Can escapees of familial AD help identify protective factors? A case report of an extremely resilient PSEN1 carrier
Michelle N.C.A. Smulders, Janna I.R. Dijkstra, Denise Visser, Lisa Vermunt, Elsmarieke Giessen, Yolande A.L. Pijnenburg, Henne Holstege, Wiesje M. van der Flier, Rik Ossenkoppele, Sven J van der Lee- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Carriers of mutations in PSEN1, PSEN2 or APP develop early‐onset Alzheimer’s dementia around a certain age depending on the specific mutation. However, some individuals “escape their fate”, meaning they remain asymptomatic far beyond their expected age at onset (EAO). We call these individuals “escapees”. A well‐known example is the resilient PSEN1 carrier that led to the identification of the protective APOEε3‐Christchurch mutation (Arboleda‐Velasquez et al., 2019). Here we present an extremely resilient PSEN1‐P264L mutation carrier where the cause of resilience has not yet been identified.
Method
Carriers of PSEN1‐P264L have an EAO of 47 (SD = 4.3 years; Ryman et al., 2014). Our patient remains asymptomatic at age 58, which less than 0.6% of mutation carriers are expected to reach unaffected. We characterized this individual over the course of eight years with neuropsychological tests (n = 9), MRI scans (n = 5), amyloid (n = 3, [18F]florbetapir) and tau (n = 3, [18F]flortaucipir) PET scans and cerebrospinal fluid (CSF; n = 1). Genetic analysis of APOE and polygenic risk score (PRS) is described.
Result
Neuropsychological test scores were within normal range at baseline and no significant cognitive decline was observed from age 50 to 58. On five consecutive MRI scans, no abnormalities or evidence of neurodegeneration was observed with visual read. At age 50, the patient was amyloid‐positive and tau‐positive in CSF (table 1). The patient was also amyloid‐positive on their first PET at age 51 (fig. 1). Widespread amyloid‐PET binding was observed, which increased over time. On tau‐PET, the patient was negative at age 51 and 53 (fig. 1), but positive at age 56, with an atypical binding pattern that shows high occipital load with relative sparing of the temporal and parietal cortex. This tau pattern and progression are remarkably similar to that seen in the escapee with the APOEε3‐Christchurch mutation. The APOE status of the patient is APOE ε3ε3 and the patient had an average PRS (+0.2SD from population average). Whole genome sequencing is ongoing.
Conclusion
We describe an “escapee” of a PSEN1 mutation in which we have not yet identified the protective factor(s). Escapees represent rare but potent resilience phenotypes that should be studied systematically.