Oxidative damage is the earliest event in Alzheimer disease

Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA. 8-hydroxyguanosine (8OHG), and an oxidized amino acid. ni trotyrosine in vulnerable neurons of patients with Alzheimer disease (AD). To determine whether oxidative damage is an early- or end-stage event in th e process of neurodegeneration in AD, we investigated the relationship betw een neuronal 80HG and nitrotyrosine and histological and clinical variables . i.e. amyloid-beta (A beta) plaques and neurofibrillary tangles (NFT), as well as duration of dementia and apolipoprotein E (ApoE1) genotype, Our fin dings show that oxidative damage is quantitatively greatest early in the di sease and reduces with disease progression, Surprisingly, we found that inc reases in AP deposition are associated with decreased oxidative damage. The se relationships are more significant in ApoE is an element of4 carriers. M oreover, neurons with NFT show a 40%-56% decrease in relative 80HG levels c ompared with neurons free of NFT. Our observations indicate that increased oxidative damage is an early event in AD that decreases with disease progre ssion and lesion formation. These findings suggest that AD is associated wi th compensatory changes that reduce damage from reactive oxygen.