The enriched effect of CHMP2B remained significant when we considered only APOE ε4 carriers; some of the AD genes became nominally significant (e.g. APP and PSEN2) and the global effect of AD genes resulted in nominal significance for rare variants and significant after multiple test correction (Total AD, OR = 14.76, P = 1.83×10−4) when we considered very rare variants (S3 Table). The gene discussed is APP; the disease is Alzheimer disease.