Unravelling Causal Genetic Biomarkers of Alzheimer’s Disease via Neuron to Gene-token Backtracking in Neural Architecture: A Groundbreaking Reverse-Gene-Finder Approach

Abstract Alzheimer’s Disease (AD) affects over 55 million people globally, yet the key genetic contributors remain poorly understood. Leveraging recent advancements in genomic foundation models, we present the innovative Reverse-Gene-Finder technology, a ground-breaking neuron-to-gene-token backtracking approach in a neural network architecture to elucidate the novel causal genetic biomarkers driving AD onset. Reverse-Gene-Finder comprises three key innovations. Firstly, we exploit the observation that genes with the highest probability of causing AD, defined as the most causal genes (MCGs), must have the highest probability of activating those neurons with the highest probability of causing AD, defined as the most causal neurons (MCNs). Secondly, we utilize a gene token representation at the input layer to allow each gene (known or novel to AD) to be represented as a discrete and unique entity in the input space. Lastly, in contrast to the existing neural network architectures, which track neuron activations from the input layer to the output layer in a feed-forward manner, we develop an innovative backtracking method to track backwards from the MCNs to the input layer, identifying the Most Causal Tokens (MCTs) and the corresponding MCGs. Reverse-Gene-Finder is highly interpretable, generalizable, and adaptable, providing a promising avenue for application in other disease scenarios.