Family history and APOE4 risk for Alzheimer’s Disease impact the neural correlates of episodic memory by early midlife

Abstract

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; 40-58yrs) 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 hippocampus, inferior parietal cortex, cingulate, and precuneus 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 MA controls . 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.peer-reviewed)

APOE4 status is related to differences in memory-related brain function in asymptomatic older adults: Baseline analysis of the PREVENT-AD task fMRI dataset

“…Our findings are consistent with our previous work on the influence of APOE4 on brain activity in middle-aged adults at risk of AD (Rajah et al, 2017) and are the first to identify recognition-related differences in brain-behavior relationships in asymptomatic older adults at risk of AD. These findings add a nuanced perspective to the study of neural processes associated with recollection vs. familiarity as well as the role of APOE4 on brain-behavior relationships in asymptomatic older adults with family history of AD, which remains poorly characterized (O'Donoghue et al, 2018).…”

“…Behaviorally, we found that both -APOE4 and +APOE4 individuals performed well on neuropsychological tests as well as our episodic memory task, with greater MoCA scores in +APOE4 individuals. These results largely align with previous studies showing no significant behavioral differences in cognitive performance on the basis of APOE4 status in younger (Taylor et al, 2017) and healthy older adults of similar demographic background (Reas et al, 2019), as well as our previous work using a similar episodic memory task in middle-aged adults at risk of AD (Rajah et al, 2017). However, given the high sensitivity of the MoCA for detecting mild cognitive impairment (Pinto et al, 2019), lower MoCA performance among -APOE4 participants may support theories suggesting that carrying an APOE4 allele may paradoxically benefit cognitive function in early and midlife (Evans et al, 2014).…”

“…Our past work demonstrated an association between episodic memory performance and changes in task-related fMRI detectable as early as middle-age (Ankudowich, Pasvanis, & Rajah, 2016) and more pronounced in APOE4 carriers or those with family history of AD (Rajah et al, 2017). These distinct associations appear in the absence of measurable behavioral differences and may be greater for the encoding and retrieval of contextual details associated with a past event, compared to general sense of familiarity (Ankudowich et al, 2016).…”

Open Science Datasets from PREVENT-AD, a Longitudinal Cohort of Pre-symptomatic Alzheimer’s Disease

“…The study design is similar to that published previously. 33,34 Participants were scanned as they encoded an object and it's left/right spatial location on the screen. Forty-eight encoding stimuli were presented one at a time for 2000 msec with a variable inter-trial interval (ITI).…”

Genetic risk of dementia modifies the impact of obesity on limbic white matter and spatial navigation behavior in cognitively healthy adults

“…In cognitively healthy individuals, APOE-e4 has been linked to vulnerabilities in spatial navigation 35 , executive function 36,37 and processing speed 38 and both APOE-e4 and FH to impairments in episodic memory 36,[39][40][41][42] . Furthermore, both APOE-e4 and FH are associated with changes in brain areas known to be affected in LOAD, such as posterior cingulate, parietal, prefrontal and temporal cortices including hippocampal and parahippocampal regions [43][44][45][46][47][48] . For instance, APOE-e4 carriers with a FH of LOAD had larger axial diffusivity in the uncinate fasciculus (UF), a pathway that connects temporal and prefrontal cortex regions 49 .…”