Clinical and biological heterogeneity in autosomal dominant Alzheimer's disease

Abstract

AbstractBackgroundPresenilin‐1 (PSEN1) mutations cause early‐onset autosomal dominant Alzheimer’s disease (ADAD) with nearly 100% penetrance, providing an opportunity to characterize the biological changes associated with preclinical AD. Over 280 different ADAD mutations are currently identified. In Antioquia, Colombia, there are two PSEN1 cohorts, including the world’s largest family with the E280A mutation (consisting of over 1,200 mutation carriers). The clinical phenotype of ADAD is similar to sporadic AD, though some cases have atypical presentations and vary in age at clinical onset and disease course. Here, we reviewed the clinical and biological profiles of these two large families with ADAD.MethodMembers of two large Colombian families with ADAD were included (PSEN1 mutations: 60 E280A carriers, 26 Ile416Thr carriers). All participants underwent a comprehensive clinical and cognitive assessment. Diagnosis of Mild Cognitive Impairment (MCI) and dementia was blind to carrier status. A subset of the E280A (n=35) and Ile416Thr (n=3) mutation carriers also underwent tau and amyloid PET imaging.ResultThe PSEN1 E280A clinical profile is characterized by memory decline beginning in the early 30s, followed by progressive impairment of other cognitive functions. These carriers develop MCI around age 44 and dementia around age 49. There is some phenotypic variability in PSEN1 E280A; some carriers present with epilepsy and ataxia. PET imaging of E280A carriers show a pattern of amyloid and tau pathology similar to that seen in sporadic AD. However, a few cases show distinct patterns of tau accumulation, involving early tau pathology in occipital and parietal regions, absence of tau in medial temporal lobe, and variable cognitive profiles. The Ile416Thr cognitive profile consists of early memory and verbal comprehension impairments. Carriers develop MCI at a mean age of 48 and progress to dementia at age 52. PET imaging of Ile416Thr carriers shows an initial pattern of tau accumulation limited to medial temporal lobe regions.ConclusionThe clinical and biological profiles of ADAD mutations can be heterogenous. Variable cognitive and clinical phenotypes may explain different trajectories of disease progression and response to treatments in clinical trials. Future studies should examine other biological similarities and differences among ADAD mutations.