O4–01–05: Rare Variants in APP and PSEN1 Genes Associated with Extreme Levels of Beta‐amyloid 42 and Tau Protein in Cerebrospinal Fluid
Alzheimer's & dementia(2013)
摘要
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.
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