Alzheimer's disease (AD) is a devastating dementia of late life that is correlated with a region-specific neuronal cell loss. Despite progress in uncovering many of the factors that contribute to the etiology of the disease, the cause of the nerve cell death remains unknown. One promising theory is that the neurons degenerate because they reenter a lethal cell cycle. This theory receives support from immunocytochemical evidence for the reexpression of several cell cycle-related proteins. Direct proof for DNA replication, however, has been lacking. We report here the use of fluorescent in situ hybridization to examine the chromosomal complement of interphase neuronal nuclei in the adult human brain. We demonstrate that a significant fraction of the hippocampal pyramidal and basal forebrain neurons in AD have fully or partially replicated four separate genetic loci on three different chromosomes. Cells in unaffected regions of the AD brain or in the hippocampus of nondemented age-matched controls show no such anomalies. We conclude that the AD neurons complete a nearly full S phase, but because mitosis is not initiated, the cells remain tetraploid. Quantitative analysis indicates that the genetic imbalance persists for many months before the cells die, and we propose that this imbalance is the direct cause of the neuronal loss in Alzheimer's disease.

https://www.jneurosci.org/content/jneuro/21/8/2661.full.pdf

DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease

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American Thoracic Society/European Respiratory Society: Standards in Diagnostik und Therapie bei Patienten mit Alpha-1-Antitrypsin-Mangel

Alzheimer's disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer's disease, early onset and the more common late onset. The genetics of early-onset Alzheimer's disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer's disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer's disease.

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Genetics of Alzheimer’s Disease

Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism characterized by increased iron absorption and deposition in the liver, pancreas, heart, joints, and pituitary gland. Without treatment, death may occur from cirrhosis, primary liver cancer, diabetes, or cardiomyopathy. In 1996, HFE, the gene for HHC, was mapped on the short arm of chromosome 6 (6p21.3). Two of the 37 allelic variants of HFE described to date (C282Y and H63D) are significantly correlated with HHC. Homozygosity for the C282Y mutation was found in 52-100% of previous studies on clinically diagnosed probands. In this review, 5% of HHC probands were found to be compound heterozygotes (C282Y/H63D), and 1.5% were homozygous for the H63D mutation; 3.6% were C282Y heterozygotes, and 5.2% were H63D heterozygotes. In 7% of cases, C282Y and H63D mutations were not present. In the general population, the frequency of the C282Y/C282Y genotype is 0.4%. C282Y heterozygosity ranges from 9.2% in Europeans to nil in Asian, Indian subcontinent, African/Middle Eastern, and Australasian populations. The H63D carrier frequency is 22% in European populations. Accurate data on the penetrance of the different HFE genotypes are not available. Extrapolating from limited clinical observations in screening studies, an estimated 40--70% of persons with the C282Y homozygous genotype will develop clinical evidence of iron overload. A smaller proportion will die from complications of iron overload. To date, population screening for HHC is not recommended because of uncertainties about optimal screening strategies, optimal care for susceptible persons, laboratory standardization, and the potential for stigmatization or discrimination.

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HFE Gene and Hereditary Hemochromatosis: A HuGE Review

W e are well into the digital information age. Digital communications and information resources affect almost every aspect of our lives— business, finance, education, government, and entertainment. Clinical medicine is highly information intensive, but it is one of the few areas of our society where computer access to information has had only limited success in selected areas such as billing and scheduling, laboratory result reporting, and diagnostic instrument systems (such as radiology and cardiology). The move to widely accepted electronic patient records (EPRs) is accelerating, however, and is inevitable because of many pressures. Among those pressures are the desire to improve health care through timely access to information and decision-support aids; the need for simultaneous access to records by doctors, nurses, and administrators in modern, integrated provider and referral systems; meeting the needs of highly mobile patients; the push toward improved cost effectiveness based on analyses of outcomes and utilization information; the need for better support of clinical research; and the growing use of telemedicine and telecare [5]. We are, of course, motivated by the great benefits to patient care and medicine that can derive from this effort. But almost daily we hear about network computer break-ins—often close to home—arousing vivid fears [4]. By putting our personal medical records online, might we be increasing the risk of exposing highly private and sensitive information to outsiders? In this article we take a systems view of privacy and information security in health care. We will put the nature of the most urgent threats to patient information privacy in perspective, the new threats that almost certainly will arise because of the technologies of digital information,

Privacy, information technology, and health care

Background. As the development and use of genetic tests have increased, so have concerns regarding the uses of genetic information. Genetic discrimination, the differential treatment of individuals based on real or perceived differences in their genomes, is a recently described form of discrimination. The range and significance of experiences associated with this form of discrimination are not yet well known and are investigated in this study. Methods. Individuals at-risk to develop a genetic condition and parents of children with specific genetic conditions were surveyed by questionnaire for reports of genetic discrimination. A total of 27,790 questionnaires were sent out by mail. Of 917 responses received, 206 were followed up with telephone interviews. The responses were analyzed regarding circumstances of the alleged discrimination, the institutions involved, issues relating to the redress of grievances, and strategies to avoid discrimination. Results. A number of institutions were reported to have engaged in genetic discrimination including health and life insurance companies, health care providers, blood banks, adoption agencies, the military, and schools. The alleged instances of discrimination were against individuals who were asymptomatic and sometimes impacted on other asymptomatic relatives. Few surveyed respondents knew of the existence of institutions such as state insurance commissions or the Medical Information Bureau, Inc., which may play roles in redress of grievances or correction of misinformation. Conclusions. Genetic discrimination is variable in form and cause and can have marked consequences for individuals experiencing discrimination and their relatives. The presence of abnormal genes in all individuals makes each person a potential victim of this type of discrimination. The increasing development and utilization of genetic tests will likely result in increased genetic discrimination in the absence of contravening measures.

Individual, Family, and Societal Dimensions of Genetic Discrimination: A Case Study Analysis

Chromosome missegregation and trisomy 21 mosaicism in Alzheimer's disease.

Recent advances in tests for the genotype for hemochromatosis and suggestions that the tests be used in mass screening programs for the disease raise the possibility of a large increase in the incidence of discrimination against people who are found to be homozygous for hemochromatosis. This paper presents cases of genetic discrimination drawn from a study of discrimination against people with a variety of genetic conditions. The cases discussed here involve employment and several types of insurance discrimination against people diagnosed with hemochromatosis who either are currently asymptomatic or whose condition is controlled by means of phlebotomies. There is no justification for these types of discrimination since people with controlled hemochromatosis suffer no excess mortality or morbidity. Our study suggests that genetic discrimination is already a serious problem and that any proposed screening program for hemochromatosis or other genetic condition must consider and attempt to mitigate its effects.

Genetic discrimination and screening for hemochromatosis.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)64399-1.pdf

Lisa N. Geller

Papers

Individual, Family, and Societal Dimensions of Genetic Discrimination: A Case Study Analysis

Chromosome missegregation and trisomy 21 mosaicism in Alzheimer's disease.

Genetic discrimination and screening for hemochromatosis.

Alzheimer's disease, Down's syndrome, and chromosome segregation

IQ and Heredity