To systematically evaluate the contributions of different factors to chemically modified siRNA efficacy, we designed and synthesized a panel of siRNAs targeting 192 sites (each 20-nt long) randomly distributed within four mRNAs that contribute to pathophysiological hallmarks of Alzheimer’s disease (AD): amyloid β precursor protein (APP), β-Secretase 1 (BACE1), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA). Here, BACE1 is linked to early-onset autosomal dominant Alzheimer disease.