The French Series of Autosomal Dominant Early Onset Alzheimer's Disease Cases: Mutation Spectrum and Cerebrospinal Fluid Biomarkers

Abstract

We describe 56 novel autosomal dominant early-onset Alzheimer disease (ADEOAD) families with PSEN1, PSEN2, and AβPP mutations or duplications, raising the total of families with mutations on known genes to 111 (74 PSEN1, 8 PSEN2, 16 AβPP, and 13 AβPP duplications) in the French series. In 33 additional families (23% of the series), the genetic determinism remained uncharacterized after this screening. Cerebrospinal fluid (CSF) biomarker levels were obtained for patients of 58 families (42 with known mutations and 16 without genetic characterization). CSF biomarkers profile was consistent with an AD diagnosis in 90% of families carrying mutations on known genes. In families without mutation, CSF biomarkers were consistent with AD diagnosis in 14/16 cases. Overall, these results support further genetic heterogeneity in the determinism of ADEOAD and suggest that other major genes remain to be characterized.

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

“…These changes may be related to preexisting deficits in the integrity of the frontal tracts that have been observed in individuals with DS 44 and that may be worsened by Aβ deposition in the frontal lobes 45 . Although BPSDs are very prominent in early AD-DS, this presentation is not unique to these individuals -it also occurs, albeit at lower rates, during the early stages of LOAD 46 and EOAD 47 , particularly in cases arising from mutations in the AD risk gene presenilin 1 (PSEN1; which maps to chromosome 14). Further studies are required to determine the earliest changes associated with the development of dementia in people who have DS, and to delineate other clinical differences between AD-DS, LOAD and familial forms of EOAD, such as the frequencies of co-morbidities that may affect the onset and progression of dementia (for example, cardiovascular disease and systemic infections).…”

“…Thus, a possible protective mechanism (or mechanisms) from triplication of an unknown gene (or genes) on chromosome 21 may be important for resistance to dementia in people with DS. Moreover, intracerebral haemorrhage (ICH) is common in individuals with Dup-APP (occurring in 20-50% of cases) [9][10][11][12][13][14]47,108 , whereas individuals with DS are generally protected from this pathology, with only occasional reports. Thus, triplication of a chromosome 21 gene (or genes) may protect against some AD co-morbidity, and further comparative study of AD-DS and Dup-APP is required to understand the mechanisms underpinning this observation.…”

“…They therefore differ from other forms of familial AD that are the result of mutations in APP, PSEN1 or PSEN2 that modulate the processing of APP and the generation of Aβ. In Dup-APP, regions of chromosome 21 triplication vary in size [8][9][10][11][12][13][14][15]47,107,108 (FIG. 2); the smallest known duplication contains only an additional copy of APP and no other coding genes 8 .…”

“…The key dosage-sensitive gene for AD-DS is likely to be APP, as an additional normal copy of this gene is sufficient to cause EOAD in the absence of trisomy of the rest of chromosome 21 47,107 …”

Quantitative detection of amyloid-β peptides by mass spectrometry: state of the art and clinical applications

“…By 2050, the estimates are quite pessimistic with more than 115.4 million people expected to develop AD [1]. Two main forms of AD coexist, sporadic AD which affects around 5% of the population after the age of 65, and familial AD, which is rare ( < 1% of the patients), often appears before the age of 65, and is linked to mutations in AD relevant genes (PSEN1-2, APP) [2]. Regardless of its form, AD is characterized by behavioral changes, memory impairments, praxis and gnosis disorders leading to a progressive loss of autonomy in patients [3].…”