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

View Article: PubMed Central - PubMed

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; 40–58 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.

No MeSH data available.


B-PLS results. A) The singular image at a bootstrap ratio threshold = ± 3.5, p < 0.001 and the brain-behavior correlation profile with 95% confidence intervals for B-PLS LV1. In the singular image red brain regions reflect positive brain saliences and blue regions reflect negative brain saliences. Activations are presented on template images of the lateral and medial surfaces of the left and right hemispheres of the brain using Caret software. The correlation profile indicates that encoding activity in positive salience regions was positively correlated with subsequent retrieval for both task in MA+ FH + APOE4 and MAcontrols; and retrieval activity in these same regions was negative correlated with retrieval accuracy on both tasks in MA+ FH + APOE4. In MA+ FH encoding and retrieval activity in positive salience regions during SE tasks was correlated with better performance on this task. Negative salience regions exhibited the inverse pattern of brain-behavior correlations. B) The singular image at a bootstrap ratio threshold = ± 3.5, p < 0.001 and the brain-behavior correlation profile with 95% confidence intervals for B-PLS LV2. The correlation profile indicates that increased encoding and retrieval activity in positive salience regions was positively correlated with memory performance on both tasks in MA+ FH + APOE4 subjects, and negatively correlated with memory performance on both tasks in MA+ FH. Negative salience regions exhibited the inverse pattern of brain-behavior correlations.
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f0015: B-PLS results. A) The singular image at a bootstrap ratio threshold = ± 3.5, p < 0.001 and the brain-behavior correlation profile with 95% confidence intervals for B-PLS LV1. In the singular image red brain regions reflect positive brain saliences and blue regions reflect negative brain saliences. Activations are presented on template images of the lateral and medial surfaces of the left and right hemispheres of the brain using Caret software. The correlation profile indicates that encoding activity in positive salience regions was positively correlated with subsequent retrieval for both task in MA+ FH + APOE4 and MAcontrols; and retrieval activity in these same regions was negative correlated with retrieval accuracy on both tasks in MA+ FH + APOE4. In MA+ FH encoding and retrieval activity in positive salience regions during SE tasks was correlated with better performance on this task. Negative salience regions exhibited the inverse pattern of brain-behavior correlations. B) The singular image at a bootstrap ratio threshold = ± 3.5, p < 0.001 and the brain-behavior correlation profile with 95% confidence intervals for B-PLS LV2. The correlation profile indicates that increased encoding and retrieval activity in positive salience regions was positively correlated with memory performance on both tasks in MA+ FH + APOE4 subjects, and negatively correlated with memory performance on both tasks in MA+ FH. Negative salience regions exhibited the inverse pattern of brain-behavior correlations.

Mentions: The B-PLS analysis identified two significant LVs. Fig. 3A presents the singular image and the corresponding bar graph depicting the brain activity-behavior correlation profile for B-PLS LV1 (accounted for 32.36% of the cross-block covariance). Table 5 lists the local maxima from this LV. Most of the peaks identified were positive brain saliences. There was a positive correlation between encoding activity in positive salience brain regions and subsequent retrieval accuracy across groups. In MAcontrols, this effect was only significant during SH encoding events; in MA+ FH subjects, this effect was only significant during SE encoding events; and in MA+ FH + APOE4 subjects, this was observed for both SE and SH encoding events. At retrieval, activity in these same regions during SE events was positively correlated with memory performance in MA+ FH, but activity in these regions during SE and SH retrieval was negatively correlated with memory performance in MA+ FH + APOE4. Therefore, LV1 identified brain regions in which: i) encoding activity was correlated with better subsequent retrieval in MAcontrols; ii) encoding and retrieval activity during SE memory tasks was positively correlated with memory performance in MA+ FH; and iii) there was a phase-related difference between activity and memory performance correlations in MA+ FH + APOE4. Positive salience brain regions identified in this LV included medial precuneus, bilateral inferior parietal cortex, anterior-medial prefrontal cortex, cingulate cortex, and hippocampus.


Family history and APOE4 risk for Alzheimer's disease impact the neural correlates of episodic memory by early midlife
B-PLS results. A) The singular image at a bootstrap ratio threshold = ± 3.5, p < 0.001 and the brain-behavior correlation profile with 95% confidence intervals for B-PLS LV1. In the singular image red brain regions reflect positive brain saliences and blue regions reflect negative brain saliences. Activations are presented on template images of the lateral and medial surfaces of the left and right hemispheres of the brain using Caret software. The correlation profile indicates that encoding activity in positive salience regions was positively correlated with subsequent retrieval for both task in MA+ FH + APOE4 and MAcontrols; and retrieval activity in these same regions was negative correlated with retrieval accuracy on both tasks in MA+ FH + APOE4. In MA+ FH encoding and retrieval activity in positive salience regions during SE tasks was correlated with better performance on this task. Negative salience regions exhibited the inverse pattern of brain-behavior correlations. B) The singular image at a bootstrap ratio threshold = ± 3.5, p < 0.001 and the brain-behavior correlation profile with 95% confidence intervals for B-PLS LV2. The correlation profile indicates that increased encoding and retrieval activity in positive salience regions was positively correlated with memory performance on both tasks in MA+ FH + APOE4 subjects, and negatively correlated with memory performance on both tasks in MA+ FH. Negative salience regions exhibited the inverse pattern of brain-behavior correlations.
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f0015: B-PLS results. A) The singular image at a bootstrap ratio threshold = ± 3.5, p < 0.001 and the brain-behavior correlation profile with 95% confidence intervals for B-PLS LV1. In the singular image red brain regions reflect positive brain saliences and blue regions reflect negative brain saliences. Activations are presented on template images of the lateral and medial surfaces of the left and right hemispheres of the brain using Caret software. The correlation profile indicates that encoding activity in positive salience regions was positively correlated with subsequent retrieval for both task in MA+ FH + APOE4 and MAcontrols; and retrieval activity in these same regions was negative correlated with retrieval accuracy on both tasks in MA+ FH + APOE4. In MA+ FH encoding and retrieval activity in positive salience regions during SE tasks was correlated with better performance on this task. Negative salience regions exhibited the inverse pattern of brain-behavior correlations. B) The singular image at a bootstrap ratio threshold = ± 3.5, p < 0.001 and the brain-behavior correlation profile with 95% confidence intervals for B-PLS LV2. The correlation profile indicates that increased encoding and retrieval activity in positive salience regions was positively correlated with memory performance on both tasks in MA+ FH + APOE4 subjects, and negatively correlated with memory performance on both tasks in MA+ FH. Negative salience regions exhibited the inverse pattern of brain-behavior correlations.
Mentions: The B-PLS analysis identified two significant LVs. Fig. 3A presents the singular image and the corresponding bar graph depicting the brain activity-behavior correlation profile for B-PLS LV1 (accounted for 32.36% of the cross-block covariance). Table 5 lists the local maxima from this LV. Most of the peaks identified were positive brain saliences. There was a positive correlation between encoding activity in positive salience brain regions and subsequent retrieval accuracy across groups. In MAcontrols, this effect was only significant during SH encoding events; in MA+ FH subjects, this effect was only significant during SE encoding events; and in MA+ FH + APOE4 subjects, this was observed for both SE and SH encoding events. At retrieval, activity in these same regions during SE events was positively correlated with memory performance in MA+ FH, but activity in these regions during SE and SH retrieval was negatively correlated with memory performance in MA+ FH + APOE4. Therefore, LV1 identified brain regions in which: i) encoding activity was correlated with better subsequent retrieval in MAcontrols; ii) encoding and retrieval activity during SE memory tasks was positively correlated with memory performance in MA+ FH; and iii) there was a phase-related difference between activity and memory performance correlations in MA+ FH + APOE4. Positive salience brain regions identified in this LV included medial precuneus, bilateral inferior parietal cortex, anterior-medial prefrontal cortex, cingulate cortex, and hippocampus.

View Article: PubMed Central - PubMed

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&ndash;58&nbsp;yrs) with a family history of late onset AD (MA+&nbsp;FH), or a combined +&nbsp;FH and apolipoprotein E &epsilon;4 allele risk factors for AD (MA+&nbsp;FH&nbsp;+&nbsp;APOE4), will exhibit differences in encoding and retrieval-related brain activity, compared to &minus;&nbsp;FH &minus;&nbsp;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 +&nbsp;FH and +&nbsp;APOE-4 risk factors for late onset AD, compared to middle-aged controls.

No MeSH data available.