Biochemical markers in persons with preclinical familial Alzheimer disease

Abstract

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 (Abeta(40), Abeta(42), F(2)-isoprostanes) and CSF (F(2)-isoprostanes, t-tau, p-tau(181), Abeta(40), Abeta(42), and Abeta(42)/Abeta(40) ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs).

Results: Plasma Abeta(42) levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of Abeta(42)/Abeta(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 Abeta(42) levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of Abeta(42) to Abeta(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 Abeta(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 Abeta(42) to Abeta(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.

Figure 1 Boxplots of plasma levels of Aβ₄₂ in familial Alzheimer disease (FAD) mutation carriers and noncarriers according to Clinical Dementia Rating (CDR) scale scores Horizontal lines represent the median, boxes represent the 25th to 75th percentile, and whiskers represent total range. FAD mutation carriers with CDR scores of 0 have significantly higher plasma Aβ₄₂ levels than either FAD mutation carriers with CDR scores of 0.5 or noncarriers.

Figure 2 Scatterplot of levels of total tau (left, T-tau) and tau phosphorylated at serine 181 (right, P-tau) in the CSF of familial Alzheimer disease (FAD) mutation carriers and noncarriers

Figure 3 Scatterplot of p-tau₁₈₁ levels in CSF according to age relative to the median age at dementia diagnosis in the family (adjusted age)