Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The Alzheimer’s disease (AD) risk gene <jats:italic>ABCA7</jats:italic> has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in the gene, both likely cause a lower <jats:italic>ABCA7</jats:italic> expression and hereby increased risk for AD. However, the exact mechanism‐of‐action remains unclear. By studying CSF biomarkers reflecting different types of AD‐related pathological processes, we aim to get a better insight in those processes and establish a biomarker profile of mutation carriers.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>The study population consisted of 228 AD patients (27 PTC mutation and 16 pathogenic expansion carriers) for whom CSF was available and <jats:italic>ABCA7</jats:italic> sequencing and VNTR genotyping had been performed. CSF levels of amyloid β (Aβ) 40 and 42, sAPP‐α and ‐β, YKL‐40 and hFABP were determined using ELISA and Meso Scale Discovery assays. We compared differences in levels of these biomarkers AD patients with or without an <jats:italic>ABCA7</jats:italic> PTC mutation or expansion, and further stratified on <jats:italic>APOE</jats:italic> e4 status.</jats:p></jats:sec><jats:sec><jats:title>Result</jats:title><jats:p>Carriers of <jats:italic>ABCA7</jats:italic> mutations/expansions had significantly lower Aβ42 levels (<jats:italic>p</jats:italic>= 0.0031) and amyloid ratio (<jats:italic>p</jats:italic>=0.020) compared to non‐carrier patients, and were threefold more likely to have abnormal Aβ42 values. The effect on amyloid biomarkers remained significant when considering PTC mutations or VNTR expansions separately. <jats:italic>APOE</jats:italic> e4 carriers had significantly lower Aβ42 (p=0.0013) and amyloid ratio (p<0.001) compared to non‐<jats:italic>APOE</jats:italic> e4 carriers. When combined, both <jats:italic>APOE</jats:italic> e4 allele and ABCA7 carrier status influenced amyloid ratio and Aβ42 levels. Remarkably, within non‐<jats:italic>APOE</jats:italic> e4 carriers, <jats:italic>ABCA7</jats:italic> mutation/expansion carriers did have significantly reduced Aβ42 levels (mean=540 pg/mL) compared to <jats:italic>ABCA7</jats:italic> non‐carriers (812 pg/mL; p=0.0051), attaining lower levels as e4 carriers (612 pg/mL). Finally, in carriers of the pathogenic expansion we observed lower YKL40 levels (p=0.011), suggesting reduced neuroinflammation.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our results highlight that carriers of <jats:italic>ABCA7</jats:italic> PTC mutations and repeat expansions show more pronounced abnormalities in CSF amyloid beta markers than non‐carrier patients, especially in non‐APOE e4 carriers. Expansion carriers also had a decrease in neuroinflammation marker YKL40. Our results suggest that reduced ABCA7 expression leads to increase in amyloid pathology and potentially a reduced inflammatory response to damage.</jats:p></jats:sec>