Glycosylated Hemoglobin Levels in Healthy Elderly Nondiabetic Men are Negatively Associated with Verbal Memory (2004)

Letter to the Editor: Type II diabetes mellitus is an established risk factor for impaired verbal memory.1 More modestly impaired glucose tolerance may also be associated with cognitive decline with age. Glycosylated hemoglobin (HbA1c) reflects the average blood glucose concentration over a 6- to 8-week period and is used in diabetic patients to monitor blood glucose control, but in people without diabetes mellitus, there is considerable variation in HbA1c, which is predictive of other morbidity, particularly in older age.2 We tested the hypothesis that higher levels of HbA1c are associated with relatively worse cognitive function in a group of healthy, unmedicated, nondiabetic elderly men. One hundred eleven healthy unmedicated male volunteers, mean age±standard deviation=67.9±1.3 (range 65.4–70.4), were recruited from the community. Screening for disease was implemented using a structured questionnaire, measurement of blood pressure, and comprehensive blood testing. Ethical permission was obtained from the Lothian Health Ethics Committee. Each volunteer underwent a battery of standard validated cognitive tests, including assessment of verbal memory (word-list learning: Rey Auditory-Verbal Memory Test; paragraph recall: Logical Memory), visuospatial memory (Visual Reproduction, Benton Visual Retention Test), verbal fluency, fluid intelligence (Raven's Standard Progressive Matrices), attention and processing speed (Digit-Symbol Substitution Test), and an estimate of prior intelligence (National Adult Reading Test). A fasting morning specimen of blood was obtained for estimation of HbA1c and plasma glucose. Testing of delayed paragraph recall, in which subjects returned for retesting of paragraph recall (Logical Memory — 24 hours delayed) was performed in 60 individuals. The mean HbA1c was 5.9%±0.36% (range 4.7–6.7), and the mean fasting plasma glucose was 5.1 mmol/L±0.53 (range 4.1–6.7). HbA1c correlated with fasting plasma glucose (r=0.23, P=.014). HbA1c was negatively and significantly correlated with two different tests of verbal memory, a test of list learning, the Rey Auditory-Verbal Learning Test (r=−0.26, P=.005), and a test of delayed paragraph recall, Logical Memory—24 hours delayed (r=−0.31, P=.018). Correlations with the remaining cognitive tests were not statistically significant but were all in the same negative direction. Fasting plasma glucose did not correlate significantly with any of the cognitive tests. In this preliminary study, these findings suggest that, even within the national normal range, relatively higher long-term blood glucose concentrations are negatively associated with verbal memory in healthy elderly men without diabetes mellitus. These data extend the established association between type II diabetes mellitus and deficits in verbal memory. The recent report that, in a large population sample of nondiabetic men, HbA1c levels are continuously associated with all-cause, cardiovascular, and ischemic heart disease mortality also parallels these findings.2 There are several possible explanations for the present association. In the shorter term, this might reflect a pathogenic role of minor fluctuations in glucose homeostasis or its regulatory factors early in the process of aging-related cognitive decline. This could involve attenuated forms of the metabolic and vascular changes of chronic hyperglycemia or subtle glycosylation of central nervous system proteins, which associates with their dysfunction.3 These mechanisms may act over several decades, because neurons are postmitotic. Another possible explanation is that is a common causal antecedent, such as low birthweight, at least partially accounts for the association. Low birthweight is associated with a higher risk of insulin resistance later in life4 and has also recently been shown to be negatively associated with cognitive function in adulthood.5 Large prospective studies will help to determine whether variations in glucose homeostasis are causally associated with variations in cognitive function, and if so, whether measures to correct impaired glucose homeostasis might affect cognitive impairment in later life.