Genomics in general practice

Disease specific topics

Alzheimer disease

Alzheimer disease


Currently, genetic testing of APOE gene variants Gene variants are small DNA sequence changes (ie additions, duplications, deletions, substitutions). These variants can have a range of effects: some may cause disease (pathogenic variant), while others do not cause disease but may modify an individual’s risk of disease (i.e may increase risk or provide a protective effect). The vast majority of gene variants are benign and do not result in disease but rather contribute to the differences between people. i considered to have limited clinical utility for diagnostic purposes, and is not recommended in clinical practice.

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

What do I need to know?

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

Research suggests that heterozygous carriers Recessive genetic conditions such as cystic fibrosis (CF) occur when a person inherits a particular genetic variant from each parent. A carrier is an individual who only has one copy of the gene variant and generally does not have symptoms, but can pass the variant to their children. Some conditions are due to a pathogenic variant in a gene on the X chromosome (X-linked inheritance). Typically, these conditions affect more males (who have the sex chromosomes XY) than females (who have the sex chromosomes XX). A woman who is a carrier of an X-linked condition has the variation on one of her X chromosomes, which she can pass on to her children. However, if the biological male has a pathogenic variant in an X chromosome gene, he will not pass it to his sons, but will pass it to all of his daughters. 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.

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 for this is uncertain.

Genetic testing

While the association of the APO-ε4 variant with AD is significant, genetic testing has limited sensitivity and specificity. The APO-ε4 variant may be included in some commercial test panels (refer to ‘Personal genomic testing’). 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. There may be broader implications for the individual and family members (ie ethical principles, health and life insurance issues).

When should I refer?

Genetic testing of APP, PSEN1 and PSEN2 may be appropriate for individuals with a family history of early onset AD particularly if there is more than one person affected in a family (≥2 affected family members; age at onset <65 years of age), and referral to genetics services is appropriate.

Further reading

  • Human Genetics Society of Australasia and Choosing Wisely Australia. Tests, treatments and procedures Sydney: NPS MedicineWise, 2016. [Accessed 6 September 2022].
  • Huq AJ, Sexton A, Lacaze P, et al. Genetic testing in dementia-A medical genetics perspective Int J Geriatr Psychiatry. 2021 Aug;36(8):1158-1170.
  • Goldman JS, Hahn SE, Catania JW, et al. Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Genet Med 2011;13(6):597–605.
  • Van Cauwenberghe C, Van Broeckhoven C, Sleegers The genetic landscape of Alzheimer disease: Clinical implications and perspectives. Genet Med 2016;18(5):421.
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