Article

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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    • "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.
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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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