Family history and APOE4 risk for Alzheimer's disease impact the neural correlates of episodic memory by early midlife.

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.

Changes in the correlation between spatial and temporal source memory performance and BOLD activity across the adult lifespan.

Studies investigating age-related functional differences associated with source memory have recently focused on the importance of clarifying the relationship between effects of age and performance on memory-related brain activations. One methodological challenge has been in discriminating between effects of age on memory-related brain activations that are independent from age-related differences in performance. In the current study, event-related functional magnetic resonance imaging (fMRI) was used to identify brain activity during spatial and temporal source encoding and retrieval across the adult lifespan. We used multivariate behavior partial least squares (B-PLS) to identify patterns of brain activity during source encoding and source retrieval that were associated with age and/or retrieval accuracy. The PLS analysis identified three significant effects. The first effect indicated that encoding and retrieval activity in fusiform, middle occipital-temporal and inferior parietal cortices increased with age and decreased with performance. The second effect showed that dorsolateral prefrontal cortex and limbic activity increased with age at encoding, and increased with performance at retrieval. The third effect indicated that activity in right ventrolateral prefrontal and bilateral hippocampus increased with age during retrieval and was differentially related to performance during encoding versus retrieval. We conclude that although some age-related differences in brain activity observed during source encoding and retrieval are associated with individual differences in performance, age-related differences in prefrontal and hippocampal areas exhibit more complex patterns of interactions between age, performance, and phase-related activity.

Changes in the modulation of brain activity during context encoding vs. context retrieval across the adult lifespan.

Age-related deficits in context memory may arise from neural changes underlying both encoding and retrieval of context information. Although age-related functional changes in the brain regions supporting context memory begin at midlife, little is known about the functional changes with age that support context memory encoding and retrieval across the adult lifespan. We investigated how age-related functional changes support context memory across the adult lifespan by assessing linear changes with age during successful context encoding and retrieval. Using functional magnetic resonance imaging (fMRI), we compared young, middle-aged and older adults during both encoding and retrieval of spatial and temporal details of faces. Multivariate behavioral partial least squares (B-PLS) analysis of fMRI data identified a pattern of whole-brain activity that correlated with a linear age term and a pattern of whole-brain activity that was associated with an age-by-memory phase (encoding vs. retrieval) interaction. Further investigation of this latter effect identified three main findings: 1) reduced phase-related modulation in bilateral fusiform gyrus, left superior/anterior frontal gyrus and right inferior frontal gyrus that started at midlife and continued to older age, 2) reduced phase-related modulation in bilateral inferior parietal lobule that occurred only in older age, and 3) changes in phase-related modulation in older but not younger adults in left middle frontal gyrus and bilateral parahippocampal gyrus that was indicative of age-related over-recruitment. We conclude that age-related reductions in context memory arise in midlife and are related to changes in perceptual recollection and changes in fronto-parietal retrieval monitoring.