UC San Diego

BACKGROUND : There are several risk factors for the development of Alzheimer's disease (AD) including the apolipoprotein E (APOE) e4 allele, an important susceptibility gene for AD, and mild cognitive impairment (MCI). The literature to date generally indicates that nondemented older adults at risk for AD by virtue of their cognitive (i.e., MCI) and/or genetic (i.e., APOE) status demonstrate reduced medial temporal lobe (MTL) volumes and divergent brain response patterns during memory encoding relative to their counterparts not at risk. METHODS : We used arterial spin labeling (ASL) functional magnetic resonance imaging (FMRI) to examine the influence of AD risk on functional brain responses to memory encoding. Participants were 43 individuals aged 60 or older. Twenty- nine individuals were classified as cognitively normal and 14 met criteria for MCI. Twenty individuals were APOE e4 carriers whereas 23 were non-e4 carriers. The risk groups were equivalent in terms of mean age, mean years of education, gender distribution, vascular risk, or medial temporal lobe (MTL) volumes. RESULTS : Individuals at genetic risk for AD by virtue of the presence of at least one APOE e4 allele demonstrated increased MTL resting state CBF relative to their non-e4 counterparts. In contrast, individuals characterized as MCI showed decreased MTL resting state CBF relative to their cognitively normal peers. There was a trend toward a cognitive status by genotype interaction for percent change CBF. In the cognitively normal group there was no difference in percent change CBF based on APOE genotype. In contrast, in the MCI group, APOE e4 carriers demonstrated significantly greater activation relative to non-e4 carriers. CONCLUSIONS : Our findings provide support for the notion that individuals at risk for AD demonstrate changes in brain function in the preclinical period prior to the onset of dementia. Further, our results suggest that abnormal resting state CBF and FMRI response pattern to memory encoding may be early indicators of brain dysfunction in individuals at risk for developing AD and, therefore, ASL MRI may provide a sensitive technique for identifying individuals at risk, monitoring changes in neural activity due to developing AD neuropathology, and assessing effectiveness of disease- modifying treatments