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Harnessing peripheral DNA methylation differences in the Alzheimer's Disease Neuroimaging Initiative (ADNI) to reveal novel biomarkers of disease.
Vasanthakumar, Aparna; Davis, Justin W; Idler, Kenneth; Waring, Jeffrey F; Asque, Elizabeth; Riley-Gillis, Bridget; Grosskurth, Shaun; Srivastava, Gyan; Kim, Sungeun; Nho, Kwangsik; Nudelman, Kelly N H; Faber, Kelley; Sun, Yu; Foroud, Tatiana M; Estrada, Karol; Apostolova, Liana G; Li, Qingqin S; Saykin, Andrew J.
Affiliation
  • Vasanthakumar A; Genomics Research Center, AbbVie, North Chicago, IL, USA. aparna.vasanthakumar@abbvie.com.
  • Davis JW; Genomics Research Center, AbbVie, North Chicago, IL, USA.
  • Idler K; Genomics Research Center, AbbVie, North Chicago, IL, USA.
  • Waring JF; Genomics Research Center, AbbVie, North Chicago, IL, USA.
  • Asque E; Genomics Research Center, AbbVie, North Chicago, IL, USA.
  • Riley-Gillis B; Genomics Research Center, AbbVie, North Chicago, IL, USA.
  • Grosskurth S; Genomics Research Center, AbbVie, North Chicago, IL, USA.
  • Srivastava G; Exploratory Statistics, AbbVie, North Chicago, IL, USA.
  • Kim S; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Nho K; Electrical and Computer Engineering, State University of New York, Oswego, NY, 13126, USA.
  • Nudelman KNH; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Faber K; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Sun Y; National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Foroud TM; National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Estrada K; Neuroscience Therapeutic Area, Janssen Research & Development, Pennington, NJ, 08534, USA.
  • Apostolova LG; Research Information Technology, Janssen Research & Development, Pennington, NJ, 08534, USA.
  • Li QS; National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Saykin AJ; Biogen, Cambridge, MA, 02142, USA.
Clin Epigenetics ; 12(1): 84, 2020 06 15.
Article in En | MEDLINE | ID: mdl-32539856
BACKGROUND: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease impacting an estimated 44 million adults worldwide. The causal pathology of AD (accumulation of amyloid-beta and tau), precedes hallmark symptoms of dementia by more than a decade, necessitating development of early diagnostic markers of disease onset, particularly for new drugs that aim to modify disease processes. To evaluate differentially methylated positions (DMPs) as novel blood-based biomarkers of AD, we used a subset of 653 individuals with peripheral blood (PB) samples in the Alzheimer's disease Neuroimaging Initiative (ADNI) consortium. The selected cohort of AD, mild cognitive impairment (MCI), and age-matched healthy controls (CN) all had imaging, genetics, transcriptomics, cerebrospinal protein markers, and comprehensive clinical records, providing a rich resource of concurrent multi-omics and phenotypic information on a well-phenotyped subset of ADNI participants. RESULTS: In this manuscript, we report cross-diagnosis differential peripheral DNA methylation in a cohort of AD, MCI, and age-matched CN individuals with longitudinal DNA methylation measurements. Epigenome-wide association studies (EWAS) were performed using a mixed model with repeated measures over time with a P value cutoff of 1 × 10-5 to test contrasts of pairwise differential peripheral methylation in AD vs CN, AD vs MCI, and MCI vs CN. The most highly significant differentially methylated loci also tracked with Mini Mental State Examination (MMSE) scores. Differentially methylated loci were enriched near brain and neurodegeneration-related genes (e.g., BDNF, BIN1, APOC1) validated using the genotype tissue expression project portal (GTex). CONCLUSIONS: Our work shows that peripheral differential methylation between age-matched subjects with AD relative to healthy controls will provide opportunities to further investigate and validate differential methylation as a surrogate of disease. Given the inaccessibility of brain tissue, the PB-associated methylation marks may help identify the stage of disease and progression phenotype, information that would be central to bringing forward successful drugs for AD.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: DNA Methylation / Alzheimer Disease / Neuroimaging / Cognitive Dysfunction Type of study: Diagnostic_studies / Observational_studies / Prognostic_studies / Risk_factors_studies / Screening_studies Limits: Aged / Aged80 / Female / Humans / Male Language: En Journal: Clin Epigenetics Year: 2020 Document type: Article Affiliation country: Estados Unidos Country of publication: Alemania

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: DNA Methylation / Alzheimer Disease / Neuroimaging / Cognitive Dysfunction Type of study: Diagnostic_studies / Observational_studies / Prognostic_studies / Risk_factors_studies / Screening_studies Limits: Aged / Aged80 / Female / Humans / Male Language: En Journal: Clin Epigenetics Year: 2020 Document type: Article Affiliation country: Estados Unidos Country of publication: Alemania