Biochemical markers in persons with preclinical familial Alzheimer disease

Background: Persons at risk for familial Alzheimer disease (FAD) provide a model in which bio-markers can be studied in presymptomatic disease. Methods: Twenty-one subjects at risk for presenilin-1 (n = 17) or amyloid precursor protein (n = 4) mutations underwent evaluation with the Clinical Dementia Rating (CDR) scale. We obtained plasma from all subjects and CSF from 11. Plasma (Aβ₄₀, Aβ₄₂, F₂-isoprostanes) and CSF (F₂-isoprostanes, t-tau, p-tau₁₈₁, Aβ₄₀, Aβ₄₂, and Aβ₄₂/Aβ₄₀ ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs). Results: Plasma Aβ₄₂ levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of Aβ₄₂/Aβ₄₀ (0.16 vs 0.11, p = 0.045) were higher in presymptomatic MCs. Among MCs, those with CDR scores of 0.5 had lower plasma Aβ₄₂ levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of Aβ₄₂ to Aβ₄₀ was also reduced in the CSF (0.08 vs 0.15, p = 0.046) of nondemented MCs compared to NCs. Total CSF tau and p-tau₁₈₁ levels were elevated in presymptomatic FAD MCs. CSF levels of F₂-isoprostanes were also elevated in MCs (n = 7, 48.6 pg/mL) compared to NCs (n = 4, 21.6 pg/mL, p = 0.031). Conclusions: Our data indicate that Aβ₄₂ is elevated in plasma in familial Alzheimer disease (FAD) mutation carriers (MCs) and suggests that this level may decrease with disease progression prior to the development of overt dementia. We also demonstrated that the ratio of Aβ₄₂ to Aβ₄₀ was reduced in the CSF of nondemented MCs and that elevations of t-tau and p-tau₁₈₁ are sensitive ndicators of presymptomatic disease. Our finding of elevated F₂-isoprostane levels in the CSF of preclinical FAD MCs suggests that oxidative stress occurs downstream to mismetabolism of amyloid precursor protein.