Low normal cerebrospinal fluid Aβ42 levels predict clinical progression in nondemented subjects
Amyloid can be measured in cerebrospinal fluid (CSF), and decreased CSF amyloid β1‐42 (Aβ1‐42) levels indicate abnormal amyloid plaque aggregation in the brain.1 Abnormally low CSF Aβ1‐42 levels in nondemented subjects are robustly associated with clinical progression.3 As such, patients with mild cognitive impairment (MCI; ie, subjects without dementia, who have impairment in memory and/or another cognitive domain) and abnormal amyloid markers have prodromal Alzheimer disease (AD).4 However, 15 to 35% of MCI subjects with normal amyloid markers develop an AD‐type dementia.5 Although their amyloid levels are normal, it has been shown that for at least a subset of subjects these levels are near the cut‐point for abnormality.6 Using a cut‐point implies that amyloid accumulation is an on–off phenomenon. However, recent longitudinal CSF studies showed in nondemented subjects that lower, normal amyloid levels can become abnormally low over time.7 Such lower normal amyloid levels have also been associated with a decline in cognitive functioning as measured with neuropsychological test scores.7 This suggests that part of the normal range of Aβ1‐42 values reflects the start of the process of amyloid accumulation. Being able to identify such a range would provide novel opportunities to intervene in the process of amyloid accumulation at a very early stage.
The objective of this study was to investigate, in nondemented memory clinic subjects, the relationship between lower normal CSF Aβ1‐42 levels and rate of clinical progression. We also tested whether Aβ1‐42 levels had additive value over the injury markers tau and tau phosphorylated at threonine 181 (p‐tau), which have been robustly associated with disease progression in nondemented subjects with abnormal CSF Aβ1‐42 levels.