Biochemical markers in persons with preclinical familial Alzheimer disease

Background: Persons at risk for familial Alzheimer disease (FAD) provide a model in which biomarkers 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 (A beta(40), A beta(42), F-2-isoprostanes) and CSF (F-2-isoprostanes, t-tau, p-tau 181, A beta(40), A beta(42), and A beta(42)/A beta(40) ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs). Results: Plasma A beta(42) levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of A beta(42)/A beta(40) (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 A beta(42) levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of A beta(42) to A beta(40) 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-tau(181) levels were elevated in presymptomatic FAD MCs. CSF levels of F-2-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 A beta(42) 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 A beta(42) to A beta(40) was reduced in the CSF of nondemented MCs and that elevations of t-tau and p-tau(181) are sensitive indicators of presymptomatic disease. Our finding of elevated F-2-isoprostane levels in the CSF of preclinical FAD MCs suggests that oxidative stress occurs downstream to mismetabolism of amyloid precursor protein.