Browsing by Author "Lee, Joseph H."
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Item Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals(American Medical Association, 2015-11) Ghani, Mahdi; Reitz, Christiane; Cheng, Rong; Vardarajan, Badri Narayan; Jun, Gyungah; Sato, Christine; Naj, Adam; Rajbhandary, Ruchita; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. Daniele; Go, Rodney C. P.; Griffith, Patrick A.; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Lee, Joseph H.; Schellenberg, Gerard D.; St. George-Hyslop, Peter; Mayeux, Richard; Rogaeva, Ekaterina; Department of Psychiatry, IU School of MedicineIMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.Item Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome(medRxiv, 2023-11-30) Edwards, Natalie C.; Lao, Patrick J.; Alshikho, Mohamad J.; Ericsson, Olivia M.; Rizvi, Batool; Petersen, Melissa E.; O’Bryant, Sid; Flores-Aguilar, Lisi; Simoes, Sabrina; Mapstone, Mark; Tudorascu, Dana L.; Janelidze, Shorena; Hansson, Oskar; Handen, Benjamin L.; Christian, Bradley T.; Lee, Joseph H.; Lai, Florence; Rosas, H. Diana; Zaman, Shahid; Lott, Ira T.; Yassa, Michael A.; Gutierrez, José; Wilcock, Donna M.; Head, Elizabeth; Brickman, Adam M.; Neurology, School of MedicineImportance: By age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer's disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors. Objective: To examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS. Design: Cross sectional analysis of neuroimaging, plasma, and clinical data. Setting: Participants were enrolled in Alzheimer's Biomarker Consortium - Down Syndrome (ABC-DS), a multisite study of AD in adults with DS. Participants: One hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (Aβ42/Aβ40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays. Main outcomes and measures: We examined the bivariate relationships of WMH, Aβ42/Aβ40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. Results: There was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. Conclusions and relevance: The findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS.Item Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome(Oxford University Press, 2024-09-25) Edwards, Natalie C.; Lao, Patrick J.; Alshikho, Mohamad J.; Ericsson, Olivia M.; Rizvi, Batool; Petersen, Melissa E.; O’Bryant, Sid; Flores Aguilar, Lisi; Simoes, Sabrina; Mapstone, Mark; Tudorascu, Dana L.; Janelidze, Shorena; Hansson, Oskar; Handen, Benjamin L.; Christian, Bradley T.; Lee, Joseph H.; Lai, Florence; Rosas, H. Diana; Zaman, Shahid; Lott, Ira T.; Yassa, Michael A.; Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC-DS) Investigators; Gutierrez, José; Wilcock, Donna M.; Head, Elizabeth; Brickman, Adam M.; Neurology, School of MedicineBy age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.Item Comparison of amyloid accumulation between Down syndrome and autosomal-dominant Alzheimer disease(Wiley, 2022) Boerwinkle, Anna H.; Gordon, Brian A.; Wisch, Julie K.; Flores, Shaney; Henson, Rachel L.; Butt, Omar Hameed; Chen, Charles D.; Benzinger, Tammie L. S.; Fagan, Anne M.; Handen, Benjamin L.; Christian, Bradley T.; Head, Elizabeth; Mapstone, Mark; Klunk, William E.; Rafii, Michael S.; O’Bryant, Sid E.; Price, Julie C.; Schupf, Nicole; Laymon, Charles M.; Krinsky-McHale, Sharon J.; Lai, Florence; Rosas, H. Diana; Hartley, Sigan L.; Zaman, Shahid; Lott, Ira T.; Silverman, Wayne; Brickman, Adam M.; Lee, Joseph H.; Allegri, Ricardo Francisco; Berman, Sarah; Chhatwal, Jasmeer P.; Chui, Helena C.; Cruchaga, Carlos; Farlow, Martin R.; Fox, Nick C.; Goate, Alison; Day, Gregory S.; Graff-Radford, Neill R.; Jucker, Mathias; Lee, Jae-Hong; Levin, Johannes; Martins, Ralph N.; Mori, Hiroshi; Perrin, Richard J.; Salloway, Stephen P.; Sanchez-Valle, Raquel; Schofield, Peter R.; Xiong, Chengjie; Karch, Celeste M.; Hassenstab, Jason J.; McDade, Eric; Bateman, Randall J.; Ances, Beau M.; Neurology, School of MedicineBackground: Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)-like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development. Method: We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) and 265 mutation-carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated-years-to-symptom-onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC-DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40. Result: The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ -23 but was not elevated in DS until EYO ≥ -15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5). Conclusion: These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5-10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.Item Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease(Nature Publishing Group, 2014-09) Nalls, Mike A.; Pankratz, Nathan; Lill, Christina M.; Do, Chuong B.; Hernandez, Dena G.; Saad, Mohamad; DeStefano, Anita L.; Kara, Eleanna; Bras, Jose; Sharma, Manu; Schulte, Claudia; Keller, Margaux F.; Arepalli, Sampath; Letson, Christopher; Edsall, Connor; Stefansson, Hreinn; Liu, Xinmin; Pliner, Hannah; Lee, Joseph H.; Cheng, Rong; Ikram, M. Arfan; Ioannidis, John P. A.; Hadjigeorgiou, Georgios M.; Bis, Joshua C.; Martinez, Maria; Perlmutter, Joel S.; Goate, Alison; Marder, Karen; Fiske, Brian; Sutherland, Margaret; Xiromerisiou, Georgia; Myers, Richard H.; Clark, Lorraine N.; Stefansson, Kari; Hardy, John A.; Heutink, Peter; Chen, Honglei; Wood, Nicholas W.; Houlden, Henry; Payami, Haydeh; Brice, Alexis; Scott, William K.; Gasser, Thomas; Bertram, Lars; Eriksson, Nicholas; Foroud, Tatiana; Singleton, Andrew B.; Department of Medical & Molecular Genetics, IU School of MedicineWe conducted a meta analysis of Parkinson’s disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as genome-wide significantItem Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer's Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome(IOS Press, 2021) Petersen, Melissa E.; Rafii, Michael S.; Zhang, Fan; Hall, James; Julovich, David; Ances, Beau M.; Schupf, Nicole; Krinsky-McHale, Sharon J.; Mapstone, Mark; Silverman, Wayne; Lott, Ira; Klunk, William; Head, Elizabeth; Christian, Brad; Foroud, Tatiana; Lai, Florence; Rosas, H. Diana; Zaman, Shahid; Wang, Mei-Cheng; Tycko, Benjamin; Lee, Joseph H.; Handen, Benjamin; Hartley, Sigan; Fortea, Juan; O’Bryant, Sid; Alzheimer’s Biomarker Consortium – Down Syndrome (ABC-DS); Medical and Molecular Genetics, School of MedicineBackground: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population. Objective: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults. Methods: Plasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome. Results: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS. Conclusion: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.