Browsing by Subject "Alzheimer's"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    APOE4 Drives Impairment in Astrocyte-Neuron Coupling in Alzheimer's Disease and Works Through Mechanisms in Early Disease to Influence Pathology
    (2023-05) Brink, Danika Marie Tumbleson; Lamb, Bruce; Bissel, Stephanie; Herbert, Brittney-Shea; Landreth, Gary; Puntambekar, Shweta; Saykin, Andrew; Zhang, Chi
    Alzheimer’s disease (AD) is a neurodegenerative disorder resulting in progressive memory loss, brain atrophy, and eventual death. AD pathology is characterized by the accumulation of neurotoxic amyloid-beta (Aβ) plaques, synapse loss, neurofibrillary tangles (NFTs), and neurodegeneration. The APOE4 allele is associated with a 3-fold increased risk for AD and results in increased Aβ plaque deposition, reduced Aβ clearance, and reduced synaptic plasticity. Although APOE expression is upregulated in microglia in AD, APOE is expressed primarily by astrocytes in the CNS. It is not well understood how astrocytic APOE drives the mechanisms that result in worsened AD outcomes. Here, digital spatial profiling and bioinformatics data suggest that APOE4 causes transcriptional dysregulation in early AD and may disrupt neuronal processes via astrocytes. Whole transcriptome data from plaque and non-plaque regions in the cortices and hippocampus of 4- and 8-month-old AD model mice expressing humanized APOE4/4 or APOE3/3 (control) were analyzed. Transcriptional dysregulation was increased in APOE4/4 AD mice compared to that in APOE3/3 at 4 but not 8 months of age, suggesting that early dysregulation of APOE4-driven disease mechanisms may shape degenerative outcomes in late-stage AD. Additionally, APOE4/4 potentially functions via plaque-independent mechanisms to influence neuronal function in early AD before the onset of pathology. Single-nuclei RNA sequencing data were obtained from human post-mortem astrocytes and the bioinformatic analyses revealed a novel astrocyte subtype that highly expresses several top genes involved in functional alterations associated with APOE4, including neuronal generation, development, and differentiation, and synaptic transmission and organization. Overall, our findings indicate that APOE4 may drive degenerative outcomes through the presented astrocyte candidate pathways. These pathways represent potential targets for investigations into early intervention strategies for APOE4/4 patients.
  • Thumbnail Image
    Item
    Biomarker-And Pathway-Informed Polygenic Risk Scores for Alzheimer's Disease and Related Disorders
    (2022-05) Chasioti, Danai; Yan, Jingwen; Saykin, Andrew J.; Nho, Kwangsik; Risacher, Shannon L.; Wu, Huanmei
    Determining an individual’s genetic susceptibility in complex diseases like Alzheimer’s disease (AD) is challenging as multiple variants each contribute a small portion of the overall risk. Polygenic Risk Scores (PRS) are a mathematical construct or composite that aggregates the small effects of multiple variants into a single score. Potential applications of PRS include risk stratification, biomarker discovery and increased prognostic accuracy. A systematic review demonstrated that methodological refinement of PRS is an active research area, mostly focused on large case-control genome-wide association studies (GWAS). In AD, where there is considerable phenotypic and genetic heterogeneity, we hypothesized that PRS based on endophenotypes, and pathway-relevant genetic information would be particularly informative. In the first study, data from the NIA Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to develop endophenotype-based PRS based on amyloid (A), tau (T), neurodegeneration (N) and cerebrovascular (V) biomarkers, as well as an overall/combined endophenotype-PRS. Results indicated that combined phenotype-PRS predicted neurodegeneration biomarkers and overall AD risk. By contrast, amyloid and tau-PRSs were strongly linked to the corresponding biomarkers. Finally, extrinsic significance of the PRS approach was demonstrated by application of AD biological pathway-informed PRS to prediction of cognitive changes among older women with breast cancer (BC). Results from PRS analysis of the multicenter Thinking and Living with Cancer (TLC) study indicated that older BC patients with high AD genetic susceptibility within the immune-response and endocytosis pathways have worse cognition following chemotherapy±hormonal therapy rather than hormonal-only therapy. In conclusion, PRSs based on biomarker- or pathway- specific genetic information may provide mechanistic insights beyond disease susceptibility, supporting development of precision medicine with potential application to AD and other age-associated cognitive disorders.
  • Thumbnail Image
    Item
    Designing a Multimodal and Culturally Relevant Alzheimer Disease and Related Dementia Generative Artificial Intelligence Tool for Black American Informal Caregivers: Cognitive Walk-Through Usability Study
    (JMIR, 2025-01-08) Bosco, Cristina; Otenen, Ege; Torres, John Osorio; Nguyen, Vivian; Chheda, Darshil; Peng, Xinran; Jessup, Nenette M.; Himes, Anna K.; Cureton, Bianca; Lu, Yvonne; Hill, Carl V.; Hendrie, Hugh C.; Barnes, Priscilla A.; Shih, Patrick C.; School of Nursing
    Background: Many members of Black American communities, faced with the high prevalence of Alzheimer disease and related dementias (ADRD) within their demographic, find themselves taking on the role of informal caregivers. Despite being the primary individuals responsible for the care of individuals with ADRD, these caregivers often lack sufficient knowledge about ADRD-related health literacy and feel ill-prepared for their caregiving responsibilities. Generative AI has become a new promising technological innovation in the health care domain, particularly for improving health literacy; however, some generative AI developments might lead to increased bias and potential harm toward Black American communities. Therefore, rigorous development of generative AI tools to support the Black American community is needed. Objective: The goal of this study is to test Lola, a multimodal mobile app, which, by relying on generative AI, facilitates access to ADRD-related health information by enabling speech and text as inputs and providing auditory, textual, and visual outputs. Methods: To test our mobile app, we used the cognitive walk-through methodology, and we recruited 15 informal ADRD caregivers who were older than 50 years and part of the Black American community living within the region. We asked them to perform 3 tasks on the mobile app (ie, searching for an article on brain health, searching for local events, and finally, searching for opportunities to participate in scientific research in their area), then we recorded their opinions and impressions. The main aspects to be evaluated were the mobile app's usability, accessibility, cultural relevance, and adoption. Results: Our findings highlight the users' need for a system that enables interaction with different modalities, the need for a system that can provide personalized and culturally and contextually relevant information, and the role of community and physical spaces in increasing the use of Lola. Conclusions: Our study shows that, when designing for Black American older adults, a multimodal interaction with the generative AI system can allow individuals to choose their own interaction way and style based upon their interaction preferences and external constraints. This flexibility of interaction modes can guarantee an inclusive and engaging generative AI experience.
  • Thumbnail Image
    Item
    Exploring the Role of Age in Alzheimer's Disease and Factors Contributing to Resilience in Older Adults
    (2025-05) Akinyemi, Oluwatosin; Jones, Josette
    Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that primarily affects older adults but can also emerge in younger individuals, presenting unique challenges. While aging is a significant risk factor, many people remain cognitively healthy despite being in high-risk groups. This suggests that other factors, such as education, lifestyle, and social engagement, may contribute to resilience against the disease. This project explores the influence of social determinants on Alzheimer’s development across different life stages. By analyzing two datasets, one covering individuals aged 18 to 96 and another focusing on ages 60 to 90, the study examines how variables like socioeconomic status, education, lifestyle habits, and health conditions impact cognitive health. Statistical methods, including regression models and comparative analysis, will identify key life stages where these factors are crucial. Additionally, the project will propose an assessment tool to evaluate the effectiveness of these interventions, laying the groundwork for future research and practical applications.
  • Thumbnail Image
    Item
    Influence of amyloid and diagnostic syndrome on non-traditional memory scores in early-onset Alzheimer's disease
    (Wiley, 2023) Bushnell, Justin; Hammers, Dustin B.; Aisen, Paul; Dage, Jeffrey L.; Eloyan, Ani; Foroud, Tatiana; Grinberg, Lea T.; Iaccarino, Leonardo; Jack, Clifford R., Jr.; Kirby, Kala; Kramer, Joel; Koeppe, Robert; Kukull, Walter A.; La Joie, Renaud; Mundada, Nidhi S.; Murray, Melissa E.; Nudelman, Kelly; Rumbaugh, Malia; Soleimani-Meigooni, David N.; Toga, Arthur; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Steven; Sha, Sharon; Turner, Raymond S.; Wingo, Thomas S.; Wolk, David A.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; Clark, David G.; LEADS Consortium; Neurology, School of Medicine
    Introduction: The Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early-onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD. Methods: We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J-curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables. Results: Compared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter-syndromic differences were noted with raw score, primacy, recency, J-curve, and stopping time. Discussion: RAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores. Highlights: RAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing-based scores add value over traditional count-based scores.