The study focused on the TREM2-TYROBP pathway. TYROBP is an
inflammatory gene involved in this pathway, but previously, it had not been
linked to the disease. TYROBP is known to interact with TREM2, a gene recently
discovered to be associated with Alzheimer's disease by Rita Guerreiro of
University College London, Thorlakur Jonsson of deCODE Genetics and their colleagues.

This work began with an integrated analysis performed on the
DNA of 376 deceased patients with LOAD, as well as gene expression data, which
revealed the relationships between a network of genes that drive central
pathways of Alzheimer's. The researchers then created a biological network
model, integrating the genes key to Alzheimer's disease and the biological
pathways they control.

"In the same way that sophisticated predictive mathematical
models drive decision making in the global financial markets … the field of
medical research has begun to rely on network models such as this to derive
meaning from vast amounts of patient data, enabling better understanding and
treatment of human disease," Dr. Christopher Gaiteri, a co-lead author of
the study and senior scientist at Sage Bionetworks, commented in a press
release.

Dr. Eric Schadt, an author of the study and director of
the Icahn Institute for Genomics and Multiscale Biology and chair of the
Department of Genetics and Genomic Sciences at Mount Sinai, called the model "a
landmark achievement, yielding valuable insights into the complex mechanism of
the disease."

LOAD is the most common form of Alzheimer's disease, and
despite extensive research, the cause of the disease is unknown, though it is attributed
to a combination of "genetic, environmental and lifestyle factors," according
to the National Institute on Aging. What is known, however, is that having the
E4 allele of the apolipoprotein gene—a gene found on chromosome 19 that carries
instructions for the coding of a protein that transports cholesterol and fats
in the bloodstream—is a genetic risk factor for the likelihood of developing
LOAD. No effective preventative or disease-modifying therapies exist for the
disease, and the incidence of LOAD is expected to double by 2050.

One of the key points of interest with this discovery, says
Schadt, is the fact that "the microglia in the brain drive immune/inflammation
processes that are causally associated with LOAD." Prior to this work,
inflammation was believed to be a result of Alzheimer's disease damaging the
brain, but their work "demonstrates that it is a driver, not a consequence of
LOAD."

"Defining the precise steps of the inflammatory response
crucial to causing Alzheimer's disease has been elusive. We are pleased to discover these novel
insights into that process," Dr. Bin Zhang, a co-lead author of the study
and an associate professor of genetics and genomic sciences at Mount Sinai,
said in a press release. "As a next step, we will evaluate drugs that impact
the TREM2-TYROBP pathway as potential therapies for the disease. This discovery
enables us to design more specific compounds that target these key steps
precisely, in contrast to existing anti-inflammatory drugs that may be less ideal
for hitting this target. "

"Currently, we see a long lag time between appearance of
amyloid on brain scans of patients and the appearance of clinical symptoms,"
added Dr. Valur Emilsson, head of systems medicine at Icelandic Heart
Association and a senior author of the paper. "An individual's inflammatory
response could well play a role in the disease progression, and an appropriate
anti-inflammatory drug, given after amyloid is detected but before symptoms
begin, could be an important part of dementia prevention."

Schadt says their prediction is that if the TYROBP pathway
is down-regulated, the progression of Alzheimer's disease should be slowed or
stopped, with the possibility that if the pathway is suppressed early enough,
it might prevent the disease. In terms of therapies that could affect the
network, Schadt notes that there are several possibilities, "even drugs such as
anti-inflammatories." This work has potential outside of Alzheimer's disease as
well, as Schadt says they are applying this approach to autism, Huntington's
disease and schizophrenia as well.

Moving forward, Schadt says the team will continue to
identify and validate therapeutics that can molecularly affect this network,
adding that they are set up to test the candidates in animal models. The
researchers will also "explore pharma partnership to develop novel therapeutics
against this work."