Genomics in general practice

Alzheimer’s disease

Last revised: 30 Nov 2018

Practice point

Currently, genetic testing of APOE gene variants is considered to have limited clinical utility for diagnostic purposes, and is not recommended in clinical practice.1,2

Genetic testing is also available for gene variants in three genes APP, PSEN1, PSEN2 that confer a very high risk for early onset familial Alzheimer’s disease (AD). However, these gene variants are responsible for only a small percentage of AD cases.2,3

The average lifetime risk of developing AD is estimated to be between 10 and 12% (until the age of 75–80 years).3–5 The ε4 variant of the APOE gene is associated with an increased risk of late-onset AD,5,6 but this risk is confounded by other factors. These factors include those that cannot be modified (eg other genetic variants, gender, family history, possibly ethnicity) and modifiable risk factors (eg diet, exercise, cardiovascular health, environment). The clinical utility of knowing ε4 status is uncertain.3,5–7

Research suggests that heterozygous carriers of the ε4 variant have an approximately threefold increase in risk of developing AD, while homozygous carriers have an approximately 15-fold increase in risk. Having a first-degree relative with AD doubles the risk of developing the disease.3,7,8

The ε4 variant is neither necessary nor sufficient to cause AD, and risk estimates are problematic given the range of confounding factors. Therefore, the clinical utility of genetic testing is uncertain.2,3

While the association of the APO-ε4 variant with AD is significant, genetic testing has limited sensitivity and specificity.2 The APO-ε4 variant may be included in some commercial test panels (refer to ‘Personal genomic testing: Summary’). Given the lack of predictive value of APO-ε4 for AD, this information may cause unnecessary anxiety for some individuals, especially given the lack of preventive or therapeutic interventions.3 There may be broader implications for the individual and family members (ie ethical principles, health and life insurance issues).3

Genetic testing may be appropriate for families with a history of early onset AD (≥2 affected family members; age at onset <65 years of age), and referral to genetics services is appropriate.2


National Library of Medicine (US), Alzheimer disease
National Library of Medicine (US), APOE gene: Normal function
National Library of Medicine (US), APOE gene


Alzheimer’s Australia

  1. Human Genetics Society of Australasia and Choosing Wisely Australia. Tests, treatments and procedures clinicians and consumers should question. Sydney: NPS MedicineWise, 2016 [Accessed 14 December 2017].
  2. Bird TD. Alzheimer disease overview. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews. Seattle, WA:University of Washington, 1998 [Accessed 14 December 2017].
  3. Goldman JS, Hahn SE, Catania JW, et al. Genetic counseling and testing for Alzheimer disease: Joint practice [Accessed 14 December 2017].
  4. guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med 2011;13(6):597–605. [Accessed 14 December 2017].
  5. Cummings JL, Cole G. Alzheimer disease. JAMA 2002;287(18):2335–38. [Accessed 14 December 2017].
  6. Seshadri S, Drachman DA, Lippa CF. Apolipoprotein E ε4 allele and the lifetime risk of Alzheimer’s disease: What physicians know, and what they should know. Arch Neurol 1995;52(11):1074–49. [Accessed 14 December 2017].
  7. Ashford JW. APOE genotype effects on Alzheimer’s disease onset and epidemiology. J Mol Neurosci 2004;23(3):157–65. [Accessed 14 December 2017].
  8. Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: Clinical implications and perspectives. Genet Med 2016;18(5):421. [Accessed 14 December 2017].
  9. Guerreiro RJ, Gustafson DR, Hardy J. The genetic architecture of Alzheimer’s disease: Beyond APP, PSENs and APOE.Neurobiol Aging 2012;33(3):437–56. [Accessed 14 December 2017].
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