The ApoE4 genotype modifies the relationship of long-term glycemic control with cognitive functioning in elderly with type 2 diabetes

Abstract

Aim To assess whether the APOE4 genotype affects the relationship of long-term glycemic control with cognitive function in elderly with type 2 diabetes (T2D). Methods Participants were cognitively normal and pertained to a Diabetes Registry which provided access to HbA1c levels and other T2D related factors since 1998. Glycemic control was defined as the mean of all HbA1c measurements available (averaging 18 measurements) per subject. Four cognitive domains (episodic memory, semantic categorization, attention/working memory and executive function), based on factor analysis and an overall cognitive score (the sum of the 4 cognitive domains) were the outcome measures. Results The analysis included 808 subjects; 107 (11.9%) subjects had ≥1ApoE4 allele. In ApoE4 carriers, higher mean HbA1c level was significantly associated with lower scores on all cognitive measures except attention/working memory (p-values ranging from 0.047 to 0.003). In ApoE4 noncarriers, higher mean HbA1c level was significantly associated with lower scores on executive function, but not with other cognitive measures—despite the larger sample size. Compared to non- carriers, there were significantly stronger associations in ApoE4 carriers for overall cognition (p=0.02), semantic categorization (p=0.03) and episodic memory (p=0.02), and the difference for executive function approached statistical significance (p=0.06). Conclusion In this cross-sectional study of cognitively normal T2D subjects, higher mean HbA1c levels were generally associated with lower cognitive performance in ApoE4 carriers, but not in non-carriers, suggesting that ApoE4 affects the relationship between long-term glycemic control and cognition, so APOE4 carriers may be more vulnerable to the insults of poor glycemic control.

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

“…For example, apoE4 enhances the differences between T2DM and non-T2DM subjects in the number of hippocampal and cortical neuritic plaques, neurofibrillary tangles, and the load of cerebral amyloid angiopathy [58]. It has also been shown that in apoE4 carriers, the degree of glucose dysregulation (evaluated by fasting blood glucose concentration and mean glycemic value, as measured by the HbA1c concentration [59]) correlates with reduced cortical thickness and that apoE4 carriers with T2DM demonstrate a level of cortical thinning comparable to that of preclinical AD [60]. Metabolic deficiencies, such as abnormally low rates of brain glucose metabolism, that are unrelated to regional amyloid burden [61] were observed in healthy apoE4-positive volunteers as young as their twenties [62].…”

APOE Genotype in the Ethnic Majority and Minority Groups of Laos and the Implications for Non-Communicable Diseases

“…In a statistical analysis of anthropometric and clinical characteristics between APOE ε4 carriers and non-carriers, only heart rate was significantly higher in APOE ε4 carriers than in non-carriers in both Lao Loum and minorities. Several reports demonstrated that APOE ε4 is associated with AD[ 40 ], cognitive decline[ 21 ], depressive symptoms[ 22 ], stroke[ 23 , 24 ], hypertension[ 25 , 26 ], coronary heart disease[ 24 , 26 ], cardiovascular[ 27 , 28 ], and diabetes[ 29 , 30 ]. Very few studies have addressed the relationship between APOE ε4 and heart rate.…”

“…Additionally, the incidence of AD may be attributable to lifestyle and nutrition [ 4 , 6 , 16 – 20 ]. On the other hand, APOE ε4 is associated not only with AD but also with cognitive decline[ 21 ], depressive symptoms[ 22 ], stroke[ 23 , 24 ], hypertension[ 25 , 26 ], coronary heart disease[ 24 , 26 ], cardiovascular disease[ 27 , 28 ], and diabetes[ 29 , 30 ]. In combination with environmental factors, APOE ε4 may influence the risk of non-communicable diseases.…”

Potential contribution of the Alzheimer׳s disease risk locus BIN1 to episodic memory performance in cognitively normal Type 2 diabetes elderly

“…These SNPs represent (according to Lambert et al (2013)) three sub-groups of variants (Table 2): Known GWAS-defined associated genes (rs6656401, rs6733839, rs10948363, rs11771145, rs9331896, rs983392, rs10792832, rs4147929); New loci reaching genome-wide significance in the discovery analysis (rs9271192, rs28834970, rs11218343, rs10498633); New loci reaching genome-wide significance in the combined discovery and replication analysis (rs35349669, rs190982, rs2718058, rs1476679, rs10838725, rs17125944, rs7274581) (Lambert et al, 2013). Although highly significant in the meta-analysis, we did not include the APOE locus in this study, since it’s relation to episodic memory and other cognitive phenotypes in the IDCD cohort was studied previously (Ravona-Springer et al, 2014). However, the APOE genotype was used as a covariate in the analysis.…”