Amyloid precursor protein metabolism and inflammation markers in preclinical Alzheimer disease

Objective: To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with suspected non-Alzheimer pathology (SNAP). Methods: We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (A beta 42, sAPP beta, beta-secretase activity), neuronal damage (total-tau [t-tau], phospho-tau [p-tau]), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging-Alzheimer's Association classification: stage 0, 1, 2, 3, and SNAP. Results: The median age in the whole cohort was 58.8 years (range 39.8-81.6). Participants in stages 2-3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPP beta than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2-3 in sAPP beta and beta-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with A beta 42, but only in APOE epsilon 4 carriers. A beta 42 correlated positively with t-tau, sAPP beta, and YKL-40 in participants with normal A beta 42. Conclusions: Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPP beta and beta-secretase activity are not useful diagnostic or staging markers in preclinical AD.