Formal Guidelines Issued for Alzheimer’s Genetic Testing

Communicating genetic information about Alzheimer’s disease to patients and families can be a daunting challenge. Clinicians and researchers faced with this task can take heart, however, because comprehensive guidelines for AD genetic testing and counseling are now available. Published in the June 2011 Genetics in Medicine and jointly issued by the American College of Medical Genetics and the National Society of Genetic Counselors, the guidelines spell out best practices for the field, and update and expand on previous recommendations the groups set forth for apolipoprotein E (ApoE) testing (see 1995 JAMA publication). For testing of asymptomatic people, the guidelines recommend adopting genetic counseling protocols pioneered for Huntington’s disease (HD), which are already in use by most AD researchers (see ARF related news story). The paper cites the Alzheimer Research Forum as one of several Web-based resources; ARF devotes a special section to early-onset familial AD and genetic testing.

Robert Green at Brigham and Women’s Hospital, Boston, said he believes the new guidelines are balanced and conservative. “I think they represent what people are essentially doing now, and reinforce good practices,” Green told ARF.

“The purpose [of the recommendations] was to give a guide to people who are not familiar with AD genetics: primary care doctors, neurologists who do not specialize in dementia, other folks who might be asked to do genetic testing,” explained first author Jill Goldman at Columbia University, New York City.

The paper distinguishes between genetic testing for dominantly inherited AD genes and that for the Alzheimer’s susceptibility gene ApoE (see below). The three early-onset familial AD genes—presenilin-1 (PS1), presenilin-2 (PS2), and amyloid precursor protein (APP)—confer almost 100 percent risk of developing AD, usually before the age of 60. Children of parents with the disease have a 50 percent chance of inheriting the gene, and may request pre-symptomatic testing.

The guidelines lay out several strong recommendations for this type of predictive testing, Goldman said. First, the gene mutation must be identified in an affected family member before any pre-symptomatic testing is done. This is because, if researchers do not know which mutation to look for, a negative test result in an asymptomatic person will not be meaningful.

Second, testing should never be offered to children, only to adults who can decide for themselves whether they want to have this genetic information. Third, researchers should follow the protocol established for HD, which includes pretest and post-test genetic counseling sessions in the presence of a patient-selected support person, as well as baseline neurological and psychiatric evaluations of the person to be tested. This procedure helps minimize the risk that a person will be overwhelmed by bad news.

After going through this process, Goldman said, most people elect not to find out their results. Those who do choose to learn their genetic makeup are “a very self-selected group of people who probably can cope with the information quite well,” she said. ARF previously interviewed coauthor Jennifer Williamson, a genetic counselor, on this topic (see ARF interview).

These guidelines are good, Lars Lannfelt at Uppsala University, Sweden, told ARF, but he personally believes researchers should be very cautious in revealing genetic information in case it does more harm than good.

Lannfelt cites an experience his group had in the 1990s when a young person who tested positive for a dominantly inherited AD gene became despondent and suicidal (see ARF related essay and ARF related essay). “I do not think I would ever recommend testing for AD genes,” Lannfelt said. He advises patients who are worried about AD to get regular checkups rather than genetic testing. “If people really understand and demand [testing], I think it is very difficult to say no,” Lannfelt said, adding that “you have to really take care of the people involved,” by offering counseling and support.

In contrast to dominantly inherited genes, testing for the AD susceptibility gene ApoE is a completely different case, Goldman said. The guidelines do not advocate for such testing. “The general consensus is, we would never deny somebody the ApoE test if he or she really wanted it, but it should not be thought of as diagnostic, and it’s not really pre-symptomatic testing,” Goldman notes. Although carrying a copy of the ApoE4 risk allele increases the odds of getting AD two- to threefold, many people with the risk allele do not get the disease, while others without the allele do develop AD. “We wish the media would stop calling [ApoE] the Alzheimer’s test,” Goldman said (see, e.g., this news story and this health website). “It is not the Alzheimer’s test, and it is not going to tell people what they really want to know.”

Green takes a slightly different view. “I do think people have a right to learn information about themselves. What remains to be seen is whether there are more constructive or less constructive ways for that information to be presented.” Green led the Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) study, which looked at the effects of telling people their ApoE genotype (see ARF related news story). Participants were a select group of highly educated volunteers, who were screened for psychiatric and anxiety disorders and carefully educated about the nature of the information, Green said.

Though they may not be representative of the public at large, he noted that these participants handled the genetic information quite well, using the knowledge to make positive changes in their lives, such as exercising or taking vitamins, that might reduce their risk of getting AD. “Increasingly, we are going to be dealing with a world where our goal is to prevent disease rather than just treat it,” Green noted. “In order to know whom to focus on for prevention, both clinicians and patients will have to become comfortable with calculating, communicating, and understanding risk information. We think what we are doing in REVEAL is very important; we think it is pointing toward the future.”

Complicating the picture is the fact that ApoE testing is now available from several commercial companies (see ARF related news story and ARF Live Discussion). This direct-to-consumer testing is disturbing to many in the field, Goldman said, because of the possibility that people may misunderstand test results. For example, most online services do not take into account family history, which is as equally important as ApoE status, Goldman cautioned. She worries about the false reassurance someone with a family history of the disease might feel upon learning he or she is negative for ApoE4. This could lead to poor decision-making, such as a failure to buy long-term care insurance. Lannfelt goes further, characterizing direct-to-consumer testing as “terrible.” Green notes, however, “The genie is out of the bottle. I don’t think there is going to be any way to prevent people who wish to understand genetic risk information from getting it.”

Another factor to consider is that genetic testing recommendations are a moving target, these scientists agreed. Guidelines will change as better AD treatments and diagnostics become available, Goldman said, and will probably be re-evaluated on a yearly basis. Lannfelt concurred.

“If we had [AD] drugs that were more effective, that would change the situation completely,” he said.

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