Abstract
The means are now at hand to conquer Alzheimer’s disease (AD). The method is to identify those at risk for the disease before clinical signs develop. That is followed by implementing measures that can effectively prevent disease development. Since biotechnology markers have shown that AD commences at least a decade before cognitive deficits set in, there is an extended window of opportunity to successfully prevent disease development. Methods of identifying those at risk include positron electron microscopy for AD senile plaques, blood or saliva analysis for elevation of the amyloid-β protein fragment terminating at position 42, and cerebrospinal fluid analysis showing a decrease in content of this protein. Of the modalities available, saliva is by far the simplest and least invasive. Once identified, those at risk can prevent disease development through self treatment by consumption of non-steroidal anti-inflammatory drugs, adhering to a Mediterranean diet, and consuming antioxidants such as quercitin which is contained in coffee.
DIMENSIONS OF THE ALZHEIMER’S DISEASE PROBLEM
It would be difficult to overstate the urgency of finding solutions to the Alzheimer’s disease (AD) problem. Alzheimer Disease International estimated that there are 35 million people suffering from this disorder at an annual cost of $604 billion. This estimate is contained in the 2010 World Alzheimer Report (http://www.alz.co.uk).
According to the World Health Organization (WHO), AD is the seventh leading cause of death in developed countries. The 2017 United States (US) Alzheimer’s Association Report estimates that more than 6 million people just in the US are living with AD. The cost of their care is estimated to be $259 billion, not including unpaid costs of volunteers. There are more than 500,000 US deaths from this cause each year. More ominously, both the WHO and US reports predict that unless effective measures of prevention and treatment AD are discovered, the number of cases may increase two to threefold by 2050.
AD does not affect young people. It is an age specific disorder, increasing dramatically with age in those vulnerable to the disease. Brookmeyer et al. [1] estimated the age-specific incidence rates of AD progressively increases from about 0.17% per year at age 65, to 0.71% at age 75, to 1.0% at age 80, and to 2.92% at age 85. These estimates were based on studies from Boston, Framingham, Rochester, and Baltimore. Such studies indicate that intervention, if it is to be successful, must be started at least a decade before the age of risk for a given individual.
PATHOGENESIS OF AD
AD is characterized by brain deposits of amyloid-β protein terminating at position 42 (Aβ42) [2]. It is a relatively insoluble peptide fraction of the amyloid-β protein precursor (AβPP). A more common fraction terminates at position 40 (Aβ40). However, this fraction is soluble and is much more readily phagocytosed. It does not accumulate in brain. If Aβ42 is permitted to accumulate in brain, it produces extracellular deposits in the form of senile plaques. These plaques stimulate an inflammatory response. The inflammatory response, in turn, fully activates the complement system [3]. This results in formation of the membrane attack complex that directly damages residual brain neurons. A progressive loss of these brain neurons occurs, which eventually results in the cognitive deficits that define clinical AD. The age of AD onset varies, presumably because the level of Aβ42 production varies. The higher the Aβ42 production, the earlier AD onset occurs. A given individual needs to decide when to begin a preventative regimen. This should be 10–15 years prior to the time a relative has come down with the disease.
We reported in 1990 that rheumatoid arthritics, who universally consume anti-inflammatory agents, were relatively spared from AD [4]. This has been confirmed in more than 17 epidemiological studies that have focused on consumption of non-steroidal anti-inflammatory drugs [5].
THERAPEUTIC ATTEMPTS
AD is a graveyard for expensive clinical drug trials. Chemistry World in its July 2014 issue reported that in the period between 2000 and 2012, 244 compounds were tested in 413 clinical trials. Only one was approved for use, indicating a failure rate of 99.6%. Even the one approved did not represent an advance. It was for memantine, an NMDA receptor antagonist, which reduces glutamatergic excitotoxicity. It is not an anti-inflammatory agent.
A research strategy that has been aggressively pursued, despite repeated failures, is to administer monoclonal antibodies against epitopes of Aβ. Antibodies are inappropriate because they must be administered parenterally and are not expected to cross the blood-brain barrier. Moreover, they are impractical as a long-term strategy. They would need to be administered parenterally at frequent intervals throughout life.
Nevertheless, enormous resources have been wasted pursuing this doomed-to-fail strategy. Two recent examples are bapineuzemab (Elan/JNJ & Pfizer) [6] and solanezumab (Lilly). Failure of the latter was announced at the 9th Clinical Trials on Alzheimer’s Disease meeting in 2016. Both underwent massive Phase III clinical trials which cost hundreds of millions of dollars, and both fell short of meeting their primary efficacy endpoints.
Reasons for this succession of failures include choosing an inappropriate target, choosing an inappropriate way of hitting a target, and commencing treatment too late to rescue cognitive function. The target is Aβ42, not Aβ40, or some other fraction of AβPP. There are other possible targets based on inhibiting the complement cascade but these have not yet been tested in clinical trials.
EPIDEMIOLOGICAL EVIDENCE OF PREVENTION
Compared with subjects in the lowest Mediterranean diet tertile, subjects in the middle tertile had an AD hazard ratio of 0.85 (95% CI, 0.63–1.16) and those in the highest tertile had a hazard ratio of 0.60 (95% CI, 0.42–0.87) (p for trend = 0.007). In a follow-up analysis, the Mediterranean diet was also associated with a reduced risk of developing mild cognitive impairment and of progression from mild cognitive impairment to AD [7].
METHODS FOR EARLY DIAGNOSIS OF AD AND PREDICTION OF LATER CLINICAL ONSET
Established methods for early diagnosis of AD include positron electron microscopy (PET) for AD senile plaques, blood or saliva analysis for elevation of Aβ42, and CSF analysis showing a decrease in content of this protein. These methodologies are expensive to carry out. Their availability is scarce and does not include the general public. The only method that might become available in the future is salivary analysis. It is already in use for DNA determination.
The average person has presently no method available for predicting vulnerability to AD other than family history. The risk of inheritance is 50% if either a parent or a sibling suffers from AD. If both parents suffered from AD, the risk increases to 75%. There will be false positives based on family history varying between 25% and 50%. False negatives are unlikely, since it would require both parents dying before the age of AD onset and all siblings being free of AD.
Saliva tests for Aβ42 may provide the widely available predictive test that is needed. Once identified, those at risk can lessen the chance of disease development by consumption of non-steroidal anti-inflammatory drugs, adhering to a Mediterranean diet, and consuming antioxidants such as quercetin which is contained in coffee [8].
False positives, as well as those at risk, can also enjoy benefits of the “Conquering AD” regimen since the benefits go well beyond AD itself. That is because several chronic degenerative disorders have an inflammatory basis. These include age related macular degeneration, Parkinson’s disease, frontal temporal dementia, multiple sclerosis, atherosclerosis, and numerous autoimmune disorders [2].
DISCLOSURE STATEMENT
Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/17-9913).