Q&A With Reisa Sperling, Brigham and Women’s Hospital, who leads the A4 trial with Paul Aisen, University of California, San Diego. Questions by Gabrielle Strobel.

Q: Many Alzforum readers have heard some reference about the Anti-Amyloid Treatment in Asymptomatic Trial, or A4 for short. What exactly is it?

A: A4 is a new secondary prevention trial effort aimed at treating older individuals at risk for developing Alzheimer’s disease dementia on the basis of having biomarker evidence of amyloid. We will test the hypothesis that decreasing amyloid burden during the preclinical stages of AD will impact “downstream neurodegeneration” and hopefully delay cognitive decline.

Q: What’s its status in December 2011?

A: We will propose the trial as part of the Alzheimer's Disease Cooperative Study’s NIA grant renewal in March 2012. It will be reviewed over the summer, and we hope to start screening in early 2013. So right now we are in the planning stages for the proposal. For example, we have determined that it will be clear that, although the ADCS budget will provide a majority of support for the trial, we will need industry partners both for drug and for PET amyloid screening. We are in the midst of talks with a variety of industry partners to find out how we make this win-win for both sides so that we can keep it an academic trial but get the support we need. We are also seeking philanthropic support.

Q: Why push for this trial now, in a tight funding climate?

A: It is critical to start these studies as soon as possible, as the cost of waiting another five to 10 years is not tenable. The overall scientific rationale for secondary prevention is strong. Plus, we have seen positive developments recently on what used to be a relative weakness, i.e., the absence of a suitable outcome measure. Specifically, there is more emerging data regarding evidence of subtle memory impairment (Rentz et al., 2011) and increased risk of cognitive decline in amyloid-positive older individuals (Villemagne et al., 2011; Morris et al., 2009). Some additional longitudinal data are currently under review and will hopefully be out in the next few months. The converging data from multiple longitudinal studies will be helpful in allowing us to design a trial that will detect decline from “normal” to subtly “abnormal” within the three-year time frame of the A4 trial.

Q: What sorts of people will the A4 trial enroll?

A: Clinically normal older individuals (over 70 years old) who will be screened with PET amyloid imaging, and are found to be “amyloid-positive.” We will pick an anti-amyloid agent that has demonstrated activity against Aβ in humans. Potential therapeutic agents need to have at least one to two years of safety data, and that narrows down possible agents. Because we are looking to treat a population without a deterministic mutation, i.e., without a near-certain genetic risk, it is important to have adequate safety data to inform normal older subjects. We will treat subjects for three years with the anti-amyloid drug or placebo, and then ideally follow them even beyond treatment to see if we can impact the trajectory of cognitive decline.

Q: How will A4 be different from DIAN?

A: Of course, we are addressing a very different population: asymptomatic individuals who may be at the earliest stage of sporadic AD, as opposed to individuals with mutations associated with autosomal-dominant AD. We will take a somewhat different tack than DIAN, in that we will likely pick one drug and do a one-arm drug versus placebo. The reason is that our primary outcome will be cognition with biomarkers as exploratory. Our preliminary analyses suggest if we really start with cognitively normal people, we will need all the power we can get to detect a slowing in the rate of cognitive decline, as these individuals decline slowly and there is variability in the rate of decline. Nevertheless, it looks like we can detect a 25-35 percent drug effect on the rate of decline on a composite cognitive measure with 300-500 subjects per arm. Thus, we will likely choose a single drug. At this point, it is likely to be a monoclonal antibody, as several of these agents have shown evidence of biological activity against Aβ in humans.

In contrast, my understanding is that DIAN will test initially three drugs in smaller trials, and use an adaptive design based on biomarkers. DIAN may also have more power to detect clinical change, because DIAN will also include carriers who are already symptomatic. That is a terrific design for DIAN, as the autosomal-dominant population is very precious and a limited resource. The “good” news for A4 is that there is a nearly unlimited supply of Baby Boomers entering the age of risk for AD, and if one-third of these individuals are amyloid-positive, there will be many potential participants. We want to do a large enough proof-of-concept study to see a signal on a clinical measure, as that is what is really needed in the field!

Q: Why prior to MCI? What are the entry criteria?

A: I believe MCI may even be too late for an anti-amyloid treatment. We know that if we pick people who have a little bit of memory trouble—who are at the mean or below on a cognitive test, or demonstrated a hint of decline, or anything that says they are not quite normal—then we increase the likelihood they will decline over three years. That makes for an efficient trial design. But I am concerned that even this might be already suboptimal for intervening with an anti-amyloid therapy alone.

Q: What would you rather do?

A: My dream is a trial that can address this question. In other words, a trial that enrolls a large enough sample of amyloid-positive people and stratifies them on the basis of whether they have any evidence of downstream neurodegeneration or memory trouble as well. Then we could directly ask this question of whether the treatment response changes depending on where in the long pathophysiological process you intervene with an anti-amyloid. Does it matter at what point you intervene in the course of preclinical AD? This is a key question. Importantly, we will also get critical natural history data from the placebo arm.

Q: What do you suspect is the answer?

A: Some people argue that the right folks to enroll are amyloid positive but before their CSF tau is very high. But up to 50 percent of the amyloid-positive cognitively normal people already have high tau before any cognitive problems. My point is, by the time there are symptoms in amyloid-positive people, the vast majority have elevated tau. So that in my mind becomes the critical question: Can we still intervene with an anti-amyloid treatment when the downstream cascade has already begun? I’d like to have a trial big enough where we can ask that question.

Q: Are the participants going to be there?

A: I think so. Another thing I am working to figure out at this point in the planning is how to increase power with international collaboration. I believe we can find 600-1,000 participants in the U.S. using the excellent site infrastructure of the ADCS. To go beyond that, we would like to collaborate with the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL), who have several hundred individuals enrolled in their natural history amyloid studies, and potentially with Bruno Vellas in France, who has a large cohort. If so, then we can go beyond 1,000 and have enough power to stratify on a number of variables.

Q: How about frequentist versus adaptive designs?

A: We have been discussing adaptive designs in which we would do an interim analysis to look at amyloid-lowering on PET and degree of decline in the placebo group, and potentially extend the trial if the placebo group has not declined enough. However, right now it is not clear that we have adequate information to make short-term decisions to adapt the design.

Q: Since we are speaking about dreams for a future trial, how about a second drug? For example, could A4 test a tau-based agent along with an anti-amyloid agent? I hear a lot of agreement that treatment combinations are the way of the future, but no one seems ready to test any.

A: If there is a tau agent with adequate safety data by 2013, we would love to do a 2x2 factorial design, but it is unlikely that there will be adequate safety data available in time, in particular, any safety data on combination therapy. Another possibility would be two anti-amyloid drugs, one that targets Aβ production and another that targets amyloid clearance. But I don’t think we should wait to start the A4 trial, and it is unlikely we will have the ability to test combination therapy in a large, long trial within the next year or two. So I think we should take our best shot with one drug now and learn all that we can about the changes in biomarkers and cognition, so that the next trials can be more efficient, allowing us to test several agents.

Q: Thank you for this interview.

This is Part 3 of a three-part series. See also Part 1 and Part 2. Download a PDF of the entire series.


  1. If one defines "AD prevention" broadly, then there already has been a recent prevention trial using biomarkers, namely, one led by Bruno Dubois of donepezil in people who met the new diagnostic criteria for prodromal AD. While the trial differs in that it used an approved drug and enrolled symptomatic patients essentially at the MCI stage, it is still worth amending this news story with discussion of that trial (see also ARF related news story). Of particular interest in this context are the endpoints used and how they affect the design of clinical trials in very early Alzheimer's such as A4, which aims at testing anti-amyloid treatments at preclinical stages. Dubois reported a 45 percent reduction in hippocampal atrophy in donepezil-treated patients versus the placebo group, with no changes in cognitive measures. That is, they detected protection when using a surrogate biomarker but not in clinical signs. This means that brain atrophy may be a more sensitive marker of AD-related neurodegeneration than current measures of cognitive decline.

    However, the trial may not have a clinical application in the short term because regulatory agencies only accept treatments with proven beneficial effects on cognition. This is probably why in the A4 trial, the investigators plan to use very subtle changes in cognitive decline as the main endpoint. An important consequence of this strategy is that the A4 trial will require 300-500 patients per arm and run for three years to achieve enough power. This is an incredibly costly design. For this reason, it is not realistic that the A4 trial becomes the paradigm to test preclinically the currently existing long list of drugs that await trial.

    Note that the donepezil trial required approximately 100 patients per arm and ran for a year. One solution is to validate as soon as possible brain atrophy as a biomarker of presymptomatic AD progression by developing longitudinal studies to establish the conversion into MCI of cognitively normal people at high risk according to PET and CSF amyloid-β measurements. This, however, may take many years.

    For the time being, another solution, as proposed by Pieter Jelle Visser, is to start screening drugs first in small trials with surrogate markers, and move to larger trials with cognitive endpoints only with successful candidates (Sperling et al., 2011). Looking at time projections, it is probable that by the time the short trials are finished, the regulatory agencies will have accepted surrogate markers to support drug approval for preclinical AD. There will then be no need to follow up in longer trials.

    In conclusion, it appears that the right strategy is to combine preclinical trials using surrogate biomarkers as endpoints with longitudinal trials to validate these biomarkers.


    . Testing the right target and right drug at the right stage. Sci Transl Med. 2011 Nov 30;3(111):111cm33. PubMed.

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News Citations

  1. DIAN Forms Pharma Consortium, Submits Treatment Trial Grant
  2. Reeling In Biomarker Data in Young Carriers, API Rocks Staging Boat

Paper Citations

  1. . Face-name associative memory performance is related to amyloid burden in normal elderly. Neuropsychologia. 2011 Jul;49(9):2776-83. PubMed.
  2. . Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Ann Neurol. 2011 Jan;69(1):181-92. PubMed.
  3. . Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol. 2009 Dec;66(12):1469-75. PubMed.

Other Citations

  1. Download a PDF of the entire series.

External Citations

  1. Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing

Further Reading


  1. . Testing the right target and right drug at the right stage. Sci Transl Med. 2011 Nov 30;3(111):111cm33. PubMed.
  2. . The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011 Sep;10(9):698-712. PubMed.