| Summary: | Mounting evidence shows that the <i>APOE</i> ε4 allele interferes with cognition in sporadic Alzheimer’s disease. Less is known about <i>APOE</i> in autosomal-dominant Alzheimer’s disease (adAD). The present study explored the effects on cognition associated with the gene–gene interactions between the <i>APOE</i> gene and the <i>APP</i> and <i>PSEN1</i> genes in adAD. This study includes mutation carriers (MC) and non-carriers (NC) from adAD families with mutations in <i>APP</i> (<i>n</i> = 28 and <i>n</i> = 25; MC and NC, respectively) and <i>PSEN1</i> (<i>n</i> = 12 and <i>n</i> = 15; MC and NC, respectively) that represent the complete spectrum of disease: AD dementia (<i>n</i> = 8) and mild cognitive impairment (MCI, <i>n</i> = 15 and presymptomatic AD, <i>n</i> = 17). NC represented unimpaired normal aging. There was no significant difference in the distribution of <i>APOE</i> ε4 (absence vs. presence) between the <i>APP</i> vs. <i>PSEN1</i> adAD genes and mutation status (MC vs. NC). However, episodic memory was significantly affected by the interaction between <i>APOE</i> and the <i>APP</i> vs. <i>PSEN1</i> genes in MC. This was explained by favorable performance in the absence of <i>APOE</i> ε4 in <i>PSEN1</i> compared to <i>APP</i> MC. Similar trends were seen in other cognitive functions. No significant associations between <i>APOE</i> ε4 and cognitive performance were obtained in NC. In conclusion, cognitive effects of <i>APOE</i>–adAD gene interaction were differentiated between the <i>PSEN1</i> and <i>APP</i> mutation carriers, indicating epistasis.
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