Increased amyloidogenic APP processing in APOE ε4-negative individuals with cerebral β-amyloidosis

Increased APP (amyloid precursor protein) processing causes beta-amyloid (Ab) accumulation in autosomal dominant Alzheimer's disease (AD), but it is unclear if it also affects sporadic A beta accumulation. We tested healthy controls and patients with mild cognitive symptoms (N = 331) in the BioFINDER study, using cerebrospinal fluid (CSF) A beta 40 as a surrogate for amyloidogenic APP processing. We find that levels of brain Ab fibrils (measured by 18F-flutemetamol PET) are independently associated with high CSF A beta 40 (P<0.001) and APOE epsilon 4 (P<0.001). The association between CSF A beta 40 and brain Ab is stronger in APOE epsilon 4-negative than in positive people (P = 0.0080). The results are similar for CSF A beta 38 and for a combination of CSF A beta 38 and CSF A beta 40. In conclusion, sporadic Ab accumulation may be partly associated with increased amyloidogenic APP production, especially in APOE epsilon 4-negative subjects. The risk for sporadic AD may consequently depend on increased Ab production, in addition to decreased A beta clearance.