Gray Matter Atrophy and Cognitive Symptoms in Alzheimer's Disease: Concordance, Mismatch, and the Moderating Role of Cognitive Reserve

Abstract

Alzheimer’s disease (AD) is characterized by progressive gray matter (GM) atrophy, which is typically detected using structural MRI. Although atrophy is often associated with cognitive impairment, the relationship is not absolute: individuals with similar levels of atrophy may exhibit considerable differences in cognitive performance. This review discusses the correlations and inconsistencies between GM atrophy and cognition in AD, as well as the factors that influence this relationship. Evidence supports this correlation, particularly between medial temporal lobe structures and memory function, and it can be observed even before clinical diagnosis. However, mismatches occur across whole-brain and regional measurements and at different disease stages, indicating that atrophy severity alone cannot fully account for the severity of cognitive impairment. Cognitive reserve (CR) is an important factor that may explain part of this mismatch. Individuals with higher CR may show more severe pathology at comparable levels of cognitive performance. However, the explanatory power of CR is limited and appears to depend on the brain region, reserve indicator, and disease stage. Other factors, including vascular burden, sex, and differences in imaging and cognitive assessment methods, may also contribute to these inconsistencies. Therefore, structural MRI should be interpreted together with CR, disease stage, and other pathological factors. Longitudinal imaging and multimodal approaches may help clarify individual differences in the relationship between atrophy and cognitive symptoms.