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

Date Published: May 10, 2018

Publisher: BioMed Central

Author(s): Steinunn Thordardottir, Elena Rodriguez-Vieitez, Ove Almkvist, Daniel Ferreira, Laure Saint-Aubert, Anne Kinhult-Ståhlbom, Håkan Thonberg, Michael Schöll, Eric Westman, Anders Wall, Maria Eriksdotter, Henrik Zetterberg, Kaj Blennow, Agneta Nordberg, Caroline Graff.


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.

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.

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.

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.

The online version of this article (10.1186/s13195-018-0374-y) contains supplementary material, which is available to authorized users.

Partial Text

Familial Alzheimer’s disease (FAD) is an early-onset form of Alzheimer’s disease inherited in an autosomal dominant fashion. Currently, mutations causing FAD have been found in three genes: the amyloid precursor protein (APP) gene on chromosome 21 [1–3], the presenilin 1 (PSEN1) gene on chromosome 14 [4], and the presenilin 2 (PSEN2) gene on chromosome 1 [5]. These FAD mutations are generally considered to be 100% penetrant and have a relatively predictable age of clinical symptom onset [6, 7]. There are significant differences between FAD mutation types in the expected age of clinical symptom onset [8, 9] as well as in clinical presentation and cognitive phenotype [10–12]. There is also variability in age at clinical onset within a given family [9], suggesting that other genetic, epigenetic, environmental, or stochastic factors may influence disease onset [9]; however, these additional modifying factors are not well known. The discovery of FAD mutations has provided new insights into the pathogenesis of Alzheimer’s disease, rendering support for the amyloid cascade hypothesis. According to this hypothesis, it is the accumulation of amyloid-β peptide in the brain that primarily initiates and drives the disease process [13].

Autosomal dominant mutations in the PSEN1 gene leading to FAD are currently considered to be almost fully penetrant. This study on two brothers born 1 year apart and both carrying the PSEN1 H163Y mutation presents the first biomarker-verified case of reduced penetrance of a PSEN1 mutation. The brothers were followed with repeated clinical evaluations over a period of 22 years, during which time the older brother, referred to as brother A, developed Alzheimer’s disease with typical progressive cognitive decline. The cognitive test results revealed a gradual decline, first in episodic memory, visuospatial ability, and executive function, then followed by deterioration in all examined cognitive domains. In contrast, no such decline was apparent in his brother, referred to as brother B. Brother A showed typical biomarker signs of Alzheimer’s disease, starting with an early decrease in CSF amyloid-β42 and later progressing to an increase in CSF T-tau and P-tau. Interestingly, however, the level of CSF amyloid-β42 of brother A returned to normal as the disease progressed. Owing to this unusual development of amyloid-β42 levels, we reanalyzed amyloid-β42 in the CSF samples from brother A and also in one of the samples from brother B. The amyloid-β42 levels in the reanalysis were lower than in the original analysis in all three samples, with brother A having pathological amyloid-β42 levels on both sampling occasions. Unfortunately, we do not have a solid explanation for this discrepancy, but it suggests that these results should be interpreted with caution. Brother A had decreased volumes of both left and right hippocampi on MRI and decreased glucose metabolism on FDG-PET observed prior to atrophy in several brain regions, including parietal and temporal areas. He also had cerebral amyloidosis observed on PiB-PET. Brother A died at the age of 64, 9 years after being diagnosed with MCI. On autopsy, typical neuropathological signs of Alzheimer’s disease were present.

The present study strongly suggests that the PSEN1 H163Y mutation has a reduced penetrance in brother B. This is supported by a longitudinal follow-up of the subject over 22 years, starting at the age of 43 (8 years before expected symptom onset) and ending at the age of 65 (14 years past the expected symptom onset), and his remaining amyloid-β biomarker-negative until the last time point with available biomarker assessment (age 60 years) and showing no cognitive decline on neuropsychological tests at the age of 65. These findings have implications for genetic counseling because one cannot assume that PSEN1 mutations are 100% penetrant and that family-specific mean age of symptom onset has greater variability than previously reported. The findings are also hypothesis-generating because they suggest the presence of a factor or factors in this individual that can be disease-modifying. Whether these factors are genetic, epigenetic, or environmental remains a subject of further study.




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