The Specific Impact of Apolipoprotein E Epsilon 2 on Cognition and Brain Function in Cognitively Normal Elders and Mild Cognitive Impairment Patients

Abstract

Variants in the apolipoprotein E (APOE) gene play an important role in the development of Alzheimer's disease (AD). Specifically, the APOE ε4 allele is an established genetic risk factor for AD, while the APOE ε2 allele is a protective factor against AD. However, the mechanism underlying this impact of APOE genotype on the pathogenesis of AD remain unclear. This study sought to investigate the influence of APOE genotype on cognition and neuroimaging features in cognitively normal (CN) elderly individuals and patients with mild cognitive impairment (MCI). A total of 177 participants were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 101 MCI patients and 76 CN individuals. A 2 × 3 (consisting of two groups and three APOE genotypes) analysis of covariance was carried out to measure the influences of diagnosis and APOE genotype on cognition and brain features, assessed based on global functional connectivity density (gFCD) and hippocampal volume. In addition, a mediation analysis was carried out to investigate the indirect influence of neuroimaging features on the relationship between APOE genotype and cognitive performance in the MCI group. This analysis revealed that APOE genotype had an influence on brain function in the bilateral precentral gyrus, right thalamus, and posterior cingulate cortex (PCC). In addition, an interactive influence between diagnosis and APOE genotype was found on general cognition, immediate memory, executive function, hippocampal volume, and gFCD in the right dorsolateral prefrontal cortex and medial prefrontal cortex (MPFC). Finally, this mediation analysis revealed that hippocampal volume and gFCD in the thalamus may mediate the relationship between APOE genotype and cognitive performance in the MCI group. Taken together, our findings provide novel insights into the neural mechanisms underlying the genetically guided pathogenic mechanisms of AD.

Apolipoprotein E Genotype e2: Neuroprotection and Its Limits

“…Notably, Conejero-Goldberg et al (2014) found that in ADNI data that MCI e4 carriers had a greater progression rate to AD, compared with e2 (HR for e4 vs. e2 was 3.95). E2 may interact with the neurodegeneration process to impact cognition, as a study by Gong et al (2019) found that the hippocampal volume and thalamus function mediated e2-associated cognitive performance in MCI, but not healthy older adults. These findings suggest that disease states could modify the APOE-cognition interaction, but more studies are warranted on this topic.…”

“…Hippocampal volumetry is a well-established marker of neurodegeneration in AD. Studies in young and middle-aged and older adults have generally shown a tendency for larger hippocampal volume in e2 carriers ( den Heijer et al, 2002 ; Fennema-Notestine et al, 2011 ; Hostage et al, 2013 ; Khan et al, 2017 ; Gong et al, 2019 ). Findings in older adults are mixed and inconsistent.…”

“…Findings in older adults are mixed and inconsistent. Large-scale studies (including ADNI, Rotterdam Study, and multi-cohort dataset) indicate that hippocampal volume in e2 is comparable to e3 homozygotes across all clinical and pre-clinical AD stages, though some studies ( den Heijer et al, 2002 ; Blair et al, 2005 ; Fan et al, 2010 ; Liu et al, 2010 ; Fennema-Notestine et al, 2011 ; Hostage et al, 2013 ; Conejero-Goldberg et al, 2014 ; Khan et al, 2017 ; Groot et al, 2018 ; Roe et al, 2018 ) (but not all Liu et al, 2010 ; Bunce et al, 2012 ; Gong et al, 2019 ) suggest that e2 may be associated with larger temporal lobe regions more broadly. Notably, a meticulously conducted 2-year follow-up study from ADNI reported that cognitively normal e2 carriers exhibited a slower rate of hippocampal atrophy, compared to e3 homozygotes, providing strong evidence toward e2’s protective role against hippocampal atrophy ( Chiang et al, 2010 ).…”

MRI-Visible Perivascular Spaces Associated With Cognitive Impairment in Military Veterans With Traumatic Brain Injury Mediated by CSF P-Tau

“…All the analyses were done in TBI group subjects and military control subjects respectively, and the interaction effect of TBI status was explored. Furthermore, as increased PVS may indicate the glymphatic system impairment, which would slow the clearance of brain waste like tau and Aβ and finally cause the occurrence of cognitive impairment, mediation analyses were done to investigate whether CSF biomarkers mediated the association between PVS and cognitive impairment using the SPSS PROCESS module ( 31 , 32 ). As there were four cognitive scales analyzed in this study, Bonferroni corrected p -value was set for 0.05/4 = 0.0125 for the analyses of cognitive scale.…”

Data_Sheet_1.PDF

“…All the analyses were done in TBI group subjects and military control subjects respectively, and the interaction effect of TBI status was explored. Furthermore, as increased PVS may indicate the glymphatic system impairment, which would slow the clearance of brain waste like tau and Aβ and finally cause the occurrence of cognitive impairment, mediation analyses were done to investigate whether CSF biomarkers mediated the association between PVS and cognitive impairment using the SPSS PROCESS module (31,32). As there were four cognitive scales analyzed in this study, Bonferroni corrected p-value was set for 0.05/4 = 0.0125 for the analyses of 1).…”