In March, the Alzheimer’s Association released its annual facts and figures on Alzheimer disease (AD). The analysis revealed some sobering numbers. AD remains the number one cause of dementia among the elderly. An estimated 5.4 million Americans suffer from the disease, and it has become the sixth leading cause of death. More importantly, among the top 10 causes of death, AD remains the only one without truly effective treatment options.
Also released this year in Alzheimer and Dementia were new diagnostic criteria and guidelines for AD, which update the diagnosis and expand the condition to those that have mild cognitive impairment (MCI) due to AD. This recognition of an earlier condition agrees with the growing evidence that AD may begin many years, even decades, before clinical signs of dementia are evident.
Also included in the new criteria is a framework for the eventual addition of biomarkers in the diagnosis.
These biomarkers include measurements of structural changes in the brain, such as reduced hippocampal volume and medial temporal atrophy, as well as CSF measurements of the prime suspects in AD, Aβ, and tau.
While Aβ and tau are each hallmarks of the disease, they also represent the major front in the fight against AD. Johnson & Johnson, Pfizer, and Elan are developing a humanized antibody to beta-amyloid, called bapineuzumab, that is meant to clear Aβ from the brain.
A study published in Lancet Neurology in 2010 by Rinne and co-authors demonstrated that treatment with bapineuzumab reduced levels of Aβ in the brain. Encouragingly, recent data suggests that improvement in cognition may be occurring with treatment. However, positive effects may be limited to noncarriers of the primary genetic risk factor for AD known as APOE4.
Two other immunological approaches to Aβ are also in the works. Baxter is developing its infused immunoglobulin product, Gammagard, for AD, and Eli Lilly is developing its own humanized antibody to Aβ called solanezumab. Each of these products has reported modest success in delaying cognitive decline in AD. Unfortunately, none of these immunological approaches have produced the type of results that the field would like to see.
Another highly anticipated class of compounds are gamma secretase inhibitors, which reduce the activity of the enzyme complex that cleaves the amyloid precursor protein and thereby lowers Aβ production. One of the first gamma secretase inhibitors to undergo extensive clinical testing, Flurizan, was developed by Myriad Genetics. Myriad ran an extensive Phase III trial in the U.S. with Flurizan, yet the study missed all its clinical endpoints.
Eli Lilly advanced another well-studied gamma secretase inhibitor called semagacestat into the clinic. Unfortunately, the semagacestat trial was halted when it was found that patients in the treatment group were deteriorating faster than those in the control group.
Bristol-Myers Squibb has also developed a gamma secretase inhibitor called BMS-708163, which was studied in 209 mild-to-moderate AD participants and met its primary objective of identifying safe and tolerable doses. No improvements in cognitive outcomes were seen, however.
One of the most promising new therapies for AD in recent memory was the compound latrepirdine, more commonly known as dimebon. In a Phase II study published in The Lancet in 2008, dimebon demonstrated improvements across the board in cognitive tests, raising expectation that a truly effective therapy was on hand. However, a replication of the study in a larger population did not yield positive results.
With the disappointing results of recent drug trials, it is vital to open new avenues to tackle AD. A large study on supplementing the diet with the omega-3 fatty acid docosahexanenoic acid (DHA) was completed in 2010 and reported in the Journal of the American Medical Association.
This comprehensive study examined 402 individuals in a placebo-controlled, double-blind, 18-month study to measure the effects of 2 grams a day of DHA on cognitive performance. Unfortunately, supplementation with DHA did not improve cognitive performance, nor did it slow progression relative to placebo.
A similar approach examined the effects of a medical food comprising ingredients designed to provide the building blocks for synapses, including uridine, omega-3 polyunsaturated fatty acids, and choline. This combination had shown impressive preclinical results.
A proof-of-concept study published in Alzheimer’s and Dementia in 2010 examined the effects among 225 participants in 12 weeks of therapy compared to placebo in a double-blind, placebo-controlled study. Encouraging results were seen among a predefined subgroup of mild AD patients, prompting additional studies currently under way.
Another avenue for intervention is the well-characterized decreased cerebral metabolism that occurs in AD. This glucose hypometabolism is one of the earliest markers of the disease and interventions in this process have met with some success.
In a study published in Neurobiology of Aging, Craft and co-authors found that nasal insulin could result in rapid increase in cognition in AD patients. Similarly, in a study of 511 mild to moderate AD subjects published in the Journal of Pharmacogenomics in 2006, Risner and co-authors found that administration of the insulin-sensitizing agent rosiglitazone improved cognitive scores. Unfortunately, larger studies did not repeat the improvements seen with rosiglitazone.
Another approach to addressing hypometabolism involves the induction of ketosis. Ketosis is defined as the presence of ketone bodies in the blood. Ketone bodies are a normal product of human physiology and are produced under conditions of low glucose availability, such as during fasting or the use of ketogenic diets. Ketone bodies are one of the few substrates the brain can use for energy.
Two recent studies examined the induction of ketosis in AD. Both reports utilized medium chain triglycerides (MCTs) to induce ketosis. Instead of being stored as fat, MCTs undergo obligate oxidation in the liver and can induce ketosis even in the presence of a normal diet.
Amidst the failures have been a number of positives that continue to propel the field forward. Development of new treatments remains a top priority for industry, advocacy associations, and government agencies.