Reduced penetrance of the PSEN1 H163Y autosomal dominant Alzheimer mutation: a 22-year follow-up study

Abstract

Background: The range of onset ages within some PSEN1 families is wide, and a few cases of reduced penetrance of PSEN1 mutations have been reported. However, published data on reduced penetrance have been limited to clinical histories, often collected retrospectively and lacking biomarker information. We present a case of reduced penetrance of the PSEN1 H163Y mutation in a carrier prospectively followed for 22 years.

Methods: Two brothers (A and B), both carriers of the H163Y mutation, were followed between 1995 and 2017. They underwent repeated clinical evaluations, neuropsychological assessments, and cerebrospinal fluid analyses, as well as brain imaging examinations with structural magnetic resonance, [¹⁸F]fluorodeoxyglucose positron emission tomography, and [¹¹C]Pittsburgh compound B positron emission tomography.

Results: Brother A was followed between 44 and 64 years of age. Cognitive symptoms due to Alzheimer's disease set in at the age of 54. Gradual worsening of symptoms resulted in admittance to a nursing home owing to dependence on others for all activities of daily living. He showed a curvilinear decline in cognitive function on neuropsychological tests, and changes on magnetic resonance imaging, positron emission tomography, and biomarkers in the cerebrospinal fluid supported a clinical diagnosis of Alzheimer's disease. Brother A died at the age of 64 and fulfilled the criteria for definitive Alzheimer's disease according to neuropathological examination results. Brother B was followed between the ages of 43 and 65 and showed no cognitive deterioration on repeated neuropsychological test occasions. In addition, no biomarker evidence of Alzheimer's disease pathology was detected, either on imaging examinations or in cerebrospinal fluid.

Conclusions: The average (SD) age of symptom onset for PSEN1 H163Y is 51 ± 7 years according to previous studies. However, we present a case of a biomarker-verified reduction in penetrance in a mutation carrier who was still symptom-free at the age of 65. This suggests that other genetic, epigenetic, and/or environmental factors modify the onset age.

Keywords: Autosomal dominant Alzheimer’s disease; CSF; Reduced penetrance; [11C]Pittsburgh compound B PET; [18F]fluorodeoxyglucose PET.

Fig. 1

Longitudinal FDG and PiB positron emission tomographic (PET) scans for brothers A and B with corresponding uptake values in SUVr(/pons) and z-scores. The two upper rows of the figure represent the longitudinal FDG and PiB PET scans for brother A during repeated follow-up examinations. The year of each examination is noted at the top of each column. The lower two rows of the figure represent the corresponding longitudinal FDG and PiB PET scans for brother B. The values included in the tables are standardized uptake value ratios (SUVr) for the ROIs in the study, with the pons used as a reference region, as well as the corresponding z-score values with respect to the control group of noncarriers. FDG z-score values less than − 1.96 and PiB z-score values greater than + 1.96 are indicated in bold italic type. FDG [¹⁸F]fluorodeoxyglucose, GM Gray matter, PiB [¹¹C]Pittsburgh compound B, SUVr Standardized uptake value ratio

Fig. 2

Hippocampal volumes of brothers A and B on magnetic resonance imaging (MRI) scans. a Cross-sectional data on the volumes of the left (LHV) and right (RHV) hippocampi of brothers A and B on MRI scans from 2009, when the brothers were 58 and 57 years old, respectively. At this time point, brother A had had an Alzheimer’s disease diagnosis for 2 years. The control group consists of 14 noncarriers without cognitive symptoms. The volumes (in mm³) have been divided by the intracranial volume (ICV) of each subject to correct for differences in head size. b Coronal MRI scans of brother A from 1995 (at the age of 44), 2001 (at the age of 50), 2006 (at the age of 55), and 2009 (at the age of 58)