Disease duration in autosomal dominant familial Alzheimer disease
Ivanna M. Pavisic, Jennifer M. Nicholas, Antoinette O’Connor, Helen Rice, Kirsty Lu, Nick C. Fox, Natalie S. Ryan
Abstract
<h3>Objective</h3> To use survival modeling to estimate disease duration in autosomal dominant familial Alzheimer disease (ADAD) and ascertain whether factors influencing age at onset also affect survival. <h3>Methods</h3> Symptomatic mutation carriers (201 presenilin 1 [<i>PSEN1</i>] and 55 amyloid precursor protein [<i>APP</i>]) from ADAD families referred to the Dementia Research Centre, between 1987 and 2019, were included. Survival was assessed with respect to age at onset, year of birth, <i>APOE</i> ε4 status, cognitive presentation, and sex using multilevel mixed-effects Weibull survival models. The contribution of mutation and family to variance in age at onset and duration was also assessed. <h3>Results</h3> Estimated mean survival was 11.6 (10.4–12.9) years and was similar for <i>APP</i> and <i>PSEN1</i> mutations. Sixty-seven percent of the variance in age at onset was explained by mutation and 72% by mutation and family together. In contrast, only 6% of the variance in disease duration was explained by mutation specificity and 18% by family membership. Irrespective of gene, survival appeared longer for successive generations and in individuals with atypical presentations. Older age at onset was associated with longer duration within <i>PSEN1</i> and shorter duration within <i>APP</i> mutation carriers. No differences in survival time were found between sexes or between mutations located before or beyond codon 200 within <i>PSEN1</i>. <h3>Conclusions</h3> Survival is influenced by mutation to a much lesser extent than age at onset. Survival time has increased over time and is longer in atypical presentations. These insights may inform the interpretation of disease-modifying therapy trials in ADAD.