In the present study, almost 16% of a community-based sample of older patients with type 2 diabetes experienced a clinically relevant decline in cognitive function after 1.6 years of follow-up. After controlling for age, education, and cognitive function, cognitive decline was predicted by urinary albumin excretion rates, whereas the use of either ACEIs or ARBs appeared to be protective. These findings were replicated in the subgroup of subjects who were cognitively normal. No clinical variables assessed an average of 7.6 years earlier predicted cognitive decline, possibly because the prevalence of microalbuminuria and the use of ACEIs or ARBs were relatively low.
Although microalbuminuria is common in the community, affecting 29% of individuals with diabetes, 16% of patients with hypertension, and 5% of healthy individuals (19
), there are few data on its association with cognitive function. Two recent cross-sectional studies have reported findings consistent with the present study. In a study of subjects with type 2 diabetes, those with microalbuminuria had lower MMSE scores (11
). In a population-based study, microalbuminuria inversely correlated with test scores of visuospatial function and motor speed in subjects with peripheral arterial disease (12
). In contrast, a study conducted in the Rancho Bernardo cohort showed no association between microalbuminuria and cognitive decline (20
Microalbuminuria is a risk factor for cardiovascular disease independently of renal function and conventional cardiovascular risk factors, and there is an increased risk even with low-grade albuminuria (19
). In the present study, urinary albumin excretion assessed as a continuous variable was more strongly associated with cognitive decline than the presence of categorical microalbuminuria or albuminuria. There was no association with renal dysfunction as assessed from creatinine clearance. Microalbuminuria has been associated with stroke and cerebral small vessel ischemia (21
); hence, a vascular mechanism may explain its effect on cognitive decline. Additional possibilities include endothelial dysfunction and chronic low-grade inflammation. Both are associated with microalbuminuria in type 2 diabetes (22
) and may have a role in the pathogenesis of Alzheimer's disease.
The protective effect of antihypertensive therapy was explained by the use of either ACEIs or ARBs. These two drug classes have nearly identical effects on the renin-angiotensin system and are known to reduce urinary albumin excretion and protect the kidney against diabetic nephropathy. Some of these beneficial effects may occur independently of blood pressure lowering, possibly by reducing inflammation in diabetic patients with microalbuminuria (23
). Blood pressure lowering has been shown to be effective in preventing stroke-related dementia, but the data on Alzheimer's disease are conflicting (24
). The use of ACEIs was associated with reduced progression to dementia in patients with mild cognitive impairment (25
) but not incident Alzheimer's disease in a population-based study (26
The strengths of the present study include its community-based sample, the large number of older diabetic subjects, the use of a clinically meaningful classification of cognitive decline, and the detailed nature of the clinical assessment, which allowed us to control for important modifiers, including education. The major limitations of the study are the relatively small sample size and the inherent features of cohort studies with potential biases at the recruitment phases and differential dropout rates. Attrition between FDS entry and recruitment to the present study was substantial. The FDS survivors who did not participate in the present cognitive study were older and more likely to have both cognitive impairment and chronic complications than those who were recruited. Because our sample was almost entirely community dwelling and relatively healthy and because the rate of decline from normal to CDR stage 0.5 found in our patients was similar to published annual conversion rates of 11.8–15.3% in aged populations (27
), the true rate of decline in diabetes may be higher. Cognitive status was not assessed at FDS entry, which would have provided useful additional prospective data. The generalizability of the findings beyond those with diabetes is uncertain.
In summary, we found that clinical cognitive decline was a common occurrence in a sample of older diabetic individuals and was predicted by increased urinary albumin excretion, a potentially modifiable risk factor. The independent inverse association between ACEI or ARB therapy and cognitive decline suggests that these drug classes act through mechanisms distinct from those which act to reduce urinary protein excretion. These findings are of potential clinical importance and further confirmatory studies are needed in both diabetic and nondiabetic populations.