Key molecular pathways leading to Alzheimer's identified

Scientists have identified key molecular pathways that ultimately lead to late-onset Alzheimer's disease, the most common form of the disorder.
Much of what is known about Alzheimer's comes from laboratory studies of rare, early-onset, familial (inherited) forms of the disease, researchers said.
"Such studies have provided important clues as to the underlying disease process, but it's unclear how these rare familial forms of Alzheimer's relate to the common form of the disease," said study leader Asa Abeliovich, associate professor of pathology and cell biology and of neurology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center (CUMC).

Non-familial Alzheimer's is complex; it is thought to be caused by a combination of genetic and environmental risk factors, each having a modest effect individually.
In the current study, researchers identified key molecular pathways that link such genetic risk factors to Alzheimer's.
The work combined cell biology studies with systems biology tools, which are based on computational analysis of the complex network of changes in the expression of genes in the at-risk human brain.

The researchers first focused on the single most significant genetic factor that puts people at high risk for Alzheimer's, called APOE4 (found in about a third of all individuals).

People with one copy of this genetic variant have a three-fold increased risk of developing late-onset Alzheimer's, while those with two copies have a ten-fold increased risk.
They found that even in the absence of Alzheimer's disease, brain tissue from individuals at high risk (who carried APOE4 in their genes) harboured certain changes reminiscent of those seen in full-blown Alzheimer's disease.
Researchers then identified a dozen candidate "master regulator" factors that link APOE4 to the cascade of destructive events that culminates in Alzheimer's dementia.
They found that a number of these master regulators are involved in the processing and trafficking of amyloid precursor protein (APP) within brain neurons.

APP gives rise to amyloid beta, the protein that accumulates in the brain cells of patients with Alzheimer's.
Among the candidate "master regulators" identified, the team further analysed two genes, SV2A and RFN219. The researchers evaluated the role of SV2A, using human-induced neurons that carry the APOE4 genetic variant.
Treating neurons that harbour the APOE4 at-risk genetic variant with levetiracetam, an anti-epileptic drug which inhibits SV2A, led to reduced production of amyloid beta.
The study also showed that RFN219 appears to play a role in APP-processing in cells with the APOE4 variant.
"Our findings suggest that both SV2A and RFN219 are candidate drug targets," said Abeliovich.

The study was published in the journal Nature.