An individual's knowledge that they carry the apolipoprotein E ( APOE) ε4 allele risk factor for Alzheimer's disease (AD) can adversely affect memory performance in cognitively healthy older adults, new research suggests.

A nested case-control study of 144 participants between the ages of 52 and 89 years showed that those who knew they had the APOE genotype performed much worse on objective verbal memory tests than those who did not know they carried the allele. They also judged their memory more harshly.

Conversely, individuals who knew they were not at genetic risk for AD had significantly higher self-rated memory scores than their counterparts who did not carry the allele but who were unaware of their risk-free status. However, memory performance test scores did not differ significantly between these 2 groups.

"For me, the most surprising aspect was seeing differences on the objective memory test," coinvestigator David P. Salmon, PhD, professor of neurosciences at the University of California, San Diego (UCSD), and from the Shiley-Marcos Alzheimer's Disease Research Center at UCSD, told Medscape Medical News.

Dr. Salmon noted that this could be explained in part by "self-efficacy," which is believing in one's own abilities.

"If you know you're carrying a risk factor for a disease that affects memory, then you may have lower self-efficacy. So if you have a lowered expectation of your memory performance, then you might be more likely to give up sooner and not put in as much effort," he explained.

"So in a sense, it's like a self-fulfilling prophecy. It just reinforces itself."

The study was published in the February issue of the American Journal of Psychiatry

Poorer Memory Performance

Although recent research has shown that knowledge of carrying the APOE genotype has little short-term psychological risk for individuals, the investigators report that they wanted to examine whether this knowledge affected cognition.

A total of 144 older adults who scored less than 130 on the Dementia Rating Scale were enrolled and genotyped. Of these, 34.7% were found to have the APOE ε4 risk factor (ε4+), and 65.3% did not (ε4-).

In the study's first phase, 74 individuals who had given their consent to be informed of their genotype status were given this information by an experienced genetic counselor. Discussions and counseling were also provided.

The second phase consisted of enrolling 70 age-matched participants who did not receive information about their APOE status.

All were then divided into 4 subgroups: the informed and uninformed ε4+ groups (n = 25 in each) and the informed and uninformed ε4- groups (n = 49 and 45, respectively).

Two objective verbal and visual memory measures, the logical memory subtest of the Wechsler Memory Scale–Revised (WMSR) and the Rey-Osterrieth Complex Figure Test, were administered to all 4 subgroups.

All participants were also asked to rate their everyday memory abilities using the 15-item Metamemory in Adulthood Questionnaire and the short form of the Memory Functioning Questionnaire.

Results showed that verbal memory scores on the WMSR were significantly worse for the informed ε4+ group than for the uninformed ε4+ group in both immediate and delayed recall ( P = .001 and P < .001, respectively).

These scores did not differ significantly between the informed and uninformed ε4- groups.

In addition, there were no significant differences between any of the groups in visual memory scores on the complex figure test.

Adverse Consequences?

Self-rated scores were significantly better for the informed ε4- group than for the uninformed ε4- group on the Metamemory Questionnaire's capacity scale ( P = .02) and on the Memory Functioning Questionnaire's retrospective functioning scale ( P = .006) and on the forgetting when reading scale ( P = .04).

Those who were in the informed ε4+ group had worse self-rated scores on the capacity scale than did the uninformed ε4+ group ( P = .048).

Finally, the uninformed ε4+ group rated their memory significantly better than the uninformed ε4- group on the capacity scale ( P = .03) and the retrospective functioning scale ( P = .002).

"Informing older adults that they have an APOE genotype…can have adverse consequences," write the investigators.

Therefore, "the patient's knowledge of his or her genotype and risk of [AD] should be considered when evaluating cognition in the elderly," they add.

Still, Dr. Salmon noted that if a patient wants to know their APOE status, they have the right.

"There's no reason to withhold the information from them. Even if they're just curious or think they might be having a problem, I'd say that's okay for them to find out if they have an increased risk of developing an Alzheimer's type dementia," he said.

"We just need to be careful that when we tell them, there could be some consequences, although I think the consequences could be mitigated. We're interested now in following up this study and looking at if behavioral or cognitive therapy after disclosure can help."

Troubling Findings

Jason Karlawish, MD, from the Neurodegenerative Disease Ethics and Policy Program at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and Robert C. Green, MD, MPH, from the Division of Genetics at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, write in an accompanying editorial that the study's main results were "remarkable findings."

"APOE genotype is a robust predictor of a person’s lifetime risk of developing sporadic Alzheimer’s disease," they write.

"In an era when hundreds of thousands of individuals have learned about their genetic risk factors for common complex disorders, including their APOE genotype, through consumer genomics companies, it is concerning that this knowledge alone may influence performance on cognitive tests."

The editorialists also note that the study's results now need to be replicated in a randomized controlled trial ― a design that was used in the recent Risk Evaluation and Education for Alzheimer's Disease (REVEAL) study.

It showed that the mood and well-being of middle-aged adults were not adversely affected by APOE knowledge. However, it did not assess effect on cognition.

"If the effect [found in the current trial] is replicated, then studies would also be warranted to test whether interventions might mitigate this effect," write Dr. Karlawish and Dr. Green.

They add that, overall, the results show that clinicians must "examine how this new model of medicine" will affect the well-being of their patients.

"They also show how cognitive impairment in aging is not simply the result of brain lesions, but a disruption in the homeostasis between the individual, the brain, and the world the person lives in ― or, in short, a disruption of the mind."

Dr. Salmon reports that he has served as a consultant for Bristol-Myers Squibb, and 1 of the other study authors reports serving on advisory panels for Elan Pharmaceuticals and Neurophage and on data and safety monitoring boards for clinical trials for Balance Pharmaceuticals, Elan Pharmaceuticals, Janssen Immunotherapy, and Pfizer. The other 2 study authors, the editorialists, and Dr. Fargo report no relevant financial relationships.

Am J Psychiatry. 2014;71:201-208, 137-139.