Browsing by Subject "Alzheimer's"

Now showing 1 - 3 of 3
  • 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
    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.