Dissociable spatial topography of cortical atrophy in early-onset and late-onset Alzheimer's disease: A head-to-head comparison of the LEADS and ADNI cohorts

Abstract

Introduction: Early-onset and late-onset Alzheimer's disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head-to-head comparison of cortical atrophy in EOAD and LOAD, using two large and well-characterized cohorts (LEADS and ADNI).

Methods: We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early-stage AD), along with cognitively unimpaired participants.

Results: After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD.

Discussion: Our findings point to the clinical utility of MRI-based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment.

Highlights: Early-onset Alzheimer's disease (EOAD) and late-onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia.

Keywords: amnestic; atypical Alzheimer's disease; disease signature; magnetic resonance imaging (MRI); neurodegeneration; non‐amnestic.

FIGURE 1

Spatial topography of cortical atrophy in early‐onset and late‐onset Alzheimer's disease (EOAD and LOAD). Colored vertices on the cortical surface indicate areas where (A) patients with EOAD showed cortical atrophy compared with cognitively unimpaired (CU) participants, (B) patients with LOAD showed cortical atrophy compared with CU participants, and (C) patients with EOAD and LOAD showed differential cortical atrophy from each other. Statistical significance for group differences between patients with AD and CU participants within each cohort was assessed using a vertex‐wise threshold corrected for multiple comparisons by controlling for false discovery rate (FDR) at p < 10⁻⁸. Group differences in the magnitude of cortical atrophy between EOAD and LOAD patients were assessed for statistical significance at a vertex‐wise threshold of p < 0.001, FDR‐corrected. Four EOAD patients were excluded from the direct comparison of EOAD and LOAD patients due to missing Mini‐Mental State Examination (MMSE) scores.

FIGURE 2

Differences in the magnitude of regional cortical atrophy between early‐onset and late‐onset Alzheimer's disease (EOAD and LOAD). Point plots show estimated marginal means of cortical atrophy (adjusted mean W‐scores) for each region of interest (ROI) in each patient group. (A) The LOAD signature and EOAD signature masks were used to extract the magnitude of global atrophy within a set of phenotypically vulnerable regions (“whole” signature ROIs). The “epicenter” ROIs were identified by constructing separate linear regression models on individual anatomic labels from each AD signature set and selecting the one with the largest effect size relative to CU participants in each cohort (see Table 2). (B) The localization of ROIs for the functional networks was based on the cortical parcellation by Yeo et al. and additional grouping of individual network labels in our prior work. DM = default mode; LIM = limbic; FP = frontoparietal; LAN = language; DA = dorsal attention; VA = ventral attention; VIS = visual; SOM = somatomotor. (C) The three standard morphometric measures were based on FreeSurfer's automatic segmentation, the volumes of which were adjusted for the estimated intracranial volume. W‐scores for the ventricles were sign‐inverted to make the interpretation of W‐scores consistent across all ROI data. Error bars indicate 95% confidence intervals. Asterisks at the bottom of each column denote statistical significance for each comparison (*p < 0.05; ***p < 0.001; ****p < 0.0001). Values at the top of each column shown in gray denote Cohen's d as a measure of effect size, corresponding to the main effect of patient group adjusted for Mini‐Mental State Examination (MMSE) and apolipoprotein E (APOE) ε4 status.

FIGURE 3

Dissociable atrophy‐cognition relationships in early‐onset and late‐onset Alzheimer's disease (EOAD and LOAD). Scatter plots show bivariate associations between regional cortical atrophy in (A) the whole EOAD and LOAD signature masks and (B) inferior parietal lobule (IPL) and anterior MTL (aMTL) (i.e., epicenters of atrophy in EOAD and LOAD, respectively) and global cognitive impairment as measured by the Mini‐Mental State Examination (MMSE). Differences in the magnitude of correlation were tested in each cohort using a method for comparing dependent associations. In both phenotypes, the magnitude of atrophy in the phenotypically most vulnerable region shows the strongest relationship to the global severity of cognitive impairment than another region where atrophy is observed.