γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Abstract

Background: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production.

Methods: For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [¹¹C]Pittsburgh compound B (PiB)-PET and brain glucose metabolism using [¹⁸F] fluorodeoxyglucose (FDG)-PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log₁₀ (phosphorylated tau 181), CSF log₁₀ (phosphorylated tau 217), and MRI-based hippocampal volume.

Findings: Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type PSEN1) were associated with earlier AAO (r=0·58; p<0·0001). GSC was associated with MMSE (β=0·08, SE 0·03; p=0·0043), CDR-SB (-0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB-PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p<0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003).

Interpretation: Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid β production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset.

Funding: US National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III.

Figure 1.. Schematic summarizing the characterization of variant-level Aβ production and γ-secretase activity.

Figure 2.. Association between cell-based measures of γ-secretase activity and age of symptom onset.

(A) Bar chart showing the individual Aβ monomer levels (% relative to total Aβ) for each of the 161 PSEN1 pathogenic variants examined as well as wild-type (WT) PSEN1. (B) The γ-secretase activity composite (% relative to wild-type PSEN1; GSC) correlated with age of symptom onset in 161 PSEN1 variants, including 105 PSEN1 variants not represented in DIAN-Obs (blue triangles) and 56 newly characterized PSEN1 variants represented in DIAN-Obs (red squares). Individual data points plotted are jittered (by adding random noise) to maintain blinding. The shaded area around the solid black linear fit line represents one s.e.m. from a linear regression. (C) Visualization of GSC scores for each of the 161 PSEN1 variants characterized.

Figure 3.. Association between cell-based γ-secretase activity and biomarker, clinical, and cognitive measures in autosomal dominant Alzheimer’s disease.

Association between variant-level γ-secretase activity composite scores (% relative to wild-type PSEN1; GSC) and in vivo imaging biomarker data from carriers of corresponding PSEN1 pathogenic variants is shown for cross-sectional Aβ PET (N = 190, covariate-adjusted PiB-PET SUVR cortical composite, A), covariate-adjusted bilateral hippocampal grey matter volume derived from structural MRI (N = 190, B), and covariate-adjusted bilateral precuneus FDG-PET SUVR (N = 162, C) from PSEN1 pathogenic variant carriers (56 unique variants represented across 190 mutation carriers). Exploratory, regional analyses comparing PiB-PET SUVRs (D), grey matter volumes (E), and FDG-PET SUVRs (F) across a range of GSC, with colors indicating t- and p-values derived from the comparison of neuroimaging data from PSEN1 carriers with variants in the lowest (most pathogenic; GSC < 33.7% relative to wild-type) vs. highest (least pathogenic; GSC > 51.6% relative to wild-type) tertiles of GSC. Associations between γ-secretase activity composite scores (GSC) for each PSEN1 variant and cross-sectional CSF Aβ 42/40 (N = 157, G), covariate-adjusted CSF log₁₀ pT181 (N = 157, H), covariate-adjusted CSF log₁₀ pT217/T217 (N = 99, I), covariate-adjusted MMSE (N = 190, J), age-adjusted CDR-SB (N = 190, K), and covariate-adjusted Wechsler Memory Scale-Revised Logical Memory Delayed Recall (N = 186, L) values from PSEN1 pathogenic variant carriers are shown. Individual data points plotted are jittered (noise added in manner that does not impact the mean or confidence intervals) to maintain blinding. The shaded area around the solid black linear fit line represents one s.e.m. from a linear regression. CSF = Cerebrospinal Fluid; pT = phosphorylated tau; MMSE = Mini Mental State Examination scores; CDR-SB = Clinical Dementia Rating Scale- Sum of Boxes.

Figure 4.. Prediction of disease progression by variant-level variations in γ-secretase activity.

To visualize how variant-level differences in γ-secretase activity may broadly alter the clinical, cognitive, and biomarker course of autosomal dominant Alzheimer’s disease, we plotted the standardized differences in core clinical, cognitive, and biomarker measures across the lifespan for DIAN-Obs participants carrying PSEN1 pathogenic variants in the lowest (A, most pathogenic tertile; GSC < 33.7% relative to wild type), middle (B, intermediate pathogenicity; GSC = 33.7% – 51.6% relative to wild-type), or highest (C; least pathogenic, GSC > 51.6% relative to wild-type) tertile for γ-secretase activity (GSC). All values are shown as z-scores relative to mutation non-carriers from DIAN-Obs. This group-level analysis was followed by an individual-level visualization of disease trajectories for pathogenic variant carriers of 2 possible variants with 25% and 75% of wild-type γ-secretase activity (GSC), respectively (D-I).