by Edmund Howe, MD, JD

Dr. Howe is Professor, Department of Psychiatry, Director, Programs in Medical Ethics, and Senior Scientist, Center for the Study of Traumatic Stress, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

Psychiatry (Edgemont) 2010;7(10):45–51


Alzheimer’s disease is a devastating illness, and patients may be exceptionally concerned that they have genes that contribute to this illness, especially if there is a family history of Alzheimer’s disease. This article reviews core findings regarding the genes that contribute to the early-onset (familial) and late-onset forms of Alzheimer’s disease and related findings regarding the needs of psychiatrists when discussing the disease with patients. Previously, clinicians believed that patients who tested positive for the APOE gene linked to late-onset Alzheimer’s disease would be harmed by this knowledge to a greater extent than those who did not know they had the gene. Thus, clinicians were strongly recommending to patients that they not have this testing. This article includes the practice-changing relevance of a recent study published in the New England Journal of Medicine, which reported that a group of patients tested for the APOE gene who found out that they were positive for this gene were not significantly harmed by having acquired this knowledge.

Key Words
Alzheimer’s disease, genetic testing, APOE gene, early-onset Alzheimer’s disease, late-onset Alzheimer’s disease, familial Alzheimer’s disease, genetic counseling


Our knowledge of how genes contribute to medical illnesses is ever increasing. Psychiatrists, like all healthcare providers, have the daunting challenge of keeping up with new findings in genetic research along with other areas of research to best serve their patients. Keeping up with genetic research is particularly important when treating patients who have or might have Alzheimer’s disease (AD). AD is a devastating illness with no cure, and so it is not surprising that certain patients, such as those with a family history of AD, may want to know whether or not they carry one of the genes that make it more likely that they will develop AD.

There are two types of AD—early-onset (familial) and late-onset—each of which has wholly different genes associated with it. There are four genes now well-known to contribute to AD. Three are linked to early-onset (familial) AD and one, the better known APOE gene, is linked to late-onset AD. It is estimated that these four genes account for less than 30 percent of the genetic variance underlying AD, thus making it likely that numerous other genes are involved.[1] Three of these genes are autosomal dominant genes that have been linked to early-onset (familial) AD: APP, PSEN1, and PSEN2. A fourth gene, the so-called “APOE” (apolipoprotein E) gene, has been linked to late-onset AD.

Familial early-onset AD occurs much less frequently than late-onset AD.[1] When it comes to treating patients with a family history of AD, however, it is important for psychiatrists to be aware of the genes linked to early-onset AD because if the APP, PSEN1, or PSEN2 gene is present in a patient, it is almost certain that that patient will develop early-onset AD. Likewise, psychiatrists should know about the APOE gene and its contribution to late-onset AD for those patients without family history who, all the same, want or feel they need to be tested for AD. This latter reason is particularly important now due to a study recently published in the New England Journal of Medicine (NEJM), which may alter what psychiatrists and other healthcare providers presently do in regard to genetic testing for AD.[2]

Up until about a year ago, healthcare providers almost universally believed that they should advise patients against APOE testing.[1–3] However, in the study published in the NEJM,[2] investigators showed that patients who learned that they were positive for the APOE gene were not as adversely affected by this knowledge as healthcare providers previously assumed. Thus, the argument becomes stronger that healthcare providers should inform patients of the option to have genetic testing when appropriate and not urge against having this testing. In other words, perhaps it is better to leave the decision of this genetic testing up to the patient.[4]

In this article, I review genetically related findings that may help psychiatrists treat patients who have been diagnosed with or are at risk of developing AD. I discuss the basics of the current genetic research in early-onset and late-onset AD.

This review is not intended to enable psychiatrists to do for patients what genetic counselors do. Rather, it is intended to assist psychiatrists in discussions regarding genetic testing with their patients so that the patients are better equipped to decide whether or not they want to obtain genetic testing and counseling as a result of these discussions.5

Genes That Contribute to Early- and Late-Onset AD

Early-onset AD. Three known genes, APP, PSEN1, and PSEN2, cause familial early-onset AD.[3,6,7]  PSEN1 was first reported in the mid-1990s; APP and PSEN2 were first reported in 2008.[8,9] Testing for these genes is generally difficult and expensive.[6]
APP, PSEN1, and PSEN2 are autosomal dominant. Thus, patients having any one of these genes will, almost certainly, develop early-onset AD. APP, PSEN1, and PSEN2 are accordingly referred to as the “pre-senile” or  “deterministic” genes for early-onset AD.[3]

Early-onset or familial AD usually occurs between the fourth and seventh decade of life.[3] Psychiatrists should suspect the possibility of early-onset AD when patients show signs of AD before age 65, and particularly before age 60.[6] Early-onset AD is uncommon, however, and occurs in less than two percent of AD cases.[1,10]

The clinical considerations important to patients in regard to genetic testing for early-onset AD are similar to those considerations important in Huntington’s disease (HD).[11,12] The pattern of autosomal dominant inheritance is the same for the two diseases. Likewise, the outcomes of each disease are profoundly negative, each occurs at middle age, and each has no cure. Patients who are genetically tested for HD or AD should have post-test genetic counseling even if the test results are negative for either disease. While it is expected that most patients would feel relieved that they do not have the genes for either disease, others might feel extremely upset. One reason for this may be that even though a patient who tests negative for the genes knows that he or she will not get HD and will be much less likely to acquire early-onset AD, the patient may feel survivor guilt if a sibling or other family member tests positive for the gene(s).[3,12]

Late-onset AD. The APOE gene contributes, though only slightly, to late-onset AD. Numerous other genes also have been found to be associated with late-onset AD, but their clinical significance, at this time, has been much less clearly determined.[13–16] Psychiatrists can use this present uncertainty to help their patients by creating hope. In other words, late-onset AD is “famously variable in its course,”[17] and psychiatrists can say truthfully two things: First, the “average” outcome for patients with AD is just that—an average; some patients may do better, some worse. Second, there may be many genes that can affect a patient’s outcome and, therefore, there can be no predetermination of specifics of an individual’s disease course. Thus, the patient with late-onset AD should be counseled that he or she might possibly do better than expected.

The APOE gene has three subtypes (isoforms or alleles): E2, E3, and E4. These subtypes are on two sites of the amino acid sequence (residues 112 and 158), encoded by a single genetic locus.[1] The E4 allele subtype has the greatest effects on AD,[1,18,19] and, thus, in this article when referring to the APOE gene, the E4 allele will be the primary subject.

The APOE gene actually contributes relatively little to late-onset AD. Its contribution is as little as five percent, though this contribution may be somewhat greater for reasons discussed later.[6] In other words, if this gene is present, it does not mean that a patient will definitely develop late-onset AD, and, conversely, if it is absent, it does not mean that a patient will not develop late-onset AD. Since this gene contributes so little, it is sometimes referred to as the “susceptibility” gene for late-onset AD.[3]

The APOE gene’s contribution to late-onset AD increases when a patient is homozygous for this gene (i.e., has a double dose of this gene—one from each parent). If a patient is heterozygous for this gene (i.e., has this gene from only one parent), his or her risk for AD increases (compared to those without the gene) but not as much as the patient who is homozygous. For example, the risk for AD in a carrier of APOE e3/e4 is estimated to be 2 to 4 times higher than a carrier of APOE e3/e3, whereas this risk in a carrier of e4/e4 increases to approximately 6 to 30 times that of carriers of e3/e3.[15,20]

The risk for late-onset AD may also increase depending on a patient’s ethnicity. The associations between risk and ethnicity are complex. For example, African Americans and Hispanics with the APOE gene (E4 allele) may be as likely as Caucasians to develop AD, but African Americans and Hispanics may be 2 to 4 times as likely to develop AD if they do not have this allele.[6,18,38]

A patient’s ethnicity and whether he or she is homozygous or heterozygous each have different contributions to AD and each exemplify potential gains for the patient from genetic counseling. Without genetic counseling, a patient may be more likely to come to the conclusion that if he or she tests positive for the APOE gene, he or she will inevitably develop AD; conversly, if negative, the patient might think that he or she definitely will not develop AD. Even with accurate, genetics-based risk estimates, patients may still “misremember” the percentages.[21] Genetic counseling may benefit patients, as these differences in contributions illustrate, because the genetic counselors can discuss with the patients how each individual risk factor specifically can affect them.[22]

Advising Patients Regarding Testing for Early-Onset AD Genes

Though familial early-onset AD genes occur infrequently, once a patient learns that he or she has one of the three genes, this can have a profound effect on the patient. One patient described waiting for these genetic testing results, for example, as like living “under the sword of Damocles.”[22] Therefore, a concern psychiatrists might want to consider first is whether patients who might learn that they are positive for the genes that contribute to early-onset AD are relatively at higher risk than other patients of later becoming suicidal.[3] This question has also been raised in regard to genetic testing for HD, for which pre-screening has sometimes been required.[23]

Patients may feel profoundly ambivalent about genetic testing, regardless of what they ultimately choose. Using past experience with HD again as an example, many patients have thought initially that they would want testing for this gene, only to later choose not to have it.[3,24]

Ethically, some healthcare providers believe that even if a patient says before being tested for early-onset AD genes that he or she will commit suicide if he or she tests positive for the gene(s), the patient should still have this testing option. These healthcare providers may believe respecting patient autonomy is ethically preferable.[24]

Research on HD and other serious autosomal dominant disorders suggests that people who test positive for the genes of these disorders may do emotionally worse later if they had prior intrusive thoughts or depression than if they did not have depression or intrusive thoughts prior to being tested for these genes.[25] Counterintuitively, patients may do better, however, if they had episodes of anxiety prior to being tested compared to those with no or less anxiety.[25] Investigators suggest that this may be due to the patient with previous episodes of anxiety “working through” the apprehension that he or she might have one of these genes and might possibly develop early-onset AD.[25]

Patients with greater anxiety before testing may, however, be too anxious to allow their emotions to be felt. This may prevent them from thinking about the implications of either test result, and thus they may be maladaptive over the longer term.[25] Thus, the massive anxiety in these patients may be denied and/or its manifestations may be “delayed.”[25] Some providers have suggested that, in these cases, anxiety, which was not present prior to testing positively, may first emerge as much as three years after a patient first learns that he or she has the gene.[25] Furthermore, these patients may show signs of anxiety early on or later on after they test positive through their behavior (e.g., try to save money inordinately and immediately, or conversely go on a spending spree [spend money while they still can]).[17] Consequently, psychiatrists should consider continuing to see a patient who has tested positive for the gene(s) that causes early-onset AD, even if the patient has not yet shown symptoms of anxiety. In other words, anxiety not previously experienced by a patient may emerge for the first time after positive genetic testing, and the patient may engage in new behaviors that he or she will later regret.

Psychiatrists might also want to “pre-consider” with these patients what defenses the patients have used in the past that have worked for them when dealing with anxiety.[21]  Psychiatrists should inform the patients, however, that their responses to this bad news may be without precedent and unique.[22]

When a patient tests positive for one of the genes that is linked to AD, the patients’ families may also be profoundly affected.
This may occur in any case, but also because the testing for these genes can be conducted prenatally.[6] In other words, the presence of these genes that cause familial early-onset AD can be detected now in embryos and fetuses. These genetic testing possibilities now allow the options of either selecting an embryo created via in-vitro fertilization that does not have such a gene for implantation in the womb or choosing abortion if the fetus is affected. Patients and their partners may differ on whether they want to pursue this type of prenatal testing and subsequently either of these two possibilities.[8,12,21,26–28]

In theory, a change in the patient can cause a change in family members, and this, in turn, can further cause changes in the patient.12 For example, family members may exclude the patient from certain activities once he or she tests positive for a gene linked to early-onset AD; the family may “unilaterally, put goals on hold or ‘fast-forward’ them; and families may discard family rituals that previously helped all feel more ‘like a family.’ ” This may adversely affect the patient.

Some families do well with the news. One family, together with the patient, for example, made a “family sport” of spotting new symptoms of the patient’s early onset AD.12 Other families, however, particularly if they have pre-existing relationship problems, may not do well. One family reported, for instance, that when their loved one tested positive for AD, it was like “putting [this family’s] chemistry on a Bunsen burner.”[12]

Research involving HD has found that the way in which patients imagine genetic testing results will affect their family and loved ones may significantly affect whether or not they choose to have the testing done.[22] This may occur whether or not what they imagine is accurate. This research also found that genetic counselors tend not to discuss with patients how to disclose the test results to their loved ones.[22] Psychiatrists, accordingly, should try to insure that such a discussion occurs, either in the psychiatrist’s office or with a genetic counselor. During this discussion, the patient should be asked to consider how he or she imagines his or her loved ones might respond to the news and how the loved ones’ reactions, in turn, might affect the patient. The patient should also be asked to consider how he or she will share the result of the test with loved ones, particularly if the result turns out positive.[22,28]

Psychiatrists should not insist that all patients have a “good reason” for wanting to be genetically tested for AD. As one patient said, “I just want to know.”[22] Likewise, psychiatrists should be open to supporting at least some patients who want to be tested right away before any genetic counseling can occur. These patients may have already emotionally prepared themselves for a positive test result.[22]  If a psychiatrist does ask a patient to wait to be tested until genetic and/or psychiatric counseling can occur, one reason may be so that the psychiatrist has the opportunity to repeatedly ask the patient whether he or she wants the testing to ensure the patient has ample time to think about it and know what he or she wants. In addition, the psychiatrist may want to inform the patient that he or she will ask the patient the same questions later.[22] The psychiatrist, for example, may say (while grinning), “You may feel angry or annoyed, but I plan to ask you these same questions later!” explaining to the patient in the same breath why.

Finally, a psychiatrist may wish to consider making arrangements so that the psychiatrist and the patient can learn the test result together.[22] Those moments—when the healthcare provider knows the result of a test and the patient does not—can be, for the patient, excruciating. Therefore, the psychiatrist can spare the patient this discomfort and avoid having to put on a “poker face,” even if for just a few moments, when he or she first meets with the patient prior to giving the patient the test result, and together the patient and the psychiatrist can learn the result of the test.

Advising Patients Regarding Testing for Late-Onset AD Genes

The APOE gene indicates only “susceptibility” to AD. Because this gene has only a slight contributory effect, many people do not want to be tested for it. They might decide, rather, that they will try to live each day as fully as possible, whether or not they eventually develop AD.21 Some patients make this same choice but do it a bit differently. They may choose not to be tested, but still pursue other measures that pose little risk but may be helpful in the event that they develop AD (e.g., taking vitamin supplements, exercising, staying active mentally through reading and crossword puzzles).[29]

Other patients may want to be tested because they believe they will feel “safer” if it turns out that they do not have the APOE gene, even knowing that this “safe” feeling may not be wholly rational. Prior to testing, however, the psychiatrist should consider whether or not to discuss with the patient the increased chance that AD will develop at an earlier age and progress more rapidly if the APOE gene is present.[30,31] If told this information, some patients who test positive may use this information to motivate themselves to engage in several preventive measures, such as exercising.[32]

The NEJM study[2] showed that even when patients test positive for the APOE gene, they may not be adversely affected. This study’s authors stated, “These data support the psychological safety of disclosing data regarding genetic-counseling protocols to screened adult children of patients with Alzheimer’s disease who request such information, despite the frightening nature of the disease and the fact that this disclosure has no clear medical benefit.”[2] It is important to note that all the patients in this study received genetic counseling. These authors add, however, that “Larger studies…will be required to detect uncommon and long-term effects, such as delayed emotional repercussions and injudicious life decisions.”[2]

The results of the NEJM study have been questioned, however.[17,33] Some individuals have questioned the very structure of this study, suggesting, for example, that the control group should have been patients who chose not to be tested as opposed to patients who tested negative. Others have questioned whether this group should be considered representative, and, thus, whether these results can be clinically generalized to apply to patients other than those who participated in this study. Those studied, for example, were all self-selected volunteers and in general were also well-educated. This study did not include people who were already severely depressed, severely anxious, or neurocognitively impaired.[2,17,21] Therefore, the results of the NEJM study may be atypical when compared to those from other patients.

Still, the finding of the NEJM study may be sufficient to warrant that psychiatrists should consider changing their behavior so that when discussing genetic testing for AD, the psychiatrist remains neutral (as opposed to encouraging a patient to not have the testing done).[4,6] This finding may be enough to “tip the balance” to now favor supporting patients to make their own choices without benefit of a psychiatrist recommendation.

In contrast to testing for the early-onset genes, testing for the APOE gene is easy and inexpensive.6  Patients can obtain results from companies that give the results directly to consumers.[2] If patients go this route for testing, then they will be without the benefit of genetic counseling. Currently, this direct-to-consumer testing is permitted in about half the states, and there is little oversight of this at the federal level.[34,35]

Psychiatrists should consider whether to inform their patients of the direct-to-consumer testing. If a psychiatrist decides to inform his or her patients of the direct-to-consumer genetic testing, he or should consider providing them with this web address:[4,6,36] The patients should also be informed that they will not receive genetic counseling should they decide to move forward with the direct-to-consumer genetic testing. The risks of not receiving genetic counseling, which should be explained to the patient, may affect not only the patient but may extend to his or her loved ones as well.[15,20,38]

Finally, the psychiatrist may also want to inform his or her patients that if they have genetic testing for AD done and the results are positive, these results could negatively affect the patients if they plan to obtain long-term healthcare insurance.[37] The Genetic Information Nondiscrimination Act of 2008 “does not prohibit companies from considering such results for long-term care, disability, or life insurance.”[17] Thus, some healthcare providers, accordingly, have advised patients that if they want to obtain this type of insurance, they should obtain the insurance first and then get APOE testing later.[8]


People differ greatly in regard to whether or not they want genetic testing for early- and late-onset AD. It is important for psychiatrists to openly discuss the risks and benefits of genetic testing for early-onset AD with their patients and their patients’ family members. The psychiatrist should not only discuss with the patient how he or she imagines his or her family might react to the news of positive test results but also how he or she might want to disclose the results of positive genetic testing to family members.

Regarding APOE testing for late-onset AD, psychiatrists may want to remain more neutral than they have in the past and let the patient decide for him- or herself whether or not to have the testing done. The psychiatrist may in particular want to discuss the advantages and disadvantages of direct-to-consumer testing and of obtaining long-term care insurance before the patient gets tested.

Experts hope that in the near future, genetic testing may enable providers to tailor new treatments to patients’ individual needs.  Effective treatments and genetic tailoring of these treatments may be sources of hope, even now, for patients who have or may have AD and those who fear they have genetically passed the disease onto their children. It is important that psychiatrists remain aware of these more recent findings regarding genetics and AD in order to better serve their patients.

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