Episodic memory impairment is a consistent, pronounced deficit in pre-clinical stages of late-onset Alzheimer's disease (AD). Individuals with risk factors for AD exhibit altered brain function several decades prior to the onset of AD-related symptoms. In the current event-related fMRI study of spatial context memory we tested the hypothesis that middle-aged adults (MA; 40–58 yrs) with a family history of late onset AD (MA+ FH), or a combined + FH and apolipoprotein E ε4 allele risk factors for AD (MA+ FH + APOE4), will exhibit differences in encoding and retrieval-related brain activity, compared to − FH − APOE4 MA controls. We also hypothesized that the two at-risk MA groups will exhibit distinct patterns of correlation between brain activity and memory performance, compared to controls. To test these hypotheses we conducted multivariate task, and behavior, partial least squares analysis of fMRI data obtained during successful context encoding and retrieval. Our results indicate that even though there were no significant group differences in context memory performance, there were significant differences in brain activity and brain-behavior correlations involving the hippocampus, inferior parietal cortex, cingulate, and precuneus cortex in MA with AD risk factors, compared to controls. In addition, we observed that brain activity and brain-behavior correlations in anterior-medial PFC and in ventral visual cortex differentiated the two MA risk groups from each other, and from MAcontrols. Our results indicate that functional differences in episodic memory-related regions are present by early midlife in adults with + FH and + APOE-4 risk factors for late onset AD, compared to middle-aged controls.

Healthy aging is associated with declines in episodic memory and with widespread cortical thinning.These parallel declines suggest that age-related changes in cortical thickness may contribute to episodic memory decline with age. The current study uses a cross-sectional study design to examine whether regional cortical thickness mediates the relationship between age and episodic memory, as measured by a context memory task for faces. Mediation and conditional mediation models were tested using bootstrapping in order to determine how age-associated changes in regional cortical thickness mediated age-associated changes in performance on the context memory task. We observed that right superior frontal cortical thickness conditionally mediated spatial context memory only in middle-aged and older adults; and right caudal middle frontal cortical thickness conditionally mediated context memory only in older adults. Left lingual cortical thickness mediated spatial context memory across the adult lifespan, but this effect was most evident at midlife. Right parahippocampal cortical thickness mediated context memory, independent of age. We conclude that our cortical thickness results were generally consistent with the posterior-to-anterior shift in aging hypothesis (Davis et al., 2008) for episodic memory. 1994).Several studies have reported age-related volumetric decline in brain regions related to encoding and/or retrieval of contextual details from episodic memory Hogstrom, Westlye, Walhovd, & Fjell, 2013;Raz, Ghisletta, Rodrigue, Kennedy, & Lindenberger, 2010;Walhovd et al., 2011). Salat et al (2004) reported reductions in cortical thickness with age in PFC, supramarginal gyrus, and calcarine sulcus, with relative preservation of lateral temporal cortex thickness. Raz et al Changes in context memory and cortical thickness across the adult lifespan 4 (2005) also reported a steady decline in PFC grey matter volumes with age, starting in young adulthood. However, five year longitudinal follow-up data indicated there was notable individual variability in how PFC volumes changed with age, with some subjects exhibiting volumetric decline, and other subjects exhibiting either no change or increased PFC volume at five year follow-up (Raz et al., 2005). In contrast to a general decrease in PFC volumes throughout adulthood, hippocampal volume decline with age exhibits a non-linear pattern. For example, Walhovd et al (2011) have reported changes in hippocampal volumes with age resembling an inverted-U shape, which was suggestive of accelerated volume loss in this region in late midlife onwards. This observation was corroborated by Fjell et al (2013). Therefore, there is significant evidence that aging is related to structural decline in several brain regions associated with episodic memory.However, fewer studies have examined whether age-related declines in brain volume and/or cortical thickness directly relates to age-related decline in episodic memory tasks. In other words, do age-related differences in regional cortical thickne...