APOLIPOPROTEIN-E GENOTYPE AND NEUROPATHOLOGICAL PHONOTYPE IN 2 MEMBERS OF A GERMAN FAMILY WITH CHROMOSOME 14-LINKED EARLY-ONSET ALZHEIMERS-DISEASE

Molecular genetic analysis was performed in two autopsy-confirmed case s of early-onset Alzheimer's disease belonging to a large German pedig ree [FAD2, according to the nomenclature of St. George-Hyslop, et al. (1987) Science 235:885-890]. The disease in this family has been linke d to chromosome 14. As gene interactions are considered to influence t he age of onset and tissue pathology in Alzheimer's disease, we have s tudied three candidate genes that could modify disease progression. In this study a new polymerase chain reaction (PCR) assay was establishe d for apolipoprotein E genotyping in archival neuropathological tissue , exon 17 of the amyloid precursor protein gene was directly sequenced , and a candidate mutation site at nucleotide (nt) 5460 of the mitocho ndrial NADH dehydrogenase subunit gene ND2 was analyzed employing PCR followed by HphI digestion. Whereas no sequence variations were detect ed in exon 17(APP) or at nt5460 of mitochondrial DNA, the apolipoprote in E genotypes of the two cases differed. Neuropathological examinatio n revealed a higher number of beta A4-positive amyloid plaques and a l arger total tissue area covered by beta A4 deposits in the epsilon 3/e psilon 3 homozygote. In contrast, the number of cortical neurofibrilla ry tangles and the number of plaques with tau-positive neurites appear ed to be higher in the epsilon 3/epsilon 4 heterozygote. Our findings support the view that the chromosome 14 genetic defect, rather than ap olipoprotein E genotype, is the preeminent factor determining Alzheime r's disease pathology in this family.