@article {pmid41283974,
year = {2025},
author = {Di Lucente, J and Rutkowsky, JM and Errico Provenzano, A and Persico, G and Zhou, Z and Jin, LW and Ramsey, JJ and Montgomery, CB and Kim, K and Giorgio, M and Maezawa, I and Cortopassi, GA},
title = {A ketogenic diet improves memory in females in the APOE4 mouse model of Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41283974},
issn = {2509-2723},
support = {5P01AG062817/NH/NIH HHS/United States ; P50HD103526/NH/NIH HHS/United States ; 2U2CDK092993/NH/NIH HHS/United States ; },
abstract = {The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), increasing AD risk about fourfold in ~ 34 million American and ~ 75 million European females. APOE4 carriers exhibit cerebral metabolic deficits decades before clinical onset. We previously demonstrated that ketogenic diet (KD), a low-carbohydrate, high-fat diet promoting ketone metabolism, confers cognitive benefits in aged C57BL/6 mice, and in the PS1/APP mouse model of early-onset AD. Here, we evaluated the effects of KD in a humanized APOE4 AD mouse model. KD significantly improved composite cognitive performance and spatial working memory, with pronounced effects in females. Synaptic plasticity, measured via long-term potentiation (LTP), was likewise enhanced exclusively in females. Transcriptomic and protein analyses revealed KD-induced activation of CREB pathway, marked by increased phosphorylation of ERK and CREB in female brains. Moreover, KD selectively reduced pro-inflammatory cytokine levels in females. These findings demonstrate sex-specific neuroprotective effects of KD in APOE4 mice and suggest its potential therapeutic role in mitigating AD risk in APOE4-positive women.},
}

@article {pmid41283680,
year = {2025},
author = {},
title = {Corrigendum to 'Autoantibodies in Alzheimer's disease: Multifaceted roles and therapeutic horizons'.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401326},
doi = {10.1177/13872877251401326},
pmid = {41283680},
issn = {1875-8908},
}

@article {pmid41283666,
year = {2025},
author = {Graninger, M and Puchhammer-Stöckl, E and Vietzen, H},
title = {Herpesvirus-host interactions in neurological diseases: the immunogenetic role of HLA-E.},
journal = {Journal of virology},
volume = {},
number = {},
pages = {e0086925},
doi = {10.1128/jvi.00869-25},
pmid = {41283666},
issn = {1098-5514},
abstract = {Human herpesviruses (HHVs) comprise nine pathogenic members, including herpes simplex virus 1, herpes simplex virus 2, varicella-zoster virus, Epstein-Barr virus, human cytomegalovirus, human herpesvirus 6A/B, human herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus. Clinical manifestations of HHV infection can range from asymptomatic cases to a broad spectrum of neurological complications, spanning from acute conditions such as encephalitis to chronic disorders including Alzheimer's disease and multiple sclerosis. By establishing latency and undergoing repeated reactivation, HHVs maintain lifelong interactions with the human immune system and shape host immune responses, exerting considerable impact on nervous system homeostasis. Individual susceptibility to, and outcomes of, HHV-associated neurological disorders depend on multiple factors, including the infecting HHV strain and host genetics. Recent evidence highlights the pivotal role of the human leukocyte antigen E (HLA-E) pathway-a non-classical major histocompatibility complex class I molecule with immunomodulatory functions-in regulating virus-host interactions. Since some HHVs manipulate HLA-E to evade immune recognition, individual variability in this axis may influence neurological outcomes. In this review, we summarize and discuss current knowledge of the role of HLA-E in herpesvirus-associated neurological diseases.},
}

@article {pmid41283456,
year = {2025},
author = {Badin, L and Van Dendaele, E and Bailly, N},
title = {Equine-Assisted Interventions: Cross Perspectives of Beneficiaries and Their Caregivers from a Qualitative Perspective.},
journal = {Geriatrics (Basel, Switzerland)},
volume = {10},
number = {6},
pages = {},
doi = {10.3390/geriatrics10060145},
pmid = {41283456},
issn = {2308-3417},
abstract = {Background: Although equine-assisted interventions (EAI) are gaining growing attention, their scientific evaluation among individuals with Alzheimer's disease (AD) living in nursing homes remains limited. This study aimed to explore the lived experiences of an EAI program from the perspectives of the participants living with AD as well as their families and professional caregivers. Methods: Thirty non-directive interviews were conducted between June and July 2024 across several nursing homes in the Centre-Val de Loire region (France). The interviews were recorded, transcribed, and analyzed using thematic analysis. Results: Four main themes emerged from the analysis: (1) the experience with the horse, reflecting a unique relationship with the animal, the activities carried out, and perceived personality traits; (2) the environment of EAI sessions, offering a break from daily routines, encouraging contact with nature, and taking place in a setting specific to this type of intervention; (3) the implementation of the program within the institutional context, highlighting logistical aspects, environmental factors, and the adherence; (4) the effects of the intervention, including enhanced social interactions, memory stimulation, emotional engagement, and behavioral benefits. Conclusions: These findings provide insight into the multiple dimensions involved in an EAI program. By giving voice to both participants and their caregivers, this study emphasizes the value of qualitative approaches in deeply understanding the meaning and impact of these non-pharmacological interventions.},
}

@article {pmid41283452,
year = {2025},
author = {Kammar-García, A and Peña-Gonzalez, P and Sigg-Alonso, J and Álvarez-Cisneros, T and Roa-Rojas, P},
title = {Validity of the Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L) for Mexican Subjects with Mild and Moderate Cognitive Impairments.},
journal = {Geriatrics (Basel, Switzerland)},
volume = {10},
number = {6},
pages = {},
doi = {10.3390/geriatrics10060141},
pmid = {41283452},
issn = {2308-3417},
abstract = {Background/Objectives: Alzheimer's disease (AD) often begins with episodic memory deficits, detectable in Mild Cognitive Impairment (MCI). The Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L) shows promise for early detection, but lacks validation in Mexico. Methods: We assessed 355 adults ≥ 60 years, classified as cognitively healthy (CHG), MCI, or mild AD, using DSM-V criteria. Participants completed neuropsychological testing including the LASSI-L. Construct, concurrent, and predictive validity were analyzed via ANOVA, correlations with the Hopkins Verbal Learning Test (HVLT), and logistic regression models controlling for age, education, and comorbidity. Results: LASSI-L scores significantly differed between groups (p < 0.0001), with recovery from proactive interference best discriminating CHG from MCI and mild AD. Strong correlations with HVLT indices supported concurrent validity. Predictive models identified semantically cued recall and free recall (CRA2 and FRB1) as robust markers, independent of education. Conclusions: LASSI-L is a valid, accessible tool for identifying typical AD-related memory impairment in older Mexican adults, supporting earlier diagnosis in low-biomarker-access settings.},
}

@article {pmid41283140,
year = {2025},
author = {Shaabanpoor Haghighi, A and Nasiri, H and Ghayourvahdat, A and Azimizonuzi, H and Ghasemi, N and Mansouri, M and Moftakhar Bazkiaei, A and Amirian, MA and Zeinali, S and Gozali, H and Rostami, R and Ayobi, M and , },
title = {Plasma lipid metabolites as biomarkers of early white matter degeneration in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70217},
pmid = {41283140},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by progressive white matter (WM) degeneration. Circulating lipid metabolites may serve as early indicators of WM microstructural changes. In this study, we investigated the associations between plasma lipid metabolites and WM integrity across the cognitive continuum.

METHODS: We included 173 participants from the Alzheimer's Disease Neuroimaging Initiative (51 cognitively normal [CN], 88 mild cognitive impairment [MCI], 34 AD) database. Plasma metabolites were quantified using targeted lipidomics, and diffusion tensor imaging (DTI) metrics were derived from 52 predefined WM regions.

RESULTS: Regression analyses revealed widespread metabolite-DTI associations in MCI, particularly within the corpus callosum. The callosal body and splenium showed significant inverse associations with phosphatidylcholines (PCs) and multiple lysophosphatidylcholines (lysoPCs) species. In AD group, inverse relationships between PCs and the internal capsule were observed.

DISCUSSION: Circulating lipid metabolites are linked to WM microstructure in both prodromal and clinical AD, supporting their potential as sensitive biomarkers of early vulnerability and disease progression.

HIGHLIGHTS: Circulating lipid metabolites link to white matter integrity in early Alzheimer's disease (AD)Phosphatidylcholines (PCs), lysophosphatidylcholines (LPCs), and propionylcarnitine associate with tract-specific diffusion magnetic resonance imaging (dMRI) metricsNo metabolite-white matter associations detected in established ADPlasma metabolites may serve as biomarkers of early white matter degeneration.},
}

@article {pmid41283139,
year = {2025},
author = {Wilson, DH and Copeland, K and Miller, M and Vasko, AJ and Hesterberg, L and Khare, M and Wolfe, M and Sheehy, P and Verberk, I and Teunissen, C},
title = {Clinical performance of scalable automated p-tau 217 multi-analyte algorithmic blood test with reduced intermediate zone using multiplexed digital immunoassay.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70215},
pmid = {41283139},
issn = {2352-8729},
abstract = {INTRODUCTION: To address an urgent need for a scalable, accurate blood test for brain amyloid pathology that provides a conclusive result for the greatest number of patients, we developed a multi-analyte algorithmic test combining phosphorylated tau (p-tau) 217 with four other biomarkers.

METHODS: Multiplexed digital immunoassays measured p-tau 217, amyloid beta 42/40, glial fibrillary acidic protein, and neurofilament light chain in 730 symptomatic individuals (training set) to establish an algorithm with cutoffs, and 1082 symptomatic individuals (validation set) from three independent cohorts to identify brain amyloid pathology.

RESULTS: The algorithmic in validation gave an area under the curve = 0.92, yielding 90% agreement with amyloid positron emission tomography and cerebrospinal fluid. Positive predictive value was 92% at 55% prevalence. The multi-marker algorithm reduced the intermediate zone ≈ 3-fold from 34.4% to 11.9% versus p-tau 217 alone. Diagnostic performance was similar across subgroups.

DISCUSSION: The LucentAD Complete multi-analyte blood test demonstrated high clinical validity for brain amyloid pathology detection while substantially reducing inconclusive intermediate results.

HIGHLIGHTS: We developed a multi-analyte blood test for assessing brain amyloid status that significantly minimizes the ambiguous "intermediate zone," a key limitation of plasma phosphorylated tau (p-tau) 217 alone.Our test combines plasma levels of p-tau 217, amyloid beta 42/40 ratio, glial fibrillary acidic protein, and neurofilament light chain for a more comprehensive evaluation of amyloid status.We rigorously validated the test's clinical performance in > 1000 samples from symptomatic individuals across three independent cohorts, using cerebrospinal fluid biomarkers and amyloid positron emission tomography as comparators.},
}

@article {pmid41283076,
year = {2025},
author = {Toccaceli Blasi, M and Borioni, MS and Nuti, F and Belvisi, D and Canevelli, M and Fabbrini, G and Bruno, G},
title = {Presenilin-1 C779T Mutation Presenting With Rapidly Progressive Dementia and Medial Temporal Lobe MRI Changes.},
journal = {Case reports in neurological medicine},
volume = {2025},
number = {},
pages = {8251065},
pmid = {41283076},
issn = {2090-6668},
abstract = {INTRODUCTION: Autosomal dominant Alzheimer's disease (ADAD), especially due to presenilin-1 (PSEN-1) gene mutations, may display a broad spectrum of clinical manifestations and neuroradiological findings. Occasionally, these manifestations may be rare and atypical, challenging the clinician's ability to recognize the disease. The description of the clinical characteristics and neuroradiological remarks of patients with specific mutations may improve clinicians' ability to identify them.

CASE PRESENTATION: We report the case of a woman who presented with early-onset, rapidly progressive dementia associated with bilateral hyperintensity of the medial temporal lobe on T2-weighted MRI. After more common etiologies were excluded, genetic testing revealed a PSEN-1 C779T mutation. Notably, her brother, who carried the same mutation, did not exhibit these atypical neuroradiological findings.

CONCLUSIONS: This case underscores the phenotypic variability associated with PSEN-1 mutations, even among individuals within the same family. Such variability and the possibility of atypical presentations may complicate the diagnostic process. In the presence of early-onset and rapidly progressive dementia associated with bilateral hyperintensity of the medial temporal lobe, ADAD and PSEN-1 mutation may be suspected and need to be addressed.},
}

@article {pmid41282933,
year = {2025},
author = {Jensen, TD and Le Guen, Y and Talozzi, L and Yang, S and Gorzynski, JE and Pena-Tauber, A and Stewart, IF and Ferasse, A and Nachun, D and Arriaga, TM and Lee, J and Catoia Pulgrossi, R and Park, J and Zhang, J and Wagner, AD and Mormino, EC and Poston, KL and Henderson, VW and He, Z and Wyss-Coray, T and Montgomery, SB and Ashley, EA and Greicius, MD},
title = {Long-read genome sequencing and multi-omics in aging and neurodegeneration.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.10.25337775},
pmid = {41282933},
abstract = {Structural variants (SVs) are a major source of genetic variation yet remain underexplored in healthy aging and neurodegenerative diseases. We performed nanopore long-read genome sequencing (lrGS) on 551 deeply-phenotyped individuals from Stanfords Aging and Memory Study and Alzheimers Disease Research Center, generating a comprehensive SV map integrated with matched methylation, transcriptomic, and proteomic data. Over 60% of SVs identified by lrGS were not detected with short-read WGS, including many poorly tagged by single-nucleotide variants (SNVs). We discovered >60,000 SV-QTLs across molecular traits and showed that SVs were more likely than SNVs to be fine-mapped as causal. Colocalization with Alzheimers and Parkinsons disease GWAS implicated SVs at multiple loci, including TMEM106B, BIN3, and NBEAL1. Multi-omic outlier enrichment and Bayesian modeling prioritized rare functional SVs near known risk genes. Combined, these data reveal widespread regulatory SVs in healthy aging and neurodegeneration, underscoring the importance of lrGS in deciphering complex genetic architecture.},
}

@article {pmid41282905,
year = {2025},
author = {Andrews, D and Golchi, S and Collins, DL and , },
title = {A digital twin methodology using real patient data for sample size reduction in Alzheimer's disease randomized controlled clinical trials.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.28.25338899},
pmid = {41282905},
abstract = {INTRODUCTION: Recruitment for Alzheimer's disease randomized controlled trials (RCTs) is difficult and expensive. To reduce RCT sample sizes, our Digital Twin Trial (DTT) methodology combines an interpretable cognitive decline prediction model with prediction-powered inference.

METHODS: For DTT participants, our model identifies similar individuals ("Digital Twins") from a retrospective database and uses their cognitive scores to predict decline. Predictions adjust observed scores, reducing variance within treatment groups. We simulated 18-month DTTs and standard RCTs using mixed effects models of decline in Alzheimer's Disease Neuroimaging Initiative subjects meeting lecanemab's Phase 3 inclusion criteria.

RESULTS: Predicted and observed change in Clinical Dementia Rating Sum-of-Boxes correlated at r = 0.4. DTTs required 1,855 subjects versus 2,170 for standard RCTs to detect a simulated 25% decline-slowing drug effect at 0.9 power. DTT Type 1 error was consistent with 0.05.

DISCUSSION: DTTs could reduce recruitment and cost burdens. Model interpretability could help clinicians trust individualized prognoses.},
}

@article {pmid41282904,
year = {2025},
author = {Schweickart, A and Batra, R and Huynh, K and Blach, C and Kueider-Paisley, A and Reddy, JS and Klein, G and Bennett, DA and Meikle, PJ and Zhang, B and De Jager, PL and Heath, L and Beck, J and Scanlan, J and Seyfried, NT and Dickson, DW and Ertekin-Taner, N and , and , and Kaddurah-Daouk, R and Arnold, M and Krumsiek, J},
title = {Sphingolipid and ceramide associations with tau pathology vary across diverse ethnoracial groups in postmortem brain tissue.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.04.25339489},
pmid = {41282904},
abstract = {Metabolic dysregulation is a hallmark of Alzheimer's disease (AD), with numerous studies characterizing metabolic pathways associated with AD onset and progression. A significant limitation of these studies has been a predominant focus on non-Hispanic white participants. Despite evidence that AD prevalence, progression, and biomarkers differ across ethnoracial groups, it remains unclear whether previously identified metabolic dysregulation in AD brains generalizes across populations. We addressed this gap by analyzing large-scale metabolomics data from 547 postmortem dorsolateral prefrontal cortex brain tissue samples of Hispanic American, Non-Hispanic African American, and White subjects, providing the largest multiethnic AD brain cohort analyzed to date. A metabolome-wide association study examined how relationships between metabolite abundance and AD neuropathology varied by ethnoracial group. Sixty metabolites exhibited significant heterogeneity with tau pathology (Braak stage), with enrichment in tricarboxylic-acid-cycle intermediates, dipeptides, and sphingolipid-ceramide pathway lipids. These findings reveal ethnoracial-specific metabolic signatures of tau pathology and emphasize the need to evaluate emerging therapeutic targets across diverse groups.},
}

@article {pmid41282856,
year = {2025},
author = {Trelle, AN and Cody, KA and Nguyen, TT and Winer, JR and Weiss, S and Sai, I and Channappa, D and Mendiola, J and Al-Rajhi, A and Raghuraman, K and Sha, SJ and Wilson, EN and Wyss-Coray, T and Wagner, AD and Maecker, HT and Mormino, EC},
title = {Plasma proteomic signatures of preclinical Alzheimer's disease biomarkers and memory in clinically unimpaired older adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.22.25338569},
pmid = {41282856},
abstract = {BACKGROUND: Multianalyte plasma proteomic panels that can accurately detect initial AD pathology in preclinical populations and simultaneously measure related biological processes relevant for disease risk are critical for advancing early detection and prognosis.

METHODS: Using the NULISAseq CNS panel, we measured plasma from 193 clinically unimpaired (CU) older adults enrolled in the Stanford Aging and Memory Study (SAMS). We evaluated correspondence of core AD-relevant biomarkers Aβ42, Aβ40, pTau217, pTau181, GFAP, NfL, Aβ42/Aβ40, and pTau217/Aβ42 measured using NULISAseq and established Lumipulse immunoassays. ROC curve analyses compared the accuracy of these biomarkers for detecting Lumipulse CSF Aβ-positivity across platforms. Linear models were applied across 124 NULISAseq proteins to examine associations with common AD risk factors, including age, female sex, and APOE- ε4, as well as with biomarkers CSF Aβ42/Aβ40 and pTau181, 18F-PI2620 Tau PET, and memory. Fold change differences in NULISAseq proteins as a function of CSF Aβ (A+) and pTau181 (T+) status were examined using Wilcoxon rank-sum tests.

RESULTS: Moderate to high correlations were observed between NULISAseq and Lumipulse AD plasma biomarkers. Across platforms, plasma pTau217/Aβ42 exhibited the highest performance in discriminating CSF A+ (NULISAseq AUC: 0.940, 95%CI: 0.885-0.995; Lumipulse AUC: 0.907, 95%CI: 0.849-0.966). Age and sex were associated with differential expression of NULISAseq targets linked to neurodegeneration, microglial activation, and inflammation. CSF A+ was associated with fold change differences in Aβ42, pTau217, pTau231, pTau181, and GFAP, while CSF T+ was additionally associated with increases in TREM1, TIMP3, SAA1, and S100A12. When stratified by AT groups, A+T-exhibited lower Aβ42 and elevated pTau217 compared to A-T-, whereas A+T+ exhibited elevated pTau231 and pTau181 compared to A+T-. Temporal cortex tau was positively associated with NULISAseq pTau217, pTau231, pTau181, and pTau217/Aβ42. Memory function was negatively associated with pTau isoforms and PRDX6, YWHAZ, ENO2, ARSA, CHI3L1, CXCL8, and FCN2. These associations remained when controlling for pTau217 and restricting to A-CU, suggesting these targets may represent AD-independent biological pathways relevant for memory function.

CONCLUSIONS: NULISAseq immunoassay-based multiplexing accurately detects AD pathology among CU older adults and identifies multiple biological pathways related to early biomarker abnormality and memory function that may become dysregulated in preclinical AD.},
}

@article {pmid41282847,
year = {2025},
author = {Hadji, M and Moradi, E and Tohka, J},
title = {Predicting Future Brain Atrophy Based on Longitudinal MRI.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.04.09.25325520},
pmid = {41282847},
abstract = {Neuron loss is a key feature of neurodegenerative diseases often leading to brain atrophy detectable through magnetic resonance imaging (MRI). Various brain atrophy measures are essential in research of Alzheimer' disease (AD) and related dementias. This study aims to forecast future annual percentage changes in hippocampal, ventricular, and total gray matter (TGM) volumes in individuals with varying cognitive statuses, from healthy to dementia. We developed a machine learning model using elastic net linear regression and tested two approaches: (1) a baseline model using predictors from a single-time-point and (2) a longitudinal model using predictors derived from longitudinal MRI. Both approaches were evaluated with MRI-only models and models that combined MRI with additional risk factors (age, sex, APOE4, and baseline diagnosis). Cross-validated Pearson correlation scores between predicted and actual annual percentage changes were 0.62 for the hippocampus, 0.51 for the ventricles, and 0.41 for TGM, using the longitudinal MRI + risk factor model. Longitudinal models consistently outperformed baseline models, and models including risk factors outperformed the MRI only model. Validation using an external dataset confirmed these findings, highlighting the value of predictors derived based on longitudinal data. We further studied the value of the predicted atrophy/enlargement rates for clinical status progression prediction across three different datasets. Predicted atrophy was a consistently better indicator of progression to mild cognitive impairment and dementia than present-day regional volumes, with the longitudinal atrophy prediction model typically outperforming the baseline model in terms of clinical status prediction. Future atrophy prediction has significant potential for assessing the risk of cognitive decline, even in cognitively unimpaired individuals, and can aid in selecting participants for clinical trials of disease-modifying drugs for AD.},
}

@article {pmid41282845,
year = {2025},
author = {Deek, RA and Balogun, WG and Zeng, X and Triana-Baltzer, G and Pascoal, TA and Kolb, HC and Snitz, B and Cohen, AD and Karikari, TK},
title = {Head-to-head comparison of plasma p-tau217 immunoassays for incipient Alzheimer's disease in community cohorts.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.07.25337434},
pmid = {41282845},
abstract = {BACKGROUND: Plasma p-tau217 is a promising biomarker for detecting incipient AD pathology, but direct comparison of different p-tau217 assays in community-based cohorts are limited.

METHODS: We evaluated two cohorts from southwestern Pennsylvania, USA; the MYHAT-NI sub-study, which included two-year longitudinal follow-up neuroimaging assessments of Aβ, tau, and cortical thickness; and the Human Connectome Project/CoBRA, targeting a 50:50 split of self-identified Black and non-Hispanic White individuals. Plasma p-tau217 was measured using four different assays: Lumipulse, Johnson&Johnson, ALZpath, and NULISA. Aβ and tau pathologies were assessed with [ [11] C]PiB PET and [ [18] F]Flortaucipir PET, respectively. Clinical Dementia Rating (CDR) and Montreal Cognitive Assessment were used to assess cognitive performance.

RESULTS: We included 344 participants (MYHAT-NI: n=111, median age 76 [IQR: 72-80], 54% female; HCP/CoBRA: n=234, median age 62 [IQR: 52-70], 65% female). All four p-tau217 assays exhibited moderate to strong cross-platform correlations (Spearman correlations of 0.40 - 0.86), and statistically equivalent AUCs (of 0.84-0.90) for determining Aβ positivity.

CONCLUSIONS: Our findings showed strong equivalent performances of plasma p-tau217 assays to identify amyloid positivity across two highly diverse cohorts of community-dwelling older adults.},
}

@article {pmid41282833,
year = {2025},
author = {Liu, T and Yang, Y and Wu, H and Unjitwattana, T and Wang, S and Kang, J and Li, Y and Garmire, LX},
title = {Linking spatial omics to patient phenotypes at the population scale by BSNMani: Bayesian scalar-on-network regression with manifold learning.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.09.25333297},
pmid = {41282833},
abstract = {Spatial omics enables the integration of high-dimensional molecular organization with clinical outcomes, yet incorporating spatial single-cell information into predictive models at the population scale remains challenging. Here, we adapted BSNMani, Bayesian scalar-on-network regression with manifold learning, to integrate subject-specific, spatially informed co-expression networks into clinical prediction. The benchmark comparison showed that the feature selection by BSNMani significantly outperformed Elastic Net and Lasso methods for prediction performance. On SEA-AD MERFISH transcriptomics cohort, BSNMani framework achieved an accuracy of 0.74 for Alzheimer's disease (AD) prediction and revealed four distinct gene-gene co-expression subnetworks with clear biological relevance, such as glutamatergic synapses and neurogenesis. Furthermore, BSNMani achieved a good survival prediction of another breast cancer cohort measured by Imaging Mass Cytometry (IMC) (C-index=0.74) with 2 subnetworks being identified. Furthermore, BSNMani can also use cell-type-specific spatial omics data to enhance the granularity and better pinpoint biological patterns. In summary, BSNMani is a powerful tool that uses high-dimensional spatial omics data for clinical outcome prediction at the population scale across diverse disease settings, revealing deep biological insights while maintaining easy interpretation.},
}

@article {pmid41282800,
year = {2025},
author = {Wojtas, AM and Rathore, S and Dammer, EB and Yu, L and Seifar, F and Gadhavi, J and Shantaraman, A and Duong, DM and Wu, F and Liu, Y and Trautwig, AN and Fox, EJ and Kelly, KM and Gearing, M and Rangaraju, S and Oveisgharan, S and Howell, GR and Schneider, JA and Lee, EB and Menon, V and Bennett, DA and Lah, JJ and Golde, TE and Johnson, ECB and McEachin, ZT and , and Wingo, AP and Wingo, TS and Levey, AI and Seyfried, NT},
title = {Multi-scale integration of human brain vascular and CSF proteomes reveals biomarkers of cerebral amyloid angiopathy linked to Alzheimer's disease risk.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.08.25337413},
pmid = {41282800},
abstract = {Cerebrovascular disease frequently co-occurs with amyloid-β (Aβ) plaques and tau tangles, the pathological hallmarks of Alzheimer's disease (AD), compounding cognitive decline. Aβ deposition is also central to cerebral amyloid angiopathy (CAA), yet peripheral biomarkers that specifically reflect CAA-related vascular pathology remain elusive. Here, we integrated proteomic, imaging, clinical, neuropathological, and genomic data from brain and cerebrospinal fluid (CSF) to define molecular signatures distinguishing CAA from plaque pathology. Proteomic profiling of 118 cerebrovascular-enriched brain samples quantified over 11,000 proteins, revealing co-expression modules enriched for extracellular matrix (ECM) components strongly linked to CAA. In CSF proteomes from 1,104 individuals, vascular ECM module proteins (e.g., CRIP1, LTBP1, PRSS23) were associated with CAA, white matter hyperintensities (WMH), microbleeds, and infarcts but not Aβ plaque burden. Integrating AD genome-wide association studies and CSF protein quantitative trait loci (pQTLs) identified CRIP1 as a candidate causal protein for AD. Carriers of the minor allele at the CRIP1 pQTL exhibited reduced CRIP1 levels, less WMH, and lower CSF levels of ECM proteins linked to CAA. In vitro, CRIP1 bound Aβ and accelerated fibril formation, providing a mechanistic link to vascular amyloid pathology. These findings establish overlapping brain and CSF biomarkers for CAA and identify CRIP1 and vascular ECM pathways as candidate targets for precision diagnostics and therapeutic intervention.},
}

@article {pmid41282793,
year = {2025},
author = {Cook, N and Yang, C and Zeng, Y and Sivasankaran, SK and Song, S and Talozzi, L and Western, D and Yang, C and Liu, Y and Le Guen, Y and Stewart, I and Young, C and , and Mormino, EC and Altmann, A and He, Z and Napolioni, V and Wingo, AP and Wingo, TS and Cruchaga, C and Sung, YJ and Greicius, MD and Belloy, ME},
title = {Integrative Genetic, Proteogenomic, and Multi-omics Analyses Reveal Sex-Biased Causal Genes and Drug Targets in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.31.25339089},
pmid = {41282793},
abstract = {Sex differences are pervasive in Alzheimer's disease, but the underlying drivers remain poorly understood. To address this, we performed sex-stratified genome-wide association studies of Alzheimer's disease in ∼1,000,000 individuals, which we subsequently integrated with proteogenomics datasets from neurological tissues to identify candidate causal genes. We further prioritized genes through additional multi-omics approaches, including quantitative trait locus summary-based mendelian randomization and colocalization. Altogether, we prioritized 125 female-biased and 21 male-biased risk genes. Female-biased pathways included amyloid, neurite, stress, clearance, and immune processes, with genes enriched for microglia and astrocyte expression. Through computational drug repurposing analyses, a set of sex hormone related drugs, converging on Epidermal Growth Factor Receptor (EGFR), were uniquely prioritized in women. Finally, we identified Haptoglobin (HP) as a female-specific gene, leveraging long-read sequencing approaches to implicate a link to oxidative stress, APOE, and hemoglobin biology. Altogether, our findings provide a portal into sex-specific precision medicine for Alzheimer's disease.},
}

@article {pmid41282790,
year = {2025},
author = {Pugh, S and Hill, M and Hwang, S and Wu, R and Jang, K and Iannone, S and O'Connor, K and O'Brien, K and Eaton, E and Johnson, K},
title = {WATCH-SS: Developing a Trustworthy and Explainable Modular Framework for Detecting Cognitive Impairment from Spontaneous Speech.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.06.25333047},
pmid = {41282790},
abstract = {Early detection of cognitive impairment (CI) is critical for timely intervention in Alzheimer's disease and AD-related dementias. To address this, we propose the Warning Assessment and Alerting Tool for Cognitive Health from Spontaneous Speech (WATCH-SS), a modular and explainable three-stage framework for detecting CI from a patient's speech sample. The framework uses detectors for five linguistic and acoustic indicators of CI, aggregates their outputs into a set of clinically interpretable summary features, and uses a predictive model for CI classification. We consider multiple approaches to implementing these detectors that range from simple, computationally efficient methods suitable for real-time analysis to strong, resource-intensive methods, better for high accuracy offine analysis. On the DementiaBank ADReSS dataset, WATCH-SS achieved strong predictive performance (AUC = 80% on the test set). This work demonstrates that a modular, feature-based approach can achieve strong performance while providing a transparent diagnostic profile, representing a significant step towards a trustworthy and clinically-usable screening tool for primary care.},
}

@article {pmid41282783,
year = {2025},
author = {Gallingani, C and Miller, ZA and Mandelli, ML and Rosen, HJ and Ezzes, Z and Lin, M and Rodriguez, D and Grinberg, LT and Spina, S and Seeley, WW and Miller, B and Gorno-Tempini, ML and Pinheiro-Chagas, P},
title = {Agentic Generative Artificial Intelligence System for Classification of Pathology-Confirmed Primary Progressive Aphasia Variants.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.28.25338977},
pmid = {41282783},
abstract = {IMPORTANCE: Accurate clinical and pathological diagnoses are essential in neurodegenerative diseases, especially given the emergence of pathology-specific disease-modifying therapies. However, diagnostic accuracy remains challenging due to heterogeneous clinical presentations, complexity of integrating multimodal data, and limited access to multidisciplinary expertise. Primary Progressive Aphasia (PPA) exemplifies these challenges, requiring specialized clinical, neuropsychological, and imaging evaluations. Generative artificial intelligence (AI), powered by large language models, may offer scalable diagnostic support in this context.

OBJECTIVE: To evaluate the diagnostic performance of an agentic generative AI system in classifying prototypical PPA cases by clinical syndrome and underlying pathology.

DESIGN: Retrospective diagnostic validation study using a multi-agent generative AI architecture simulating expert-level reasoning.

SETTING: Single tertiary academic referral center (University of California San Francisco, Memory and Aging Center).

PARTICIPANTS: Fifty-four individuals with a definite diagnosis of PPA and post-mortem confirmation (18 semantic [svPPA], 17 logopenic [lvPPA], 19 nonfluent [nfvPPA]), selected as prototypical cases with congruent clinical, imaging, and pathological profiles.

EXPOSURE: Multimodal input data, including clinical notes, neuropsychological and language assessments, and MRI brain images, were processed through a multi-agent architecture. The system generated diagnostic predictions under two conditions: (1) open-ended diagnosis from a set of 15 neurodegenerative clinical syndromes; (2) constrained classification of PPA variant and underlying neuropathology.

MAIN OUTCOMES AND MEASURES: Generative AI system diagnostic accuracy for clinical syndrome and pathology, based on expert clinical diagnoses and post-mortem confirmations as gold standard.

RESULTS: In the open-ended setting, the system correctly identified PPA in 49 of 54 cases (90.7%, chance level=6.7%). When constrained to PPA, it achieved 100% accuracy for svPPA and nfvPPA, and 94.1% for lvPPA as primary prediction. Neuropathological predictions were most accurate for FTLD-TDP type C (100%) and FTLD-4R tau (100%), and high for Alzheimer's disease (94.4%). The full diagnostic pipeline of all 54 cases was completed in under 10 minutes.

CONCLUSIONS AND RELEVANCE: The AI system demonstrated expert-level performance in classifying prototypical PPA cases, integrating multimodal data and mirroring specialist reasoning. Its speed and accuracy support its potential role in extending access to specialized diagnostic expertise, particularly in non-tertiary settings. Further validation in larger and more heterogeneous populations is warranted.},
}

@article {pmid41282780,
year = {2025},
author = {Yang, B and Earnest, T and Bilgel, M and Albert, MS and Johnson, SC and Davatzikos, C and Erus, G and Masters, CL and Resnick, SM and Miller, MI and Bakker, A and Morris, JC and Benzinger, TLS and Gordon, BA and Sotiras, A and , and , },
title = {Predicting future cognitive impairment in preclinical Alzheimer's disease using multimodal imaging: a multisite machine learning study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.15.25337507},
pmid = {41282780},
abstract = {UNLABELLED: Predicting the likelihood of developing Alzheimer's disease (AD) dementia in at-risk individuals is important for the design of and optimal recruitment for clinical trials of disease-modifying therapies. Machine learning (ML) has been shown to excel in this task; however, there remains a lack of models developed specifically for the preclinical AD population, who display early signs of abnormal brain amyloidosis but remain cognitively unimpaired. Here, we trained and evaluated ML classifiers to predict whether individuals with preclinical AD will progress to mild cognitive impairment or dementia within multiple fixed time windows, ranging from one to five years. Models were trained on regional imaging features extracted from amyloid positron emission tomography and magnetic resonance imaging pooled across seven independent sites and from two amyloid radiotracers ([ [18] F]-florbetapir and [ [11] C]-Pittsburgh-compound-B). Out-of-sample generalizability was evaluated via a leave-one-site-out and leave-one-tracer-out cross-validation. Classifiers achieved an out-of-sample receiver operating characteristic area-under-the-curve of 0.66 or greater when applied to all except one hold-out sites and 0.72 or greater when applied to each hold-out radiotracer. Additionally, when applying our models in a retroactive cohort enrichment analysis on A4 clinical trial data, we observed increased statistical power of detecting differences in amyloid accumulation between placebo and treatment arms after enrichment by ML stratifications. As emerging investigations of new disease-modifying therapies for AD increasingly focus on asymptomatic, preclinical populations, our findings underscore the potential applicability of ML-based patient stratification for recruiting more homogeneous cohorts and improving statistical power for detecting treatment effects for future clinical trials.

HIGHLIGHTS: Machine learning can predict future cognitive impairment in preclinical Alzheimer'sModels achieved high out-of-sample ROC-AUC on external sites and PET tracersModels were able to distinguish cognitively stable from decliners in the A4 cohortML cohort enrichment enhanced secondary treatment effect detection in the A4 cohort.},
}

@article {pmid41282776,
year = {2025},
author = {Uffelmann, E and Wightman, DP and Bahrami, S and Shadrin, AA and Fominykh, V and Ojima, T and Jiang, C and Benner, C and Moreno, E and Campos, AI and Thomassen, JQ and Minois-Genin, E and Wu, HM and Walters, GB and Sherva, R and Lin, T and Bryois, J and Krebs, K and Schipper, M and Narita, A and Serretti, A and Simonsen, AH and van Seumeren, AL and Corbett, A and Knapskog, AB and Hartmann, AM and den Braber, A and van Harten, AC and Harder, A and Rongve, A and Madsen, BO and Tijms, BM and Aagaard, B and Lichtwarck, B and Kirsebom, BE and Creese, B and Reynolds, CA and Hägg, S and Karlsson, I and Erikstrup, C and Mikkelsen, C and Ballard, C and Aarsland, D and Shigemizu, D and Rujescu, D and Gudbjartsson, D and Aakhus, E and Sørensen, E and Stordal, E and Duits, FH and Wolters, FJ and Blanc, F and Biessels, GJ and Selbæk, G and Bråthen, G and Tamiya, G and Waldemar, G and Seelaar, H and Eyjolfsdottir, H and Holstege, H and Bundgaard, H and Zetterberg, H and Ullum, H and Skoog, I and Medbøen, IT and Saltvedt, I and Feiring, IH and Rektorova, I and Gaziano, JM and Haavik, J and Hjerling-Leffler, J and Luo, J and Snaedal, J and Vijverberg, EGB and Sealock, JM and Blennow, K and Nordengen, K and Persson, K and Scheffler, K and Matsuda, K and Ozaki, K and Pihlstrøm, L and Athanasiu, L and Pålhaugen, L and Hulsman, M and Waern, M and Averina, M and Wettergreen, M and Moksnes, MR and Huisman, M and Yamamoto, M and Toft, M and Panizzon, MS and Bruun, MT and Ghanbari, M and Franc, M and Pedersen, NL and Bell, NY and Tesi, N and Pedersen, OB and Frei, O and Bousiges, O and Svenningsson, P and Visser, PJ and Li, QS and Hauger, R and Zhang, R and Namba, S and Sando, SB and Kern, S and Djurovic, S and Thordardottir, S and Phung, TN and Truelsen, T and Werge, T and Hansen, TF and Kyosaka, T and Engstad, T and Fladby, T and Merritt, V and Bergh, S and van der Flier, WM and Wang, R and Stahl, EA and Hooli, B and , and , and , and , and , and , and , and , and , and , and , and , and , and Davis, LK and Logue, MW and Lehto, K and Zettergren, A and Brumpton, BM and Zeng, J and Visscher, PM and O'Reilly, PF and Mahajan, A and Ferreira, M and Okada, Y and van der Lee, SJ and Ostrowski, SR and Frikke-Schmidt, R and Stefansson, H and Heilbron, K and Andreassen, OA and Posthuma, D},
title = {Genomic analyses reveal new insights into Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.10.25337470},
pmid = {41282776},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050 [1] . AD is highly heritable, with twin-based heritability estimates of 60-80% [2] . While 1,200 causal loci are predicted to exist for AD [3] , approximately 80 have been associated with AD in two recent studies [4,5] , suggesting that many loci remain to be discovered [6] . Here, we analyzed data from 183,620 AD cases and 2.6 million controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and identified microglia and, for the first time, several neuronal cell types enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a single-nucleotide polymorphism (SNP) heritability of 19%. Together, our findings offer insights into the genetic architecture and potential pathobiology of AD, as well as specific targets for future drug development research.},
}

@article {pmid41282773,
year = {2025},
author = {Ackley, SF and La Joie, R and Caunca, M and Mukherjee, S and Choi, SE and Trittschuh, EH and Crane, PK and Hayes-Larson, E and , },
title = {Substituting Blood-Based Biomarkers for Imaging Measures in Alzheimer's Disease Studies: Implications for Sample Size and Bias.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.06.25339696},
pmid = {41282773},
abstract = {BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) pathology are appealing options in large population-based studies due to their low cost, minimal invasiveness, and feasibility of collection in non-clinical settings. Despite these benefits, blood-based biomarkers have lower test-retest reliability than neuroimaging measures like amyloid positron emission tomography (amyloid-PET) Centiloids; trade-offs in power and bias remain unexplored.

METHODS: We use data from Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) studies, which include both amyloid-PET and blood-based measures, to assess differences in statistical power, required sample size, and bias when replacing a neuroimaging measure with a blood-based measure. We use simulations parameterized based on these studies to show potential implications of using plasma p-tau181 or p-tau217, blood-based AD biomarkers, in place of Centiloids from amyloid-PET, when the biomarker is either the exposure or the outcome in an analysis of interest.

RESULTS: We demonstrated that substituting amyloid-PET Centiloids with a blood-based measure of p-tau can substantially reduce power, requiring 3 to 6 times the sample size to achieve 80% power compared to amyloid-PET. In addition, using a blood-based biomarker as the exposure can introduce significant regression dilution bias, attenuating estimated associations.

CONCLUSIONS: Due to their lower cost and ease of collection compared with neuroimaging, blood-based biomarkers facilitate AD pathology measures on larger, more diverse samples with longitudinal follow-up. Consideration of the sample sizes they necessitate and their potential for bias is critical for the design and interpretation of studies employing these biomarkers.},
}

@article {pmid41282767,
year = {2025},
author = {Dhanam, S and Sanderson-Cimino, M and Taylor, JC and Paolillo, EW and Fregly, R and Kwang, W and Maruff, P and Wise, A and Heuer, HW and Forsberg, LK and Kramer, JH and Boeve, BF and Rosen, HJ and Mackin, RS and Weiner, MW and Nosheny, RL and Boxer, AL and Staffaroni, AM and , },
title = {Remote, self-administered, smartphone cognitive testing in a registry-based cohort: Feasibility, reliability, and validity findings.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.28.25338686},
pmid = {41282767},
abstract = {BACKGROUND: Remote, smartphone-based cognitive testing may improve access to cognitive assessments for Alzheimer's disease and related dementias. We evaluated the feasibility, reliability, and validity of unsupervised smartphone-based cognitive tests in a registry-based cohort.

METHODS: Adults without a record of cognitive impairment (N=1,815; ages 18-92) were recruited from the UCSF Brain Health Registry to complete unsupervised ALLFTD-mApp cognitive tasks three times over two weeks. Reliability was assessed with correlations between sessions. Linear regression models tested associations of ALLFTD-mApp tasks with demographics, self- and informant-rated cognitive concerns (Everyday Cognition Surveys; ECog), and web-based cognitive testing (CogState Brief Battery; CBB).

RESULTS: Adherence was high (82.2%) and usability favorable. Test-retest reliability was moderate to strong (ρs = 0.61-0.85, all ps < .001). Lower ALLFTD-mApp scores were associated with older age, lower education, cognitive concerns, and worse CBB performance.

CONCLUSION: Findings support the feasibility, reliability, and validity of the ALLFTD-mApp in adults without a record of cognitive impairment.},
}

@article {pmid41282727,
year = {2025},
author = {Chernek, P and Yazdi, BG and Hojjati, SH and Ozoria, S and Calimag, J and Wang, XH and Modarresi, A and Picha, SG and Chiang, G and Razlighi, QR},
title = {Age-enhancing cognitive ability shows similar attenuation in task evoked brain networks with aging and preclinical AD.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.02.25339341},
pmid = {41282727},
abstract = {Brain aging - with and without pre-clinical Alzheimer's disease (AD) pathology - are associated with deterioration in the brain networks' coherence and/or co-activation/deactivation as well as with decline in most cognitive abilities, paving the road for a network-based conceptualization of the brain normal versus pathological aging. However, certain cognitive abilities, like crystallized memory, improve with age, which complicates the explanation of these changes solely through age-related decline in the brain networks. Using a cross-sectional cohort of 259 participants (62 young, and 197 older), which underwent two task-based (one declining and another improving with age), and one resting-state fMRI scans, plus a positron emission tomography scan (to determine preclinical amyloid accumulation), we found that the brain networks' co-activation/deactivation, but not coherence, significantly attenuate with age and/or AD pathology even in the task for which performance improves by age. Interestingly, we also found that an increase in the networks' co-activation/deactivation, but not coherence, was associated with an improvement in task performance. Finally, we provided preliminary evidence that the brain networks lose their task-evoked deactivations with age before their coherence. These findings shed light on the process of functional aging in the brain networks, differentiate functional aging of the brain networks' coherence at rest versus their task-evoked co-activation/deactivation, and emphasize the more dominant role of the task-evoked brain activity in understanding aging brain function and distinguishing it from preclinical AD.},
}

@article {pmid41282720,
year = {2025},
author = {Khorsand, B and Teichrow, D and Ghanbarian, E and Zheng, L and Sajjadi, SA and Glover, CM and Grill, JD and Rabin, LA and Ezzati, A},
title = {Scalable Markers for Early Cognitive Decline: Plasma p-tau217, Subjective Cognitive Concerns, and Digital Testing: Results from the A4/LEARN studies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.14.25338009},
pmid = {41282720},
abstract = {BACKGROUND AND OBJECTIVES: Although amyloid positron emission tomography (PET) and Cerebrospinal fluid (CSF) biomarkers remain the standard for confirming Alzheimer's disease (AD) pathology, their use is impractical for screening or routine prognostic assessment. Plasma phosphorylated tau 217 (p-tau217), subjective cognitive concerns, and computerized cognitive testing are non-invasive, scalable, and feasible to implement in large populations. We tested whether these measures independently predict the onset of cognitive impairment and whether combining them improves prognostic accuracy.

METHODS: We analyzed 1,071 cognitively unimpaired adults aged 65-85 years from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial (amyloid-positive; solanezumab or placebo arms) and the parallel Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort (amyloid-negative). At baseline, participants completed plasma p-tau217 measurement, the Cognitive Function Index (CFI), and the Cogstate Computerized Battery (CCB). Over 240 weeks of follow-up, incident impairment was defined as conversion from a Global Clinical Dementia Rating Score (CDR-GS) of 0 to 0.5 or higher. The predictive value of each measure for subsequent decline was examined after adjustment for demographic and genetic covariates.

RESULTS: During the follow-up, 365 of 1,071 participants (34.1%) developed cognitive impairment. Higher plasma p-tau217 (per-standard-deviation increase) was associated with higher odds of converting to CDR-GS>0 across all cohorts: A4-Placebo (HR=1.56; 95% CI, 1.37-1.78), A4-Solanezumab (HR=1.46; 95% CI, 1.29-1.65), LEARN (HR=1.25; 95% CI, 1.05-1.48). Similarly, higher CFI predicted incident impairment: A4-Placebo (HR=1.59; 95% CI, 1.42-1.79), A4-Solanezumab (HR=1.67; 95% CI, 1.47-1.91), LEARN (HR=1.37; 95% CI, 1.12-1.68). Lower CCB also conferred higher risk: A4-Placebo (HR=0.76; 95% CI, 0.65-0.91), A4-Solanezumab (HR=0.73; 95% CI, 0.62-0.87), LEARN (HR=0.68; 95% CI, 0.53-0.87). In models including all three predictors, each remained independently associated with progression.

CONCLUSION: Plasma p-tau217, subjective cognitive concerns, and computerized cognitive testing each independently predicted progression to cognitive impairment in cognitively unimpaired older adults. Together, these non-invasive and scalable measures provide practical tools for risk stratification years before clinical diagnosis. Combining biological, subjective, and digital markers may support earlier detection in clinical care and enhance efficiency in prevention trial enrollment.},
}

@article {pmid41282690,
year = {2025},
author = {Fisher, DW and Mehta, R and Morrow, CB and Kerr, KF and Jayadev, S and Domoto-Reilly, K and Schrift, MJ and Darvas, M},
title = {Affective Neuropsychiatric Symptom Metrics in the National Alzheimer's Coordinating Center Dataset.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.23.25338479},
pmid = {41282690},
abstract = {BACKGROUND: In dementia research, affective neuropsychiatric symptoms (NPS) - depression, anxiety, and apathy - remain understudied. Improving strategies to accurately identify clinically relevant NPS is essential for more robust research.

OBJECTIVES: We sought to determine how often objective metrics and clinical gestalt metrics agree on NPS presence or absence. We further sought to determine optimal cut-offs for affective NPS presence/absence using the Neuropsychiatric Inventory Questionnaire (NPI-Q) severity ratings.

METHODS: We assessed agreement for NPS presence/absence among 5 different depression metrics, 4 anxiety metrics, and 2 apathy metrics via Jaccard indices using the National Alzheimer's Coordinating Centers (NACC) dataset. Analysis included exploring different NPIQ severity rating thresholds of >0, >1, >2, and 0 and >1.

RESULTS: NPIQ cut-off >1 for presence and =0 for absence of an NPS led to the best agreement with other metrics. However, there was poor agreement for NPS presence across depression metrics (6%) and across anxiety metrics (7%). Choice of metric could greatly skew the frequency of an NPS being present. All 3 affective NPS were more common in Lewy Body Disorder compared to Alzheimer's Disease or Vascular Cognitive Impairment, regardless of metric.

CONCLUSIONS: Though NPIQ severity rating cut-off choice should depend on study design, using a severity score of >1 for presence and =0 for absence may best fit clinical gestalt for affective NPS. Lewy Body Disorders present with more affective NPS than other common dementia etiologies. Future consensus on criteria for depression and anxiety syndromes in dementia may improve their identification.},
}

@article {pmid41282689,
year = {2025},
author = {Ruan, X and Lu, S and Fu, S and Ahn, J and Chen, F and Li, R and Wen, A and Wang, L and Onyema, E and Tang, V and Liu, H},
title = {A Self-Explainable Dynamic Risk Monitoring Framework for Predicting Alzheimer's Disease and Related Dementias.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.20.25338232},
pmid = {41282689},
abstract = {BACKGROUND: Alzheimer's Disease and Related Dementias (ADRD) affect millions worldwide and can begin over a decade before symptoms appear. ADRD are generally irreversible once clinical symptoms appear, making early prediction and intervention critical. While neuroimaging improves prediction, its availability restricts use at the population level. Electronic Health Record (EHR) data offers a scalable alternative, but existing models often overlook three key challenges: irregular clinical encounters, severe data sparsity, and the need for interpretability. To address these gaps, we propose GRU-D-RETAIN, a temporal deep learning architecture combines GRU-D's strength in parameterized missing imputation with RETAIN's explainable attention mechanism, enabling real-time risk monitoring at arbitrary clinical encounters with meaningful interpretations.

METHODS: We identified 15,172 ADRD cases (age>=50) and 145,443 gender and date of birth matched controls from 6M patients in the University of Texas (UT) Physician EHR system. EHR were retrieved for each individual up to 10 years before ADRD diagnosis, and a random follow-up initiation date was assigned to simulate a real-world 10-year follow-up practice. Competing models including GRU-D-RETAIN, GRU-D, LSTM, Logit static, and Logit dynamic were trained on 6-fold cross-validation chunks and applied to the held-out to estimate performance.

RESULTS: The scarcity of EHR records beyond 10 years before ADRD diagnosis precludes the development of valid predictive models beyond this timeframe. At the 10- year mark, only diagnoses of hypertension and hyperlipidemia exceeded 1% among ADRD cases. After randoming follow-up initiation date, GRU-D-RETAIN exhibited performance closely matching that of GRU-D across the entire follow-up period, both showing improved accuracy as follow-up time increases. Without applying data availability cut-off, both models achieved AUROC of 0.6 and 0.7 at 2-year and 8-year follow-up, respectively, significantly outperforming competing models. Data availability plays a more critical role than follow-up length in determining prediction performance. For example, 1 year of follow-up with 15% data availability yields comparable performance (AUROC of 0.75 and average precision of 0.5) to 7.5 years of follow-up with 10% data availability. For individual ADRD cases, GRU-D-RETAIN offered overall consistent explanations across training folds. However, certain folds produced different explanations at both the timestep and feature levels, despite yielding similar risk predictions.

CONCLUSION: We demonstrate that EHR data can support dynamic ADRD risk monitoring up to 10 years before diagnosis, though model utility depends highly on data completeness. GRU-D-RETAIN enables real-time risk monitoring with explainable attention weights at both timestep and feature levels, aiding clinicians in interpreting the output and identifying high-risk patients as well as potential key risk factors at individual level. This framework is broadly applicable to other conditions expecting irregular clinical encounters and requiring dynamic and interpretable risk assessment.},
}

@article {pmid41282686,
year = {2025},
author = {Okorie, M and Jonson, C and Oddi, AP and Castruita, PA and Fulton-Howard, B and Yaffe, K and Yokoyama, JS and Udeh-Momoh, C and Andrews, SJ and , },
title = {Cross-Ancestry Polygenic Risk Scores Enhance Alzheimer's Disease Risk Prediction in Multiethnic Cohorts.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.03.25337285},
pmid = {41282686},
abstract = {INTRODUCTION: Genome-wide association studies (GWAS) have identified 80+ genetic loci associated with Alzheimer's disease (AD), enabling the development of polygenic risk scores (PRS). However, the predictive accuracy of PRS in diverse populations remains low. Here, we evaluated the predictive accuracy of single-, multi-, and cross-ancestry AD-PRS models across multi-ancestral populations.

METHODS: We used AD GWAS summary statistics from European, African, Amerindian, and East Asian populations to construct AD-PRS for each target population. Model performance was assessed by estimating odds ratios, R [2] , and AUC.

RESULTS: The cross-ancestry Bayesian PRS model demonstrated the highest predictive performance in non-European populations. It was significantly associated with poorer cognitive function, lower Aβ 42 CSF levels, and the most severe category of Aβ and tau neuropathological burden, as well as a clinical AD latent variable in a multi-ancestral validation cohort.

DISCUSSION: Inclusive genetic datasets and cross-ancestry PRS models are needed to enhance the transportability of AD-PRS across multi-ancestral populations.

RESEARCH IN CONTEXT: Systematic review: Using diverse GWAS datasets to construct AD-PRS is a promising yet underexplored approach to improve risk prediction accuracy across different populations. Integrating diverse base GWAS datasets and evaluating various PRS models can enhance model performance, but such approaches have not yet been widely applied to multi-ancestral cohorts to measure AD risks or abnormalities in biomarkers.Interpretation: Incorporation of ancestrally diverse base GWAS datasets enhanced the association between PRS and AD risk across multiple populations. Leveraging both these diverse discovery datasets and a Bayesian framework markedly improved model performance, extending its potential clinical applicability beyond AD case-control classification to the prediction of biomarker abnormalities.Future directions: Future research should prioritize the validation of cross-ancestry PRS models in larger and more heterogeneous populations, alongside systematic benchmarking against an expanding repertoire of PRS methodologies. Clinical implementation of AD-PRS will require rigorous validation in large, diverse as well as community-based populations to ensure reproducibility and generalizability, thereby enhancing its translational relevance.

HIGHLIGHTS: Single-ancestry PRS is only predictive in participants of European populations.Cross-ancestry PRS improves risk predictions in non-European participants.Cross-ancestry PRS is associated with abnormal Aβ and tau pathology and cognitive declineCross-ancestry PRS is associated with the AD latent variable in a multi-ancestral cohort.},
}

@article {pmid41282675,
year = {2025},
author = {, and , and , and , and Bellenguez, C and , and , and , and , and , },
title = {Consensus meta-analysis of genome-wide association studies for Alzheimer's disease and related dementia.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.20.25338060},
pmid = {41282675},
abstract = {To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementia (ADRD), we performed a meta-analysis of European ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, including 16 which are novel, and 56 which are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 novel) requiring further external validation. A polygenic score combining the effect of the ADRD loci except APOE was primarily associated with AD rather than non-AD pathology. Individuals in the 10 [th] decile of the score had a 2-fold increased risk to present with Braak neurofibrillary tangles stage above 5 and moderate/severe neuritic amyloid plaque pathology at death compared to individuals in the median score group.},
}

@article {pmid41282670,
year = {2025},
author = {Rathore, S and Dammer, EB and Shantaraman, A and Wu, F and Duong, DM and Fox, EJ and Johnson, ECB and Lah, JJ and , and Seyfried, NT and Levey, AI},
title = {Cerebrospinal fluid proteomics for predictive assessment of Alzheimer's Disease risk.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.24.25337921},
pmid = {41282670},
abstract = {Alzheimer's disease (AD) involves early molecular changes beyond amyloid-β (Aβ) and tau, that create heterogeneous disease biology, giving rise to variable disease initiation and highly variable longitudinal trajectories. Accurately predicting trajectories is vital for design of clinical trials and for clinical care, yet current CSF and PET biomarkers provide limited predictive capabilities despite their excellent diagnostic value. We performed CSF proteomics using tandem-mass-tag mass spectrometry in 1,104 ADNI participants with extensive longitudinal assessments. Machine learning-derived protein panels accurately predicted two classes of outcomes. First, they identified several key inflection points along the disease trajectory, including onset of 1) amyloid plaque pathology (Aβ- to Aβ+; AUC=0.88), 2) symptoms (asymptomatic to symptomatic; AUC=0.89), and 3) functional decline (MCI [due-to-AD] to AD Dementia; AUC=0.88). Second, protein panels forecast longitudinal trajectories of decline, spanning both clinical domains (cognition and function) and pathological process, including tau accumulation measured by tau-PET neocortical standardized uptake value ratio (SUVR) and neurodegeneration indexed by hippocampal volume and FDG-PET SUVR. Proteomics panels outperformed conventional CSF- and PET-based Aβ and tau markers. Importantly, these predictions were driven by novel mechanisms, spanning synaptic signaling, proteostasis, metabolic stress, vascular remodeling, and immune dysregulation, that anchor distinct inflection points and shape long-term trajectories. Together, these findings position CSF proteomics as a powerful approach for anticipating disease onset and progression, with direct implications for patient stratification and personalized intervention.},
}

@article {pmid41282659,
year = {2025},
author = {Lantero-Rodriguez, J and Janelidze, S and Palmqvist, S and Braun-Wohlfahrt, LS and Vavra, J and Bali, D and Orduña Dolado, A and Mattsson-Carlgren, N and Stomrud, E and Zetterberg, H and Blennow, K and Hansson, O and Montoliu-Gaya, L and Salvadó, G},
title = {P-TAU205 IS A BIOMARKER LINKED TO TAU-PET ABNORMALITY: A CROSS-SECTIONAL AND LONGITUDINAL STUDY.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.21.25338437},
pmid = {41282659},
abstract = {Current fluid biomarkers for Alzheimer's disease (AD) track amyloid-β (Aβ) pathology more strongly than tau, even though clinical and cognitive decline relate more closely to tau. We evaluated cerebrospinal fluid (CSF) phosphorylated tau at epitope 205 (p-tau205), measured using immunoassays, as a biomarker of tau aggregation. A total of 2,069 samples from the BioFINDER-2 (n=1,364) and BioFINDER-1 (n=705) cohorts spanning the full AD continuum were analyzed to assess cross-sectional and longitudinal associations with imaging and clinical measures. CSF p-tau205 levels were elevated in both biologically and clinically advanced disease stages. In Aβ-positive individuals, cross-sectional p-tau205 correlated with Aβ-PET (R[2]=0.26), tau-PET (R[2]=0.29), cortical atrophy (R[2]=0.14) and cognition (MMSE, R[2]=0.14). Baseline p-tau205 predicted subsequent Aβ accumulation (R[2]=0.44) and tau-PET uptake (R[2]=0.33), and increased more steeply over time in Aβ-positive than Aβ-negative participants (β[95%CI]=0.16[0.12-0.21], p<0.001). Longitudinal p-tau205 change related to cortical thinning (R[2]=0.32) and cognitive decline (R[2]≥0.41). Incorporating Aβ42/40, p-tau217 and p-tau205 into a CSF-based staging model, the final p-tau205-positive stage showed the strongest cortical atrophy, cognitive impairment, and risk of incident dementia (HR=6.40[4.28-9.59]). These findings support CSF p-tau205 as a valuable marker for biological staging and progression monitoring in AD.},
}

@article {pmid41282422,
year = {2025},
author = {Nada, H and Wolber, G and Gabr, MT},
title = {Targeting CAPON to modulate the CAPON-NOS Axis: a computational approach.},
journal = {Computational and structural biotechnology journal},
volume = {27},
number = {},
pages = {4813-4824},
pmid = {41282422},
issn = {2001-0370},
abstract = {The carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) serves as a critical regulatory protein controlling nitric oxide (NO) signaling across multiple physiological and pathological processes which encompass neurological, cardiac and metabolic functions. These diverse physiological roles of CAPON marks it as a key therapeutic target for conditions associated with its dysregulation. Despite this therapeutic potential there are no specific CAPON or nNOS/CAPON modulators which have been developed to date, highlighting a significant gap in targeted drug discovery. Herein, we report the first strategy specifically focused on disrupting the nNOS/CAPON protein-protein interface. Through screening of a chemical library composed of 4.6 million compounds and 13 molecular dynamics simulations, nine potential hit compounds were identified. This work represents a foundational step toward developing targeted therapies for CAPON-mediated disorders. Beyond identifying these promising hits, our approach introduces three python-based drug discovery tools: (i) a Python-based toolset for NMR structural analysis, clustering and visualization, (ii) accelerated ligand preparation toolkit, (iii) Automated hit prioritization pipeline based on multi-method consensus scoring approach that takes in account docking scores and MMGBSA. Collectively, these tools form an accelerated drug discovery pipeline that automates most of the virtual screening process and offers a scalable computational framework to support future drug discovery targeting protein-protein interactions.},
}

@article {pmid41282261,
year = {2025},
author = {Bohnen, N and Hout, AV and Roytman, S and Carli, G and Wigstrom, T and Kanel, P},
title = {The Polynomial Progression Subtype Inference Algorithm.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7199106/v1},
pmid = {41282261},
issn = {2693-5015},
abstract = {Longitudinal assessments are currently the gold standard for modeling progression of diseases, but they delay prognosis and increase burden on patients and healthcare systems. Cross-sectional inference offers a valuable alternative, enabling earlier patients' stratification and broader accessibility. Initial success in this direction has been found with the SuStaIn algorithm (Young et al. 2018)but computational and conceptual shortcomings hamper its usefulness. Here we introduce a more effective algorithm, PPSI, which is orders of magnitude faster, easier to interpret, equally or more accurate, applicable to more complex bidirectional phenomena, and can be fitted with many more variables at once. We demonstrate PPSI's utility using longitudinal prediction in Alzheimer's disease (ADNI database), clinical subtype recovery in breast cancer (TCGA-BRCA), and measurement of robustness under simulated conditions. To promote broad usability, we provide an extensive plotting suite for model exploration and diagnostics, and a graphical user interface that allows non-programmers to use the tool. While PPSI and SuStaIn are both able to derive useful subtypes from data, PPSI dramatically improves computational efficiency, enabling the inclusion of thousands of features and reducing runtimes from hours to seconds. PPSI is a performant interactive tool which makes disease progression modeling accessible to any subject matter expert.},
}

@article {pmid41282259,
year = {2025},
author = {Sabourin, S and Thrasher, C and Smith, R and Belanger-Mayer, K and Thibodeau, B and Kelly, R and Richard, R and Salinero, A and Abi-Ghanem, C and Batchelder, M and Groom, E and Temple, S and Pumiglia, K and Zuloaga, K},
title = {Sex Specific Effects of a High Fat Diet on Metabolism, Cognition, and Pathology in the Tg-SwDI Mouse Model of Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7686971/v1},
pmid = {41282259},
issn = {2693-5015},
abstract = {Background Alzheimer's disease (AD) is the leading cause of dementia in the US, with over 80% of affected individuals experiencing comorbid metabolic disease. Along with age and sex, metabolic syndrome and prediabetes are known risk factors for developing dementia and AD, highlighting the complex nature of the disease. How these risk factors affect cerebral amyloid angiopathy (CAA) is less well studied. As such, we examined the effect of diet-induced metabolic syndrome and sex on cognition, neuroinflammation, and pathology in the Tg-SwDI mouse model of AD and CAA. Methods Male and female Tg-SwDI and WT mice were fed a low fat (LFD; 10% fat) or high fat (HFD; 60% fat) diet from 3 to 10 months of age. Metabolic, cognitive, and neuropathology outcomes were assessed. Results All HFD-fed mice gained weight and exhibited impaired glucose tolerance. Metabolic disturbances were most severe in AD females receiving HFD. In both males and females, HFD-fed AD mice showed increased anxiety-like behavior, decreased locomotor activity, and impaired episodic memory in the open field and novel object recognition tests, respectively. HFD-fed AD females specifically exhibited spatial memory deficits in the Barnes maze. Hippocampal microgliosis, activated microglia, and astrogliosis were more severe in AD mice, but this effect was blunted by HFD in females in the cornu ammonis 1. HFD-fed AD females had greater amyloid plaques and CAA in the thalamus compared to LFD-fed AD controls. All metrics of neuroinflammation significantly correlated with CAA pathology in the thalamus. Conclusion AD females experienced greater metabolic, cognitive, and pathologic effects in response to a HFD compared to AD males and WT controls. These observations provide a better understanding of how metabolic disease may differentially affect the development of dementia in men and women.},
}

@article {pmid41282256,
year = {2025},
author = {Dennison, JL and Miller, MA and Sharma, A and Cherry, AM and Djuraskovic, I and Chapple, JP and Timmons, JA and Pitsillides, AA and Wahlestedt, C and Volmar, CH},
title = {Experimental menopause in 3xTg-AD mice exacerbates metabolic, inflammatory, and osteologic phenotypes aligned with Alzheimer's disease pathology.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7769003/v1},
pmid = {41282256},
issn = {2693-5015},
abstract = {Background Alzheimer's disease (AD) is neurodegenerative disease characterized by the accumulation of amyloid-beta plaques and phosphorylated tau. An estimated 7.2 million Americans are currently living with AD, nearly two-thirds of which are women. Sex differences in AD prevalence and pathology are well established, however the mechanisms underlying these differences are understudied. There are compelling links between menopause and AD, but few established common molecular mechanisms partly due to the lack of representative experimental models. Methods and results Here, we induce an accelerated ovarian failure (OF) model of menopause in the triple-transgenic AD (3xTg-AD) mouse, using ovotoxin 4-vinylcyclohexene diepoxide (VCD) mediated follicular depletion, leading to a loss of circulating progesterone and an increase in plasma follicle-stimulating hormone (FSH) levels-hormonal changes that closely mirror those observed in human menopause. OF exacerbated peripheral phenotypes associated with AD, namely insulin resistance, inflammation, and bone mass and architecture modifications resembling osteoporosis. OF aggravated age-related impaired glucose tolerance and caused insulin resistance. Additionally, plasma levels of four proinflammatory cytokines- IL-5, IL-6, TNF-α, and CXCL- were all increased in OF mice compared to non-menopausal AD mice. Meanwhile, OF mice display heightened bone loss phenotype, a condition with known links to AD risk and pathology. Conclusion In summary, accelerated ovarian failure presents key metabolic, inflammatory, and skeletal phenotypes associated with AD, indicating that it can be useful for the identification of novel therapeutic targets. *Jessica L. Dennison, Maggie A. Miller, and Aikta Sharma all contributed equally to this work and share authorship.},
}

@article {pmid41282248,
year = {2025},
author = {Frank, LE and Flack, N and Faulk, C and Block, AJ and Bartz, JC and Larsen, PA},
title = {Epigenetic Changes Associated with the Progression of Prion Disease in Syrian Hamsters (Mesocricetus auratus).},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7850591/v1},
pmid = {41282248},
issn = {2693-5015},
abstract = {Prion diseases are fatal neurodegenerative disorders that affect mammals, including Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. During the disease, abnormally folded prion proteins induce misfolding of normal prion proteins, leading to neurotoxic fibrils and plaques. Epigenetic mechanisms, particularly DNA methylation, are increasingly implicated in prion-like diseases (e.g., Alzheimer's disease), but their role in prion pathogenesis remains unclear. To investigate, we used nanopore sequencing and RNAseq to measure genome-wide methylation and gene expression in the brains of Syrian hamsters (Mesocricetus auratus) experimentally infected with a hamster-adapted murine synthetic prion strain (n = 9) and age-matched mock-infected controls (n = 9) at 80, 120, and 160 days post-infection (dpi). We identified 1,586, 1,692, and 2,429 differentially methylated regions (DMRs) at 80, 120, and 160 dpi, respectively. Early and mid-stage prion disease (80 and 120 dpi) were skewed toward hypermethylation, whereas late-stage prion disease (160 dpi) was skewed toward hypomethylation. Gene ontology (GO) of nearest genes to DMRs at 160 dpi included terms related to neuron regulation and signaling, neurodevelopment, and cellular stress pathways. We identified 178 differentially expressed genes (DEGs) at 80 dpi, 90 at 120 dpi, and 616 at 160 dpi. The majority of DEGs were downregulated at 80 dpi, and at 120 and 160 dpi, most DEGs were upregulated. Overlap in DEGs across timepoints was limited, and GO terms were related to upregulation of disease/injury response and cell death pathways in later timepoints. Overall, we found stage-specific responses to infection with a transcriptional shift from suppression of immune pathways to widespread immune and inflammation pathway activation. These findings indicate dynamic epigenetic and transcriptional changes marked by progressive and heterogeneous disruption of neuronal structure, function, and communication.},
}

@article {pmid41282231,
year = {2025},
author = {Taga, M and Fujita, M and Parghi, N and Haage, V and Teich, AF and Schneider, JA and Bennett, DA and Zhang, Y and De Jager, PL},
title = {Automated image segmentation uncovers the role of CD74 high human microglia in cognitive decline.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7851255/v1},
pmid = {41282231},
issn = {2693-5015},
abstract = {The role of activated microglia in Alzheimer's disease (AD) is well established; the proportion of stage III activated microglia has been associated with AD and cognitive decline, but this morphologically defined subtype is relatively uncommon (1-2% of microglia) and its cellular function is unknown. Single-cell RNA-sequencing revealed CD74 as a marker gene that is enriched in immunologically active microglial subtypes associated with AD. Here, we evaluated the relationship between CD74 expression, AD-related traits, and microglial morphology using dorsolateral prefrontal cortex samples from two brain collections (ROSMAP: n=63, NYBB: n=91). An image segmentation pipeline using CellProfiler was developed to extract features from entire tissue sections. The pipeline automatically delineated gray and white matter regions and segmented 1,120,780 gray matter microglia. In a meta-analysis of the two datasets, we find an increase in frequency of microglia with high CD74 expression (CD74 [high]) in relation to AD dementia (p = 0.038), particularly in the phase of terminal, accelerated cognitive decline before death. These microglia have a more rounded, amoeboid shape (ROSMAP: p = 1.4×10 [-6] ; NYBB: p = 2×10 [-13]) which is a characteristic morphology of activated stage III microglia. Results were consistent across both datasets, highlighting the robustness of our cellular segmentation approach. This study identifies a potential role for CD74 [high] microglia and the CD74 ligand MIF in cognitive decline, and it provides evidence for a partially overlapping but distinct role for CD74 [high] microglia and morphologically defined stage III microglia, whose functional properties have remained poorly understood. These CD74 [high] microglia appear to be enriched for genes involved in cytokine response for class I and II antigen presentation, as well as regulation of T cell proliferation. These findings begin to link microglial subtypes defined by single-cell transcriptomic data with those characterized by classical morphological criteria to resolve the roles of different microglial functions to distinct stages in the trajectory to AD.},
}

@article {pmid41282210,
year = {2025},
author = {Benzinger, T and Hoagey, D and McKay, N and Joseph-Mathurin, N and Flores, S and Doering, S and Hornbeck, R and Smith, T and Scott, J and Chen, G and Massoumzadeh, P and LaMontagne, P and Wang, Q and Hassenstab, J and Ponisio, M and Denny, A and Balls-Berry, J and Snider, J and Stark, S and Xiong, C and Schindler, S and Perrin, R and Shimony, J and Goyal, M and Vlassenko, A and Raichle, M and Morris, J and Raji, C and Gordon, B},
title = {The Knight Alzheimer Research Imaging (KARI) dataset: a comprehensive multimodal resource for exploring aging, preclinical, and symptomatic Alzheimer disease pathology.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7962593/v1},
pmid = {41282210},
issn = {2693-5015},
abstract = {Alzheimer disease (AD) remains a significant global public health challenge, requiring robust multimodal datasets to elucidate its prolonged preclinical phase, improve early detection, advance understanding of disease trajectories, and guide intervention strategies. To address this, the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) at Washington University in St. Louis established the Knight Alzheimer Research Imaging (KARI) dataset. This paper characterizes this dataset emphasizing its phenotypical depth and longitudinal scope, detailing comprehensive multimodal neuroimaging from 1,645 participants (aged 42-97) across 6,217 acquisitions. Spanning the AD spectrum from healthy aging to symptomatic disease, the cohort undergoes extensive longitudinal imaging using structural and functional magnetic resonance imaging (MRI) alongside positron emission tomography (PET) tracers for amyloid and tau pathology. This is complemented by rich clinical, cognitive, genetic, and biomarker data. In addition to raw imaging, the dataset provides quality-controlled processed outputs, including anatomical segmentations and biomarker quantification. By making this data accessible to researchers, the Knight ADRC aims to accelerate discoveries in pathophysiology, biomarker identification, and therapeutic development.},
}

@article {pmid41282187,
year = {2025},
author = {O'Brien, EK and Cox, T and Fernandez, S and Bourgeat, P and Porter, T and Goudey, B and Doecke, JD and Masters, CL and Fripp, J and Nho, K and Villemagne, VL and Cruchaga, C and Rowe, CC and Saykin, AJ and Dore, V and Laws, SM},
title = {Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7911284/v1},
pmid = {41282187},
issn = {2693-5015},
abstract = {Accumulation of brain amyloid beta (Aβ) is a key pathological hallmark of Alzheimer's disease (AD) and begins many years before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which this accumulation exceeds a critical threshold, may enable early intervention and treatment to slow or prevent the onset of AD. We utilised published genome-wide association studies (GWAS) to develop polygenic scores (PGS) based on AD risk (PGS risk) and resilience (PGS resilience). We tested whether these could predict (i) whether an individual was an accumulator of Aβ ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ is estimated to exceed a threshold of 20 centiloids (CL)('Estimated Age at onset of Aβ'; AAO-Aβ) among 2175 participants (1158 with AAO Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. Additionally, we conducted genome-wide association studies (GWAS) of these traits and developed phenotype-specific PGSs using cross-validation (CV). Higher PGS risk was associated with a greater risk of being an accumulator and a younger AAO-Aβ. When stratified by number of APOE ε4 alleles, PGS risk predicted Accumulator Status in APOE ε4 heterozygotes, and AAO-Aβ in ε4 non-carriers and heterozygotes, with the same directions of effect as were seen in the whole cohort. PGS resilience was not significantly associated with Accumulator Status, but higher PGS resilience was associated with later AAO-Aβ overall and in ε4 heterozygotes. Trait-specific PGSs, developed using CV, were not significantly associated with either trait overall and the direction of association varied across CV folds. Polygenic scores, alongside other risk factors, may be useful for identifying individuals at risk of accumulating Aβ, and predicting the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.},
}

@article {pmid41282170,
year = {2025},
author = {Gardner, K and Lange, TE and Perna, MK and Wells, SI and Williams, MT and Vorhees, CV and Solomon, MB and Vinnedge, LMP},
title = {Dek Loss Induces Sex-Dependent, Task-Specific Cognitive Deficits and Reprograms the Hippocampal Transcriptome in Mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7577113/v1},
pmid = {41282170},
issn = {2693-5015},
abstract = {Cognitive decline with aging, and some neurodegenerative conditions like Alzheimer's disease, disproportionately affects females yet few mechanisms beyond steroid hormone signaling fully explain this sex-specific vulnerability. The chromatin-remodeling DEK protein, upregulated by estrogen and progesterone and broadly expressed in the brain, including the hippocampus, may be one such mechanism. We have previously linked DEK loss with indices of neuronal dysfunction, including increased DNA damage, impaired neurite development, and apoptosis, suggesting a potential neuroprotective role. Here, we investigated the molecular and behavioral consequences of Dek loss in vivo. Female Dek constitutive knockout (cKO) mice exhibited a sex-specific behavioral phenotype, with impairments in sensorimotor gating, as measured by pre-pulse inhibition, and in reversal learning in the Morris Water Maze. These findings are suggestive of deficits in pre-attentive sensory processing and cognitive flexibility, respectively. Notably, these cognitive deficits were not observed in male Dek cKO mice and were not attributable to differences in general learning ability, locomotor activity, or anxiety-like behavior. The absence of impairment in object recognition and conditioned fear learning and memory in females suggests that the effects of DEK loss are task-specific and likely brain region-specific. Transcriptomic analysis of hippocampal tissue revealed differentially expressed genes related to inflammation, metabolism, and neuropeptide signaling in all Dek -cKO mice, along with a distinct female-specific transcriptomic profile indicative of impaired neuronal function. Combined, we report for the first time that DEK supports certain aspects of cognitive function, particularly in females. These data may be relevant for understanding sex differences in some cognitive disorders.},
}

@article {pmid41282157,
year = {2025},
author = {Liu, W and Shimogori, T},
title = {Spatiotemporal Brain Transcriptomics Reveal Risk Gene Hot-Spots in Major Neuropsychiatric Disorders.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7667905/v1},
pmid = {41282157},
issn = {2693-5015},
abstract = {The temporal onset of polygenic brain disorders has been closely linked to the developmental dynamics of genome-wide risk gene expression. In this study, we systematically characterized the spatiotemporal expression patterns of these risk genes and their relevance in differentiating major neuropsychiatric disorders. We analyzed genome-wide risk gene sets for Intelligence Quotient (IQ), Autism Spectrum Disorders (ASD), Attention Deficit Hyperactive Disorder (ADHD), Tourette's Syndrome (TS), Obsessive Compulsive Disorder (OCD), Anorexia Nervosa (ANO), Neuroticism, Panic disorder, Major Depressive Disorder (MDD), Bipolar Disorder (BIP), Schizophrenia (SZ), Epilepsy, Alzheimer's Disease (AD), and Parkinson's Disease (PD). Our results reveal distinct patterns of spatiotemporal enrichment across these traits, allowing their classification into three clusters. To validate the biological significance of these enrichment patterns, we integrated clinical MRI datasets and confirmed structural alterations within the identified spatiotemporal "hot-spots". Furthermore, by combining gene co-expression network analysis and single-cell transcriptomic data, we delineated the cell-type specificity and functional pathways underlying risk gene enrichment. In situ hybridization data from the marmoset brain further provided a comprehensive map of risk gene related module expression. This work reinforces the link between dynamic gene expression and disease mechanisms, while highlighting potential biomarkers and therapeutic targets arising from these identified "hot-spots" and pathways.},
}

@article {pmid41282153,
year = {2025},
author = {Capdevila-Bayo, M and Rossi, R and de Rojas, I and Puerta, R and Guzmán, L and Carrasco, M and Muñoz-Morales, Á and Olivé, C and Montrreal, L and García-González, P and Bayón-Buján, P and Miguel-Romero, A and Calm, B and Sotolongo-Grau, O and Orellana, A and Tatinya, N and Martínez, M and Alegret, M and Sanz-Cartagena, P and Fernández, MV and Marquié, M and Valero, S and Montalbán, X and Camins, A and Ramírez, A and Martí, M and Pividori, MI and Boada, M and Ruiz, A and Ettcheto, M and Cano, A},
title = {A peripheral proteomic signature of Alzheimer's disease is identified in the plasma extracellular vesicles of mild cognitive impairment patients from a memory clinic: the BIOPEXAL study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7847549/v1},
pmid = {41282153},
issn = {2693-5015},
abstract = {Aims: Alzheimer's disease (AD) is commonly diagnosed when neuronal damage is already established and irreversible. Achieving an accurate differential diagnosis in the preclinical and mild cognitive impairment (MCI) stage is one of the greatest challenges nowadays. Nanotechnological analysis of plasma extracellular vesicles (pEVs) are gaining attention as a promising tool for the early detection of AD pathology. This study aims to evaluate the proteomic profile of pEVs from patients with MCI and AD dementia to explore their potential as AD screening tools. Methods: pEVs were isolated by ultracentrifugation from 144 patients with MCI A-T-, MCI A+T+, and AD dementia. Nanoparticle tracking analysis and cryo-TEM were used to characterize the pEVs. CSF, serum and pEVs proteomics were carried out by using the multiplex PEA technology of Olink [®] proteomics, Inflammation and Neurology Explore 384 panels (768 proteins). Results: Characterization results showed that isolated plasma fraction corresponded in shape, size and concentration to EVs. Many pEVs neurology proteins involved in AD pathology significantly correlated (r > ± 0.30, p < 0.05) with their CSF homonyms, but not with their serum's. pEVs' proteome correlated with common AD signatures (CSF Aβ42 and pTau181, plasma pTau181, MMSE, NBACE, and Qalb) showing similar patterns to those observed with CSF biomarkers. Several pEVs neurology proteins didn't exhibit differences between the MCI A+T+ and AD dementia groups, whilst they did with MCI A-T-. Proteins in pEVs showed strong correlations with several measures of brain atrophy in MRI. Several neurology pEV proteins predicted conversion from MCI to AD dementia. Moreover, some of these showed a significant diagnostic accuracy of AD pathology. Conclusion: Preliminary results suggest that EVs biomarker signature could reflect AD pathology in the prodromal stages of AD continuum. However, further experiments are still needed for a better understanding of EVs' role in AD development and pathology dissemination.},
}

@article {pmid41282152,
year = {2025},
author = {Joshi, A and Sanna, PP},
title = {Single-Cell Multi-Modal Differential Analysis of the Human Neo-Cortex in HIV Infection Reveals Similarities with Hallmarks of Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7636879/v1},
pmid = {41282152},
issn = {2693-5015},
abstract = {Cognitive impairment in people with HIV (PWH) remains prevalent despite viral suppression. To provide insights into the cellular mechanisms of pathogenesis, we carried out a multi-modal pan cell-type specific differential analysis of the frontal cortex of PWH. We show cell type-specific dysregulations of oxidative phosphorylation, glycolysis, ribosomes and translation, DNA damage, and neuroinflammation in PWH. Key genes and pathways identified showed a considerable overlap with transcriptional hallmarks of Alzheimer's disease (AD) and involved AD vulnerable cell types, among others. We computed several differentially accessible chromatin sites in all major cell-types. Neuronal genes with perturbed chromatin accessibility regions were enriched in synaptic signaling genes supporting an epigenetic contribution to cognitive impairment in HIV. Convergent mechanisms of pathogenesis between HIV and AD support that broad therapeutic targets can be identified to ameliorate neurodegeneration and neuroinflammation in HIV and neurodegenerative conditions such as AD.},
}

@article {pmid41282120,
year = {2025},
author = {Li, M and Niu, S and Xu, Y and Li, J and Hu, X and Liu, D and Atik, M and Xu, X and Wang, L and Taner, NE and Tao, C},
title = {Bridging the Computational-Experimental Gap: Leveraging Large Language Model to Prioritize Alzheimer's Therapeutics Based on Comparison of Learning Models.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7811754/v1},
pmid = {41282120},
issn = {2693-5015},
abstract = {Alzheimer's Disease (AD) [1] is a progressive neurodegenerative disorder with limited therapeutic options, driving interest in drug repurposing to accelerate treatment discovery. Drug repurposing has emerged as a promising strategy to accelerate therapeutic discovery by repositioning existing drugs for new clinical indications. Recent computational repurposing approaches, including knowledge graph reasoning, transcriptomic signature analysis, and integrative literature mining, have demonstrated strong predictive capabilities [2] . However, these methods often yield divergent drug rankings, which makes it difficult to decide which candidates to advance for experimental follow-up and results in substantial gaps between computational predictions and feasible in vivo validation [2] .To bridge this computational-experimental gap, we proposed an advanced prioritization framework leveraging large language models (LLMs). Our method systematically evaluated three state-of-the-art (SOTA) and representative computational methods (TxGNN [3] , Composition-based Graph Convolutional Network (CompGCN) [4] , and a regularized logistic regression (RLR) [5] , to analyze both their predictive performance and pharmaceutical class distributions. By integrating the strengths and divergences of these models, we generated a unified, streamlined list of 90 candidate drugs for further prioritization. We then utilized an LLM-based agent to perform evidence synthesis from biomedical literature abstracts for each candidate. This process mimics expert manual curation but significantly reduces human effort and time by efficiently distilling vast textual data into actionable insights. Applying consistent and transparent selection criteria, we obtained a refined and prioritized list of drug candidates suitable for subsequent in vivo experimental validation. The robustness and clinical relevance of our framework were validated using real-world data from Alzheimer's patient cohorts, clinical trial registries, and expert pharmacological reviews. This comprehensive validation confirmed that our LLM-driven approach enhances efficiency, consistency, scalability, and generalizability. By integrating computational predictions with scalable evidence synthesis and multifaceted validation, our framework facilitated rapid and informed prioritization of repurposed drugs. Our framework can potentially accelerate the translational pathway toward viable AD therapeutics. Moreover, the versatility of our framework can also be applied to drug repurposing efforts for other diseases beyond AD.},
}

@article {pmid41282103,
year = {2025},
author = {Deek, RA and Balogun, WG and Zeng, X and Triana-Baltzer, G and Pascoal, TA and Kolb, HC and Snitz, B and Cohen, AD and Karikari, TK},
title = {Head-to-head comparison of plasma p-tau217 immunoassays for incipient Alzheimer's disease in community cohorts.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7754328/v1},
pmid = {41282103},
issn = {2693-5015},
abstract = {Background : Plasma p-tau217 is a promising biomarker for detecting incipient AD pathology, but direct comparison of different p-tau217 assays in community-based cohorts are limited. Methods : We evaluated two cohorts from southwestern Pennsylvania, USA; the MYHAT-NI sub-study, which included two-year longitudinal follow-up neuroimaging assessments of Aβ, tau, and cortical thickness; and the Human Connectome Project/CoBRA, targeting a 50:50 split of self-identified Black and non-Hispanic White individuals. Plasma p-tau217 was measured using four different assays: Lumipulse, Johnson&Johnson, ALZpath, and NULISA. Aβ and tau pathologies were assessed with [ [11] C]PiB PET and [ [18] F]Flortaucipir PET, respectively. Clinical Dementia Rating (CDR) and Montreal Cognitive Assessment were used to assess cognitive performance. Results : We included 344 participants (MYHAT-NI: n=111, median age 76 [IQR: 72-80], 54% female; HCP/CoBRA: n=234, median age 62 [IQR: 52-70], 65% female). All four p-tau217 assays exhibited moderate to strong cross-platform correlations (Spearman correlations of 0.40 - 0.86), and statistically equivalent AUCs (of 0.84-0.90) for determining Aβ positivity. Conclusions : Our findings showed strong equivalent performances of plasma p-tau217 assays to identify amyloid positivity across two highly diverse cohorts of community-dwelling older adults.},
}

@article {pmid41282102,
year = {2025},
author = {Frazier, M and Kaur, T and Stauff, J and Winton, WP and Henderson, BD and Dumond, AS and Shao, X and Raffel, DM and Frey, KA and Kilbourn, MR and Brooks, AF and Scott, PJH},
title = {IND-Enabling Preclinical Studies of [11C]COU, a Trapped Metabolite PET Radiotracer for Monoamine Oxidase-B.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7762445/v1},
pmid = {41282102},
issn = {2693-5015},
abstract = {[ [11] C]COU is a trapped metabolite radiotracer for in vivo analysis of Monoamine Oxidase B activity using positron emission tomography (PET) imaging. [ [11] C]COU has the potential to quantify astrocytosis in the early stages of Alzheimer's disease, providing an earlier marker of disease than currently available for staging disease progression. Prior preclinical studies have demonstrated the efficacy of this radiotracer in preclinical imaging studies, warranting the translation for clinical evaluation. In this paper, we describe results of the requisite preclinical studies required to obtain approval for translation of [ [11] C]COU into first-in-human studies. Development and validation of a production method that conforms to the quality requirements described in the US Pharmacopeia was accomplished, along with preclinical rodent studies to determine human radiation dose estimates and a single acute dose pharmacology and toxicology study to establish that an injected mass dose 100-fold higher than the proposed PET imaging dose was below the no-observed-adverse-effect level (NOAEL). The production method was validated in triplicate, yielding [ [11] C]COU in sufficient radiochemical yield (9.3 ± 0.008%), radiochemical purity (99.2 ± 0.002%) and molar activity (4471 ± 1744 Ci/mmol) for routine clinical use, and providing a product that was sterile and met (or exceeded) all quality control requirements for human use. Dosimetric analysis determined that the effective human dose of [ [11] C]COU is 0.005mSv/MBq, also acceptable for clinical use. Lastly, no observable adverse effects were noted at 86 µg/kg in rodent toxicology studies (100x the proposed human dose). From these results we received approval to advance [ [11] C]COU into clinical studies.},
}

@article {pmid41282097,
year = {2025},
author = {Sundermann, EE and Banks, SJ and Bondi, MW and Martinez, MA and Biegon, A and Rotblatt, LJ and Hildebrandt, T},
title = {Sex Differences in the Relationship of Biomarker Change to Memory Decline in Early Alzheimer's Disease: an Observational Cohort Study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7661592/v1},
pmid = {41282097},
issn = {2693-5015},
abstract = {Background Alzheimer's disease (AD) exhibits sex differences in pathology and cognitive trajectories. Understanding how these differences manifest across the Alzheimer's continuum can improve early detection, diagnostics, and interventions. We examined sex differences in how cerebrospinal fluid pTau181/Aβ42 ratio changes relate to verbal memory decline across the preclinical and mild cognitive impairment (MCI) stages of AD. Methods In this retrospective, longitudinal, observational study, data were extracted from 404 participants (age range: 55-87.8, 98% non-Hispanic White) of the Alzheimer's Disease Neuroimaging Initiative cohort study who were classified as either preclinical AD (69 females, 68 males) or MCI (113 females, 151 males) at baseline and had CSF pTau181/Aβ42 ratio and cognitive assessment data at at-least two timepoints. Using regression models, we examined the relationship between changes in CSF pTau181/Aβ42 and verbal memory and the moderating role of sex and AD stage over a mean follow-up period of 4 years. Verbal memory was represented by a composite z-score averaging Immediate and Delayed Recall z-scores of the Rey Auditory Verbal Learning Test. Covariates included baseline age, education, and apolipoprotein E genotype. Results A significant sex x diagnostic group x biomarker change interaction (ꞵ=-17.47, 95%CI = 27.60 to -7.33, p = .001) indicated that sex differences in the relationship between changes in CSF pTau181/Aβ42 ratio and verbal memory differed by disease stage. While males in the preclinical AD stage showed steeper memory decline than females with increasing pTau181/Aβ42 ratios, this difference was not statistically significant. In contrast, in the mild cognitive impairment stage, a significant sex X biomarker change interaction (ꞵ=10.17, 95% CI = 4.94 to 15.40, p < .001) in the MCI stage indicated that females exhibited significantly steeper memory decline associated with increasing pTau181/Aβ42 ratios compared to males. Conclusion Sex differences in the relationship between AD biomarker levels and cognitive decline vary by disease stage. Although not statistically significant, females demonstrated resilience to memory decline in the preclinical stage, whereas, in the MCI stage, they experienced significantly steeper memory loss compared to males. Results suggest that accounting for sex in biomarker-based methods of disease detection and tracking can improve early detection and intervention in both sexes.},
}

@article {pmid41282094,
year = {2025},
author = {Kesler, SR and Lewis, KA and Cuevas, H and Flowers, E},
title = {Temporal dysregulation of PPARG-PRKAG2 co-expression in gray matter: Implications for cognitive decline and intervention targets in type 2 diabetes.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7907793/v1},
pmid = {41282094},
issn = {2693-5015},
abstract = {Background: Type 2 diabetes mellitus (T2DM) is associated with increased risk for cognitive decline and diagnosis of Alzheimer's disease (AD). The mechanisms of T2DM related dementia remain unclear. Methods: Brain magnetic resonance imaging was retrospectively obtained for 1,802 adults (age 66 +/- 9 years, 47% male) of whom N = 271 had T2DM. We applied an accelerated longitudinal design and imaging transcriptomics to non-invasively examine the group-level trajectories of PPARG and PRKAG2 co-expression in gray matter. Results: Gene expression trajectories differed significantly between T2DM and controls (χ[2] = 13.82, p = 0.001). Co-expression was higher in early stages and then weakened in later stages among T2DM, while remaining stable over time in controls. PPARG and PRKAG2 co-expression was significantly associated with cognitive function in controls (F = 3.17, p < 0.001) but not T2DM (F = 7.72, p = 0.299) suggesting dysregulated or failed compensatory mechanisms. Individuals with T2DM not taking metformin demonstrated unstable gene co-expression over time compared to those taking metformin (χ[2] = 12.42, p = 0.006). Conclusions: The convergence of PPARG -mediated metabolic remodeling and PRKAG2 /AMPK-driven energy sensing may act as a coordinated neuroprotective mechanism, upregulated in response to cellular stress in both pathological (T2DM) and normative (aging) contexts. However, these processes appear to become dysregulated in T2DM, potentially resulting in cognitive decline and increased risk for dementia.},
}

@article {pmid41282082,
year = {2025},
author = {Tognoni, CM and Biswas, RG and Suar, ZM and Carreras, I and Dedeoglu, A and Jenkins, BG},
title = {Protection of multiple aspects of Alzheimer's disease pathology using dietary supplementation with taurine.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7483320/v1},
pmid = {41282082},
issn = {2693-5015},
abstract = {As Alzheimer's disease (AD) continues to rise amongst the aging population, preventative measures such as dietary or lifestyle changes represent an attractive option to mitigate the burden. Taurine, known for its antioxidant and anti-inflammatory properties, may also play a neuroprotective role. This study investigates the protective effects of taurine supplementation in 5xFAD mice. Taurine was administered through drinking water at doses of 0, 500, 1000, 2000, 4000 mg/kg/day, with no change in water consumption or body mass was observed. Postmortem markers of neuroinflammation using cytokine profiling demonstrated that 2000 mg/kg/day was effective at invoking a protective response against AD progression. An acute dose of this concentration, in older mice, was also sufficient at protecting the dentate gyrus against gliosis and preventing volume loss. Supplementation of taurine for 1-2 months in older mice also led to a small, reduction in the Aβ42 burden. This suggests that both long-term and acute administration of taurine can mitigate pathological characteristics of AD. High-resolution magic angle spinning magnetic resonance spectroscopy (HRMAS-MRS) was used to analyze and differentiate the molecular profile of 3 key AD-affected regions: frontal cortex, ventral and dorsal hippocampus. Significant changes in 5 metabolites (GABA, glutamate, NAA, aspartate and scyllo-inositol) were observed in AD at two different ages (3-4 months and 8 months). Taurine moved a number of metabolites including NAA and glutamate closer to the wild-type profile consistent with neuroprotection. Overall, these findings support dietary taurine supplementation as a promising preventative strategy for AD.},
}

@article {pmid41282065,
year = {2025},
author = {Seijo, MA and Banerjee, A and Hernandez, CM},
title = {Network-Level Organization of Systemic Inflammation Reflects Early Alzheimer's-Like Behavioral Changes.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7482654/v1},
pmid = {41282065},
issn = {2693-5015},
abstract = {Systemic immune alterations are increasingly recognized as features of Alzheimer's disease (AD), yet their network-level organization in preclinical models is poorly understood. We profiled 66 circulating cytokines and growth factors in young adult TgF344-AD and wild-type rats, reduced the data into five inflammatory profiles via principal component analysis, and mapped these profiles onto protein-protein interaction networks. Multivariate analyses revealed genotype- and sex-dependent network organization, with distinct modules enriched for extracellular matrix-linked interleukin signaling or systemic pro-inflammatory cytokine receptor signaling. Regression analyses controlling for genotype and sex linked these networks to specific behavioral domains: extracellular matrix-associated interleukins predicted altered intertemporal choice, whereas pro-inflammatory cytokine receptor signaling correlated with reduced motivation. These findings provide evidence consistent with systemic inflammatory network remodeling at prodromal stages in a preclinical AD model of AD-like pathology and outline a mechanistically interpretable analytical framework with clear translational potential for integrating peripheral immune signatures with behavioral outcomes across species.},
}

@article {pmid41282064,
year = {2025},
author = {Akinyemi, T and Pola, I and Tan, K and Olalusi, O and Yaria, J and Ogunde, G and Traichel, W and Rahmouni, N and Oguntiloye, O and Fagbemi, A and Cadmus, E and Popoola, F and Therriault, J and Ogunronbi, M and Olujobi, D and Famuyiwa, O and Akinyemi, J and Pascoal, T and Owolabi, M and Rosa-Neto, P and Momoh, CTU and Ladokun, O and Romero-Ortuno, R and Ogunniyi, A and Lawlor, B and Kalaria, R and Akinyemi, R},
title = {Blood-based Biomarkers of Alzheimer's Disease and Neurodegeneration in an Indigenous African Cohort using both SIMOA and NULISA Platforms.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7688955/v1},
pmid = {41282064},
issn = {2693-5015},
abstract = {Background In low- and middle-income countries, Alzheimer's disease and related dementias (ADRD) constitute a growing public health burden. Indeed, the lack of awareness and easy screening tools, such as blood-based biomarkers, leaves many patients undiagnosed. In this study, we explored the core biomarkers of AD in an indigenous African cohort (VALIANT) to assess their relevance and potential utility to aid clinical diagnosis. Methods Nigerian African older adults (n = 967; ≥50 years) participating in the VALIANT study completed a baseline cross-sectional evaluation with associated clinical diagnosis. We quantified phosphorylated tau (p-tau 217), glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and amyloid beta (Aβ42 and Aβ40) levels in plasma with both the Single Molecule Assay (SIMOA, Quanterix) and Nucleic acid-Linked Immuno-Sandwich Assay (NULISA, Alamar) platforms. Results In agreement with previous findings, core AD biomarkers were associated with disease severity both in clinical diagnostic and clinico-pathological groups, with stepwise increases of p-tau 217, NfL and GFAP from cognitively unimpaired (CU) to dementia (p < 0.05). These results were consistent across both SIMOA and NULISA platforms. Comparison between sexes showed higher levels of biomarkers in male participants across diagnostic groups. We identified a significant effect of apoE E4 proteotype on p-tau217 levels after adjusting for age and sex but no significant effect on the other AD biomarkers. Conclusion This first application of cutting-edge plasma AD biomarker immunoassay using two ultrasensitive platforms in an indigenous African cohort showed good concordance and underscores the relevance and utility of blood-based biomarkers of AD in diverse populations. Additionally, sex differences could unveil biological distinctions inherent in the African population.},
}

@article {pmid41282061,
year = {2025},
author = {Lizińczyk, AM and Pankiewicz, JE and Cullina, WL and Franco, LA and Sullivan, PM and Sadowski, MJ},
title = {APOE Genotype Differentially Modulates Prion Pathology in a Mouse Model.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7820890/v1},
pmid = {41282061},
issn = {2693-5015},
abstract = {APOE polymorphism affects the risk of occurrence and the rate of progression in several neurodegenerative diseases including Alzheimer's disease, primary tauopathies, α-synucleinopathy, and age-related macular degeneration, but its role in prionoses remains unestablished. Using APOE targeted replacement (TR) mice, we investigated how APOE genotype affects key neurodegenerative mechanisms involved in prion pathology. Male and female ε2/ε2 , ε3/ε3 , and ε4/ε4 APOE -TR mice were inoculated with 22L mouse-adapted scrapie strain or normal brain homogenate and monitored with behavioral testing from 10-week post inoculation (wpi.) onward. Mice were euthanized at 23 wpi. when all prion-infected animals were symptomatic, and their brains were analyzed for multiple neuropathological, biochemical, and transcriptomic metrics. ε4/ε4 22L mice featured the shortest disease latency time, the worst neurological score, and the highest load of spongiform lesions. ε2/ε2 22L mice performed significantly better than ε4/ε4 22L mice but significantly worse than ε3/ε3 22L animals. Numerous aspects of PrP proteinopathy were exacerbated in the presence of the ε4 allele including increased PrP [Sc] accumulation, reduced PrP solubility, and increased PrP oligomerization. These metrics were comparable between ε2/ε2 22L and ε3/ε3 22L mice. Prion pathology significantly increased brain apolipoprotein (apo) E levels, with the greatest increase in ε4/ε4 22L mice. All apoE isoforms formed complexes with conformationally altered PrP, but this interaction was the strongest in ε4/ε4 22L mice. ε4/ε4 22L mice had the highest load of reactive microglia and astrocytes and upregulation of transcriptomic markers typical of neurodegenerative microglia and astrocytes, followed by ε2/ε2 22L , with ε3/ε3 22L having the lowest. Thus, APOE polymorphism differentially regulates the progression of prion pathology attributable to two ε4 -affected mechanisms: increased conversion and accumulation of PrP [Sc] and worsened prion-associated neuroinflammation. Though less severely than ε4 , the ε2 allele also increased the inflammatory response, rendering disease outcome worse relative to the ε3 allele. Our findings suggest both ε4 and ε2 alleles are disadvantageous determinants in prion pathology.},
}

@article {pmid41281735,
year = {2025},
author = {van Maanen, E and Robey, S and Bennacef, I and Duffull, S and Egan, MF and Kennedy, ME and Stone, JA},
title = {Modeling amyloid plaque turnover dynamics improves characterization of drug effects.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70169},
pmid = {41281735},
issn = {2352-8737},
abstract = {INTRODUCTION: Effect on amyloid plaque as measured by positron emission tomography imaging with Centiloid standardization of two therapeutic approaches targeting amyloid beta (Aβ) was investigated using exposure-response modeling.

METHODS: Individual-level verubecestat data from the APECS trial were pooled with summary-level data from the literature for amyloid monoclonal antibodies (mAbs) and fitted in a joint non-linear mixed-effects model.

RESULTS: An indirect-response (turnover) model with verubecestat inhibiting plaque formation and mAbs stimulating plaque removal well represented the data. The estimated plaque elimination half-life was 6.4 years. Daily verubecestat 40 mg was estimated to reduce formation by 91.8%. Aducanumab 10 mg/kg every 4 weeks (Q4W), donanemab 1400 mg Q4W, gantenerumab 1200 mg Q4W, and lecanemab 10 mg/kg Q2W were estimated to increase the removal rate by 9.3-, 18.6-, 5.3-, and 13.8-fold, respectively.

DISCUSSION: The model provides a fundamental measure of drug effects on plaque, independent of disease stage and study-design factors, improving cross-study comparisons and enabling predictions.

HIGHLIGHTS: The plaque turnover model describes natural progression and BACE and mAb intervention.The model estimation of the underlying plaque elimination half-life is 6.4 years.Approach improves cross-study comparison independently of population and study design.Predictions of alternative regimens/therapeutic approaches will aid future study design.},
}

@article {pmid41281734,
year = {2025},
author = {Wang, D and Florian, H and Lynch, SY and Robieson, W and Zhuang, R and Kusiak, C and Ross, JL and Walsh, JR and Graff, O},
title = {Using AI-generated digital twins to boost clinical trial efficiency in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70181},
pmid = {41281734},
issn = {2352-8737},
abstract = {INTRODUCTION: Machine learning models leverage baseline data to create artificial intelligence (AI)-generated digital twins (DTs)-individualized predictions of each participant's clinical outcomes if they had received placebo. Incorporating DTs may increase statistical power or reduce required sample sizes in Phase 2 or 3 trials, and therefore improve efficiency in Alzheimer's disease (AD) trials. Here we demonstrate these properties using data from an AD Phase 2 clinical trial (AWARE, NCT02880956).

METHODS: A conditional restricted Boltzmann machine (CRBM) model was trained on historical clinical trials and observational data from 6736 unique subjects after data harmonization to generate DTs of participants from the AWARE trial. The AWARE trial enrolled 453 subjects with mild cognitive impairment (MCI) or mild AD. DTs were assessed as prognostic covariates to evaluate gains in variance and sample size reduction.

RESULTS: Positive partial correlation coefficients were found between DTs and change score from baseline in key cognitive assessments ranging from 0.30 to 0.39 at Week 96 in the AWARE trial. These correlations were consistent with validation results from three independent trials, which ranged from 0.30 to 0.46. Total residual variance was reduced by ~9% to 15% with DTs. While maintaining statistical power, DTs could reduce total sample size by ~9% to 15%, and control arm sample size by 17% to 26% in future AD trials.

DISCUSSION: Efficiency was improved in AD clinical trials using machine learning models to generate prognostic DTs by including them in statistical analysis modeling. This methodology aligns with regulatory guidance and represents an application of machine learning models suitable for the analysis of pivotal trial data. Validated DTs have the potential to improve clinical development efficiency in AD and in other neurological indications.

HIGHLIGHTS: Digital twins (DTs) were generated by artificial intelligence (AI) models trained on historical datasets.Use of digital twin (DT) as a covariate in the analysis model can reduce treatment effect variability.By coupling DT with the analysis model, trial sample size can be reduced.DT technology was accepted by the U.S. Food and Drug Administration and European Medicines Agency for applications in clinical trials.},
}

@article {pmid41281561,
year = {2025},
author = {Melamed, I and Buckley, C and Bayko, ME and Williams, JL and Or-Geva, N},
title = {Does C1 esterase inhibitor play a role in post COVID-19 neurological symptoms? A randomized, double-blind, placebo-controlled, crossover, proof-of-concept study.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1523814},
pmid = {41281561},
issn = {1664-2295},
abstract = {BACKGROUND: Many patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience neurologic changes post-infection, which has been hypothesized to be due to dysregulation in the infectious-immune axis that leads to a neuro-immune response. This immune dysfunction has been termed "Alzheimer's of the Immune System" or AIS and there are several immune factors that may play a key role. These include, among others, complement activation due to low levels of C1-esterase inhibitor (C1-INH) and function, and a decrease in signaling of Toll-like receptor (TLR)-3. We propose that C1-INH replacement may upregulate the immune dysfunction, thereby improving neurological symptoms.

METHODS: In this randomized, double-blind, placebo-controlled, crossover, proof-of-concept study, adults experiencing SARS-CoV-2 post-viral fatigue syndrome for >4 weeks post-recovery from coronavirus disease 2019 (COVID-19) infection were randomized 1:1 to two arms: Arm 1 (C1-INH for 8 weeks, then placebo for 8 weeks) or to Arm 2 (placebo for 8 weeks, then C1-INH for 8 weeks). Patients were assessed for adult executive function, abnormal cognitive decline, depression [Beck Depression Inventory-II (BDI-II)], migraine, fatigue [Fatigue Severity Scale (FSS)] and pain (Short-form McGill Pain Questionnaire). Percent change in TLR signaling in response to zymosan was compared with controls at baseline, Week 8 and Week 16. Safety was assessed throughout.

RESULTS: At this interim analysis, 36 patients with SARS-CoV-2 post-viral fatigue syndrome had completed the two 8-week treatment periods. In Arm 1, trends toward improvements from baseline at Week 8 of C1-INH therapy were observed in BDI-II score (-8.7 points), mean FSS score (0.6 points), and mean McGill Pain Questionnaire score (-0.4 points). These improvements were either sustained or worsened at Week 16, following crossover to placebo. The outcomes in Arm 2 were compatible with those in Arm 1. Patients with SARS-CoV-2 post-viral fatigue syndrome had low levels of TLR-related signaling biomarkers compared with healthy controls.

CONCLUSION: This proof-of-concept study demonstrates sustained dysregulation of the immune system after COVID-19 infection. Improvements in depression, fatigue, and pain were observed with C1-INH treatment in patients with SARS-CoV-2 post-viral fatigue syndrome, indicating C1-INH may be a potential therapeutic target.

CLINICAL TRIAL REGISTRATION: The study was registered on September 21, 2024, with the identifier number NCT04705831.},
}

@article {pmid41281560,
year = {2025},
author = {Sun, Q and Wang, F},
title = {Using artificial intelligence and radiomics to analyze imaging features of neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1624867},
pmid = {41281560},
issn = {1664-2295},
abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's and Parkinson's are characterized by complex, multifactorial progression patterns that challenge early diagnosis and personalized treatment planning.

METHODS: To address this, we propose an integrated AI-radiomics framework that combines symbolic reasoning, deep learning, and multi-modal feature alignment to model disease progression from structural imaging and behavioral data. The core of our method is a biologically informed architecture called NeuroSage, which incorporates radiomic features, clinical priors, and graph-based neural dynamics. We further introduce a symbolic alignment strategy (CAIS) to ensure clinical interpretability and cognitive coherence of the learned representations.

RESULTS AND DISCUSSION: Experiments on multiple datasets-including ADNI, PPMI, and ABIDE for imaging, and YouTubePD and PDVD for behavioral signals-demonstrate that our approach consistently outperforms existing baselines, achieving an F1 score of 88.90 on ADNI and 85.43 on PPMI. These results highlight the framework's effectiveness in capturing disease patterns across imaging and non-imaging modalities, supporting its potential for real-world neurodegenerative disease monitoring and diagnosis.},
}

@article {pmid41281523,
year = {2025},
author = {Li, YP and Niu, Y and Ding, H and Chen, Z and Zhang, Q},
title = {Potential role of meningeal lymphatic drainage in repetitive transcranial magnetic stimulation-induced cognitive improvement: A call for further research.},
journal = {World journal of psychiatry},
volume = {15},
number = {11},
pages = {111985},
pmid = {41281523},
issn = {2220-3206},
abstract = {Mild cognitive impairment (MCI), which is a high-risk transitional phase leading to Alzheimer's disease, is characterized by mild memory deficits and specific cognitive dysfunctions. Without effective intervention, a significant proportion of patients with MCI progress to dementia. However, current pharmacological treatments are characterized by side effects and poor patient compliance. Therefore, it is necessary to develop effective, noninvasive alternative treatments. Repetitive transcranial magnetic stimulation (rTMS) is becoming a widely studied noninvasive treatment for central nervous system disease. The therapeutic effects of rTMS on patients with MCI and its underlying mechanism are noteworthy issues. Recently, a growing number of studies have shown that meningeal lymphatic vessel damage may be related to cognitive dysfunction. Whether the improvement of the meningeal lymphatic system is an important mechanism through which rTMS improves the clinical manifestations of MCI is worthy of further study.},
}

@article {pmid41281504,
year = {2025},
author = {Teixeira, AL and Kim, Y and Cordeiro, TM and de Erausquin, GA and Rocha, NP},
title = {Agitation in Alzheimer's disease: From assessment to therapeutics.},
journal = {World journal of psychiatry},
volume = {15},
number = {11},
pages = {109581},
pmid = {41281504},
issn = {2220-3206},
abstract = {Agitation is a neuropsychiatric syndrome characterized by excessive motor and/or verbal behaviors, with or without aggressive behaviors. The prevalence of agitation in Alzheimer's disease varies from 5% to over 50%. Multiple factors have been implicated in its pathophysiology, including disease stage, comorbidity with other symptoms (e.g., psychosis, anxiety/depression), and psychosocial factors. Ruling out delirium and identifying environmental triggers are fundamental steps in the management of agitation in Alzheimer's disease. For establishing an effective therapeutic plan, it is important to define duration, severity, and potential for harm. While non-pharmacological approaches are considered the first line of intervention, pharmacological agents are frequently used in the treatment of agitation. Antipsychotics are commonly used in acute agitation. For chronic agitation, serotonin-selective reuptake inhibitors, especially citalopram and escitalopram, are often preferred due to safety concerns associated with the long-term use of antipsychotics. Promising novel strategies, such as new compounds and neuromodulation, are likely to be incorporated into agitation therapeutics in the next few years.},
}

@article {pmid41281435,
year = {2025},
author = {Wang, J and Huang, L and Sun, L and Guo, Q and He, Y and Jing, Y},
title = {Mood Symptoms are Associated With Cognitive Status, Brain Amyloid-Beta Deposition, and Plasma Biomarkers.},
journal = {Depression and anxiety},
volume = {2025},
number = {},
pages = {7515712},
pmid = {41281435},
issn = {1520-6394},
mesh = {Humans ; Male ; Female ; *Amyloid beta-Peptides/metabolism/blood ; Aged ; Biomarkers/blood ; Middle Aged ; *Cognitive Dysfunction/blood/metabolism/psychology ; *Alzheimer Disease/blood/metabolism/psychology ; *tau Proteins/blood ; Positron-Emission Tomography ; *Brain/metabolism/diagnostic imaging ; },
abstract = {BACKGROUND: Previous studies have indicated an association between mood symptoms and cognitive decline in the Alzheimer's disease (AD) spectrum. Amyloid-beta (Aβ) deposition in the brain, which is a core pathological characteristic of AD, along with the presence of plasma biomarkers, such as phosphorylated tau protein (p-tau), constitutes an early predictive indicator for AD. We attempted to explore the relationship between mood symptoms and the presence of AD-related plasma biomarkers in patients with brain Aβ deposition.

METHOD: We included 2612 participants aged ≥50 years (707 males; average age 66.98 ± 7.75 years) in this study. We used the Hamilton depression rating scale (HAMD) and Hamilton anxiety rating scale (HAMA) to assess mood symptoms. Cognitive status was categorized into AD, mild cognitive impairment (MCI), subjective cognitive decline (SCD), and normal cognition (NC). We used analysis of covariance (ANCOVA) to compare mood symptoms assessment scores in different cognitive groups after making adjustments for age, gender, and education. Linear regression analysis was used to investigate the association between mood scores and plasma biomarker levels, adjusting for positivity in Aβ PET imaging.

RESULTS: Compared to NC patients, patients with AD exhibited higher levels of depression (mean of 4.72 versus 3.39, p < 0.05), whereas patients with SCD exhibited higher levels of anxiety (mean of 6.28 versus 4.26, p < 0.05). After accounting for brain Aβ deposition and presence of plasma biomarkers, the plasma neurofilament light chain (NFL) levels (B = 0.211, SE = 0.059, p=0.001) were associated with HAMD scores. The plasma p-tau181 levels (B = 1.328, SE = 0.576, p=0.025) were associated with HAMA scores.

CONCLUSION: Plasma biomarkers have significant potential in predicting anxiety and depressive symptoms in individuals with brain Aβ deposition. This can aid the early clinical diagnosis and intervention of AD.},
}

Humans
Male
Female
*Amyloid beta-Peptides/metabolism/blood
Aged
Biomarkers/blood
Middle Aged
*Cognitive Dysfunction/blood/metabolism/psychology
*Alzheimer Disease/blood/metabolism/psychology
*tau Proteins/blood
Positron-Emission Tomography
*Brain/metabolism/diagnostic imaging

@article {pmid41281281,
year = {2025},
author = {Jing, S and Wang, Y and Liu, Y and Luo, Y and Wen, X and Ma, Y and Zhu, H and Chen, G and Ouyang, X},
title = {Folic acid as a potential therapeutic agent for Alzheimer's disease: Effects on inflammatory cytokines, amyloid deposition, and neurotransmitter metabolism.},
journal = {Journal of medical biochemistry},
volume = {44},
number = {7},
pages = {1551-1557},
pmid = {41281281},
issn = {1452-8258},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by neuroinflammation and amyloid deposition. Folic acid (FA), a B vitamin, may improve the course of AD by modulating inflammation and neuroprotection. This study aimed to investigate the effects of FA supplementation on serum inflammatory cytokines (IL-1b, IL-6, TNF-a), amyloid (Ab1-42), Tau proteins, and neurotransmitters (GABA, 5-HT, Ach) in AD patients.

METHODS: We conducted a follow-up-controlled trial; 114 AD patients were included and randomly divided into a control group (donepezil treatment) and an experimental group (donepezil + FA treatment) for 3 months. Inflammatory factors, Ab1-42, Tau, neurotransmitter levels and nutritional status were assessed before and after treatment.

RESULTS: The total effective rate of the experimental group (89.47%) was significantly higher than that of the control group (75.44%), and the levels of inflammatory factors (IL-1b, IL-6, and TNF-a), Ab1-42, and Tau were significantly lower (P<0.05), and neurotransmitters (GABA, 5-HT, and Ach) and nutritional indexes (albumin and hemoglobin) were substantially higher.

CONCLUSIONS: FA supplementation can effectively delay AD progression by inhibiting neuroinflammation, reducing amyloid deposition, regulating neurotransmitter metabolism and improving nutritional status.},
}

@article {pmid41281210,
year = {2025},
author = {Wu, J and Risk, BB and James, TA and Seyfried, N and Loring, DW and Goldstein, FC and Levey, AI and Lah, JJ and Qiu, D},
title = {Non-linear associations of amyloid-$β$ with resting-state functional networks and their cognitive relevance in a large community-based cohort of cognitively normal older adults.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41281210},
issn = {2331-8422},
abstract = {BACKGROUND: Non-linear alterations in brain network connectivity may represent early neural signatures of Alzheimer's disease (AD) pathology in cognitively normal older adults. Understanding these changes and their cognitive relevance could provide sensitive biomarkers for early detection. Most prior studies recruited participants from memory clinics, often with subjective memory concerns, limiting generalizability.

METHODS: We examined 14 large-scale functional brain networks in 968 cognitively normal older adults recruited from the community using resting-state functional MRI, cerebrospinal fluid (CSF) biomarkers (amyloid-$β$ 1-42 [A$β$], total tau, phosphorylated tau 181), and neuropsychological assessments. Functional networks were identified using group independent component analysis.

RESULTS: Inverted U-shaped associations between CSF A$β$ and functional connectivity were observed in the precuneus network and ventral default mode network (DMN), but not in the dorsal DMN, indicating network-specific vulnerability to early amyloid pathology. Higher connectivity in A$β$-related networks, including dorsal and ventral DMN, precuneus, and posterior salience networks, was associated with better visual memory, visuospatial, and executive performance. No significant relationships were observed between CSF tau and functional connectivity.

CONCLUSIONS: Using a large, community-based cohort, we demonstrate that non-linear alterations in functional connectivity occur in specific networks even during the asymptomatic phase of AD. Moreover, A$β$-related network connectivity is cognitively relevant, highlighting functional brain networks as promising imaging markers for early detection and prognosis of AD.},
}

@article {pmid41280882,
year = {2025},
author = {Zolnour, A and Azadmaleki, H and Haghbin, Y and Taherinezhad, F and Nezhad, MJM and Rashidi, S and Khani, M and Taleban, A and Sani, SM and Dadkhah, M and Noble, JM and Bakken, S and Yaghoobzadeh, Y and Vahabie, AH and Rouhizadeh, M and Zolnoori, M},
title = {LLMCARE: early detection of cognitive impairment via transformer models enhanced by LLM-generated synthetic data.},
journal = {Frontiers in artificial intelligence},
volume = {8},
number = {},
pages = {1669896},
pmid = {41280882},
issn = {2624-8212},
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) affect nearly five million older adults in the United States, yet more than half remain undiagnosed. Speech-based natural language processing (NLP) provides a scalable approach to identify early cognitive decline by detecting subtle linguistic markers that may precede clinical diagnosis.

OBJECTIVE: This study aims to develop and evaluate a speech-based screening pipeline that integrates transformer-based embeddings with handcrafted linguistic features, incorporates synthetic augmentation using large language models (LLMs), and benchmarks unimodal and multimodal LLM classifiers. External validation was performed to assess generalizability to an MCI-only cohort.

METHODS: Transcripts were obtained from the ADReSSo 2021 benchmark dataset (n = 237; derived from the Pitt Corpus, DementiaBank) and the DementiaBank Delaware corpus (n = 205; clinically diagnosed mild cognitive impairment [MCI] vs. controls). Audio was automatically transcribed using Amazon Web Services Transcribe (general model). Ten transformer models were evaluated under three fine-tuning strategies. A late-fusion model combined embeddings from the best-performing transformer with 110 linguistically derived features. Five LLMs (LLaMA-8B/70B, MedAlpaca-7B, Ministral-8B, GPT-4o) were fine-tuned to generate label-conditioned synthetic speech for data augmentation. Three multimodal LLMs (GPT-4o, Qwen-Omni, Phi-4) were tested in zero-shot and fine-tuned settings.

RESULTS: On the ADReSSo dataset, the fusion model achieved an F1-score of 83.32 (AUC = 89.48), outperforming both transformer-only and linguistic-only baselines. Augmentation with MedAlpaca-7B synthetic speech improved performance to F1 = 85.65 at 2 × scale, whereas higher augmentation volumes reduced gains. Fine-tuning improved unimodal LLM classifiers (e.g., MedAlpaca-7B, F1 = 47.73 → 78.69), while multimodal models demonstrated lower performance (Phi-4 = 71.59; GPT-4o omni = 67.57). On the Delaware corpus, the pipeline generalized to an MCI-only cohort, with the fusion model plus 1 × MedAlpaca-7B augmentation achieving F1 = 72.82 (AUC = 69.57).

CONCLUSION: Integrating transformer embeddings with handcrafted linguistic features enhances ADRD detection from speech. Distributionally aligned LLM-generated narratives provide effective but bounded augmentation, while current multimodal models remain limited. Crucially, validation on the Delaware corpus demonstrates that the proposed pipeline generalizes to early-stage impairment, supporting its potential as a scalable approach for clinically relevant early screening. All codes for LLMCARE are publicly available at: GitHub.},
}

@article {pmid41280755,
year = {2025},
author = {Tutubala, TE and Egunlusi, AO and Fisher, D and Dube, A and Joubert, J},
title = {Nanomedicine Solutions for Alzheimer's Disease: A Critical Review of Therapeutic Nanoparticle Strategies.},
journal = {ACS omega},
volume = {10},
number = {45},
pages = {53633-53657},
pmid = {41280755},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a debilitating disorder marked by progressive memory and cognitive function loss. Current treatments, including acetylcholinesterase and N-methyl-d-aspartate receptor inhibitors, offer symptomatic relief but lack disease-modifying effects. The recent approval of aducanumab, an antibody clearing amyloid beta plaques, brings hope, though its therapeutic benefits are controversial. AD's etiology is multifactorial, involving over 40 genetic variants, and remains poorly defined. Nanotechnology offers a promising avenue for optimized drug candidates, addressing challenges such as solubility, stability, and blood-brain barrier permeation. This review explores nanoformulations targeting key AD aspects, including amyloid beta, Tau protein, oxidative stress, and neuroinflammation. Notably, multifunctional nanocarriers present a comprehensive approach, demonstrating the potential for effective AD therapy. Despite extensive research, only a small fraction of these studies progress to clinical trials. Continuous nanomedicine research is poised to play a vital role in future AD management, providing innovative solutions to this devastating disease.},
}

@article {pmid41280597,
year = {2025},
author = {Shalak, M and Sreemantula, HS and Amaechi, E and Mousavi, S},
title = {Clinical course of myxedema coma in an Alzheimer's disease patient and co-founding of J wave: A case report.},
journal = {Journal of family medicine and primary care},
volume = {14},
number = {10},
pages = {4400-4403},
pmid = {41280597},
issn = {2249-4863},
abstract = {Myxedema coma is a rare condition and is associated with a high mortality rate. Management has been based on the medical experience due to its rarity. Here, we are presenting a case of a 78-year-old African American woman with Alzheimer's disease and primary hypothyroidism, who presented to the emergency department with altered sensorium, hypotension, severe hypothermia, and bradycardia. She was diagnosed with myxedema coma and admitted to the medical intensive care unit (ICU). Despite appropriate management, including early administration of intravenous thyroxine (FT4), the patient's hospital course was complicated. She went into multi-organ system failure, requiring multiple re-intubations due to the poor mental status. Although thyroid stimulating hormone (TSH) and T4 reached normal levels, there was no improvement in the patient's mental status which could be due to multiple factors including dementia at baseline, development of delirium and functional deconditioning later in her course. Myxedema Coma seen in elderly patients with dementia poses significant morbidity and mortality. Hence, a primary care physician or a geriatrician's role becomes crucial in maintaining proper follow-up of these patients to alleviate the above outcomes.},
}

@article {pmid41280565,
year = {2025},
author = {Li, Y and Zhou, X and Song, Z and Zhao, T and Rong, J and Chen, J and Zhao, C and Hu, Q and Li, X and Li, C and Sun, Z and Gao, Y and Patel, JS and Chaudhary, A and Yuan, H and Liang, SH},
title = {Radiosynthesis and evaluation of a carbon-11 labeled PET ligand for imaging of O-GlcNAcase.},
journal = {American journal of nuclear medicine and molecular imaging},
volume = {15},
number = {5},
pages = {183-192},
pmid = {41280565},
issn = {2160-8407},
abstract = {O-GlcNAcase (OGA) is a key enzyme involved in regulating the dynamic cycling of O-GlcNAc modifications on intracellular proteins. OGA has emerged as a promising therapeutic target for neurodegenerative diseases, including Alzheimer's disease. In this report, we present the radiosynthesis and preclinical assessment of a novel carbon-11 labeled positron emission tomography (PET) radioligand [[11]C]1 (codenamed OGA-2504) targeting OGA. The aminopyrimidine-based compound 1 and its corresponding desmethyl precursor were synthesized efficiently with good chemical yields. Radiosynthesis of [[11]C]1 was accomplished via [11]C-methylation, yielding an 8% decay-corrected radiochemical yield with high purity (>98%) and high molar activity (92.5 GBq/µmol). [[11]C]1 exhibited moderate lipophilicity (LogD = 2.11) and excellent in vivo stability in serum. However, preliminary PET imaging revealed low brain uptake and slow clearance of [[11]C]1 in mice, suggesting a need for further structural optimization to enhance brain penetration.},
}

@article {pmid41280486,
year = {2025},
author = {Taube, PS and Fernandes, D and Vasconcelos, AA and Costa, JAS and de Araujo, MP and Lima, AKO and Wahab, N and Dos Santos, EKL and de Oliveira, MI and da Silva, JP and Andriani, KF and da Silva Oliveira, TP and Sampaio, MC and de Campos Braga, H and de Araújo, ACS and Gul, K},
title = {Perspectives and state-of-the-art use of metal-derived, porous nanomaterials and metallo-drugs for biomedical applications.},
journal = {3 Biotech},
volume = {15},
number = {12},
pages = {416},
pmid = {41280486},
issn = {2190-572X},
abstract = {Due to a combination of genetic, environmental, and behavioral factors, the number of infectious and non-infectious diseases affecting humans has been rising. Many illnesses are in the forefront of research and development such as neoplasms of different forms, chronic conditions related to inflammation and lifestyle (e.g., cancer, diabetes mellitus, Alzheimer's and Parkinson's diseases) and infectious diseases that are difficult to treat (e.g., due to drug resistance). Due to current challenges in diagnosis and treatment of diseases and health conditions, the field of nanotechnology has witnessed numerous advancements. In particular, metal-based, porous nanomaterials and metallo-drugs have gained attention due to their ability to be used for various diagnostic and therapeutic applications. These systems exhibit excellent physicochemical properties, with amenable functionalization and varying optical, scattering and electronic properties, enabling for both imaging and therapy of diseases (i.e., theranostics), involving techniques such as photoacoustic imaging, magnetic resonance imaging (MRI), computed tomography (CT), photothermal therapy (PTT), photodynamic therapy (PDT) and radiotherapy. This review discusses the important aspects of metal nanoparticles, porous-based materials and metallo-drugs for biomedical applications, exploring their physical and chemical characteristics, cellular/molecular processes and biopotencies that make them effective in treating a variety of illnesses or diseases.},
}

@article {pmid41280332,
year = {2025},
author = {Wu, Z and Yu, S and Tian, D and Cheng, L and Jing, J},
title = {Microglial TREM2 and cognitive impairment: insights from Alzheimer's disease with implications for spinal cord injury and AI-assisted therapeutics.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1705069},
pmid = {41280332},
issn = {1662-5102},
abstract = {Cognitive impairment is a frequent but underrecognized complication of neurodegenerative and traumatic central nervous system disorders. Although research on Alzheimer's disease (AD) revealed that microglial triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in inhibiting neuroinflammation and improving cognition, its contribution to cognitive impairment following spinal cord injury (SCI) is unclear. Evidence from AD shows that TREM2 drives microglial activation, promotes pathological protein clearance, and disease-associated microglia (DAM) formation. SCI patients also experience declines in attention, memory, and other functions, yet the specific mechanism of these processes remains unclear. In SCI, microglia and TREM2 are involved in inflammation and repair, but their relationship with higher cognitive functions has not been systematically examined. We infer that TREM2 might connect injury-induced neuroinflammation in the SCI with cognitive deficits, providing a new treatment target. Artificial intelligence (AI) offers an opportunity to accelerate this endeavor by incorporating single-cell transcriptomics, neuroimaging, and clinical data for the identification of TREM2-related disorders, prediction of cognitive trajectories, and applications to precision medicine. Novel approaches or modalities of AI-driven drug discovery and personalized rehabilitation (e.g., VR, brain-computer interface) can more precisely steer these interventions. The interface between lessons learned from AD and SCI for generating new hypotheses and opportunities for translation.},
}

@article {pmid41280324,
year = {2025},
author = {Leri, M and Bertolini, A and Diaz, M and Marongiu, R},
title = {Editorial: Estrogens and neurodegeneration: a link between menopause and Alzheimer's disease in women.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1727385},
pmid = {41280324},
issn = {2296-889X},
}

@article {pmid41280313,
year = {2025},
author = {Leng, SY and Yang, QH and Yuan, Y and Chen, B and Chen, H and Ban, W and Zhang, J},
title = {Exercise modulation of gut microbiota in Alzheimer's disease: pathophysiological mechanisms and therapeutic perspectives.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1677896},
pmid = {41280313},
issn = {1663-4365},
abstract = {As global life expectancy increases, Alzheimer's disease (AD) has become a major public health concern. The gut microbiota plays a pivotal role in regulating the central nervous system, influencing both behavior and cognitive functions in AD through direct and indirect mechanisms. Physical exercise has been shown to positively modulate the diversity and composition of the gut microbiota, emerging as a significant factor in slowing AD progression. A growing body of research highlights the dynamic interactions between exercise, gut microbiota, and AD, revealing that exercise can alter the synthesis and metabolism of key neuroactive substances, such as glutamate and aspartate, thereby enhancing cognitive function. Moreover, exercise influences peripheral and central immune responses via microbiota modulation, reducing neuroinflammation, amyloid-β (Aβ) deposition, and tau phosphorylation. Exercise also regulates gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs), which are crucial for alleviating neuroinflammation and maintaining the integrity of the blood-brain barrier (BBB). This review synthesizes recent advances in the molecular mechanisms underpinning the exercise-microbiota-AD axis, offering new therapeutic perspectives for AD.},
}

@article {pmid41280311,
year = {2025},
author = {Hossen, F and Hung, J and Odeh, H and Sun, GY and Lee, JC},
title = {Cytosolic phospholipase A2 links tau pathology to insulin signaling impairment in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1671986},
pmid = {41280311},
issn = {1663-4365},
abstract = {Although impaired insulin signaling in the brain has been recognized as a key factor in the development and progression of Alzheimer's disease (AD), the underlying mechanisms remain incompletely understood. Given that overactivation of cytosolic phospholipase A2 (cPLA2) has been implicated in AD, we tested the hypothesis that oligomeric tau (oTau) activates cPLA2, which in turn negatively affects Caveolin-1 (Cav-1) and insulin signaling. In the cerebral cortex and hippocampus of 12-months-old 3xTg-AD mice, we observed an upregulation of phosphorylated cPLA2 (p-cPLA2), accompanied by downregulation of Cav-1 and impaired insulin signaling. Specifically, we found significant decreases in insulin receptor-α (IR-α) and insulin receptor-β (IR-β) expression, along with increased levels of phospho-insulin receptor substrate 1 at Ser307 [p-IRS-1 (Ser307)] and decreased levels of p-IRS-1 (Tyr895), compared to wild-type (WT) mice. To further investigate the role of cPLA2 in insulin signaling impairment in AD, we demonstrated that oTau activated cPLA2 in primary mouse cerebral endothelial cells (CECs), leading to Cav-1 downregulation and disrupted insulin signaling. Notably, these detrimental effects of oTau on Cav-1 and insulin signaling were abolished when cPLA2 expression was depleted using small interfering RNA (siRNA). In conclusion, our study highlights the pivotal role of cPLA2 in regulating Cav-1 function and insulin signaling in AD, offering insights into potential therapeutic targets for mitigating insulin resistance associated with the disease.},
}

@article {pmid41280310,
year = {2025},
author = {Inamdar, A and Bugadannavar, P and Palled, M and Umarani, S and Salve, P and Gurupadayya, B and Patil, P and Sharma, H},
title = {Biological determinants of blood-based biomarker levels in Alzheimer's disease: role of nutrition, inflammation, and metabolic factors.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1614962},
pmid = {41280310},
issn = {1663-4365},
abstract = {OBJECTIVES: The review discusses the effect of biological determinants such as nutritional deficiency, systemic inflammation, and metabolic disorders affect blood-based biomarker (BBBM) levels, influencing their use in diagnosing, prognosticating, and treatment in Alzheimer's disease (AD). While the individual contributions of neuroinflammation, brain insulin resistance, and micronutrient deficiencies to AD pathology are well-established, a significant knowledge gap exists in understanding their intricate, synergistic interactions. This review proposes a novel integrated framework of bidirectional crosstalk where these three factors create a self-perpetuating cycle of neurodegeneration.

METHODS: A comprehensive literature review was conducted, including all aspects of epidemiological and biological context associated with vitamins, micronutrients, and dietary patterns; inflammatory cytokines; insulin resistance; metabolic syndrome; and hormonal changes. Emerging integrative approaches such as multi-omics, AI modeling, and systems biology were also reviewed for their possible refinement in biomarker interpretation.

RESULTS: The results prove that the deprivation of vitamins E, D, B12, and antioxidants contributes to oxidative stress and subsequent neuroinflammation that changes levels of blood-based biomarkers. A chronic state of inflammation caused by cytokines like IL-6, IL-18, and TNF-α represents a major link to the formation of increased amyloid plaques and tau tangles. Metabolically deregulated states, such as insulin resistance, dyslipidemia, and thyroid imbalance, further alter variability in biomarkers. All these factors would act together to affect the expression of key biomarkers-Aβ, p-tau, and neurofilament light chain (NFL). Individualized interpretation, stratified clinical trials, and digital monitoring tools are potentially effective for achieving better diagnostic precision and boosting treatment efficacy.

CONCLUSION: To a large extent, factors must all be understood thoroughly from multiple biological angles to improve early diagnosis, risk prevention, and treatment personalization in AD. Future studies should develop integrative models that consider nutrition, metabolism, and inflammation to address and fully exploit biomarker utility as well as support precision medicine approaches.},
}

@article {pmid41280213,
year = {2025},
author = {Ali, SH and Osmaniye, D and Kaplancıklı, ZA},
title = {Synthesis and biological evaluation of novel hydrazone derivatives for the treatment of Alzheimer's disease.},
journal = {RSC advances},
volume = {15},
number = {53},
pages = {45729-45743},
pmid = {41280213},
issn = {2046-2069},
abstract = {In recent years, Alzheimer's disease has emerged as a silent epidemic neurodegenerative disorder. Due to its complex pathophysiology, there has been significant scientific interest in developing effective treatments that go beyond symptomatic relief. The main aim is to improve patients' quality of life and lower the death rate associated with Alzheimer's disease. Since this has not yet been achieved, continued research on Alzheimer's disease remains a global priority. In this study, a total of 27 hybrid molecules (D1a-D1i, D2a-D2i, and D3a-D3i) were designed based on the molecular scaffold of donepezil, a well-known acetylcholinesterase inhibitor (AChEI). These hybrids incorporate dihydrothiazolyl hydrazone and phenyl piperidine moieties. All compounds were synthesized and characterized using IR, NMR, and HRMS spectroscopy, and subsequently evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition using the in vitro Ellman method. Evaluation of biological activity revealed that compound D1f exhibited the highest inhibitory activity against the AChE enzyme, with an IC50 of (0.039 ± 0.001 Mm). In contrast, none of the compounds showed significant inhibitory activity against the BChE enzyme. Cytotoxicity testing of compound D1f on NIH3T3 fibroblast cells demonstrated non-cytotoxic effects (IC50 = 3.324 ± 0.155 µM) and the highest selectivity index (SI = 85.231), respectively. Molecular docking and molecular dynamics simulations verified the stable binding affinity and favorable interactions of compound D1f within the active site of acetylcholinesterase (AChE). The results further demonstrated that the AChE enzyme preserved its structural integrity and compactness throughout its interaction with D1f. Collectively, these observations highlight D1f as a promising lead molecule for subsequent optimization and development of novel anti-Alzheimer's therapeutic agents.},
}

@article {pmid41280138,
year = {2025},
author = {Wang, YH and Xie, Y and Ding, PL and Ge, JW and Xie, L and Wu, DH and Xin, C},
title = {Analysis of the potential regulatory mechanism of PIEZO1 in Alzheimer's disease based on RNA sequencing.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {936-946},
pmid = {41280138},
issn = {2667-2421},
abstract = {The ion channel protein PIEZO1 regulates complex processes in Alzheimer's disease (AD). This study explored the regulatory mechanism of PIEZO1 in AD using bioinformatic analysis, aiming to identify AD-associated genes and potential therapeutic strategies. RNA sequencing (RNA-seq) data based on an in vitro model of AD were obtained from the Gene Expression Omnibus (GEO) database, and differential expression analysis was performed using the DESeq2 R package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted on the identified differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) and principal component analysis (PCA) were also performed on the gene expression data. PCA clustering revealed overall significant differences among the three groups of samples (control, AD, and PF-562271 intervention group). All DEGs in the three sample groups were subjected to k-means hierarchical clustering, revealing four clusters. The matrix antigen plot indicated multiple changes in the average millions of fragments per thousand bases value of each gene among the groups. Functional annotation was performed for the DEGs between the two groups, and GSEA identified both activated and inhibited pathways, distinguishing the groups. Notably, the expression of PIEZO1 was higher in the AD group than in the control group. This study confirmed elevated PIEZO1 expression in astrocyte AD models, which is associated with the regulation of the extracellular matrix, cell-substrate adhesion, synaptic migration, and other related functions and pathways.},
}

@article {pmid41280128,
year = {2025},
author = {Raikes, AC and Bhattrai, A and Wang, T and Wiegand, JP and Brinton, RD},
title = {Humanized APOE mouse brain volume increases over age irrespective of sex and APOE genotype: Implications for translational validity to the human.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.27.684892},
pmid = {41280128},
issn = {2692-8205},
abstract = {Translational validity of mouse models of human aging and late-onset Alzheimer's disease (LOAD) risk are essential for both fundamental mechanistic science and therapeutic development. Given that the strongest risk factors for LOAD are age, female sex, and APOE-ε4 carriership, models must reflect these biological variables and disease phenotypes. The use of mouse models with humanized APOE (hAPOE) is a key strategy to advance translational validity. To initially address translational validity of the hAPOE mouse model, we conducted ex-vivo magnetic resonance imaging analysis of brain volumes in male and female mice across APOE genotypes (ε3/ε3, ε3/ε4, ε4/ε4) and ages corresponding to a human lifespan of approximately 30-70 years (6-25 months in mice). The primary outcomes indicated that total MRI brain volume increased with age (an average of 2.12mm3 per month), irrespective of sex or APOE genotype. Additionally, APOE-ε4 carriers had greater total brain volumes than non-carriers. No sex differences were observed in total brain volume. Voxelwise analyses revealed a pattern of localized morphometric changes independent of differences in total brain volume. Age-related volumetric increases were distributed across subcortical regions (e.g., thalami, hippocampi), while age-related decreases were evident across cortical regions, notably the bilateral parieto-temporal and frontal lobes. Additionally, sex differences were evident after controlling for total brain volume, with females showing greater cortex-dominant volumes while males showed a pattern of greater volumes in regions including cerebellar cortices, olfactory bulbs, and striata. No genotypic effects were observed in the voxelwise analysis after correcting for multiple comparisons, suggesting that APOE genotype does not drive localized volume differences independent of total brain volume. These findings indicate that, at the MRI level of analysis, this humanized APOE mouse model does not recapitulate the volumetric atrophy typically seen in human brain aging and Alzheimer's disease. The results suggest that humanized APOE alone is insufficient to induce the LOAD atrophy phenotype. This model may better serve as a platform for studying vulnerable aging rather than a primary model for progressive neurodegenerative atrophy.},
}

@article {pmid41280115,
year = {2025},
author = {Bartman, S and Hunter, D and Gaspar, L and Tobias-Wallingford, H and Zamor, D and Sinclair, DA and Coppotelli, G and Ross, JM},
title = {DNA Break-Induced Epigenetic Alterations Promote Plaque Formation and Behavioral Deficits in an Alzheimer's Disease Mouse Model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.21.683739},
pmid = {41280115},
issn = {2692-8205},
abstract = {The dramatic increase in human longevity over recent decades has contributed to a rising prevalence of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). While accumulating evidence implicates DNA damage and epigenetic alterations in the pathogenesis of AD, their precise mechanistic role remains unclear. To address this, we developed a novel mouse model, DICE (Dementia from Inducible Changes to the Epigenome), by crossing the APP/PSEN1 (APP/PS1) transgenic AD model with the ICE (Inducible Changes to the Epigenome) model, which allows for the controlled induction of double-strand DNA breaks (DSBs) to stimulate aging-related epigenetic drift. We hypothesized that DNA damage induced epigenetic alterations could influence the onset and progression of AD pathology. After experiencing DNA damage for four weeks, DICE mice, together with control, ICE, and APP/PS1 mice, were allowed to recover for six weeks before undergoing a battery of behavioral assessments including the open-field test, light/dark preference test, elevated plus maze, Y-maze, Barnes maze, social interaction, acoustic startle, and pre-pulse inhibition (PPI). Molecular and histological analyses were then performed to assess Aβ pathology and neuroinflammatory markers. Our findings reveal that DNA damage-induced epigenetic changes significantly affect cognitive behavior and alters Aβ plaque morphology and neuroinflammation as early as six months of age. These results provide the first direct evidence that DNA damage can modulate amyloid pathology in a genetically susceptible AD model. Future studies will be aimed at investigating DNA damage- induced epigenetic remodeling across additional models of AD and neurodegeneration to further elucidate its role in brain aging and disease progression.},
}

@article {pmid41280080,
year = {2025},
author = {Karat, BG and Farahani, MV and Davidson, M and Thurairajah, A and Taha, A and Schmitz, TW and Khan, AR and , },
title = {Hippocampal grey matter changes across scales in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.15.682705},
pmid = {41280080},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disease of the central nervous system, characterized by deterioration in cognitive function including extensive memory impairment. The hippocampus, a medial temporal lobe region, is a key orchestrator in the encoding and retrieval of memory and is believed to be one of the first regions to deteriorate in AD. In this work we examined hippocampal macrostructure (specifically gyrification and thickness) and microstructure in Alzheimer's disease (AD) and mild cognitive impairment (MCI) relative to healthy aged controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We first utilized an iterative training paradigm to adapt an existing deep learning approach for capturing hippocampal topology to elderly individuals as well as individuals with potential hippocampal degeneration. Using this new model, we found notable decreases in both thickness and gyrification in AD and MCI across both the subfields and anterior-posterior axis. Using the diffusion tensor representation derived from diffusion MRI data, we found significant increases in the mean diffusivity across the extent of the hippocampus in AD and MCI, which may be related to a number of changes such as loss of neuronal cells, decreased fiber density, demyelination, and increased presence of CSF. Examining the primary direction of diffusion relative to canonical hippocampal axes, we found distinct diffusion orientation shifts in AD and MCI throughout the anterior-posterior extent of the subiculum and CA1. Specifically, we found a decrease in diffusion oriented tangentially, and an increase in diffusion oriented along the long-axis. This could potentially be related to the known degeneration of the perforant path, which is greatly affected in AD and is a largely tangential oriented pathway. The AD-related changes in diffusion orientations were found to not have significant spatial overlap with AD-related changes in mean diffusivity, suggesting that they may be capturing distinct spatially-localized disease processes. Finally, we showed that the macro- and microstructure of the hippocampus in AD changed less across age relative to MCI and controls. As well, the age-related hippocampal macrostructure changes in MCI appeared indistinguishable from healthy aging.},
}

@article {pmid41280078,
year = {2025},
author = {Koplik, SE and Yu, AM and Shelby, MR and Fonseca, GC and Roco, CM and Zhang, Y and Bogard, N and Sabo, AK and Rosenberg, AB and Linder, J and Seelig, G},
title = {Massively parallel assay of human splice variants reveals cis-regulatory drivers of disease-associated and cell type-specific splicing regulation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.12.681955},
pmid = {41280078},
issn = {2692-8205},
abstract = {Splice-disrupting variants (SDVs) underlie many human diseases, yet systematic functional maps of their effects across cell types remain limited. We developed Cell-type Oriented Massively Parallel reporter Assay of Splicing Signatures (COMPASS) to measure splicing outcomes for 87,546 single and double variants across more than 1,700 genes in five human cell lines of diverse tissue origin. COMPASS targets disease relevant gene sets, including ACMG actionable genes and SFARI autism-associated genes, enabling systematic dissection of splicing impacts in health and disease. Our measurements reveal numerous SDVs, including ClinVar variants currently classified as variants of uncertain significance. Using prime editing, we validate variant effects in the genome for ClinVar variants in BIN1 , a gene implicated in Alzheimer's disease, cancer, and cardiac pathology. Benchmarking our MPRA against state-of-the-art predictive models shows that while these approaches capture broad variant effects, important gaps remain. Our data reveal putative RNA-binding protein motifs whose disruption drives splicing changes, providing mechanistic insight into variant impact. Finally, cross-cell line comparisons reveal a distinct subset of variants that drive cell type-specific splicing programs. This study delivers the largest cell type-resolved, base-resolution atlas of splicing variant effects to date, providing a resource to support variant reclassification in clinical genomics and aid in the selection of therapeutic targets.},
}

@article {pmid41280070,
year = {2025},
author = {Shin, K and Brown, W and Tian, Y and Gopinath, T and Bobkov, AA and Marinelli, F and Marassi, FM},
title = {Structural basis for lipid binding by the blood protein vitronectin, a component of HDL.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.01.685992},
pmid = {41280070},
issn = {2692-8205},
abstract = {Vitronectin (Vn) is a multifunctional blood glycoprotein involved in cell adhesion and migration, blood coagulation, and inflammation. It is a component of the high-density lipoprotein (HDL) proteome, and often found associated with the calcified, lipid-rich, protein deposits that are a hallmark of age-related macular degeneration, Alzheimer's disease, atherosclerosis and other aging-related diseases. Here we explored the molecular basis for lipid binding by Vn using isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR) and all-atom molecular dynamics (MD) simulations. The data reveal a hydrophobic groove on the surface of the hemopexin-like (HX) domain of Vn, that is capable of binding phosphatidylcholine (PC). Conformational landscape analyses of multiple, independent MD simulations identify key structural motifs and intermolecular contacts mediating the association of Vn with PC, and show that lipid binding is guided by interactions with positively charged and hydrophobic residues that organize the lipids in a tail-to-tail bilayer-like arrangement within the groove. Collectively, the data establish a comprehensive structural model for Vn association with HDL and provide mechanistic insight into its accumulation within lipid-rich deposits characteristic of age-related pathologies.},
}

@article {pmid41280056,
year = {2025},
author = {McNeme, S and Kumar, A and Yim, YY and Hughes, BW and St Romain, C and Li, Y and Kumar, A and Bao, Q and Estill, M and Fan, S and Takatka, N and Chen, EP and Rivera, M and Chen, H and Robison, AJ and Machius, M and Haggarty, SJ and Chin, J and Nestler, EJ and Zhou, J and Rudenko, G},
title = {Efficient in vivo pharmacological inhibition of ΔFOSB, an AP1 transcription factor, in brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.21.683721},
pmid = {41280056},
issn = {2692-8205},
abstract = {UNLABELLED: ΔFOSB, an unusually stable member of the AP1 family of transcription factors, mediates long-term maladaptations that play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesias, and several other chronic neurological and psychiatric conditions. We have recently identified that 2-phenoxybenzenesulfonic acid-containing compounds disrupt the binding of ΔFOSB to DNA in vitro in cell-based assays, and one such compound, JPC0661, disrupts ΔFOSB binding to genomic DNA in vivo in mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the ΔFOSB/JUND bZIP heterodimer in the co-crystal structure. Here, we generated a panel of analogs of JPC0661 with the goal of establishing structure-activity relationships and improving its in vivo efficacy by replacing the amino-pyrazolone cap moiety with various substituents. We show that one such analog, YL0441, disrupts the binding of ΔFOSB to DNA in vitro and in vivo , and suppresses ΔFOSB-function in cell-based assays. Importantly, infusion of YL0441 into the hippocampus of APP mice (a mouse model for Alzheimer's disease) leads to virtually complete loss of ΔFOSB bound to genomic DNA by CUT&RUN sequencing. Our findings corroborate that DNA binding/release of AP1 transcription factors can be controlled via small molecules, even by analogs of a compound that binds to a groove outside of the DNA-binding cleft, and that our lead can be optimized via medicinal chemistry to yield a highly efficacious inhibitor of ΔFOSB function in vivo . These findings define a strategy to design small-molecule inhibitors for other AP1- and AP1-related transcription factors.

IN BRIEF: We demonstrate the creation of a highly effective inhibitor, YL0441, of ΔFOSB, an AP1 transcription factor, which decreases the number of ΔFOSB-bound sites to genomic DNA by ∼94% upon in vivo infusion to the hippocampus of APP mice, a mouse model for Alzheimer's disease. This work generates a highly novel probe compound to assess the therapeutic value of ΔFOSB in vivo , a transcription factor with a critical role in mediating long-term changes in gene expression in several neuropsychiatric disorders in addition to Alzheimer's disease, including drug addiction, seizure-related cognitive decline, and dyskinesias.},
}

@article {pmid41280038,
year = {2025},
author = {Terzioglu, G and Karp, ES and Heuer, SE and Haage, VC and De Jager, PL and Young-Pearse, TL},
title = {INPP5D/SHIP1 is a dual regulator of endo-lysosome function and selective phagocytosis in human microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.27.684632},
pmid = {41280038},
issn = {2692-8205},
abstract = {INPP5D, the gene encoding SHIP1, is genetically associated with Alzheimer's disease (AD) risk and plays a central role in regulating immune function. Here, we aimed to elucidate the mechanism by which SHIP1 mediates its role in suppressing inflammatory pathways, with a focus on human microglia. Our findings illuminate an essential role for SHIP1 in endosome maturation and lysosomal function. We show that SHIP1 localizes to both the plasma membrane and to endo-lysosomal compartments and binds to the CapZ family of proteins, which are important for endosome maturation. Reduction of SHIP1 levels via genome editing impairs endosome maturation and lysosomal function, leading to lipid droplet accumulation and leakage of lysosomal cathepsin B into the cytosol, which in turn activates the NLRP3 inflammasome. CITE-seq profiling of SHIP1-deficient microglia revealed a shift from an immune-responsive state toward a DAM-like, phagocytic state, accompanied by impaired response to LPS and enhanced phagocytosis of synaptic material and apoptotic neurons via TREM2. While amyloid-β uptake was not affected, amyloid-β accumulated intracellularly due to defective lysosomal degradation, further driving lipid droplet formation. Together, these results identify SHIP1 as a regulator of endo-lysosomal function and selective phagocytosis of lipid-rich substrates in microglia. These findings have important implications for therapeutic hypotheses that target SHIP1 for treatment of AD, autoimmune diseases, and cancer.},
}

@article {pmid41279998,
year = {2025},
author = {Kostylev, MA and Butan, C and Roseman, GP and Liu, Y and Gopal, P and Strittmatter, SM},
title = {Distinct Filament Conformation for Receptor-Bound Amyloid-ß from Alzheimer's Disease Brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41279998},
issn = {2692-8205},
abstract = {Alzheimer's disease is triggered by amyloid-ß, with symptoms linked to synapse loss. Oligomeric amyloid-ß, rather than monomeric or fibrillar amyloid-ß, has been proposed to be the proximate mechanistic cause, but the relevant molecular characteristics have remained unclear. Here, we define a distinct receptor-bound amyloid-ß pool in Alzheimer's brain by release with a receptor antagonist and purification to homogeneity. Receptor-bound amyloid-ß is ten times more abundant than free unbound amyloid-ß. The amyloid-ß associated with receptor is composed of 65 nm long filaments with prion protein binding at its tips. There is no evidence for an oligomeric Aß state interacting with human brain receptors. Cryo-electron microscopy shows two symmetric S-shaped monomers per filament rung. The tilt between rung monomers, twist along the filament axis, amino terminal conformation and amyloid seeding properties distinguish this structure from plaque-associated amyloid-ß filaments of the same brain. High tip:length ratio is critical for prion protein receptor interaction and synaptic damage. Characterizing receptor-bound amyloid-ß filament provides insight into neuronal dysfunction separate from plaque aggregation.},
}

@article {pmid41279986,
year = {2025},
author = {Hensen, T and Khatib, L and Patel, L and McDonald, D and González, A and MahmoudianDehkordi, S and Blach, C and , and Knight, R and Kaddurah-Daouk, R and Thiele, I},
title = {Personalised whole-body modelling links gut microbiota to metabolic perturbations in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.28.685084},
pmid = {41279986},
issn = {2692-8205},
abstract = {The human gut microbiome has been linked to metabolic disturbances in Alzheimer's disease (AD). However, the mechanisms by which gut microbes might influence metabolic dysfunction in AD remain poorly understood. Previously, we used constraint-based metabolic modelling to associate an increased risk of AD with altered production of microbiome-derived metabolites. In this study, we investigated whether these previous results can also be identified in AD patients. Therefore, we created personalised whole-body metabolic models from gut metagenomics samples from 34 AD dementia patients, 51 individuals with mild cognitive impairments, and 298 healthy controls. These in silico models were profiled to predict the metabolic influences of gut microbiomes on blood metabolites with previously reported alterations in AD. We found an increased capacity of AD host-microbiome co-metabolism to produce S-adenosyl-L-methionine, L-arginine, creatine, taurine, and formate in the blood of AD dementia patients and patients with mild cognitive impairments. The metabolic predictions were then mechanistically linked to gut microbial changes in AD. This analysis identified that increased relative abundances of Bacteroides uniformis and Bacteroides thetaiotamicron were key factors driving the predicted metabolic changes. Furthermore, the predicted altered microbial influences on blood metabolites were also associated with allelic variations in the APOE risk gene in healthy individuals, which confirmed our previous findings. In conclusion, we identified blood metabolites whose perturbations in AD may be influenced by gut microbiota and predicted the key microbial drivers for these metabolic influences. These findings may facilitate the development of microbiome-informed treatments of AD.},
}

@article {pmid41279926,
year = {2025},
author = {Ishida-Takaku, T and Combs, CK},
title = {Exploring Proteomic Differences in PBMCs for Sex-Specific Insights into Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.31.685960},
pmid = {41279926},
issn = {2692-8205},
abstract = {Peripheral blood mononuclear cells (PBMCs) offer a minimally invasive window into systemic biology and immune dysregulation in Alzheimer's disease (AD). We performed quantitative proteomic profiling of PBMCs from male and female AD patients and controls to assess sex differences. AD was associated with proteomic remodeling, with complement activation, coagulation, and neuronal signaling enriched in males, whereas females showed increased steroid hormone secretion, lipid metabolism, and acute-phase response with reduced translation and DNA maintenance. Despite distinct patterns, both sexes exhibited immune and hemostatic activation, underscoring shared systemic mechanisms and the need for sex-specific biomarkers and therapeutic strategies in AD.},
}

@article {pmid41279882,
year = {2025},
author = {Tang, R and Yin, J and Weinberg, B and Lin, H and Lu, J and Gate, D and Klementieva, O and Cheng, JX},
title = {Mid-Infrared Photothermal Mesoscopy with Millimeter Field of View and Sub-micron Spatial Resolution.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.03.686410},
pmid = {41279882},
issn = {2692-8205},
abstract = {By optically sensing mid-infrared absorption through a visible probe beam, mid-infrared photothermal (MIP) microscopy has emerged as a powerful tool for chemical imaging with micromolar sensitivity and submicron spatial resolution. The adoption of spatially multiplexed camera-based widefield detection further enhanced the imaging speed. However, current widefield MIP systems suffer from a small field of view (FOV)-typically tens of square micrometers, which constrains their utility in large-area tissue imaging applications. Here, we report a laser-scan MIP mesoscope that achieves millimeter-scale FOV while preserving submicron resolution. By leveraging an all-reflective laser scanning architecture, low-magnification and medium numerical-aperture objectives, and a defocused signal collection scheme, our MIP mesoscope achieves a 1.2 × 1.2 mm [2] FOV, 650 nm lateral resolution, and microsecond-scale pixel dwell time. In vivo chemical imaging of whole Caenorhabditis elegans and high-throughput detection of beta-amyloids in both mouse and human brain tissues associated with Alzheimer's disease are demonstrated.},
}

@article {pmid41279801,
year = {2025},
author = {Markov, Y and Priyanka, A and Xu, L and Wang, W and Thrush-Evensen, K and Gonzalez, J and Borrus, D and Kasamoto, J and Sehgal, R and Zou, G and Fraij, J and Carlyle, BC and Horvath, S and Bennett, DA and Zhao, H and van Dyck, CH and Lam, TT and Levine, ME and Higgins-Chen, AT},
title = {Beyond the Genotype: A Multi-Omic Analysis of APOEe4's Role in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.16.682426},
pmid = {41279801},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is characterized by widespread molecular dysregulation, with the APOEe4 allele recognized as its strongest genetic risk factor. However, the mechanisms by which APOEe4 drives distinct molecular changes - whether by exacerbating pathology or triggering compensatory responses - remain incompletely understood. We generated and analyzed proteomic, epigenetic, and genetic data from post-mortem dorsolateral prefrontal cortex samples of a uniquely APOEe4-enriched subset of the Religious Orders Study and Memory and Aging Project (ROSMAP). Specifically, we generated DIA LC-MS proteomic data (n = 302), analyzed previously generated DNA methylation profiles from our group (n = 310), and used published whole-genome sequencing data (n = 254) to compute polygenic risk scores (PRS). In this cohort, 69% (n = 214) were APOEe4 carriers, and 19.6% (n = 42) of them showed no pathological evidence of AD based on NIA-Reagan criteria, enabling identification of APOEe4-related risk and resilience mechanisms. In the absence of AD, APOEe4 carriers exhibited lower levels of 27 proteins, suggesting early synaptic (e.g., VAMP1, SYN3, CASKIN1) and metabolic (e.g., GLUD1, PI4KA) vulnerability. By contrast, APOEe4 carriers with AD displayed marked upregulation of inflammatory and proteostatic proteins (e.g., GNAO1, AHNAK, FGG, HEBP1, APEX1, RAB4A, SLC12A5, LRP1, BAG6) and hypermethylation of cg06329447 in ELAVL4. Network analyses highlighted convergent disruptions in synaptic transmission, metabolism, and proteostasis - key pathways altered in APOEe4-associated AD. Mediation analyses identified GRIPAP1 and GSTK1 as top protein mediators (accounting for ∼26-33% of APOEe4's effect), with VAMP1, CASKIN1, DPP3, SYN3, and FGG each contributing ∼9-15%. ELAVL4 hypermethylation also mediated ∼12% of the APOEe4 effect, linking epigenetic dysregulation to disease risk. To assess whether the identified proteins reflected broader genetic risk for AD or were specific to APOEe4, we calculated PRS both excluding and including the APOE genomic region. While the non-APOE PRS showed no association with identified molecular markers, the APOE-inclusive PRS was significantly associated with eight AD-related proteins in carriers, indicating they are not explained by polygenic risk outside of APOE. Finally, predictive modeling stratified by APOEe4 status revealed that in non-carriers, PRS most effectively classified AD (AUC = 0.73), whereas in carriers, proteomic and epigenetic markers outperformed PRS (AUC up to 0.74). Together, these findings demonstrate that APOEe4 confers AD risk through early synaptic and metabolic disruptions and later-stage inflammatory and epigenetic changes, laying the groundwork for genotype-tailored biomarker development and therapeutic strategies.},
}

@article {pmid41279783,
year = {2025},
author = {Soto-Faguás, CM and O'Niel, A and Mueller, PA and Sanchez-Molina, P and Woltjer, RL and Raber, J and Unni, VK},
title = {The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.05.686857},
pmid = {41279783},
issn = {2692-8205},
abstract = {Apolipoprotein E (APOE) genotype is well known to influence both amyloid-β (Aβ) and tau pathologies and risk for Alzheimer's disease (AD), but it also affects α-synuclein (α-syn) levels, Lewy pathology and risk of dementia in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The APOE-R136S (Christchurch, CC) point mutation has been shown to protect against AD pathology and dementia, however, the molecular mechanisms underlying this protection and its effects on α-syn pathology are not well understood. Using CRISPR/Cas9 technology, we created a CC arginine-to-serine point mutation at the conserved location in mouse APOE (R128S) to understand its effects on Aβ, tau and α-syn pathologies. We crossed these APOE CC mice to 5xFAD, PS19 and A53T-αSyn-GFP (A53T) mice. Using these various double mutant mice, we tested the effect of mouse APOE CC on different proteinopathies, including Aβ, tau, Aβ-induced tau after paired helical filament (PHF)-tau intracortical injections, and α-syn after preformed fibril (PFF) intracortical and intramuscular injections. We used immunohistochemical, biochemical and behavioral measures to test for protective effects of APOE CC on these different proteinopathies. Heterozygous (Het) and homozygous (Hom) APOE CC mice showed increased plasma cholesterol and triglyceride levels, as seen in humans, but no differences in body or brain weight, or life expectancy. APOE CC decreased Aβ-induced tau pathologies in PHF-tau injected 5xFAD;Hom mice but did not change Aβ-plaque pathology in 5xFAD mice or tau pathology in PS19 mice. Although Aβ levels, tau levels and mouse sex correlated strongly with the behavioral performance, we only detected subtle effects of APOE CC on anxiety-like behaviors in crosses with 5xFAD, PS19 and PHF-tau injected 5xFAD mice. Interestingly, Het and Hom APOE CC mice both showed reduced formation and spread of Lewy pathology in brain after intracortical α-syn PFF injection and reduced formation in spinal cord after α-syn PFF injection into the hindlimb gastrocnemius muscle in A53T mice. Our study emphasizes the protective effects of the APOE CC variant against different proteinopathies important for dementia and movement disorders, including Aβ plaque, tau and α-syn, and suggests that targeting APOE CC could provide new therapeutic strategies for AD, DLB and PD.},
}

@article {pmid41279774,
year = {2025},
author = {Yang, W and Watkins, KL and DeCasien, AR and O'Neill, MB and Bohlen, MO and O'Day, DR and Duran, M and Qiu, C and Meleshko, A and Vo, A and Menke, M and Calderon, D and , and Sallet, J and Higham, JP and Martínez, MI and Trapnell, C and Starita, LM and Montague, MJ and Platt, ML and Chiou, KL and Shendure, J and Snyder-Mackler, N},
title = {Single-cell, multi-region profiling of the macaque brain across the lifespan.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.31.685880},
pmid = {41279774},
issn = {2692-8205},
abstract = {Brain aging is a complex process with profound health and societal consequences. However, the molecular and cellular pathways that govern its temporal progression-along with any cell type-, region-, and sex-specific heterogeneity in such progression-remain poorly defined. Here, we present a transcriptomic atlas of 5.3 million cells from 582 samples spanning 11 brain regions of 55 rhesus macaques (29 female, 26 male), aged 5 months (early life) to 21 years (late adulthood). We annotate 12 major cell classes and 225 subclusters, including region-specific subtypes of excitatory and inhibitory neurons, astrocytes, and ependymal cells. We identify a vulnerable excitatory neuron population in the superficial cortical lamina and a cortical interneuron population that are less abundant later in life, along with subtle, region-specific, age-associated compositional differences in subpopulations of microglia and oligodendrocytes, whose detection required single-cell resolution. Finally, we chart convergent and divergent age-associated molecular signatures across brain regions and cell classes-where some of these signatures are sex-specific and could underlie sex biases in neurological disorders. We find that age-associated transcriptional programs not only overlap substantially with those seen in Alzheimer's disease (AD), but also unfold along distinct temporal trajectories across brain regions, suggesting that aging and AD may share molecular roots that emerge at different life stages and in region-specific, sex-specific windows of vulnerability. This work provides a temporal, regional, and sex-stratified atlas of the aging primate brain, offering insights into cell type-specific vulnerabilities and regional heterogeneity with translational human relevance.},
}

@article {pmid41279762,
year = {2025},
author = {Onos, KD and Marola, O and Uyar, A and Chie, JAKHC and Kanyinda, J and Persohn, SC and Eldridge, K and Elk, K and Walker, AE and Carter, GW and Sasner, MJ and Territo, PR and Howell, G},
title = {WSB.APP/PS1 mice develop age-dependent cerebral amyloid angiopathy, cerebrovascular deficits, and white matter damage, which are modified by humanized APOE alleles.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.08.681261},
pmid = {41279762},
issn = {2692-8205},
abstract = {Vascular contributions are now widely accepted to play a key role in many cases of dementia, including Alzheimers disease (AD), that commonly manifest as cerebral small vessel diseases, including cerebral amyloid angiopathy (CAA). However, the mechanisms by which vascular contributions such as CAA contribute dementias such as AD are not well understood. This is due in part to the lack mouse models that develop robust CAA, hampering our ability to develop therapies that target vascular deficits. To address this, we have explored the use of distinct genetic contexts to enhance the face validity of mouse models for AD. We have previously identified the WSB/EiJ (WSB) strain as a model that shows increased susceptibility to CAA in the presence of the APP/PS1 amyloid driver, compared to the commonly used C57BL/6J (B6) strain. Here, we now perform an in-depth characterization of WSB.APP/PS1 and its WSB wild type (WT) counterpart, assessing male and female mice, at 4, 8, and 12 months of age (M). We show that WSB.APP/PS1 mice show mild CAA at 8M, with robust CAA being apparent at 14M. Transcriptional profiling showed strong correlation to AMP-AD gene expression modules highlighting the human relevance of WSB.APP/PS1 mice and predicted white matter deficits at 14M that was confirmed by immunofluorescence. PET/CT showed blood flow and metabolic deficits, and modifications in small vessel morphology in 8M WSB.APP/PS1 compared to WSB WT mice. We tested whether cerebrovascular reactivity deficits in WSB WT mice may underly the susceptibility to CAA, but interestingly, they did not show age-dependent decline in reactivity that was observed in B6 mice. Finally, using an allelic series of humanized apolipoprotein E (APOE), we show that APOE4 increased the extent of CAA in WSB.APP/PS1 mice, compared to APOE2 and APOE3, but in a sex-dependent manner. Collectively, these data show the utility of the WSB strain to uncover mechanisms of vascular contributions to Alzheimers disease and related dementias.},
}

@article {pmid41279752,
year = {2025},
author = {Mandal, P and Trushina, E and Arnold, M and Kaddurah-Daouk, R and Baloni, P},
title = {Mitochondrial bioenergetic signatures differentiate asymptomatic from symptomatic Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.04.686626},
pmid = {41279752},
issn = {2692-8205},
abstract = {Asymptomatic Alzheimer's disease (AsymAD) refers to individuals who, despite exhibiting amyloid-β plaques and tau pathology comparable to Alzheimer's disease (AD), maintain cognitive performance similar to cognitively normal individuals. The resilience mechanism in these AsymAD individual remains understudied. We performed a systematic analysis comparing AsymAD and AD across multiple cohorts (ROSMAP, Banner and Mount Sinai), brain regions (BA6, BA9, BA36 and BA37) and neuronal and glial cell types using proteomics and transcriptomics data. AsymAD brains exhibited preserved mitochondrial bioenergetics, characterized by enhanced oxidative phosphorylation (OXPHOS), electron transport chain (ETC) activity, fatty acid and lipid metabolism, and branched-chain amino acid (BCAA) utilization. Pathways regulating mitochondrial complex biogenesis and calcium homeostasis were also upregulated. Key mitochondrial proteins such as MRPL47, CPT2, BCAT2, and IDH2, were consistently upregulated in AsymAD, whereas MACROD1 was downregulated. At the cellular level, excitatory neurons, including superficial, mid-layer, and deep-layer subtypes, exhibited the most preserved mitochondrial function, whereas vulnerable inhibitory subtypes, including PVALB and SST neurons, showed increased cellular abundance and bioenergetic activity. In contrast, microglia and oligodendrocytes proportions were reduced in AsymAD relative to AD. Our findings identify preserved mitochondrial bioenergetics as a defining feature of resilience in AD and suggest that enhancing NADH metabolism via NAD+ precursor-based interventions may potentially help in maintaining cognitive function despite amyloid and tau pathology.},
}

@article {pmid41279751,
year = {2025},
author = {Garza, IT and Snyder, B and Holmes, SK and Pearce, KM and Knight, K and Bailey, RM},
title = {Preclinical Development of a Vectorized Artificial miRNA Gene Therapy for Tauopathies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.12.681935},
pmid = {41279751},
issn = {2692-8205},
abstract = {Tauopathies, including Alzheimer's disease, are neurodegenerative disorders characterized by the accumulation of microtubule-associated protein tau, which is closely linked to cognitive decline. Reduction of tau is a potential and promising strategy for addressing tau-linked brain disorders. We report the development of a therapeutic approach using adeno-associated virus mediated delivery of an artificial microRNA targeting human tau. In a tauopathy mouse model, we demonstrate that a one-time intra-cisterna magna administration of vector resulted in reduced total tau, decreased pathological tau seeds, fewer tau inclusions, and amelioration of tau-related neuropathology. Notably, intervention at late disease stages, after onset of tau deposition and neurodegeneration, improved quality of life and extended survival. We further demonstrated the durability of therapeutic benefit and defined the minimally effective dose in tauopathy mice. These findings provide preclinical support for the advancement of a vectorized tau-lowering strategy as a disease-modifying approach for tauopathies and enable progression towards an investigational new drug application.},
}

@article {pmid41279729,
year = {2025},
author = {Sherman, E and Qiu, K and Roberts, R and Shichman, L and Li, S and Sun, H and Ide, L and Tucker, A and Lee, S and Gniadzik, W and Shin, JB and Sol-Church, K and Kapur, J and Zhang, A and Erisir, A and Jiang, L and , },
title = {Modeling Alzheimer's Disease with APOE4 Neuron-Glial Brain Assembloids Reveals IGFBPs as Therapeutic Targets.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.17.683162},
pmid = {41279729},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease (AD) research has been hindered by the lack of models that faithfully recapitulate the full profile of disease progression in a human genetic background. We developed a 3D assembloid model ("Masteroid") using iPSC-derived neurons, astrocytes, and microglia from APOE4/4 and isogenic control lines. Neurons were seeded with tau oligomers, then combined with astrocytes and microglia to form mature 3D Masteroids, followed by amyloid-β oligomer exposure. After four weeks, AD-Masteroids exhibited hallmark pathologies, including extracellular amyloid-β deposits, intracellular tau aggregation, neurodegeneration, astrogliosis, and microglial activation, with APOE4 exacerbating all phenotypes. Single-cell RNA sequencing further identified novel roles of IGFBP pathways in amyloid-β and tau-mediated pathology. This innovative platform provides a robust system to dissect cellular and molecular mechanisms of AD progression and offers a powerful tool for therapeutic discovery.

HIGHLIGHTS: The 3D human neuron-glia assembloid ("Masteroid"), composed of neurons, astrocytes, microglia, and oligodendrocytes, faithfully recapitulates human brain ultrastructure and intercellular interactions.Exposure to oligomeric tau and Aβ induced hallmark Alzheimer's pathologies, including amyloid deposition, tau aggregation, neurodegeneration, and gliosis.The APOE4 genotype exacerbated all pathological features, highlighting its role in driving multicellular interactions that accelerate disease progression.The IGF signaling axis was identified as a key mediator of Aβ- and tau-induced pathology and a potential therapeutic target.},
}

@article {pmid41279711,
year = {2025},
author = {James, EI and Saunders, M and Lee, KK and Guttman, M and Nath, A},
title = {Tau4RD fibril polymorphism is imprinted during early aggregation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41279711},
issn = {2692-8205},
abstract = {Microtubule-associated protein tau forms characteristic fibrillar species in many neurodegenerative diseases. Neurofibrillary tangles, tau deposits observed in Alzheimer's disease (AD), contain a mixture of amyloid-type polymorphic fibrils called paired helical filaments (PHFs) and straight filaments. The formation of heterogenous fibril populations is observed in other diseases and when tau aggregation is induced in vitro with polyanionic species. This suggests that tau's structural transition from a conformational ensemble to various amyloid morphologies is a controlled and, therefore, controllable process. Despite many years of work toward describing aggregation intermediates that could address open questions such as whether fibril polymorphism is imprinted at the start of aggregation or arises due to conformational conversions, our understanding of amyloid structure remains predominantly based on observations of mature fibrils. It is unclear whether these processes are mutually exclusive and to what extent we can bias intermediate conformations toward less toxic states. Here to address the challenge of studying aggregation intermediates and tau's structural conversion, we apply pulsed hydrogen-deuterium exchange with mass spectrometry (pulsed HDX-MS), which revealed differences in the subpopulations formed by tau4RD (a truncated tau construct) within seconds of initiating aggregation with polyphosphate and within hours of heparin-induction. This work begins to address the gap in knowledge regarding whether amyloid polymorphism is directly imprinted during nucleation or results from structural rearrangement during later stages of aggregation.},
}

@article {pmid41279691,
year = {2025},
author = {Liu, X and Luo, L and Pritschet, L and Mao, Y and Han, F and Proctor, DN and Liu, X},
title = {Early menopause is associated with reduced global brain activity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.10.681622},
pmid = {41279691},
issn = {2692-8205},
abstract = {Menopause affects the aging process in women through significant ovarian hormone production decline in midlife. Women who experience early menopause face an accelerated physiological aging rate, along with impaired memory and increased risks of neurodegenerative diseases. However, it remains elusive how the timing of menopause affects brain activity, which could be crucial for understanding menopause-related acceleration of aging and increased risk of dementia. Recent studies have revealed a highly structured infra-slow (< 0.1 Hz) global brain activity across species and linked it to arousal and memory functions, as well as waste clearance in Alzheimer's diseases (AD). In this study, we examined how this global brain activity relates to age of menopause using resting-state fMRI data from the Human Connectome Project-Aging dataset. We found that women who experienced earlier menopause (mean menopausal age 45±3.5 yr) exhibited weaker global brain activity (p = 5.0 × 10 [-4]) with reduced coupling to cerebrospinal fluid (CSF) flow (p = 0.017) compared to age-matched later-menopausal women (mean menopausal age 54±1.2 yr). Differences appeared mainly in higher-order brain regions, where activation levels correlated with memory performance in earlier but not in intermediate or later menopausal women. These findings highlight brain activity changes linked to early menopause, suggesting a potential mechanism underlying memory decline and the increased risk of AD and dementias in early-onset menopausal women.},
}

@article {pmid41279689,
year = {2025},
author = {Schurman, CA and Kaur, G and Kaya, S and Bons, J and Aguirre, CG and Liu, Q and King, CD and Wilson, KA and Baker, HL and Hady, M and Luna, NM and Bieri, G and Villeda, SA and Ellerby, LM and Schilling, B and Alliston, T},
title = {Alzheimer's disease risk factor APOE4 exerts dimorphic effects on female bone.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.16.682922},
pmid = {41279689},
issn = {2692-8205},
abstract = {Individuals diagnosed with Alzheimer's disease (AD) are at an increased risk of bone fractures. Conversely, a diagnosis of osteoporosis in women is the earliest known predictor for AD. However, mechanisms responsible for the coupled decline in cognitive and skeletal health remain unclear. Proteomic analysis of cortical bone from aged mice revealed neurological disease-associated proteins that are highly enriched in aged mouse bones, including apolipoprotein E (Apoe) and amyloid precursor protein. Further, Apoe localized specifically to bone-embedded osteocytes with expression twice as high in aged female bone as in young or male counterparts. In humans, APOE allele variants carry differing AD risk with age. To investigate APOE allelic roles in bone, we utilized a humanized APOE knock-in mouse model that expresses either the protective APOE2, the neutral APOE3, or the AD risk factor APOE4, and analyzed bone and hippocampus from the same mice. APOE4 exerted strong sex-specific effects on the bone transcriptome and proteome, relative to APOE2 or APOE3. Interestingly, the APOE4-associated perturbation in the female bone proteome was more pronounced than the corresponding alterations observed in the hippocampus. APOE4 protein causes bone fragility in females, but not males, even without changes in cortical bone structure. These bone quality deficits arose from suppression of osteocyte perilacunocanalicular remodeling. We find that APOE4 is a new molecular culprit capable of disrupting osteocyte maintenance of bone quality as early as midlife in a manner that disproportionately affects females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment, and treatment for bone fragility, in females.},
}

@article {pmid41279643,
year = {2025},
author = {Yu, D and Germann, J and Murtaza, G and Hajdarovic, KH and Babcock, KR and Dehkordi, SK and Jackson, AC and Delalle, I and Orr, ME and Zare, H and Singh, R and Noble, WS and Vlassenko, AG and Goyal, MS and Webb, AE},
title = {HypoAD: volumetric and single-cell analysis reveals changes in the human hypothalamus in aging and Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.08.681270},
pmid = {41279643},
issn = {2692-8205},
abstract = {Alterations in metabolism, stress response, sleep, circadian rhythms, and neuroendocrine processes are key features of aging and neurodegeneration. These fundamental processes are regulated by the hypothalamus, yet how its functionally distinct subregions and cell types change during human aging and Alzheimer's Disease (AD) remains largely unexplored. Here, we present HypoAD , a comprehensive atlas of the human hypothalamus in aging and AD, integrating high-resolution MRI from 202 individuals with single-nucleus RNA-seq (snRNA-seq) of 614,403 nuclei from young, AD, and age-matched non-dementia controls. Our analysis reveals that hypothalamic subregions governing metabolism, stress, and circadian rhythms are particularly vulnerable, exhibiting significant changes in both volumes and gene expression during aging and AD. At the molecular level, machine learning models identified the inflammatory response and regulators of circadian rhythms as key cellular predictors of AD. These signatures were reflected in specific cell types: microglia transitioned to a pro-inflammatory state, while inhibitory neurons within sleep-and circadian-regulating hypothalamic subregions showed the most profound transcriptional alterations, including disruptions in ligand-receptor interactions and G-protein-coupled receptor signaling. Together, HypoAD provides a high-resolution volumetric map and a comprehensive transcriptomic atlas of the human hypothalamus in aging and AD, linking lifestyle and behavioral changes to their underlying volumetric and molecular pathways. Additionally, HypoAD provides a framework to investigate hypothalamic dysfunction and establishes a roadmap for targeted interventions aimed at mitigating physiological disruptions to potentially slow disease progression.},
}

@article {pmid41279621,
year = {2025},
author = {Sun, X and Mews, M and Wheeler, NR and Benchek, P and Gu, T and Gomez, L and Ray, N and Reitz, C and Naj, AC and Below, JE and Tosto, G and Cornejo-Olivas, M and Byrd, GS and Feliciano-Astacio, BE and Celis, K and Rajabli, F and Kunkle, BW and Pericak-Vance, MA and Haines, JL and Griswold, AJ and Bush, WS},
title = {Multi-ancestry Transcriptome-Wide Association Study Reveals Shared and Population-Specific Genetic Effects in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.03.686160},
pmid = {41279621},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) risk differs across ancestral populations, yet most genetic studies have focused on Non-Hispanic White (NHW) cohorts. We conducted a multi-population transcriptome-wide association study (TWAS) using whole-blood RNA-seq and genotype data from reported NHW (n=235), African American (AA; n=224), and Hispanic (HISP; n=292) participants in MAGENTA. Using SuShiE for multi-population fine-mapping, we identified credible sets of eQTLs for 8,748 genes and improved fine-mapping precision relative to analyses using fewer populations. eQTL effects were largely shared across populations, with population-specific regulation for a subset of genes. Population-stratified TWAS and sample size-weighted meta-analysis (FUSION + MAFOCUS) prioritized and and fine-mapped nine genes (FDR<0.05, PIP>0.8), including established AD loci (BIN1, PTK2B, DMPK) with consistent effects across populations. Importantly, at BIN1 we fine-mapped regulatory variants associated with gene expression and AD risk beyond the GWAS index SNP-most notably rs11682128, which is only in modest LD with rs6733839 (r^2≈0.34)-demonstrating that multi-population TWAS can implicate additional functional variants not captured by single-SNP GWAS signals. We also discovered a novel association between COG4 expression and AD in NHW, implicating Golgi apparatus function. Using independent SuShiE-derived models from TOPMed MESA (PBMC), several associations replicated directionally across ancestries, with statistical significance most evident in NHW. Our results show that multi-population fine-mapping improves eQTL resolution and TWAS interpretability, reveals regulatory variants beyond GWAS index SNPs, and underscores the need to expand non-European AD cohorts to resolve shared and population-specific mechanisms.},
}

@article {pmid41279564,
year = {2025},
author = {Carey, A and Buzhdygan, T and Fossati, S},
title = {LACK OF OXYGEN AND/OR GLUCOSE DIFFERENTIALLY POTENTIATES Aβ40 E22Q - AND Aβ42-INDUCED CEREBRAL ENDOTHELIAL CELL DEATH, BARRIER DYSFUNCTION AND ANGIOGENESIS IMPAIRMENT.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.05.680546},
pmid = {41279564},
issn = {2692-8205},
abstract = {BACKGROUND: Disrupted brain hemodynamics and cerebrovascular damage resulting in cerebral hypoperfusion occur early within Alzheimer's Disease (AD) pathogenesis. Cerebral hypoperfusion is also an extremely common consequence of cardiovascular risk factors and diseases (CVRFs/CVDs), which usually manifest in midlife, when AD pathology initiates, and actively contribute to AD onset and progression. Previously our lab has demonstrated that the vasculotropic Dutch mutant, AβQ22, and Aβ42 promote endothelial cells (ECs) apoptosis, barrier permeability, and angiogenic impairments. Prior research has indicated that hypoperfusion promotes analogous EC dysfunction. Aβ deposition occurs within a hypoperfused environment in AD, but whether exposure of cerebral ECs to Aβ under hypoperfusion results in potentiated cerebral EC dysfunction through activation of common molecular mechanisms remained unknown.

METHODS: Human cerebral ECs were treated with Aβ40-Q22 or Aβ42, glucose deprivation (GD), or a combination of both, under normoxia or hypoxia conditions. Cell death mechanisms (apoptosis/necrosis), endothelial barrier dysfunction/permeability (TEER/barrier-regulating proteins/proinflammatory activation), and angiogenesis impairment (vessel branching/VEGF signaling) were evaluated.

RESULTS: Reduction of glucose and/or oxygen potentiates Aβ-induced cerebral EC death, barrier instability, junction protein dysregulation, inflammatory activation, and angiogenesis/wound healing failure. In particular, hypoperfusion exacerbates AβQ22-mediated cerebral EC apoptosis, TEER/ZO1 decreases, ICAM1, IL6, and IL8 upregulation, monocyte migration, and wound healing impairments. Differentially, when in combination with Aβ42, hypoperfusion more strongly potentiates cerebral EC necrosis as well as increases in MMP2, phosphorylated claudin-5, IFNγ, and IL12p70 expression. Additionally, this study identified that GD exerts stronger effects on promoting increases in cerebral EC caspase-3 activation, apoptosis, and MMP2/ICAM1 expression, while hypoxia particularly increases necrosis, ZO1 expression, and pro-angiogenic protein expression.

CONCLUSIONS: This study reveals specific and selective mechanisms through which hypoxia, low glucose and amyloidosis mutually operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in AD/CAA comorbid with hypoperfusion conditions.

HIGHLIGHTS: Depriving cerebral endothelial cells of glucose and/or oxygen potentiates Aβ-induced endothelial dysfunction, differentially promoting increased cell death, barrier instability and dysregulation of blood brain barrier proteins, inflammatory activation, and angiogenesis and wound healing failure, in relation to the specific peptide and low glucose or oxygen conditions.Under hypoperfusion conditions, AβQ22 more strongly exacerbates increases in apoptosis, ICAM1, IL6, and IL8 expression, and monocyte migration and decreases in TEER, ZO1 expression, and wound healing, revealing that the vasculotropic AβQ22 produces even stronger vascular effects when in combination with hypoperfusion.Under hypoperfusion conditions, Aβ42 more strongly potentiates increases in necrosis and MMP2, phosphorylated claudin-5, IFNγ, and IL12p70 expression.Glucose deprivation exerts stronger effects on increasing caspase-3 activation, apoptosis, and MMP2 and ICAM1 expression, while hypoxia displays stronger effects on increasing necrosis and ZO1 and pro-angiogenic protein expression.We demonstrated that AβQ22 more intensely promotes vascular dysfunction when in combination with hypoperfusion conditions versus Aβ42.verall, results from this study point to the importance of monitoring and preventing cerebral hypoperfusion particularly during midlife, when AD pathology begins to develop, to prevent this early pathology from working with Aβ to create a more detrimental dementia trajectory, and highlights new targets for possible therapeutic or preventive strategies.},
}

@article {pmid41279558,
year = {2025},
author = {Garcia-Contreras, M and Lima, C and Alsop, E and Kaszala, B and Meechoovet, B and Purnell, B and Jiang, N and Saftics, A and Tang, C and Walsh, OD and Holland, S and Fay, J and Smith, B and Sigdel, KP and Van Keuren-Jensen, K and Jovanovic-Talisman, T and Das, S},
title = {State-dependent release of extracellular particles with distinct α2,6-sialylation patterns and small RNA cargo related to neuroinflammation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.30.684535},
pmid = {41279558},
issn = {2692-8205},
abstract = {Neuroinflammation is a significant contributor to neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and related dementias; yet peripheral biomarkers for neuroinflammation remain an unmet medical need. Microglia, the resident immune cells of the central nervous system, play a dual role in maintaining homeostasis under physiological conditions and driving neuronal damage when chronically dysregulated. One mechanism by which microglia influence their environment is through the release of extracellular vesicles (EVs) and non-vesicular extracellular particles (NVEPs), which can serve as biomarkers the reflect cellular states. Here, we systematically isolated and characterized microglia-derived EVs and NVEPs under pro- and anti-inflammatory conditions and profiled their small RNA cargo by small RNA sequencing. We validated these findings in human iPSC-derived microglia and further recapitulated them in EVs and NVEPs from mouse brain and plasma. Using an engineered mouse model, we were able to isolate plasma microglia-specific EVs in vivo and demonstrated that their RNA cargo reflects their inflammatory state. Importantly, microglial EVs and NVEPs display distinct α2,6-sialylation patterns and small RNA signatures implicated in neurological diseases. These findings demonstrate that microglia-derived EVs and NVEPs cargo reflect microglial cellular state and establish them as putative minimally non-invasive biomarkers of early-stage neurodegenerative diseases.},
}

@article {pmid41279545,
year = {2025},
author = {Jiang, B and Wang, S and Xie, J and Kim, H and Tukker, AM and Wang, J and Bowman, AB and Yuan, C and Baloni, P},
title = {Neuronal subtype-specific metabolic changes in neurodegenerative and neuropsychiatric diseases predicted via a systems biology-based approach.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.03.686281},
pmid = {41279545},
issn = {2692-8205},
abstract = {Understanding how distinct neuronal subtypes contribute to Alzheimer's disease (AD) pathology remains a major challenge. Patient-derived induced pluripotent stem cell (iPSC) studies have shown neuronal subtype-specific molecular and pathological signatures, yet the underlying metabolic shifts driving this selective vulnerability are not completely understood. Here we present iNeuron-GEM, the first manually curated, genome-scale metabolic network of human neurons that integrates transcriptomic and metabolic knowledge to resolve subtype-specific metabolic states. By coupling iNeuron-GEM with single nucleus RNA sequencing data from post-mortem human cohort studies, ROSMAP and SEA-AD, we capture neuronal subtype-specific metabolic features and fluxes and identify perturbations in lipid and energy metabolism across excitatory and inhibitory neurons. Integrative analysis with NPS-AD data shows overlapping metabolic disruptions in AD and schizophrenia (SCZ), suggesting shared molecular vulnerabilities between neurodegenerative and neuropsychiatric disorders. We also developed a computational pipeline to infer transcriptional regulation of metabolic pathways and identify NR6A1 and NR3C1 as important regulators of lipid dysregulation in AD neurons. Our study establishes iNeuron-GEM as a framework to identify neuronal subtype-specific metabolic vulnerabilities in complex brain disorders.},
}

@article {pmid41279514,
year = {2025},
author = {Palani, RS and Williams, CG and Thacker, D and Silvers, R and Qian, F and Weinreb, PH and Mueller, LJ and Linse, S and Griffin, RG},
title = {Aducanumab Binding to Aβ1-42 Fibrils Alters Dynamics of the N-Terminal Tail While Preserving the Fibril Core.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.01.686027},
pmid = {41279514},
issn = {2692-8205},
abstract = {UNLABELLED: Aducanumab, a human IgG1 antibody with plaque-clearing effects and modest clinical benefit, binds selectively to aggregated Aβ via the N-terminal region. Yet, the molecular details of how the antibody engages Aβ 1-42 fibrils remain unresolved. Using magic-angle spinning nuclear magnetic resonance, we show that binding of aducanumab preserves the overall architecture of the Aβ 1-42 fibril core while inducing significant structural and dynamic perturbations in the N-terminal region. Antibody binding markedly reduces flexibility in this domain, with the appearance of sidechain resonances from residues D1, E3, and histidine (likely H6) in dipolar-based experiments. These sidechains-previously observed only in scalar-coupling spectra of the unbound state-indicate rigidification of residues that were dynamic. The interaction extends to S8 and Y10, indicating broader fibril engagement than the minimal epitope (residues 3-7) defined in fragment-based studies. Perturbations in the C-terminal segment (G37-A42) are consistent with its spatial proximity to the antibody-bound N-termini of neighboring monomers. Cryo-TEM images reveal fibrils bundling in the presence of aducanumab, consistent with lateral association via antibody cross-linking, supporting a model where surface coating and steric hindrance suppress secondary nucleation. This mode of action restricts monomer access to catalytic sites on fibril surface, resulting in partial inhibition (∼three-fold reduction) of secondary nucleation. The effect depends on high avidity and relatively high stoichiometry, but is ultimately limited by antibody size relative to N-terminal spacing along the fibril. These findings provide atomic-level insights into aducanumab's binding mode and supply a structural framework for understanding antibody-mediated fibril recognition and for guiding next-generation therapies targeting Aβ aggregates in Alzheimer's disease.

SIGNIFICANCE STATEMENT: Understanding how therapeutic antibodies interact with amyloid-β (Aβ) fibrils is crucial for developing effective Alzheimer's disease treatments. Magic angle spinning NMR provides atomic-level insights into the binding of aducanumab to mature Aβ 1-42 fibrils. Aducanumab binding preserves the fibril's core structure but slows the dynamics of the N-terminal domain of Aβ. This interaction, which spans D1 to S8 and extends to Y10 on the fibril surface, is consistent with a mechanism in which N-terminal binding by the antibody interferes with aggregation steps like secondary nucleation. These findings detail how aducanumab engages its target fibril and provides insights relevant to other clinically approved antibodies and next-generation therapies that recognize the Aβ N-terminal region.},
}