Written by: Rob Philibert, MD PhD
Medically reviewed by: Rob Philibert, MD PhD
Frederick Nietzsche famously stated, “that which does not kill us makes us stronger.” Frequently, this saying is used by individuals ranging from parents to physicians to rationalize the imposition of unwanted requirements, such as otherwise unwanted exercise. In this regard, the clinicians are usually right. But is Nietzsche’s rule true for conditions such as Alzheimer’s Disease as well?
There certainly is some precedent. For example, cystic fibrosis (CF) is a potentially fatal autosomal recessive disease that occurs when an individual inherits two defective copies of the cystic fibrosis transmembrane transporter (CFTR) gene. However, epidemiological studies have suggested that those who inherit only one defective copy of the gene are more resistant to cholera or tuberculosis, bacterial diseases that together still kill tens of thousands of people annually. Hence, the strong protective value of one defective copy of the CFTR gene explains its commonality in the gene pool and provides good reason to believe that other factors which cause one disease can protect us from another.
This may be true for heart disease as well. Over the past several years, scientists have shown that a disorder of the bone marrow referred to as clonal hematopoiesis (CH) increases the risk for heart disease. The bone marrow provides a nursery for the growth of the stem cells that produce red and white blood cells. Occasionally, these rapidly dividing stem cells will mutate in such a manner that they grow more quickly than the surrounding cells. Over the course of decades, even a small advantage in reproductive rate can lead to the more rapidly dividing cells replacing the nonmutated cells. If this “clonal” stem cell line replaces more than 1 or 2% of the white blood cells (WBCs) in circulation, this is referred to as CH. Like many disorders of cell proliferation, CH becomes more common as we age. At least 10% of all of those over the age of 70 have some degree of CH. Unfortunately, generally speaking, being diagnosed with CH is not welcome news because it is associated with an increased risk for both cancer and coronary heart disease (CHD).
However, recently released studies suggest that there may be a silver lining to the dark cloud of CH for those concerned about the risk of dementia. Specifically, a leading theory for Alzheimer’s Disease (AD), the most common form of dementia, stipulates that AD is caused by the failure of brain specific immune cells referred to as microglia to clear inflammatory protein aggregates resulting in the death of neurons responsible for memory and cognition. Using archived data, a group of researchers from the TOPMed Consortium is now reporting that in those with CH, the mutant WBCs appear to supplement the failing glial cells’ efforts to remove these proteinaceous protein plaques and provide protection against AD.
These findings are creating renewed interest in the Alzheimer’s disease research community that immunotherapy may be a powerful tool to reverse the effects of aging on the brain; it just may be getting the right balance of immune cell activation. This is not easy to achieve. Although it removes some plaques, the recent FDA approved drug called Aducanumab, which is an antibody that targets the amyloid protein, may not clear enough amyloid plaques to be clinically effective. Conversely, immunization approaches can clear amyloid brain plaques in patients. Unfortunately, in prior clinical trials, these anti-amyloid protein vaccines have caused unacceptably high rates of severe side effects related to high levels of immune activation. The question is whether there is a middle ground of immune activation that can clear the plaques without killing the patient. In that regard, the findings from the TOPMed consortium are extremely intriguing. Because the precursor cells for the brain microglia all originate from the bone marrow, their findings suggest that it may be possible to prevent or treat Alzheimer’s Disease by modestly elevating brain microglia activity by supplementing the aging cells with newly created cells targeted to the brain. Unfortunately, developing and testing those potential therapies could take decades. But from a mechanistic point of view, there seems to be no fundamental barrier that could prevent this risk factor for heart disease from being transformed into a new treatment for Alzheimer’s.
But while these treatments are being developed, it is still important to focus on the prevention of heart disease, which is the leading cause of death in the United States and an important cause of other types of dementia including multi-infarct dementia. Fortunately, using some of the same subjects used by the TOPMed Consortium, we have developed Epi+Gen CHD, a state-of-the-art integrated genetic epigenetic test for detecting risk for coronary heart disease. In head-to-head testing, Epi+Gen CHD™ markedly outperformed archaic lipid-based tests in predicting risk for heart disease.
As we strive to build a better future for ourselves, we should use the best medical tools available. If you believe that you may be at risk for heart disease, try Epi+Gen CHD™. It could be your NextGen guide for healthier cardiovascular aging even if your physician recommends more vigorous exercise.
Resources:
- https://royalsocietypublishing.org/doi/10.1098/rsif.2006.0154
- https://www.nejm.org/doi/full/10.1056/NEJMoa1701719
- https://www.embopress.org/doi/full/10.15252/emmm.201606210
- https://www.medrxiv.org/content/10.1101/2021.12.10.21267552v1
- https://immunityageing.biomedcentral.com/articles/10.1186/1742-4933-1-2
- https://www.futuremedicine.com/doi/full/10.2217/epi-2021-0123