Early Alzheimer's disease genetics
The genetics community working on Alzheimer's disease and related dementias has made remarkable progress in the past 20 years. The cumulative efforts by multiple groups have lead to the identification of three autosomal dominant genes for early onset AD. These are the amyloid-beta protein precursor gene (APP), and the genes encoding presenilin1 and 2. The knowledge derived from this work has firmly established Abeta as a critical disease molecule and lead to candidate drugs currently in treatment trials. Work on a related disease, frontotemporal dementia with parkinsonism - chromosome 17 type has also added to our understanding of pathogenesis by revealing that tau, the protein component of neurofibrillary tangles, is also a critical molecule in neurodegeneration. Lessons learned that still influence work on human genetics include the need to recognize and deal with genetic heterogeneity, a feature common to many genetic disorders. Genetic heterogeneity, if recognized, can be source of information. Another critical lesson is that clinical, molecular, and statistical scientists need to work closely on disease projects to succeed in solving the complex problems of common genetic disorders.
Available from: Magnus Johannsson
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ABSTRACT: Neðst á síðunni er hægt að nálgast ritgerðina í heild sinni með því að smella á hlekkinn View/Open Previous studies on first-degree relatives of Alzheimer’s disease (AD) patients have revealed a higher risk of developing dementia, and that subtle cognitive impairment can be detected before overt clinical signs appear using neuropsychological tests. Findings on children of AD patients are very scarce within the literature. The main aim of this study was to explore the cognitive development of adult children (AC) of AD patients in Icelandic pedigrees selected from an ongoing genetic research, over a seven-year period. The subjects were 83 AC (age range 46-74) with a family history of AD and a control group (NC) constituting 30 individuals (age range 48-73) without any known first-degree relative with dementia. Cognitive abilities were assessed using neuropsychological tests of orientation, verbal and non-verbal memory, abstract reasoning, language, concentration, mental speed, and visuo-spatial and constructional abilities. Participants with known central or peripheral nervous disorders were excluded from the study. Primary results revealed no statistical difference between the two groups on any of the neuropsychological tests from time 1 to time 2, over a seven year period. These findings place the onset of subtle cognitive impairments in adult children of AD patients after the age of 60 years. When comparing the AC group to 76 AD patients and 92 siblings of AD patients, participating in the genetic study, one AC had stronger resemblance to the AD group than other AC on the neuropsychological measures. Furthermore, 10% of the AC group had stronger resemblance to the siblings of AD patient in the neuropsychological measures than the rest of the group, indicating a possible trend within the AC group.
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ABSTRACT: Alzheimer disease, a progressive neurodegenerative disorder of hitherto unknown etiology leading progressively to severe incapacity and death, has become the pandemic of the 21(st) century. On World Alzheimer Day, September 21, 2006, the 100(th) anniversary of the first description of the clinical and histological findings in this disorder by A. Alzheimer, was celebrated. This retrospective review of the most important events and advances in Alzheimer research presents its early history in which only clinical and histologic signs of this peculiar disease were described. Electron microscopy, quantitative morphology and modern biochemistry emerging in the second half of the 20(th) century opened a new era in dementia research with description of the ultrastructure and biochemistry of senile plaques and neurofibrillary tangles, the major disease markers of AD. Advances in the development of clinical, neuropathological, and neuroimaging criteria, modern instruments and algorithms in the diagnosis of the disorder followed, enabling long-term studies and more exact diagnosis of AD and related disorders. Landmark studies were the development of operational criteria for the post mortem diagnosis of AD based on semiquantitative assessment and developmental patterns of its major markers. Basic research gave insight into the molecular genetics and pathophysiology of AD, and, based on the biochemical findings, new pharmacological treatment options were opened. Recently, biological and other surrogate, in particular functional neuroimaging, markers allow an early detection of presymptomatic stages of AD, their risk factors and progression which, in the future, might be prevented or at least slowed by new therapeutic approaches. Since the etiology of AD is hitherto unknown, causative therapies are still not available. The paper discusses future research needs and challenges for developing new diagnostic strategies for early and accurate detection of neurodegenerative processes leading to dementia, better epidemiologic and gender data as well as more insights into the pathogenic cascade of AD and other dementing disorders which will depend on international networks and close cooperation between clinicians, neuroscientists, caregivers, public health institutions, and individual sponsors.
Journal of Neural Transmission 12/2006; 113(11):1603-23. DOI:10.1007/s00702-006-0578-3 · 2.40 Impact Factor
Available from: Bosiljka Plecas-Solarovic
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ABSTRACT: Chromosomal alterations are a feature of both aging and Alzheimer's disease (AD). This study examined if premature centromere division (PCD), a chromosomal instability indicator increased in AD, is correlated with aging or, instead, represents a de novo chromosomal alteration due to accelerating aging in AD. PCD in peripheral blood lymphocytes was determined in sporadic AD patients and gender and age-matched unaffected controls. Metaphase nuclei were analyzed for chromosomes showing PCD, X chromosomes with PCD (PCD,X), and acrocentric chromosomes showing PCD. AD patients, regardless of age, demonstrated increased PCD on any chromosome and PCD on acrocentric chromosomes in both genders, whereas an increase in frequency of PCD,X was expressed only in women. This cytogenetic analysis suggests that PCD is a feature of AD, rather than an epiphenomenon of chronological aging, and may be useful as a physiological biomarker that can be used for disease diagnosis.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 12/2010; 65(12):1269-74. DOI:10.1093/gerona/glq148 · 5.42 Impact Factor
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