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Background  Alzheimer’s disease (AD) represents the most common form of dementia in elder populations with approximately 30 million cases worldwide. Genome wide genotyping and sequencing studies have identified many genetic variants associated with late-onset Alzheimer’s disease (LOAD). While most of these variants are associated with increased risk of developing LOAD, only limited number of reports focused on variants that are protective against the disease.    Methods  Here we applied a novel approach to uncover protective alleles against AD by analyzing genetic and phenotypic data in Mount Sinai Biobank and Electronic Medical Record (EMR) databases.    Results  We discovered a likely loss-of-function small deletion variant in the caspase 7 (CASP7) gene associated with significantly reduced incidence of LOAD in carriers of the high-risk APOE ε4 allele. Further investigation of four independent cohorts of European ancestry revealed the protective effect of the CASP7 variant against AD is most significant in homozygous APOE ε4 allele carriers. Meta analysis of multiple datasets shows overall odds ratio = 0.45 ( p  = 0.004). Analysis of RNA sequencing derived gene expression data indicated the variant correlates with reduced caspase 7 expression in multiple brain tissues we examined.    Conclusions  Taken together, these results are consistent with the notion that caspase 7 plays a key role in microglial activation driving neuro-degeneration during AD pathogenesis, and may explain the underlying genetic mechanisms that anti-inflammatory interventions in AD show greater benefit in APOE ε4 carriers than non-carriers. Our findings inform potential novel therapeutic opportunities for AD and warrant further investigations.    Electronic supplementary material  The online version of this article (doi:10.1186/s12864-016-2725-z) contains supplementary material, which is available to authorized users.

A loss of function variant in CASP7 protects against Alzheimer’s disease in homozygous APOE ε4 allele carriers