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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.
230 views reported since publication in 2021.