APOE Genotypes Associate With Cognitive Performance but Not Cerebral Structure: Diabetes Heart Study MIND

Abstract

OBJECTIVEDementia is a debilitating illness with a disproportionate burden in patients with type 2 diabetes (T2D). Among the contributors, genetic variation at the apolipoprotein E locus (APOE) is posited to convey a strong effect. This study compared and contrasted the association of APOE with cognitive performance and cerebral structure in the setting of T2D.RESEARCH DESIGN AND METHODSEuropean Americans from the Diabetes Heart Study (DHS) MIND (n = 754) and African Americans from the African American (AA)-DHS MIND (n = 517) were examined. The cognitive battery assessed executive function, memory, and global cognition, and brain MRI was performed.RESULTSIn European Americans and African Americans, the APOE E4 risk haplotype group was associated with poorer performance on the modified Mini-Mental Status Examination (P < 0.017), a measure of global cognition. In contrast to the literature, the APOE E2 haplotype group, which was overrepresented in these participants with T2D, was associated with poorer Rey Auditory Verbal Learning Test performance (P < 0.032). Nominal associations between APOE haplotype groups and MRI-determined cerebral structure were observed.CONCLUSIONSCompared with APOE E3 carriers, E2 and E4 carriers performed worse in the cognitive domains of memory and global cognition. Identification of genetic contributors remains critical to understanding new pathways to prevent and treat dementia in the setting of T2D.

Apolipoprotein E Genotype e2: Neuroprotection and Its Limits

“…It is unclear if e2 has a protective role on cognition of older adults. Older adults who are e2 carriers performed significantly better on cognitive domains pertaining to the frontal network (e.g., processing speed, attention, and executive functions) in some studies ( Sinclair et al, 2017 ), while the majority of findings did not find any significant associations with e2 or even demonstrated adverse effects on cognitive performance ( Greenwood et al, 2000 ; Bennett et al, 2009 ; Alfred et al, 2014 ; Marioni et al, 2016 ; Palmer Allred et al, 2016 ; Lancaster et al, 2017 ). Verbal fluency (phonemic and categorical), language, and visual-spatial functioning were not significantly associated with e2 in all studies that examined these domains.…”

“…It is also postulated that the effect of e2 may be more prominent in old-older adults (≥75) ( Staehelin et al, 1999 ; Rajan et al, 2019 ) and in women ( Hyman et al, 1996 ; Davies et al, 2014 ; Shinohara et al, 2016b ). Whether there is a racial difference in the effect of e2 is inconclusive, as only three studies ( Blair et al, 2005 ; Palmer Allred et al, 2016 ; Rajan et al, 2019 ) included ethnically diverse samples and only one found a significantly smaller effect in African-Americans compared to Caucasian Americans ( Blair et al, 2005 ).…”

Sex-Related Differences in Brain Volumes and Cerebral Blood Flow Among Overweight and Obese Adults With Type 2 Diabetes: Exploratory Analyses From the Action for Health in Diabetes Brain Magnetic Resonance Imaging Study

“…Among those with mild cognitive impairment, APOE-ε4 alleles are more strongly associated with lower hippocampal volumes among women compared with men (35). However, the relationship between APOE genotype and cognition may be altered among individuals with T2DM, for example APOE-ε2 may not be protective (36).…”

GSK‐3β activation mediates apolipoprotein E4‐associated cognitive impairment in type 2 diabetes mellitus: A multicenter, cross‐sectional study

“…2,3 The precise mechanisms by which T2DM increases the risk for AD are not fully understood, but substantial evidence links AD risk to insulin resistance and impaired insulin signaling in T2DM. 4 Apolipoprotein E (ApoE) genotype is the most consistently observed genetic contributor to late-onset AD. There are three alleles of ApoE gene, namely ε2, ε3, and ε4, which encode ApoE2, ApoE3, and ApoE4 protein, respectively.…”

“…T2DM and AD share many pathophysiological features, such as insulin resistance, deregulated glucose metabolism, peripheral oxidative and inflammatory stress, amyloid aggregation, and neurodegeneration 2,3 . The precise mechanisms by which T2DM increases the risk for AD are not fully understood, but substantial evidence links AD risk to insulin resistance and impaired insulin signaling in T2DM 4 …”