Effect of high-risk SORL1 variants on clinical presentation in symptomatic Alzheimer’s disease

Abstract Background Rare, high-risk variants in SORL1 are established genetic contributors to Alzheimer’s disease (AD), but their impact on clinical presentation remains uncharacterized. This study investigates the effect of rare high-risk SORL1 variant ( SORL1 hi ) carriers on the clinical presentation, cognitive decline and time from diagnosis to death in symptomatic AD. Methods Patients with a biomarker-confirmed diagnosis of symptomatic AD and available genetic information ( n = 1546, age at diagnosis 64.3 ± 7, 52% female, 69% APOE ε4 carriers) were included from the Amsterdam Dementia Cohort. SORL1 hi carriers were identified per established criteria, and wild-type (WT) carriers ( n = 1511) served as controls. Baseline assessments included family history, neuropsychological testing, cerebrospinal fluid (CSF) AD core biomarkers (Aβ42, pTau-181, total tau), MRI visual rating (Fazekas) and quantitative analysis of cortical thickness and subcortical volumes and EEG ratings. Longitudinal data on cognitive decline (median interval 2.1 years, interquartile range (IQR) 1.1–3.4) and time between diagnosis and death (median 7.0 years, IQR 6.7–7.2) were collected. Associations of SORL1 hi carriers with these variables were analyzed using linear, logistic, Cox regression models, as well as linear mixed-effects models, adjusting for age, sex and education, with exploratory analyses stratified by APOE ε4 status. Results We identified 35 SORL1 hi carriers, with 28 unique variants (21 missense, 6 protein truncating, 1 in-frame insertion). Compared with WT, SORL1 hi carriers more often had an affected first-degree relative (71% vs. 45%, P = 0.006). Carriers were comparable to WT in terms of MMSE at baseline and MMSE decline over time, neuropsychological profiles, CSF biomarkers, MRI measures, EEG, and mortality rate after diagnosis. Stratified analyses showed that SORL1 hi ε4 non-carriers showed higher CSF pTau-181 and t-Tau biomarker concentrations and had a shorter time to death than WT ε4 non-carriers. Discussion SORL1 hi variant carriers presented with a clinical endophenotype comparable to symptomatic WT AD patients, suggesting that SORL1 genetic deficits can result in a typical AD end-stage. These findings support targeting SORL1-mediated pathways as an out-of-the-box, but viable strategy for AD. Future studies should characterize the biological changes in presymptomatic SORL1 hi carriers in comparison to sporadic AD. These findings highlight that genetic screening is essential to identify SORL1 carriers in clinical practice.