Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene. J Neurol

Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery Fazakerley, Liverpool, UK.
Journal of Neurology (Impact Factor: 3.84). 03/2006; 253(2):139-58. DOI: 10.1007/s00415-005-0019-5
Source: PubMed

ABSTRACT It is now 10 years since the first report of mutations in the presenilin genes that were deterministic for familial autosomal dominant Alzheimer's disease. The most common of these mutations occurs in the presenilin-1 gene (PSEN1) located on chromosome 14. In the ensuing decade, more than 100 PSEN1 mutations have been described. The emphasis of these reports has largely been on the novelty of the mutations and their potential pathogenic consequences rather than detailed clinical, neuropsychological, neuroimaging and neuropathological accounts of patients with the mutation. This article reviews the clinical phenotypes of reported PSEN1 mutations, emphasizing their heterogeneity, and suggesting that other factors, both genetic and epigenetic,must contribute to disease phenotype.

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    • "In addition to typical memory impairment, it is widely known that atypical symptoms such as behaviour disturbance, movement disorders, pyramidal tract signs, myoclonus or seizures frequently occur in familial Alzheimer's disease with PSEN1 or APP mutations (Rossor et al., 1993; Cabrejo et al., 2006; Larner and Doran, 2006, 2009). We observed a significantly higher frequency of pyramidal signs and dysarthria as well as potentially increased incidence of seizures and myoclonus, but not extrapyramidal signs, during their disease course, compared to sporadic Alzheimer's disease adjusted by Braak neurofibrillary tangles stage (Supplementary material and Supplementary Table 6). "
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    ABSTRACT: Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-β accumulation and other neuropathological features in familial Alzheimer's disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer's disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post-mortem brains of familial Alzheimer's disease (n = 10; age at death: 50.0 ± 8.6 years) with mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1), sporadic Alzheimer's disease (n = 19; age at death: 84.7 ± 7.8 years), neurologically normal elderly without amyloid-β accumulation (normal ageing; n = 13, age at death: 82.9 ± 10.8 years) and neurologically normal elderly with extensive cortical amyloid-β deposits (pathological ageing; n = 15; age at death: 92.7 ± 5.9 years). The levels of amyloid-β40, amyloid-β42, APP, apolipoprotein E, the synaptic marker PSD95 (now known as DLG4), the astrocyte marker GFAP, other molecules related to amyloid-β metabolism, and tau were determined by enzyme-linked immunosorbent assays. We observed that familial Alzheimer's disease had disproportionate amyloid-β42 accumulation in subcortical areas compared with sporadic Alzheimer's disease, whereas sporadic Alzheimer's disease had disproportionate amyloid-β42 accumulation in cortical areas compared to familial Alzheimer's disease. Compared with normal ageing, the levels of several proteins involved in amyloid-β metabolism were significantly altered in both sporadic and familial Alzheimer's disease; however, such changes were not present in pathological ageing. Among molecules related to amyloid-β metabolism, the regional distribution of PSD95 strongly correlated with the regional pattern of amyloid-β42 accumulation in sporadic Alzheimer's disease and pathological ageing, whereas the regional distribution of APP as well as β-C-terminal fragment of APP were strongly associated with the regional pattern of amyloid-β42 accumulation in familial Alzheimer's disease. Apolipoprotein E and GFAP showed negative regional association with amyloid-β (especially amyloid-β40) accumulation in both sporadic and familial Alzheimer's disease. Familial Alzheimer's disease had greater striatal tau pathology than sporadic Alzheimer's disease. In a retrospective medical record review, atypical signs and symptoms were more frequent in familial Alzheimer's disease compared with sporadic Alzheimer's disease. These results suggest that disproportionate amyloid-β42 accumulation in cortical areas in sporadic Alzheimer's disease may be mediated by synaptic processes, whereas disproportionate amyloid-β42 accumulation in subcortical areas in familial Alzheimer's disease may be driven by APP and its processing. Region-specific amyloid-β42 accumulation might account for differences in the relative amounts of tau pathology and clinical symptoms in familial and sporadic Alzheimer's disease.
    Brain 03/2014; 137(5). DOI:10.1093/brain/awu046 · 10.23 Impact Factor
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    • "Interestingly, this might reflect the fact that although both mutations typically result in early-onset familial AD (age of onset: 52–59 years), PS1(A79V) is considered a ''weak'' mutation with a slowly progressing pathogenesis, whereas patients carrying the APP(K724N) mutation typically suffer from a rapid pathogenesis (Larner and Doran, 2006). "
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    ABSTRACT: Increasing evidence suggests that elevated Aβ42 fractions in the brain cause Alzheimer's disease (AD). Although γ-secretase modulators (GSMs), including a set of nonsteroidal anti-inflammatory drugs (NSAIDs), were found to lower Aβ42 in various model systems, NSAID-based GSMs proved to be surprisingly inefficient in human clinical trials. Reasoning that the nonhuman and nonneuronal cells typically used in pharmaceutical compound validation might not adequately reflect the drug responses of human neurons, we used human pluripotent stem cell-derived neurons from AD patients and unaffected donors to explore the efficacy of NSAID-based γ-secretase modulation. We found that pharmaceutically relevant concentrations of these GSMs that are clearly efficacious in conventional nonneuronal cell models fail to elicit any effect on Aβ42/Aß40 ratios in human neurons. Our work reveals resistance of human neurons to NSAID-based γ-secretase modulation, highlighting the need to validate compound efficacy directly in the human cell type affected by the respective disease.
    Stem Cell Reports 12/2013; 1(6):491-8. DOI:10.1016/j.stemcr.2013.10.011 · 5.64 Impact Factor
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    • "Moreover, there is a clear correlation between the onset of the disease and seizure incidence (Amatniek et al., 2006), which also correlates with an increased production of A␤ 42 , supporting the idea that A␤ is an important cause for aberrant neuronal activity. From the other side, mutations in presenilin-1 (PS-1) and the majority of the cases with early-onset dementia also showed epilepsy (Larner and Doran, 2006). In a recent study, it has been shown that overexpression of the APP intracellular domain (AICD) increases the susceptibility to spontaneous seizures, deficits in LTP and seizure-induced drug generation (Vogt et al., 2011). "
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