In 1901, the German Psychiatrist Alois Alzheimer clinically examined a patient called Auguste Deter who was admitted to the insane asylum of Frankfurt am Main for behavior changes, including suspiciousness directed toward her husband. Over the course of her hospital stay, a decline in memory and other cognitive changes were noticed, a pattern that was considered atypical of a classical psychiatric disorder. Therefore, when she died on April 8, 1906, Alzheimer performed a post mortem examination of her brain at the request of the superintendent of the mental asylum. Under the microscope, he observed two types of protein deposits, a clump of proteins outside the brain cell, the neuron, that he called a “plaque” and twisted proteins inside the cell that were called “neurofibrillary tangles.” Since then, thousands of scientists have spent billions of dollars worldwide to better characterize these proteins biochemically and to study the underlying biology of what is commonly known as Alzheimer’s disease (AD). Plaques and tangles are presumed to be central to the underlying cause of the disease and need to be identified in post mortem tissue for a definitive diagnosis of AD.
Fast forward 115 years: On June 7, the Food and Drug Administration (FDA) approved the drug Aducanumab for the treatment of AD — the first drug approved by the agency for AD since 2003. The drug is an antibody that binds to the protein Beta Amyloid in the brain, the protein that forms the core of the plaque described by Alois Alzheimer. What makes this remarkable is that the drug was approved for clinical care over the objection of the FDA’s own advisory panel, which recommended non-approval of the drug for clinical use. Two large studies offered conflicting evidence on whether the drug is effective in slowing the progressive memory loss that characterizes AD clinically. In an unprecedented move, three scientists from the independent committee that advised the FDA have resigned in protest. The drug can only be administered by intravenous infusion and is expected to cost around $56,000 annually, thereby driving up health care costs considerably and adding to the burden on Medicare. It is associated with potentially serious side effects like swelling of the brain and bleeding, tilting the risk — benefit ratio in favor of risk.
Part of the challenge in the AD field is distinguishing a biomarker of the disease from a legitimate therapeutic target. A biomarker is a laboratory-based metric that is consistently associated with a disease, one that can be objectively measured, used to diagnose and monitor the disease, including the impact of treatment and the eventual income. In order to be effective, the biomarker needs to be closely linked to the underlying mechanism of the disease. But, importantly, the biomarker is not typically the cause of the disease. Medicine is replete with examples of biomarkers that are useful in the diagnosis and monitoring of the disease process, while not directly contributing to the disease itself.
Clinically, A beta, the plaque protein, and tau, the protein that constitutes the tangles, can be helpful in confirming the diagnosis, or at least increasing the diagnostic confidence, that a patient has AD clinically. Positron emission tomographic (PET) scans of the brain, and biochemical measurements of A beta and tau in the fluid that surrounds the brain and spinal cord (cerebrospinal fluid) and, more recently, in blood have demonstrated that these measures can help clarify the diagnosis in certain patient groups. In other words, they may be clinically relevant biomarkers of AD. Yet, they are mostly used in research settings and not in routine clinical practice.
For the last several decades, the field of experimental therapeutics of AD has focused on developing compounds that lower the levels of A Beta in the brain with the expectation that this will result in clinical improvement. All trials, to this point, have been unsuccessful in improving clinical outcomes. Compounds that lower tau levels in the brain are also in various stages of clinical trials, and none has passed regulatory review to date. In the case of A beta plaque protein, clinical trials, including the recently approved compound, lower A beta levels in the brain, but this does not result in discernible clinical improvement. This may be the classical case of shooting the biological messenger, meaning targeting the protein that provides useful information about the disease without contributing to the disease itself. If plaques and tangles are legitimate targets for drug development, lowering their levels in the brain should result in clinical improvement. That has not been demonstrated thus far.
Alzheimer’s disease and related dementias were once called “silent epidemics.” They are no longer silent. Their impact is devastating to patients and families and visible throughout the world. We are desperate for a treatment. However, we need treatments that work, as demonstrated by the evidence that emerges from well-conducted clinical trials. Let us choose targets carefully, avoid the false dawn, and always remember that biomarkers are not effective targets for drug development.
Dr. Anand Kumar (anandk@uic.edu) is a professor and head of the Department of Psychiatry at the University of Illinois, Chicago; he is past president of The American Association for Geriatric Psychiatry. Dr. Charles Nemeroff (cnemeroff@austin.utexas.edu) is chairman of the Department of Psychiatry at Dell Medical School within the University of Texas, Austin, and past president of the American College of Neuropsychopharmacology.
