Last week, the National Institute of Health announced funding of four research studies designed to find new treatments for Alzheimer’s Disease.  The studies will help answer these questions:

• Will drugs that reduce the levels of beta amyloid protein (ABeta) in the brain be more effective if they are   taken before people exhibit symptoms of Alzheimer’s disease?
• Will vigorous exercise reduce the amount of ABeta in the brain?
• Will drugs that lower adrenalin in the brain reduce agitation in Alzheimer’s patients?
• Will advanced methods of sampling spinal fluid and plasma reliably speed up research efforts?

 

All the studies will be conducted under the auspices of the Alzheimer’s Disease Cooperative Study (ADCS), a national consortium of academic and medical centers.  The NIH will provide $11 million for these studies in 2013, and expects to fund up to $55 million over the three year span of these research projects.

 Past Research Findings

A hallmark of Alzheimer’s disease is the presence of high levels of amyloid protein (ABeta) in the brain.  Until recently, the only definitive diagnosis of Alzheimer’s disease occurred upon autopsy.  In the past few years, researchers have identified genes associated with Alzheimer’s disease, and they have developed scanning techniques that can measure and mark the amount of ABeta.

Despite these successes, researchers do not yet understand the biologic mechanisms that trigger Alzheimer’s disease.   They know that ABeta causes “plaques” to form on the brain, and they have learned that after these plaques form,  Alzheimer patients develop high levels of another protein, Tau, which forms“tangles” of protein on the brain.

Researchers do not yet know what triggers the abnormal accretion of these proteins, or the relationship between them.  The goal of much research is to reduce the level of these proteins once they are generated, or prevent their production.  Several research trials ended their Phase 3 clinical trials this past fall, and most failed to demonstrate efficacy in stopping or slowing the progression of Alzheimer’s.  Researchers are now hypothesizing that treatment programs must start well before the onset of symptoms, because at that point, the brain is too damaged by the disease process to respond to drugs.  Analogies are made to the treatment of coronary disease when medication to control cholesterol and blood pressure are most effective when started well before evidence of heart disease appears.

The rest of this blog discusses the primary research trial the NIH is supporting in this round of funding, the A4 study, which will test the hypothesis that drugs given to people before they develop symptoms of Alzheimer’s disease will be more effective in slowing down or preventing the development of Alzheimer’s.  Subsequent blogs will describe the other research trials that are receiving NIH funding this year.

 The Anti-Amyloid Trial (A4)

 The bulk of the NIH funding just announced will support the study of anti-amyloid treatment in asymptomatic people (the A4 Study).  This study will test Eli Lilly’s Solanezumab, a drug that completed a clinical trial on people with mild to moderate cognitive impairment last fall.

The initial trial results suggested that Solanezumab had no statistically significant impact on the progression of Alzheimer’s disease.  However, a further review of the data by the ADCS showed that participants with only mild cognitive impairment had a measurable slowing in cognitive decline and a reduction of amyloid in their spinal fluid.

The A4 study will select 1,000  participants over the age of 70, whose brain scans show abnormal levels of amyloid, but whose cognitive testing show no or only very mild cognitive impairment.  The participants will be divided into two groups, one of which will receive a placebo, and the other group will receive Solanezumab.  Participants will be followed for 3 years, and will undergo periodic PET scans and cognitive testing to track the progression of cognitive decline and changes in the brain.

This trial will give further information about whether anti-amyloid drugs can be more effective in either slowing the rate of decline or preventing decline if given before the disease has become symptomatic.  The principal investigator for this trial is Reisa Sperling of the Brigham and Women’s Hospital.

Heather Sawitsky