The field of Alzheimer research has reached an impasse after more than 100,000 clinical and scientific papers published in the last 40 years, because there is yet no hope, no effective treatment, and no knowledge of what causes this dementia.
It has become increasingly clear that part of the explanation for the lack of therapeutic advancement in Alzheimer’s disease (AD) lies in the unyielding quagmire resulting from the premise that AD is caused by the excessive production in the brain of a sticky substance called amyloid-β (Aβ). However, considerable data indicates this conclusion is not supported by evidence-based medicine, especially from a clinical perspective.
So, if the Aβ peptide is not the culprit of this devastating disease, what is?
We and others have submitted that AD is a vascular disorder with neurodegenerative consequences and, as proof of concept, we have presented compelling evidence from epidemiologic, neuroimaging, pharmacologic, clinical, and experimental data derived from our own studies and those of others in support of this proposal. Physicians should be aware that conventional wisdom has not appreciably improved AD pathology or disease outlook in the last 100 years since Alois Alzheimer first described the neurodegeneration that characterizes this dementia. Nor has the prevailing paradigm that Aβ causes AD engendered much hope that the future management and treatment of this disorder will result in a better quality of life for AD victims.
One is reminded that in the field of gastroenterology, the “acid-ulcer” hypothesis went similarly nowhere for decades in curing or understanding peptic ulcer disease until Barry Marshall and Robin Warren “discovered” in 1982, the spiral shaped-bacterium, H. pylori, from gastric biopsies and proved they were the underlying cause of gastritis and peptic ulcers. Before Marshall and Warren’s pathologic studies, it occurred to few experts that no antacid of any kind cured ulcer disease and therefore acid secretion could not possibly be the cause of the disease. Mindset for the acid-ulcer hypothesis that Warren and Marshall encountered are often hard to dispel even when evidence outweighs cherished convictions.
A strong association is now known to exist between cardiovascular and cerebrovascular pathology and AD. This association targets the elderly individual over age 60 and in the past was believed to only promote vascular dementia. The cardio-cerebral pathologic risk factors associated with AD appear to generate chronic cerebral hypoperfusion, a strong marker of AD and vascular dementia. A number of cardiac structural lesions involving valvular or ventricular dysfunction can result in a sustained reduction of cardiac output, which lowers cerebral blood flow. In addition, carotid artery stenosis, stemming from intima media thickening or vessel plaque formation, are also capable of chronically reducing blood flow to the brain, a process linked to cognitive deterioration. Elderly patients with such cardiac or extracranial vessel pathology are most likely to be seen by a general or family practice physician. It is essential that clinical assessment of the non-demented elderly person with mild memory complaints be referred for cost-effective screening using brain imaging, echocardiography, and carotid artery Doppler ultrasound. These tools may identify correctable or treatable risk factors contributing to brain hypoperfusion and the onset of cognitive decline. Such a clinical approach may have an important impact in reducing the number of new AD cases and the catastrophic socio-economic burden this disorder is expected to have on the U.S. healthcare system in the near future.
Consequently, it would appear that it is in the patients’ urgent interest and a prime scientific responsibility to recognize the possibility that conventional wisdom with respect to the Aβ hypothesis has thus far been incorrect in the classification and clinical management of AD. The proposal that AD is caused by vascular factors and advanced aging needs to be proved right or wrong as the case may be but it must be done with a sense of urgency because incipient AD patients cannot wait.
Most scientists are aware that their vision of a problem can be shaped by their assumptions. When the facts do not fit the theory, it is time to move on, not fester on the uncooperative facts by inventing other worthless facts that spiral into the original mistaken conclusion.
The village wisdom, passed on from generation to generation, used to say that when you discover that you are a riding a dead horse, the best strategy is to dismount. It is time to get off the dead horse that so far has only provided knee-jerk dogma and an absence of clinically useful measures. This action will be helpful so we can get on with more constructive research that searches for a valid pathway to defeat one of the most important medical challenges of this century.