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Stanford Extreme Phenotypes in Alzheimer's Disease (StEP AD) Project

The overall goals are to identify and characterize novel genetic variants that promote resilience to AD pathology in the presence of the APOE4 allele or that drive pathogenesis in the absence of the APOE4 allele. We hypothesize that healthy older APOE4 carriers will carry functional variants rarely or never detected in a large cohort of AD patients and that early-onset cases lacking the APOE4 allele will carry functional variants rarely or never detected in a large cohort of healthy older controls. We prioritize candidate protective (or causal) variants using deep phenotyping—such as amyloid PET, spinal fluid proteomics, induced pluripotent stem cell (iPSC)-derived neurons, and post-mortem brain tissue—to characterize molecular pathways.

Long Read Sequencing (LRS) of AD-relevant Genes

LRS can provide high-fidelity, single-chromosome sequencing across a span of 10-30 kilobases. This allows for ground-truth haplotypes and detection of large structural variants and tandem repeats commonly missed in standard short-read sequencing. Currently, we are focusing on the APOE locus to disentangle complex LD patterns and identify, for example, high and low risk APOE4 haplotypes.

Replication and Validation Datasets

We use many different publicly available datasets--that include healthy controls, patients with mild cognitive impairment, and patients with AD--to try and replicate the genetic associations we find. Additionally, we use transcriptomics and proteomics data to elucidate the functional mechanisms of genetic mutations. These datasets include:

  • UK Biobank
  • Alzheimer's Disease Sequencing Project (ADSP)
  • Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study
  • Alzheimer's Disease Neuroimaging Initiative (ADNI)
  • Accelerating Medicine Partnership in Alzheimer's Disease (AMP-AD)
  • Accelerating Medicine Partnership in Parkinson's Disease (AMP-PD)