Anne Kinhult‐Ståhlbom

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: C]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.

OBJECTIVES: The aim of this study was to investigate cognitive performance including preclinical and clinical disease course in carriers and non-carriers of autosomal-dominant Alzheimer's disease (adAD) in relation to multiple predictors, that is, linear and non-linear estimates of years to expected clinical onset of disease, years of education and age. METHODS: Participants from five families with early-onset autosomal-dominant mutations (Swedish and Arctic APP, PSEN1 M146V, H163Y, and I143T) included 35 carriers (28 without dementia and 7 with) and 44 non-carriers. All participants underwent a comprehensive clinical evaluation, including neuropsychological assessment at the Memory Clinic, Karolinska University Hospital at Huddinge, Stockholm, Sweden. The time span of disease course covered four decades of the preclinical and clinical stages of dementia. Neuropsychological tests were used to assess premorbid and current global cognition, verbal and visuospatial functions, short-term and episodic memory, attention, and executive function. RESULTS: In carriers, the time-related curvilinear trajectory of cognitive function across disease stages was best fitted to a formulae with three predictors: years to expected clinical onset (linear and curvilinear components), and years of education. In non-carriers, the change was minimal and best predicted by two predictors: education and age. The trajectories for carriers and non-carriers began to diverge approximately 10 years before the expected clinical onset in episodic memory, executive function, and visuospatial function. CONCLUSIONS: The curvilinear trajectory of cognitive functions across disease stages was mimicked by three predictors in carriers. In episodic memory, executive and visuospatial functions, the point of diverging trajectories occurred approximately 10 years ahead of the clinical onset compared to non-carriers. (JINS, 2017, 23, 195-203).

Attempts to develop markers for the earliest possible diagnosis of Alzheimer's disease (AD) have led to an increasing impact of studies in subjects carrying autosomal dominantly inherited genes that lead to the rare early-onset familial form of Alzheimer's disease (eoFAD). These subjects are predestined to develop AD, which makes studies in presymptomatic subjects an unique possibility to study the earliest pathological changes in the brain in the process of developing AD and following them a way to depict the disease time course. Neuroimaging by means of positron emission tomography (PET) has shown that cerebral changes in glucose metabolism and accumulation of fibrillar amyloid plaques are early events in the disease process. Few PET studies have though tried to investigate the role of neuroinflammation as a pathological hallmark of AD and thereby mostly focused on the activation of microglia. As a starting point in a series of longitudinal investigations we recently published longitudinal data on presenilin 1 (PS1) mutation carriers, who were in average about twenty years before the expected onset of the disease (Schöll et al., Neurobiology of Aging, 2009). 18F-Fluorodeoxyglucose (FDG) PET revealed thalamic glucose hypometabolism and an 11C-PIB PET scan in one symptomatic mutation carrier high PIB uptake in AD typical brain regions with eminently elevated levels in striatum. In the current longitudinal study, we enrolled presymptomatic and symptomatic members of different Swedish families harboring mutations in the PS1 gene and the ‘Swedish’ and the ‘Arctic’ APP gene mutations. We use the PET tracers 18F-FDG to investigate cerebral glucose metabolism, 11C-PIB for cerebral amyloid load measurements, and 11C-Deprenyl to visualize astrocytosis as a component of neuroinflammatory processes. The acquired PET data will be set in relationship to neuropsychological test results and the interrelation between different tracers and different mutations examined. Application of multiple PET tracers in members of families harboring eoFAD mutations will provide important information about the time course and properties of AD pathology and about differences between eoFAD mutations.

The amyloid precursor protein (APP) is processed either by α -secretase in a nonamyloidogenic pathway, generating sAPP α, or in an amyloidogenic pathway where BACE1 cleaves APP releasing sAPPβ. Studies have shown that sAPP α and sAPPβ are unaltered or mildly elevated in MCI and sporadic AD. We compared the levels of sAPP α and sAPPβ between carriers of mutations leading to familial Alzheimer disease (PSEN1, APPswe and APParc) and non-carriers from the same families. Cerebrospinal fluid samples were collected from a total of 36 subjects, 6 PSEN1 mutation carriers, 9 APPswe carriers, 4 APParc carriers and 17 non-carriers (table 1). Concentrations of sAPP α and sAPPβ were determined using the MSD sAPP α/sAPP b Multiplex assay (Meso Scale Discovery, Gaithersburg, Maryland, USA). The levels of sAPP α and sAPPβ in mutation carriers (M+) and non-carriers (M-) were compared using the Mann-Whitney U-test. When comparing all mutation carriers with non-carriers, or PSEN1 carriers with non-carriers, there was no significant difference in the levels of sAPP α or sAPPβ. The carriers of the APPswe mutation however had significantly lower levels of both sAPP α and sAPPβ compared to the non-carriers and the APParc carriers had significantly higher levels of sAPP β than the non-carriers. There was no correlation between sAPP α or sAPPβ levels and years to expected disease onset in any of the groups. Autosomal dominant mutations leading to familial Alzheimer disease can be associated with high or low levels of sAPP α and sAPP β, depending on the specific mutation. The lower sAPPβ levels in APPswe mutation carriers are expected as the mutation destroys the neo-epitope recognized by the capturing antibody in the sAPP β assay. It is tempting to speculate that the levels of mutated sAPPβ in fact are elevated given the established effect of the APPswe mutation on BACE1-mediated APP-processing.