Alzheimer’s disease is characterized by two signature proteins, the amyloid plaques, outside of brain cells, and the Tau tangles, inside brain cells. Although these pathological hallmarks of Alzheimer’s disease were first described by Dr. Alois Alzheimer well over 100 years ago, the pathogenesis has not yet been clearly defined. Current FDA-approved and investigational treatments are based on the most popular theory, the “amyloid cascade hypotheses”, which describes a “trigger-bullet” process where the extracellular amyloid plaque triggers the hyper phosphorylation of the intracellular Tau forming insoluble neurofibrillary tangles.
These pathologic changes appear to begin decades prior to the onset of neurodegeneration and clinical symptoms. However, they can also be seen with normal aging. In fact when Dr. Alzheimer first described the disease pathologically, the presence of the amyloid plaque was already well-known and felt to be a part of normal aging. Some older individuals develop a very large amount of amyloid plaque (termed “pathological aging”) with virtually no Tau tangles, and although some may have abnormal neuropsych testing, they do not appear to develop dementia. Hence, both proteins need to be present to make the pathological diagnosis of definite Alzheimer’s disease, although in rare cases, a patient with dementia can present a large amount of tangles with few plaques (termed “tangle predominant Alzheimer’s disease”).
Two of the strongest risk factors for the development of Alzheimer’s dementia are (1) advancing age, with the incidence and prevalence doubling every 5 years over the age of 65, as well as (2) genetic predisposition. The rare cases of early onset Alzheimer’s disease, with the clinical age of onset typically in the 30s to 50s, are familial and inherited in an autosomal dominant fashion. Three major mutations have been linked to those cases, the most common one being on Presenilin. For the more typical late onset Alzheimer’s disease, which represent over 95 percent of patients, multiple gene changes have been described.
Contrary to the familial form of the disease, those do not predict who will develop the disease but instead indicate an increased risk. The most well-known one is the ApoE4 allele. On the other hand, some gene changes have been shown to be protective against the development of Alzheimer’s disease, such as the ApoE2 allele as well as the more recently discovered “Icelandic Mutation”. The Icelandic mutation prevents the cleavage of the amyloid precursor protein and thus the formation of amyloid plaques. The presence of this mutation, affecting about 1 in a 100 inhabitants of Iceland, results in a significant decrease in the development of Alzheimer’s disease and appears to have a protective effect even in patients with the ApoE4 allele.
FDA-approved pharmacologic treatments for Alzheimer’s disease are symptomatic, they target the symptoms of the disease, not its causes (the plaques and the tangles). These treatments have proven disappointing over the last 20 years or so since first introduced. The last FDA-approved treatment for Alzheimer’s dementia, Memantine, was approved over 10 years ago. Other approaches have come from medical food. Axona is a coconut oil-based medical food currently regulated by the FDA and has been available for about 5 years. A phase 3 clinical trial is ongoing, which if positive may lead to FDA approval of Axona as the most recent pharmacologic/metabolic strategy to treat Alzheimer’s disease. Based on earlier phase 2 trials, it appears to be effective only in patients who are ApoE4 negative.
These treatments however are only symptomatic and typically have limited short-lived efficacy, if any. Research is looking at disease modifying treatments, targeting the causes of the disease. There are multiple ongoing clinical trials targeting both the amyloid plaques and Tau tangles. Thus far, at least with the efforts targeting the amyloid protein, the results have not been as good as expected. However, these proteins begin to form decades prior to the onset of clinical symptoms and it is felt that perhaps in those studies the patients began treatment too late in the disease. Indeed, patients who began treatment with very minimal symptoms did seem to show a better response. An ongoing study, in part sponsored by the National Institute of Health, is targeting patients who have amyloid plaques, as documented by an amyloid labeling cerebral PET scan, but no symptoms of dementia. It is hoped that by removing the amyloid, the progression of the disease can be prevented or slowed down.
Two patients with the same amount of plaques and tangles could have their memory affected at different levels. This well-known “disconnect” has been attributed to environmental factors during life such as mental and physical stimulation, socialization, a diet high in polyphenols (antioxidants), found in bright fruits and dark vegetables, and low in saturated and trans-fats. Likewise it appears that a low carbohydrate diet may be good for more than glycemic and weight control. Stress management may also play a role with regards to lowering Cortisol levels leading to lower glucose and insulin levels. Patients with Alzheimer’s disease display impaired glucose utilization by the brain prior to the onset of symptoms. Axona, the coconut oil medical food, exploit this observation by supplying ketone bodies for the brain to utilize instead of glucose. It likewise appears that patients with Alzheimer’s disease may have low brain omega-3 fatty acids, which are a very important part of cell membrane integrity and cell signaling. Dietary intake of these unsaturated fats may play a role in modifying the development of Alzheimer’s disease pathology. Numerous studies have also shown that mild exercise, such as walking 30-40 minutes 3 times per week has a favorable effect on cognitive function, possibly mediated through an increased release of Brain Derived Neurotrophic Factor and resultant synaptic health and synaptic sprouting. Likewise, learning, through reading and other forms of mental stimulation, appears to be associated with increased synaptic formation and stabilization or improvement of cognitive functions with results at least as good as the currently available pharmacologic treatments and at no risk or cost to the patient. These strategies can be implemented alone or along with the available and soon to come pharmacologic options.
By Ira Goodman, MD
Ira Goodman, MD, is Director of Neurosciences at Compass Research. He is a board-certified neurologist specializing in Parkinson’s disease and memory disorders such as dementia and Alzheimer’s disease. Dr. Goodman is also an associate professor of neurology at the University of Central Florida College of Medicine, as well as an associate clinical professor of neurology at the University of Florida College of Medicine. Goodman was named “Top Neurologist in the Country” by U.S. News & World Report and ranked “Top Neurologist in Central Florida” for 14 consecutive years by Orlando Magazine. To contact Compass Research, please call 407-426-9299.