Video 6: Polygenic Risk for Alzheimer’s
In collaboration with BrainMind, Dr. Isaacson introduces the polygenic risk of Alzheimer’s
disease and how to approach treating Alzheimer’s for each individual.

About Dr. Richard Isaacson:
Dr. Richard Isaacson is the founder and former Director of the Alzheimer’s Prevention Clinic at the Weill Cornell Memory Disorders Program. He is currently the director of Brain Health at the Atria Institute. A leading expert on Alzheimer’s Disease (AD), Dr. Isaacson is passionate about providing the latest evidence-based options for treatment and risk reduction. His research focuses on individualized clinical management of AD using emerging principles of precision medicine. He also oversees a robust AD therapeutics and education research program.

Polygenic Risk
● Multiple genes acting in combination to increase or decrease the risk of developing
disorders
● APOE4 variant (described in Video 4) is most commonly associated with Alzheimer’s
risk.
● Besides the APOE4 variant, how do different genes interact together to understand
increasing or decreasing the risk of Alzheimer's disease?
○ If each gene pathway can be identified, we may be able to prevent Alzheimer’s by
intervening with these genes.

Non-Genetic Considerations
● Medical comorbidities, vascular risk factors, environmental exposure, etc.

The combination of all of these assessments allows for more accurate risk analysis of getting Alzheimer’s disease.

Examples of Other Genes
1. TOMM40 gene: depending on the chain length, increases or decreases APOE4 variants
risk
2. Inflammatory genes: inflammation can fast forward Alzheimer’s disease pathology
a. Ex: TNF Alpha gene (Tumor Necrosis Factor-Alpha) - in combination with APOE4,
increases Alzheimer’s risk by 6 times.

Understanding Risk
● How to understand a person’s genetic risk across their entire polygenome?
Steps:
1. Whole Genome Sequencing (WGS)
a. A comprehensive method for analyzing entire genomes
2. Identify Risk Genes
3. Specific Gene Intervention
a. Understand the biological function of the risk genes and intervene accordingly
b. Precision medicine approach
● Other approach includes polygenic risk score which can help to understand a person’s
risk in a more precise way

Barriers to WGS Implementation
● Tedious, labor-intensive, requires lots of experts, thousands of dollars

Example Case Study
● Herpes: potential causative agent in people developing Alzheimer’s Disease
Identifying the Gene: Susan has APOE4 and herpes simplex 1 gene that makes her more susceptible to the herpes simplex 1 virus
Potential Treatment: Give Susan an antiviral agent to suppress the viral replication, which suppresses inflammatory cascade preventing the amyloid build-up
Potential Result: Delayed or prevented Alzheimer’s disease

What’s needed to treat Alzheimer’s?
● Precision Medicine: Using a person’s genes and biology to personalize their treatment
plan (i.e. cholesterol, metabolism, inflammatory markers, nutritional markers)

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