What if we think of Alzheimer’s not as one disease, but three separate ones, with overlapping symptoms? Researchers behind a new study say Alzheimer’s encapsulates three distinct molecular conditions, and that a better understanding of each could be a lifeline for failed Alzheimer’s treatment efforts and future research.
So far, the scientific research community’s decades-long search for an Alzheimer’s cure has largely been concentrated around identifying key hallmarks of the disease, such as beta-amyloid and tau proteins that aggregate in the brain, and targeting these pathologies with experimental therapies. But time and time again, drugs designed to stop Alzheimer’s by counteracting the buildup of beta-amyloid plaques and tau tangles have failed in human trials.
Increasingly, researchers are exploring other theories, prodding the link between Alzheimer’s and factors such as viruses or the gut microbiome. Unfortunately, no new approach has led to the creation of a drug that has been proven to prevent or halt the onset of Alzheimer’s — yet. In fact, so far, 99 percent of the drugs tested to treat the condition fail.
For some, the latest source of optimism lies in a new study, recently published in Science Advances: Researchers at the Icahn School of Medicine in Mount Sinai have found that Alzheimer’s can be subtyped into three molecularly distinct categories. According to Bin Zhang, an author of the study, if this discovery holds, it could go a long way into explaining the failure of previous attempts to secure an effective drug. It could even mean that drugs that were considered failures in the past may be able to treat one of the three subtypes effectively.
“This research can rescue many failed drugs,” Zhang told Being Patient. “Even if a drug is effective for 10 to 20 percent of people and they can be added together [through molecular subtyping], a cure can be made for a vast majority of the specific subtype.”
The team of researchers used molecular signatures and network regulator genes to classify people into five molecular subtypes of Alzheimer’s, which in turn represented three major subclasses of the condition. This subtyping was ratified using independent postmortem brain RNA data.
Interestingly, this categorization could not be explained by differences in the pathology of beta-amyloid and tau in the brain. In addition, the subtypes were independent of age and disease severity. Ultimately, Zhang’s team found, each subtype is distinct from the pathological connotations of the disease — meaning while these subtypes share the same symptoms, they may not be effectively targeted by the same treatments.
Zhang and his team see these findings as a suggestion that our traditional conception of Alzheimer’s — that it is a disease that can be cured by a drug that addresses the aggregations of beta-amyloid and tau — could be wrong, From this subtyping information, the researchers concluded that three separate conditions exist, each of which can create the symptoms that we call Alzheimer’s today, “Based upon current research and failed drug trials, beta-amyloid starts to look like a consequence, not a cause, of Alzheimer’s disease,” Zhang said.
However, he added, further research is required to discern the role of tau in the development, emergence and progression of neurodegeneration.
Zhang believes these findings have “profound implications for drug development.” Namely, he said, drugs should target the molecular mechanism of Alzheimer’s, instead of focusing on its pathology. “You have to target each subtype specifically,” he said.