During two recent all-day discussions with academic, funding, and industry leaders, and now in a published article, Eric Reiman, Pierre Tariot, and Jessica Langbaum of the Banner Alzheimer’s Institute in Phoenix, Arizona, have laid out a vision for pre-symptomatic treatment trials that emphasize use of biomarkers to evaluate investigational drugs in people who find themselves in a particularly precarious situation. These are people who face the highest known risk of developing AD symptoms in the next five years but are still cognitively normal at the time they enter a given trial. The scientists make a case for offering the most promising treatments to people confronting this risk, while at the same time propelling a troubled AD clinical trials field into a new era of prevention research where their investigational drugs might work better. Call it an AD trials version of doing well while doing good. (See Parts 1 and 2 in this series.) This story describes who would gain access to trials offered by the Alzheimer’s Prevention Initiative (API).

One such group is middle-aged carriers of the E280A PS1 mutation discovered by Francisco Lopera in the state of Antioquia in central/northwestern Colombia. Together with Kenneth Kosik at the University of California, Santa Barbara, who co-identified this mutation in 1997 (Lopera et al., 1997), Reiman, Tariot, and Lopera are jointly preparing for this trial. Lopera and numerous collaborators in U.S. labs have analyzed this form of AD for 20 years, demonstrating plaque deposition (Lemere et al., 1996), abnormalities in cerebral perfusion (Johnson et al., 2001), modification by ApoE (Pastor et al., 2003), and describing its early onset (Arango-Lasprilla et al., 2007). Lopera, a neurologist, and his colleagues have followed many relatives in this kindred for several decades.

The E280A mutation affects the largest group of people worldwide of the more than 200 presenilin mutations known to date. Size matters, because the extreme rarity of autosomal-dominant AD severely limits the power of clinical research and indeed is one reason why the Dominantly Inherited Alzheimer Network (DIAN) has banded together across three continents. Living members of the E280A family tree number about 5,000 individuals spread among 25 families who live in the historically isolated region of Antioquia, Colombia. Nearly half of this “family” live in the city of Medellin, the capitol of Antioquia. Some 1,000 of those are estimated, and 400 already known, to carry the mutation. More than 100 currently known carriers are cognitively normal and older than 40, i.e., candidates for a pre-symptomatic trial now, according to Reiman. Some 2,000 family members have been genotyped, and more may choose to obtain genetic testing once a treatment trial is on offer.

Carriers start noticing subtle memory problems from age 40 on, Lopera said. Their median age of onset for MCI is 45, 47 for AD dementia. Certain cognitive tests, such as the Buschke memory test and tests measuring intrusion errors, can flag those who are likely to develop dementia 10 years before they do, Lopera said at an API planning meeting held October 2009 in Phoenix.

To take place successfully in Colombia, the proposed trial and attendant observational research will need to clear added cultural, financial, and logistic hurdles, as many trial participants are poor and have but a grade-level education. The effort requires political sensitivity and compassionate support of the study population with appropriate community services, Reiman emphasized. But it is nonetheless doable, Lopera assured attendees at the October 2009 meeting in Phoenix. “The families in Colombia are waiting for us to find the solution,” Lopera said. At the same meeting, Kosik confirmed, “These people are very keen to participate in clinical trials. They know they are likely to get this disease.”

They know from witnessing the disease in their families, not based on their carrier status. Because genetic counseling is unavailable in Colombia, Lopera does not disclose the PS1 test result. For the trial, too, participants would not learn their genotype. To balance the scientific need for randomization and placebo control with the ethical responsibility to protect study participants, the API scientists intend to treat only carriers with study drug, no non-carriers, and to enroll non-carriers into the control group so the study can be blinded. For deeper insight into the discovery and cultural circumstances of this Andean kindred, see The Fortune Teller, Kosik’s eloquent 1999 essay in The Sciences.

For this trial, Reiman and his colleagues have obtained initial funding to start screening some 1,000 relatives for inclusion. More funding is needed to conduct the trial and support participating local communities in consultation with Lopera and his team.

Because the Colombian families face essentially the same genetic form of AD as do participants in the ongoing DIAN, the API and DIAN have decided to join forces for what will be complementary pre-symptomatic AD trials in eFAD gene carriers. DIAN started out as—and is currently enrolling for—an NIA-supported observational study to characterize the pre-symptomatic phase of AD in cognitively normal carriers using a suite of biomarkers much like those in ADNI; DIAN plans for treatment studies based primarily on biomarker endpoints. In contrast, API is starting out as a clinical trials program; it aims to relate a treatment’s biomarker effects to clinical outcomes. But both efforts share the vision of pre-symptomatic treatment trials that richly embed biomarkers, and there is much they could do together. For example, if both initiatives run drug trials, family members in one initiative who don’t meet inclusion criteria for a given trial at the time they undergo screening may well qualify for a trial in the sister initiative, Reiman said. For its part, DIAN is exploring options to offer a clinical trial in about the same time frame as API (see Part 2). Coordinating with DIAN may, in turn, help Lopera and the API team to expand observational biomarker studies in Antioquia.

In addition, the API leaders have set their sights on a second group of people at exceptionally high risk of AD. They are those who carry two copies of the AD risk allele ApoE4 and have aged to near the median age of onset for this disease, 68. ApoE4 is a risk gene, not a deterministic one. Still, past the age of 60, the risk of developing AD in people with two ApoE4 genes grows so high that a secondary prevention trial becomes feasible, Reiman argued. Their relative risk of AD rises to 30:1 in community-based prospective research, and to 60-90 percent in cohort or case-control studies. Scientists in Phoenix agreed that the absolute risk of AD in this age group remains to be better defined; however, a large enough percentage of ApoE4 homozygous people at that age develop AD symptoms within the next five years that it becomes statistically possible to detect a difference between treatment and placebo.

Moreover, prior observational imaging and biomarker studies have provided a body of evidence suggesting that the brains of many people with this combined genetic/age risk already show signature AD-like changes (Reiman et al., 2001; Reiman et al., 2005; Chen et al., 2007; Reiman et al., 2009; Thambisetty et al., 2010). Their memory declines faster as they age, too (Caselli et al., 2009). In the ApoE API trial, also, imaging and biomarker measures would play a lead role, both to measure a drug effect and to tie drug-induced biomarker changes to later clinical protection. The details of how to accomplish this were the topic of intense discussion at an industry advisory meeting of the Banner scientists hosted in Phoenix last month; the trial’s basic premise drew wide support.

Such trials in ApoE4-positive people would begin to answer the question in the minds of some scientists of whether autosomal-dominant AD and late-onset AD will respond to the same kinds of treatment. In essence, this trial would make it possible to start assessing whether results from the Antioquia and DIAN trial hold true more broadly for the vast majority of people with AD.

How would the scientists pull off this trial? The ApoE4/4 genotype occurs in some 3 percent of the U.S. population, and current power calculations based on prior observational research call for some 400 trial participants. Many people who are initially screened for a study fail one of its inclusion criteria and some change their minds about enrolling; therefore, the API researchers are aiming to recruit for screening some 20,000 to 50,000 people between the ages of 60 and 80. Prospective participants would undergo genotyping for ApoE; people who have already done so in the course of their cardiovascular care, or as users of personal genomics services, would be eligible as well. In order to reach this many people interested in participating in such a study, the API researchers are building a screening registry. They are also reaching out to other scientific groups who have registries or are already working with ApoE-genotyped volunteers for observational studies, from ADNI to ADCS to adult children studies, as well as epidemiological cohorts and REVEAL.

For this trial, the API researchers currently envision disclosing ApoE genotype to participants, but they intend to manage this process carefully in accordance with findings from the REVEAL studies of ApoE genotype disclosure. “This study found that people weather genotype information better than previous scientific consensus groups had expected,” Reiman said in Phoenix (see also ARF Live Discussion). In general, concerns about ApoE genotype disclosure are seen to become less acute once a trial is on offer because it gives people a way to fight their risk beyond lifestyle changes, scientists in Phoenix agreed. One downside of disclosure the API scientists are weighing is that all participants’ adult children would automatically know that they carry at least one copy of ApoE4, increasing their own lifetime risk, even if they did not seek that information. Avoiding disclosure is possible but would require including non-carriers, hence drive up cost. The API scientists are hoping that the National Institute on Aging will support their initiative and allow them to seek federal funding for it this year.

For both trials, the researchers initially suggested a five-year, double-blind, placebo-controlled design with clinical, cognitive, FDG and amyloid PET, structural MRI, and CSF measurement at various visits. The scientists would analyze data midway through the trial to see whether, as judged largely on the basis of the biomarker data, the treatment was likely doing any good. Then, they either would continue or declare the initial treatment futile and switch to a different one. This design was intensely debated (see Part 4 of this series) and is not etched in stone yet, Reiman said. Whichever final design details prevail, the key point about the overall initiative is that it could provide a foundation and much-needed impetus for additional pre-symptomatic, randomized controlled trials in the future, he noted. On this, attendees at both API planning meetings agreed.

Also for both trials, the API researchers stressed that they wish to conduct them as much as possible in a pre-competitive fashion. A drive to seize common ground and work jointly on problems that hold back all otherwise competing pharma companies has buoyed ADNI and the ADCS. “The public-private collaboration on ADNI has worked so well that now we think we can do anything,” said Paul Aisen of the University of California, San Diego, who heads ADCS and participates in ADNI and DIAN. Representatives from different pharma companies as well as from the Foundation of the NIH agreed, and Reiman clearly wants to capitalize on the momentum. One way in which API foresees doing so is by tying joint funding and advice to open public access to the biomarker data these trials will generate. These data may speed the qualification of a surrogate marker, which in turn would boost the clinical development of AD treatments in general, not just the particular one(s) chosen for the API trials. This point, however, proved to be sticky. Once one competitor’s drug is on the table, shared interests “get stuck in quicksand,” as one pharma attendee phrased it. The day’s discussion made clear that a bright line emerges where drugs are concerned, especially investigational ones, and carving out real meaning for the “one for all, all for one” spirit will take creative thinking and deft negotiation. But everyone professed to the cause, at least verbally thus far (see Part 4).—Gabrielle Strobel.

This is Part 3 of a five-part series. See also Part 1, Part 2, Part 4, Part 5. See also a PDF of the entire series.


  1. The API project is important and valid, but I'd like to point out one oversight in this story. While the two study populations targeted at present are primarily selected on the basis of genetic risk, the non-genetic risk factors for AD, such as cardiovascular conditions and lifestyle risks, are significant. How intervening in these non-genetic risks will measure up against a drug treatment is unknown. In other words, treating an ApoE4/4 individual who also exercises and eats a Mediterranean diet may have a very different outcome compared to one who does not. Perhaps another benefit of the families in Antioquia is the relative uniformity of their lifestyle risks. Their diets and exercise levels are quite similar throughout the population.

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News Citations

  1. Phoenix: Vision of Shared Prevention Trials Lures Pharma to Table
  2. Phoenix: Can Alzheimer’s Prevention Initiative Break a Catch-22?
  3. Phoenix: For Shared Prevention Trials, Devil Is in the Details
  4. Phoenix: Making Trials Work for Patient, Sponsor, Regulator

Webinar Citations

  1. Susceptibility Testing and Risk Assessment in Alzheimer Disease

Paper Citations

  1. . Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997 Mar 12;277(10):793-9. PubMed.
  2. . The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med. 1996 Oct;2(10):1146-50. PubMed.
  3. . Presenilin-1-associated abnormalities in regional cerebral perfusion. Neurology. 2001 Jun 12;56(11):1545-51. PubMed.
  4. . Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann Neurol. 2003 Aug;54(2):163-9. PubMed.
  5. . Cognitive changes in the preclinical phase of familial Alzheimer's disease. J Clin Exp Neuropsychol. 2007 Nov;29(8):892-900. PubMed.
  6. . Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3334-9. PubMed.
  7. . Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8299-302. PubMed.
  8. . Correlations between apolipoprotein E epsilon4 gene dose and whole brain atrophy rates. Am J Psychiatry. 2007 Jun;164(6):916-21. PubMed.
  9. . Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6820-5. PubMed.
  10. . APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol. 2010 Jan;67(1):93-8. PubMed.
  11. . Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med. 2009 Jul 16;361(3):255-63. PubMed.

Other Citations

  1. PDF of the entire series

External Citations

  1. Dominantly Inherited Alzheimer Network (DIAN)
  2. The Fortune Teller

Further Reading