Towards cascading genetic risk in Alzheimer's disease

Abstract

Alzheimer's disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer's disease. Here, we investigate whether genetic risk for Alzheimer's disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimer's disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer's disease, in addition to opening therapeutic windows for targeted interventions.

Keywords: APOE; Alzheimer’s disease; biomarker; longitudinal progression; polygenic risk.

Figure 1

Hazard ratios for the conversion from A−T− to A+T−. (A) Forest plot depicting the HRs for all covariates in the model. (B) Estimated survival curves stratified by APOE-e4 genotype. (C) Estimated survival curves stratified by PRS percentile (5%, 50% and 95%). APOEe2 = number of APOE-e2 alleles; APOEe4 = number of APOE-e4 alleles; Edu = years of education; HR = hazard ratio; PRS = polygenic risk score, scaled to zero mean and unit standard deviation.

Figure 2

Hazard ratios for the conversion from A+T− to A+T+. (A) Forest plot depicting the hazard ratios for all covariates in the model. (B) Estimated survival curves stratified by APOE-e4 genotype. (C) Estimated survival curves stratified by PRS percentile (5%, 50% and 95%). APOEe2 = number of APOE-e2 alleles; APOEe4 = number of APOE-e4 alleles; Edu = years of education; PRS = polygenic risk score, scaled to zero mean and unit standard deviation.

Figure 3

Survival curves for PET-only and CSF-only analyses. The top row (A–D) is based on results from AT(N) definitions based exclusively on PET biomarkers (amyloid and tau), with a cut-off of 1.45 for tau PET. The bottom row (E–H) relied on CSF biomarkers (ABETA42 and pTAU), with a cut-off of 26 for pTau. The two left columns (A, B, E and F) display the progression probability from A−T− to A+T− stratified by APOE-e4 genotype and PRS quantile (5%, 50% and 95%). The two right columns (C, D, G and H) display the progression probability from A+T− to A+T+.