Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain.

BACKGROUND The relative contribution of mutations in the presenilin (PSEN) and amyloid precursor protein genes to autosomal dominant and other early-onset Alzheimer disease (AD) cases is not well established. OBJECTIVES To clarify the respective contribution of the amyloid precursor protein and PSEN mutations to autosomal dominant AD and to determine its contribution to sporadic and familial nonautosomal dominant early-onset AD and familial late-onset AD in a referral-based Spanish population. SUBJECTS AND METHODS Ninety-four patients with AD (60 with early-onset AD and 34 with late-onset AD) from 82 independent families were studied. According to the family history, patients were classified into the following groups: autosomal dominant, familial nonautosomal dominant, and sporadic. Mutational analysis of the coding regions of the amyloid precursor protein, presenilin 1, and presenilin 2 was performed in all patients. Apolipoprotein E was also genotyped. RESULTS Of the 60 early-onset cases, 44 from 36 families had a positive family history (11 with autosomal dominant AD and 25 with familial nonautosomal dominant AD) and 16 were sporadic. The frequency of mutations was 54.6% (6/11) among the autosomal dominant group, 6.2% (1/16) among the sporadic group, and 4% (1/25) among the familial nonautosomal dominant AD group. Most PSEN mutations (92%) would have been detected using a cutoff age of 58 years. The apolipoprotein E epsilon4 allele frequency was increased among early-onset AD without PSEN mutations. CONCLUSIONS More than half of the families with autosomal dominant early-onset AD can be explained by coding mutations in the PSEN genes. In the familial and sporadic early-onset groups mutations are rare. When family history is unavailable, an age of 58 years may be used as a cutoff point for genetic analysis. The increased apolipoprotein E epsilon4 allele in patients without PSEN mutations confirms that it is an important risk factor in the cause of non-PSEN early-onset AD.