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CSF BIOMARKER PROFILE OF ABCA7 MUTATION CARRIERS HIGHLIGHTS AMYLOID-BETA PATHOLOGY
Abstract
Aims
Rare premature termination codon (PTC) mutations and expansion of a variable number of tandem repeats (VNTR) polymorphism in the Alzheimer’s disease (AD) risk gene ABCA7 likely increase risk of AD through haploinsufficiency. ABCA7 has suggested functions in lipid metabolism and the immune system, possibly affecting APP metabolism, but the exact mechanisms through which ABCA7 reduction causes AD remain unclear. Studying CSF biomarkers reflecting different pathological processes in mutation carriers could shed light on these mechanisms.
Methods
We conducted ELISA assays for eight AD-related biomarkers on the CSF of 229 AD patients for whom ABCA7 VNTR length determination was performed, including 28 PTC mutation carriers and 16 pathogenic expansion carriers. For reference, 75 controls were included. We investigated the effect of expression-reducing mutations and VNTR length on amyloid-beta (Aβ) 40 and 42, the amyloid 42/40 ratio, t-tau, p-tau, sAPP-α and -β, YKL-40 and hFABP.
Results
Carriers of expression-reducing mutations had significantly lower Aβ42 levels (p=0.0075) and amyloid ratio (p=0.0039) compared to non-carriers. The effect on Aβ42 levels was limited to non-APOE4 carriers (p=0.020). An increased VNTR length was associated with increased p-tau levels (p=0.036) and decrease in amyloid ratio (p=0.029). Other biomarkers, reflecting neuroinflammation and vascular pathology, were not altered in relation to ABCA7 variants.
Conclusions
Our results highlight that ABCA7 PTC and repeat expansion carriers show differences in CSF amyloid beta markers, but not in CSF biomarkers reflecting other pathophysiological aspects of AD. This suggests that reduced ABCA7 expression leads to increase in amyloid pathology, especially in non-APOE4 carriers.