O4–01–05: Rare Variants in APP and PSEN1 Genes Associated with Extreme Levels of Beta‐amyloid 42 and Tau Protein in Cerebrospinal Fluid

The primary constituents of the hallmark pathological features of Alzheimer Disease (AD), beta-amyloid (Aβ42), tau, and phosphorylated tau, are also the current leading cerebrospinal fluid (CSF) biomarkers. Pathogenic mutations and high-risk variants for AD can be identified using CSF-based biomarkers in endophenotype-oriented approaches. We performed deep-sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals (n=224) with extreme (15% bottom and top) Aβ42, tau, or p-tau CSF levels using next-generation sequencing. Follow-up series included 510 participants with CSF biomarkers levels, 1031 sporadic AD cases, 824 unrelated controls, probands from NIA-LOAD families (n=595), and 4,058 individuals from the GERAD1 Consortium. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, PSEN1, p.E318G (rs17125721) showed a significant association with high CSF tau (p=9.2×10-4) and ptau (P=1.8×10 -3) levels. We also found a strong association of low Aβ42 CSF levels with carriers of the p.E318G variant in the presence of at least one APOE ε4 allele (OR=18.3 IC=2.0–166.8) compared to APOE ε4 alone (OR=4.5, IC=3.4–6.0). The interaction between APOE and p.E318G was replicated in two independent case-control series. The meta-analysis (n=5,161) showed that individuals carrying p.E318G and at least one APOE ε4 allele exhibit a higher risk for AD (OR=10.1, 95% IC= 4.7–20.9) than for the APOE ε4 allele alone (OR=4.1, 95% IC=3.9–5.0). Additionally, p.E318G is present in 5.3% of a large (n=565) clinical series of LOAD families. In 1.4% of these families, p.E318G followed the segregation pattern of the disease. p.E318G carriers exhibit a lower age at onset than non-carriers (73.9 yr vs. 78.2 yr; p = 0.01). Fine mapping analysis showed that the minor allele of an APP SNP (rs456728) was associated with lower CSF tau (p=2.6×10-5) and ptau (p=9.8×10-5) levels, and with higher CSF Aβ42 (p=0.01) levels. Rs456728 is less frequent among individuals with low Aβ42 CSF levels (OR=0.53 CI=0.35–0.81). This study highlights the importance of the endophenotype approach, particularly using CSF biomarkers for genetic studies It also provides supporting evidence to the pathogenicity of genetic variants.