Insulin is differentially related to cognitive decline and atrophy in Alzheimer's disease and aging

Abstract

We assessed the relationship of insulin resistance with cognitive decline and brain atrophy over two years in early Alzheimer's disease (AD, n=48) and nondemented controls (n=61). Intravenous glucose tolerance tests were conducted at baseline to determine insulin area-under-the-curve (AUC). A standard battery of cognitive tasks and MRI were conducted at baseline and 2-year follow-up. In nondemented controls, higher baseline insulin AUC was associated with 2-year decline in global cognitive performance (beta=-0.36, p=0.005). In early AD, however, higher insulin AUC was associated with less decline in global cognitive performance (beta=0.26, p=0.06), slower global brain atrophy (beta=0.40, p=0.01) and less regional atrophy in the bilateral hippocampi and cingulate cortices. While insulin resistance is associated with cognitive decline in nondemented aging, higher peripheral insulin may have AD-specific benefits or insulin signaling may be affected by systemic physiologic changes associated with AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Figure 1. Relationship of Insulin and Cognitive Decline in Nondemented Controls

Insulin area under the curve over a three-hour intravenous glucose tolerance test is associated with cognitive decline over two years in older adults without dementia, with increasing insulin levels associated with greater decline in cognition. Cognitive measures are corrected for age, sex, and education and presented in the figure as standardized values.

Figure 2. Relationship of Insulin and Whole Brain Atrophy in Early Alzheimer’s Disease

Insulin area-under-the-curve in response to a three hour intravenous glucose tolerance test is associated with brain atrophy in individuals with early Alzheimer’s disease, with increasing insulin levels associated with less brain atrophy. Atrophy measures are corrected for age and sex and presented in the figure as standardized values (thus, positive values do not represent increased brain volume over two years). Brain volume declined in 37 AD participants, was unchanged in one, and increased in one (0.2%) over the two year study.

Figure 3. Insulin and Regional Brain Volume in Early Alzheimer’s Disease

Insulin area-under-the-curve was related to regional atrophy in limbic regions (identified by yellow, reflecting Z scores > 3.25, k>100, p<.001 uncorrected). Results are displayed overlaid on the A) sagittal, B) coronal, and C) axial views of a standard, spatially normalized MRI. The relationship between insulin and regional atrophy in the cingulate cortex is visible in A and B, the medial temporal cortex in B, and the orbitofrontal cortex in C. The anatomical location and description of brain regions is in Table 3. D) The scatterplot demonstrates the relationship of insulin and gray matter volume atrophy in the largest cluster (right hippocampus/parahippocampal gyrus) in individuals with early AD.