Autosomal-dominant Alzheimer's disease: A review and proposal for the prevention of Alzheimer's disease

Department of Neurology, Washington University School of Medicine, 660 S, Euclid, Campus Box 8111, St Louis, MO 63110, USA. .
Alzheimer's Research and Therapy (Impact Factor: 3.98). 01/2011; 3(1):1. DOI: 10.1186/alzrt59
Source: PubMed

ABSTRACT Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including the international Dominantly Inherited Alzheimer Network and this network's initiative for clinical trials. Clinical trials in autosomal-dominant Alzheimer's disease may test the amyloid hypothesis, determine the timing of treatment, and lead the way to Alzheimer's disease prevention.

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Available from: Bart De Strooper, Sep 26, 2015
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    • "Decoding AD gene mutations is important because not only does it provide a more sophisticated understanding of the pathobiology in EO-FAD, but might assist in the identification of at-risk patients for early treatment interventions in the future [11] [12]. In this report, we will present the clinical, neuropsychological, imaging and molecular data of two family members with a novel PSEN1 missense mutation. "
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    ABSTRACT: Mutations in the presenilin 1 (PS1) gene (PSEN1) are associated with familial Alzheimer disease (FAD). Here, we report on a 50-year-old patient presenting with progressive deterioration of his short-term memory and a family history of early-onset dementia. Diagnostic workup included a neuropsychological examination, structural magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) biomarkers including total tau, phosphorylated tau, and Aβ42 levels, as well as sequencing relevant fragments of the genes PSEN1, PSEN2, and APP. Additionally, we were able to obtain archival paraffin-embedded cerebellar tissue from the patient's father for cosegregation analysis. Clinical, neuropsychological and MR imaging data were indicative of early-onset Alzheimer disease. Furthermore, CSF biomarkers showed a typical pattern for Alzheimer disease. DNA sequencing revealed a heterozygous nucleotide transition (c.824C>T) in exon 8 of PSEN1, leading to an amino acid change from alanine to valine at codon 275 (Ala275Val). The same mutation was found in an archival brain specimen of the patient's demented father, but not in a blood sample of the non-demented mother. This mutation alters a conserved residue in the large hydrophilic loop of PS1, suggesting pathogenic relevance. Cosegregegation analysis and the structural as well as the presumed functional role of the mutated and highly conserved residue suggest FAD causing characteristics of the novel PSEN1 mutation Ala275Val.
    Neuroscience Letters 02/2014; 566. DOI:10.1016/j.neulet.2014.02.034 · 2.03 Impact Factor
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    • "The discovery of monogenic forms of Alzheimer's Disease (AD) has allowed improved knowledge of the physiopathology which, in turn, has allowed the design of new therapeutic strategies. After 20 years of basic and clinical research, understanding the early phases of monogenic AD has become pivotal in order to develop and test the efficacy of the newest target-therapeutic approaches [4]. Even though most monogenic forms of AD have been described in familial early onset AD, recent findings suggest a wider spectrum of clinical presentation, including late-onset and sporadic forms. "
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    ABSTRACT: The discovery of monogenic forms of Alzheimer's Disease (AD) associated with mutations within PSEN1, PSEN2, and APP genes is giving a big contribution in the understanding of the underpinning mechanisms of this complex disorder. Compared with sporadic form, the phenotype associated with monogenic cases is somewhat broader including behavioural disturbances, epilepsy, myoclonus, and focal presentations. Structural and functional imaging show typical early changes also in presymptomatic monogenic carriers. Amyloid imaging and CSF tau/A β ratio may be useful in the differential diagnosis with other neurodegenerative dementias, especially, in early onset cases. However, to date any specific biomarkers of different monogenic cases have been identified. Thus, in clinical practice, the early identification is often difficult, but the copresence of different elements could help in recognition. This review will focus on the clinical and instrumental markers useful for the very early identification of AD monogenic cases, pivotal in the development, and evaluation of disease-modifying therapy.
    11/2013; 2013(6543):689591. DOI:10.1155/2013/689591
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    • "ADAD is caused by a dominant mutation in one of three genes: amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2). Although ADAD accounts for less than 1% of all AD cases [16], its clinical and pathological phenotypes are largely similar to those of sporadic, late-onset AD (LOAD) [17,18]. Children of an affected ADAD parent have a 50% chance of inheriting the mutated allele. "
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    ABSTRACT: The Dominantly Inherited Alzheimer Network (DIAN) is an international registry of individuals at risk for developing autosomal dominant Alzheimer's disease (AD). Its primary aims are to investigate the temporal ordering of AD pathophysiological changes that occur in asymptomatic mutation carriers and to identify those markers that herald the transition from cognitive normality to symptomatic AD. DIAN participants undergo longitudinal evaluations, including clinical and cognitive assessments and measurements of molecular and imaging AD biomarkers. This review details the unique attributes of DIAN as a model AD biomarker study and how it provides the infrastructure for innovative research projects, including clinical trials. The recent design and launch of the first anti-amyloid-beta secondary prevention trial in AD, led by the related DIAN Trials Unit, also are discussed.
    Alzheimer's Research and Therapy 10/2013; 5(5):48. DOI:10.1186/alzrt213 · 3.98 Impact Factor
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