Age-related differences in memory and executive functions in healthy APOE ɛ4 carriers: the contribution of individual differences in prefrontal volumes and systolic blood pressure

Abstract

Advanced age and vascular risk are associated with declines in the volumes of multiple brain regions, especially the prefrontal cortex, and the hippocampus. Older adults, even unencumbered by declining health, perform less well than their younger counterparts in multiple cognitive domains, such as episodic memory, executive functions, and speed of perceptual processing. Presence of a known genetic risk factor for cognitive decline and vascular disease, the ɛ4 allele of the apolipoprotein E (APOE) gene, accounts for some share of those declines; however, the extent of the joint contribution of genetic and physiological vascular risk factors on the aging brain and cognition is unclear. In a sample of healthy adults (age 19-77), we examined the effects of a vascular risk indicator (systolic blood pressure, SBP) and volumes of hippocampus (HC), lateral prefrontal cortex (lPFC), and prefrontal white matter (pFWM) on processing speed, working memory (WM), and recognition memory. Using path analyses, we modeled indirect effects of age, SBP, and brain volumes on processing speed, WM, and memory and compared the patterns of structural relations among those variables in APOE ɛ4 carriers and ɛ3 homozygotes. Among ɛ4 carriers, age differences in WM were explained by increase in SBP, reduced FWM volume, and slower processing. In contrast, lPFC and FWM volumes, but not BP, explained a share of age differences in WM among ɛ3 homozygotes. Thus, even in healthy older carriers of the APOE ɛ4 allele, clinically unremarkable increase in vascular risk may be associated with reduced frontal volumes and impaired cognitive functions.

Figure 1

Representative examples of manual measurement of regions of interest. Images are in radiological orientation. A. Example of lateral prefrontal cortex ROI; B. Example of prefrontal white matter ROI (from same slice as A.); C. Depiction of hippocampal ROI.

Figure 2

Age differences in regional volumes for APOE ε4 carriers (empty circles, dashed line) and ε3 homozygotes (filled circles, sold line).

Figure 3

Nested path models for ApoE ε4 carriers and ApoE ε3 homozygotes from reduced grouped mediational models. Only significant direct paths are shown. A. Models for mediation of associations with processing speed and working memory; B. Models for mediation of associations with recognition memory for items and associations. * p < .05, ** p < .01, *** p < .001