Patients asking about &lt;i&gt;APOE&lt;/i&gt; gene test results? Here’s what to tell them

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doi:doi: 10.12788/jfp.0397

Applied Evidence

Patients asking about APOE gene test results? Here’s what to tell them

J Fam Pract. 2022 May;71(4):E1-E7 | doi: 10.12788/jfp.0397

By

Shana D. Stites, PsyD, MS, MA

Nicholas M. Vogt, MD, PhD

Deborah Blacker, MD, ScD

Malia Rumbaugh, MS, LGC

Monica W. Parker, MD

for the Advisory Group on Risk Evidence Education for Dementia (AGREED)

This guidance can help shape the conversations you have with patients who want to understand the results of their gene and biomarker testing for Alzheimer disease.

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References

1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2018;14:535-562. doi: 10.1016/j.jalz.2018.02.018 PMCID:PMC5958625

2. Langlois CM, Bradbury A, Wood EM, et al. Alzheimer’s Prevention Initiative Generation Program: development of an APOE genetic counseling and disclosure process in the context of clinical trials. Alzheimers Dement Transl Res Clin Interv. 2019;5:705-716. doi: 10.1016/j.trci.2019.09.013

3. Frank L, Wesson Ashford J, Bayley PJ, et al. Genetic risk of Alzheimer’s disease: three wishes now that the genie is out of the bottle. J Alzheimers Dis. 2018;66:421-423. doi: 10.3233/JAD-180629

4. Qian J, Wolters FJ, Beiser A, et al. APOE-related risk of mild cognitive impairment and dementia for prevention trials: an analysis of four cohorts. PLOS Med. 2017;14:e1002254. doi: 10.1371/journal.pmed.1002254

5. Sperling RA, Jack CR, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367-385. doi: 10.1016/j.jalz.2011.05.2351

6. FDA. November 6, 2020: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement. Published November 12, 2020. Accessed January 14, 2021. www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-2020-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting

7. Cummings J. Why aducanumab is important. Nat Med. 2021;27:1498-1498. doi: 10.1038/s41591-021-01478-4

8. Alexander GC, Karlawish J. The problem of aducanumab for the treatment of Alzheimer disease. Ann Intern Med. 2021;174:1303-1304. doi: 10.7326/M21-2603

9. Mullard A. More Alzheimer’s drugs head for FDA review: what scientists are watching. Nature. 2021;599:544-545. doi: 10.1038/d41586-021-03410-9

10. Rosenberg A, Mangialasche F, Ngandu T, et al. Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: from finger to world-wide fingers. J Prev Alzheimers Dis. 2019:1-8. doi: 10.14283/jpad.2019.41

11. FDA. Commissioner of the FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions. Published March 24, 2020. Accessed November 7, 2020. www.fda.gov/news-events/press-announcements/fda-allows-marketing-first-direct-consumer-tests-provide-genetic-risk-information-certain-conditions

12. Blell M, Hunter MA. Direct-to-consumer genetic testing’s red herring: “genetic ancestry” and personalized medicine. Front Med. 2019;6:48. doi: 10.3389/fmed.2019.00048

13. Ekstrand B, Scheers N, Rasmussen MK, et al. Brain foods - the role of diet in brain performance and health. Nutr Rev. 2021;79:693-708. doi: 10.1093/nutrit/nuaa091

14. Cherian L, Wang Y, Fakuda K, et al. Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet slows cognitive decline after stroke. J Prev Alzheimers Dis. 2019;6:267-273. doi: 10.14283/jpad.2019.28

15. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020;396:413-446. doi: 10.1016/S0140-6736(20)30367-6

16. Livingston PG, Sommerlad A, Orgeta V, et al. The Lancet International Commission on Dementia Prevention and Care. 2017. Accessed March 30, 2022. https://discovery.ucl.ac.uk/id/eprint/1567635/1/Livingston_Dementia_prevention_intervention_care.pdf

17. Peters U. What is the function of confirmation bias? Erkenntnis. April 2020. doi: 10.1007/s10670-020-00252-1

18. Barnes LL, Bennett DA. Cognitive resilience in APOE*ε4 carriers—is race important? Nat Rev Neurol. 2015;11:190-191. doi: 10.1038/nrneurol.2015.38

19. Farrer LA. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278:1349. doi: 10.1001/jama.1997.03550160069041

20. Evans DA, Bennett DA, Wilson RS, et al. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003;60:185. doi: 10.1001/archneur.60.2.185

21. Chung WW, Chen CA, Cupples LA, et al. A new scale measuring psychologic impact of genetic susceptibility testing for Alzheimer disease. Alzheimer Dis Assoc Disord. 2009;23:50-56. doi: 10.1097/WAD.0b013e318188429e

22. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-613. doi: 10.1046/j.1525-1497.2001.016009606.x

23. Yesavage JA, Sheikh JI. 9/Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165-173. doi: 10.1300/J018v05n01_09

24. Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N Engl J Med. 2009;361:245-254. doi: 10.1056/NEJMoa0809578

25. Lineweaver TT, Bondi MW, Galasko D, et al. Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am J Psychiatry. 2014;171:201-208. doi: 10.1176/appi.ajp.2013.12121590

26. Karlawish J. Understanding the impact of learning an amyloid PET scan result: preliminary findings from the SOKRATES study. Alzheimers Dement J Alzheimers Assoc. 2016;12:P325. doi: 10.1016/j.jalz.2016.06.594

27. Stites SD. Cognitively healthy individuals want to know their risk for Alzheimer’s disease: what should we do? J Alzheimers Dis. 2018;62:499-502. doi: 10.3233/JAD-171089

28. Milne S, Lomax C, Freeston MH. A review of the relationship between intolerance of uncertainty and threat appraisal in anxiety. Cogn Behav Ther. 2019;12:e38. doi: 10.1017/S1754470X19000230

29. Hebert EA, Dugas MJ. Behavioral experiments for intolerance of uncertainty: challenging the unknown in the treatment of generalized anxiety disorder. Cogn Behav Pract. 2019;26:421-436. doi: 10.1016/j.cbpra.2018.07.007

30. Stites SD, Karlawish, J. Stigma of Alzheimer’s disease dementia: considerations for practice. Pract Neurol. Published June 2018. Accessed January 31, 2019. http://practicalneurology.com/2018/06/stigma-of-alzheimers-disease-dementia/

31. Solomon A, Turunen H, Ngandu T, et al. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurol. 2018;75:462. doi: 10.1001/jamaneurol.2017.4365

32. Peters R, Warwick J, Anstey KJ, et al. Blood pressure and dementia: what the SPRINT-MIND trial adds and what we still need to know. Neurology. 2019;92:1017-1018. doi: 10.1212/WNL.0000000000007543

33. Musunuru K, Hershberger RE, Day SM, et al. Genetic testing for inherited cardiovascular diseases: a Scientific Statement from the American Heart Association. Circ Genom Precis Med. 2020;13: e000067. doi: 10.1161/HCG.0000000000000067

34. Margaglione M, Seripa D, Gravina C, et al. Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke. Stroke. 1998;29:399-403. doi: 10.1161/01.STR.29.2.399

35. National Institute on Aging. Alzheimer’s disease genetics fact sheet. Reviewed December 24, 2019. Accessed April 10, 2022. www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet

36. Belluck P, Kaplan S, Robbins R. How Aduhelm, an unproven Alzheimer’s drug, got approved. The New York Times. Published July 19, 2021. Updated Oct. 20, 2021. Accessed December 1, 2021. www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them