Molecular subtyping of alzheimer’s disease with consensus non-negative matrix factorization

Alzheimer’s disease (AD) is a heterogeneous disease and exhibits
diverse clinical presentations and disease progression. Some pathological
and anatomical subtypes have been proposed. However, these subtypes
provide a limited mechanistic understanding for AD. Leveraging
gene expression data of 222 AD patients from The Religious Orders Study
and Memory and Aging Project (ROSMAP) Study, we identified two AD
molecular subtypes (synaptic type and inflammatory type) using consensus
non-negative matrix factorization (NMF). Synaptic type is characterized by
disrupted synaptic vesicle priming and recycling and synaptic plasticity.
Inflammatory type is characterized by disrupted IL2, interferon alpha and
gamma pathways. The two AD molecular subtypes were validated using
independent data from Gene Expression Omnibus. We further demonstrated
that the two molecular subtypes are associated with APOE genotypes,
with synaptic type more prevalent in AD patients with E3E4
genotype and inflammatory type more prevalent in AD patients with E3E3
genotype (p = 0.031). In addition, two molecular subtypes are
differentially represented in male and female AD, with synaptic type more
prevalent in male and inflammatory type in female patients (p =
0.051). Identification of AD molecular subtypes has potential in
facilitating disease mechanism understanding, clinical trial design, drug
discovery, and precision medicine for AD.