Alzheimer’s disease is often seen as a single monolithic disease, but an increasing amount of evidence is showing that this might not necessarily be the case. In a new study, researchers propose there are at least three major molecular subtypes of Alzheimer's disease. It’s still relatively early days for the research, but they hope the work could help illuminate more about this increasingly common disease. Many questions hang over Alzheimer’s disease, not least because it can affect different people in very different ways. Some people have a slow and steady cognitive decline, while others experience a sudden decline. Some people may experience problems with language and communication, but others won’t. Some may even start to suffer from psychosis and lose their grip on reality, while others don’t. There also appear to be some physical differences. The buildup of sticky proteins such as Tau neurofibrillary tangles and amyloid-beta plaques between nerve cells in the brain is widely considered to be a hallmark of Alzheimer’s. However, recent years have witnessed growing recognition that beta-amyloid plaque buildup may not be the whole story. For one, not all people who supposedly die of Alzheimer’s have any significant amount of plaque in their brains during post-mortem examinations. Equally, some people have a plaque buildup, yet do not show any cognitive decline during their lifetime. As further evidence that plaque is not necessarily the key to the disease, clinical trials of anti-amyloid drugs have proved to be a flop when it comes to preventing Alzheimer's. For the new research, reported in the journal Science Advances, scientists used RNA sequencing data on 1,543 samples taken from five brain regions of hundreds of deceased patients with Alzheimer’s disease, as well as healthy controls for comparison. This highlighted how many cases of Alzheimer’s can fit into three different subsets – A, B, and C – based on the combination of different dysregulated biological pathways. These pathways include tau-mediated neurodegeneration, amyloid-β neuroinflammation, synaptic signaling, immune activity, mitochondria organization, and myelination. Importantly, the buildup of tau and amyloid-beta plaque was only found to be significantly increased in certain subtypes and not others. Some previous research has also suggested Alzheimer’s might have some link to a heightened immune response, but this new analysis found that some subsets of disease did not show any signs of an increased immune response. The researchers also found similar subtypes of the disease in mouse brains. This may in part explain why a number of high-profile drug trials have appeared to be successful in mice but later failed in humans, as the trials were muddling up subtypes. The researchers state their findings need to be affirmed by other studies, but they’re holding high hopes for the work. For one, molecular subtyping of Alzheimer’s disease could have researchers identify key biomarkers that doctors can look out for and make an earlier diagnosis before the disease takes its toll. In the long run, they hope it could even help pave the way towards the discovery of potential drug targets. Source
