Protective variants in Alzheimer’s Disease from healthy elderly APOE‐ε4 participants

Abstract

AbstractBackgroundPresence of the APOE‐ε4 allele is the most consistently confirmed genetic risk factor for late‐onset Alzheimer’s disease (AD) in white, non‐Hispanic populations, but the associated risks observed in African Americans and Hispanics are somewhat lower. The objective of this study was to identify protective variants that could modify or reduce the effect of APOE‐ε4 on AD risk.MethodsWe analyzed WGS data in over 3500 individuals from 600 multiplex AD families of non‐Hispanic White (NHW) and Caribbean Hispanic (CH) ancestry to identify protective variants in AD. APOE ε4 homozygosity was found in 48 healthy individuals over the age of 70, and APOE ε4 heterozygosity was found in 155 healthy individuals over the age of 80 were present in families with two of more affected samples. Protective variants were found segregating in the APOE ε4 homozygote and heterozygote individuals. We required that these variants be rare (MAF<0.1%) in GnomAD and prioritized exon coding variants that were putatively damaging to the resulting protein product. Novel or rare coding mutations segregating in ε4 unaffected subjects were tested for the effects on the age of onset of symptoms.ResultsWe identified 632 putatively protective variants that were present in at least 1% of APOE ε4 carriers and were absent in those with other APOE genotypes. 67 protective variants were present in both NHW and CH families. Pathway analysis of these segregating variants in APOE ε4 carriers are enriched in pathways involved in biological pathways and molecular functions such “actin binding”, “microtubule binding”, “extracellular matrix structural constituent”. These results suggest that protective variants promote activity of the extracellular matrix and cytoskeletal proteins leading to enhanced clearing of Aβ peptides. Variants in NBEAL1 delayed the age of onset in AD by 8.33 years respectively.ConclusionsWGS in CH and NHW families multiply affected by AD identified some healthy elderly, non‐demented APOE ε4 carriers with rare coding variants associated with delayed age of onset. Characterizing the functional role of these protective variants in AD will facilitate the creation of tractable models for investigation of disease mechanisms and potential therapies.