Alzheimers disease is a progressive form of dementia that results in problems with memory, thinking and behavior. It often starts with abnormal aggregation and deposition of beta-amyloid and tau, followed by neuronal damage such as atrophy of the hippocampi, and finally leads to behavioral deficits. Despite significant progress in finding biomarkers associated with behavioral deficits, the underlying causal mechanism remains largely unknown. Here we investigate whether and how hippocampal atrophy contributes to behavioral deficits based on a large-scale observational study conducted by the Alzheimers Disease Neuroimaging Initiative (ADNI). As a key novelty, we use 2D representations of the hippocampi, which allows us to better understand atrophy associated with different subregions. It, however, introduces methodological challenges as existing causal inference methods are not well suited for exploiting structural information embedded in the 2D exposures. Moreover, our data contain more than 6 million clinical and genetic covariates, necessitating appropriate confounder selection methods. We hence develop a novel two-step causal inference approach tailored for our ADNI data application. Analysis results suggest that atrophy of CA1 and subiculum subregions may cause more severe behavioral deficits compared to CA2 and CA3 subregions. We further evaluate our method using simulations and provide theoretical guarantees.
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