The effects of aging and Alzheimer's disease on cerebral cortical anatomy: specificity and differential relationships with cognition

Abstract

Although both normal aging and Alzheimer's disease (AD) are associated with regional cortical atrophy, few studies have directly compared the spatial patterns and magnitude of effects of these two processes. The extant literature has not addressed two important questions: 1) Is the pattern of age-related cortical atrophy different if cognitively intact elderly individuals with silent AD pathology are excluded? and 2) Does the age- or AD-related atrophy relate to cognitive function? Here we studied 142 young controls, 87 older controls, and 28 mild AD patients. In addition, we studied 35 older controls with neuroimaging data indicating the absence of brain amyloid. Whole-cortex analyses identified regions of interest (ROIs) of cortical atrophy in aging and in AD. Results showed that some regions are predominantly affected by age with relatively little additional atrophy in patients with AD, e.g., calcarine cortex; other regions are predominantly affected by AD with much less of an effect of age, e.g., medial temporal cortex. Finally, other regions are affected by both aging and AD, e.g., dorsolateral prefrontal cortex and inferior parietal lobule. Thus, the processes of aging and AD have both differential and partially overlapping effects on specific regions of the cerebral cortex. In particular, some frontoparietal regions are affected by both processes, most temporal lobe regions are affected much more prominently by AD than aging, while sensorimotor and some prefrontal regions are affected specifically by aging and minimally more by AD. Within normal older adults, atrophy in aging-specific cortical regions relates to cognitive performance, while in AD patients atrophy in AD-specific regions relates to cognitive performance. Further work is warranted to investigate the behavioral and clinical relevance of these findings in additional detail, as well as their histological basis; ROIs generated from the present study could be used strategically in such investigations.

Fig. 1

A) The cortical signature of aging: map of cortical atrophy across the hemispheres in normal aging. B) The cortical signature of AD: map of cortical atrophy across the hemispheres in AD. C) Binarized map showing areas affected by aging only (blue), by AD only (red) and areas affected by both processes (purple). Maps are presented on the semi-inflated cortical surface of an average brain with dark gray regions representing sulci and light gray regions representing gyri. The color scale at the bottom of A and B represents the statistical significance of the thickness difference with yellow indicating regions with smaller p values. See Table 2 for quantitative metrics of the amount of atrophy in each region.

Fig. 2

Top) “AD signature” ROIs. Labels A, B, C, F and H are AD-specific ROIs, where atrophy is seen primarily in AD. Labels D, E, G and I are aging-AD overlap ROIs, where atrophy is seen in both aging and AD. Bottom) “aging-specific” ROIs, where atrophy is seen primarily in normal aging with minimal additional effect of AD.

Fig. 3

Mean cortical thickness across A) aging-specific ROIs showing that little additional atrophy is present in AD beyond that of normal aging; B) AD-specific ROIs showing relative sparing of these regions in normal aging and prominent atrophy in AD relative to normal aging; and C) aging-AD overlap ROIs, showing atrophy effects in normal aging and AD of relatively similar magnitude. In all graphs, the group of PiB-PET negative (OCPibneg) individuals is shown to demonstrate that the findings in a group of older adults known not to have amyloid pathology by this marker are very similar to the findings in the larger group of older controls whose pathologic status is unknown, supporting the hypothesis that these are truly age-associated effects. Graphs show mean cortical thickness (z) within each set of ROIs across the four groups, normalized to the young subject group mean. Error bars indicate 1 standard error of the mean. YC: young control; OC: older control; OCPibneg: PiB-negative older control; AD: Alzheimer's disease.

Fig. 4

Mean cortical thickness (z) across the eight “aging-specific” ROIs across both split-half samples of OCs and YCs. The atrophy effect in all aging regions is remarkably similar across the two split half samples. Error bars indicate 1 standard error of the mean.

Fig. 5

A) Correlation of the general cognitive factor score with mean cortical thickness across aging-specific regions (squares) and with mean cortical thickness across AD-specific regions (circles) in OCs only. B) Correlation of the general cognitive factor score with mean cortical thickness across aging-specific regions (squares) and with mean cortical thickness across AD-specific regions (circles) in ADs only.

Fig. 6

Eta² matrix of similarity of effects between four AD-signature maps and two aging-signature maps.