From the DEPARTMENT OF CLINICAL NEUROSCIENCE Karolinska Institutet, Stockholm, Sweden MEMORY, GENES, AND BRAIN IMAGING: RELATING THE APOE GENE TO BRAIN FUNCTION AND STRUCTURE

Alzheimer’s disease (AD) is the most common form of dementia. An important goal for current AD research is to find preclinical markers of impending disease. Apolipoprotein E ε4 (APOE ε4) is the chief known genetic risk factor for AD. A number of neuroimaging studies have reported structural and functional brain alterations in non-demented APOE ε4-carriers. Such results have tentatively been interpreted as early signs of impending dementia, but the findings have been inconsistent across studies. To further address this issue, the overall aim of this thesis was to examine asymptomatic cognitively well-functioning APOE ε4-carriers with magnetic resonance imaging (MRI) techniques, together with longitudinal neuropsychological testing. Study I revealed that carriers of APOE ε4 expressed reduced functional brain activity during incidental episodic encoding. In the parietal cortex, a genetic dose-effect was seen such that the activity reduction was more pronounced for homozygous than heterozygous APOE ε4-carriers. In addition, it was found that APOE ε4-carriers had structural changes in white-matter tracts in the hippocampus and the posterior corpus callosum (Study II), and grey matter reductions in the hippocampus (Study III). Study IV demonstrated that the degree of functional activity in the parietal cortex predicted subsequent episodic memory decline within the group of APOE ε4-carriers. Collectively, the results suggest that a combination of genetic, neuropsychological, and neuroimaging strategies is beneficial in predicting AD development. LIST OF PUBLICATIONS I. Lind J., Persson J., Ingvar M., Larsson A., Cruts M., Van Broeckhoven C., Adolfsson R., Bäckman L., Nilsson L-G., Petersson K. M., and Nyberg L. (2006) Reduced functional brain activity response in cognitively intact apolipoprotein E ε4 carriers. Brain, 129, 1240-48. II. Persson J., Lind J., Larsson A., Ingvar M., Cruts M., Van Broeckhoven C., Adolfsson R., Nilsson L-G., and Nyberg L. (2006) Altered brain white matter integrity in healthy carriers of the APOE ε4 allele: A risk for Alzheimer's disease. Neurology, 66:1029-33. III. Lind J., Larsson A., Persson J., Ingvar M., Nilsson L-G., Bäckman L., Adolfsson R., Cruts, M., Sleegers K., Van Broeckhoven C., and Nyberg L. (2006) Reduced hippocampal volume in non-demented carriers of the apolipoprotein E ε4: Relation to chronological age and recognition memory. Neuroscience Letters, 396:23–27. IV. Lind J., Ingvar M., Persson J., Sleegers K., Van Broeckhoven C., Adolfsson R., Nilsson L-G., and Nyberg L. (2006) Parietal cortex activation predicts memory decline in apolipoprotein E ε4 carriers. NeuroReport, 17:1683-1686.