Results from the current study demonstrate that fasting insulin levels vary according to MCI diagnostic subtype and sex, and thus suggest a complex relationship between insulin and cognitive functioning in nondiabetic older adults. Multiple observational studies demonstrate a connection between diabetes and increased risk for cognitive impairment and dementia [52
]; however, reports from nondiabetic cohorts that examine markers of insulin resistance such as hyperinsulinemia have been less consistent. Several studies report that cognitive decline coincides with increasing hyperinsulinemia [25
], while others have shown a nonlinear relationship, such that both high and low levels of circulating insulin are associated with poorer cognitive functioning and increased dementia risk [30
]. A recent prospective study (combining the PROSPER and Rotterdam cohorts) however, found no association between insulin resistance and fasting glucose levels for baseline cognitive measures and subsequent cognitive decline [54
]. In addition, reports suggest that both high and low levels of insulin secretion are related to cognitive impairment and dementia risk, resulting in an inverted U-shaped relationship between fasting insulin levels and cognitive functioning [36
]. Our results may help clarify factors that determine this U-shaped curve by suggesting that plasma insulin differs according to cognitive diagnosis, but only when diagnostic subtype, sex, and APOE genotype are taken into consideration.
Our results show that women with MCI-a had lower
fasting plasma insulin levels than all other groups. A potential explanation for these findings, although speculative, is related to reduced insulin secretion that may occur as a result of oxidative damage to pancreatic beta cells in some people with early or pre-diabetes [20
]. Along these lines, Burns and colleagues reported that adults with early AD who had lower insulin levels in response to a glucose challenge showed more cognitive impairment and brain atrophy, results that may suggest impaired insulin secretory capacity in these subjects [58
]. This finding supports our premise that women with MCI-a may have lower fasting insulin levels on average due to impaired insulin secretion, a hypothesis that cannot be confirmed in the present study. Interestingly, insulin levels in brain may be reduced at an earlier stage of dementia in women. Gil-Bea et al. [60
] recently reported reduced CSF insulin levels in both men and women with AD, but only in women with MCI. Conversely, our results demonstrate elevated fasting plasma insulin levels in older men with MCI-a or MCI-na, although the effect was more robust for MCI-na
, a cognitive pattern that has been associated with impaired vascular functioning [61
]. The negative impact of insulin resistance and compensatory hyperinsulinemia on vascular functioning is well-documented [62
], and the prevalence of vascular disease is elevated in those with consistently high insulin levels [64
]. The Honolulu Heart Program, which specifically measured fasting insulin in older men, found that hyperinsulinemia was associated with increased coronary artery disease, angina, peripheral vascular disease, stroke, dyslipidemia, hypertension, and obesity [65
]. Our results suggest that non-diabetic men with higher plasma insulin levels may also be at greater risk for impaired cognitive function associated with vascular disease.
Our findings indicating sex differences with regard to insulin levels and cognitive functioning, although unique, are not surprising. Sex differences in the development and expression of chronic disease, including diabetes, have long been noted. Endogenous sex hormones may play a role in the relative risk for developing diabetes, such that higher circulating androgens are associated with greater diabetes risk in women and lower risk in men [31
]. As visceral fat accumulates following menopause, there is an associated increase in androgen receptors, which likely influences the increased prevalence of type 2 diabetes in women in this age bracket [32
]. As mentioned above, diabetes appears to raise the risk for cardiovascular disease differently in men and women. Together with our findings, it is possible that cognitive function and dementia risk are differentially affected by disruptions in insulin activity as a function of sex.
Our APOE results are consistent with reports indicating a relationship between insulin resistance, cognitive functioning, and dementia risk may be most commonly observed for adults without an ε4 allele [34
]. This observation suggests that APOE-ε4 carriage and insulin resistance may represent two pathways that lead to similar disease endpoints. In men without an ε4 allele in our sample, plasma insulin was higher for MCI-a than for men with normal cognitive functioning, while women without an ε4 allele had lower plasma insulin as described above. These results suggest the possibility that ε4− participants’ risk for MCI-a (and thus AD) may be associated with sex-specific differences in plasma insulin. Interestingly, in ε4+ adults, elevated fasting insulin was associated with an increased prevalence of nonamnestic MCI only, irrespective of sex. Again, this suggests that hyperinsulinemia may exert negative vascular effects, independent of AD-associated neuropathology. These findings are exploratory, however, due to small cell sizes in the ε4+ group, and thus limit our ability to interpret these findings too strongly.
One unique aspect of this study is the relatively advanced age of the participants. There is increasing evidence that multiple chronic health conditions, including hypertension, obesity, and hyperlipidemia, are associated with adverse consequences related to cognitive function and dementia risk primarily when present during middle age. Interestingly, it appears that during perimenopause, women undergo a “metabolic shift” that occurs in conjunction with the decline in circulating sex hormones. Nondiabetic women demonstrate higher fasting insulin and decreased insulin sensitivity in comparison with their male counterparts when measured at midlife. This pattern is reversed in both older and younger subjects, with men in these age groups typically showing decreased insulin sensitivity as compared to women . This dramatic and relatively sudden metabolic change occurs at the same time as the well-documented increased risk for cardiovascular disease in women. Thus, the negative associations of high fasting plasma insulin in women may be more apparent when measured during midlife. Further exploration into the role of circulating insulin at midlife and later will help to elucidate whether age and sex differentially influence the effects of peripheral hyperinsulinemia, which in turn impact overall AD prevalence.
Due to feasibility constraints in this large, elderly sample, we were unable to obtain a more accurate estimate of insulin resistance other than fasting plasma insulin, such as a hyperinsulinemic euglycemic clamp or modified insulin suppression test, nor did we have access to fasting glucose levels which would permit calculation of the homeostasis model assessment of insulin resistance (HOMA-IR). Such techniques provide more sensitive measurement of insulin resistance than fasting plasma insulin, and may represent valuable future tools with which to further explore the association between insulin resistance and cognitive function in late life. We also did not have access to sex hormone levels in this sample; future analyses that examine the relationship between sex hormones, insulin, and cognition in older adults will help to further illuminate the nature of the sex differences described here. In addition, we were unable to obtain clinical and laboratory data regarding the presence of diabetes, and thus we relied on self-reported diabetic history. Insulin values reported throughout the literature are consistently skewed to the right, suggesting that most “normal” samples include participants with undiagnosed diabetes. Our nondiabetic sample had mean insulin values that were significantly lower than the excluded diabetic group by self-report; nonetheless, the skewed distribution suggests that the study sample likely included participants with as yet undiagnosed diabetes. This method of relying on self-reported diabetes, however, is consistent with other similar studies [27
], and permits the exclusion of people for whom fasting insulin may be affected by anti-diabetic medication use.
Another limitation of this study is the cross-sectional design, which does not permit examination of the effects of plasma insulin on cognition over time in either men or women. Longitudinal follow up of this sample, once available, will undoubtedly provide valuable information concerning the effects of baseline fasting plasma insulin on cognition over time, and eventually help to clarify whether higher plasma insulin levels lead to a differential relative risk for dementia with regard to sex and APOE status. Also given the large sample size, participants were diagnosed with MCI based on psychometric performance, and were not examined by a clinician unless their CASI score fell below a pre-determined threshold or unless they reported notable functional problems that warranted a full evaluation to identify dementia (as opposed to identifying MCI). Finally, when the sample was divided into groups on the basis of diagnostic subtype, sex, and APOE genotype, some of the resulting cell sizes were quite small, thus limiting confidence regarding the results of subgroup analyses.
Our findings demonstrating that men and women with amnestic and nonamnestic MCI had different fasting plasma insulin levels, suggest that either too much or too little circulating insulin may have detrimental consequences on cognitive functioning in older adults, and that this relationship may depend upon sex and APOE genotype. If confirmed, these results may indicate disparate processes by which insulin resistance can exert a negative influence in the brains of older adults. Future studies will help determine whether insulin resistance, diabetes, and cardiovascular disease produce differential effects on cognition and dementia risk in men and women.