Variant-dependent heterogeneity in amyloid β burden in autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analyses of an observational study

Abstract

Background: Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid β (Aβ) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP.

Methods: We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aβ biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aβ1-42 (Aβ42), and levels of Aβ1-40 (Aβ40).

Findings: Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p<0·0001), despite similar progression on the clinical dementia rating (p>0·7), and CSF Aβ42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses.

Interpretation: Autosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using Aβ PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of Aβ levels are not interchangeable and might reflect different Aβ-driven pathobiological processes.

Funding: National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development.

Figure 1:. Categorization of autosomal dominant Alzheimer’s disease pathogenic variants:

Data from 347 participants in the DIAN observational study with available PiB-PET and CSF measures were used in the analysis. The locations of the 62 unique pathogenic variants in PSEN1, PSEN2, and APP in this dataset are represented in panels A-C. As this dataset contained a large number of unique pathogenic variants, individual variants in PSEN1, PSEN2, and APP were categorized (Panel D) based on the affected protein domain (Dataset A) or by whether pathogenic variants were before or after codon 200 in PSEN1 (Dataset B). In dataset A, only variant categories with > 10 pathogenic variant carriers were retained as distinct groups. Carriers from variant groupings with fewer than 10 participants were retained as Ungrouped carriers. For Dataset B, only PSEN1 pathogenic variant carriers and their family members were retained in the analysis. Further detail for variant groupings is shown in Supplemental Table 1 and 2.

Figure 2:. Trajectories of Amyloid Burden Across EYO:

Amyloid burden in autosomal dominant Alzheimer’s disease pathogenic variant carriers (red) and non-carriers (blue) as assessed by PiB PET (A; cortical mean) and CSF Aβ42 (B). Gray dashed line corresponds to age of expected symptom onset. In both PET and CSF assessments, evidence of increased amyloid burden is seen in pathogenic variant carriers compared to non-carriers at least 10 years prior to symptom onset. Individual data points suggest substantial inter-individual variation in amyloid burden measured by PiB PET (C) and by CSF Aβ42 (D) in pathogenic variant carriers (only carriers shown in C and D; level of impairment coded with shapes and colors using the Clinical Dementia Rating global score - CDR).

Figure 3:. Amyloid Burden and Functional Decline Considering Variant Groupings:

Trajectories of PiB PET (A,D), CSF Aβ42 (B, E), and Clinical Dementia Rating (CDR) sum of boxes (C,F) across variant groupings. In panels A-C, individual variants were categorized according to the protein domain affected by the underlying genetic variation. In panels D-F, PSEN1 pathogenic variant carriers were grouped based on whether the identified variant in PSEN1 was before or after codon 200. No significant differences between variant groupings were observed in CSF Aβ42 or in CDR sum of boxes (panels B, C, E, and F), but significant variant-dependent variations in amyloid PET signal were observed using both the domain- and codon-based groupings (A,D; Supplemental Figure 2). * denotes FDR corrected p ≤ 0.05 for each variant grouping by EYO interaction compared to all other pathogenic variant carriers; † denotes FDR corrected p ≤ 0.0001 for carriers of PSEN1 variants prior to codon 200 compared to those carriers of variants post codon 200.

Figure 4:. Variant-dependent Variations in PiB PET: Illustrative Cases:

PiB-PET images from autosomal dominant Alzheimer’s disease pathogenic variant carriers starting from early, pre-symptomatic stages of disease (left) to later stages with recognized clinical impairment (right) as measured by the global Clinical Dementia Rating (CDR) and CDR Sum of Boxes. CSF Aβ42, cortical and striatal mean PiB values, and variant grouping are shown below each image (Transmembrane Domain: TM; Estimated Years to Symptom Onset: EYO). These images were chosen to demonstrate the heterogeneity present in β-amyloid measures across the course of autosomal dominant Alzheimer’s disease. Examples of striatal predominant patterns are shown in Supplemental Figure 5.

Figure 5:. Longitudinal PiB PET:

Individual pathogenic variant carriers are plotted in panel A, with each point representing a PiB PET measurement and lines connecting observations from the same participant. To examine how amyloid PET signal may vary longitudinally by stage of disease, variant carriers were separated into early asymptomatic, late asymptomatic, and impaired phases of autosomal dominant Alzheimer’s disease, and the yearly change in PiB PET signal was calculated from the available longitudinal data (panel B). P-values shown are FDR corrected.

Figure 6:. Variant-dependent Variability in Regional Amyloid Burden:

Trajectories of striatal mean PiB SUVR across EYO with pathogenic variants grouped according to affected protein domain (A) or in PSEN1 carriers with genetic variants before or after codon 200 (B). Individual variant categories from panel A are depicted in panels C-K, with cortical mean shown in colored solid lines and striatal mean in gray dashed lines. + denotes p ≤ 0.05 for main effect of variant grouping relative to other pathogenic variant carriers; † indicates p ≤ 0.0005 for the presence of a codon-based grouping by EYO interaction; * indicates p ≤ 0.05 for comparison of cortical to striatal PiB PET SUVR within each variant grouping. P-values are FDR corrected.