Cerebrospinal Fluid Markers for Alzheimer's Disease over the Lifespan: Effects of Age and the APOEε4 Genotype

In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-beta(1-42) (A beta(1-42)) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of A beta(1-42) and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOE epsilon 4 allele, on the CSF A beta(1-42) and pTau181 concentrations in 280 adults with normal cognition across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF A beta(1-42) and pTau181, and of the APOE epsilon 4 genotype on the A beta(1-42) levels in the cognitively normal participants. Carrying the APOE epsilon 4 allele was associated with a significant decrease of the A beta(1-42) concentrations in middle-aged and older participants. In the group of participants with AD, the A beta(1-42) levels were significantly lower in the APOE epsilon 4 carriers compared to the non-carriers. These findings demonstrate significant age effects on the CSF A beta(1-42) and pTau181 across lifespan. They also suggest that the decrease of A beta(1-42), but not the increase of pTau181 CSF levels is accelerated by the APOE epsilon 4 genotype in middle-aged and older adults with normal cognition.