What is involved in genetic testing for Alzheimer's disease?

Genetic Testing for Alzheimer's Disease

Genetic testing for Alzheimer's disease should follow a structured protocol that includes comprehensive genetic counseling, risk assessment, and appropriate test selection based on family history patterns, with testing primarily recommended for early-onset Alzheimer's disease (EOAD) with autosomal dominant patterns rather than for common late-onset forms. 1

Types of Alzheimer's Disease and Associated Genetic Testing

Early-Onset Alzheimer's Disease (EOAD)

• Occurs before age 65
• May have strong genetic component
• Testing recommended for:
  • Symptomatic individuals with EOAD and family history of dementia
  • Individuals with EOAD and unknown family history (e.g., adoption)
  • Families with autosomal dominant pattern with one or more EOAD cases
  • Relatives of someone with a confirmed EOAD mutation 1
• Genes tested:
  • PSEN1 (Presenilin 1) - most common
  • PSEN2 (Presenilin 2)
  • APP (Amyloid Precursor Protein)

Late-Onset Alzheimer's Disease (LOAD)

• Occurs after age 65
• More common form (90% of cases)
• Genetic susceptibility testing (APOE) is not clinically recommended due to limited clinical utility and poor predictive value 1
• APOE ε4 allele increases risk but is neither necessary nor sufficient to cause disease

Genetic Testing Process

Pre-Testing Phase

1. Detailed Family History Collection

   • Obtain ≥3-generation family history
   • Document age of onset of neurological/psychiatric symptoms
   • Record dementia diagnosis methods
   • Note current ages or ages at death of relatives
   • Confirm AD diagnosis with medical records when possible 1

2. Risk Assessment

   • Analyze pedigree to determine if pattern is consistent with:
     • EOAD vs. LOAD
     • Autosomal dominant vs. familial vs. sporadic inheritance 1

3. Pre-Test Genetic Counseling

   • Inform patient that no proven interventions currently exist to prevent or stop AD progression
   • Review general AD risk (10-12% lifetime risk in general population)
   • Discuss inheritance patterns and risk to offspring (50% for autosomal dominant forms)
   • Explore psychological impact of testing
   • Assess patient's psychological state and readiness for testing 1

Testing Protocol

1. For EOAD Testing:

   • Ideally test an affected family member first
   • Neurological examination for asymptomatic patients
   • Psychological assessment (may require psychiatrist/psychologist consultation)
   • Obtain informed consent
   • Determine testing approach (stepwise beginning with PSEN1 or panel testing) 1

2. Testing Logistics:

   • Discuss where results will be kept
   • Identify support person to accompany patient to results session
   • Review possible outcomes (positive, negative, variant of uncertain significance)
   • Discuss potential impact on insurance and genetic discrimination protections 1

Post-Testing Phase

1. Results Disclosure
   • Provide results in person with support person present
   • Revisit plans for sharing results with family members
   • Arrange follow-up plan to check on patient's wellbeing
   • Consider additional counseling sessions as needed 1

Common Pitfalls and Caveats

1. APOE Testing Limitations

   • Despite commercial availability, APOE testing is not recommended for predicting AD risk
   • Direct-to-consumer genetic testing for AD risk is not advised 1
   • Even with negative APOE ε4 results, first-degree relatives still face 2-4 fold increased risk 1

2. Psychological Considerations

   • Testing may trigger depression, anxiety, or suicidal ideation in some individuals
   • Postpone testing if patient shows signs of untreated depression or recent significant stressors 1
   • Research shows most individuals cope effectively with results when using standardized counseling protocols 1

3. Family Dynamics

   • Testing symptomatic individuals is often requested by relatives concerned about their own risk
   • Be alert to potential conflicts of interest within families
   • Consider family meetings to discuss impact of testing and respect for privacy preferences 1

4. Pediatric Testing

   • Genetic testing for AD in children is not recommended
   • Limited clinical utility due to variable symptoms and age of onset
   • No preventive or curative interventions currently available 1

5. Emerging Considerations

   • Recent research suggests APOE testing may have relevance for assessing safety profiles of new anti-amyloid-β therapies 2
   • This represents a potential shift in the clinical utility of APOE testing

Genetic testing for Alzheimer's disease requires careful consideration of the benefits and risks for each patient, with appropriate pre- and post-test counseling to ensure informed decision-making and psychological support throughout the process.