Semantic memory activation in individuals at risk for developing Alzheimer disease.

OBJECTIVE To determine whether whole-brain, event-related fMRI can distinguish healthy older adults with known Alzheimer disease (AD) risk factors (family history, APOE epsilon4) from controls using a semantic memory task involving discrimination of famous from unfamiliar names. METHODS Sixty-nine cognitively asymptomatic adults were divided into 3 groups (n = 23 each) based on AD risk: 1) no family history, no epsilon4 allele (control [CON]); 2) family history, no epsilon4 allele (FH); and 3) family history and epsilon4 allele (FH+epsilon4). Separate hemodynamic response functions were extracted for famous and unfamiliar names using deconvolution analysis (correct trials only). RESULTS Cognitively intact older adults with AD risk factors (FH and FH+epsilon4) exhibited greater activation in recognizing famous relative to unfamiliar names than a group without risk factors (CON), especially in the bilateral posterior cingulate/precuneus, bilateral temporoparietal junction, and bilateral prefrontal cortex. The increased activation was more apparent in the FH+epsilon4 than in the FH group. Unlike the 2 at-risk groups, the control group demonstrated greater activation for unfamiliar than familiar names, predominately in the supplementary motor area, bilateral precentral, left inferior frontal, right insula, precuneus, and angular gyrus. These results could not be attributed to differences in demographic variables, cerebral atrophy, episodic memory performance, global cognitive functioning, activities of daily living, or depression. CONCLUSIONS Results demonstrate that a low-effort, high-accuracy semantic memory activation task is sensitive to Alzheimer disease risk factors in a dose-related manner. This increased activation in at-risk individuals may reflect a compensatory brain response to support task performance in otherwise asymptomatic older adults.