Journal of the International Neuropsychological Society

Research Articles

Epistasis between APOE and nicotinic receptor gene CHRNA4 in age related cognitive function and decline


a1 Center for Study of Human Cognition, Department of Psychology, University of Oslo, Norway

a2 Department of Biological and Medical Psychology, University of Bergen, Norway

a3 Kavli’s Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital, Bergen, Norway

a4 Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway


Healthy participants (n = 237) aged 45–79 were tested neuropsychologically with tests of memory, speed, and cognitive control and followed up for 3–5 years (mean, 3.4 years). The sample was genotyped for apolipoprotein E (APOE) and CHolinergic Receptor for Nicotine Alpha 4 (CHRNA4), and genetic effects on cognitive function at initial testing and on cognitive decline was studied. We predicted relatively stronger effects of APOE on memory, and of CHRNA4 on speeded tasks. The predictions were partially confirmed, but we found interactive effects of APOE and CHRNA4 in several cognitive domains. Being an APOE ε4/CHRNA4 TT carrier was associated with slower and less efficient performance, and with steeper decline in speed tasks and in delayed recall. Age dependent genetic effects were found for both APOE and CHRNA4, where old participants (60–79 years) showed a negative influence of TT carrier status on initial memory performance, but a tendency for steeper memory decline in ε4 carriers. Inconsistent and small effects of APOE reported in previous studies of healthy groups may be caused by failure to consider epistasis of APOE with nicotinic receptor and other genes. (JINS, 2010, 16, 424–432.)

(Received September 03 2009)

(Reviewed February 11 2010)

(Accepted February 18 2010)


c1 Correspondence and reprint requests to: Ivar Reinvang, Department of Psychology, Center for the Study of Human Cognition, University of Oslo, Box 1094 Blindern, N-0317 Oslo, Norway. E-mail: