Genetic testing for Alzheimer disease. Practical and ethical issues.

The dissection of the heterogeneous genetics of the Alzheimer diseases (ADs) is currently more advanced than in any other common disease. Not only are 3 uncommon autosomal dominant mutation loci identified, but universally inherited susceptibility polymorphisms associated with risk and age of onset distributions for familial and "sporadic" AD are also confirmed. The utility of testing for mutations of the amyloid precursor protein and the presenilin 1 and presenilin 2 genes conforms to strategies in common use for rare mutations. The selection of patients with very early-onset AD, especially those with family histories of the disease, will increase the possibility of diagnosis. All testing should be performed using recommended counseling procedures. Apolipoprotein E (ApoE) susceptibility polymorphisms are genetic risk factors but do not allow prediction of the age of onset of AD for cognitively normal individuals. Recent large, collaborative studies have found that when ApoE genotyping is used sequentially in diagnosis following criteria-based evaluations, the specificity of early diagnosis is significantly increased. For patients clinically diagnosed with AD who carried an ApoE epsilon 4 allele, the positive predictive value was 94% and 97% in 2 multicenter collaborative series. The utility of ApoE genotyping is reviewed and recommendations for early use in diagnosis are explained. There are ethical, social, actuarial, and legal problems currently associated with genetic testing and these concerns are also discussed.