmax classifier achieving 99.87% accuracy. Comparative analyses further validate the superiority of NEDA-DL over existing methods. By integrating structural and functional neuroimaging insights, this approach enhances diagnostic precision and supports clinical decision-making in Alzheimer's disease detection.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Deep Learning
*Neuroimaging/methods
Early Diagnosis
Magnetic Resonance Imaging/methods
Positron-Emission Tomography/methods
Male
Female
Brain/diagnostic imaging
Diagnosis, Computer-Assisted/methods

@article {pmid40595771,
year = {2025},
author = {Dehkordi, SK and Sajedi, S and Heshmat, A and Orr, ME and Zare, H},
title = {Identification of markers for neurescence through transcriptomic profiling of postmortem human brains.},
journal = {npj aging},
volume = {11},
number = {1},
pages = {57},
pmid = {40595771},
issn = {2731-6068},
support = {R01AG068293/AG/NIA NIH HHS/United States ; R01AG068293/AG/NIA NIH HHS/United States ; R01AG068293/AG/NIA NIH HHS/United States ; GC-201908-2019443//Alzheimer's Drug Discovery Foundation/ ; R21NS125171/NS/NINDS NIH HHS/United States ; RF1NS112391/NS/NINDS NIH HHS/United States ; I01BX005717//Rainwater Charitable Foundation and US Department of Veterans Affairs/ ; },
abstract = {Neuronal senescence (i.e., neurescence) is an important hallmark of aging and neurodegeneration, but it remains poorly characterized in the human brain due to the lack of reliable markers. This study aimed to identify neurescence markers based on single-nucleus transcriptome data from postmortem human prefrontal cortex. Using an eigengene approach, we integrated three gene panels: (a) SenMayo, (b) canonical senescence pathway (CSP), and (c) senescence initiating pathway (SIP), to identify neurescence signatures. We found that paired markers outperform single markers; for instance, by combining CDKN2D and ETS2 in a decision tree, a high accuracy of 99% and perfect specificity (100%) were achieved in distinguishing senescent neurons (i.e, neurescent). Differential expression analyses identified 324 genes that are overexpressed in neurescent. These genes showed significant associations with important neurodegeneration-related pathways, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Interestingly, several of these overexpressed genes are linked to mitochondrial dysfunction and cytoskeletal dysregulation. These findings provide valuable insights into the complexities of neurescence, emphasizing the need for further exploration of histologically viable markers and validation in broader datasets.},
}

@article {pmid40595720,
year = {2025},
author = {Montoliu-Gaya, L and Bian, S and Dammer, EB and Alcolea, D and Sauer, M and Martá-Ariza, M and Ashton, NJ and Belbin, O and Fuchs, J and Watson, CM and Ping, L and Duong, DM and Nilsson, J and Barroeta, I and Lantero-Rodriguez, J and Videla, L and Benejam, B and Roberts, BR and Blennow, K and Seyfried, NT and Levey, AI and Carmona-Iragui, M and Gobom, J and Lleó, A and Wisniewski, T and Zetterberg, H and Fortea, J and Johnson, ECB},
title = {Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {6003},
pmid = {40595720},
issn = {2041-1723},
mesh = {Humans ; *Down Syndrome/cerebrospinal fluid/genetics ; *Alzheimer Disease/cerebrospinal fluid/genetics/pathology ; Female ; Male ; Proteomics/methods ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Middle Aged ; tau Proteins/cerebrospinal fluid ; Age of Onset ; Adult ; Young Adult ; Proteome ; },
abstract = {Almost all individuals with Down Syndrome (DS) develop Alzheimer's disease (AD) by mid to late life. However, the degree to which AD in DS shares pathological changes with sporadic late-onset AD (LOAD) and autosomal dominant AD (ADAD) beyond core AD biomarkers such as amyloid-β (Aβ) and tau is unknown. Here, we used proteomics of cerebrospinal fluid from individuals with DS (n = 229) in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort to assess the evolution of AD pathophysiology from asymptomatic to dementia stages and compared the proteomic biomarker changes in DS to those observed in LOAD and ADAD. Although many proteomic alterations were shared across DS, LOAD, and ADAD, DS demonstrated more severe changes in immune-related proteins, extracellular matrix pathways, and plasma proteins likely related to blood-brain barrier dysfunction compared to LOAD. These changes were present in young adults with DS prior to the onset of Aβ or tau pathology, suggesting they are associated with trisomy 21 and may serve as risk factors for DSAD. DSAD showed an earlier increase in markers of axonal and white matter pathology and earlier changes in markers potentially associated with cerebral amyloid angiopathy compared to ADAD. The unique features of DSAD may have important implications for treatment strategies in this population.},
}

Humans
*Down Syndrome/cerebrospinal fluid/genetics
*Alzheimer Disease/cerebrospinal fluid/genetics/pathology
Female
Male
Proteomics/methods
Biomarkers/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Aged
Middle Aged
tau Proteins/cerebrospinal fluid
Age of Onset
Adult
Young Adult
Proteome

@article {pmid40595567,
year = {2025},
author = {Su, Y and Li, H and Zhang, W and Tao, S and Wang, Q and Zhang, X and Zhou, M and Huang, X and Wang, C and Tang, Y and Chen, H and Verkhratsky, A and Zha, Z and Niu, J and Yi, C},
title = {Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5621},
pmid = {40595567},
issn = {2041-1723},
support = {32170980//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32271034//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Animals ; *Connexin 43/metabolism/genetics/antagonists & inhibitors ; *Microglia/metabolism/drug effects/pathology ; Disease Models, Animal ; *Amyloidosis/metabolism/pathology/genetics/drug therapy ; Mice ; Humans ; *Alzheimer Disease/metabolism/pathology/genetics ; *Cognitive Dysfunction/metabolism/pathology/drug therapy ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Male ; Mice, Knockout ; Amyloid beta-Protein Precursor/genetics/metabolism ; Neuroprotection ; Female ; Presenilin-1/genetics/metabolism ; Plaque, Amyloid/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD), the leading cause of senile dementia, lacks effective therapies. While microglia are central to AD pathology, key therapeutic targets remain unclear. Here we identify microglial connexin43 (Cx43) hemichannels as a regulator of microglial reactivity in AD, positioning them as a promising therapeutic target. Post-mortem AD patient tissue showed elevated Cx43 levels in periplaque microglia. In the APPswe/PS1dE9 (APP/PS1) mouse model of amyloidosis, we demonstrated that microglial Cx43 hemichannels correlated with microglial malfunction, which in turn exacerbated β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout shifts microglia to a neuroprotective phenotype, enhancing the microglia-plaque interaction while suppressing neurotoxicity, thereby mitigating the progression of AD-like pathology. We developed TAT-Cx43@LNPs, a Cx43 hemichannel-targeting peptide delivered by a lipid nanoparticle system, which effectively delayed and rescued β-amyloid-related neuropathology and cognitive impairment in APP/PS1 mice. This study provides evidence for advancing Cx43 hemichannel targeting therapy into clinical trials.},
}

Animals
*Connexin 43/metabolism/genetics/antagonists & inhibitors
*Microglia/metabolism/drug effects/pathology
Disease Models, Animal
*Amyloidosis/metabolism/pathology/genetics/drug therapy
Mice
Humans
*Alzheimer Disease/metabolism/pathology/genetics
*Cognitive Dysfunction/metabolism/pathology/drug therapy
Mice, Transgenic
Amyloid beta-Peptides/metabolism
Male
Mice, Knockout
Amyloid beta-Protein Precursor/genetics/metabolism
Neuroprotection
Female
Presenilin-1/genetics/metabolism
Plaque, Amyloid/pathology/metabolism

@article {pmid40595564,
year = {2025},
author = {Wu, CC and Tsantilas, KA and Park, J and Plubell, D and Sanders, JA and Naicker, P and Govender, I and Buthelezi, S and Stoychev, S and Jordaan, J and Merrihew, G and Huang, E and Parker, ED and Riffle, M and Hoofnagle, AN and Noble, WS and Poston, KL and Montine, TJ and MacCoss, MJ},
title = {Enrichment of extracellular vesicles using Mag-Net for the analysis of the plasma proteome.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5447},
pmid = {40595564},
issn = {2041-1723},
support = {U19 AG065156/AG/NIA NIH HHS/United States ; P30 AG013280/AG/NIA NIH HHS/United States ; U01 DK137097/DK/NIDDK NIH HHS/United States ; R01 NS115114/NS/NINDS NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; F31 AG069420/AG/NIA NIH HHS/United States ; T32 AG066574/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Proteome/metabolism/analysis ; Alzheimer Disease/blood/diagnosis ; *Proteomics/methods ; Male ; Female ; Parkinson Disease/blood/diagnosis ; Aged ; Chromatography, Liquid ; *Blood Proteins/metabolism ; Middle Aged ; Mass Spectrometry ; ROC Curve ; Case-Control Studies ; Biomarkers/blood ; Machine Learning ; },
abstract = {Extracellular vesicles (EVs) in plasma are composed of exosomes, microvesicles, and apoptotic bodies. We report a plasma EV enrichment strategy using magnetic beads called Mag-Net. Proteomic interrogation of this plasma EV fraction enables the detection of proteins that are beyond the dynamic range of liquid chromatography-mass spectrometry of unfractionated plasma. Mag-Net is robust, reproducible, inexpensive, and requires <100 μL plasma input. Coupled to data-independent mass spectrometry, we demonstrate the measurement of >37,000 peptides from >4,000 proteins. Using Mag-Net on a pilot cohort of patients with neurodegenerative disease and healthy controls, we find 204 proteins that differentiate (q-value < 0.05) patients with Alzheimer's disease dementia (ADD) from those without ADD. There are also 310 proteins that differ between individuals with Parkinson's disease and without. Using machine learning we distinguish between individuals with ADD and not ADD with an area under the receiver operating characteristic curve (AUROC) = 0.98 ± 0.06.},
}

Humans
*Extracellular Vesicles/metabolism
*Proteome/metabolism/analysis
Alzheimer Disease/blood/diagnosis
*Proteomics/methods
Male
Female
Parkinson Disease/blood/diagnosis
Aged
Chromatography, Liquid
*Blood Proteins/metabolism
Middle Aged
Mass Spectrometry
ROC Curve
Case-Control Studies
Biomarkers/blood
Machine Learning

@article {pmid40595476,
year = {2025},
author = {Giorgio, J and Jonson, C and Wang, Y and Yokoyama, JS and Wang, J and Jagust, WJ and , },
title = {Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5812},
pmid = {40595476},
issn = {2041-1723},
support = {23AARF-1026883/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Neocortex/metabolism/pathology/diagnostic imaging ; Female ; *Entorhinal Cortex/metabolism/pathology/diagnostic imaging ; Male ; *Receptors, Immunologic/genetics/metabolism ; *tau Proteins/metabolism ; *Apolipoprotein E4/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Aged ; *Membrane Glycoproteins/genetics/metabolism ; Aged, 80 and over ; Sex Factors ; Cohort Studies ; },
abstract = {The canonical Alzheimer's Disease (AD) pathological cascade posits that the accumulation of amyloid beta (Aβ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a multi-cohort study (ADNI, A4, HABS-HD) of 1354 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and APOE-ε4 homozygotes are more susceptible to the effects of Aβ on the primary accumulation of tau, with greater EC tau for a given level of Aβ. Furthermore, we observed for individuals who have rare risk variants in TREM2 and/or APOE-ε4 homozygotes there was a greater spread of primary tau from the EC into the neocortex. These findings offer insights into the function of sex, APOE and microglia in AD progression and have implications for determining personalised treatment with drugs targeting Aβ and tau.},
}

Humans
*Neocortex/metabolism/pathology/diagnostic imaging
Female
*Entorhinal Cortex/metabolism/pathology/diagnostic imaging
Male
*Receptors, Immunologic/genetics/metabolism
*tau Proteins/metabolism
*Apolipoprotein E4/genetics/metabolism
*Alzheimer Disease/genetics/metabolism/pathology/diagnostic imaging
Amyloid beta-Peptides/metabolism
Aged
*Membrane Glycoproteins/genetics/metabolism
Aged, 80 and over
Sex Factors
Cohort Studies

@article {pmid40595369,
year = {2025},
author = {Bright, A and Akay, LA and Blanchard, J and Tsai, LH},
title = {Emerging connections between myelin and Alzheimer's disease.},
journal = {Nature cell biology},
volume = {},
number = {},
pages = {},
pmid = {40595369},
issn = {1476-4679},
}