  Alzheimer's disease (AD) is a heterogeneous, multifactorial neurodegenerative
disorder characterized by beta-amyloid, pathologic tau, and neurodegeneration.
There are no effective treatments for Alzheimer's disease at a late stage,
urging for early intervention. However, existing statistical inference
approaches of AD subtype identification ignore the pathological domain
knowledge, which could lead to ill-posed results that are sometimes
inconsistent with the essential neurological principles. Integrating systems
biology modeling with machine learning, we propose a novel pathology steered
stratification network (PSSN) that incorporates established domain knowledge in
AD pathology through a reaction-diffusion model, where we consider non-linear
interactions between major biomarkers and diffusion along brain structural
network. Trained on longitudinal multimodal neuroimaging data, the biological
model predicts long-term trajectories that capture individual progression
pattern, filling in the gaps between sparse imaging data available. A deep
predictive neural network is then built to exploit spatiotemporal dynamics,
link neurological examinations with clinical profiles, and generate subtype
assignment probability on an individual basis. We further identify an
evolutionary disease graph to quantify subtype transition probabilities through
extensive simulations. Our stratification achieves superior performance in both
inter-cluster heterogeneity and intra-cluster homogeneity of various clinical
scores. Applying our approach to enriched samples of aging populations, we
identify six subtypes spanning AD spectrum, where each subtype exhibits a
distinctive biomarker pattern that is consistent with its clinical outcome.
PSSN provides insights into pre-symptomatic diagnosis and practical guidance on
clinical treatments, which may be further generalized to other
neurodegenerative diseases.
