@article {pmid40841001,
year = {2025},
author = {Zheng, X and Jia, G and Zhao, Y and Yan, T},
title = {Involvement of four alga toxins in the risks of human neurodegenerative diseases: Toxicogenomic data mining and bioinformatics analysis.},
journal = {Journal of environmental sciences (China)},
volume = {158},
number = {},
pages = {151-164},
doi = {10.1016/j.jes.2025.02.036},
pmid = {40841001},
issn = {1001-0742},
mesh = {Humans ; *Neurodegenerative Diseases/chemically induced/epidemiology ; Computational Biology ; *Marine Toxins/toxicity ; Toxicogenetics ; Data Mining ; Amino Acids, Diamino/toxicity ; Okadaic Acid/toxicity ; Oxocins/toxicity ; Cyanobacteria Toxins ; Microcystins ; },
abstract = {Alga toxins have recently emerged as an environmental risk factor, especially to neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. However, the association between the alga toxins β-N-methylamino-L-alanine (BMAA), brevetoxin B, cyanoginosin LR, okadaic acid and neurodegenerative diseases remains inadequately investigated. Therefore, the aim of this study was to elucidate the potential associations. Four sets of differentially expressed genes related with BMAA, brevetoxin B, cyanoginosin LR and okadaic acid in Homo sapiens and genes linked to neurodegenerative disease development were respectively collected from the Comparative Toxicogenomic Database. Metascape analysis and cluster community analysis of four alga toxins highlighted protein-protein interaction enrichment and hub genes, while biological processes analysis showed that the dominant pathways involved in harmful effects triggered by four alga toxins were the apoptotic signaling pathway, regulation of amyloid protein formation, inflammatory response and endoplasmic reticulum stress. Genes related to the interactions between four alga toxins and neurodegenerative diseases were selected and analyzed, revealing that the relevant pathways and genes were those involved in apoptotic mitochondrial changes and neuroinflammatory response pathways. The adverse outcome pathway frameworks were constructed according to the analysis results for toxins and associated neurodegenerative diseases. These discoveries provide a new perspective for us to gain a deeper understanding of the neurotoxic effects of four alga toxins.},
}

Humans
*Neurodegenerative Diseases/chemically induced/epidemiology
Computational Biology
*Marine Toxins/toxicity
Toxicogenetics
Data Mining
Amino Acids, Diamino/toxicity
Okadaic Acid/toxicity
Oxocins/toxicity
Cyanobacteria Toxins
Microcystins

@article {pmid40840983,
year = {2025},
author = {Rahman, M and Tabassum, A and Sultana, S and Saha, T and Nayeem, MAJ and Jahan, I and Hasan, I and Hayat, S and Papri, N and Islam, Z},
title = {Epidemiology and risk factors of Alzheimer's disease and related dementias in South and Southeast Asia: a systematic review and meta-analysis protocol.},
journal = {BMJ open},
volume = {15},
number = {8},
pages = {e105955},
doi = {10.1136/bmjopen-2025-105955},
pmid = {40840983},
issn = {2044-6055},
mesh = {Humans ; Systematic Reviews as Topic ; *Alzheimer Disease/epidemiology ; Risk Factors ; Meta-Analysis as Topic ; Asia, Southeastern/epidemiology ; Prevalence ; *Dementia/epidemiology ; Research Design ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) impacts over 55 million individuals worldwide and remains the leading cause of dementia (60-70% of cases). By 2050, South and Southeast Asia are projected to have an older adult population more than double, bearing a major share of Alzheimer's disease burden. This will exert a heavy strain on healthcare systems, particularly in resource-limited countries where support and infrastructure are already stretched. Despite this, no review has yet explored the regional epidemiology and associated risk factors in this context. Thus, this study protocol outlines to synthesise prevailing evidence from these densely populated regions, particularly low- and middle-income nations within South and Southeast Asia.

METHODS: This review will include studies that reported epidemiological characteristics including prevalence, age of onset, mortality, and risk factors of AD and related dementias comprising in South and Southeast Asian regions. Studies published in any language from inception to date will be extracted from PubMed, Scopus, CINAHL, EMBASE and APA PsycNet, following Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. We will also search grey literature sources and screen the reference lists of the articles selected for full-text review to identify additional relevant studies. Observational studies including case-control, cohort, and cross-sectional designs reporting desired outcomes will be included and appraised for quality assessment with the modified Newcastle-Ottawa Scale (mNOS). The included articles will be appraised by two independent reviewers, with a third resolving any conflicts. Pooled estimates of prevalence, age of onset and mortality will be analysed using random effect meta-analysis (REML) model. Associated risk factors, including modifiable and non-modifiable will be narratively synthesised. Forest plots will be used to visualise the findings, and heterogeneity across the included studies will be assessed using the I² and Cochrane's Q statistics. Potential publication bias will be assessed using a funnel plot along with the Begg's and Egger's tests. Sensitivity and subgroup analyses will also be conducted to assess the robustness of pooled estimates and to explore potential sources of heterogeneity. Statistical analysis will be conducted using Rstudio (v.4.3.2) and GraphPad Prism V.9.0.2.

ETHICS AND DISSEMINATIONS: The systematic review is focused on the analysis of secondary data from published literature; thus, no ethical approval will be needed. The protocol will follow international standard guidelines, findings will be reported in a reputed journal and disseminated through (inter)national conferences, webinars and key stakeholders to inform policy, research and AD management strategies.

PROSPERO REGISTRATION NUMBER: CRD 420251047105.},
}

Humans
Systematic Reviews as Topic
*Alzheimer Disease/epidemiology
Risk Factors
Meta-Analysis as Topic
Asia, Southeastern/epidemiology
Prevalence
*Dementia/epidemiology
Research Design

@article {pmid40840974,
year = {2025},
author = {Steinacker, P and Werner, L and Tarabuko, A and Al-Ali, I and Mechawar, N and Pryce, CR and Cattane, N and Poggi, G and Al Shweiki, MR and Graf, H and Großkopf, H and Halbgebauer, S and Oeckl, P and Barba, L and Meier, L and Abu-Rumeileh, S and Marston, H and Bornemann, KD and Hengerer, B and Danzer, KM and Schönfeldt-Lecuona, C and Otto, M},
title = {Evidence for reduced synaptic protein SNAP-25 in cerebrospinal fluid in major depressive disorder and schizophrenia.},
journal = {BMJ mental health},
volume = {28},
number = {1},
pages = {},
doi = {10.1136/bmjment-2025-301752},
pmid = {40840974},
issn = {2755-9734},
mesh = {Humans ; *Synaptosomal-Associated Protein 25/cerebrospinal fluid ; *Depressive Disorder, Major/cerebrospinal fluid/diagnosis ; *Schizophrenia/cerebrospinal fluid/diagnosis ; Male ; Female ; Adult ; Middle Aged ; Biomarkers/cerebrospinal fluid ; Retrospective Studies ; Neurogranin/cerebrospinal fluid ; Bipolar Disorder/cerebrospinal fluid ; Sensitivity and Specificity ; },
abstract = {BACKGROUND: Decreased cerebrospinal fluid (CSF) levels of synaptic proteins, possibly reflecting impaired synaptic function, have been observed in major depressive disorder (MDD).

OBJECTIVE: To investigate the diagnostic utility of the soluble N-ethylmaleimide-sensitive-factor attachment receptor (SNARE) complex protein, synaptosomal-associated protein of 25 kDa (SNAP-25), for MDD.

METHODS: Overall, 208 participants with one of MDD, schizophrenia (SCZ) or bipolar disorder (BD), and healthy controls (HCs) were retrospectively enrolled. CSF levels of SNAP-25 were assessed relative to MDD characteristics and the diagnostic potential was analysed. In subgroups of patients, CSF levels of presynaptic neurexin 3 (NRXN3), postsynaptic neurogranin (NRGN) and Alzheimer's disease biomarkers were measured for comparison.

FINDINGS: SNAP-25 levels, but not the levels of the other synaptic markers, were significantly decreased in MDD compared with HCs, allowing for discrimination with 68% sensitivity and 67% specificity. SNAP-25 was not associated with MDD severity or antidepressant medication. Compared with HCs, SCZ also displayed decreased SNAP-25 enabling discrimination with 64% sensitivity and 77% specificity. There were strong correlations between levels of synaptic proteins and established Alzheimer pathology markers, with subtle differences in the association pattern between disorders.

DISCUSSION: Our data suggest that SNAP-25, NRXN3 and NRGN versus beta-amyloid and phosphorylated tau protein 181 (ptau) are regulated differentially across psychiatric disorders and that SNAP-25 has a moderate diagnostic potential for MDD and SCZ. We propose that CSF SNAP-25 level might represent an integrated readout of reduced synaptic function, rather than of synaptic degeneration, in MDD. Further studies are needed to analyse whether this potential can be increased by using multimarker measurements and whether it will be possible to subtype psychiatric disorders according to synaptic involvement in pathophysiology.

CLINICAL IMPLICATIONS: SNAP-25 and other synaptic proteins in CSF might aid diagnosis and subtyping of MDD and SCZ. The current development of sensitive methods to also determine synaptic proteins in blood samples from patients will advance the validation of the biomarker potential and contribute to understanding of synaptic involvement in the pathophysiology of MDD and SCZ.},
}

Humans
*Synaptosomal-Associated Protein 25/cerebrospinal fluid
*Depressive Disorder, Major/cerebrospinal fluid/diagnosis
*Schizophrenia/cerebrospinal fluid/diagnosis
Male
Female
Adult
Middle Aged
Biomarkers/cerebrospinal fluid
Retrospective Studies
Neurogranin/cerebrospinal fluid
Bipolar Disorder/cerebrospinal fluid
Sensitivity and Specificity

@article {pmid40840855,
year = {2025},
author = {Cheng, K and Hu, J and Ni, L and Xue, Q and Zhang, D and Zhang, Y and Huang, C and Wang, L},
title = {Decreased brain entropy in the left pallidum is associated with memory impairment in obese individuals: Evidence from resting-state fMRI.},
journal = {Brain research},
volume = {},
number = {},
pages = {149896},
doi = {10.1016/j.brainres.2025.149896},
pmid = {40840855},
issn = {1872-6240},
abstract = {BACKGROUND: Obesity significantly increases not only the incidence and mortality rates of cardiovascular diseases, diabetes, and other metabolic disorders, but also elevates the risk of cognitive impairment-related conditions such as Alzheimer's disease by 3 to 5 times. Based on some brain regions related to reward drive, this study combined brain entropy (BEN) and resting state functional connectivity (RSFC) to explore the neural basis of obesity-induced memory impairment.

METHODS: Based on resting-state functional magnetic resonance imaging (rs-fMRI) data from 23 obese individuals and 36 healthy controls, the BEN values of some brain regions related to reward drive (Nucleus accumbens, Pallidum, Caudate, and Anterior cingulate cortex) were calculated. Mediation analysis was performed to examine whether body mass index (BMI) mediates the relationship between BEN and memory quotient (MQ). Additionally, whole-brain functional connectivity analysis was conducted based on regions showing significant BEN differences.

RESULTS: The BEN in left pallidum (lPAL) was significantly reduced in the obese group compared to controls (p = 0.005). Moreover, BMI mediated the relationship between lPAL entropy and MQ (Indirect effect: 0.2227, 95 % CI [0.0866, 0.3658]). Functional connectivity analysis revealed decreased connectivity between the lPAL and the right superior parietal gyrus, cerebellar Crus II, and cerebellar VIIB in the obese group, along with increased connectivity between the lPAL and the right pallidum.

CONCLUSION: BMI fully mediates the reduced brain complexity of the left pallidum in obese individuals, which is associated with memory impairment and is accompanied by changes in specific functional connectivity patterns. These findings provide new insights into the neural substrates of obesity-related cognitive decline.},
}

@article {pmid40840806,
year = {2025},
author = {Mundorf, A and Merklein, SA and Borawski, J and Ocklenburg, S},
title = {Dementia and Handedness: Meta-analyses.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106345},
doi = {10.1016/j.neubiorev.2025.106345},
pmid = {40840806},
issn = {1873-7528},
abstract = {Hemispheric asymmetries are a core feature of brain organization and may influence neurodegenerative processes. Handedness has been proposed as a behavioral marker of lateralization, but its relevance in dementia remains unclear. To determine whether individuals with dementia, including Alzheimer's disease, differ from healthy controls in the prevalence of left-, mixed-, and non-right-handedness (left- and mixed-handedness), frequentist and Bayesian meta-analytic approaches were used. First, a systematic literature search following PRISMA guidelines was conducted in PubMed and Google Scholar through March 2025 using the terms: "((dementia) OR (Alzheimer's disease)) AND (handedness)." Inclusion criteria required studies to (1) report handedness for both dementia and control groups, (2) not match participants for handedness, and (3) provide sufficient statistical data. Eighteen studies (N = 13,282 dementia patients, N = 18,540 controls) met the criteria. Frequentist meta-analyses showed that individuals with dementia were significantly less likely to be non-right-handed (OR = 0.90, 95% CI: 0.83-0.97, p = 0.01) and mixed-handed (OR = 0.71, 95% CI: 0.59-0.85, p = 0.01) compared to controls. However, sensitivity analyses excluding the largest study rendered these associations non-significant, indicating limited robustness. Bayesian meta-analyses supported the null hypothesis with moderate-to-strong evidence across all handedness categories (BF10 = 0.06-1.06). Exploratory Bayesian meta-regressions tested dementia subtype as a moderator and revealed no significant effects. In conclusion, while handedness differences in dementia appear small and sensitive to study design, emerging patterns, particularly in mixed-handedness, may reflect subtle disruptions in hemispheric specialization. Further research may clarify whether such traits provide early behavioral signals of neurodegenerative changes.},
}

@article {pmid40840451,
year = {2025},
author = {Das, A and Lakhani, C and Terwagne, C and Lin, JT and Naito, T and Raj, T and Knowles, DA},
title = {Leveraging functional annotations to map rare variants associated with Alzheimer disease with gruyere.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2025.07.016},
pmid = {40840451},
issn = {1537-6605},
abstract = {Increased availability of whole-genome sequencing (WGS) has facilitated the study of rare variants (RVs) in complex diseases. Multiple RV association tests are available to study the relationship between genotype and phenotype, but most do not fully leverage the availability of variant-level functional annotations. We propose genome-wide rare variant enrichment evaluation (gruyere), an empirical Bayesian framework that complements existing methods by learning global, trait-specific weights for functional annotations to improve variant prioritization. We apply gruyere to WGS data from the Alzheimer's Disease Sequencing Project to identify Alzheimer disease (AD)-associated genes and annotations. Growing evidence suggests that the disruption of microglial regulation is a key contributor to AD risk, yet existing methods have not examined rare non-coding effects that incorporate such cell-type-specific information. To address this gap, we (1) define per-gene non-coding RV test sets using predicted enhancer and promoter regions in microglia and other brain cell types (oligodendrocytes, astrocytes, and neurons) and (2) include cell-type-specific variant effect predictions (VEPs) as functional annotations. gruyere identifies 13 significant genetic associations not detected by other RV methods, four of which remain significant in omnibus tests. We find that deep-learning-based VEPs for splicing, transcription factor binding, and chromatin state are highly predictive of functional non-coding RVs. Our study establishes a robust framework incorporating functional annotations, coding RVs, and cell-type-associated non-coding RVs to perform genome-wide association tests, uncovering AD-relevant genes and annotations.},
}

@article {pmid40840144,
year = {2025},
author = {Espinoza-Gutiérrez, HA and López-Salido, SC and Flores-Soto, ME and Tejeda-Martínez, AR and Bañuelos-Pineda, J and Viveros-Paredes, JM},
title = {β-Caryophyllene's potential modulation of the renin-angiotensin system: Implications for anosmia and neuroinflammation in the olfactory circuitry.},
journal = {International immunopharmacology},
volume = {164},
number = {},
pages = {115373},
doi = {10.1016/j.intimp.2025.115373},
pmid = {40840144},
issn = {1878-1705},
abstract = {The sense of smell perceives odorants via the olfactory circuitry. Sense of smell is essential for multiple species, while its loss in humans (Anosmia) has been described in COVID-19, Parkinson's and Alzheimer's diseases, where neuroinflammation is a common denominator. Olfactory circuitry is proximal to the respiratory tract, therefore, is susceptible to foreign particles intromission that trigger neuroinflammation. The brain Renin-Angiotensin System (RAS) influence neuroinflammation through its counter-regulatory axes: The pro-inflammatory Renin/(Pro)Renin Receptor ((P)RR) axis and the anti-inflammatory Angiotensin-Converting Enzyme 2 (ACE2)/Angiotensin-(1-7) (Ang-(1-7))/Mas Receptor (MasR) axis. Certain phytochemicals with angiotensinergic activity may improve neuroinflammation. Among these, β-Caryophyllene, stands out for its bicyclic sesquiterpenoid structure and its activity toward multiple targets, including the Cannabinoid Receptor 2 and the peripheral ACE2/Ang-(1-7)/MasR axis. It is still unknown whether β-Caryophyllene affects the brain RAS, especially in vulnerable regions to neuroinflammation, like the olfactory circuitry. This study aims to explore the angiotensinergic effect of β-Caryophyllene on anosmia and the neuroinflammation of the olfactory circuitry. Male BALB/c mice were intranasally administered with lipopolysaccharide and orally treated with β-Caryophyllene for seven days. Multiple parameters concerning RAS, olfaction, neuroinflammation, cell death and stress were evaluated. Results demonstrate that β-Caryophyllene improved anosmia, increased ACE2 and Ang-(1-7) levels, reduced pro-inflammatory cytokines as well as reduced corticosterone levels and cell death. Molecular docking showed favorable interactions between β-Caryophyllene and ACE2. Therefore, β-Caryophyllene could be useful against anosmia and neuroinflammation due to the possible regulation of the RAS.},
}

@article {pmid40839938,
year = {2025},
author = {Becker, JL and MacDonald, ME and Vessey, KA and Williams, RJ},
title = {Choroid plexus volume and its association with cognitive performance across the lifespan: Links to sleep quality and healthy brain aging.},
journal = {Neurobiology of aging},
volume = {156},
number = {},
pages = {40-49},
doi = {10.1016/j.neurobiolaging.2025.08.003},
pmid = {40839938},
issn = {1558-1497},
abstract = {The choroid plexus (ChP) is implicated in inflammation and supports the clearance of waste byproducts, particularly those related to the pathogenesis of Alzheimer's disease. Increases in ChP volume have been associated with older age and cognitive decline in both clinical and healthy cohorts. However, the clearance of waste products in the brain is also related to sleep, and sleep quality may contribute to ChP dysfunction and cognitive decline. In the present work, it was therefore hypothesized that the association between age and cognitive performance is mediated by ChP volume, however this is conditional on sleep quality. A moderated-mediation model was tested on a sample (N = 590) of healthy adults aged 18-87 years from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN). Results showed that the relationship between increasing age and decreased cognitive performance was partially mediated by ChP volume, however, this was not conditional on sleep quality. A moderation analysis indicated that the relationship between ChP volume and cognitive performance was moderated by age, with ChP enlargement associated with worse cognitive performance in participants older than 62 years. In participants younger than 62 years, sleep duration was associated with cognitive performance, but ChP volume was not. These findings provide support for the sensitivity of ChP volume to cognitive performance in older adults.},
}

@article {pmid40839917,
year = {2025},
author = {He, F and Hofmann, J and Poeta, E and Monti, B and Crouzier, L and Maurice, T and Decker, M},
title = {Vitamin K-Trolox synergism realized in hybrid neuroprotectant with potent anti-ferroptosi/oxytosis activity, reduced toxicity, and in vivo efficacy in Alzheimer's disease mouse model.},
journal = {European journal of medicinal chemistry},
volume = {299},
number = {},
pages = {118068},
doi = {10.1016/j.ejmech.2025.118068},
pmid = {40839917},
issn = {1768-3254},
abstract = {In pursuit of developing advanced neuroprotective agents for neurodegenerative disorders, we rationally designed a series of novel hybrid molecules through structural integration of a vitamin K derivative with well-known antioxidants (ferulic acid, melatonin, α-lipoic acid, and Trolox, respectively). Systematic pharmacological evaluation revealed that most hybrids exhibited superior antioxidant activity in both DPPH radical scavenging and ORAC assays. Among these, a Trolox-vitamin K conjugate (compound 16e) emerged as a promising compound, demonstrating exceptional neuroprotective efficacy across multiple neuronal injury models, including oxytosis, ferroptosis, and ATP depletion in HT22 hippocampal neurons. Mechanistic studies confirmed that this compound preserved synergistic cytoprotective effects of its parent pharmacophores against ferroptosis while concurrently exhibiting immunomodulatory activity in microglial cells. Notably, it significantly ameliorated Aβ25-35-induced cognitive deficits in a murine Alzheimer's disease model at a very low dose (0.1 mg/kg, i.p.), outperforming conventional neuroprotectants in therapeutic potency. These findings position this Trolox/vitamin K hybrid molecule as a neuroprotective candidate with translational potential for treating neurodegenerative pathologies.},
}

@article {pmid40839866,
year = {2025},
author = {Cornelius, G and Hodgson, W and Maguire, R and Egan, K},
title = {Wearable Technology, Smart Home Systems, and Mobile Apps for the Self‑Management of Patient Outcomes in Dementia Care: Systematic Review.},
journal = {Journal of medical Internet research},
volume = {27},
number = {},
pages = {e65385},
doi = {10.2196/65385},
pmid = {40839866},
issn = {1438-8871},
mesh = {*Dementia/therapy ; Humans ; *Mobile Applications ; *Wearable Electronic Devices ; Quality of Life ; *Self-Management ; },
abstract = {BACKGROUND: The dementia landscape has evolved, with earlier diagnoses, improved prevention understanding (eg, modifiable factors), and new treatments. Emerging digital technologies (eg, wearables, smart home systems, and mobile apps) offer self‑management opportunities; yet, gaps persist regarding integration into the care needs and preferences of people with dementia. Broader gaps remain concerning intervention design; adaptation; and implementation, including effectiveness, study quality, and accessibility.

OBJECTIVE: This systematic review aims to synthesize and critically appraise existing literature on digital self-management technologies (wearables, smart home systems, and mobile apps) intended to reduce dementia-associated behaviors, enhance self-management, and improve quality of life (QoL). It evaluates intervention characteristics, effectiveness, accessibility, study design, and methodological quality according to international standards.

METHODS: A systematic search across 9 databases (PubMed, Scopus, ACM Digital Library, CINAHL, PsycInfo, Web of Science, IEEE Xplore, Embase, and MEDLINE) identified relevant English‑language studies published between January 1, 2013, and September 30, 2023. Search terms covered dementia, QoL, behavioral and self‑management strategies, and digital technologies. Eligible studies involved adults with dementia using wearable, smart home, or mobile technologies targeting QoL, behavior, and autonomy. Two reviewers independently appraised study design, hardware, and intervention purpose. Outcomes were mapped to the Nursing Outcomes Classification and benchmarked against National Institute for Health and Care Excellence quality standard 184. Accessibility was evaluated by availability, cost, usability, and context. Bias mitigation included a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)‑guided strategy and PROSPERO registration. Methodological quality and bias were assessed using the Mixed Methods Appraisal Tool, the Critical Appraisal Skills Program, and a bespoke characterization framework.

RESULTS: Twenty-four studies evaluated interventions based on wearables, smart home systems, or apps for people with dementia and carers. Outcomes centered on neurocognition (24/24, 100%), self-care (17/24, 71%), and health behavior (13/24, 54%). Identified needs included managing distress (15/24, 62%) and supporting carers (15/24, 62%). Technologies included commercial tools (activity trackers, health-based wearables, and digital prompters) but were often inaccessible due to complex setup requirements and ongoing support needs. Substantial methodological heterogeneity precluded meta-analysis, necessitating narrative synthesis. Study quality was generally good to excellent, but samples were small, reporting incomplete, and outcomes unblinded. Only 1 (17%) of 6 randomized controlled trials reported effect sizes, indicating moderate decline in QoL at 24 months; effectiveness in other studies remains uncertain.

CONCLUSIONS: Research on digital technologies for dementia self‑management shows benefits, particularly with off‑the‑shelf devices and mobile apps supporting person‑centered outcomes. Notable limitations include inadequate participant diversity (eg, atypical dementias and minoritized populations) and insufficient high‑quality research on QoL and behavioral outcomes, such as symptom management and self‑control. Future research must prioritize innovative solutions enhancing accessibility and usability, emphasizing simplified configuration, personalized adaptability, and effective training and support structures.

TRIAL REGISTRATION: PROSPERO CRD42023461841; https://www.crd.york.ac.uk/PROSPERO/view/CRD42023461841.},
}

*Dementia/therapy
Humans
*Mobile Applications
*Wearable Electronic Devices
Quality of Life
*Self-Management

@article {pmid40839564,
year = {2025},
author = {Larsson, V and Hall, S and Blennow, K and Hansson, O},
title = {Olfactory dysfunction and amyloid-positivity in Parkinson's disease-longitudinal analysis of cognitive decline and cerebrospinal fluid markers.},
journal = {PloS one},
volume = {20},
number = {8},
pages = {e0325560},
doi = {10.1371/journal.pone.0325560},
pmid = {40839564},
issn = {1932-6203},
mesh = {Humans ; *Parkinson Disease/cerebrospinal fluid/complications/physiopathology ; Male ; Female ; Biomarkers/cerebrospinal fluid ; Aged ; Longitudinal Studies ; *Cognitive Dysfunction/cerebrospinal fluid ; Middle Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Olfaction Disorders/cerebrospinal fluid ; Cross-Sectional Studies ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; },
abstract = {BACKGROUND: Olfactory dysfunction is a common non-motor symptom in Parkinson's disease (PD). The objective was to evaluate the association between olfaction in PD with cross-sectional and longitudinal assessments of clinical variables and novel cerebrospinal fluid (CSF) markers.

METHODS: Patients with PD and baseline olfactory function assessed using the Brief Smell Identification Test (B-SIT) were included from the BioFINDER-1 cohort. Clinical variables, CSF measures and disease status were assessed longitudinally for up to 11 years. CSF was analyzed using Roche Elecsys® NeuroToolKit, including biomarkers of neurodegeneration, glial activation, neuroinflammation and the core Alzheimer disease biomarkers.

RESULTS: A total of 172 patients with PD were included, 63 with normal olfactory function and 109 with hyposmia. No differences were seen in clinical variables at baseline. Glial fibrillary acidic protein was the only CSF marker differing at baseline, being elevated in hyposmic patients with PD (12.25 ± 3.87 vs 10.46 ± 3.68, p = 0.001). At follow-up, olfactory function declined predominantly in patients with normal olfaction at baseline (β = -0.25 [-0.40 to -0.12], p = 0.001). Patients with PD with both olfactory dysfunction and amyloid-positivity (defined by the CSF Aβ42/Aβ40 ratio) declined faster in several cognitive and motor measures. Olfaction and amyloid-status were independently associated with increased risk of progressing to dementia (B-SIT score, HR = 0.77 [0.67-0.88] and amyloid-positivity, HR = 4.47 [2.30-8.67]).

CONCLUSIONS: Olfactory dysfunction and amyloid-positivity are independently associated with a higher rate of cognitive decline and progression to dementia in patients with PD. Novel CSF markers of neurodegeneration and glial-activity do not differ depending on olfactory status in PD.},
}

Humans
*Parkinson Disease/cerebrospinal fluid/complications/physiopathology
Male
Female
Biomarkers/cerebrospinal fluid
Aged
Longitudinal Studies
*Cognitive Dysfunction/cerebrospinal fluid
Middle Aged
*Amyloid beta-Peptides/cerebrospinal fluid
*Olfaction Disorders/cerebrospinal fluid
Cross-Sectional Studies
Glial Fibrillary Acidic Protein/cerebrospinal fluid

@article {pmid40839331,
year = {2025},
author = {Rocha-de-Lossada, C and Burguera, N and Fernández, J and Ribeiro, F and Ursell, P and Serrano-Castro, PJ and Dick, HB},
title = {Cataract Surgery in Cognitive Impairment: Navigating the Accessibility Challenge in European Healthcare.},
journal = {Ophthalmology and therapy},
volume = {},
number = {},
pages = {},
pmid = {40839331},
issn = {2193-8245},
abstract = {This narrative review examines the challenges of providing cataract surgery to people living with cognitive impairment within European healthcare systems. It highlights the significant unmet need for improved ophthalmological management of this vulnerable population, given the established link between visual impairment, cognitive decline, and quality of life. While the benefits of cataract surgery in improving vision and cognition are well-documented, significant inconsistencies exist across European healthcare systems regarding protocols and access. The review examines the relationship between cognitive impairment and cataract surgery outcomes, identifies gaps in current practices, and proposes potential solutions to improve access and outcomes for this patient group, emphasizing the need for person-centered care, integrated pathways, and improved pre- and post-operative management. Ultimately, the authors advocate for a more coordinated and holistic approach involving ophthalmologists, geriatricians, and cognitive impairment specialists to ensure comprehensive care for this population.},
}

@article {pmid40839240,
year = {2025},
author = {Hsu, YC and Lin, MC and Su, MH and Cheng, CF and Pan, YJ and Fan, CC and Chen, CY and Wu, CS and Wang, SH},
title = {Education as a Modifier of Genetic Influence on Cognitive Ability in Older Adults.},
journal = {Behavior genetics},
volume = {},
number = {},
pages = {},
pmid = {40839240},
issn = {1573-3297},
support = {CG-112-GP-10, CG-113-GP-10, CG-114-GP-10, NHRI-EX109-10931PI, NHRI-EX110-10931PI, NHRI-EX111-10931PI//National Health Research Institutes/ ; NSTC111-2628-B-400-004-MY3//National Science and Technology Council/ ; },
abstract = {Whether education modifies genetic influences on cognition has not been fully explored, especially in non-European populations. Using the older adult cohort from the Taiwan Biobank of East Asian populations, this study aimed to investigate the modifying effect of education on the association of the apolipoprotein E (APOE) ε4 allele and polygenic scores (PGS) for Alzheimer's disease (PGSAD), cognitive performance (PGSCP), education attainment (PGSEA), and schizophrenia (PGSSCZ) with cognitive ability. Participants aged > 60 years were included in this cohort study. The Mini-Mental State Examination (MMSE) was used for cognitive assessment of 27,343 individuals at baseline (mean age: 63.57 years), and follow-up data were available for 6,273 participants. Linear regression models were employed to examine the association between genetic factors and baseline MMSE scores and MMSE decline and further stratified by education to test the modifying effect. The APOE ε4 allele, PGSAD, PGSCP, PGSEA, and PGSSCZ were associated with baseline MMSE but not MMSE decline. The positive effects of the PGSCP and PGSEA on baseline MMSE, and negative effect of the PGSSCZ on baseline MMSE and MMSE decline were higher for individuals with lower education. This study demonstrated the transferability of European-derived PGSs to older community samples of East Asian populations. Education mitigates specific genetic effects on cognition, which supports and extends cognitive reserve theory. Promoting cognitive health in older adults by extending education is of importance, especially for populations with higher genetic predispositions and lower education attainment.},
}

@article {pmid40839147,
year = {2025},
author = {Mohamed Yusof, NIS and Ramasamy, K and Mohd Fauzi, F},
title = {Elucidating the Neuroprotective Mechanism of 5,7-Dimethoxyflavone and 5,7',4'-Trimethoxyflavone Through In Silico Target Prediction and in Memory-Impaired Mice.},
journal = {Neurochemical research},
volume = {50},
number = {5},
pages = {274},
pmid = {40839147},
issn = {1573-6903},
mesh = {Animals ; Mice ; Molecular Docking Simulation/methods ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Flavones/pharmacology/therapeutic use ; Male ; *Memory Disorders/drug therapy/metabolism/chemically induced ; Maze Learning/drug effects ; Computer Simulation ; Hippocampus/drug effects/metabolism ; Lipopolysaccharides ; },
abstract = {5,7-dimethoxyflavone (DMF) and 5,7,4'-trimethoxyflavone (TMF) are natural methoxyflavones known for their potential neuroprotective properties. This study investigates their mechanisms of action through in silico target predictions and memory-impaired mice. Ligand-based and proteochemometric models were used to predict potential protein targets, followed by molecular docking using PyRx and Discovery Video Visualiser. To validate these findings, DMF and TMF (10/20/40 mg/kg) were administered to LPS-induced mice for 21 days. Morris Water Maze (MWM) and Open Field Test (OFT) were conducted to assess cognitive functions. Expression levels of predicted targets were determined by RT-PCR, and enzyme-linked immunosorbent assay was conducted to measure BDNF, Aβ, and pro-inflammatory markers. GABRA1, GABRG2, 5-HT2A, IGF1R, and 5-HT2C were predicted for DMF. Meanwhile, GABRG2, 5-HT2A, 5-HT2B, and 5-HT2C were predicted for TMF. Molecular docking showed DMF formed strong binding interactions with GABRA1 and GABRG2 (9.40 kcal/mol), interacting with His102 and Tyr160. Meanwhile, TMF formed strong binding interactions with 5-HT2A (- 9.30 kcal/mol) interacting with Ser242 and Ser159. TMF enhanced spatial memory in MWM, while both compounds reduced anxiety-related measures in OFT. DMF significantly upregulated hippocampal mRNA of GABRA1, 5-HT2A, and 5-HT2C, while TMF increased GABRG2, 5-HT2B, and 5-HT2C expression. Additionally, both compounds significantly reduced Aβ, IL-1β, IL-6, and TNF-α levels, while DMF-treated groups significantly increased BDNF level. These findings suggest that DMF and TMF exert neuroprotective effects when administered prophylactically, acting through distinct molecular targets involved in neurotransmission and inflammation. Their multi-target activity makes them promising candidates for early intervention in Alzheimer's disease.},
}

Animals
Mice
Molecular Docking Simulation/methods
*Neuroprotective Agents/pharmacology/therapeutic use
*Flavones/pharmacology/therapeutic use
Male
*Memory Disorders/drug therapy/metabolism/chemically induced
Maze Learning/drug effects
Computer Simulation
Hippocampus/drug effects/metabolism
Lipopolysaccharides

@article {pmid40839108,
year = {2025},
author = {Mukherjea, N and Khandelwal, A and Saluja, R and Kalra, N},
title = {The Role of the human microbiome in neurodegenerative diseases: A Perspective.},
journal = {Current genetics},
volume = {71},
number = {1},
pages = {17},
pmid = {40839108},
issn = {1432-0983},
mesh = {Humans ; *Neurodegenerative Diseases/microbiology ; *Microbiota ; Parkinson Disease/microbiology ; *Gastrointestinal Microbiome ; Alzheimer Disease/microbiology ; Inflammasomes ; Inflammation/microbiology ; },
abstract = {Advances in diagnostics, therapeutics, and large-scale clinical studies have significantly expanded our understanding how human health is shaped by the microorganisms that colonize the body since birth. This article explores the rapidly evolving field of human microbiome research, focusing upon how microbial communities influence neurological health and contribute to the development of neurodegenerative diseases (NDs). Multiple factors, including age, lifestyle, and immunological memory, are recognized as major determinants of an individual's microbiome composition, which in turn can influence the onset and the progression of disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions have been linked to mechanisms including the aggregation of pathogenic proteins (e.g., amyloid-β and α-synuclein), inflammation driven by activation of the Toll-like receptor (TLR) signaling pathway, the NLRP3 inflammasome, as well as the modulatory effect of microbial metabolites such as short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS). The article also highlights ongoing research and emerging strategies aimed at leveraging the human microbiome for better diagnosis, and management of NDs.},
}

Humans
*Neurodegenerative Diseases/microbiology
*Microbiota
Parkinson Disease/microbiology
*Gastrointestinal Microbiome
Alzheimer Disease/microbiology
Inflammasomes
Inflammation/microbiology

@article {pmid40839040,
year = {2025},
author = {Pedrosa, ME and Martin, V and Fernandes, MH and Gomes, PS},
title = {Gingipain inhibitors as an innovative therapy for periodontal and associated-systemic diseases: a systematic review.},
journal = {Clinical oral investigations},
volume = {29},
number = {9},
pages = {418},
pmid = {40839040},
issn = {1436-3771},
mesh = {*Gingipain Cysteine Endopeptidases/antagonists & inhibitors ; Humans ; *Periodontal Diseases/drug therapy ; *Cysteine Proteinase Inhibitors/therapeutic use/pharmacology ; Porphyromonas gingivalis/enzymology ; },
abstract = {UNLABELLED: Periodontal diseases (PDs) are prevalent chronic inflammatory conditions linked to the progression of systemic disorders. Gingipains, cysteine proteases produced by Porphyromonas gingivalis, are key virulence factors involved in PD pathogenesis and host-tissue degradation. Inhibiting these enzymes has emerged as a promising therapeutic approach.

OBJECTIVE: This systematic review evaluates the potential of gingipain inhibitors in the management of PDs and related systemic conditions.

METHODS: A systematic search was conducted across PubMed, Scopus, and Web of Science using the PICOS framework. Studies were evaluated based on their objectives, experimental models, inhibitor types, and outcomes.

RESULTS: Seven preclinical studies met the inclusion criteria. No clinical studies were identified. In preclinical models, gingipain inhibitors demonstrated consistent therapeutic benefits, including reduced inflammation, bacterial load, and tissue destruction in PDs, as well as improved outcomes in cardiovascular and AD models. Dual inhibitors targeting both Rgp and Kgp enzymes were more effective than single-target agents.

CONCLUSION: Gingipain inhibitors hold promise as therapeutic agents for PDs and associated systemic diseases. However, the absence of clinical studies highlights the need for further development and clinical evaluation to support their translational potential.

CLINICAL RELEVANCE: By targeting specific and key components of host-bacterium interactions, gingipain inhibitors represent a promising adjunctive therapy for modulating periopathogen virulence factors, thereby mitigating the progression of PDs and associated systemic diseases.},
}

*Gingipain Cysteine Endopeptidases/antagonists & inhibitors
Humans
*Periodontal Diseases/drug therapy
*Cysteine Proteinase Inhibitors/therapeutic use/pharmacology
Porphyromonas gingivalis/enzymology

@article {pmid40838975,
year = {2025},
author = {Yao, J and Wang, S and Deng, C and Ren, H and Zhang, K and Liu, Q and Wang, Y and Yue, T and Yan, B},
title = {Harnessing Nanotechnology for Cellular Health through Strategic Modulation and Nanoscale Control of Electron Mobility.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.5c04030},
pmid = {40838975},
issn = {1936-086X},
abstract = {Excessive oxidative stress in human cells is linked to aging and underpins pathologies such as Alzheimer's disease, diabetes, and cancer. Understanding the molecular mechanisms behind this is crucial, and to this end, cell models that can produce varying levels of oxidative stress are essential. This work has achieved this by creating a library of gold nanoparticles (GNPs) with diverse ferrocene-containing ligands and incorporating them into human cells in nontoxic doses. These GNPs create cell models with different levels of oxidative stress. The roles of these ligands in controlling oxidative stress were elucidated through first-principles calculations. It was found that substituents covalently adjacent to the ferrocene in the ligand significantly influence electron mobility within the ferrocene group, thereby playing a predominant role (75.6%) in modulating the redox activity of the GNPs. In contrast, the presence of distal substituents, which are not directly bonded to ferrocene, was found to have a lesser (24.4%) yet noteworthy impact on this activity through intramolecular interactions adjusting atomic charge redistribution. This mechanistic understanding of how nanostructures control cellular redox activities enriches our knowledge of nanobio interactions. It also introduces advanced methods for precisely regulating cellular oxidative stress levels and represents a significant advancement in leveraging nanotechnology for targeted redox therapies.},
}

@article {pmid40838713,
year = {2025},
author = {Noor, SM and Reddy, DH and Srikanth, Y and Viswanadh, MK and Dumala, N and Chakravarthy, G and Nalluri, BN and Naryanarao, A and Duguluri, S and Yadagiri, G and Prasanna, VS and Sundaram, S and Gujjari, L and Ramakrishna, K},
title = {Morin hydrate: a comprehensive review on therapeutic potential in treating neurological diseases.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/1028415X.2025.2544605},
pmid = {40838713},
issn = {1476-8305},
abstract = {Background: Morin hydrate is a polyphenolic flavonoid present in various vegetables, fruits, nuts, and sea products. It has been reported to offer multiple protective effects against a range of diseases, including cancer, cardiovascular, liver, neurological, metabolic, and renal disorders.Objective: This review highlights the molecular mechanisms and therapeutic potential of Morin in neurological diseases, including Parkinson's disease, Alzheimer's disease, traumatic brain injury, neuropathic pain, stroke, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, depression, anxiety, sleep, encephalopathy, schizophrenia, and psychosis, etc.Methods: The research and review articles were collected from the Pubmed, Scopus, Web of Science, and Google Scholar databases using 'Morin' and the above-mentioned neurological diseases as keywords.Results: The neuroprotective effects of Morin are primarily attributed to its ability to mitigate oxidative stress, inflammation, excitotoxicity, calcium dysregulation, mitochondrial dysfunction, neurotransmitter alterations, protein modifications, and enzymatic inhibition.Conclusion: Despite its promising pharmacological profile, the clinical adaptation of Morin for combating neurological diseases requires further validation through comprehensive preclinical and clinical investigations.},
}

@article {pmid40838707,
year = {2025},
author = {Allison, TR and La'ulu, SL and Doyle, K and Nelson, HA},
title = {Evaluation of preanalytical factors on quantification of amyloid-β (1-42), phosphorylated tau 181, and total tau in cerebrospinal fluid.},
journal = {Laboratory medicine},
volume = {},
number = {},
pages = {},
doi = {10.1093/labmed/lmaf044},
pmid = {40838707},
issn = {1943-7730},
abstract = {INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers for Alzheimer disease are US Food and Drug Administration approved and implemented on automated platforms, allowing for widespread use and higher throughput. Although low-bind polypropylene tubes for accurate quantification of amyloid-β (Aβ) have been well studied, less is known about the impact of other common preanalytical variables on quantification of biomarkers for Alzheimer disease. This study evaluated the effects of refrigerated transportation and hemolysis on the concentrations of Aβ42, phosphorylated tau 181, and total tau.

METHODS: The Roche Diagnostics Elecsys β-Amyloid (1-42) CSF II, Elecsys Phospho-Tau (181P) CSF, and Elecsys Total-Tau CSF assays were used on the Roche cobas pro e 801 platform to measure protein concentrations in residual CSF samples. Paired-difference testing was performed to determine the effects of simulated transportation and hemolysis on each analyte.

RESULTS: For all 3 analytes, less than 10% difference was observed between the concentrations measured on day 0 and after 14 days of transportation and refrigeration. In contrast, 2.26 g/L free hemoglobin resulted in more than 10% negative bias in Aβ42 measurement compared with the 0 g/L control but did not affect phosphorylated tau 181 or total tau concentrations.

DISCUSSION: Refrigerated transportation did not affect the analysis of Aβ42, phosphorylated tau 181, or total tau, whereas hemolysis can negatively affect results of Aβ42.},
}

@article {pmid40838518,
year = {2025},
author = {Howard, CW and Reich, M and Luo, L and Pacheco-Barrios, N and Alterman, R and Rios, AS and Guo, M and Luo, Z and Friedrich, H and Pines, A and Montaser-Kouhsari, L and Drew, W and Hart, L and Meyer, G and Rajamani, N and Friedrich, MU and Milanese, V and Lozano, A and , and Picht, T and Faust, K and Horn, A and Fox, MD},
title = {Cognitive outcomes of deep brain stimulation depend on age and hippocampal connectivity in Parkinson's and Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70498},
doi = {10.1002/alz.70498},
pmid = {40838518},
issn = {1552-5279},
support = {//Canadian Clinician Investigator Program/ ; },
mesh = {Humans ; *Deep Brain Stimulation/methods ; *Parkinson Disease/therapy/physiopathology ; *Alzheimer Disease/therapy/physiopathology ; *Hippocampus/physiopathology/pathology ; Male ; Female ; Aged ; *Cognition/physiology ; Age Factors ; Subthalamic Nucleus ; Middle Aged ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: Here we contrast cognitive outcomes of deep brain stimulation (DBS) in Parkinson's disease (PD) with Alzheimer's disease (AD) to isolate the shared effect of DBS upon cognition while filtering out disease-specific effects. Based on prior literature, we evaluate how DBS connectivity to the hippocampus influences cognition. We then evaluate how patient factors moderate this relationship.

METHODS: We studied electrode locations and cognitive outcomes in patients who received subthalamic nucleus (STN) DBS for PD (2 datasets: n = 33, n = 28) or fornix DBS for AD (1 dataset: n = 46). We then investigate the moderating effect of patient factors and similarities across diseases.

RESULTS: DBS site connectivity to the hippocampus was cognitively deleterious in PD but beneficial in AD. The opposite findings were driven by patient age. This effect was mediated by age-related hippocampal atrophy.

DISCUSSION: The shared cognitive effects of DBS across PD and AD depend on hippocampal connectivity and age.

HIGHLIGHTS: Cognition can be positively or negatively modulated in the same manner across diseases. Contrary to current clinical practice, older Parkinson's disease (PD) patients may benefit from deep brain stimulation (DBS). Our results support limiting enrollment to patients over 65 for Alzheimer's disease (AD) DBS, an emerging therapy currently in a phase 3 clinical trial. Hippocampal volume mediates the impact of DBS, suggesting patient atrophy must be considered in patient-specific care.},
}

Humans
*Deep Brain Stimulation/methods
*Parkinson Disease/therapy/physiopathology
*Alzheimer Disease/therapy/physiopathology
*Hippocampus/physiopathology/pathology
Male
Female
Aged
*Cognition/physiology
Age Factors
Subthalamic Nucleus
Middle Aged
Magnetic Resonance Imaging

@article {pmid40838403,
year = {2025},
author = {Rodríguez Sarmiento, RM},
title = {A Career Long Effort to Discover a Drug to Treat Neurodegenerative Diseases. My Adventures with γ-Secretase for the Treatment of Alzheimer's.},
journal = {Chimia},
volume = {79},
number = {7-8},
pages = {509-515},
doi = {10.2533/chimia.2025.509},
pmid = {40838403},
issn = {0009-4293},
mesh = {*Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy ; Humans ; *Drug Discovery ; *Neurodegenerative Diseases/drug therapy ; Amyloid beta-Peptides/metabolism ; },
abstract = {Neurodegenerative diseases encompass a range of chronic diseases marked by the progressive loss of structure or function of the nervous system, particularly within areas of the brain such as the neurons (or nerve cells). This degeneration leads to a decline in cognitive abilities, motor skills, and other neurological functions. The progression can be gradual, occurring over years or even decades, and often leads to significant disability and, ultimately, death. Alzheimer's disease (AD) is the most prevalent degenerative disease that affects cognition and that rises dramatically with age. It is a progressive, chronic disease that occurs when nerve cells in the brain die. Current treatments largely address symptoms without altering or reversing disease progression. However, recent advancements with amyloid-β (Aβ) antibodies validate Aβ as a therapeutic target for AD. This article details my long-term experience as a medicinal chemist and project leader working on γ-secretase, a key target in AD drug discovery. I will share initial insights from a multi-disciplinary effort to discover a disease modifying treatment for Alzheimer's disease.},
}

*Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors
*Alzheimer Disease/drug therapy
Humans
*Drug Discovery
*Neurodegenerative Diseases/drug therapy
Amyloid beta-Peptides/metabolism

@article {pmid40838204,
year = {2025},
author = {O'Donald, F and Calia, C and Parra, MA},
title = {Examining the Cognitive Underpinnings of Functional Decline in Prodromal Alzheimer's Disease: Insights From the Details of Functions of Everyday Life (DoFEL) Scale.},
journal = {Journal of aging research},
volume = {2025},
number = {},
pages = {2610700},
pmid = {40838204},
issn = {2090-2204},
abstract = {Available assessments for early-stage Alzheimer's disease (AD) identify neuropsychological and functional impairments, which rarely correlate in the early disease stages. The ability to bind information in memory declines in preclinical AD stages. However, it is unclear whether such cognitive deficits underlie functional impairment in prodromal AD stages. This study investigates whether incorporating memory binding, a function that is a sensitive cognitive marker for early-stage AD, into a functional assessment tool can reveal the cognitive underpinnings of daily activities. The Details of Function of Everyday Life (DoFEL) scale was revised, and its latent structure was explored through principal axis factoring in a nonclinical sample (n = 559). Dementia professionals subsequently reviewed the revised DoFEL for content validity, followed by confirmatory factor analysis in another nonclinical sample (n = 135). Additionally, 49 participants with mild cognitive impairment (MCI) and 33 healthy controls completed the DoFEL, Addenbrooke's Cognitive Examination-Revised (ACE-R) and a Visual Short-Term Memory Binding Task (VSTMBT). Correlation analysis and binomial regression were used to examine the relationship between DoFEL scores and cognitive measures and to assess its ability to differentiate between healthy controls and MCI patients. The revised DoFEL showed satisfactory structural and construct validity, although some items lacked content validity. Significant negative associations were found between DoFEL scores and ACE-R (r = -0.66, p < 0.001) as well as VSTMBT (r = -0.52, p=0.003) performances. Binomial regression demonstrated the DoFEL's effectiveness in distinguishing healthy controls from MCI patients (AUC = 0.95). These findings suggest that linking memory binding with functional performance could enhance functional assessment in early-stage AD.},
}

@article {pmid40838083,
year = {2025},
author = {Sekikawa, A and Wharton, W and Murray-Krezan, C and Wu, M and Chang, Y and Snitz, BE and Coccari, M and Yang, S and Love, ML and Cusick, D and Wang, R and Li, M and Park, C and Li, J and DeConne, TM and Smith, C and Verble, DD and Lancet, MQ and Foroud, T and Kim, T and Nadkarni, NK and Mettenburg, JM and Zamora, E and Lopez, OL and Hughes, TM},
title = {ACE trial design: Equol targeting estrogen receptor-β in vascular and cognitive aging.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70144},
pmid = {40838083},
issn = {2352-8737},
abstract = {INTRODUCTION: Equol, a gut microbiome-derived metabolite of soy isoflavone daidzein, functions as a selective estrogen receptor beta (ERβ) agonist. In preclinical studies, it has demonstrated vascular protective and antioxidant effects, with emerging evidence suggesting potential neuroprotective properties. However, its role in preventing vascular aging and cognitive decline in humans remains unexplored. The Arterial Stiffness, Cognition, and Equol (ACE) trial investigates whether daily equol supplementation can slow the progression of arterial stiffness, brain white matter lesions, and cognitive decline in older adults without dementia.

METHODS: ACE is a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted at the University of Pittsburgh, Wake Forest University, and Emory University. Community-dwelling adults aged 65 to 85 years without dementia were enrolled and randomized 1:1 to receive either 10 mg/day of equol or placebo for 24 months. The primary outcome is arterial stiffness assessed by carotid-femoral pulse wave velocity. Secondary outcomes include white matter lesions detected on the brain magnetic resonance imaging and cognitive function as assessed by the Preclinical Alzheimer Cognitive Composite. Power calculations were based on a planned sample size of 400 participants, accounting for an anticipated 20% attrition rate.

RESULTS: A total of 1783 individuals were pre-screened, and 764 underwent in-person eligibility assessment. Of these, 369 participants were randomized into two groups: Arm A (n = 185) and Arm B (n = 184). The randomized sample self-reported as 52% women and 22% Black/African American participants. Baseline demographic and clinical characteristics were well balanced between the two arms, indicating successful randomization.

DISCUSSION: ACE successfully enrolled a racially diverse population of older adults and achieved near-target recruitment. ACE is the first large-scale trial to evaluate whether equol, a selective ERβ agonist, can impact vascular and cognitive aging, paving the way for precision nutrition strategies in dementia prevention.

HIGHLIGHTS: We detail the first randomized controlled trial of equol, an estrogen receptor beta (ERβ) agonist, for vascular and cognitive aging.The study tested equol's effects on arterial stiffness, white matter lesions, and cognition.The multisite trial enrolled 369 self-reported White and Black older adults aged 65 to 85 years.The trial investigated a novel dietary metabolite targeting ERβ pathways.},
}

@article {pmid40837866,
year = {2025},
author = {Hebert, S and Pederson, EN and Ouyang, Z},
title = {Newly Identified Genetic Associations of Alzheimer Disease by Conditional Selective Inference: Potential Implications for the Tau Hypothesis.},
journal = {Bioinformatics and biology insights},
volume = {19},
number = {},
pages = {11779322251358309},
pmid = {40837866},
issn = {1177-9322},
abstract = {Over 6 million people are estimated to have been living with Alzheimer disease (AD) in 2020, with another 12 million living with Mild Cognitive Impairment (MCI). Research has been conducted to evaluate genetic links to AD, but more research is needed to improve early disease detection and improve patient outcomes. Diagnostic, demographic information, and single nucleotide polymorphism (SNP) data were collected by the Alzheimer's Disease Neuroimaging Initiative (ADNI). We performed LASSO regression with conditional selective inference to perform feature selection on the SNPs and other predictors (which included education, race, and marital status), which reduced the number of SNPs from 55 106 to 13 and removed all non-SNP predictors except years of education and marital status. The included SNPs reside in genes that have clinical significance and may be associated with diseases that affect cognitive performance. The results propose the alternative alleles for 7 SNPs are associated with increased risk of AD/MCI diagnosis, while 6 SNPs are associated with decreased risk of diagnosis. The results point to a new potential pathway of disease regarding the PAK5 gene and the Tau protein hypothesis, which is supported by previous research. This research may have clinical implications and should be further studied.},
}

@article {pmid40837824,
year = {2025},
author = {Amofa-Ho, PA and Fiala, JA and Levy, SA and Marie Ross, K and Walker, AF and Smith, GE},
title = {Interrelationships of Social Determinants with Cognition, Vascular Health, and Physical Functioning.},
journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging},
volume = {1},
number = {2},
pages = {},
pmid = {40837824},
issn = {2997-3805},
abstract = {OBJECTIVES: The primary aim of the current analysis was to evaluate the cumulative effect of different social determinants of health (SDoH) factors on vascular burden, cognition, and physical functioning.

METHODS: We conducted a secondary data analysis of the Midlife in the United States (MIDUS 2) cross-sectional study using data from participants aged 55 and older. Measures derived from the Framingham Stroke Risk Profile, Brief Test of Adult Cognition by Telephone, and physical functioning scores from the Medical Outcomes Study - Short Form 36 items (MOS-SF36) were used to represent vascular burden, cognition, and intermediate activities of daily living, respectively. SDoH variables included education, income, health insurance, stress, and support from family and friends. Associations were evaluated using a composite-based structural equation model (c-SEM) embedded in an overall SEM.

FINDINGS: Among MIDUS participants with no clinical diagnosis of cognitive impairment or neurological disorder (N=568; mean age=64.6), higher education, less stress, and higher income significantly contributed to the SDoH composite. Positive SDoH was associated with better physical functioning (beta=-0.21, p<0.001) and higher cognition (beta=0.54, p<0.001). Significant direct effects of SDoH on vascular burden (beta=-0.12, p<0.05) and cognition (beta=0.51, p< 0.001) and of vascular burden on cognition (beta=-0.28, p<0.001) were found. Mediation analysis indicated that the unique effects of SDoH on cognition remained significant after controlling for vascular burden (beta=0.04, p< 0.05). After accounting for vascular burden and cognition, SDoH did not have a significant unique effect on physical functioning.

CONCLUSION: Our results support the disablement theory, suggesting that factors outside of the disease model (such as SDoH factors) impact diseases that underlie physical and functional limitations.},
}

@article {pmid40837818,
year = {2025},
author = {Si, JY and Lin, ZY and Gan, DG and Zhang, XY and Liu, YN and Hu, YX and Bao, YP and Wang, XQ and Sun, HQ and Yu, X and Lu, L},
title = {Informed consent competency assessment for brain-computer interface clinical research and application in psychiatric disorders: A systematic review.},
journal = {World journal of psychiatry},
volume = {15},
number = {8},
pages = {107593},
pmid = {40837818},
issn = {2220-3206},
abstract = {BACKGROUND: Brain-computer interface (BCI) technology is rapidly advancing in psychiatry. Informed consent competency (ICC) assessment among psychiatric patients is a pivotal concern in clinical research.

AIM: To analyze the assessment of ICC and form a framework with multi-dimensional elements involved in ICC of BCI clinical research among psychiatric disorders.

METHODS: A systematic review of studies regarding ICC assessments of BCI clinical research in patients with six kinds of psychiatric disorders was conducted. A systematic literature search was performed using PubMed, ScienceDirect, and Web of Science. Peer-reviewed articles and full-text studies were included in the analysis. There were no date restrictions, and all studies published up to February 27, 2025, were included.

RESULTS: A total of 103 studies were selected for this review. Fifty-eight studies included ICC factors, and forty-five were classified in ICC related ethical issues of BCI research in six kinds of psychiatric disorders. Executive function impairment is widely recognized as the most significant factor impacting ICC, and processing speed deficits are observed in schizophrenia, mood disorders, and Alzheimer's disease. Memory dysfunction, particularly episodic and working memory, contributes to compromised ICC. Five core ethical issues in BCI research should be addressed: BCI specificity, vulnerability, autonomy, dynamic ICC, comprehensiveness, and uncertainty.

CONCLUSION: A Five-Dimensional evaluative framework, including clinical, ethical, sociocultural, legal, and procedural dimensions, is constructed and proposed for future ICC research in BCI clinical research involving psychiatric disorders.},
}

@article {pmid40837802,
year = {2025},
author = {He, YN and Zhu, HH and Zhou, ZH and Qu, KK},
title = {Exosomal microRNAs in common mental disorders: Mechanisms, biomarker potential and therapeutic implications.},
journal = {World journal of psychiatry},
volume = {15},
number = {8},
pages = {108933},
pmid = {40837802},
issn = {2220-3206},
abstract = {To illustrate the mechanisms of exosomal microRNAs (miRNAs) in common mental disorders, and explore their potential as diagnostic biomarkers and therapeutic targets, a systematic literature review of relevant studies on exosomal miRNAs in mental disorders was conducted. Data from cell experiments, animal models, and clinical studies were analyzed and combined to study the mechanisms and roles of exosomal miRNAs in various mental disorders. Research has shown that exosomal miRNAs, such as miR-146a, miR-223, miR-125b, and miR-451a, affect Alzheimer's disease (AD) formation by regulating key pathways such as toll-like receptor 4 (TLR4) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), respectively. MiR-146a-5p regulates the occurrence of schizophrenia through the Notch pathway. TLR4 regulates miR-146a and miR-155 in major depressive disorder (MDD), and miR-144-5p regulates the disease through PI3K/Akt. Exosomal miR-484, miR-652-3p, miR-142-3p, miR-21a-3p, and miR-21-5p regulate key pathways in bipolar disorder, autism spectrum disorder, and Rett syndrome (e.g., TLR4, PI3K/Akt, and Epha4/TEK) and have an influence on mental disorders. Exosomal miRNAs are involved in the occurrence of mental disorders through TLR4, PI3K/Akt, and Epha4/TEK pathways, which provides a clearer understanding of disease cognition. Of these pathways, the TLR4 and PI3K/Akt pathways play a role in AD, MDD, and neurodevelopmental disorders, which can be used as an effective breakthrough in the study of mental disorders. Exosomal miRNAs could also serve as diagnostic biomarkers and therapeutic targets, providing new insights into precise interventions for mental disorders.},
}

@article {pmid40837623,
year = {2025},
author = {van Weesep, L and Özçelik, R and Pennings, M and Criscuolo, E and Ottmann, C and Brunsveld, L and Grisoni, F},
title = {Identifying 14-3-3 interactome binding sites with deep learning.},
journal = {Digital discovery},
volume = {},
number = {},
pages = {},
pmid = {40837623},
issn = {2635-098X},
abstract = {Protein-protein interactions are at the heart of biological processes. Understanding how proteins interact is key for deciphering their roles in health and disease, and for therapeutic interventions. However, identifying protein interaction sites, especially for intrinsically disordered proteins, is challenging. Here, we developed a deep learning framework to predict potential protein binding sites to 14-3-3 - a 'central hub' protein holding a key role in cellular signaling networks. After systematically testing multiple deep learning approaches to predict sequence binding to 14-3-3, we developed an ensemble model that achieved a 75% balanced accuracy on external sequences. Our approach was applied prospectively to identify putative binding sites across medically relevant proteins (ranging from highly structured to intrinsically disordered) for a total of approximately 300 sequences. The top eight predicted peptide sequences were experimentally validated in the wet-lab, and binding to 14-3-3 was confirmed for five out of eight sequences (K d ranging from 1.6 ± 0.1 μM to 70 ± 5 μM). The relevance of our results was further confirmed by X-ray crystallography and molecular dynamics simulations. These sequences represent potential new binding sites within the 14-3-3 interactome (e.g., relating to Alzheimer's disease as the binding to tau is not the new part), and provide opportunities to investigate their functional relevance. Our results highlight the ability of deep learning to capture intricate patterns underlying protein-protein interactions, even for challenging cases like intrinsically disordered proteins. To further the understanding and targeting of 14-3-3/protein interactions, our model was provided as a freely accessible web resource at the following URL: https://14-3-3-bindsite.streamlit.app/.},
}

@article {pmid40837525,
year = {2025},
author = {Nagai, M and Sible, IJ and Tully, PJ and Po, SS and Dasari, TW},
title = {The effect of visit-to-visit blood pressure variability on cognitive function: state-of the-art.},
journal = {Cerebral circulation - cognition and behavior},
volume = {9},
number = {},
pages = {100392},
pmid = {40837525},
issn = {2666-2450},
abstract = {Visit-to-visit blood pressure (BP) variability (VVV) is a risk factor for cognitive impairment and cognitive decline, but several studies have recently shown that VVV also increases the risk of Alzheimer's disease (AD). Although the relationship between VVV and AD has been extensively studied, its pathophysiology is instructive due to its association with vascular stiffness, cerebral circulatory failure, decreased cardiac function, and AD pathology such as amyloid β and tau-proteins. This review article focuses on the relationship between VVV and cognitive function and summarizes recent studies and the underlying pathophysiology that appears to be mediated by systemic hemodynamic disruption.},
}

@article {pmid40837385,
year = {2025},
author = {Liu, J and Dong, K and Deng, Q and Zou, Z and Chen, S and Feng, N and Wang, J and Huang, H and Wu, Q},
title = {Regulation of aging-related chronic diseases by dietary polyphenols: An updated overview.},
journal = {Current research in food science},
volume = {11},
number = {},
pages = {101163},
pmid = {40837385},
issn = {2665-9271},
abstract = {With the aging of the population, diseases of aging such as Alzheimer's disease, diabetes and coronary heart disease are gradually becoming a key concern in global health. Dietary polyphenols, as a natural antioxidant with biological activities such as anti-inflammatory, anti-glycation, and anticancer, can effectively prevent and treat these diseases through a variety of mechanisms. However, the current means of prevention and control for these age-related diseases are still insufficient, especially the lack of reviews and studies on systematic regulation from a dietary perspective. Therefore, in this paper, we will review the bioactivity of dietary polyphenols and their regulatory mechanisms on aging-related diseases, the relationship between dietary polyphenols and cell signaling pathways and the microbiome, and the creation of polyphenol-based functional anti-aging foods, so as to provide new ideas and methods for the intervention of geriatric diseases from the perspective of dietary regulation.},
}

@article {pmid40837078,
year = {2025},
author = {Govindarajan, R and Thirunadanasikamani, K and Napa, KK and Sathya, S and Murugan, JS and Priya, KGC},
title = {Corrigendum to "Development of an explainable machine learning model for Alzheimer's disease prediction using clinical and behavioural features" [MethodsX 15 (2025) 103491].},
journal = {MethodsX},
volume = {15},
number = {},
pages = {103556},
doi = {10.1016/j.mex.2025.103556},
pmid = {40837078},
issn = {2215-0161},
abstract = {[This corrects the article DOI: 10.1016/j.mex.2025.103491.].},
}

@article {pmid40836982,
year = {2024},
author = {Grados, M and Salehi, M and Lotfi, A and Dua, S and Xie, I},
title = {A selective review of inhibitors of protein kinase C gamma: a neuroplasticity-related common pathway for psychiatric illness.},
journal = {Frontiers in drug delivery},
volume = {4},
number = {},
pages = {1364037},
pmid = {40836982},
issn = {2674-0850},
abstract = {Psychotropics are currently developed and marketed with a limited understanding of their mechanism of action. The notion that protein kinase C (PKC) activity is highly relevant to learning and memory function stems from experiments in the 1980s, which associated protein kinase alpha (pka) and pkc to animal models of associative learning, opening an area of exploration for psychotropic development. The PKC family consists of several isoforms, including PKC alpha, beta1, beta1, gamma, delta and epsilon among others. In particular, PKC gamma (PRKCG) is highly brain-expressed and is singled out as a candidate for modulation in psychiatric illness. With hundreds of identified substrates, PRKCG affects multiple pathways relevant for regulation of neuronal health. In this review, converging lines of evidence are presented in the context of psychotropic drug action, which point to downregulation of PKC activity as a potential common mechanism across several psychiatric disorders. Using this mechanism through more targeted psychotropic action may then be used to develop agents that further ameliorate psychiatric symptom expression. Psychotropics including fluoxetine, tricyclics, lithium, valproate, ketamine and others are explored in relation to their effect of PKC, finding that across all drugs examined, a downregulation with chronic-but not acute-use constitutes their putative effect in ameliorating symptoms. This effect is compounded by findings that suggest that PKCs, and PRKCG in particular, promote neuroplastic effects by their downregulation. This effect is in contrast to PKC activators, which have been used in neurodegenerative disorders such as Alzheimer's disease. Cross-disorder mechanisms need to continue to be explored in neuropsychiatric illness and targeted treatments developed in turn to address treatment-resistant conditions.},
}

@article {pmid40836942,
year = {2025},
author = {Jutten, RJ and Burling, JE and Slade, E and Thompson, JC and Fu, JF and Birkenbihl, C and Properzi, MJ and Marshall, GA and Amariglio, RE and Papp, KV and Johnson, KA and Price, JC and Sperling, RA and Rentz, DM},
title = {The Mobile Toolbox for remote, self-administered cognitive assessment in older adults: associations with in-clinic cognitive testing and Alzheimer's disease biomarkers.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70160},
pmid = {40836942},
issn = {2352-8729},
abstract = {INTRODUCTION: Remote, smartphone-based cognitive assessments such as the Mobile Toolbox (MTB) may increase the accessibility of Alzheimer's disease (AD) clinical trials. We examined the feasibility of the MTB among cognitively unimpaired (CU) older adults and investigated its associations with standardized in-clinic cognitive testing and amyloid and tau positron emission tomography imaging.

METHODS: A total of 100 CU older adults self-administered the MTB remotely on their personal devices. Linear regression models correcting for demographics investigated associations of MTB fluid and crystallized cognition composites with in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) scores, global amyloid-beta burden and tau deposition in the medial-temporal lobe and neocortex.

RESULTS: Most participants completed the MTB without requiring assistance (81%) or reminders (61%). MTB fluid cognition scores were positively associated with PACC-5 scores and negatively with tau deposition in the medial-temporal lobe and neocortex.

DISCUSSION: These findings suggest that the MTB may provide a feasible approach to capture cognitive processes relevant in preclinical AD.

HIGHLIGHTS: The Mobile Toolbox (MTB) is a remote smartphone-based cognitive assessment.We deployed the MTB in CU older adults with Alzheimer's disease (AD) biomarkers.We show how the MTB may facilitate cognitive assessment in preclinical AD research.},
}

@article {pmid40836826,
year = {2025},
author = {Mozafar, M and Shahbazi, S and Amirian, MA and Shekari, K and Sepahvand, N and Esmaeili, M and Amini, A and Shakeri, S and Mirhosseini, H and Mayeli, M and , },
title = {High‑Resolution T2 MRI Volumetry of Medial Temporal Lobe Subregions Predicts Cognitive Decline Across the Alzheimer's Disease Continuum.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/23279095.2025.2546951},
pmid = {40836826},
issn = {2327-9109},
abstract = {Atrophy of medial temporal lobe (MTL) subregions is an early biomarker of Alzheimer's disease (AD). This study aimed to examine the relationship between MTL subregion volumes and cognitive performance in patients across the AD continuum. We analyzed data from 276 participants using the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 74 cognitively normal (CN), 110 subjective memory complaints (SMC), 37 early mild cognitive impairment (EMCI), 35 late mild cognitive impairment (LMCI), and 20 AD participants. MTL subregions volumes were measusing high-resolution T2-weighted MRI, and analyses were adjusted for age, education, APOE ε4 status, and intracranial volume (ICV). Significant atrophy in regions such as the cornu ammonis (CA), dentate gyrus (DG), subiculum (SUB), entorhinal cortex (ERC), and Brodmann area 35 (BA35) was found in AD participants compared with other groups. In AD, poorer Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-13) performance was associated with reduced CA, DG, BA35, and parahippocampal cortex (PHC) volumes. In LMCI, lower Mini-Mental State Examination (MMSE) scores were associated with atrophy in CA and SUB. Diminished Montreal Cognitive Assessment (MoCA) scores were linked to reduced ERC volumes in CN, as well as with atrophy in BA35, ERC and CA subfields among AD patients. In LMCI, poorer Trail Making Test, Part B performance (i.e., longer completion time) was related to smaller Brodmann area 36 (BA36), collateral sulcus (CS), and PHC subregion volumes, whereas in the AD, it was related to BA36 only. Poorer immediate memory recall in AD was associated with atrophy in CA, DG, while in early stages of MCI, poorer verbal learning scores correlated with atrophy in the CA, DG, BA35, SUB, and CS regions. Moreover, diminished Logical Memory Delayed Recall was associated with atrophy in the CA, BA35, and PHC subfields among AD subjects. These findings support the value of atrophy in MTL subregions as potential imaging markers for detecting and monitoring cognitive decline across the AD continuum.},
}

@article {pmid40836645,
year = {2025},
author = {Liu, T and Li, X},
title = {The Crosstalk Between Protective and Detrimental Interleukin (IL)-1 Family of Cytokines in Alzheimer's Disease.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {9},
pages = {e70460},
doi = {10.1002/jbt.70460},
pmid = {40836645},
issn = {1099-0461},
support = {//Project no. (2024 Foshan self-funded science and technology innovation project (2420001004404), Education and Department of Guangdong Province (2024GCZX011))./ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/immunology ; Humans ; *Interleukin-1/metabolism/immunology ; Animals ; },
abstract = {Alzheimer's disease (AD) is a long-term, progressive, degenerative disorder. One of the most important pathological characteristics of AD is the deposition of β-amyliod (Aβ) peptide, which initiates a spectrum of cerebral neuroinflammation. Vascular changes also play an important role in the pathophysiology of the disease. Cytokines, secreted by immune cells, can facilitate cell-to-cell signaling and influence the functions of the central nervous system (CNS). These important mediators of the immune system, which are known to orchestrate various molecular and cellular mechanisms in both physiological and pathological situations, can be upregulated or downregulated, leading to a complex crosstalk with numerous receptors mediating pro-inflammatory and/or anti-inflammatory actions. In particular, the interleukin (IL)-1 family of cytokines has been implicated to significantly correlate with AD pathogenesis among other cytokines in the CNS. The IL-1 family of cytokines is essential in both the innate and adaptive immune responses. This pleiotropic family of cytokines includes IL-1α, IL-1β, IL-1 receptor antagonist (RA), IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36RA, IL-37, and IL-38. Recent studies have demonstrated that the upregulation of pro-inflammatory cytokines, such as IL-1α and IL-1β, or the downregulation of anti-inflammatory mediators, exerts multifaceted influences on both neurodegeneration and neuroprotection. The lack of effective treatment for AD necessitates the search for new drugs that target several processes in the disease's pathology. This review aims to give a comprehensive overview of the emerging roles of the IL-1 family of cytokines in AD pathology and to explain their perspectives on introducing novel strategies for effective therapeutic/neuropsychiatric management of AD in clinical settings by discussing both the pathogenic and protective roles of these cytokines.},
}

*Alzheimer Disease/metabolism/pathology/immunology
Humans
*Interleukin-1/metabolism/immunology
Animals

@article {pmid40836427,
year = {2025},
author = {Liu, Y and Ning, Z and Dai, Q and Zhang, X and Xiao, Y and Zhang, Z and Guo, D and Chen, J and Li, Y and Li, W and Xiao, S and Tang, Y},
title = {Intravenously injected hPSC-derived pericytes for Alzheimer's disease: neuroprotection and vascular repair via extracellular vesicles.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2025.08.024},
pmid = {40836427},
issn = {1525-0024},
abstract = {Intravenously injected human pluripotent stem cell (hPSC)-derived pericytes and their extracellular vesicles (EVs) represent promising therapeutic strategies for neurological diseases. Our study aimed to investigate the effects and mechanisms of intravenous transplantation for treating Alzheimer's disease (AD), with a focus on elucidating the critical role of EV-related mechanisms. We generated pericytes (hPSC-CNC PCs) from hPSC derived cranial neural crest (CNC) and employed 12-month-old 5xFAD mice as an advanced stage AD model. We investigated memory function, intracerebral β-amyloid (Aβ) deposition, blood-brain barrier (BBB) permeability, neuronal morphology, and associated protein expressions in mice to determine the therapeutic effects of intravenous administration of hPSC-CNC PCs or EVs. MiRNA sequencing was conducted to identify potential downstream pathways. We found that intravenous administration of hPSC-CNC PCs improved memory function of aged AD mice, concurrently reducing pathological deposits and BBB leakage, and enhancing neurofunctional outcomes via EVs. Furthermore, miRNA-486-5p in EVs might potentially promote neurovascular repair through various mechanisms. Our results demonstrated that EVs from hPSC-CNC PCs exert protective effects against AD.},
}

@article {pmid40836188,
year = {2025},
author = {Phuna, ZX and Vijayabalan, S and Panda, BP and Shivashekaregowda, NKH and Shaikh, MF and Madhavan, P},
title = {Improved cognition and memory via PLGA nanoparticle-mediated delivery of curcumin and piperine in an in vivo Alzheimer's disease model.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {40836188},
issn = {2190-3948},
support = {TUFR/2017/002/04//Taylor's University/ ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that causes dementia, impaired cognitive function, and disorientation. Studies have revealed that curcumin and piperine were found to be neuroprotective for patients with dementia. Nevertheless, both compounds are known for their poor solubility. To address issues related to poor bioavailability, polymeric nanoparticles loaded with curcumin and piperine, in combination, were fabricated and characterized through physicochemical, surface morphology, drug-excipient compatibility, and bioavailability studies. The nanoparticle with the highest bioavailability was selected for pharmacokinetics and pharmacodynamics studies. Optimized Poly (D, L-lactide-co-glycolide) nanoparticles loaded with curcumin and piperine, which we refer to as functional nanoparticles (FNP), were successfully developed using the emulsion diffusion-high-pressure homogenization-solvent evaporation (EHS) technique with Poloxamer 188 as the stabilizer. Among nine formulations obtained, FNP1 had a particle size of 116.6 ± 2.13 nm and a zeta potential of -27.9 ± 1.51 mV. Saturation solubility and in vitro drug release studies demonstrated an enhanced solubility of curcumin and piperine in FNP1 compared to the pure compounds. Oral administration of FNP1 in a streptozotocin (STZ)-induced AD rat model resulted in significant improvement of spatial memory, as demonstrated by both the Morris Water Maze and Passive Avoidance tests. Further histology studies, which involved staining the cortex and hippocampus regions, revealed a significantly reduced number of pyramidal cells with extensive nuclear pyknosis and degeneration, a finding previously observed in untreated STZ-induced AD rats. This study concluded that the polymeric nanoparticle developed, FNP1, had successfully improved the solubility and bioavailability of curcumin and piperine, thereby enhancing cognitive and memory impairment in STZ-induced AD rats.},
}

@article {pmid40836166,
year = {2025},
author = {Praisthy Lj, C and Kushwah, R and Dubey, S and Kumar, V and Jain, S},
title = {Pharmacotherapeutic potential of daidzein: insights into mechanisms and clinical relevance.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40836166},
issn = {1568-5608},
abstract = {Daidzein, a soy-derived isoflavone, has gained significant attention due to its diverse pharmacological properties, including antioxidant, anti-inflammatory, and estrogenic activities. This review synthesizes current research on daidzein's biological effects, focusing on its role in chronic diseases, such as cancer, osteoporosis, cardiovascular disorders, and neurodegenerative conditions. Mechanistically, daidzein exerts its effects through estrogen receptor modulation, activation of antioxidant pathways, and regulation of inflammatory mediators. Studies have demonstrated its potential in inhibiting cancer cell proliferation, improving bone mineral density, and reducing oxidative stress in cardiovascular diseases. Furthermore, daidzein's neuroprotective effects suggest promise in managing neurodegenerative disorders like Alzheimer's and Parkinson's disease. Despite its therapeutic potential, the bioavailability and metabolism of daidzein remain critical challenges, with interindividual variability influencing its efficacy. Advances in nanotechnology and formulation strategies aim to enhance its bioavailability and therapeutic applications. This review underscores the need for well-designed clinical trials to validate daidzein's efficacy and safety across different populations. Future research should also explore synergistic effects with other bioactive compounds to maximize its clinical utility.},
}

@article {pmid40836165,
year = {2025},
author = {Bayat, A and Mirmomeni, G and Aiken, S and Jafari, Z},
title = {Meta-Analyses of Auditory Evoked Potentials as Alzheimer Biomarkers.},
journal = {Ear and hearing},
volume = {},
number = {},
pages = {},
doi = {10.1097/AUD.0000000000001718},
pmid = {40836165},
issn = {1538-4667},
abstract = {OBJECTIVES: Alterations in auditory evoked potential (AEP) parameters have been associated with sensory memory deficits and may serve as biomarkers for cognitive decline. This systematic review and meta-analysis aimed to evaluate the effectiveness of AEPs in the early detection of Alzheimer disease (AD).

DESIGN: The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. A comprehensive search was performed across five electronic databases (EMBASE, Scopus, Cochrane Library, Web of Science, PubMed, and CINAHL) from their inception until August 2024, without restrictions on date or language. The methodological quality of evidence was assessed using the Crew Critical Appraisal Tool. Data were extracted on the latency and amplitude of five AEP components, including auditory P50 gating, mismatch negativity, and late-latency responses (N100, N200, P300), comparing patients with AD to age-matched control peers.

RESULTS: Out of 437 publications, 54 articles were selected for review, with most rated as having high methodological quality. The analysis revealed a significantly larger P50 gating amplitude (p < 0.001) in patients with AD. Furthermore, patients with AD demonstrated significantly prolonged latencies and reduced amplitudes for N100, N200, and P300 components (p ≤ 0.001) compared with controls. Among all AEPs, P300 latency exhibited the largest effect size. Funnel plot analysis and Egger's regression test showed no evidence of publication bias.

CONCLUSIONS: Our findings support the clinical utility of AEPs in early AD detection, with the P300 response identified as the most accurate electrophysiological measure for distinguishing patients with AD from the control group. These results highlight the value of incorporating AEPs into clinical assessment protocols to enhance early-stage AD diagnosis and monitoring, thereby facilitating timely interventions and the development of personalized treatment strategies.},
}

@article {pmid40835985,
year = {2025},
author = {Al-Rajab, M and Lu, J and Amawi, S and Elmehalawy, N and Babillie, B and Alasmi, Y and Ibrahim, HS and Ellahham, S and Sawsaa, A and Al Zraiqat, S},
title = {A smart secure virtual reality immersive application for alzheimer's and dementia patients.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {30584},
pmid = {40835985},
issn = {2045-2322},
support = {19300840//United Al-Saqer Grants Initiative and Abu Dhabi University's Office of Research and Sponsored Programs/ ; 19300840//United Al-Saqer Grants Initiative and Abu Dhabi University's Office of Research and Sponsored Programs/ ; 19300840//United Al-Saqer Grants Initiative and Abu Dhabi University's Office of Research and Sponsored Programs/ ; 19300840//United Al-Saqer Grants Initiative and Abu Dhabi University's Office of Research and Sponsored Programs/ ; 19300840//United Al-Saqer Grants Initiative and Abu Dhabi University's Office of Research and Sponsored Programs/ ; 19300840//United Al-Saqer Grants Initiative and Abu Dhabi University's Office of Research and Sponsored Programs/ ; 19300840//United Al-Saqer Grants Initiative and Abu Dhabi University's Office of Research and Sponsored Programs/ ; 19300840//United Al-Saqer Grants Initiative and Abu Dhabi University's Office of Research and Sponsored Programs/ ; 19300840//United Al-Saqer Grants Initiative and Abu Dhabi University's Office of Research and Sponsored Programs/ ; 19300840//United Al-Saqer Grants Initiative and Abu Dhabi University's Office of Research and Sponsored Programs/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Virtual Reality ; Aged ; Male ; Quality of Life ; Female ; *Dementia/therapy/psychology ; Artificial Intelligence ; Aged, 80 and over ; },
abstract = {Alzheimer's disease (AD) poses significant challenges for the elderly, leading to cognitive decline, social isolation, and lower quality of life. Current interventions often require cumbersome wearable devices e.g. the camera-based monitoring that may raise privacy concerns. However, these issues are not fully addressed previously. To fill this gap, this research proposes a new framework in non-invasive combination of Virtual Reality (VR), Voice recognition, and Artificial Intelligence (AI) to act as a supportive system for people with AD. The system provides a brand-new approach that tailored cognitive stimulation and companionship through the immersive VR scenarios, memory games, virtual trips, and an AI assistant together as a single platform. The AI-based assessment of the patient is employed to ensure that the experience is more relevant and helpful to the patient. The voice recognition is the most simple and easy user-interface. The security measures include access controls, encryption and continuous monitoring of cloud patient data. The initial study has been promising evidenced by the outcome of involving patients with Alzheimer's and dementia, their families, and clinicians. Participants reported heightened interest, better quality of life, less sense of isolation, and improved cognitive functioning, which have particularly achieved one of our goals, in patients' well-beings in mental healthcare. The research indicates a significant step forward enhancing the quality of support for both cognitive function and social interaction for older adults with AD and dementia. In comparison with other currently existing systems, our newly developed integrated framework has made additional contributions to the areas of AD in dynamic cognitive adaptation, bilingual interaction, and secure real-time personalized system.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Virtual Reality
Aged
Male
Quality of Life
Female
*Dementia/therapy/psychology
Artificial Intelligence
Aged, 80 and over

@article {pmid40835849,
year = {2025},
author = {Riang'a, RM and Mwangi, EM and Nagarajan, N and Agoi, F and Mwangala, PN and Gross, AL and Ikanga, J and Langa, KM and Miguel, E and Gichu, M and Ehrlich, JR and Ngugi, AK},
title = {Contextualization of Harmonized Cognitive Assessment Protocol (HCAP) in an aging population in rural low-resource settings in Africa: Experiences and strategies adopted to optimize effective adaption of cognitive tests in Kenya.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70552},
pmid = {40835849},
issn = {1552-5279},
support = {R21AG077042//National Institute of Aging of the National Institute of Health/ ; //University of Michigan Center for Global Health Equity/ ; U24AG065182//Harmonized Cognitive Assessment Protocol Network/ ; P30AG012846//Michigan Center on the Demography of Aging's HRS Partner Studies Network/ ; },
mesh = {Humans ; Kenya ; *Rural Population ; Female ; Male ; Aged ; Pilot Projects ; Longitudinal Studies ; *Neuropsychological Tests/standards ; *Aging/psychology ; Middle Aged ; Aged, 80 and over ; },
abstract = {Cross-cultural adaptation of cognitive assessments is crucial for detecting Alzheimer's disease (AD) and related dementias (ADRD) in aging populations. This study documents the adaptation of the Harmonized Cognitive Assessment Protocol (HCAP) for a pilot study on the Longitudinal Study of Health and Aging in Kenya (LOSHAK) in rural Kilifi County, Kenya, highlighting challenges and strategies for optimizing outcomes. As part of the LOSHAK feasibility phase, cognitive tests including: the Swahili Mental State Examination, 10-word recall, animal naming, story recall, clock drawing, and making change, were administered to 202 participants (≥45 years) from the Kaloleni/Rabai Health and Demographic Surveillance System (KRHDSS). Measures were adapted culturally and linguistically, and trained local enumerators conducted home-based assessments. Low literacy (60.1% had no schooling), linguistic diversity, cultural norms, and infrastructure limitations influenced assessments. Key adaptations included translation, culturally relevant modifications, flexible administration, and community engagement. Contextualized cognitive assessments improve validity in rural resource-limited settings, offering insights for future research. HIGHLIGHTS: This is a narrative qualitative study documenting the experiences and Strategies Adopted to Optimize Effective Adaption of Cognitive Tests in Longitudinal Study of Health and Aging in Kenya (LOSHAK). This article documents the adaptation and contextualization of the Harmonized Cognitive Assessment Protocol (HCAP) for a pilot study on health and aging (LOSHAK) in rural Kilifi County, Kenya, focusing on the challenges and strategies employed to optimize outcome. HCAP tests were administered as part of the feasibility and pilot phase of the LOSHAK, the aim of which was to validate measures and optimize data collection procedures. The median age of the 202 study participants was 64, with 57.4% being female. A majority (62.5%) were not currently working, and nearly 70% fell within the two poorest wealth quintiles. The rural setting presented unique challenges including: low literacy rates (60.1% of participants had no schooling), diverse language use (primarily Giriama and Swahili), limited infrastructure (e.g., 44.8% of households had electricity), restrictive cultural norms that influenced data collection (e.g., in-home interviews were often conducted outdoors with destructions). Key adaptations included: translating and culturally adapting test items (e.g., using local Swahili dialects and culturally relevant examples), recruiting and training local enumerators who were familiar with the community, culture and language, iterative pre-testing and using roleplay helped to ensure that enumerator scoring was consistent, accurate, and reliable. contextualization of tool and data collection strategies included: adjusting data collection methods to accommodate cultural practices and environmental limitations, for example, allowing respondents to use their preferred language for "animal naming," using paper and pen for some test items for which participants experienced difficulty using tablets, paying close special attention to time and season of administration, and adopting strategies to minimize background noise and other environmental distractions (e.g., due to rain, lunch hour, planting and harvesting, and school holidays). Prior to data collection, it was essential to engage local community health volunteers (CHVs), build rapport with participants, explain the study, and describe the idiosyncrasies of cognitive testing. The study emphasizes the importance of cultural sensitivity, linguistic appropriateness, and community engagement in cognitive assessment in diverse, resource-constrained settings. The findings offer practical recommendations for researchers aiming to conduct cognitive assessments in similar populations, contributing to the development of culturally sensitive and effective tools for understanding and addressing cognitive health in aging populations.},
}

Humans
Kenya
*Rural Population
Female
Male
Aged
Pilot Projects
Longitudinal Studies
*Neuropsychological Tests/standards
*Aging/psychology
Middle Aged
Aged, 80 and over

@article {pmid40835596,
year = {2025},
author = {Molokanova, E and Zhou, T and Vasupal, P and Cherkas, VP and Narute, P and Ferraz, MSA and Reiss, M and Almenar-Queralt, A and Chaldaiopoulou, G and de Souza, JS and Hemati, H and Downey, F and Olajide, OO and Thörn Perez, C and Puppo, F and Mesci, P and Pfaff, SL and Kireev, D and Muotri, AR and Savchenko, A},
title = {Non-genetic neuromodulation with graphene optoelectronic actuators for disease models, stem cell maturation, and biohybrid robotics.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {7499},
pmid = {40835596},
issn = {2041-1723},
support = {1R43MH124563//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 1R01MH128365//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; MH123828//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; DISC2-13866//California Institute for Regenerative Medicine (CIRM)/ ; 1R43AG076088//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 5R44DA050393//U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ ; 1R43NS122666//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS123642//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 1R01ES033636//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; },
mesh = {*Graphite/chemistry ; *Robotics/methods/instrumentation ; Induced Pluripotent Stem Cells/cytology ; Humans ; Organoids/cytology ; Neurons/cytology ; Brain/cytology ; Alzheimer Disease/pathology/therapy ; Optogenetics/methods ; Cell Differentiation ; Animals ; },
abstract = {Light can serve as a tunable trigger for neurobioengineering technologies, enabling probing, control, and enhancement of brain function with unmatched spatiotemporal precision. Yet, these technologies often require genetic or structural alterations of neurons, disrupting their natural activity. Here, we introduce the Graphene-Mediated Optical Stimulation (GraMOS) platform, which leverages graphene's optoelectronic properties and its ability to efficiently convert light into electricity. Using GraMOS in longitudinal studies, we found that repeated optical stimulation enhances the maturation of hiPSC-derived neurons and brain organoids, underscoring GraMOS's potential for regenerative medicine and neurodevelopmental studies. To explore its potential for disease modeling, we applied short-term GraMOS to Alzheimer's stem cell models, uncovering disease-associated alterations in neuronal activity. Finally, we demonstrated a proof-of-concept for neuroengineering applications by directing robotic movements with GraMOS-triggered signals from graphene-interfaced brain organoids. By enabling precise, non-invasive neural control across timescales from milliseconds to months, GraMOS opens new avenues in neurodevelopment, disease treatment, and robotics.},
}

*Graphite/chemistry
*Robotics/methods/instrumentation
Induced Pluripotent Stem Cells/cytology
Humans
Organoids/cytology
Neurons/cytology
Brain/cytology
Alzheimer Disease/pathology/therapy
Optogenetics/methods
Cell Differentiation
Animals

@article {pmid40835473,
year = {2025},
author = {Naeshiro, Y and Kitani-Morii, F and Kasai, T and Tanaka, E and Kobayashi, F and Ohara, T},
title = {Amyloid Clearance and Transient CSF Aβ40 Reduction in a Case of ARIA-E/H Following Lecanemab Treatment.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.6070-25},
pmid = {40835473},
issn = {1349-7235},
abstract = {We herein report a case of amyloid-related imaging abnormality (ARIA)-E/H following lecanemab treatment in a 70-year-old man with mild cognitive impairment due to Alzheimer's disease. Generalized seizures occurred after the third infusion and were accompanied by FLAIR hyperintensity, microbleeds, and a minor acute infarct. Amyloid PET revealed focal clearance of amyloid plaques in the ARIA-affected regions. CSF Aβ40 levels transiently decreased by ~30% during the ARIA episode, whereas Aβ42 remained stable, thereby increasing the Aβ42/40 ratio. These findings suggest that ARIA may facilitate focal amyloid clearance and that CSF Aβ40 reduction may serve as a potential biomarker for ARIA onset and resolution.},
}

@article {pmid40835432,
year = {2025},
author = {Chen, J and Zhao, S and Zhou, Y and Wang, L and Chen, Q and Zheng, K},
title = {APOE4 reprograms microglial lipid metabolism in Alzheimer's disease: Mechanisms and therapeutic implications.},
journal = {Bioscience trends},
volume = {},
number = {},
pages = {},
doi = {10.5582/bst.2025.01148},
pmid = {40835432},
issn = {1881-7823},
abstract = {The apolipoprotein E ε4 (APOE ε4) allele, the strongest genetic risk factor for late-onset Alzheimer's disease (AD), induces cell-type-specific disturbances in brain lipid metabolism. Although impacting astrocytes and neurons, its most pronounced effects occur in microglia, where it causes energy metabolism deficits and promotes the formation of lipid droplet-accumulating microglia, triggering a cascade of neurodegenerative responses. This review comprehensively examines how microglial APOE4-driven lipid metabolic dysregulation exacerbates neuroinflammation and compromises phagocytic capacity, particularly in the clearance of amyloid-β, phosphorylated-tau, and pathological synapses. Mechanistically, microglial APOE4 activates neuroinflammation via LilrB3-mediated type I interferon signaling and induces lipid metabolic imbalance through PU.1/NF-κB-driven transcriptional reprogramming and ER stress-SREBP2 activation. These disturbances exacerbate neuroinflammation, promote lipid droplet accumulation and cholesterol overload, impair lysosomal function, and ultimately compromise microglial phagocytosis. The resulting disruption of neuron-microglia interactions further amplifies neurotoxicity in AD. Furthermore, this review summarizes emerging therapeutic strategies targeting APOE4-related pathway in microglia. By synthesizing these insights, this review highlights the multifaceted role of microglial APOE4 in AD pathology, with particular emphasis on the central role of lipid metabolism dysregulation, and provides new intervention ideas for reducing its damage to brain function.},
}

@article {pmid40835353,
year = {2025},
author = {Khojaste-Sarakhsi, M and Haghighi, SS and Fatemi Ghomi, SMT},
title = {A 3D multi-modal multi-scale end-to-end classifier for Alzheimer's disease diagnosis.},
journal = {Medical engineering & physics},
volume = {143},
number = {},
pages = {104382},
doi = {10.1016/j.medengphy.2025.104382},
pmid = {40835353},
issn = {1873-4030},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Imaging, Three-Dimensional ; Magnetic Resonance Imaging ; Aged ; Positron-Emission Tomography ; Male ; Cognitive Dysfunction/diagnostic imaging ; Female ; },
abstract = {This study presents a novel 3D multi-modal multi-scale end-to-end classifier to enhance Alzheimer's Disease (AD) diagnosis by integrating MRI, PET, age, and MMSE cognitive test scores. Leveraging a ResNet-inspired architecture with trainable multi-scale convolutional scaling, the classifier categorizes subjects into four classes-Normal Control (NC), Stable Mild Cognitive Impairment (sMCI), Progressive Mild Cognitive Impairment (pMCI), and AD-capturing both structural and functional brain pathology. A tailored fusion strategy (MA_PC) processes MRI with age and PET with MMSE in parallel branches, optimizing complementary information use. Extensive experiments using the ADNI dataset, a five-fold cross-validation scheme, and an unseen test set demonstrate that MA_PC with convolutional scaling achieves superior performance, outperforming commonly used fusion strategies as well as pre-trained 3D ResNets designed for medical imaging applications. A comparative analysis reveals that 4-class classification consistently surpasses a 3-class approach (NC, MCI, AD), highlighting the model's ability to distinguish subtle AD progression stages. These findings highlight the critical role of advanced data fusion and scaling methods in enhancing AD diagnosis accuracy and underscore the potential of multi-modal CNNs in advancing medical imaging research.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Imaging, Three-Dimensional
Magnetic Resonance Imaging
Aged
Positron-Emission Tomography
Male
Cognitive Dysfunction/diagnostic imaging
Female

@article {pmid40835172,
year = {2025},
author = {Santiago, J and Poceviciute, D and Vogel, J and , and Brinkmalm, G and Wennström, M},
title = {Retinal tau phosphorylation in Alzheimer's disease: A mass spectrometry study.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107057},
doi = {10.1016/j.nbd.2025.107057},
pmid = {40835172},
issn = {1095-953X},
abstract = {INTRODUCTION: Most neurodegenerative diseases, including Alzheimer's disease (AD) and multiple sclerosis (MS), feature abnormal tau phosphorylation (p-tau) in the brain. Prior immunostaining studies have shown p-tau accumulation in the AD retina, suggesting it may mirror brain tau pathology.

METHODS: We used mass spectrometry to quantify p-tau peptides in matched retinal and hippocampal samples from non-demented controls (NC, n = 8), AD (n = 12), and MS (n = 4). We compared p-tau levels across diagnoses and analysed correlations between retinal p-tau variants, hippocampal p-tau, and neuropathological changes.

RESULTS: Tau peptides phosphorylated at T181, S199/S202, T231, T231 + T235, S396 + T403/S404, and T403/S404 were detected in retinas. Total tau phosphorylation and phosphorylation at S199/S202 and T231 were significantly higher in AD cases compared to NC. These two, along with p-tau S396 + T403/S404, were also higher in cases with high amyloid-beta (Aβ) Braak stages compared to those with low Aβ Braak stages. Higher Aβ stages were also correlated with higher peak intensities of p-tau S199/S202 and S396 + T403/S404, and retinal p-tau S396 + T403/S404 and T403/S404 correlated with neurofibrillary tangle (NFT) Braak stages. Additionally, p-tau S396 + T403/S404 in the retina was associated with corresponding phosphorylation in the hippocampus.

CONCLUSION: Our findings reveal both overlapping and distinct p-tau patterns in retina and hippocampus, with a notable link for p-tau S396 + T403/S404. This enhances our understanding of tauopathies in both tissues and supports retinal tau as a promising biomarker for AD diagnosis and monitoring.},
}

@article {pmid40835019,
year = {2025},
author = {Gao, S and Wang, J and Chen, J},
title = {The role of mitophagy in perioperative neurocognitive disorder: from mechanisms to implications.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.08.028},
pmid = {40835019},
issn = {1873-7544},
abstract = {Perioperative neurocognitive disorder (PND) is a significant neurological complication in aging perioperativepatients, seriously impacting their postoperative recovery and cognition as well as quality of life. The occurrence of PND is closely related to various factors, including neuroinflammation and oxidative stress, while the exact mechanism is still unknown. Mitophagy is a specialized form of autophagy and maintains cellular homeostasis by selectively degrading damaged and dysfunctional mitochondria, serving as a crucial quality control mechanism to ensure the mitochondrial network's integrity and functionality. Mitophagy has been proved to be involved in the onset and progression of major neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Recently, findings indicated that mitophagy may also play critical roles in the pathogenesis of PND, and the mechanisms may involve ubiquitin-dependent pathways (such as the PINK1/Parkin pathway) and non-ubiquitin-dependent pathways (such as the BNIP3/FUNDC1 pathway). Studies indicated that the PINK1/Parkin pathway is impaired in the animal PND models. In contrast, the BNIP3/ FUNDC1 pathway is neuroprotective by promoting mitophagy under stress conditions such as hypoxia. In addition, abnormal Tau protein aggregation and ferroptosis are correlated with mitophagy and PND in animal studies. In this review, we focused on the role and detailed mechanism of mitophagy in the occurrence and development of PND, as well as on possible potential targets involving mitophagy modulation.},
}

@article {pmid40835006,
year = {2025},
author = {McMillan, JD and Wang, S and Wohlfahrt, J and Guergues, J and Stevens, SM and Thinakaran, G},
title = {Proteomic characterization of the Alzheimer's disease risk factor BIN1 interactome.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101055},
doi = {10.1016/j.mcpro.2025.101055},
pmid = {40835006},
issn = {1535-9484},
abstract = {The gene BIN1 is the second-largest genetic risk factor for late-onset Alzheimer's disease (LOAD). It is expressed in neurons and glia in the brain as cell-type-specific and ubiquitous isoforms. BIN1 is an adaptor protein that regulates membrane dynamics in many cell types. Previously, we reported that BIN1 predominantly localizes to presynaptic terminals in neurons and regulates presynaptic vesicular release. However, the function of neuronal BIN1 in relation to LOAD is not yet fully understood. A significant gap in the field is the unbiased characterization of neuronal BIN1-interacting proteins and proximal neighbors. To address this gap and help define the functions of neuronal BIN1 in the brain, we employed TurboID-based proximity labeling to identify proteins biotinylated by the neuronal BIN1 isoform 1-TurboID fusion protein (BIN1iso1-TID) in cultured mouse neuroblastoma (N2a) cells in vitro and in adult mouse brain neurons in vivo. Label-free quantification-based proteomic analysis of the BIN1iso1-TID biotinylated proteins led to the discovery of 360 proteins in N2a cells and 897 proteins in mouse brain neurons, identified as BIN1iso1-associated (proximal) or interacting proteins. A total of 92 proteins were common in both datasets, indicating that these are high-confidence BIN1-interacting or proximity proteins. SynapticGO analysis of the mouse brain dataset revealed that BIN1iso1-TurboID labeled 159 synaptic proteins, with 60 corresponding to the synaptic vesicle cycle. Based on phosphorylation site analysis of the neuronal BIN1iso1-TID interactome and related kinase prediction, we selected and validated AAK1, CDK16, SYNJ1, PP2BA, and RANG through immunostaining and proximity ligation assays as members of the BIN1 interactome in the mouse brain. This study establishes a foundation for further investigations into the function of neuronal BIN1 by identifying several previously unknown proximal and potential interacting proteins of BIN1.},
}

@article {pmid40835004,
year = {2025},
author = {Sun, Y and Xia, L and Xu, X and Wang, X and Guo, J and Cheng, R and Yang, N and Shen, L and Liu, N and Mo, X and Liu, L},
title = {Plasma ceramide mediates the association of peripheral T cells with Alzheimer's disease.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.08.027},
pmid = {40835004},
issn = {2090-1224},
abstract = {INTRODUCTION: Neuroinflammation involving peripheral immune cells, particularly T lymphocytes, has been implicated in Alzheimer's disease (AD) progression. Metabolic dysregulation in sphingolipid pathways may influence neuroinflammatory processes in AD pathogenesis. However, the specific roles of T cell subsets and their interactions with metabolic pathways in AD pathogenesis remain unclear.

OBJECTIVES: To determine the causal contributions of peripheral T cell subsets to AD risk and investigate whether blood metabolites mediate this association.

METHODS: We integrated single-cell RNA sequencing with flow cytometry to identify dynamic alterations in T cell subsets during AD progression. Adoptive transfer experiments in APP/PS1 mice validated the functional roles of specific T cell populations. Two-sample Mendelian randomization (MR) evaluated causal relationships between T cell traits and AD risk, while two-step MR assessed the mediating role of blood metabolites.

RESULTS: CD4 effector memory (EM) and CD8 central memory (CM) T cells expanded in AD patients, particularly during mild cognitive impairment. Adoptive transfer of either CD4 EM or CD8 CM T cells into APP/PS1 mice exacerbated cognitive deficits and amyloid-β pathology. MR revealed causal associations of CM CD8br % T cell (OR = 1.22, 95 % CI: 1.07-1.39, P = 0.002) and EM CD4+ % CD4+ (OR = 1.09, 95 % CI: 1.01-1.18, P = 0.027) with AD risk. Elevated plasma ceramide levels were also causally associated with increased AD risk (OR = 1.34, 95 % CI: 1.10-1.64, P = 0.004), with CD4 EM influencing ceramide levels (OR = 1.03, 95 % CI: 1.01-1.06, P = 0.020). Ceramide mediated 11.20 % of the effect between CD4 EM and AD pathogenesis.

CONCLUSION: This study identifies CD4 EM and CD8 CM T cells as key drivers of AD-related neuroinflammation and uncovers a possible immunometabolic pathway linking CD4 EM, ceramide metabolism, and AD risk, suggesting potential targets for early diagnosis and therapeutic intervention.},
}

@article {pmid40834958,
year = {2025},
author = {Ciaffaglione, V and Grasso, G and Lanza, V and Sciacca, MFM and Zimbone, S and Giuffrida, ML and Iacobucci, C and Di Ianni, A and Calcagno, D and Grasso, G and Alloni, A and Orsini, F and Fraser, P and Fioriti, L and Milardi, D},
title = {SUMO-2 activity is inhibited by non-covalent interactions with the Aβ peptide: an exploration of potential pathogenic mechanisms in Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {146632},
doi = {10.1016/j.ijbiomac.2025.146632},
pmid = {40834958},
issn = {1879-0003},
abstract = {SUMOylation is a post-translational modification involving the addition of SUMO isoforms to target proteins and plays a role in various biological processes, including neurodegenerative diseases and ocular pathologies. This study investigates the interaction between SUMO-2 and amyloid (Aβ) peptides, key contributors to Alzheimer's disease, using techniques like cross-linking mass spectrometry, surface plasmon resonance and biolayer interferometry. Data are available via ProteomeXchange with identifier PXD066055. The results show that Aβ1-40 and Aβ1-42 bind more strongly to SUMO-2 than to ubiquitin, with binding driven by specific hydrogen bonds and hydrophobic interactions. SUMO-2 was found to inhibit the conversion of Aβ into β-sheet structures and impede Aβ aggregation. Notably, Aβ competes with SUMO-2 canonical substrates for binding, completely hindering SUMOylation reactions in vitro. Identifying SUMO-2/Aβ1-42 adducts in cellular extracts and live cells further highlights the biological significance of these interactions. Overall, the findings indicate that Aβ peptides impair SUMO-2 function, pointing to the necessity for more research on the implications of SUMOylation in Alzheimer's disease.},
}

@article {pmid40834628,
year = {2025},
author = {Rodríguez-Fernández, B and González-Escalante, A and Genius, P and E Evans, T and Ortiz-Romero, P and Minguillón, C and Kollmorgen, G and Ashton, NJ and Zetterberg, H and Blennow, K and Gispert, JD and Navarro, A and Suárez-Calvet, M and Sala-Vila, A and Crous-Bou, M and Vilor-Tejedor, N and , },
title = {Longitudinal association of shorter leukocyte telomere length with CSF biomarker dynamics across early Alzheimer's disease stages in at-risk individuals.},
journal = {EBioMedicine},
volume = {119},
number = {},
pages = {105886},
doi = {10.1016/j.ebiom.2025.105886},
pmid = {40834628},
issn = {2352-3964},
abstract = {BACKGROUND: Short telomere length (TL), a hallmark of biological ageing, has been associated with an increased risk of Alzheimer's disease (AD), but its pathophysiological role remains unclear. This study explored the relationship between blood leukocyte TL (LTL), cerebrospinal fluid (CSF) AD biomarkers changes, and brain structure across early stages of the AD continuum.

METHODS: We included 346 cognitively unimpaired participants (aged 49-71) from the ALFA cohort, enriched for AD risk (53.2% APOE-ε4 carriers; 34% amyloid-positive). LTL was measured at baseline (visit 0) using quantitative PCR. Associations were assessed between baseline LTL and CSF biomarkers at visit 1 (mean follow-up from baseline = 3.98 years, SD = 1.02), and with changes in CSF biomarkers between visits 1 and 2 (mean interval = 3.45 years, SD = 0.58). Cortical thickness in ageing- and AD-vulnerable brain regions was evaluated by magnetic resonance imaging (MRI) at visit 1. Analyses were stratified by APOE-ε4 status and amyloid-tau (AT) profiles. Mediation models tested whether CSF biomarkers mediated LTL-cortical thickness associations.

FINDINGS: Shorter LTL was associated with higher astrocytic reactivity at visit 1 and with increased synaptic dysfunction over time. Among APOE-ε4 carriers and AT-positive individuals, shorter LTL was associated with higher p-tau181 and neurodegeneration markers. Shorter LTL was associated with greater cortical thickness in ageing- and AD-vulnerable regions, partially mediated by astrocytic reactivity biomarkers.

INTERPRETATION: These findings suggest that shorter telomeres are associated with early AD-related biological changes, potentially via mechanisms involving astrocytic reactivity and brain structural alterations. LTL may serve as an early marker of vulnerability to neurodegenerative processes in at-risk populations.

FUNDING: AARG-19-618265; PI19/00119; LCF/PR/GN17/10300004; TriBEKa-17-519007; # SLT002/16/00201.},
}

@article {pmid40834382,
year = {2025},
author = {},
title = {Alzheimer Disease, de Quervain Tenosynovitis, Degenerative Meniscal Tears, Pet Therapy, Herpes Simplex Virus, Bone Stress Injuries.},
journal = {American family physician},
volume = {112},
number = {2},
pages = {215},
pmid = {40834382},
issn = {1532-0650},
}

@article {pmid40834163,
year = {2025},
author = {Oliveira, FF and Almeida, SS and Chen, ES and Bertolucci, PHF and Smith, MC},
title = {Associations between selected genetic variants and lipid profile variability in response to statins in Alzheimer's disease: a prospective observational study.},
journal = {Sao Paulo medical journal = Revista paulista de medicina},
volume = {143},
number = {4},
pages = {e2024160},
doi = {10.1590/1516-3180.2024.0160.27112024},
pmid = {40834163},
issn = {1806-9460},
mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy/blood ; Prospective Studies ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Female ; Male ; Aged ; Atorvastatin/therapeutic use ; Middle Aged ; *Lipids/blood ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Triglycerides/blood ; *Genetic Variation/genetics ; Cholesterol/blood ; Simvastatin/therapeutic use ; Polymorphism, Single Nucleotide ; Lipid Metabolism/genetics/drug effects ; Aged, 80 and over ; Polymorphism, Genetic/genetics ; },
abstract = {BACKGROUND: Lipid profiles are largely determined by genetic variants, and lipid metabolism plays a crucial role in Alzheimer's disease.

OBJECTIVE: To investigate whether lipid profile variability in response to diverse statins could be affected by cholesterol metabolism-related genetic variants in Alzheimer's disease..

DESIGN AND SETTING: This prospective observational pharmacogenetic study was conducted at the Universidade Federal de São Paulo (Unifesp), Brazil.

METHODS: Consecutive outpatients were prospectively followed for lipid profile variations over one year, estimated by the associations between statin therapy and the following variants: rs2695121 (NR1H2), rs3846662 (HMGCR), rs11669576 (LDLR8), rs5930 (LDLR10), rs5882 and rs708272 (CETP), rs7412 and rs429358 (APOE), and ACE insertion/deletion polymorphism.

RESULTS: All polymorphisms in the 189 patients were in Hardy-Weinberg equilibrium. Statins resulted in lower total cholesterol and LDL cholesterol levels, whereas the effects on HDL cholesterol varied according to the statin used. Atorvastatin resulted in lower triglyceride level variations than simvastatin. APOE-ε4 carriers showed a better response to atorvastatin in elevating HDL-cholesterol than APOE-ε4 non-carriers. Carriers of the ACE insertion allele had cumulatively lower total cholesterol and LDL-cholesterol levels, regardless of statin therapy, but lower triglyceride levels when using atorvastatin. Carriers of rs11669576-G had lower total cholesterol and LDL-cholesterol levels when using simvastatin, and lower total cholesterol and triglycerides when using atorvastatin. Concerning CETP haplotypes, carriers of rs5882-A and rs708272-A benefitted the most from statins, which lowered total cholesterol and increased HDL-cholesterol levels, and from atorvastatin lowering triglycerides; however, the effects of atorvastatin lowering total cholesterol and LDL-cholesterol were more pronounced for carriers of rs5882-GG/rs708272-GG.

CONCLUSION: Lipid profile variations may be pharmacogenetically mediated in Alzheimer's disease, thus, confirming their high heritability.},
}

Humans
*Alzheimer Disease/genetics/drug therapy/blood
Prospective Studies
*Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
Female
Male
Aged
Atorvastatin/therapeutic use
Middle Aged
*Lipids/blood
Cholesterol, HDL/blood
Cholesterol, LDL/blood
Triglycerides/blood
*Genetic Variation/genetics
Cholesterol/blood
Simvastatin/therapeutic use
Polymorphism, Single Nucleotide
Lipid Metabolism/genetics/drug effects
Aged, 80 and over
Polymorphism, Genetic/genetics

@article {pmid40834019,
year = {2025},
author = {Guo, Y},
title = {Mendelian randomization study of self-reported long sleep duration, short sleep duration, and insomnia and cognitive function.},
journal = {PloS one},
volume = {20},
number = {8},
pages = {e0330782},
doi = {10.1371/journal.pone.0330782},
pmid = {40834019},
issn = {1932-6203},
mesh = {Humans ; *Sleep Initiation and Maintenance Disorders/genetics/physiopathology ; *Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Self Report ; *Sleep/genetics ; *Cognition/physiology ; Genome-Wide Association Study ; Male ; Time Factors ; Female ; Sleep Duration ; },
abstract = {BACKGROUND AND AIMS: Causal relationship between sleep duration and cognitive function remains unclear. This study used a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between self-reported short sleep duration, insomnia and long sleep duration and cognitive function.

METHODS: A total of 26 single nucleotide polymorphisms (SNPs) associated with short sleep duration, 240 associated with insomnia, and 7 associated with long sleep duration were extracted from a genome-wide association study primarily based on European ancestry, to be used as instrumental variables. Summary-level statistics were obtained from the Dementia genome-wide association studies database. MR estimation was performed using the inverse variance weighted (IVW) method as the primary method, supplemented by MR-Egger regression and weighted median estimator methods. Finally, multiple sensitivity analyses were performed to obtain robust and valid estimates.

RESULTS: Based on IVW methods, short sleep duration showed a harmful impact on cognitive performance score (beta = -0.15, 95% CI: -0.27 to -0.02, P = 0.02, IVW), fluid intelligence score (beta = -0.38; 95% CI: -0.65 to -0.11; P = 0.006, IVW), memory performance (beta = -0.10, 95% CI: -0.20 to -0.0005; P = 0.04, IVW) and Trail Making (TM) test (TM: interval in trail 2 path, beta = 0.11, 95% CI: 0.01 to 0.21; P = 0.03, IVW; TM: duration to complete trail 2 path, beta = 0.11, 95% CI: 0.002 to 0.22; P = 0.04, IVW). In addition, insomnia was causally associated with Alzheimer's disease (OR = 1.13, 95% CI = 1.02-1.24, p = 0.02, IVW). However, due to the limited number of SNPs (n = 7) available as instruments for long sleep duration, there was no strong evidence to support a causal effect of long sleep duration on cognitive outcomes.

CONCLUSIONS: This study suggests self-reported short sleep duration was causally associated with cognitive decline and self-reported insomnia was causally associated with increased risk of Alzheimer's disease in individuals of European ancestry. The evidence of causality between long sleep duration and cognitive function requires further investigation. These results may have implications for public health interventions aimed at reducing the risk of cognitive decline.},
}

Humans
*Sleep Initiation and Maintenance Disorders/genetics/physiopathology
*Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Self Report
*Sleep/genetics
*Cognition/physiology
Genome-Wide Association Study
Male
Time Factors
Female
Sleep Duration

@article {pmid40833947,
year = {2025},
author = {Spencer, B and Marr, RA and Gindi, R and Potkar, R and Michael, S and Adame, A and Rockenstein, E and Verma, IM and Masliah, E},
title = {Correction: Peripheral Delivery of a CNS Targeted, Metalo-Protease Reduces Aβ Toxicity in a Mouse Model of Alzheimer's Disease.},
journal = {PloS one},
volume = {20},
number = {8},
pages = {e0330647},
doi = {10.1371/journal.pone.0330647},
pmid = {40833947},
issn = {1932-6203},
abstract = {[This corrects the article DOI: 10.1371/journal.pone.0016575.].},
}

@article {pmid40833911,
year = {2025},
author = {Wei, Y and Abrol, A and Lah, J and Levey, AI and Calhoun, VD},
title = {From Symptomatic to Pre-symptomatic: Adaptive Knowledge Distillation for Early Alzheimer's Detection Using Functional MRI.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2025.3597261},
pmid = {40833911},
issn = {1558-2531},
abstract = {Alzheimer's disease (AD) progresses from asymptomatic changes to clinical symptoms, underscoring the critical need for early detection to facilitate timely treatment. Functional magnetic resonance imaging (fMRI) offers non-invasive biomarkers for detection, but current methods fail to reliably identify pre-symptomatic individuals due to two key challenges: (1) Subtle, anatomically distinct fMRI patterns in pre-symptomatic cases that resemble healthy controls more than symptomatic patients, and (2) Severe class imbalance in real-world data, where healthy controls vastly outnumber pre-symptomatic subjects. To address this, we reconceptualize AD diagnosis as a multi-stage distillation task, where insights from easier-to-detect symptomatic cases guide pre-symptomatic detection. We propose a novel margin-aware knowledge distillation (KD) framework with two innovations: (1) We leverage Unbalanced Optimal Transport (UOT) for Feature Distillation to flexibly adapt to anatomical differences in brain patterns caused by neurodegeneration and ensure effective distillation from later to earlier disease stages. (2) We propose Self-Distillation with Dynamic Margins to combat class imbalance by adaptively refining the classification boundary. We evaluate our proposed framework across four distinct base models and demonstrate its superiority over state-of-the-art KD methods. Additionally, we show the significance of various brain regions in identifying pre-symptomatic subjects, as well as how features are transferred during distillation. These contributions advance the development of more precise diagnostic tools and foster a deeper understanding of early disease manifestations, marking a significant stride towards more reliable and earlier AD diagnosis.},
}

@article {pmid40833693,
year = {2025},
author = {Dai, J and Chau, T and Corrada, MM and Manson, SM and O'Connell, J and Jiang, L},
title = {Race and Ethnicity and Comorbidities Among Medicare Beneficiaries With Young-Onset Dementia.},
journal = {JAMA network open},
volume = {8},
number = {8},
pages = {e2528001},
doi = {10.1001/jamanetworkopen.2025.28001},
pmid = {40833693},
issn = {2574-3805},
mesh = {Humans ; United States/epidemiology ; Female ; Male ; Cross-Sectional Studies ; *Dementia/ethnology/epidemiology ; Middle Aged ; Comorbidity ; *Medicare/statistics & numerical data ; Age of Onset ; Prevalence ; *Ethnicity/statistics & numerical data ; *Racial Groups/statistics & numerical data ; },
abstract = {IMPORTANCE: Young-onset dementia (YOD), which develops before age 65 years, can bring additional challenges to patients and their caregivers. The prevalence of YOD and its associated comorbidities across US racial and ethnic populations remain unclear.

OBJECTIVE: To estimate the prevalence of YOD and examine associations between comorbidities and YOD among Medicare beneficiaries in various racial and ethnic groups.

This cross-sectional study used data from January 2022 to December 2022. Data were extracted from the Centers for Medicare & Medicaid Services 2022 Medicare Beneficiary Summary File (MBSF) for Medicare beneficiaries aged 45 to 64 years with almost-continuous fee-for-service coverage in 2022. The MBSF Research Triangle Institute race code was used to identify Hispanic, non-Hispanic American Indian and Alaska Native, non-Hispanic Asian, non-Hispanic Black, and non-Hispanic White populations.

EXPOSURES: Comorbidities examined include diabetes, cardiovascular disease (CVD), hyperlipidemia, hypertension, depression, chronic kidney disease without end-stage kidney disease (ESKD), ESKD, liver disease, cancer, chronic obstructive pulmonary disease, traumatic brain injury (TBI), alcohol use disorder, drug use disorder, tobacco use disorder, and hearing loss.

MAIN OUTCOMES AND MEASURES: The outcome was YOD, defined as Alzheimer disease and related dementias (ADRD) occurring in individuals aged 45 to 64 years. YOD was identified using end-of-year indicators of ADRD from the MBSF 30 Chronic Conditions Data file. The age-standardized prevalence of YOD in 2022 was calculated using the direct standardization method, with White adults in our sample as the standard population across age groups.

RESULTS: In 2022, among a total of 2 189 231 Medicare beneficiaries aged 45 to 64 years, 71 092 (3.25%) received a diagnosis of YOD. Black adults had the highest age-standardized YOD prevalence (13 149 beneficiaries [3.76%]). Among beneficiaries aged 45 years and older with ADRD, the proportions of YOD were approximately 2 to 3 times higher among Black (13 149 beneficiaries [7.01%]), American Indian and Alaska Native (655 beneficiaries [6.49%]), and Hispanic (6090 beneficiaries [4.77%]) individuals compared with White (49 818 beneficiaries [2.89%]) and Asian (1380 beneficiaries [2.12%]) individuals. In addition, Black, Hispanic, and American Indian and Alaska Native adults had a higher prevalence of most examined comorbidities than White adults. Many comorbidities, such as TBI (odds ratio [OR] range, 8.80-14.77), depression (OR range, 4.19-5.12), and CVD (OR range, 3.54-5.49), were associated with YOD.

CONCLUSIONS AND RELEVANCE: This cross-sectional study found that Medicare beneficiaries from minoritized racial and ethnic groups younger than 65 years experienced a higher burden of YOD. Improved early detection and enhanced care coordination may help address the needs of Medicare beneficiaries with YOD, especially those from minoritized racial and ethnic groups with multiple comorbidities.},
}

Humans
United States/epidemiology
Female
Male
Cross-Sectional Studies
*Dementia/ethnology/epidemiology
Middle Aged
Comorbidity
*Medicare/statistics & numerical data
Age of Onset
Prevalence
*Ethnicity/statistics & numerical data
*Racial Groups/statistics & numerical data

@article {pmid40833681,
year = {2025},
author = {Karmakar, S and Biswas, P},
title = {Local Structure and Dynamics of Hydration Water in Amyloid-β Aggregation and Caffeine-Mediated Inhibition.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c02934},
pmid = {40833681},
issn = {1520-5207},
abstract = {The self-assembly of amyloid-β (Aβ) peptides into amyloid fibrils is a hallmark of Alzheimer's disease (AD). This study explores the hydration structure of the amyloid dimer both with and without the inhibitor caffeine via all-atom, explicit-solvent molecular dynamics simulations combined with the umbrella sampling method. This study highlights the relatively unexplored role of protein-water interactions in both aggregation and caffeine-mediated inhibition of Aβ. The effect of caffeine on the hydration environment of the Aβ dimer is evaluated through the solvent-accessible surface area, tetrahedral order parameter, hydrogen bonding analysis, and the survival probability of water molecules within the hydration shell. The results demonstrate that the Aβ dimer in the absence of the inhibitor is more prone to aggregation and is less exposed to water compared to the dimer in the presence of caffeine. Water molecules are found to be more ordered around the dimer with the inhibitor than the one without it. The dynamics of hydration water molecules is found to be slower around the dimer without the inhibitor than the dimer with the inhibitor. These findings provide novel insights into the role of hydration water in Aβ aggregation and its caffeine-mediated inhibition.},
}

@article {pmid40833486,
year = {2025},
author = {Isik, S and Alhelwani, S and Sahsahi, A and Balcilar, H and Yeman-Kiyak, B},
title = {Plant-derived exosome-like nanovesicles: mechanisms and molecular understanding in neurological disorders with potential therapeutic applications.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {40833486},
issn = {2190-3948},
abstract = {Exosomes are nano vesicles secreted by the cells that play an essential role in intercellular communication, enabling the transport of bioactive molecules, including proteins, lipids, and nucleic acids. Among them, plant-derived exosome-like nanovesicles have attracted considerable interest due to their prospective therapeutic implications, especially for neurological disorders. This article provides an overview of the biogenesis of plant-derived exosome-like nanovesicles, compares their characteristics with mammalian-derived exosomes, and investigates their bioavailability and chemical composition. The article also discusses the mechanisms through which they are uptaken by cells, highlighting several cellular uptake pathways and their significance for targeted drug delivery. Moreover, it explains the molecular basis of neurological disorders and investigates how plant-derived exosome-like nanovesicles regulate intracellular signaling pathways, providing potential therapeutic benefits. Finally, it provides the latest advancements in engineering research, emphasizing biochemical modifications on the exosomal surface, loading therapeutic molecules into exosomes, and exosomes derived from genetically engineered plants, for more effective therapies in neurological disorders.},
}

@article {pmid40833393,
year = {2025},
author = {Wei, Z and Dong, X and Sun, Y},
title = {Design of Red Fluorescence Ce-Based Carbon Dots of High and Balanced Multiple Functions against Alzheimer's β-Amyloid Fibrillization.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c10137},
pmid = {40833393},
issn = {1944-8252},
abstract = {The intricate pathophysiology of Alzheimer's disease (AD), characterized by β-amyloid (Aβ) deposition, oxidative stress, and neuroinflammation, presents significant challenges for conventional single-target therapeutic approaches, thereby necessitating the development of innovative multifunctional theranostic strategies. Herein, red fluorescence cerium-based carbon dots (CCP-CD) were designed and synthesized via a one-step solvothermal method by purposely selecting curcumin (Cur) for inhibitory and anti-inflammatory effects, Ce(NO3)3·6H2O for enhancing antioxidant activity, and p-phenylenediamine (p-PD) for modulating fluorescence property as precursors. The as-prepared CCP-CD potently suppressed Aβ fibrillization and strongly eliminated multiple reactive oxygen species (ROS) (·OH, O2[·-], DPPH·) at low concentrations (1-10 μg/mL). Moreover, CCP-CD facilitates detection of Aβ plaques through a turn-on red fluorescence mechanism for both in vitro and in vivo imaging and quantification. In vitro assays showed that CCP-CD markedly attenuated Aβ-induced cytotoxicity and increased cell viability from ∼60 to 95%, as well as exhibited excellent anti-inflammatory effects by reducing the levels of TNF-α and IL-6 in BV-2 cells. In vivo experiments revealed that CCP-CD effectively suppressed Aβ plaque formation in the AD nematodes and prolonged the lifespan from 13 to 20 d. The unique structural characteristics of CCP-CD, including its conjugated aromatic framework, reversible Ce[3+]/Ce[4+] redox pair, and abundant O- and N-containing functional groups, facilitate balanced multiple therapeutic and diagnostic functions. The work has thus provided an exceptional nanoagent for detecting Aβ and fighting against Aβ-associated toxicities.},
}

@article {pmid40833319,
year = {2025},
author = {Agarwal, U and Verma, S and Gandhi, V and Patil, VM and Tonk, RK},
title = {Multitarget 8-methoxypsoralens against Alzheimer's disease: extraction, synthesis, in vitro and in silico studies.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/17568919.2025.2546776},
pmid = {40833319},
issn = {1756-8927},
abstract = {AIM: Alzheimer's disease poses a serious global health challenge, and there is an urgent need for novel therapeutic agents, as existing drugs have limited efficacy and notable adverse effects. Chromenones, known for their diverse biological activities, have emerged as promising drug candidates for AD treatment due to their capacity to target multiple enzymes. In this study, investigated the chromenone derivative 8-methoxypsoralen (8-MOP) as a potential multi-target inhibitor of key AD targets, highlighting the importance of the scaffold in target-based drug design.

MATERIAL AND METHODS: 8-MOP, a phytochemical extracted and isolated from parsley leaves, was utilized to synthesize new derivatives, which were then screened against enzymes involved in AD progression (BACE1, AChE, BuChE) and targets involved in oxidative pathways (DPPH, NO). In support of the in vitro activity, in silico ADMET predictions and docking experiments were performed.

RESULTS AND CONCLUSIONS: Among the synthesized compounds, 3d and 3e demonstrated significant inhibitory effects against the chosen targets, exhibiting IC50 values between 5.8 ± 0.13 μM and 13 ± 0.12 μM. Furthermore, the docking experiments showed important binding interactions of these compounds with BACE1, AChE, and BuChE. The study demonstrates the potential of 8-MOP derivatives for targeting AD drug targets.},
}

@article {pmid40833037,
year = {2025},
author = {Li, ZJ and Zhang, ZY and Jiang, YY and Liu, YM and Wang, J and Wang, YL and Qin, TY and Zhu, MQ},
title = {Construction of High-Performance Wash-Free Aβ Probes Based on Amino Group Optimization and Amphiphilic Molecular Engineering Strategies.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c01741},
pmid = {40833037},
issn = {1520-6882},
abstract = {β-Amyloid (Aβ) protein is a misfolded protein that plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) and is recognized as one of the primary pathological hallmarks of this disorder. Despite significant advancements in developing fluorescent probes for Aβ detection, research on the specific impact of end-group substituents on probe performance and the design of high-performance, wash-free Aβ probes remains limited. In this study, we designed and synthesized a series of water-soluble Aβ fluorescent probes, X-PYOH and X-PYC6, using a styrene pyridinium cation as the core structure by varying the end-group substituents. We systematically investigated their hydrophilicity/hydrophobicity, optical properties, Aβ detection capability, and imaging performance. The results demonstrated that among the various amino-substituted X-PYOH probes, PL-PYOH exhibited superior Aβ sensing, affinity, anti-interference capacity, Aβ plaque labeling performance, and wash-free characteristics. In contrast, PZ-PYOH and CT-PYOH showed poor Aβ detection performance. By modification of the substituents at the pyridinium cation end to decrease their hydrophilicity and preparation of X-PYC6 (PZ-PYC6, CT-PYC6), the responsiveness and affinity to Aβ fibrils were significantly enhanced, and the labeling performance of Aβ plaques was markedly improved. In conclusion, optimizing the types of amino substituents and balancing hydrophilicity and hydrophobicity can lead to the development of high-performance, wash-free imaging Aβ probes.},
}

@article {pmid40832981,
year = {2025},
author = {Keller, PC and Sappok, T},
title = {Dementia in Intellectual Disability: An Exploratory Investigation of Comorbidity Patterns and Diagnostic Outcomes.},
journal = {Journal of intellectual disability research : JIDR},
volume = {},
number = {},
pages = {},
doi = {10.1111/jir.70016},
pmid = {40832981},
issn = {1365-2788},
support = {//Bielefeld University/ ; },
abstract = {BACKGROUND: Dementia is more prevalent and tends to manifest earlier in individuals with intellectual disabilities (ID) compared to the general population. Acquiring specific knowledge about comorbidities and diagnostic findings in individuals with ID who have dementia, as opposed to those with ID without dementia, is essential. Such insights are crucial for enhancing the quality of care.

METHODS: The study was applied in a German outpatient clinic for people with ID and mental illnesses from February 2018 to September 2022. An exploratory comparison was conducted to identify differences in somatic and psychiatric comorbidities, laboratory results, cerebrospinal fluid results, neuroimaging, medication and challenging behaviour in people with ID with (n = 13, mean age: 54 years, 69% female) and without dementia (n = 73, mean age: 53 years, 48% female).

RESULTS: In this sample, persons with ID who have dementia are more likely to have Down syndrome and less likely to have affective disorders. They received antidementia drugs more often and atypical high-potency antipsychotics less often compared to persons with ID without dementia. All other clinical data showed no differences.

CONCLUSIONS: Interestingly, no differences in somatic diseases (except Down syndrome) or laboratory and neuroimaging results could be found between people with ID with and without dementia. However, the diagnosis of dementia was associated with a reduced frequency of affective disorders and a reduced prescription of antipsychotics compared to the clinical sample without dementia. Due to the exploratory character of the study, replication in a much larger sample is necessary.},
}

@article {pmid40832968,
year = {2025},
author = {Zhang, X and Chu, S and Huang, Y and Li, Z and Song, J and Wang, P and Su, Y and Zhang, Z and Xie, Z},
title = {Atractylenolide III Mitigates Alzheimer's Disease by Enhancing Autophagy via the YY1-TFEB Pathway.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70069},
pmid = {40832968},
issn = {1099-1573},
support = {2024ZY1027//Special Research Project of Henan Province on Traditional Chinese Medicine/ ; 82274612//National Natural Science Foundation of China/ ; 23HASTIT044//Program for Science & Technology Innovation Talents in Universities of Henan Province/ ; 231111312900//Key Research and Development Program of Henan Province/ ; 232301420085//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; 232301420093//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; 242301420019//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; },
abstract = {Autophagy dysregulation serves as a significant pathogenic factor in Alzheimer's disease (AD), with transcription factor EB (TFEB) acting as a pivotal transcription factor that governs the process of autophagy. Atractylenolide III (AT-III), a terpenoid compound found in medicinal Atractylodes macrocephala Koidz, is well-known for its role in antioxidant and anti-inflammatory activities. The purpose of this study is to explore the beneficial impact of AT-III on AD pathology and identify the mechanisms involved. C. elegans CL4176, SH-SY5Y APPSWE, and APP/PS1 mice were used to investigate the efficacy and possible mechanism of AT-III on the treatment of AD. AT-III reduced amyloid protein (Aβ) deposition in C. elegans CL4176 heads, prolonged the paralysis time, and reduced Aβ levels in SH-SY5Y APPSWE cells. AT-III improved the learning and memory ability of APP/PS1 mice and decreased the deposition of Aβ plaques. Transcriptomics and experimental validation showed that AT-III stimulated transcription and translation of autolysosome-associated genes. AT-III enhanced co-localization of LC3 and LAMP2 with Aβ in APP/PS1 mice. Meanwhile, AT-III increased TFEB transcriptional activity, mRNA, and protein levels in the nucleus. Furthermore, AT-III enhanced the expression of Yin Yang 1 (YY1) protein, an upstream regulator of TFEB, and led to the stimulation of autophagy and lysosome biogenesis both in vivo and in vitro. The observed effects were reversed upon silencing YY1. AT-III may regulate the YY1-TFEB pathway, thereby restoring autophagy flux disturbances and ameliorating AD-related pathological changes and cognitive decline. This study provides a promising lead compound for intervention in AD.},
}

@article {pmid40832908,
year = {2025},
author = {Wretlind, A and Xu, J and Chen, W and Velayudhan, L and Ashton, NJ and Zetterberg, H and Proitsi, P and Legido-Quigley, C},
title = {Lipid profiling reveals unsaturated lipid reduction in women with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70512},
doi = {10.1002/alz.70512},
pmid = {40832908},
issn = {1552-5279},
support = {R344-2020-989//Lundbeck Fonden/ ; //AddNeuroMed Consortium/ ; ARUK-SRF2016A-3 C//Alzheimer's Research Trust/ ; },
mesh = {Humans ; *Alzheimer Disease/blood ; Female ; Aged ; *Cognitive Dysfunction/blood ; Lipidomics ; Male ; *Lipids/blood ; Sex Factors ; Cohort Studies ; *Fatty Acids, Unsaturated/blood ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease that disproportionately affects women. This study aimed to investigate sex-specific single lipids associated with AD.

METHODS: Plasma samples from 841 participants, comprising 306 individuals with AD, 165 with mild cognitive impairment (MCI), and 370 cognitively healthy controls were curated from the AddNeuroMed cohort. Lipidomics identified 268 single lipids for each sample. We investigated sex-specific associations from lipid modules and single lipids to AD and probed for causality with mediation analyses.

RESULTS: Three modules associated with AD in the female subset and one in the male subset (P < 0.05). In the female participants with AD, lipid families containing highly unsaturated fatty acids were reduced and those containing saturated lipids were increased (q value < 0.05). The effects of unsaturated phospholipids on AD were not mediated via cholesterol, low-density lipoprotein, or apolipoprotein B.

DISCUSSION: Women with AD have lower unsaturated plasma lipid levels compared to controls.

HIGHLIGHTS: Lipid profiling showed lipid changes associated with Alzheimer's disease (AD) exclusively in women. Women with AD had fewer highly unsaturated lipids and more saturated lipids. Unsaturated phospholipids affected AD independently of cholesterol, low-density lipoprotein, or apolipoprotein B. Sex-stratified analysis is key to understanding the different manifestations of AD.},
}

Humans
*Alzheimer Disease/blood
Female
Aged
*Cognitive Dysfunction/blood
Lipidomics
Male
*Lipids/blood
Sex Factors
Cohort Studies
*Fatty Acids, Unsaturated/blood
Aged, 80 and over

@article {pmid40832838,
year = {2025},
author = {Gammone, M and Catania, G and Moro, A and Barbieri, M and Cattani, D and Zanini, M and Moreschi, GC and Sasso, L and Bagnasco, A},
title = {Nursing Literature Mapping in Neurodegenerative Diseases: A Scoping Review.},
journal = {Journal of clinical nursing},
volume = {},
number = {},
pages = {},
doi = {10.1111/jocn.70075},
pmid = {40832838},
issn = {1365-2702},
abstract = {AIM: To explore the topics and themes covered in published research studies in nursing about neurodegenerative disease, synthesise the available evidence, and discuss future directions.

DESIGN: Scoping review following the Joanna Briggs Institute guidelines.

METHODS: A multi-step search strategy was applied across different databases to identify studies published in English or Italian up to September 2023. Data were analysed using a Nursing Data Matrix based on the nursing meta-paradigm and the Child Health and Nutrition Research Initiative (CHNRI) 4D-framework. Screening and data extraction were performed independently by pairs of reviewers; data were extracted and thematically analysed to identify existing research questions and potential priorities.

DATA SOURCES: Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, and Embase databases were searched for studies published from 2013 to 2023.

RESULTS: A total of 351 studies met inclusion criteria. The majority of studies originated from the United States (35%). Parkinson's disease and Alzheimer's disease were the most studied conditions, while rare diseases were scarcely represented. Most studies focused on nursing care (39%), with limited attention to rehabilitation (0.8%) and cost-effectiveness (1%). Although 70% of articles included at least one nurse author, 22% lacked any nursing authorship despite addressing nursing-related topics. Thematic and matrix analyses revealed an uneven distribution of research, with a predominance of descriptive studies and limited work in discovery-oriented research.

CONCLUSION: This review provides a comprehensive overview of nursing research in neurodegenerative diseases, highlighting key themes and gaps. The findings informed the preliminary identification of new nursing research priorities in neurodegenerative diseases to guide future studies and enhance evidence-based nursing care.

The study highlights key trends and gaps in nursing research on neurodegenerative diseases, calling for a more inclusive, equitable, and comprehensive research agenda.

REPORTING METHOD: PRISMA-ScR guidelines.

This study did not include patient or public involvement in its design, conduct or reporting.

Review registration was done on Open Science Framework, and can be viewed at https://osf.io/tn5v9 (https://doi.org/10.17605/OSF.IO/TN5V9).},
}

@article {pmid40832805,
year = {2025},
author = {Aguilar Gamas, CF and López Diaz-Guerrero, NE and Gómez-Crisóstomo, NP and De la Cruz-Hernández, EN and Zazueta, C and Ramírez-Camacho, I and Márquez-Álvarez, CM and Martínez-Abundis, E},
title = {Obesity and Alzheimer´s disease: unraveling the impact of chronic consumption of high-fat or high-sucrose diets on neurodegeneration and mitochondrial dysfunction.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/1028415X.2025.2546950},
pmid = {40832805},
issn = {1476-8305},
abstract = {BACKGROUND: The global incidence of obesity and metabolic disorders has been associated with alterations in the central nervous system, prominently featuring increased oxidative stress and heightened production of amyloid beta peptide (AB), stemming from mitochondrial dysregulations, which potentially contribute to the onset of neurodegenerative disorders like Alzheimer disease.

AIMS: In this study, we sought to ascertain whether chronic consumption of unbalanced diets by rats leads to elevated AB production and accumulation in brain structures, driving neuronal damage and mitochondrial dysfunction.

METHODS: Male Wistar rats were fed with unbalanced diets rich in sucrose or lard for 12 months. Subsequently, we evaluated zoometric and biochemical parameters, including glucose tolerance, serum cholesterol, and triglycerides, alongside spatial memory. Additionally, AB accumulation, oxidative stress markers, and mitochondrial respiratory chain activity were analyzed in mitochondria and homogenates from the hippocampus and cerebral cortex.

RESULTS: In our results, both dietary interventions induced abdominal obesity and spatial memory deterioration, associated to glucose metabolism disturbance, mitochondrial dysfunction, and increased oxidative stress. Nevertheless, AB accumulation was evident only in the mitochondria of rats fed with the sucrose-enriched diet.

CONCLUSIONS: With these findings, we show that, although excessive consumption of fat or sucrose drives to obesity, only the last could potentially bridge the gap between obesity and neurodegenerative pathogenesis, thereby highlighting the relevance of lifestyle and diet quality, bringing a way to develop preventive strategies.},
}

@article {pmid40832784,
year = {2025},
author = {Akgun, B and Gulyayev, AV and Coker, M and Hamilton-Nelson, KL and Olalusi, O and Adams, LD and Akinwande, K and Whitehead, PG and Diala, S and Ogunronbi, M and Laux, RA and Akpalu, A and Starks, TD and Sarfo, FS and Chavez, J and Lwere, K and Beecham, GW and Akinyemi, JO and Obiako, R and Ndetei, D and Caban-Holt, A and Ayele, B and Ogrocki, P and Griswold, AJ and Zaman, AF and Mena, PR and Martinez, IM and Blanton, SH and Okubadejo, N and Damasceno, A and Kalaria, R and Cuccaro, ML and McInerney, KF and , and , and Bush, WS and Kunkle, BW and Ogunniyi, A and Vance, JM and Akinyemi, RO and Haines, JL and Reitz, C and Byrd, GS and Rajabli, F and Pericak-Vance, MA},
title = {ABCA7 deletion lowers age at onset of Alzheimer's disease and interacts with APOE ε4 synergistically in African-ancestry populations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70583},
doi = {10.1002/alz.70583},
pmid = {40832784},
issn = {1552-5279},
support = {//National Institute on Aging of National Institutes of Health/ ; U19AG074865/AG/NIA NIH HHS/United States ; U01AG076482/AG/NIA NIH HHS/United States ; R01AG072547/AG/NIA NIH HHS/United States ; U01AG084545/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/ethnology ; Female ; Male ; Age of Onset ; *Apolipoprotein E4/genetics ; *ATP-Binding Cassette Transporters/genetics ; Aged ; Genotype ; Genetic Predisposition to Disease ; Aged, 80 and over ; Middle Aged ; Black or African American/genetics ; Gene Deletion ; White ; },
abstract = {INTRODUCTION: Apolipoprotein E (APOE) and ABCA7 genes are among the strongest heritable risk factors for Alzheimer's disease (AD) in African-ancestry (AA) populations. APOE 𝜀4 affects both risk and age at onset (AAO), with lower risk in AA populations. This study evaluates the independent and interactive effects of the AA-specific ABCA7 frameshift deletion and APOE 𝜀4 allele on AAO.

METHODS: We analyzed 3510 AA individuals, including AD cases and controls. Cox regression models assessed the effects of ABCA7 deletion, APOE genotypes, and their interactive influence on AAO.

RESULTS: APOE ε3/ε4 carriers with the ABCA7 deletion had a significantly shorter survival compared to ε3/ε4 carriers without the deletion. No significant differences were found between deletion carriers and non-carriers with APOE ε3/ε3 or ε4/ε4 genotypes.

DISCUSSION: Our study showed that the ABCA7 deletion lowered the AAO of AD in APOE ε3/ε4 carriers from AA populations. These findings suggest that the AA-specific ABCA7 deletion and the APOE ε4 allele have synergistic effects on AAO.

HIGHLIGHTS: AA-specific ABCA7 deletion lowers AAO of AD in APOE ε3/ε4 carriers from AA populations. Findings suggest an interaction between ABCA7 deletion and APOE ε4 on AAO. APOE ε4 has a strong, dose-dependent effect on AAO of AD in AA individuals. ABCA7 deletion impact on AAO of AD is stronger in females with APOE ε3/ε4.},
}

Humans
*Alzheimer Disease/genetics/ethnology
Female
Male
Age of Onset
*Apolipoprotein E4/genetics
*ATP-Binding Cassette Transporters/genetics
Aged
Genotype
Genetic Predisposition to Disease
Aged, 80 and over
Middle Aged
Black or African American/genetics
Gene Deletion
White

@article {pmid40832731,
year = {2025},
author = {Zhang, Y and Wen, B and Jiao, Y and Liu, Y and Guo, X and Wu, Y and Li, J and Han, L and Xu, Y and Gao, X and Qi, Y and Cheng, Y and He, Y and Tian, W},
title = {SCRIPT: Predicting Single-Cell Long-Range Cis-Regulation Based on Pretrained Graph Attention Networks.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e05021},
doi = {10.1002/advs.202505021},
pmid = {40832731},
issn = {2198-3844},
support = {32370719 32170667 82394432 92249302//National Natural Science Foundation of China/ ; 2023SHZDZX02//Shanghai Municipal Science and Technology Major Project/ ; REI/1/5234-01-01//The King Abdullah University of Science and Technology (KAUST) Office of Research Administration (ORA)/ ; REI/1/5414-01-01//The King Abdullah University of Science and Technology (KAUST) Office of Research Administration (ORA)/ ; REI/1/5289-01-01//The King Abdullah University of Science and Technology (KAUST) Office of Research Administration (ORA)/ ; REI/1/5404-01-01//The King Abdullah University of Science and Technology (KAUST) Office of Research Administration (ORA)/ ; REI/1/5992-01-01//The King Abdullah University of Science and Technology (KAUST) Office of Research Administration (ORA)/ ; URF/1/4663-01-01//The King Abdullah University of Science and Technology (KAUST) Office of Research Administration (ORA)/ ; 5940//Center of Excellence on Generative AI/ ; 5932//Center of Excellence for Smart Health/ ; },
abstract = {Single-cell cis-regulatory relationships (CRRs) are essential for deciphering transcriptional regulation and understanding the pathogenic mechanisms of disease-associated non-coding variants. Existing computational methods struggle to accurately predict single-cell CRRs due to inadequately integrating causal biological principles and large-scale single-cell data. Here, SCRIPT (Single-cell Cis-regulatory Relationship Identifier based on Pre-Trained graph attention networks) is presented for inferring single-cell CRRs from transcriptomic and chromatin accessibility data. SCRIPT incorporates two key innovations: graph causal attention networks supported by empirical CRR evidence, and representation learning enhanced through pretraining on atlas-scale single-cell chromatin accessibility data. Validation using cell-type-specific chromatin contact and CRISPR perturbation data demonstrates that SCRIPT achieves a mean AUC of 0.89, significantly outperforming state-of-the-art methods (AUC: 0.7). Notably, SCRIPT obtains an over twofold improvement in predicting long-range CRRs (>100 Kb) compared to existing methods. By applying SCRIPT to Alzheimer's disease and schizophrenia, a framework is established for prioritizing disease-causing variants and elucidating their functional effects in a cell-type-specific manner. By uncovering molecular genetic mechanisms undetected by existing computational methods, SCRIPT provides a roadmap for advancing genetic diagnosis and target discovery.},
}

@article {pmid40832697,
year = {2025},
author = {Kang, S and Kafetsouli, D and Ford, J and Wong, J and Bracoud, L and Suhy, J and Giannakopoulou, P and Udeh-Momoh, C and Russ, TC and Ritchie, C and Alexopoulou, Z and Salinas, C and Saad, ZS and Novak, G and Robinson, O and Middleton, LT},
title = {Prevalence and risk factors of cerebral microhemorrhages and superficial siderosis in cognitively unimpaired older adults: analysis from the CHARIOT-PRO SubStudy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70594},
doi = {10.1002/alz.70594},
pmid = {40832697},
issn = {1552-5279},
support = {//Janssen Research & Development, LLC, a Johnson & Johnson company/ ; NIHR200180//NIHR ARC Dementia Fellowship/ ; MR/S03532X/1//UKRI Future Leaders Fellowship/ ; MR/Y02012X/1//UKRI Future Leaders Fellowship/ ; //Takeda/ ; //Merck/ ; //Gates Ventures/ ; },
mesh = {Humans ; Aged ; Female ; Male ; Risk Factors ; Cross-Sectional Studies ; Aged, 80 and over ; *Cerebral Hemorrhage/epidemiology/diagnostic imaging ; Prevalence ; Middle Aged ; Apolipoprotein E4/genetics ; *Siderosis/epidemiology ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/metabolism ; Prospective Studies ; },
abstract = {INTRODUCTION: Cerebral microhemorrhages (CMHs) and superficial siderosis (SS) are relatively common side effects of anti-amyloid immunotherapies, termed amyloid-related imaging abnormalities (ARIA-H). They are also observed in treatment-naïve older adults. This study explored relationships with modifiable and non-modifiable risk factors.

METHODS: This cross-sectional study included 1414 cognitively unimpaired, treatment-naïve individuals aged 60 to 85 years from the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy. Relationships between CMHs/SS and cardiovascular risk factors, amyloid beta (Aβ) load, apolipoprotein E (APOE) ε4 status, educational attainment, and white matter hyperintensities were investigated using regression analyses and structural equation modeling.

RESULTS: CMHs were observed in 8.3% of participants and SS in 1.3%. Significant risk factors for CMHs included age and hypertension. Higher education attainment appeared to have a protective effect. Elevated amyloid is a risk factor, particularly when adjusting for APOE ε4 status in individuals aged 70 or younger.

DISCUSSION: Increasing age and hypertension are significant risk factors of CMHs. Higher educational attainment may offer a protective effect.

HIGHLIGHTS: Of the 1414 participants from the CHARIOT-PRO SubStudy (CPSS), CMHs were present in 118 (8.3%), and SS was present in 18 (1.3%). Age and hypertension were identified as significant risk factors for CMHs, and the latter had a stronger association with the presence of CMHs among female participants. Having a bachelor's degree or higher was found to be protective. Elevated brain amyloid burden, particularly when adjusted for APOE ε4 carrier status, was identified as a risk factor in individuals aged 70 years and below.},
}

Humans
Aged
Female
Male
Risk Factors
Cross-Sectional Studies
Aged, 80 and over
*Cerebral Hemorrhage/epidemiology/diagnostic imaging
Prevalence
Middle Aged
Apolipoprotein E4/genetics
*Siderosis/epidemiology
Magnetic Resonance Imaging
Amyloid beta-Peptides/metabolism
Prospective Studies

@article {pmid40832647,
year = {2025},
author = {Ancidoni, A and Salemme, S and Marconi, D and Bellomo, G and Pani, SM and Locuratolo, N and Lacorte, E and Lombardo, FL and Bacigalupo, I and Fabrizi, E and Canevelli, M and Sciancalepore, F and Lorenzini, P and Palazzesi, I and Paggetti, A and Della Gatta, F and Piscopo, P and Salvi, E and Zambri, F and Di Nolfi, A and Palermo, V and Sciattella, P and Bini, C and Mennini, FS and Bianchi, CBNA and Landoni, F and Giannini, MA and Di Fiandra, T and Vanacore, N and , and , and , },
title = {Advancing dementia care: a review of Italy's public health response within the WHO Global Action Plan and European strategies.},
journal = {BMJ public health},
volume = {3},
number = {2},
pages = {e002250},
pmid = {40832647},
issn = {2753-4294},
abstract = {INTRODUCTION: Dementia is a growing global public health priority, with the WHO Global Action Plan (GAP) calling for coordinated efforts worldwide. Italy, one of the oldest nations globally, faces a significant challenge with approximately 2 million individuals living with dementia or mild cognitive impairment. In response, the Italian Fund for Alzheimer's and other Dementias (IFAD) was established in 2020 to align national efforts with the WHO GAP's objectives. This study analyses IFAD activities from 2021 to 2023, offering insights into Italy's public health response to dementia and its relevance to global strategies.

METHODS: We conducted a structured, iterative review of all activities coordinated by the Italian Dementia Observatory (OssDem-Istituto Superiore di Sanità (ISS)) within IFAD 2021-2023. Global, regional and national documents on dementia prevention, care and support were retrieved from official websites, institutional repositories and targeted web searches using the keywords 'dementia', 'brain health' and 'ageing'. Two reviewers independently screened and extracted data with a predefined matrix mapped to the seven WHO GAP Action Areas. Human-subject studies cited had independent ethics approval and informed consent; no new data were collected for this review.

RESULTS: IFAD activities led to substantial progress in dementia care services, with memory clinics, residential care facilities and daycare centres mapped, revealing regional disparities in service provision. Modifiable risk factors accounted for 39.5% of dementia cases in Italy, with an estimated 67 000 cases preventable through risk reduction. National guidelines were developed to standardise dementia care pathways, and training programmes addressed gaps in HP and caregiver preparedness, particularly highlighted by the COVID-19 pandemic.

DISCUSSION: Italy's experience provides valuable lessons for countries facing similar demographic challenges. The IFAD extension to 2024-2026 aims to address persistent regional disparities and further implement national guidelines and prevention strategies. By integrating Italy's progress with broader international frameworks, the Italian model can inform global efforts to enhance dementia care, highlighting the importance of scalable, regionally adapted strategies for addressing the growing global burden of dementia.},
}

@article {pmid40832531,
year = {2025},
author = {Yuan, S and El Gaamouch, F and Cho, S and Kuncewicz, K and Nada, H and Gabr, MT},
title = {Discovery of a Small Molecule TREM2 Agonist with Improved In Vitro Pharmacokinetic Profile and Validated Target Engagement.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {8},
pages = {1634-1640},
pmid = {40832531},
issn = {1948-5875},
abstract = {The microglial lipid-sensing receptor TREM2 is a promising therapeutic target for Alzheimer's disease. We report the discovery of C1, a racemic structural analog of the clinical-stage TREM2 agonist VG-3927. Synthesized via a concise, modular, and enantioselective-free route using sequential Suzuki couplings, C1 enables rapid scaffold diversification. Compared to VG-3927, this stereochemically simplified derivative exhibits superior microglial phagocytosis and activates TREM2 signaling in HEK293-hTREM2/DAP12 cells, demonstrating validated target engagement. Direct binding of C1 to TREM2 was unequivocally confirmed by both surface plasmon resonance (SPR) and microscale thermophoresis (MST). Critically, C1 displays a superior in vitro pharmacokinetic profile to VG-3927: enhanced metabolic stability in human and mouse liver microsomes, favorable passive permeability (PAMPA), and a CNS-compatible log D7.4. Docking studies suggest a potential binding mode for C1 within TREM2's extracellular domain, revealing key interactions. These attributes establish C1 as an accessible and pharmacokinetically favorable lead compound with strong potential for developing TREM2-targeted therapies.},
}

@article {pmid40832438,
year = {2025},
author = {Faulstich, NG and Hilmi Omar, S and John O-Brien, C and Ojo, DT and Brewer, PC and Nathaniel, EI and Goodwin, R and Roley, L and Imeh-Nathaniel, A and Nathaniel, TI},
title = {Sex differences in clinical risk factors for Alzheimer's dementia patients with early-onset and late-onset.},
journal = {Frontiers in global women's health},
volume = {6},
number = {},
pages = {1601375},
pmid = {40832438},
issn = {2673-5059},
abstract = {BACKGROUND: The objective of this study is to identify the risk factors that contribute to sex differences in patients with Alzheimer dementia (AD), specifically focusing on Early-Onset Alzheimer's Dementia (EAOD) and Late-Onset Alzheimer Dementia (LOAD). Additionally, the study aims to determine whether these risk factors differ between male and female EAOD and LOAD patients.

METHODS: Our retrospective cohort study included a total of 6,212 patients diagnosed with either EOAD or LOAD from February 2016 to August 2020. Among this population, 687 patients (11.06%) were diagnosed with EOAD, while 5,525 patients (88.94%) had LOAD. We conducted a univariate analysis to identify differences in risk factors between male and female AD patients. A multivariate analysis was also performed to predict specific risk factors associated with male and female EOAD and LOAD patients.

RESULTS: In the adjusted analysis, males with LOAD were found to have significantly higher odds of several comorbidities, including dyslipidemia [Odds Ratio (OR) = 1.720, 95% Confidence Interval (CI) = 1.489-1.987, p < 0.001], peripheral vascular disease (OR = 2.324, 95% CI = 1.828-2.955, p < 0.001), obstructive sleep apnea (OR = 2.330, 95% CI = 1.768-3.070, p < 0.001), and pneumonia (OR = 1.235, 95% CI = 1.004-1.520, p = 0.046). In contrast, females with LOAD were associated with lower odds of having hypertension (OR = 0.715, 95% CI = 0.623-0.820, p < 0.001), osteoporosis (OR = 0.310, 95% CI = 0.254-0.380, p < 0.001), urinary tract infections (OR = 0.638, 95% CI = 0.521-0.782, p < 0.001), congestive heart failure (OR = 0.626, 95% CI = 0.481-0.815, p < 0.001), and rheumatoid arthritis. In male patients with EAOD the analysis indicated a strong association with gait dysfunction (OR = 10.797, 95% CI = 3.257-35.792, p < 0.001), peripheral vascular disease (OR = 3.835, 95% CI = 1.767-8.321, p < 0.001), and Chronic Obstructive Pulmonary Disease (COPD) (OR = 5.984, 95% CI = 2.186-16.381, p < 0.001). Conversely, females with EOAD were associated with significantly lower odds of experiencing cerebrovascular accidents (OR = 0.347, 95% CI = 0.155-0.778, p < 0.001), osteoporosis (OR = 0.345, 95% CI = 0.155-0.778, p = 0.030), and anxiety (OR = 0.412, 95% CI = 0.203-0.833, p = 0.014).

CONCLUSIONS: Our findings indicate sex differences in the risk factors for EAOD and LOAD patients. Understanding these risk factors can help us develop strategies to improve diagnostic accuracy, create targeted interventions, and enhance clinical outcomes for both male and female EAOD and LOAD patients.},
}

@article {pmid40832432,
year = {2025},
author = {, and Boquet-Pujadas, A and Anagnostakis, F and Yang, Z and Tian, YE and Duggan, MR and Erus, G and Srinivasan, D and Joynes, CM and Bai, W and Patel, PJ and Walker, KA and Zalesky, A and Davatzikos, C and Wen, J},
title = {Multi-organ AI Endophenotypes Chart the Heterogeneity of Pan-disease in the Brain, Eye, and Heart.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.09.25333350},
pmid = {40832432},
abstract = {Disease heterogeneity and commonality pose significant challenges to precision medicine, as traditional approaches frequently focus on single disease entities and overlook shared mechanisms across conditions [1] . Inspired by pan-cancer [2] and multi-organ research [3] , we introduce the concept of "pan-disease" to investigate the heterogeneity and shared etiology in brain, eye, and heart diseases. Leveraging individual-level data from 129,340 participants, as well as summary-level data from the MULTI consortium, we applied a weakly-supervised deep learning model (Surreal-GAN [4,5]) to multi-organ imaging, genetic, proteomic, and RNA-seq data, identifying 11 AI-derived biomarkers - called Multi-organ AI Endophenotypes (MAEs) - for the brain (Brain 1-6), eye (Eye 1-3), and heart (Heart 1-2), respectively. We found Brain 3 to be a risk factor for Alzheimer's disease (AD) progression and mortality, whereas Brain 5 was protective against AD progression. Crucially, in data from an anti-amyloid AD drug (solanezumab [6]), heterogeneity in cognitive decline trajectories was observed across treatment groups. At week 240, patients with lower brain 1-3 expression had slower cognitive decline, whereas patients with higher expression had faster cognitive decline. A multi-layer causal pathway pinpointed Brain 1 as a mediational endophenotype [7] linking the FLRT2 protein to migraine, exemplifying novel therapeutic targets and pathways. Additionally, genes associated with Eye 1 and Eye 3 were enriched in cancer drug-related gene sets with causal links to specific cancer types and proteins. Finally, Heart 1 and Heart 2 had the highest mortality risk and unique medication history profiles, with Heart 1 showing favorable responses to antihypertensive medications and Heart 2 to digoxin treatment. The 11 MAEs provide novel AI dimensional representations for precision medicine and highlight the potential of AI-driven patient stratification for disease risk monitoring, clinical trials, and drug discovery.},
}

@article {pmid40832424,
year = {2025},
author = {Kim, MS and Park, S and Kim, JH and Myung, W and Song, M and Do, R and Nho, K and Kim, E and Hwang, S and Yu, Z and Natarajan, P and Kim, HJ and Son, HJ and Park, WY and Sui, Y and Fahed, AC and Ellinor, PT and Ali, M and Gong, K and Cruchaga, C and Yon, DK and Seo, J and Shin, JY and Jo, DG and Won, HH},
title = {ACE inhibition increases Alzheimer's disease risk by promoting tau phosphorylation.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.11.25333412},
pmid = {40832424},
abstract = {Reportedly, over 60% of individuals in the USA aged 65 or older take antihypertensive medications, making it crucial to evaluate their potential impact on dementia. Alzheimer's disease (AD), the most prevalent form of dementia, develops insidiously over decades, effectively precluding clinical trials of antihypertensive drug effects on AD risk. Through a triangulation approach integrating large-scale human genetics, population-based study, and rigorous experimental models, we identified that angiotensin-converting enzyme (ACE) inhibitors were associated with increased AD risk, with no significant associations observed for other antihypertensive classes, including angiotensin II receptor blockers and calcium channel blockers. Multi-omics Mendelian randomization analyses revealed that genetically proxied reductions in ACE expression and ACE protein levels in serum, cerebrospinal fluid, and brain tissues were causally associated with increased AD risk via exacerbated tau phosphorylation. A cohort study of 338,645 UK Biobank participants, followed for more than 10 years, also found an association between genetically predicted low serum ACE levels and the increased incidence of AD. Experimental validation using P301S tau transgenic mice and human iPSC-derived neurons confirmed that pharmacological ACE inhibition intensified tau phosphorylation and aggregation, cognitive impairment, neuroinflammation, and glial activation, predominantly in the hippocampal region. Multiple lines of evidence established a specific link between ACE inhibition and tau-driven neurodegeneration, underscoring the importance of carefully tailored antihypertensive strategies to prevent dementia risk, and identifying ACE as a viable therapeutic target for AD and other tau-related neurodegenerative conditions.},
}

@article {pmid40832399,
year = {2025},
author = {Zhang, B and McEvoy, LK and Nguyen, S and Espeland, MA and Rapp, SR and Horvath, S and Lu, A and LaCroix, AZ and Nievergelt, CM and Maihofer, AX and Resnick, SM and Mielke, MM and Beckman, K and Li, D and Silver, B and Manson, JE and Ferrucci, L and Shadyab, AH},
title = {Epigenetic clocks and longitudinal plasma biomarkers of Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.12.25333453},
pmid = {40832399},
abstract = {INTRODUCTION: Chronological age is the strongest risk factor for Alzheimer's disease and related dementias (ADRD). However, the association of accelerated biological aging relative to chronological age with ADRD pathology is unclear.

METHODS: In a cohort of 2,366 cognitively unimpaired older women from the Women's Health Initiative Memory Study, we examined associations of five baseline measures of epigenetic age acceleration (EAA) with 15-year changes in plasma ADRD biomarkers.

RESULTS: At baseline, higher AgeAccelPheno was associated with lower amyloid-β42 to amyloid-β40 (Aβ42:Aβ40) ratio, and higher AgeAccelGrim2 was associated with elevated neurofilament light (NfL). Longitudinally, higher DunedinPACE - which measures the pace of biological aging - was associated with faster increases in phosphorylated tau at threonine 181 (p-tau181), p-tau217, NfL, and glial fibrillary acidic protein (GFAP) over 15 years.

DISCUSSION: Accelerated biological aging, particularly as indicated by DunedinPACE, was associated with increasing levels of plasma ADRD biomarkers over time.},
}

@article {pmid40832393,
year = {2025},
author = {Cohen, BM and Koh, E and Levental, KR and Levental, I and Sonntag, KC},
title = {Specific Lipid Abnormalities Are Inherently Associated with Late-Onset Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.08.25333304},
pmid = {40832393},
abstract = {INTRODUCTION: Lipid abnormalities have been observed in brain, CSF, and blood in association with late-onset Alzheimer's disease (LOAD). It is unknown which abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived neural lines.

METHODS: iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Lipidomics analyses were performed on whole cell and mitochondrial extracts.

RESULTS: Large reductions in cholesterol esters (CE) and imbalances in fatty acids (FA) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids.

DISCUSSION: The findings identify abnormalities in CE and FA as likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.},
}

@article {pmid40832377,
year = {2025},
author = {Gong, Z and Laporte, JP and Guo, AY and Bae, J and Fox, NY and de Rouen, A and Zhang, N and Taranath, A and de Cabo, R and Egan, JM and Ferrucci, L and Bouhrara, M and , },
title = {Axonal Degeneration Across the Alzheimer's Disease Spectrum: A Longitudinal MRI and Fluid Biomarker Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.13.25333630},
pmid = {40832377},
abstract = {With global dementia rates rising sharply, there is an urgent need for sensitive biomarkers to detect cognitive changes and predict dementia risk. White matter degeneration, especially axonal loss, is increasingly recognized as an early hallmark of Alzheimer's disease (AD), but its temporal trajectory and its relationship with cognition have not been established. We utilized a novel MRI-derived Axonal Density Index (ADI) to longitudinally investigate axonal degeneration and cognitive decline in the ADNI cohort. Linear mixed-effects models showed cognitively impaired individuals had lower baseline ADI and faster axonal degeneration compared to cognitively normal subjects. In cognitively impaired individuals, higher baseline ADI predicted slower prospective cognitive deterioration and lower dementia risk, while greater longitudinal ADI declines correlated with cognitive worsening and increased dementia risk. Notably, ADI outperformed cerebrospinal fluid biomarkers of AD pathology in predicting cognitive outcomes. Our original findings position axonal degeneration as an early AD feature and ADI as a promising biomarker for early detection, disease phenotyping and monitoring, and intervention targets.},
}

@article {pmid40832323,
year = {2025},
author = {Zwang, TJ and Zhang, J and Gelb-Bicknell, R and Wolf, N and Chanchykov, V and Zhu, H and Agastra, E and Devine, A and Holbrook, AJ and Bennett, RE and Hyman, BT},
title = {Tau drives cell specific functional isolation of the hippocampal formation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.10.669580},
pmid = {40832323},
issn = {2692-8205},
abstract = {A major challenge in understanding Alzheimer's disease is linking changes that occur across different biological scales. For example, how do changes in individual neurons build into widespread network disruptions? To address this, we used flexible mesh electronics to record neuronal activity for six months in ThyTau22 mice, a model of tauopathy that accumulates mutant human tau with age. Electrophysiology was recorded simultaneously from the hippocampus and entorhinal cortex of awake, behaving mice. At all ages we observed neuron-level, tau-driven silencing including ages without detectable tangles or cell-death. We found an unexpected phenomenon: neurons silenced by tau spontaneously recover individual firing patterns, yet these neurons fail to regain normal network interactions. Thus, as the animals age, disrupted network-level activity emerges. Specifically, we observe a global decrease in excitatory interactions and a breakdown in gamma-band coherence, which is particularly disrupted between the entorhinal cortex and hippocampus. These observations reveal a temporal relationship between neuronal silencing and impaired network connectivity, which also contributes to a progressive disruption in the excitatory/inhibitory balance. This ultimately disconnects viable entorhinal-hippocampal connections, physiologically isolating the hippocampus. Importantly, this network dysfunction is not driven by neuron loss, but by the failure of neurons to re-establish proper network interactions after silencing. This reveals a previously unrecognized mechanism by which mutant tau can destabilize neural systems. Further, these experiments indicate that a therapeutic window may exist where neuronal function and network activity might still be restored prior to irreversible degeneration.},
}

@article {pmid40832298,
year = {2025},
author = {McFadden, SA and Fang, Y and Quinn, K and Peck, MR and Chapman, JE and Hill, T and Bartke, A and Hascup, ER and Hascup, KN},
title = {Surgical Removal of Visceral Adipose Tissue has Therapeutic Benefit in Male APP [NL-F] Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.07.669175},
pmid = {40832298},
issn = {2692-8205},
abstract = {PURPOSE: Visceral white adipose tissue (vWAT) accumulation causes systemic inflammation, insulin resistance, metabolic syndrome, and senescent cell accumulation that are risk factors for Alzheimer's disease (AD). Visceral fat removal (VFR) improves metabolism and reduces proinflammatory cytokines. We hypothesized that VFR removal in AD mice would improve metabolism and cognition.

METHODS: Male and female APP [NL-F] mice underwent sham or vWAT surgical resection (epididymal and perirenal) at 4 (pre-symptomatic) and 16 (symptomatic) months of age to understand interventional and therapeutic effects, respectively. At 18 months of age, glucose metabolism and novel object recognition (NOR) memory were assayed followed by assessment of body composition and tissue-specific markers of metabolism, cell senescence, inflammation, or amyloid accumulation.

RESULTS: Male and female APP [NL-F] mice showed distinct VFR responses. In pre-symptomatic males, increased vWAT lipolysis and hepatic lipogenesis led to ectopic liver lipid accumulation, with reduced adiponectin and leptin, elevated visfatin, and impaired glucose metabolism. Symptomatic males showed reduced vWAT lipogenesis, enhanced hepatic lipolysis, glycolysis, and glycogenesis, lowering liver lipids and improving insulin sensitivity. Only symptomatic males improved NOR, linked to elevated hippocampal learning and memory markers. Female vWAT reaccumulation was due to increased lipogenesis and lower lipolysis. Pre-symptomatic females had lower hepatic lipogenesis, while glycolysis and glycogenesis declined with disease progression. Hippocampal senescence and inflammation were elevated early in the disease that persisted symptomatically.

CONCLUSIONS: Sex-specific differences in glucose and lipid metabolism and lipid accumulation underlie the divergent responses to VFR in APP [NL-F] mice, with symptomatic males showing the only beneficial outcomes in metabolism and cognition.},
}

@article {pmid40832295,
year = {2025},
author = {Gharavi-Naeini, L and Shu, Z and Alem, F and Feng, S and Chilin, LD and Feng, P and Wu, Y},
title = {HSV-1 infection induces brain cofilin hyperphosphorylation in the 5×FAD Alzheimer's Disease mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.10.669568},
pmid = {40832295},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a degenerative neurological disease characterized by various biological signatures, including synaptic dysfunction, β-amyloid plaques, hyperphosphorylated Tau, cofilin-actin rods, and Hirano bodies, all of which are linked to the actin cytoskeleton and its regulators. Additionally, the presence of herpes simplex virus type 1 (HSV-1) in the brains of AD patients has long been suggested as a contributing factor for AD. However, mechanisms by which HSV-1 accelerates AD pathogenesis remain poorly understood. Here we report that HSV-1 infection induces hyperphosphorylation of cofilin in the brains of 5×FAD mice. Cofilin is an actin depolymerizing factor, and its S3 phosphorylation inactivates cofilin's activity to depolymerize actin filaments. These findings facilitate the understanding of impacts of HSV-1 infection on the development of Alzheimer's disease and have implications in AD therapeutics.},
}

@article {pmid40832283,
year = {2025},
author = {Naseri, NN and Xu, T and Chantarawong, S and Patrie, SM and Kelleher, NL and Sharma, M and Shalem, O and Rhoades, E},
title = {Specific Combinations of Physiological Tau Phosphorylation Regulate Tau-Microtubule Interactions in Developing Neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.09.669485},
pmid = {40832283},
issn = {2692-8205},
abstract = {Tau phosphorylation is a defining feature of Alzheimer's disease, yet it also plays an essential physiological role in stabilizing microtubules (MTs) during normal neuronal development. While individual phosphorylation sites have been well-studied in pathology, it remains largely unknown how combinatorial phosphorylation is regulated under physiological conditions. Here, we uncover distinct, site-specific phosphorylation patterns on tau in developing human neurons. With top-down mass spectrometry we find that functional, endogenous tau is highly modified, with up to 21 phosphates per molecule. We identify patterns of co-occurrence between phosphorylation sites that are in proximity in the linear protein sequence, such as epitopes S202/T205/T212/T217 and T231/S235/S262. Moreover, these phospho-epitopes define discrete pools of tau and regulate tau-MT interactions in coordination, providing a mechanism for fine-tuning the binding of tau to MTs. Intriguingly, we find that co-occurring phospho-epitopes are dynamically regulated in response to changes in MT integrity; chemical perturbation of neuronal MTs promotes rapid tau dephosphorylation by phosphatase PP2a at most sites to enhance tau-MT interactions and counteract destabilization. We then use the PS19 tauopathy mouse model to demonstrate that developmental and pathological tau phosphorylation patterns partially overlap, and that co-occurring phospho-epitopes exhibit similar associations with the insoluble fraction in aged mice. Our results reveal an isoform-dependence on the effects of site-specific tau phosphorylation on its behavior. Together, these findings define a combinatorial phosphorylation code that modulates tau's physiological function in neurons and raises the possibility that MT destabilization precedes tau phosphorylation in disease. This work provides a mechanistic framework for distinguishing functional from pathological tau phosphorylation, with implications for the development of therapies that specifically target disease-associated tau proteoforms.},
}

@article {pmid40832270,
year = {2025},
author = {Aydin, AG and Manoj, P and Ramadan, F and Youssef, E and Rajan, S and Torres, E and Bieszczad, KM},
title = {Sound-evoked auditory neurophysiological signals are a window into prodromal functional differences in a preclinical model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.07.669134},
pmid = {40832270},
issn = {2692-8205},
abstract = {Hearing has been identified as the largest modifiable mid-life risk factor for Alzheimer's Disease (AD), despite that its link to dementia remains unclear. Here we identify a biomarker of AD risk in an auditory neural signal using the non-invasive, rapidly acquired, and clinically translatable auditory brainstem response (ABR) in normal hearing knock-in rats (Swedish familial AD risk variant to Amyloid precursor protein, App [S] ; male and female). While ABR morphology has been proposed as a biomarker for AD, we report a novel biomarker derived from multidimensional parametric feature extraction on the distribution statistics of repeated single traces of the ABR that increases its potential for clinical utility with sensitivity and specificity. We report accurate prediction of AD genetic risk in both young and aged animals: App [S] rats separate clearly from humanized controls in both sex- and age-dependent manners. Notably, auditory learning in young adulthood normalized the ABR signature in App [S] rats with maintained effects into older age, altogether supporting a central neural generator of auditory dysfunction related to AD risk. These preclinical findings show how ABRs could provide a very early biomarker for detection of AD risk and lay the groundwork to test the synergy of auditory and cognitive functions in human dementia.},
}

@article {pmid40832254,
year = {2025},
author = {Denault, WRP and Sun, H and Carbonetto, P and Liu, A and De Jager, P and Bennet, D and , and Wang, G and Stephens, M},
title = {fSuSiE enables fine-mapping of QTLs from genome-scale molecular profiles.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.17.670732},
pmid = {40832254},
issn = {2692-8205},
abstract = {Molecular quantitative trait locus (QTL) studies seek to identify the causal variants affecting molecular traits like DNA methylation and histone modifications. However, existing fine-mapping tools are not well suited to molecular traits, and so molecular QTL analyses typically proceed by considering each variant and each molecular measurement independently, ignoring the LD among variants and the spatial correlation in effects between nearby sites. This severely limits accuracy in identifying causal variants and quantifying their molecular trait effects. Here, we introduce fSuSiE (``functional Sum of Single Effects''), a fine-mapping method that addresses these challenges by explicitly modeling the spatial structure of genetic effects on molecular traits. fSuSiE integrates wavelet-based functional regression with the computationally efficient ``Sum of Single Effects'' framework to simultaneously finemap causal variants and identify the molecular traits they affect. In simulations, fSuSiE identified causal variants and affected CpGs more accurately than methods that ignore spatial structure. In applications to DNA methylation and histone acetylation (H3K9ac) data from the ROSMAP study of the dorsolateral prefrontal cortex, fSuSiE achieved dramatically higher resolution than existing methods (e.g., identifying 6,355 single-variant methylation credible sets compared to only 328 from an existing approach). Applied to Alzheimer's disease (AD) risk loci, fSuSiE identified potential causal variants colocalizing with AD GWAS signals for established genes, including CASS4 and CR1/CR2, suggesting specific potential regulatory mechanisms underlying these AD risk loci.},
}

@article {pmid40832248,
year = {2025},
author = {Houmam, S and Siodlak, D and Pham, KD and Salinas-Salinas, C and Ocañas, SR and Freeman, WM and Rice, HC},
title = {Protocol to isolate oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons from a single mouse brain using magnetic-activated cell sorting.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.08.666877},
pmid = {40832248},
issn = {2692-8205},
abstract = {The isolation of specific cell types of the brain is essential to study cell-type-specific differences in complex neurological diseases such as Alzheimer's disease. This protocol isolates oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons from a single mouse brain. The process involves gentle tissue homogenization, debris removal, and sequential sorting of five distinct cell types. We validate cell purity and viability using flow cytometry and RT-qPCR. This protocol is well-suited for a range of downstream applications, including genomics, transcriptomics, and proteomics.},
}

@article {pmid40832216,
year = {2025},
author = {Bartlett, MJ and Erickson, RP and Frye, J and Doyle, KP and Pires, PW and Witte, MH},
title = {Manual lymph drainage massage of the head and neck improves cognition and reduces pathological biomarkers in the 5x-FAD mouse model of Alzheimers disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.08.669361},
pmid = {40832216},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) affects 6.9 million people over the age of 65 in the US and is expected to double by 2060. While FDA approved immunotherapies slow cognitive decline in some individuals with AD, they do not improve cognition, are costly, and have significant side-effects. Therefore, new targets, approaches, and treatments for AD are a necessity. There are no FDA approved therapies for AD that target the brain's lymphatic system. It is well established that the toxic protein, amyloid-beta (Aβ), accumulates in the AD brain. Recent studies have shown that Aβ is cleared via interstitial fluid and cerebrospinal fluid through a pathway involving the glymphatic system-meningeal lymphatic vessels-leading to deep and superficial cervical lymphatic vessels and nodes. Therefore, any blockage along this route can cause inefficient drainage and result in pathological buildup of Aβ, which can lead to AD. Here, we propose a new approach to treating AD by manual lymph drainage (MLD), which is a light skin massage traditionally used to reduce fluid accumulation in lymphedema. This therapy has also been demonstrated to be safe in individuals with AD, but its effects on cognition and biomarkers of AD has never been investigated. In this study we demonstrate that repeated MLD of the head and neck, including the superficial cervical lymphatic vessels (scLVs), improves cognitive function in AD as measured in both the Y-maze and nest-building tests. We also show that this coincides with a reduction in plasma levels of neurofilament light chain (NfL), a non-specific biomarker for neuronal cell death and axonal damage. MLD was also shown to reduce Aβ in the hippocampus of these mice. Combined, this data provides compelling proof-of-principle evidence for the potential of MLD as a standalone or adjunct therapy in the treatment of AD.},
}

@article {pmid40832110,
year = {2025},
author = {Androni, X and Boyd, RJ and Rosenberg, PB and Mahairaki, V},
title = {Psychedelics meet human brain organoids: insights into proteomics and potential for Alzheimer's disease treatment.},
journal = {Frontiers in dementia},
volume = {4},
number = {},
pages = {1605051},
pmid = {40832110},
issn = {2813-3919},
abstract = {Alzheimer's disease (AD) is characterized by a long preclinical phase lasting more than a decade before the onset of its clinical phase of mild cognitive impairment (MCI) or dementia. Recent advances in psychedelic research underscore numerous neuroplastogenic and anti-inflammatory alterations induced by these compounds, making them promising therapeutic candidates for AD. In this mini review, we will briefly summarize the existing literature using human cerebral organoids to study the molecular and metabolic changes caused by various psychedelic compounds, focusing on their potential therapeutic applications for AD.},
}

@article {pmid40831763,
year = {2025},
author = {B S, P and Talwar, P},
title = {Influence of palmitoylation in axonal transport mechanisms in neurodegenerative diseases.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1613379},
pmid = {40831763},
issn = {1662-5102},
abstract = {Progressive functional loss and death of neurons are characteristics of neurodegenerative diseases such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). These diseases are often linked with disruptions in axonal transport and synaptic functions. Accumulation of misfolded proteins is observed as a commonly shared pathology for these diseases, where aberrant accumulation of amyloid beta (Aβ), tau, α-synuclein (α-syn) and TAR DNA-binding protein 43 (TDP-43), are found in AD, PD and ALS, respectively. These accumulations are observed to be involved in disrupting axonal transport and compromising neuronal survival. Axonal transport is an essential process where proper functioning of the transport mechanism is important for maintaining neuronal hemostasis by transporting of proteins, organelles and neurotransmitter complexes. This review explores the role of palmitoylation in regulating neuronal axonal transport and their impact on other neuronal functions along with neurodegeneration mechanisms. Palmitoylation is a reversible lipid modification, which is widely studied second to phosphorylation. Enzymes like palmitoyl acyltransferases and acyl-protein thioesterases are responsible for attachment and detachment of palmitic acid causing palmitoylation and depalmitoylation of neuronal proteins. In axonal transport, palmitoylation influences the localization and functioning of the proteins, which connectively plays a role in synaptic stability by interacting with synaptic scaffolding proteins and neurotransmission receptors.},
}

@article {pmid40831622,
year = {2025},
author = {Olexson, MP and Vera, AO and Ro, C and Enos, CW},
title = {Systemic therapy targeting psoriatic inflammation is associated with decreased incidence of dementia: An observational retrospective cohort study.},
journal = {JAAD international},
volume = {22},
number = {},
pages = {88-90},
pmid = {40831622},
issn = {2666-3287},
}

@article {pmid40831583,
year = {2025},
author = {Zhang, Y and Li, H and Yang, J and Ma, H},
title = {Physical activity and neuroinflammation: a bibliometric analysis of research progress and future perspectives.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1602724},
pmid = {40831583},
issn = {1663-4365},
abstract = {BACKGROUND: Neuroinflammation is a common pathological feature of neurodegenerative and psychiatric diseases and is closely related to the dysfunction of the nervous system. In recent years, an increasing number of studies have shown that physical activity (PA) has a significant regulatory effect on neuroinflammation. However, a comprehensive analysis of research in this field is currently lacking, including the evolution of knowledge structures, interdisciplinary trends, and dynamic shifts in research hotspots.

METHODS: This study retrieved relevant literature from the Web of Science Core Collection database for the period from 2004 to 2025. The search strategy was TS = (("physical activit*" OR exercis* OR "exercise training") AND ("neuroinflammat*" OR "neuro inflammatory" OR "neuro-inflammatory")), with the document type limited to Articles and Reviews. After screening, a total of 661 eligible articles were included for bibliometric analysis. The analysis tools used were the Bibliometrix R package and VOSviewer, which were employed to visualize the results of the literature analysis.

RESULTS: From 2004 to 2025, the number of publications in this field showed a yearly increasing trend, with an annual growth rate of 15.05%. China and the United States were the main contributing countries, publishing 122 and 111 articles, respectively. In terms of journals, the International Journal of Molecular Sciences ranked first with 36 articles and a total of 799 citations. Among the institutions, Karolinska Institute led the way in terms of citation counts, amassing a total of 391 citations. Regarding author keywords, "Alzheimer's disease," "microglia," and "older adults" were the three most frequently occurring keywords. Research hotspots have gradually shifted from the early focus on hippocampal function and neuroinflammation mechanisms to current directions such as neurodegenerative diseases, microglial regulation, and the gut-brain axis.

CONCLUSION: This study systematically reviewed the research progress in the field of PA and neuroinflammation from 2004 to 2025 using bibliometric methods and revealed the research hotspots, trends, and thematic evolution in this field. It provides a systematic scientific basis for scholars to understand the field, optimize research directions, and develop intervention strategies.},
}

@article {pmid40831513,
year = {2025},
author = {Zafari, R and Kamroo, A and Nabizadeh, F},
title = {Association of Growth-Associated Protein 43 with White Matter Alterations in Patients with Cognitive Decline.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7004572/v1},
pmid = {40831513},
issn = {2693-5015},
abstract = {Background Alzheimer's disease (AD) is the most common cause of dementia, characterized by a considerable decline in memory. The aggregation of amyloid-beta (Aβ) plaques and tau tangles is the primary pathology of AD. Recently, growth-associated protein 43 (GAP-43) has been suggested as a reliable biomarker in the early diagnosis of patients with AD continuum. Objectives In this study, we aimed to observe the association of white matter (WM) features detected by diffusion tensor imaging (DTI) with the cerebrospinal fluid (CSF) level of GAP-43 in patients with cognitive impairment. Methods Information from 132 participants from different ATN groups, including 62 with A-/TN-, 16 with A+/TN-, 30 with A-/TN+, and 24 with A+/TN + pathology were enrolled from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We observed the association of CSF GAP-43 with DTI findings among patients with AD spectrum by using a linear regression model adjusted for age, sex, period of education, and APOE Ɛ4 status. Results Our findings suggested a significant association for CSF GAP-43 concentration with WM features in the inferior cerebellar peduncle in the A-/TN- group as well as WM in the cerebral peduncle, anterior corona radiata, and the left sagittal stratum of patients with A+/TN- pathology. In addition, a significant relation was reported between DTI findings in the cingulum cingulate, fornix, body, and splenium of the corpus callosum of patients with A-/TN + with CSF GAP-43 concentration. A similar significant association was shown in the posterior limb of the internal capsule of the A+/TN + group. Moreover, a significant association was found between CSF level of GAP-43 and the performance of A+/TN + and A+/TN- groups in cognitive tests. Conclusions Our study observed a significant association between CSF GAP-43 concentration and WM microstructural findings in different brain tracts of patients with various ATN groups, suggesting GAP-43 as a reliable and accurate biomarker in the early detection of patients with cognitive decline. Further longitudinal investigations with other imaging methods can provide more evidence on the role of GAP-43 in the detection of brain damage among patients with AD spectrum.},
}

@article {pmid40831509,
year = {2025},
author = {Goodheart, A and Yoo, CH and Fassini, A and Dagnew, T and Ye, R and Striar, R and Quan, M and Rattray, A and Meyer, T and Peterec, E and Lee, H and Fiedler, S and Hooker, J and Wey, HY and Wang, C and Gomperts, S},
title = {Imaging brain class I histone deacetylase changes in the Lewy body dementias and Parkinson's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6647341/v1},
pmid = {40831509},
issn = {2693-5015},
abstract = {Background: Histone deacetylases (HDACs) are epigenetic molecules responsible for regulation of gene transcription. Altered expression of HDACs has been linked to neurodegenerative disease. Here, we used the class I HDAC PET radioligand [ [11] C]Martinostat to quantify and map changes in these molecules in the brain in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In this cross-sectional study, we acquired brain PET-MR with [ [11] C]Martinostat in 14 DLB (median age 70 years (IQR 14), 21% female), 10 PD (median age 70 (8), 20% female) including four with cognitive impairment and six without, and 17 healthy control (HC) participants (median age 62 (14), 47% female). [ [11] C]Martinostat uptake was compared amongst groups using whole brain voxel-wise analysis and targeted region of interest (ROI)-based approaches, adjusted for age and sex. Regional expression was also quantified in postmortem brain bank samples. Results: Compared to HC, [ [11] C]Martinostat uptake in DLB was increased in precentral gyrus (ROI p = 0.044) and putamen (p < 0.001) , as well as in cognitive and limbic circuitry including anterior cingulate (p = 0.042) and entorhinal cortex (p = 0.023). [ [11] C]Martinostat uptake in DLB was decreased in inferior parietal cortex p < 0.001) compared to HC, consistent with prior observations in Alzheimer's disease. In PD, [ [11] C]Martinostat uptake was also increased in precentral gyrus (p = 0.019 in those with normal cognition, p = 0.047 in those with impaired cognition), correlating with both disease duration and stage. In cognitively impaired PD, [ [11] C]Martinostat uptake was additionally reduced in inferior parietal cortex (p = 0.011), similar to DLB. In postmortem DLB tissue, class I HDAC expression was elevated in anterior cingulate cortex (isoform 1 p = 0.041, isoform 3 p = 0.024) and reduced in inferior parietal cortex (isoform 1 p < 0.001). Conclusions: These findings reveal evidence of elevated class I HDACs in motor cortex in PD and bidirectional changes in their regional expression in the Lewy body dementias.},
}

@article {pmid40831271,
year = {2025},
author = {Takakuwa, M and Izuo, N and Chino, K and Yano, Y and Yokose, J and Shigetsura, Y and Nitta, A},
title = {Construction of Shati/Nat8l Plasmid Vectors, and Analysis of Mitochondrial Function Mediated by Shati/Nat8l Against Amyloid β Toxicity.},
journal = {Neuropsychopharmacology reports},
volume = {45},
number = {3},
pages = {e70041},
doi = {10.1002/npr2.70041},
pmid = {40831271},
issn = {2574-173X},
support = {AdAMS JP22H04922//Japan Society for the Promotion of Science/ ; JP21H02632//Japan Society for the Promotion of Science/ ; JPMJSP2145//Japan Science and Technology SPRING/ ; //Tamura Science and Technology Foundation/ ; //Smoking Research Foundation/ ; //Kobayashi Foundation/ ; },
mesh = {*Amyloid beta-Peptides/toxicity ; Animals ; *Mitochondria/metabolism/drug effects ; Mice ; Plasmids/genetics ; Genetic Vectors ; Humans ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/drug effects ; Peptide Fragments/toxicity ; },
abstract = {In Alzheimer's disease (AD), the accumulation of senile plaques composed of neurotoxic amyloid β (Aβ) is known to be one of the causes. Shati/Nat8l, a gene related to neuropsychiatric disorders, encodes an enzyme that biosynthesizes N-acetyl aspartate (NAA) from aspartate and acetyl CoA. Studies on AD patients and model mice show that NAA and Shati/Nat8l are associated with AD pathology. We previously demonstrated that hippocampal overexpression of Shati/Nat8l in 5xFAD mice, an AD model, improved cognitive suppress without altering the number or size of Aβ plaques. To investigate the cellular mechanisms underlying the neuroprotective effects of Shati/Nat8l on Aβ neurotoxicity, we constructed a vector containing the full-length Shati/Nat8l sequence and transfected it into Neuro-2a cells to produce a stably Shati/Nat8l-overexpressing cell line (N2A-Shati). N2A-Shati cells expressed threefold higher Shati/Nat8l mRNA levels compared with a control cell line (N2A-Control). Treatment with Aβ for 48 h reduced the viability of N2A-Shati and N2A-Control cells at concentrations ≧ 0.03 μM compared to their own vehicle. Exposure to 0.03 μM Aβ for 24 h did not induce any detectable changes in mitochondrial mass or mitochondrial membrane potential in either N2A-Control or N2A-Shati cells. However, N2A-Shati cells demonstrated reduced pyruvate dehydrogenase kinase 1 (Pdk1) mRNA expression and enhanced nuclear respiratory factor 1 (Nrf1) and mitochondrial transcription factor A (Tfam) mRNA expression levels. These results suggest that, although Shati/Nat8l does not significantly affect cell viability, mitochondrial mass, or membrane potential, it could modulate specific intracellular pathways.},
}

*Amyloid beta-Peptides/toxicity
Animals
*Mitochondria/metabolism/drug effects
Mice
Plasmids/genetics
Genetic Vectors
Humans
Cell Line, Tumor
Membrane Potential, Mitochondrial/drug effects
Peptide Fragments/toxicity

@article {pmid40831250,
year = {2025},
author = {Fang, L and Peng, R and Xia, L and Zhuang, GL},
title = {Active Learning-Assisted Exploration of [PO40Mo12][3-] for Alzheimer's Therapy Insights.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e08702},
doi = {10.1002/advs.202508702},
pmid = {40831250},
issn = {2198-3844},
support = {22471004//National Natural Science Foundation of China/ ; 92461305//National Natural Science Foundation of China/ ; 22072135//National Natural Science Foundation of China/ ; LTGY23B010001//Zhejiang Provincial Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD), involving amyloid-β (Aβ) aggregation, has potential therapeutic modulators in polyoxometalates (POMs) like [PMo12O40][3-]. To clarify their inhibitory mechanisms, a multiscale computational strategy integrating active-learning Bayesian Optimization (BO) and density functional theory (DFT) is employed to explore low-energy configurations of isolated amino acids, [PMo12O40][3] [-]-amino acid complexes, and [PMo12O40][3] [-]-peptide systems. Hydrogen bonding and Coulombic repulsion dominate adsorption stability. Crucially, oxygen atoms in the [PMo12O40][3] [-] cluster form multiple weak interactions (e.g., van der Waals, hydrophobic) with alkyl side-chain hydrogens in Aβ peptides. The synergistic effect of these weak interactions induces robust binding between the POM and peptide chains, stabilizing a tightly bound complex that sterically hinders Aβ self-assembly. Notably, simulations predict that the cluster preferentially targets hydrophobic amino acids with alkyl chains (valine, lysine, leucine, isoleucine) located in Aβ regions critical for aggregation-specifically, namely Aβ12, Aβ16-18, Aβ24, Aβ28, Aβ31-32, Aβ34-36, and Aβ39-41. These insights highlight the role of multivalent weak interactions in POM-mediated inhibition and identify key interfacial residues for therapeutic targeting.},
}

@article {pmid40831183,
year = {2025},
author = {Sampath, R and Baskar, M},
title = {Biomarker extraction-based Alzheimer's disease stage detection using optimized deep learning approach.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251360394},
doi = {10.1177/13872877251360394},
pmid = {40831183},
issn = {1875-8908},
abstract = {BackgroundCognitive decline and memory loss in Alzheimer's disease (AD) progresses over time. Early diagnosis is crucial for initiating treatment that can slow progression and preserve daily functioning. However, challenges such as overfitting in prediction models, underutilized biomarker features, and noisy imaging data hinder the accuracy of current detection methods.ObjectiveThis study proposes a novel deep learning-based framework aimed at improving the identification of AD stages while addressing the limitations of existing diagnostic techniques.MethodsStructural MRI scans are employed as the primary diagnostic tool. To enhance image quality, contrast-limited adaptive histogram equalization and wavelet soft thresholding are applied for noise reduction. Biomarker segmentation focuses on ventricular and hippocampal abnormalities, optimized using a firefly algorithm. Dimensionality reduction is performed via Linear Discriminant Analysis to minimize overfitting. Finally, a Deep Belief Network optimized using the Cuckoo Search algorithm is employed for classification and feature learning.ResultsThe proposed framework demonstrates improved performance over existing methods, achieving a 0.66% increase in accuracy and a 0.0345% decrease in error rate for AD stage detection.ConclusionsThis deep learning strategy shows promise as an effective tool for early and accurate AD stage identification. Enhanced segmentation, dimensionality reduction, and classification contribute to its improved performance, offering a meaningful advancement in AD diagnostics.},
}

@article {pmid40830882,
year = {2025},
author = {Lyckenvik, T and Olsson, M and Forsberg, M and Wasling, P and Zetterberg, H and Hedner, J and Hanse, E},
title = {Sleep reduces CSF concentrations of beta-amyloid and tau: a randomized crossover study in healthy adults.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {84},
pmid = {40830882},
issn = {2045-8118},
}

@article {pmid40830653,
year = {2025},
author = {Lin, W and Chen, H and Zhang, Z and Zhang, Y and Wang, X and Guo, Y and Qin, H and Liu, T and Chen, F},
title = {Multimodal MRI reveals impaired glymphatic function with choroid plexus enlargement and cerebrospinal fluid expansion in alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {30409},
pmid = {40830653},
issn = {2045-2322},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/physiopathology/pathology ; Male ; *Choroid Plexus/diagnostic imaging/pathology/physiopathology ; Female ; Aged ; *Glymphatic System/diagnostic imaging/physiopathology/pathology ; Cognitive Dysfunction/diagnostic imaging/cerebrospinal fluid ; *Magnetic Resonance Imaging/methods ; *Cerebrospinal Fluid/diagnostic imaging ; Diffusion Tensor Imaging ; Middle Aged ; Biomarkers/cerebrospinal fluid ; Aged, 80 and over ; Case-Control Studies ; Multimodal Imaging/methods ; },
abstract = {There is increasing evidence that cerebrospinal fluid (CSF) circulation plays a key role in the pathophysiology of Alzheimer's disease (AD), although the underlying mechanisms remain poorly understood. This study evaluated CSF circulation in patients with AD using magnetic resonance imaging (MRI)-derived measures, including choroid plexus (CP) volume, CSF volume, and diffusion tensor imaging along the perivascular space (DTI-ALPS) index. The study included 188 participants: 28 with AD, 40 with mild cognitive impairment (MCI), 66 with subjective cognitive decline (SCD), and 54 normal controls (NCs). Participants underwent structural T1-weighted MRI, diffusion tensor imaging, clinical assessment, and plasma biomarker analysis. After adjustments for age, sex, and education, group differences in the DTI-ALPS index, CP volume, and CSF volume were examined. Correlation and mediation analyses were conducted to assess the relationships of clinical parameters with DTI-ALPS index, CP volume, and CSF volume. The AD group exhibited a significantly lower DTI-ALPS index and higher CP and CSF volumes compared with the MCI, SCD, and NC groups. The DTI-ALPS index showed a strong negative correlation with both CP and CSF volumes, whereas CP volume was positively correlated with CSF volume. Mediation analysis revealed interactive relationships among the DTI-ALPS index, CP volume, and CSF volume. This study demonstrates that CSF circulation is disrupted in AD patients. Additionally, CP volume influences glymphatic drainage through its effects on CSF volume, indicating a potential role in AD pathophysiology.},
}

Humans
*Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/physiopathology/pathology
Male
*Choroid Plexus/diagnostic imaging/pathology/physiopathology
Female
Aged
*Glymphatic System/diagnostic imaging/physiopathology/pathology
Cognitive Dysfunction/diagnostic imaging/cerebrospinal fluid
*Magnetic Resonance Imaging/methods
*Cerebrospinal Fluid/diagnostic imaging
Diffusion Tensor Imaging
Middle Aged
Biomarkers/cerebrospinal fluid
Aged, 80 and over
Case-Control Studies
Multimodal Imaging/methods

@article {pmid40830651,
year = {2025},
author = {Jung, DH and Son, G and Wang, SM and Yoo, SJ and Jahanshahi, A and Lim, HK and Moon, C},
title = {Nasal Aβ42 mirrors brain amyloid dynamics and cognitive decline across the Alzheimer's disease continuum.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {30413},
pmid = {40830651},
issn = {2045-2322},
support = {RS-2020-NR049577//National Research Foundation of Korea/ ; HI18C0154//Korea Health Industry Development Institute/Republic of Korea ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging/pathology ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; *Cognitive Dysfunction/metabolism/diagnostic imaging ; Aged ; *Brain/metabolism/diagnostic imaging/pathology ; Positron-Emission Tomography ; *Peptide Fragments/metabolism ; Biomarkers/metabolism ; Aged, 80 and over ; Disease Progression ; Middle Aged ; *Amyloid/metabolism ; },
abstract = {Early, non-invasive assessment of Alzheimer's disease (AD) progression remains a key challenge. This study evaluated whether nasal amyloid-β42 (Aβ42) levels reflect brain amyloid dynamics and cognitive decline. Nasal discharge from 161 individuals, ranging from cognitively unimpaired to AD dementia, was analyzed using ELISA, alongside neuropsychological assessments and amyloid PET imaging. Moderate nasal Aβ42 levels (9.53-11.10 pg/mL) were positively associated with PET amyloid burden and cognitive decline, identifying a critical transitional disease stage. Conversely, the highest Aβ42 levels showed weaker correlations, suggesting a non-linear progression. The pattern of nasal Aβ42 mirrored brain amyloid accumulation, which peaks and stabilizes in later disease stages. These findings highlight nasal Aβ42 as a promising, scalable biomarker for tracking AD pathology and offer the first evidence linking it with brain amyloid PET. This supports its potential use in both clinical and longitudinal research settings.},
}

Humans
*Alzheimer Disease/metabolism/diagnostic imaging/pathology
*Amyloid beta-Peptides/metabolism
Male
Female
*Cognitive Dysfunction/metabolism/diagnostic imaging
Aged
*Brain/metabolism/diagnostic imaging/pathology
Positron-Emission Tomography
*Peptide Fragments/metabolism
Biomarkers/metabolism
Aged, 80 and over
Disease Progression
Middle Aged
*Amyloid/metabolism

@article {pmid40830532,
year = {2025},
author = {Sarkar, S and Gharami, K and Mondal, A and Padmanabhan, K and Paidi, RK and Srikumar, BN and Biswas, SC},
title = {TIMP-1 enhances Akt and BDNF signaling in neurons to reduce synaptic and cognitive deficits in 5xFAD mouse model of Alzheimer's disease.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {178},
pmid = {40830532},
issn = {2051-5960},
support = {LS-243/2021//Department of Science and Technology, Ministry of Science and Technology, India/ ; OLP-115//CSIR - Indian Institute of Chemical Biology/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics/complications ; *Brain-Derived Neurotrophic Factor/metabolism ; *Tissue Inhibitor of Metalloproteinase-1/metabolism/pharmacology ; Mice, Transgenic ; *Neurons/metabolism/pathology/drug effects ; Disease Models, Animal ; Signal Transduction/physiology/drug effects ; Mice ; *Proto-Oncogene Proteins c-akt/metabolism ; *Synapses/metabolism/pathology ; Hippocampus/metabolism/pathology ; *Cognitive Dysfunction/metabolism ; Humans ; Male ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {Glial-secreted molecules influence neuronal function in Alzheimer's disease (AD), but their mechanisms of action are partially understood. Anti-inflammatory cytokine tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is secreted by astrocytes early in response to amyloid-β and is suggested to have a neuroprotective function. We demonstrated that TIMP-1 levels are increased in 7-day-old 5xFAD versus wild-type mice but are drastically decreased from two months onwards. Administration of TIMP-1 protein in 5xFAD mice ameliorated AD-associated cognitive impairments. TIMP-1 regulated both neuronal apoptosis and autophagy by binding to CD63 receptors in an AD model. Synaptosomal and electrophysiological studies revealed that TIMP-1 reduces AD-related synaptic deficits, likely by promoting post-synaptic long-term potentiation in the hippocampus, independent of pre-synaptic activity. TIMP-1 induced brain-derived neurotrophic factor (BDNF) and BDNF-mediated post-synaptic signaling. These findings suggest that TIMP-1 functions as a multifunctional cytokine with protective and long-term benefits for neurons and may be a promising therapeutic candidate in AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics/complications
*Brain-Derived Neurotrophic Factor/metabolism
*Tissue Inhibitor of Metalloproteinase-1/metabolism/pharmacology
Mice, Transgenic
*Neurons/metabolism/pathology/drug effects
Disease Models, Animal
Signal Transduction/physiology/drug effects
Mice
*Proto-Oncogene Proteins c-akt/metabolism
*Synapses/metabolism/pathology
Hippocampus/metabolism/pathology
*Cognitive Dysfunction/metabolism
Humans
Male
Mice, Inbred C57BL
Amyloid beta-Protein Precursor/genetics

@article {pmid40830505,
year = {2025},
author = {Chang, HI and Ma, MC and Huang, KL and Huang, CG and Huang, SH and Huang, CW and Lin, KJ and Chang, CC},
title = {Optimizing timing and cost-effective use of plasma biomarkers in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {194},
pmid = {40830505},
issn = {1758-9193},
support = {NSTC113-2321-B-182A-005//National Science and Technology Council/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/diagnosis/economics ; *Biomarkers/blood ; Male ; Female ; Aged ; *Cost-Benefit Analysis ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Positron-Emission Tomography ; Neurofilament Proteins/blood ; Aged, 80 and over ; Machine Learning ; Glial Fibrillary Acidic Protein/blood ; Middle Aged ; Peptide Fragments/blood ; },
abstract = {BACKGROUND AND OBJECTIVES: Early and cost-effective identification of amyloid positivity is crucial for Alzheimer's disease (AD) diagnosis. While amyloid PET is the gold standard, plasma biomarkers such as phosphorylated tau 217 (pTau217) provide a potential alternative. This study evaluates the diagnostic accuracy of a combined-panel approach using machine learning models and evaluated the biomarker significance.

METHODS: We enrolled 371 participants, including AD (n = 143), non-AD (n = 159), and cognitively unimpaired (CU, n = 69) controls. Combined panels of pTau217, pTau181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), Aβ42/40, and total tau were measured prior to the amyloid PET scan. The multiclass logistic (LR) regression, support vector machines, decision trees, and random forests (RF)-were applied to classify amyloid positivity (A+) at all stages or at early clinical stages (1-3). In AD, we tested whether the biomarker may define the clinical stagings.

RESULTS: When benchmarked against amyloid PET, plasma biomarker-based stratification achieves an optimal balance between diagnostic accuracy and cost-effectiveness. The multi-class LR performed equivalently with RF model in identifying A+. The combined plasma panel reached an > 92% accuracy in identifying A+, with performance increasing to 93.4% at early clinical stages. We ranked the importance of individual biomarkers and pTau217 alone achieved comparable accuracy (> 90%) and was the top-ranked biomarker in the LR or RF model. NFL and GFAP correlated significantly with Mini-Mental State Examination; however, these plasma biomarkers did not enhance clinical staging stratification.

DISCUSSION: The use of multiclass LR model enhances amyloid classification, particularly at earlier clinical stages. While the combined-panel approach is most accurate, pTau217 alone provides a cost-effective alternative for screening. These findings support the integration of plasma biomarkers and ML into clinical workflows for early detection and patient stratification.},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging/diagnosis/economics
*Biomarkers/blood
Male
Female
Aged
*Cost-Benefit Analysis
tau Proteins/blood
Amyloid beta-Peptides/blood
Positron-Emission Tomography
Neurofilament Proteins/blood
Aged, 80 and over
Machine Learning
Glial Fibrillary Acidic Protein/blood
Middle Aged
Peptide Fragments/blood