Is there genetic testing for Alzheimer's disease?

Genetic Testing for Alzheimer's Disease

Yes, genetic testing for Alzheimer's disease exists, but it should only be performed in specific clinical contexts with proper genetic counseling, as it has limited clinical utility for most individuals.

Types of Genetic Testing Available

Early-Onset Alzheimer's Disease (EOAD) Testing

• Testing is available for mutations in three genes associated with autosomal dominant EOAD 1:
  • Amyloid precursor protein (APP)
  • Presenilin 1 (PSEN1)
  • Presenilin 2 (PSEN2)
• These mutations are rare but highly penetrant, accounting for less than 5% of all AD cases 1, 2
• About 40-80% of autosomal dominant EOAD cases can be explained by mutations in these genes 1

Late-Onset Alzheimer's Disease (LOAD) Testing

• APOE genotyping is available but not clinically recommended for predictive purposes 1, 3
• APOE has three variants (ε2, ε3, and ε4), with ε4 conferring increased risk 3:
  • Heterozygotes (one ε4 allele): 2-3 fold increased risk
  • Homozygotes (two ε4 alleles): 2-10 fold increased risk
• Approximately 50-70% of people with AD carry at least one ε4 allele 1, 3

When Genetic Testing Should Be Considered

For Symptomatic Individuals

• Testing for EOAD genes (PSEN1, PSEN2, APP) should be offered in these situations 1:
  • Symptomatic individuals with EOAD (onset before age 60-65) with family history of dementia
  • Symptomatic individuals with EOAD with unknown family history (e.g., adoption)
  • Individuals from families with autosomal dominant pattern of dementia with one or more EOAD cases

For Asymptomatic Individuals

• Testing should only be considered when there is:
  • A known mutation in the family
  • Proper genetic counseling following protocols similar to those used for Huntington's disease
  • Appropriate psychological support before and after testing 1

Important Considerations and Limitations

• Direct-to-consumer APOE testing is not advised 1
• Genetic testing should only occur with genetic counseling by someone with expertise in this area 1
• For asymptomatic testing, ideally an affected family member should be tested first 1
• A negative test result in the absence of a known familial mutation is ambiguous 1
• Genetic testing for susceptibility loci (e.g., APOE) has limited clinical utility and poor predictive value 1
• Currently, there are no proven pharmacologic or lifestyle interventions that can prevent AD or stop its progression based on genetic status 1

Genetic Counseling Process

• Obtain a ≥3-generation family history with attention to:

  • Age of onset of neurologic/psychiatric symptoms
  • Type of dementia and diagnostic method
  • Current ages or ages at death 1

• Risk assessment should determine if family history is consistent with:

  • EOAD vs. LOAD
  • Autosomal dominant, familial, or sporadic inheritance 1

• Discuss potential outcomes of testing:

  • Positive result
  • Negative result
  • Variant of uncertain significance 1

• Address psychological impact and insurance implications 1, 3

Common Pitfalls to Avoid

• Testing without proper genetic counseling
• Misinterpreting a negative result when no familial mutation is known
• Assuming APOE testing can definitively predict who will develop AD
• Neglecting the psychological impact of learning genetic status 3
• Assuming inevitable decline in APOE4 carriers (many never develop dementia) 3

Genetic testing for Alzheimer's disease has important implications for diagnosis, family planning, and research, but its clinical utility remains limited by the lack of disease-modifying treatments and the complex, multifactorial nature of most AD cases.