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

genes

The APOE ε4 Allele Affects Cognitive Functions Differently in Carriers of APP Mutations Compared to Carriers of PSEN1 Mutations in Autosomal-Dominant Alzheimer’s Disease