Diabetes mellitus (DM) is a common condition from middle age and beyond. By age 65 about 20% of the population carries a diagnosis of DM, mainly type 2 diabetes [30
]. DM affects the kidney, heart, peripheral nerves and retina, in addition to the brain.
Alterations in midlife glycemic control and DM almost certainly have greater consequences for cognitive function than late-onset DM presumably because of the longer duration of exposure, although a more metabolically aggressive disease might also occur at younger ages. A metaanalysis [32
] observed that the magnitude of risks for dementia were generally higher when DM was diagnosed at midlife versus later life.
The evidence linking DM to late-life cognitive impairment includes its associations with cognitive decline in middle age [6
], cognitive decline in later life, mild cognitive impairment [38
], AD*c [40
] and VaD [40
]. In general, associations have been stronger for VaD than for AD*c. Not all studies show an association between dementia and DM [52
], however, perhaps because of the age when DM was ascertained.
The nature of the cognitive deficits associated with DM provides some clues as to DM’s brain targets. DM is associated with impairment of both amnestic and non-amnestic cognitive functions, but the association with non-amnestic dysfunction has been shown to be of greater magnitude [38
]. Less amnestic and greater non-amnestic cognitive dysfunction would be more consistent with involvement of white matter pathways, basal ganglia or thalamus, which in turn are loci expected to undergo infarction as a result of CVP.
DM is associated with structural brain changes that can be detected on imaging [53
]. In a metaanalysis, the major changes on imaging associated with DM were brain atrophy, lacunar infarcts and to a less extent, white matter hyperintensities [58
]. In the Atherosclerosis Risk in Communities (ARIC) study that included persons in late middle age (50–73 yr), there was a 4 to 7% increased risk of ventricular enlargement for each 10mg/dL of fasting blood sugar elevation [53
]. In the Cardiovascular Health Study (CHS), DM was associated with brain atrophy only in women. The CHS population was 65 and older [59
]. Perhaps the less consistent associations in the CHS are a result of the older age of the subjects.
Neuropathological studies of diabetics also show an increased number of brain microinfarcts and lacunar infarcts compared to non-diabetics [60
]. Several studies have shown that diabetics with dementia have a lower burden of β-amyloid pathology [60
DM could cause also brain injury through non-CVP mechanisms. Hyperglycemia and impaired control of insulin homeostasis might have a direct effect on brain β-amyloidosis [64
]. Insulin degrading enzyme (IDE), an enzyme that is involved in insulin trafficking, is also a key enzyme that degrades β-amyloid. With increases in peripheral insulin levels in midlife in type 2 diabetics, brain insulin levels could be raised [68
]. Insulin might compete with β-amyloid for binding to IDE; thus, elevated insulin levels would lead to decreased β-amyloid clearance, and raised β-amyloid levels in the brain.
Because most patients with DM are treated with either oral hypoglycemic agents or insulin, it may be very difficult to determine whether treatments alter clinical-pathological correlations in DM. Severity of DM is more likely to be associated with the use of insulin, whereas hyperglycemia that doesn’t exceed 125 mg/dL might not be treated with medication at all. Since more severe DM will almost always be treated with insulin, the unique contributions of DM severity and insulin use to structural and neuropathological changes may not be resolvable. With insulin use, the impact of DM severity versus episodes of hypoglycemia must also be considered in evaluating dementia risk.
Based on imaging and neuropathological evidence, microvascular disease is a very strong candidate mechanism to account for the impact of DM on late-life cognitive impairment. DM as a microvascular disease could influence the course of AD*p by decreasing
the threshold at which AD*p produces clinical effects, even if DM itself had no direct impact on AD*p-mediated neurodegeneration. If this were the case, then for a given level of cognitive impairment, persons with diabetes should have less
AD*p, which in fact has been observed [60
]. An alternative hypothesis is that the metabolic or ischemic injury caused by DM facilitates
β-amyloid pathology, tau pathology or both. In this alternative model, DM would be associated with more
AD*p. The evidence so far does not support this latter model.