Neuroimage Genomic analysis for Alzheimer's Subphenotypes

Objective
The objective of the proposed study is to establish the connection between Alzheimer’s Disease-related genomic markers and neuroimaging phenotypes and their association with the clinical onset of dementia. We hypothesize that a) genomic factors are associated with diverse Alzheimer’s Disease-related neuropathological and clinical progression patterns; and b) the genotype-phenotype interaction is dynamic along the Alzheimer’s Disease progression trajectory, which in turn regulates the clinical progression of dementia.

Study design
We plan to develop data-driven computational models using multi-modal imaging-genomics information, to test these hypotheses with the following two Specific Aims: (1) construct clinically relevant computational neuroimaging-genomic fingerprints to characterize distinctive subtypes of Alzheimer’s Disease neuropathological patterns, and (2) Construct clinically explainable subtype-aware AI models with effective genomic-neuroimaging information fusion to achieve accurate prediction of disease progression of Alzheimer’s Disease.

Analysis plan
I will construct and validate harmonized models by utilizing the available data from the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium, which is a multi-institutional effort that harmonized phenotypical data of 22k participants collected from 31 AD-related cohorts to produce a large-scale, racially diverse, standardized set of clearly defined data.

1. We will develop semi-supervised machine-learning-based classification frameworks to explore the complex genotype-phenotype associations that determine distinctive neuroimaging-based pathological progression patterns.

2. We will also develop machine-learning model predictions of future AD-specific neuropathological biomarkers. More specifically, we aim to predict the progression of cortical Aβ levels for identifying pre-symptomatic subjects, and progression of tau levels for symptomatic subjects.

Alzheimer’s Disease (AD) is a complex neurodegenerative disease with multiple variations of pathologies that affect the brain function, eventually leading to cognitive decline. Individual variations of our gene might be associated with different subtypes of the disease. Thus, it is important to explore the disease characteristics within the various AD subtypes to achieve personalized diagnosis and precision medicine, and eventually developing effective treatments for AD. The objective of this proposal is to study the connection between AD-related genomic markers and neuroimaging phenotypes and their association with the clinical onset of dementia.