Wendy S. Meschino, MD, CCFP, FRCPC, FCCMG
Department of Genetics,
North York General Hospital,
The last decade has seen important gene discoveries for early-onset, autosomal dominant forms of Alzheimer disease and other dementias. The genes include presenilin 1, presenilin 2 and amyloid precursor protein (APP) for Alzheimer disease, the tau gene for frontotemporal dementia (FTD) and notch3 for CADASIL. Testing for one or more of these genes is available in research laboratories in Canada and in a private US lab. Testing for presenilin 1 is indicated for patients affected with early-onset (< 60 years) Alzheimer disease. If an affected family member is unavailable (i.e. deceased), testing an unaffected first-degree relative can be considered when there are two or more affected early-onset cases in the family.
Patients requesting pre-symptomatic (predictive) testing should be referred for appropriate genetic counselling, including a full discussion of the risks and benefits of predictive testing. The following points should be considered before proceeding: Is the choice to have testing informed and free from coercion? What are the reasons for knowing or not knowing? What are the potential effects on other members of the family? Is there a potential for insurance, employer or other forms of discrimination?
For the majority of Alzheimer disease (95%), which occurs after age 60, no major dominantly inherited genes have been found. In most cases, the disease occurs sporadically in families. However in approximately 15-25%, the etiology has a complex genetic basis with both inherited and environmental modifying factors. One such genetic modifier is the e4 allele of the apolipoprotein E gene, which has been associated with a decreased age of onset, especially when homozygous. As it is neither necessary nor sufficient for onset of the disease, testing for e4 has limited utility and is not recommended in the pre-symptomatic situation. A search for other late-onset Alzheimer genes is in progress. In this regard, genetic testing on a research basis may be considered when samples can be obtained from two or more affected family members.