Apolipoprotein E isoforms and the development of low and high Braak stages of Alzheimer's disease-related lesions

In recent research, apolipoprotein-E (apoE) polymorphism has been shown to influence the formation of neurofibrillary changes and the accumulation of beta/A4-amyloid, the histopathological hallmarks of Alzheimer's disease (AD). Clinical studies associate the apoE allele epsilon 4 with earlier onset of the disease, although the clinical speed of progression remains unchanged. Time course estimates have also provided evidence which indicates that the clinical phase of AD constitutes only 10-20% of the total time span needed for the development of this slowly progressing degenerative brain disorder. Due to the lack of reliable clinical tests for the detection of pre-symptomatic stages of AD, we set out with an autopsy approach to monitor neuropathology of the long pre-clinical phase of AD. This study examined beta/A4-peptide deposition and the formation of neurofibrillary changes staged according to the Braaks' classification in groups of individuals matched for age and sex with different genotypes. In comparison with epsilon 3 homozygotes, the presence of the epsilon 4 allele is statistically associated with a higher stage of beta/A4-peptide deposition and neurofibrillary change formation (chi(2)-test, P < 0.01 for beta/A4-stage and P < 0.001 for neurofibrillary changes). The effect of the epsilon 2 allele differs. Its presence is associated with a lower stage of neurofibrillary pathology in individuals below the age of 80 but with a higher stage thereafter compared to age- and sex-matched epsilon 3 homozygotes. Accordingly, the statistical juxtaposition of individuals over 80 years with epsilon 4 alleles and those with epsilon 2 alleles showed no significant difference with respect to the stages. Our findings indicate that apoE-variants have different effects on the speed of histopathology formation, even in the pre-clinical stages of AD. This suggests that clinical onset, course and pathogenesis of AD are influenced by the apoE genotype.