Basic Science and Pathogenesis

Alzheimer Disease (AD) is a highly polygenic dementia that presents with relatively earlier onset (≤65yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations.

We used data from EOAD cases ≤ 70 and controls > 70 to ensure they would not develop AD. genome-wide association study (GWAS) and trans-ancestry meta-analysis were performed for non-Hispanic European (EUR, N_Case=6,282, N_Control=13,386), African (AFR N_Case=782, N_Control=3,663) and East Asian (ASN: N_Case=375, N_Control=838 CO) ancestries. We performed QTL mapping and in-silico annotation to identify the functional gene for each genome-wide loci, and PRS and LDSC to compare the genetic architecture of EOAD vs LOAD RESULT: We identified a total of 15 genome-wide significant loci, 7 already reported to be associated with LOAD and 8 novel loci. Of the novel loci: six were found in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, eQTL, pQTL and functional annotations, we nominate four novel functional genes (CDH12, FOLH1, ALG10B and LRRC25) for four loci that are involved in microglia activation, glutamate production, and signaling pathways. LOAD-derived PRS showed a strong association with EOAD (R²=0.170, p <10^-300, and R²=0.048, p = 1.20×10^-143: for PRS with and without APOE). LDSC found strong overall genetic covariance between EOAD and LOAD (rg=0.791, p = 6.80×10^-12) CONCLUSION: These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.