Browsing by Subject "Apolipoproteins E"
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Item Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease(Wiley, 2022) Joseph-Mathurin, Nelly; Llibre-Guerra, Jorge J.; Li, Yan; McCullough, Austin A.; Hofmann, Carsten; Wojtowicz, Jakub; Park, Ethan; Wang, Guoqiao; Preboske, Gregory M.; Wang, Qing; Gordon, Brian A.; Chen, Charles D.; Flores, Shaney; Aggarwal, Neelum T.; Berman, Sarah B.; Bird, Thomas D.; Black, Sandra E.; Borowski, Bret; Brooks, William S.; Chhatwal, Jasmeer P.; Clarnette, Roger; Cruchaga, Carlos; Fagan, Anne M.; Farlow, Martin; Fox, Nick C.; Gauthier, Serge; Hassenstab, Jason; Hobbs, Diana A.; Holdridge, Karen C.; Honig, Lawrence S.; Hornbeck, Russ C.; Hsiung, Ging-Yuek R.; Jack, Clifford R., Jr.; Jimenez-Velazquez, Ivonne Z.; Jucker, Mathias; Klein, Gregory; Levin, Johannes; Mancini, Michele; Masellis, Mario; McKay, Nicole S.; Mummery, Catherine J.; Ringman, John M.; Shimada, Hiroyuki; Snider, B. Joy; Suzuki, Kazushi; Wallon, David; Xiong, Chengjie; Yaari, Roy; McDade, Eric; Perrin, Richard J.; Bateman, Randall J.; Salloway, Stephen P.; Benzinger, Tammie L. S.; Clifford, David B.; Dominantly Inherited Alzheimer Network Trials Unit; Neurology, School of MedicineObjective: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). Methods: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. Results: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation.Item Apolipoprotein E (APOE) Genotype and Outcome in Infants with Hypoxic-Ischemic Encephalopathy (HIE)(Springer Nature, 2014) Cotten, C. Michael; Goldstein, Ricki F.; McDonald, Scott A.; Goldberg, Ronald N.; Salhab, Walid A.; Carlo, Waldemar A.; Tyson, Jon E.; Finer, Neil N.; Walsh, Michele C.; Ehrenkranz, Richard A.; Laptook, Abbot R.; Guillet, Ronnie; Schibler, Kurt; Van Meurs, Krisa P.; Poindexter, Brenda B.; Stoll, Barbara J.; O'Shea, T. Michael; Duara, Shahnaz; Das, Abhik; Higgins, Rosemary D.; Shankaran, Seetha; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; Pediatrics, School of MedicineBackground: Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE). Methods: We conducted a cohort study of infants who survived HIE and had 18-22 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/-, and e2/-. Results: A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/-, and 14 (10%) were of the e2/- genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the e3/e3 genotype, 25 and 26% among those with and without the e2 allele, and 18 and 29% among those with and without the e4 allele, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups. Conclusion: Disability was not associated with the APOE genotype in this cohort of HIE survivors.Item Influence of Genetic Variation on Plasma Protein Levels in Older Adults Using a Multi-Analyte Panel(Public Library of Science, 2013-07-23) Kim, Sungeun; Swaminathan, Shanker; Inlow, Mark; Risacher, Shannon L.; Nho, Kwangsik; Shen, Li; Foroud, Tatiana M.; Petersen, Ronald C.; Aisen, Paul S.; Soares, Holly; Toledo, Jon B.; Shaw, Leslie M.; Trojanowski, John Q.; Weiner, Michael W.; McDonald, Brenna C.; Farlow, Martin R.; Ghetti, Bernardino; Saykin, Andrew J.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of MedicineProteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases. Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease pathophysiology. Effects of individual single nucleotide polymorphisms (SNPs) within a gene were analyzed for corresponding plasma protein levels using genome-wide association study (GWAS) genotype data and proteomic panel data with 132 quality-controlled analytes from 521 Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Linear regression analysis detected 112 significant (Bonferroni threshold p=2.44×10(-5)) associations between 27 analytes and 112 SNPs. 107 out of these 112 associations were tested in the Indiana Memory and Aging Study (IMAS) cohort for replication and 50 associations were replicated at uncorrected p<0.05 in the same direction of effect as those in the ADNI. We identified multiple novel associations including the association of rs7517126 with plasma complement factor H-related protein 1 (CFHR1) level at p<1.46×10(-60), accounting for 40 percent of total variation of the protein level. We serendipitously found the association of rs6677604 with the same protein at p<9.29×10(-112). Although these two SNPs were not in the strong linkage disequilibrium, 61 percent of total variation of CFHR1 was accounted for by rs6677604 without additional variation by rs7517126 when both SNPs were tested together. 78 other SNP-protein associations in the ADNI sample exceeded genome-wide significance (5×10(-8)). Our results confirmed previously identified gene-protein associations for interleukin-6 receptor, chemokine CC-4, angiotensin-converting enzyme, and angiotensinogen, although the direction of effect was reversed in some cases. This study is among the first analyses of gene-protein product relationships integrating multiplex-panel proteomics and targeted genes extracted from a GWAS array. With intensive searches taking place for proteomic biomarkers for many diseases, the role of genetic variation takes on new importance and should be considered in interpretation of proteomic results.Item MicroRNAs on the move: microRNAs in astrocyte-derived ApoE particles regulate neuronal function(Elsevier, 2021) Karahan, Hande; Dabin, Luke C.; Tate, Mason D.; Kim, Jungsu; Medical and Molecular Genetics, School of MedicineIn this issue of Neuron, Li et al. (2021) demonstrate that ApoE lipoprotein particles shuttle miRNAs from astrocytes to neurons, leading to inhibition of cholesterol biosynthesis and an increase in histone acetylation in neurons.Item Neuropathological correlates and genetic architecture of microglial activation in elderly human brain(Springer Nature, 2019-01-24) Felsky, Daniel; Roostaei, Tina; Nho, Kwangsik; Risacher, Shannon L.; Bradshaw, Elizabeth M.; Petyuk, Vlad; Schneider, Julie A.; Saykin, Andrew; Bennett, David A.; De Jager, Philip L.; Radiology and Imaging Sciences, School of MedicineMicroglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. Here we report that the proportion of morphologically activated microglia (PAM) in postmortem cortical tissue is strongly associated with β-amyloid, tau-related neuropathology, and the rate of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE ε4, the strongest genetic risk factor for Alzheimer's disease, and mediation models support an upstream role for microglial activation in Alzheimer's disease via accumulation of tau. Further, we identify a common variant (rs2997325) influencing PAM that also affects in vivo microglial activation measured by [11C]-PBR28 PET in an independent cohort. Thus, our analyses begin to uncover pathways regulating resident neuroinflammation and identify overlaps of PAM's genetic architecture with those of Alzheimer's disease and several other traits.Item Patients asking about APOE gene test results? Here's what to tell them(Frontline Medical Communications, 2022) Stites, Shana D.; Vogt, Nicholas M.; Blacker, Deborah; Rumbaugh, Malia; Parker, Monica W.; Advisory Group on Risk Evidence Education for Dementia (AGREED); Medical and Molecular Genetics, School of MedicineThis guidance can help shape the conversations you have with patients who want to understand the results of their gene and biomarker testing for Alzheimer disease.Item Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease(Wiley, 2023) Qiao, Min; Lee, Annie J.; Reyes-Dumeyer, Dolly; Tosto, Giuseppe; Faber, Kelley; Goate, Alison; Renton, Alan; Chao, Michael; Boeve, Brad; Cruchaga, Carlos; Pericak-Vance, Margaret; Haines, Jonathan L.; Rosenberg, Roger; Tsuang, Debby; Sweet, Robert A.; Bennett, David A.; Wilson, Robert S.; Foroud, Tatiana; Mayeux, Richard; Vardarajan, Badri N.; Medical and Molecular Genetics, School of MedicineObjective: To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. Methods: Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE-ε4 carriers and non-carriers. Results: PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE-ε4 allele (OR = 1.74 [1.53-1.91]) compared with APOE-ε4 carriers (1.53 [1.4-1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e-05). Stratifying by APOE-ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE-ε4 carriers (14.5% higher at age 80, p = 0.002) and non-carriers (26% higher at 80, p < 10e-05). Recurrence risk for siblings conferred by a co-sibling in the highest PRS quintile increased from 4% between the ages of 65-74 years to 39% at age 85 and older. Interpretation: PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non-carries of APOE-ε4.Item Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders(Springer Nature, 2024) Hwang, Hye M.; Yamashita, Satoshi; Matsumoto, Yu; Ito, Mariko; Edwards, Alex; Sasaki, Junko; Dutta, Dipankar J.; Mohammad, Shahid; Yamashita, Chiho; Wetherill, Leah; Schwantes-An, Tae-Hwi; Abreu, Marco; Mahnke, Amanda H.; Mattson, Sarah N.; Foroud, Tatiana; Miranda, Rajesh C.; Chambers, Christina; Torii, Masaaki; Hashimoto-Torii, Kazue; Medical and Molecular Genetics, School of MedicineA hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.Item The National Institute on Aging Late-Onset Alzheimer’s Disease Family Based Study: A resource for genetic discovery(Wiley, 2022) Reyes-Dumeyer, Dolly; Faber, Kelley; Vardarajan, Badri; Goate, Alison; Renton, Alan; Chao, Michael; Boeve, Brad; Cruchaga, Carlos; Pericak-Vance, Margaret; Haines, Jonathan L.; Rosenberg, Roger; Tsuang, Debby; Sweet, Robert A.; Bennett, David A.; Wilson, Robert S.; Foroud, Tatiana; Mayeux, Richard; Medical and Molecular Genetics, School of MedicineIntroduction: The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD). Methods: Recruitment focused on families with two living affected siblings and a third first-degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E (APOE) genotypes, genome-wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families. Results: APOE genotype modified the age-at-onset in many large families. Novel variants and known variants associated with early- and late-onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics. Discussion: The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD.