Translational Neurogenomics & Alzheimer Biomarkers Laboratory - Yang Lab

SCIENCE

The Yang Lab combines cutting-edge multi-omics approaches with neuropathology, neuroimaging, cognitive/clinical, and plasma biomarker data from human subjects to investigate genetic, molecular, and cellular underpinnings of AD and related disorders (ADRD). We focus on generating and analyzing large-scale data derived from human subjects.

Shared and distinct mechanisms across Alzheimer’s disease and related disorders

Alzheimer’s disease (AD) rarely attacks the brain alone. Studies analyzing human brain samples have shown that most (>95%) clinically diagnosed AD cases have at least one additional neuropathology that significantly contributes to cognitive decline and dementia (e.g., TDP-43, vascular disease, α-synuclein). We pair multi-omic data with extensive human clinical, neuroimaging, and pathology phenotypes to determine shared and distinct molecular and cellular perturbations across multiple neurodegenerative pathologies that often co-exist in the same patient. We are leading a large NIH-funded project generating RNA-Seq, proteomics, and single-cell multi-ome data from n=480 human amygdala samples (R01 AG080667, PI Hyun-Sik Yang). The amygdala is a hotbed for Aβ, tau, TDP-43, and ⍺-synuclein; we will establish a comprehensive biological atlas of ADRD by generating the largest multi-omic dataset from the human subcortical brain structure.

Selected Publications

  • Yang HS, Teng L, Kang D, Menon V, Ge T, Finucane HK, Schultz AP, Properzi M, Klein HU, Chibnik LB, Schneider JA, Bennett DA, Hohman TJ, Mayeux RP, Johnson KA, De Jager PL, Sperling RA. Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease. Nat Commun. 2023 Nov 30;14(1):7659. PubMed Central PMCID: PMC10689816.
  • Klein HU, Trumpff C, Yang HS, Lee AJ, Picard M, Bennett DA, De Jager PL. Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain. Mol Neurodegener. 2021 Nov 6;16(1):75. PubMed Central PMCID: PMC8572491
  • Cain A, Taga M, McCabe C, Green GS, Hekselman I, White CC, Lee DI, Gaur P, Rozenblatt-Rosen O, Zhang F, Yeger-Lotem E, Bennett DA, Yang HS, Regev A, Menon V, Habib N, De Jager PL. Multicellular communities are perturbed in the aging human brain and Alzheimer’s disease. Nat Neurosci. 2023 Jul;26(7):1267-1280.
  • Yang HS, White CC, Klein HU, Yu L, Gaiteri C, Ma Y, Felsky D, Mostafavi S, Petyuk VA, Sperling RA, Ertekin-Taner N, Schneider JA, Bennett DA, De Jager PL. Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology. Neuron. 2020 Aug 5;107(3):496-508.e6. PubMed Central PMCID: PMC7416464.
  • Rabin JS*, Yang HS*, Schultz AP, Hanseeuw BJ, Hedden T, Viswanathan A, Gatchel JR, Marshall GA, Kilpatrick E, Klein H, Rao V, Buckley RF, Yau WW, Kirn DR, Rentz DM, Johnson KA, Sperling RA, Chhatwal JP. Vascular Risk and β-Amyloid Are Synergistically Associated with Cortical Tau. Ann Neurol. 2019 Feb;85(2):272-279. PubMed Central PMCID: PMC6351182.
  • Yang HS, Chhatwal JP, Xu J, White CC, Hanseeuw B, Rabin JS, Papp KV, Buckley RF, Schultz AP, Properzi MJ, Gatchel JR, Amariglio RE, Donovan NJ, Mormino EC, Hedden T, Marshall GA, Rentz DM, Johnson KA, De Jager PL, Sperling RA. An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults. J Alzheimers Dis. 2019;68(3):1161-1170. PubMed Central PMCID: PMC6571137.
  • De Jager PL, Yang HS, Bennett DA. Deconstructing and targeting the genomic architecture of human neurodegeneration. Nat Neurosci. 2018 Oct;21(10):1310-1317. PubMed PMID: 30258235. Review.
  • Yang HS, Yu L, White CC, Chibnik LB, Chhatwal JP, Sperling RA, Bennett DA, Schneider JA, De Jager PL. Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study. Lancet Neurol. 2018 Sep;17(9):773-781. PubMed Central PMCID: PMC6154505.
  • Yang HS, White CC, Chibnik LB, Klein HU, Schneider JA, Bennett DA, De Jager PL. UNC5C variants are associated with cerebral amyloid angiopathy. Neurol Genet. 2017 Aug;3(4):e176. PubMed Central PMCID: PMC5515600.
  • White CC*, Yang HS*, Yu L, Chibnik LB, Dawe RJ, Yang J, Klein HU, Felsky D, Ramos-Miguel A, Arfanakis K, Honer WG, Sperling RA, Schneider JA, Bennett DA, De Jager PL. Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data. PLoS Med. 2017 Apr;14(4):e1002287. PubMed Central PMCID: PMC5404753.
Immune Dysregulation in Alzheimer’s Disease

Genome-wide association studies have strongly suggested the central causal role of immune dysfunction in Alzheimer’s disease (AD) pathogenesis. However, how the immunogenetic AD risk translates into human disease phenotypes such as amyloid-β, tau, neuroinflammation, and cognitive decline remains unclear. We leverage our collaborator network and direct access to DNA and biofluid samples from hundreds of older adults (see The Alzheimer’s Biomarkers Consortium) to study immune dysregulation in AD, focusing on the preclinical (presymptomatic) stages of AD. Supported by the NIH (K23 AG062750, PI Hyun-Sik Yang) and philanthropic donations, we are currently generating PBMC single-cell transcriptome data from the Harvard Aging Brain Study, which will be analyzed with longitudinal neuroimaging and clinical data.

Selected Publications

    • Yang HS*, Yau WW*, Carlyle BC, Trombetta BA, Zhang C, Shirzadi Z, Schultz AP, Pruzin JJ, Fitzpatrick CD, Kirn DR, Rabin JS, Buckley RF, Hohman TJ, Rentz DM, Tanzi RE, Johnson KA, Sperling RA, Arnold SE, Chhatwal JP. Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer’s disease. Brain. 2024 Feb 5:awae034. doi: 10.1093/brain/awae034. Online ahead of print. PMID: 38315899
    • Yang HS, Teng L, Kang D, Menon V, Ge T, Finucane HK, Schultz AP, Properzi M, Klein HU, Chibnik LB, Schneider JA, Bennett DA, Hohman TJ, Mayeux RP, Johnson KA, De Jager PL, Sperling RA. Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease. Nat Commun. 2023 Nov 30;14(1):7659. PubMed Central PMCID: PMC10689816.
    • Yang HS*, Zhang C*, Carlyle BC, Zhen SY, Trombetta BA, Schultz AP, Pruzin JJ, Fitzpatrick CD, Yau WW, Kirn DR, Rentz DM, Arnold SE, Johnson KA, Sperling RA, Chhatwal JP, Tanzi RE. The plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults. Alzheimers Dement. 2022 Apr;18(4):645-653. PubMed Central PMCID: PMC8695625
The Alzheimer’s Biomarkers Consortium (ABC)

The Yang Lab leads the newly established Remondi Alzheimer’s Biomarkers Consortium (ABC) at BWH, the largest AD/ADRD biobanking program at the BWH Department of Neurology. Our community-based cross-sectional study, the Davis Memory and Aging Cohort (study flyer), has recruited over 800 participants who finished a brief cognitive exam and donated blood samples. We recruit BWH cognitive neurology and lumbar puncture clinic patients, including patients currently getting lecanemab (monoclonal anti-Aβ antibody) treatment, to study biomarker predictors of disease progression and treatment responses. We collect, process, store, and analyze biosamples from multiple observational studies, including the Harvard Aging Brain Study. Overall, we manage cross-sectional and longitudinal biosamples from over 1,200 individuals, with the longest follow-up of 12+ years. The Alzheimer’s Biomarkers Consortium (ABC) provides a solid foundational infrastructure to support our scientific mission to translate advances in AD biology into real-world precision patient care.

Back To Top