Uncovering atrophy progression pattern and mechanisms in individuals at risk of Alzheimer's disease

Abstract

Alzheimer's disease is associated with pre-symptomatic changes in brain morphometry and accumulation of abnormal tau and amyloid-beta pathology. Studying the development of brain changes prior to symptoms onset may lead to early diagnostic biomarkers and a better understanding of Alzheimer's disease pathophysiology. Alzheimer's disease pathology is thought to arise from a combination of protein accumulation and spreading via neural connections, but how these processes influence brain atrophy progression in the pre-symptomatic phases remains unclear. Individuals with a family history of Alzheimer's disease (FHAD) have an elevated risk of Alzheimer's disease, providing an opportunity to study the pre-symptomatic phase. Here, we used structural MRI from three databases (Alzheimer's Disease Neuroimaging Initiative, Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease and Montreal Adult Lifespan Study) to map atrophy progression in FHAD and Alzheimer's disease and assess the constraining effects of structural connectivity on atrophy progression. Cross-sectional and longitudinal data up to 4 years were used to perform atrophy progression analysis in FHAD and Alzheimer's disease compared with controls. PET radiotracers were also used to quantify the distribution of abnormal tau and amyloid-beta protein isoforms at baseline. We first derived cortical atrophy progression maps using deformation-based morphometry from 153 FHAD, 156 Alzheimer's disease and 116 controls with similar age, education and sex at baseline. We next examined the spatial relationship between atrophy progression and spatial patterns of tau aggregates and amyloid-beta plaques deposition, structural connectivity and neurotransmitter receptor and transporter distributions. Our results show that there were similar patterns of atrophy progression in FHAD and Alzheimer's disease, notably in the cingulate, temporal and parietal cortices, with more widespread and severe atrophy in Alzheimer's disease. Both tau and amyloid-beta pathology tended to accumulate in regions that were structurally connected in FHAD and Alzheimer's disease. The pattern of atrophy and its progression also aligned with existing structural connectivity in FHAD. In Alzheimer's disease, our findings suggest that atrophy progression results from pathology propagation that occurred earlier, on a previously intact connectome. Moreover, a relationship was found between serotonin receptor spatial distribution and atrophy progression in Alzheimer's disease. The current study demonstrates that regions showing atrophy progression in FHAD and Alzheimer's disease present with specific connectivity and cellular characteristics, uncovering some of the mechanisms involved in pre-clinical and clinical neurodegeneration.

Keywords: Alzheimer’s disease; brain atrophy; protein propagation; serotonin receptor; structural connectivity.

Graphical Abstract

Figure 1

Five main steps of the method for the three modalities used in this study. The data were first acquired from three different databases (Step 1). Then, all neuroimaging data were processed using different software specific to each modality, followed by QC (Step 2). Subsequently, each brain map was parcellated using the Cammoun atlas with 448 cortical regions (Step 3), and the site effect was regressed out using the ComBat software (Step 4). Last, we ensured that each group [participants with an FHAD or with Alzheimer's disease and HCs (when applicable)] had a similar age and men/women proportion at baseline (Step 5).

Figure 2

Brain atrophy progression in individuals with an FHAD and patients with Alzheimer's disease. (A) Baseline atrophy (W-scores with age and sex effects in normal aging regressed out) in FHAD and Alzheimer's disease. (B) Positive and negative β-values associated with higher and lower atrophy progression in FHAD and Alzheimer's disease compared with HCs. Regions with more baseline atrophy overlap with regions with less atrophy progression. (C) Cortical regions showing significant atrophy progression (negative atrophy progression in blue, positive atrophy progression in green) in FHAD and Alzheimer's disease after FDR corrections. Statistical analyses were conducted using linear mixed models with random intercepts and slopes (including group, age, sex, education, BMI, APOe4 status and APOe4 × age interaction as covariates) and post hoc tests. The analyses included data from 153 subjects with FHAD, 156 subjects with Alzheimer's disease and 116 HCs.

Figure 3

Brain atrophy progression in the seven resting-state Yeo networks in individuals with an FHAD and patients with Alzheimer's disease. (A) Positive and negative β-values associated with higher [white area: b-values range = (0–0.002)] and lower [grey area: b-values range = [−0.002 to 0)] atrophy progression in each of the Yeo networks in FHAD and Alzheimer's disease. In Alzheimer's disease, both the limbic network and DMN demonstrated significantly lower atrophy progression compared with HCs. Conversely, the somatosensory network showed an increased rate of atrophy progression. The mean atrophy progression within each network was compared across the three groups (n_FHAD = 153, n_{Alzheimer's disease} = 156 and n_HC = 116) using linear mixed models with random intercepts and slopes, followed by post hoc tests. Covariates included group, age, sex, education, BMI, APOE4 status and the APOE4 × age interaction. The asterisk (*) indicates statistically significant values (P-value_FDR < 0.05). Regions shown correspond to the areas in each of the Yeo networks. (B) Pearson's correlations between average baseline atrophy (W-score) in each of the Yeo networks and the MoCA score, which evaluates general cognitive abilities, in FHAD (n = 128) and Alzheimer's disease (n = 88). Alzheimer's disease participants with higher baseline atrophy in the DA network, FP network and DMN had lower MoCA scores, indicating more cognitive deficits. SM, somatomotor network; VA, ventral attention network.

Figure 4

Relationships between brain atrophy, tau aggregates and beta-amyloid (Aβ) plaques distribution in individuals with an FHAD and Alzheimer's disease. The patterns of tau aggregates (A) and Aβ plaques (B) distribution at baseline (Bl) (FHAD: n_tau = 96, n_Aβ = 165; Alzheimer's disease: n_tau = 58, n_Aβ = 145) were significantly and negatively correlated with the atrophy progression only in Alzheimer's disease (*P-value_spin < 0.05). Significant and positive correlations were also found between baseline atrophy and both tau aggregates and Aβ plaques distribution in FHAD and Alzheimer's disease. All correlations (Pearson's r, n_regions = 448) were compared with null coefficient distributions using a model preserving spatial auto-correlation between regions. The dots represent the spatial correlation coefficients for each group, while the asterisks (*) indicate statistically significant values after comparison with a spatial null distribution (1000 spins, P-value_spin < 0.05). min, minimum; max, maximum.

Figure 5

Relationships with structural connectivity in participants with an FHAD and patients with Alzheimer's disease. (A) Shows the spatial correlations (Pearson's r, n_regions = 448) between cortical atrophy progression in a given region and that in its structurally connected (SC) regions in both FHAD (n_Baseline = 153) and Alzheimer's disease (n_Baseline = 156). The upper row depicts correlations using a connectivity matrix from healthy adults (n_HC = 70), while the bottom row displays correlations using the group-specific connectivity matrices (n_FHAD = 78, n_{Alzheimer's disease} = 72). (B) Illustrates the spatial Pearson's correlations (n_regions = 448) between brain atrophy progression (n_FHAD = 153, n_{Alzheimer's disease} = 156), baseline atrophy (n_FHAD = 153, n_{Alzheimer's disease} = 156), tau aggregates (n_FHAD = 96, n_{Alzheimer's disease} = 58), and beta-amyloid (Aβ) plaques (n_FHAD = 165, n_{Alzheimer's disease} = 145) distribution in a region and those in its structurally connected regions, using group-specific structural connectivity matrices (n_FHAD = 78, n_{Alzheimer's disease} = 72). In FHAD, all the correlations were significant, while in Alzheimer's disease, only the correlation with atrophy progression was not significant. The dots represent the spatial correlation coefficients for each group, while the asterisks (*) indicate statistically significant values after comparison with a spatial null distribution (1000 spins, P-value_spin < 0.05). Bl, baseline; P-val_spin: P-value after spin test with spatial auto-correlation.

Figure 6

Serotonin and glutamate receptor distribution related to brain atrophy in individuals with an FHAD and Alzheimer's disease. (A) The spatial distribution of the serotonin 5-HT6 receptor (n = 30) in cortical regions (n = 448) was negatively correlated with atrophy progression in both FHAD (n_Baseline = 153) and Alzheimer's disease (n_Baseline = 156) but was only significant in Alzheimer's disease after comparison with a spatial null distribution and FDR correction. (B) Positive and significant correlations were observed between the serotonin 5-HT6 receptor distribution (n = 30) and baseline atrophy (n_FHAD = 153, n_{Alzheimer's disease} = 156) in both groups, suggesting that the negative correlations most likely reflect a ceiling effect. In addition, the distribution of the serotonin 5-HT1B receptor (n = 88) was significantly correlated with baseline atrophy, but only in FHAD. Finally, significant correlations were observed between the metabotropic glutamate receptor 5 (mGluR5) distribution (n = 123) and baseline atrophy (n_FHAD = 153, n_{Alzheimer's disease} = 156) in both groups. All correlations were spatial Pearson's correlations performed across 448 cortical regions. The dots represent the spatial correlation coefficients for each group, while the asterisks (*) indicate statistically significant values after comparison with a spatial null distribution and FDR correction (1000 spins, P-value_spin-FDR < 0.05).