Oxidative Damage Is the Earliest Event in Alzheimer Disease

TLDR

The study aimed to determine whether oxidative damage is an early or late event in Alzheimer’s disease by examining its relationship with amyloid‑β plaques, neurofibrillary tangles, dementia duration, and ApoE genotype. Researchers assessed neuronal 8‑hydroxyguanosine and nitrotyrosine levels in relation to amyloid‑β plaques, neurofibrillary tangles, dementia duration, and ApoE genotype. Oxidative damage, measured by 8OHG and nitrotyrosine, peaks early in Alzheimer’s disease and declines as the disease progresses, with higher amyloid‑β deposition and neurofibrillary tangles—especially in ApoE ε4 carriers—associated with reduced oxidative markers, suggesting compensatory mechanisms that lower reactive‑oxygen damage over time.

Abstract

Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA, 8-hydroxyguanosine (8OHG), and an oxidized amino acid, nitrotyrosine in vulnerable neurons of patients with Alzheimer disease (AD). To determine whether oxidative damage is an early- or end-stage event in the process of neurodegeneration in AD, we investigated the relationship between neuronal 8OHG and nitrotyrosine and histological and clinical variables, i.e. amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT), as well as duration of dementia and apolipoprotein E (ApoE) genotype. Our findings show that oxidative damage is quantitatively greatest early in the disease and reduces with disease progression. Surprisingly, we found that increases in Aβ deposition are associated with decreased oxidative damage. These relationships are more significant in ApoE ε4 carriers. Moreover, neurons with NFT show a 40%–56% decrease in relative 8OHG levels compared with neurons free of NFT. Our observations indicate that increased oxidative damage is an early event in AD that decreases with disease progression and lesion formation. These findings suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen.