  Alzheimer's 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, leading to Alzheimer's Disease (AD). The aim
of this paper is to map the genetic-imaging-clinical pathway for AD in order to
delineate the genetically regulated brain changes that drive disease
progression based on the Alzheimer's Disease Neuroimaging Initiative (ADNI)
dataset. We develop a novel two-step approach to delineate the association
between high-dimensional 2D hippocampal surface exposures and the Alzheimer's
Disease Assessment Scale (ADAS) cognitive score, while taking into account the
ultra-high dimensional clinical and genetic covariates at baseline. Analysis
results suggest that the radial distance of each pixel of both hippocampi is
negatively associated with the severity of behavioral deficits conditional on
observed clinical and genetic covariates. These associations are stronger in
Cornu Ammonis region 1 (CA1) and subiculum subregions compared to Cornu Ammonis
region 2 (CA2) and Cornu Ammonis region 3 (CA3) subregions.
