Cancer has been termed the emperor of maladies, but no illness carries quite the cruelty of Alzheimer’s disease as it unwinds both memory and cognitive function. It may have been best described by Indian author, Devdutt Pattanaik: “Alzheimer’s is the death of imagination.”

Genetic research that could prevent or treat Alzheimer’s — weapons to prolong a healthy mind — are under study. The caveat is that the human subjects recruited into trials must be willing to know if they carry the DNA markers that may predispose them to subsequent dementia. Is it better to know, while you still have your mind, that you may be at higher risk of losing it?

The gene with the strongest influence on later Alzheimer’s development is called ApoE4, explains Jessica Langbaum, PhD, associate director of the Alzheimer’s Prevention Initiative (API) and principal scientist at Banner Alzheimer’s Institute in Phoenix. The API Generation Study is enrolling more than 1,000 people who carry the most telling genetic signature for Alzheimer’s onset, two copies of the ApoE4 gene. Under study are two experimental interventions, a vaccine and an inhibitor.

“The Alzheimer’s Prevention Initiative is a multipartner, collaborative program that’s doing clinical trials in people who, based on their age and genetics, are at highest risk of developing cognitive symptoms of Alzheimer’s,” she says. “The Generation Study, in partnership with Novartis and Amgen, is enrolling people who are at highest risk for the most common form of Alzheimer’s in later life.”

The Generation Study exists in two parts, and thus there are two consent forms.

“In the first part, individuals consent to receiving their genetic ApoE4 test results and to be followed for a one-year period to monitor the short-term and longer-term impact of receiving [those genetic results],” Langbaum says.

Individuals who are invited into the study may have zero, one, or two copies of the cognitive-disabling ApoE4 gene, with the risk of developing Alzheimer’s ascending accordingly. The psychological effect of receiving this information, particularly for those at the highest risk with two copies of the gene, is addressed on initial consult and periodically thereafter.

“They meet with a genetic counselor or other healthcare professionals,” Langbaum says. “They are told their ApoE4 results and are monitored over time. Those that have two copies of the ApoE4 gene, after they have been told their genetic information, are invited into the more traditional clinical trial phase to be randomized to receive either an active immunotherapy drug, a base inhibitor drug or matching placebo [for each arm of the study]. They will be followed up for up to eight years to see if treatment delays the onset of cognitive impairment or a diagnosis of dementia.”


Whether they are in the randomized trial or not, all participants who agree to receive genetic test results are told those results in person by a genetic counselor and followed up by phone at regular intervals after that initial meeting.

“They receive a phone call soon thereafter within a two- to seven-day window,” she says. “We check in on them as well as assess [any signs of] depression, anxiety, and other measures of psychological well-being. Then they are followed up six weeks thereafter, then six months and 12 months.”

Langbaum and colleagues were careful to construct the IRB-approved trial in a way that participation does not reveal genetic status or risk factors for Alzheimer’s.

“Recruitment in the study has to be done in such a way so that the invitation in and of itself does not disclose your ApoE4 results,” she says. “In fact, we want people with a variety of ApoE4 results to come in because we really want to learn how receiving the genetic information is tolerated. Smaller studies have looked at this and said it is very safe and well tolerated to learn your ApoE4 test results. But most of those studies did not involve large numbers of people who are the highest risk — that is, they carry two copies of the ApoE4 gene. This study allows us to look at the impact of learning your genetic testing results if you have zero, one, or two copies.”

Participants can enter the trial through GeneMatch, a web-based program and registry with partners across the country. Those who enter the program through this method are provided a cheek swab kit to use at home. The swab is sent to an affiliated lab for DNA extraction and genetic testing. “Afterward, the DNA is destroyed and the results are kept in a safe and secure database,” Langbaum says. “We have an algorithm that we run that invites selected individuals — we don’t ever publicly disclose what that ratio is. It could be people with one, two, or zero copies of the ApoE4 gene. We invite them to participate in the Generation Study, but let them know that they have to be willing to learn their ApoE4 test results. The choice is always theirs whether they participate or not, and we also let them know that people with a variety of ApoE4 profiles are receiving this invitation.”

If the gene match participants accept the study invitation, they are then passed along to the enrolling Generation site closest to them to sign a consent that they will receive their test results. Compared to past studies and general perceptions, Langbaum and colleagues have found the risk is relatively low, but development of subsequent Alzheimer’s cannot be ruled in or out regardless of the genetic results.

“We worked with an epidemiologist to analyze data from several different cohort studies to be able to tell participants information about their risk of developing Alzheimer’s dementia by age 85,” she says. “[We found] if you have two copies of the ApoE4 gene, then the risk ranges from 30% to 50% of developing Alzheimer’s dementia by age 85. We also acknowledge that there are factors that can either increase your risk or decrease your risk — things like family history, a history of heart disease. For the most part, our initial people are coming back and saying, ‘Wow, that’s much lower than I thought it was.’ But we can’t give a very accurate [estimate]. We can’t say to this individual, ‘Your risk is 47%.’ We are not there yet.’”

The purpose of the study is to test whether two investigational drugs called CAD106 immunotherapy and CNP520, administered separately, can slow down the onset and progression of clinical symptoms associated with Alzheimer’s in participants at the risk to develop clinical symptoms based on their age (60-75 years) and genotype. Both drugs target amyloid plaque in the brain, a biomarker for increased risk of dementia.

Implications for Other Research

The study owes a debt to prior oncology research, and holds the promise to repay that to other areas of research that reach such an ethical impasse.

“It is a model not only for Alzheimer’s disease, but for other neurodegenerative diseases and other disease areas,” Langbaum says. “For example, oncology has made a great deal of progress at disclosing genetic results. In fact, in our model for genetic testing and disclosures, we have really learned a lot from our colleagues in oncology. As we move into this, we are telling healthy people their genetic risk and trying to see if we can prevent the onset of cognitive impairments.”

In that sense, this line of research is nearing the edge of the known map in terms of genetic disclosures in clinical trials.

“In a way, we are giving these people a label that they never had before,” she says. “This is an important new space that we are in of research. How do we continue to monitor the well-being of these individuals and what protections are available for these people?”

For instance, the Genetic Information Nondiscrimination Act (GINA) of 2008 doesn’t clearly cover this situation, she says.

“There are many caveats to [genetic test disclosure] — long-term care insurance and things like that,” she says. “We have to make people aware of all these factors before we disclose. This is uncharted territory from a federal protections standpoint.”

The trial requires agreement of disclosure of results to participate, but some people don’t want to know for their own reasons, or because it may end on up their medical records as a pre-existing condition.

“Most people say they may get their life insurance in place beforehand,” she says. “Others say they are not interested because they are afraid of the unintended consequences when it comes to their medical and long-term care insurance.”