One year closes and another begins. Here are the 2012 Alzheimer’s disease research highlights, as well as new directions that we will likely be heading during 2013.
The Horizon: What Does 2013 Hold in Store?
- Genetic Insights: Among the important discoveries of 2012 was the identification of a genetic mutation that protects people from developing Alzheimer's disease. The mutation in Amyloid Precursor Protein (APP) significantly decreases the amount of beta-amyloid a person makes (about 40 percent), conferring a resistance to developing Alzheimer's. Just to review, all neurons secrete APP, and APP is cleaved by two scissor-like proteins, gamma secretase and beta secretase. This leads to the production of beta-amyloid, a toxic protein fragment that accumulates in the brain over time, causing brain cell damage eventually leading to dementia.During 2012, we also saw the identification of numerous Alzheimer's disease susceptibility genes. The Alzheimer’s Disease Genetics Consortium reported genetic analysis of more than 11,000 people with Alzheimer’s disease and a nearly equal number of elderly people who have no symptoms of dementia. Three other consortia contributed confirming data from additional people, bringing the total number of people analyzed to over 54,000. Until recently, only four genes associated with late-onset Alzheimer's had been confirmed, with the gene for apolipoprotein E-e4, also called APOE4, having the largest effect on risk. These findings added another five — cMS4A, CD2AP, CD33, ABCA7 and EPHA1 — thereby doubling the number of genes known to contribute Alzheimer's disease. Later in the year, an additional susceptibility gene was identified, TREM2, also using genome-wide sequencing. The manner in which these genes contribute to Alzheimer's disease are being carefully scrutinized, as each may represent a potential target for treatment.
- New Steps to Understanding Prevention: In 2012, we saw the launch of an unprecedented clinical trial, being run by an international collaboration of researchers in academia and industry, to prevent dementia due to Alzheimer's disease by treating patients with a drug before any cognitive symptoms appear. The trial, called the Alzheimer's Prevention Initiative (API), is being led by Eric Reiman, M.D., at the Banner Alzheimer’s Institute in Phoenix, Arizona, and Francisco Lopera, M.D., and his colleagues at the University of Antioquia in Colombia. During the past two years, these scientists and their colleagues have enrolled members of the world’s largest kindred afflicted with a mutation that leads to early onset Alzheimer's.
- Forward Movement in Vaccine Study: The results of the Phase I study of Novartis’ CAD106 vaccine against beta-amyloid is another notable moment in Alzheimer's research from 2012. This is the second vaccine study for Alzheimer's disease. The first human vaccination trial in Alzheimer's (Elan’s AN-1792) was done almost a decade ago and was discontinued due to adverse reaction. In contrast, CAD106 was well tolerated and will hopefully be used in a larger, Phase 2 study.
- Other learnings: During last summer, there was a flurry of results from multiple Phase 3 trials for Alzheimer's. The results of two Phase 3 trials of intravenous bapineuzumab, a monoclonal antibody against beta-amyloid, showed that it failed to meet its primary endpoints in patients with mild to moderate Alzheimer’s disease. However, data from Eli Lilly’s solanezumab study, as well as the independent ADCS analysis of the trial, showed that the drug slowed down the rate of cognitive decline in patients with mild Alzheimer's disease by about 34 percent. Moreover, in looking at subjects who had positive amyloid PET scans, there was a statistically significant change in total beta-amyloid in cerebral spinal fluid (CSF), a biomarker of Alzheimer's disease. Both of these findings are quite exciting. A Phase 3 study of solanezumab in mild Alzheimer's disease is being planned.We also saw the end of the gamma-secretase inhibitor, avagacestat, which followed in the footsteps of another drug in the same class, semagacestat. Both were shown to have trends toward worsening cognition as an adverse effect. Meanwhile beta-secretase inhibitors, as well as gamma-secretase ‘modulators’ move forward in the drug pipeline and are thought to hold great promise. In addition, the FDA approval of Amyvid as an amyloid imaging tracer for PET scans represents a major milestone in the clinical evaluation of Alzheimer's. Other tracers are being developed and may be approved this upcoming year.
We eagerly await the results from the Phase 3 clinical trial of Intravenous immunoglobulin (IGIV) in mild to moderate Alzheimer's. In addition, the launch of the Down Syndrome Biomarker Initiative (DSBI) will undoubtedly help us better understand how Alzheimer's develops in Down Syndrome and perhaps identify novel biomarkers of Alzheimer's. Additional data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN) studies are expected, focusing on identifying the earliest changes seen in the Alzheimer's brain. Additional clinical trials in Alzheimer's and presymptomatic Alzheimer's are ongoing, with several new compounds being prepared for launch in mid-2013. One of these includes the intranasal insulin study, which has had positive early results and is being conducted by the ADCS.We look forward to keeping you updated on what is happening in the world of Alzheimer's research in the upcoming year and are optimistic that there will be great developments in the field in 2013. Stay tuned. Michael S. Rafii, M.D., Ph.D.
Director, Memory Disorders Clinic Associate Medical Core Director, Alzheimer's Disease Cooperative Study
University of California San Diego This post originally appeared in Alzheimer's Insights, an ADCS Blog.