Tracking the Path of Alzheimer's Disease: Insights from the Integration of Cognitive and Structural Measures

Abstract

Mild cognitive impairment (MCI) is recognised as a transitory state between healthy aging and Alzheimer’s disease (AD) dementia, although not all individuals with MCI progress to AD dementia. The cognitive and brain structural profiles of individuals along the at-risk AD clinical continuum remain under investigation, and determinants of whether an individual with MCI will progress to AD dementia remain unclear. The overall aim of this study was to identify markers of early cognitive and structural changes in individuals with subjective cognitive decline (SCD), amnestic MCI (aMCI), multi-domain MCI (mMCI), and AD dementia. We investigated the relationship between these measures and their ability to predict MCI outcomes. Participants from the Dementia Prevention Research Clinics underwent comprehensive neuropsychological assessment and magnetic resonance imaging at baseline (n = 237) and at two-year follow-up (n = 167 for cognitive data, n = 136 for imaging data). T1 weighted scans enabled analyses of structural measures of cortical thickness and volume. We utilised a combination of general linear model and non-parametric partial least squares (PLS) approaches. Our cross-sectional analysis identified early volumetric atrophy and cortical thinning, predominantly observable in the temporal, frontal, and inferior parietal cortices across individuals along the at-risk AD continuum. Our brain-behaviour PLS analysis revealed unique correlations between cognitive domains and structural measures, which were generally stronger in the cognitively impaired group. Our longitudinal PLS analysis indicated that atrophy rates increased along the at-risk AD continuum, particularly in the middle temporal, cingulate, and insula regions. The MCI groups demonstrated differential longitudinal changes in cognitive performance in the Attention/Working Memory, Processing Speed, Language/Semantic, Verbal Learning and Memory, and Executive Function Inhibition domains compared to Cognitively Normal (CN) and SCD groups. Finally, MCI conversion to AD dementia was associated with poorer baseline performance in memory and executive measures and widespread baseline atrophy, particularly in the temporal, middle frontal, and cingulate regions. Understanding the cognitive and structural patterns along the at-risk AD continuum and elucidating the relationship between these measures can aid the differentiability of groups along this continuum and facilitate early detection and intervention of individuals at increased risk of progressing to AD dementia.