Long-term Variability in Glycemic Control Is Associated With White Matter Hyperintensities in APOE4 Genotype Carriers With Type 2 Diabetes

Abstract

OBJECTIVEWe assessed whether the apolipoprotein ε4 (APOE4) genotype affects the relationship of variability in long-term glycemic control (measured by HbA1c SD of multiple measurements) with white matter hyperintensities (WMHs) in elderly patients with type 2 diabetes (T2D).RESEARCH DESIGN AND METHODSWMH volume was generated from structural T1 and fluid-attenuated inversion recovery MRI in each subject. The analysis included 124 subjects; 27 (21.8%) had one or more APOE4 alleles.RESULTSHbA1c variability was associated with significantly higher WMH in APOE4 carriers (r = 0.47, P = 0.03), controlling for age, sex, mean HbA1c, number of follow-up years, and a composite of cardiovascular risk factors, but not in noncarriers (r = −0.04, P = 0.71; P for interaction = 0.050).CONCLUSIONSThe results suggest that the APOE4 genotype affects the relationship of long-term glycemic control with WMH load so that APOE4 carriers may be more vulnerable to the insults of poor control.

Postprandial Hyperglycemia Is Associated With White Matter Hyperintensity and Brain Atrophy in Older Patients With Type 2 Diabetes Mellitus

“…Finally, the number of study participants was relatively small. However, our sample size was largely comparable to that of a previous study that found that patients with AD-related pathological changes are susceptible to glucose changes associated with the progression of WMH ( Livny et al, 2016 ). Additional longitudinal studies with a large sample size may provide further evidence to confirm our findings.…”

“…The pathogenesis of WMH is most likely driven by ischemia resulting from hypertensive small vessel disease, but amyloid angiopathy may also be another underlying cause of extensive WMH ( Tomimoto, 2015 ). More recently, carriage of the apolipoprotein E4 genotype was reported to affect the relationship between glucose alterations and WMH ( Livny et al, 2016 ; Cox et al, 2017 ). Thus, patients with AD have a variety of pathologies, including small vessel disease, and may be more susceptible to the effects of glucose exacerbation on WMH progression.…”

“…Some studies have focused on the association between HbA1c or fasting plasma glucose levels and WMH; however, the results of these studies were inconsistent ( Bryan et al, 2014 ; Exalto et al, 2014 ; Geijselaers et al, 2015 ; Raffield et al, 2016 ; Schneider et al, 2017 ). More recently, an association between fluctuations in HbA1c levels and WMH was reported in diabetes patients who carry the apolipoprotein E4 allele ( Livny et al, 2016 ), which is a strong genetic risk factor for AD. Additionally, apolipoprotein E4 carriers who are elderly and have diabetes or higher HbA1c levels exhibited greater WMH progression than other individuals ( Cox et al, 2017 ).…”

The Association of Depressive Symptoms With Brain Volume Is Stronger Among Diabetic Elderly Carriers of the Haptoglobin 1-1 Genotype Compared to Non-carriers

“…Results were essentially unaffected by the inclusion of white matter hyperintensities (partial correlation for interaction on total frontal lobe r = −0.16; p = 0.03, and on superior frontal gyrus r = −0.16; p = 0.02). Similarly, additional secondary analyses added a cardiovascular risk composite to the primary model, which was the first principal component of a factor analysis consisting of systolic and diastolic blood pressure, LDL and HDL, cholesterol, and creatinine (26); or levels of inflammatory markers (CRP and Il-6). Results were mildly attenuated, and remained significant for the interaction of Hp genotype and depressive symptoms on total frontal lobe volume and superior frontal gyrus and trend level for the interaction on white matter hyperintensities volume (Supplementary Table 1).…”

Association of the Glycemic Fluctuation as well as Glycemic Control with the Pancreatic β-cell Function in Japanese Subjects with Type 2 Diabetes Mellitus

“…Given that the fluctuation of the blood glucose levels seems to lead to the aggravation of various diseases, such as atherosclerosis and dementia, especially in elderly subjects (12, 19), we hypothesized that the fluctuation of the blood glucose levels was more closely associated with the remnant β-cell function in elderly subjects (≥65 years old) and examined this point in the present study. However, contrary to our expectations, no marked difference was noted in the results between relatively young subjects and elderly subjects.…”