Browsing by Subject "Apolipoprotein E"
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Item Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference(Wiley, 2024) Kloske, Courtney M.; Belloy, Michael E.; Blue, Elizabeth E.; Bowman, Gregory R.; Carrillo, Maria C.; Chen, Xiaoying; Chiba-Falek, Ornit; Davis, Albert A.; Di Paolo, Gilbert; Garretti, Francesca; Gate, David; Golden, Lesley R.; Heinecke, Jay W.; Herz, Joachim; Huang, Yadong; Iadecola, Costantino; Johnson, Lance A.; Kanekiyo, Takahisa; Karch, Celeste M.; Khvorova, Anastasia; Koppes-den Hertog, Sascha J.; Lamb, Bruce T.; Lawler, Paige E.; Le Guen, Yann; Litvinchuk, Alexandra; Liu, Chia-Chen; Mahinrad, Simin; Marcora, Edoardo; Marino, Claudia; Michaelson, Danny M.; Miller, Justin J.; Morganti, Josh M.; Narayan, Priyanka S.; Naslavsky, Michel S.; Oosthoek, Marlies; Ramachandran, Kapil V.; Ramakrishnan, Abhirami; Raulin, Ana-Caroline; Robert, Aiko; Saleh, Rasha N. M.; Sexton, Claire; Shah, Nilomi; Shue, Francis; Sible, Isabel J.; Soranno, Andrea; Strickland, Michael R.; Tcw, Julia; Thierry, Manon; Tsai, Li-Huei; Tuckey, Ryan A.; Ulrich, Jason D.; van der Kant, Rik; Wang, Na; Wellington, Cheryl L.; Weninger, Stacie C.; Yassine, Hussein N.; Zhao, Na; Bu, Guojun; Goate, Alison M.; Holtzman, David M.; Neurology, School of MedicineIntroduction: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. Methods: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. Results: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. Discussion: Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. Highlights: APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.Item Comorbidities in early-onset sporadic versus presenilin-1 mutation-associated Alzheimer disease dementia: Evidence for dependency on Alzheimer disease neuropathological changes(Oxford University Press, 2025) Sepulveda-Falla, Diego; Villegas Lanau, Carlos Andrés; White, Charles, III; Serrano, Geidy E.; Acosta-Uribe, Juliana; Mejía-Cupajita, Barbara; Villalba-Moreno, Nelson David; Lu, Pinzhang; Glatzel, Markus; Kofler, Julia K.; Ghetti, Bernardino; Frosch, Matthew P.; Restrepo, Francisco Lopera; Kosik, Kenneth S.; Beach, Thomas G.; Pathology and Laboratory Medicine, School of MedicineStudying comorbidities in early onset Alzheimer disease (AD) may provide an advantageous perspective on their pathogenesis because aging factors may be largely inoperative for these subjects. We compared AD comorbidities between early-onset sporadic cases and American and Colombian cases with PSEN1 mutations. AD neuropathological changes (ADNC) were very severe in all groups but more severe in the PSEN1 groups. Lewy body disease and cerebral white matter rarefaction were the most common (up to 60%) of AD comorbidities, followed by arteriolosclerosis (up to 37%), and large-vessel atherosclerosis (up to 20%). Differences between the 3 groups included earlier age of onset in the American PSEN1 cases, shorter disease duration in sporadic cases, and more frequent large-vessel atherosclerosis and cerebral amyloid angiopathy in the Colombian PSEN1 cases. Logistic regression models adjusted for age and sex found the presence of a PSEN1 mutation, an apolipoprotein ε4 allele and TDP-43 pathology to predict an earlier age of onset; Hispanic ethnicity and multiracial subjects were predictive of severe CAA. Comorbidities are common in early onset AD and should be considered when planning clinical trials with such subjects. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.Item Contribution of clinical information to the predictive performance of plasma β-amyloid levels for amyloid positron emission tomography positivity(Frontiers Media, 2023-03-14) Chun, Min Young; Jang, Hyemin; Kim, Hee Jin; Kim, Jun Pyo; Gallacher, John; Allué, José Antonio; Sarasa, Leticia; Castillo, Sergio; Pascual-Lucas, María; Na, Duk L.; Seo, Sang Won; DPUK; Radiology and Imaging Sciences, School of MedicineBackground: Early detection of β-amyloid (Aβ) accumulation, a major biomarker for Alzheimer's disease (AD), has become important. As fluid biomarkers, the accuracy of cerebrospinal fluid (CSF) Aβ for predicting Aβ deposition on positron emission tomography (PET) has been extensively studied, and the development of plasma Aβ is beginning to receive increased attention recently. In the present study, we aimed to determine whether APOE genotypes, age, and cognitive status increase the predictive performance of plasma Aβ and CSF Aβ levels for Aβ PET positivity. Methods: We recruited 488 participants who underwent both plasma Aβ and Aβ PET studies (Cohort 1) and 217 participants who underwent both cerebrospinal fluid (CSF) Aβ and Aβ PET studies (Cohort 2). Plasma and CSF samples were analyzed using ABtest-MS, an antibody-free liquid chromatography-differential mobility spectrometry-triple quadrupole mass spectrometry method and INNOTEST enzyme-linked immunosorbent assay kits, respectively. To evaluate the predictive performance of plasma Aβ and CSF Aβ, respectively, logistic regression and receiver operating characteristic analyses were performed. Results: When predicting Aβ PET status, both plasma Aβ42/40 ratio and CSF Aβ42 showed high accuracy (plasma Aβ area under the curve (AUC) 0.814; CSF Aβ AUC 0.848). In the plasma Aβ models, the AUC values were higher than plasma Aβ alone model, when the models were combined with either cognitive stage (p < 0.001) or APOE genotype (p = 0.011). On the other hand, there was no difference between the CSF Aβ models, when these variables were added. Conclusion: Plasma Aβ might be a useful predictor of Aβ deposition on PET status as much as CSF Aβ, particularly when considered with clinical information such as APOE genotype and cognitive stage.Item Deletion of miR‐33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice(Wiley, 2024) Tate, Mason; Wijeratne, H. R. Sagara; Kim, Byungwook; Philtjens, Stéphanie; You, Yanwen; Lee, Do-Hun; Gutierrez, Daniela A.; Sharify, Daniel; Wells, Megan; Perez-Cardelo, Magdalena; Doud, Emma H.; Fernandez-Hernando, Carlos; Lasagna-Reeves, Cristian; Mosley, Amber L.; Kim, Jungsu; Biochemistry and Molecular Biology, School of MedicineIntroduction: Rare variants in ABCA1 increase the risk of developing Alzheimer's disease (AD). ABCA1 facilitates the lipidation of apolipoprotein E (apoE). This study investigated whether microRNA-33 (miR-33)-mediated regulation of this ABCA1-APOE pathway affects phenotypes of an amyloid mouse model. Methods: We generated mir-33+/+;APP/PS1 and mir-33-/-;APP/PS1 mice to determine changes in amyloid pathology using biochemical and histological analyses. We used RNA sequencing and mass spectrometry to identify the transcriptomic and proteomic changes between our genotypes. We also performed mechanistic experiments by determining the role of miR-33 in microglial migration and amyloid beta (Aβ) phagocytosis. Results: Mir-33 deletion increases ABCA1 levels and reduces Aβ accumulation and glial activation. Multi-omics studies suggested miR-33 regulates the activation and migration of microglia. We confirm that the inhibition of miR-33 significantly increases microglial migration and Aβ phagocytosis. Discussion: These results suggest that miR-33 might be a potential drug target by modulating ABCA1 level, apoE lipidation, Aβ level, and microglial function. Highlights: Loss of microRNA-33 (miR-33) increased ABCA1 protein levels and the lipidation of apolipoprotein E. Loss of miR-33 reduced amyloid beta (Aβ) levels, plaque deposition, and gliosis. mRNAs and proteins dysregulated by miR-33 loss relate to microglia and Alzheimer's disease. Inhibition of miR-33 increased microglial migration and Aβ phagocytosis in vitro.Item Differential diagnosis of amnestic dementia patients based on an FDG-PET signature of autopsy-confirmed LATE-NC(Wiley, 2023) Grothe, Michel J.; Moscoso, Alexis; Silva-Rodríguez, Jesús; Lange, Catharina; Nho, Kwangsik; Saykin, Andrew J.; Nelson, Peter T.; Schöll, Michael; Buchert, Ralph; Teipel, Stefan; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineIntroduction: Limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is common in advanced age and can underlie a clinical presentation mimicking Alzheimer's disease (AD). We studied whether an autopsy-derived fluorodeoxyglucose positron emission tomography (FDG-PET) signature of LATE-NC provides clinical utility for differential diagnosis of amnestic dementia patients. Methods: Ante mortem FDG-PET patterns from autopsy-confirmed LATE-NC (N = 7) and AD (N = 23) patients were used to stratify an independent cohort of clinically diagnosed AD dementia patients (N = 242) based on individual FDG-PET profiles. Results: Autopsy-confirmed LATE-NC and AD groups showed markedly distinct temporo-limbic and temporo-parietal FDG-PET patterns, respectively. Clinically diagnosed AD dementia patients showing a LATE-NC-like FDG-PET pattern (N = 25, 10%) were significantly older, showed less abnormal AD biomarker levels, lower APOE ε4, and higher TMEM106B risk allele load. Clinically, they exhibited a more memory-predominant profile and a generally slower disease course. Discussion: An autopsy-derived temporo-limbic FDG-PET signature identifies older amnestic patients whose clinical, genetic, and molecular biomarker features are consistent with underlying LATE-NC.Item Distinctive Temporal Trajectories of Alzheimer's Disease Biomarkers According to Sex and APOE Genotype: Importance of Striatal Amyloid(Frontiers Media, 2022-02-07) Kim, Jun Pyo; Chun, Min Young; Kim, Soo-Jon; Jang, Hyemin; Kim, Hee Jin; Jeong, Jee Hyang; Na, Duk L.; Seo, Sang Won; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicinePurpose: Previously, sex and apolipoprotein E (APOE) genotype had distinct effects on the cognitive trajectory across the Alzheimer's disease (AD) continuum. We therefore aimed to investigate whether these trajectory curves including β-amyloid (Aβ) accumulation in the cortex and striatum, and tau accumulation would differ according to sex and APOE genotype. Methods: We obtained 534 subjects for 18F-florbetapir (AV45) PET analysis and 163 subjects for 18F-flortaucipir (AV1451) PET analysis from the Alzheimer's Disease Neuroimaging Initiative database. For cortical Aβ, striatal Aβ, and tau SUVR, we fitted penalized splines to model the slopes of SUVR value as a non-linear function of baseline SUVR value. By integrating the fitted splines, we obtained the predicted SUVR curves as a function of time. Results: The time from initial SUVR to the cutoff values were 14.9 years for cortical Aβ, 18.2 years for striatal Aβ, and 22.7 years for tau. Although there was no difference in cortical Aβ accumulation rate between women and men, striatal Aβ accumulation was found to be faster in women than in men, and this temporal difference according to sex was more pronounced in tau accumulation. However, APOE ε4 carriers showed faster progression than non-carriers regardless of kinds of AD biomarkers' trajectories. Conclusion: Our temporal trajectory models illustrate that there is a distinct progression pattern of AD biomarkers depending on sex and APOE genotype. In this regard, our models will be able to contribute to designing personalized treatment and prevention strategies for AD in clinical practice.Item The Impact of Amyloid Burden and APOE on Rates of Cognitive Impairment in Late Life Depression(IOS Press, 2021) Rhodes, Emma; Insel, Philip S.; Butters, Meryl A.; Morin, Ruth; Bickford, David; Tosun, Duygu; Gessert, Devon; Rosen, Howie J.; Aisen, Paul; Raman, Rema; Landau, Susan; Saykin, Andrew; Toga, Arthur; Jack, Clifford R.; Weiner, Michael W.; Nelson, Craig; Mackin, R. Scott; Alzheimer’s Disease Neuroimaging Initiative; ADNI Depression Project; Radiology and Imaging Sciences, School of MedicineBackground: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. Objective: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-β (Aβ) burden. Methods: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aβ burden. Results: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls (H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aβ positivity was associated with worse performance on Logical Memory I (p = 0.044), Logical Memory II (p = 0.011), and Trail Making Test -B (p = 0.032), and APOEɛ4 genotype was associated with worse performance on Logical Memory I (p = 0.022); these relationships did not differ between LLD and ND. Conclusion: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer's disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.Item Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer's disease(Wiley, 2022) Jun, Gyungah R.; You, Yang; Zhu, Congcong; Meng, Gaoyuan; Chung, Jaeyoon; Panitch, Rebecca; Hu, Junming; Xia, Weiming; The Alzheimer’s Disease Genetics Consortium; Bennett, David A.; Foroud, Tatiana M.; Wang, Li-San; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Au, Rhoda; Lunetta, Kathryn L.; Ikezu, Tsuneya; Stein, Thor D.; Farrer, Lindsay A.; Medical and Molecular Genetics, School of MedicineIntroduction: The apolipoprotein E (APOE) ɛ2 allele reduces risk against Alzheimer's disease (AD) but mechanisms underlying this effect are largely unknown. Methods: We conducted a genome-wide association study for AD among 2096 ɛ2 carriers. The potential role of the top-ranked gene and complement 4 (C4) proteins, which were previously linked to AD in ɛ2 carriers, was investigated using human isogenic APOE allele-specific induced pluripotent stem cell (iPSC)-derived neurons and astrocytes and in 224 neuropathologically examined human brains. Results: PPP2CB rs117296832 was the second most significantly associated single nucleotide polymorphism among ɛ2 carriers (P = 1.1 × 10-7 ) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 × 10-27 ). PPP2CB expression was correlated with phosphorylated tau231/total tau ratio (P = .01) and expression of C4 protein subunits C4A/B (P = 2.0 × 10-4 ) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 × 10-7 ). Discussion: PP2A may be linked to classical complement activation leading to AD-related tau pathology.Item The role of ApoE-mediated microglial lipid metabolism in brain aging and disease(Wolters Kluwer, 2023-01-23) Yen, Jui-Hung Jimmy; Yu, I-Chen Ivorine; Microbiology and Immunology, School of MedicineMicroglia are a unique population of immune cells resident in the brain that integrate complex signals and dynamically change phenotypes in response to the brain microenvironment. In recent years, single-cell sequencing analyses have revealed profound cellular heterogeneity and context-specific transcriptional plasticity of microglia during brain development, aging, and disease. Emerging evidence suggests that microglia adapt phenotypic plasticity by flexibly reprogramming cellular metabolism to fulfill distinct immune functions. The control of lipid metabolism is central to the appropriate function and homeostasis of the brain. Microglial lipid metabolism regulated by apolipoprotein E (ApoE), a crucial lipid transporter in the brain, has emerged as a critical player in regulating neuroinflammation. The ApoE gene allelic variant, ε4, is associated with a greater risk for neurodegenerative diseases. In this review, we explore novel discoveries in microglial lipid metabolism mediated by ApoE. We elaborate on the functional impact of perturbed microglial lipid metabolism on the underlying pathogenesis of brain aging and disease.Item Virtual reality cognitive intervention for heart failure: CORE study protocol(Alzheimer’s Association, 2022-03-15) Jung, Miyeon; Apostolova, Liana G.; Moser, Debra K.; Gradus-Pizlo, Irmina; Gao, Sujuan; Rogers, Jeff L.; Pressler, Susan J.; School of NursingIntroduction: Heart failure (HF) is a prevalent, serious chronic illness that affects 6.5 million adults in the United States. Among patients with HF, the prevalence of attention impairment is reported to range from 15% to 27%. Although attention is fundamental to human activities including HF self-care, cognitive interventions for patients with HF that target improvement in attention are scarce. The COgnitive intervention to Restore attention using nature Environment (CORE) study aims to test the preliminary efficacy of the newly developed Nature-VR, a virtual reality-based cognitive intervention that is based on the restorative effects of nature. Nature-VR development was guided by Attention Restoration Theory. The target outcomes are attention, HF self-care, and health-related quality of life (HRQoL). Our exploratory aims examine the associations between attention and several putative/established HF biomarkers (eg, oxygen saturation, brain-derived neurotrophic factor, apolipoprotein E, dopamine receptor, and dopamine transporter genes) as well as the effect of Nature-VR on cognitive performance in other domains (ie, global cognition, memory, visuospatial, executive function, and language), cardiac and neurological events, and mortality. Methods: This single-blinded, two-group randomized-controlled pilot study will enroll 74 participants with HF. The Nature-VR intervention group will view three-dimensional nature pictures using a virtual reality headset for 10 minutes per day, 5 days per week for 4 weeks (a total of 200 minutes). The active comparison group, Urban-VR, will view three-dimensional urban pictures using a virtual reality headset to match the Nature-VR intervention in intervention dose and delivery mode, but not in content. After baseline interviews, four follow-up interviews will be conducted to assess sustained effects of Nature-VR at 4, 8, 26, and 52 weeks. Discussion: The importance and novelty of this study consists of using a first-of-its kind, immersive virtual reality technology to target attention and in investigating the health outcomes of the Nature-VR cognitive intervention among patients with HF.