Genetic Screening in Alzheimer's Disease

By Tanzi, Rudolph E.; Blacker, Deborah | Generations, Spring 2000 | Go to article overview
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Genetic Screening in Alzheimer's Disease

Tanzi, Rudolph E., Blacker, Deborah, Generations

Current usefulness-and limits-as well as future prospects for genetic profiling as a component of prevention and treatment.

Alzheimer's disease is a progressive neurode-- generative disorder responsible for the vast majority of dementia in the elderly population. Over the past two decades a number of genes have been associated with the disease, and consequently, limited genetic testing is now marketed for it. Genetic testing is potentially useful for diagnosis in demented patients, early detection in those with mild cognitive impairment, and early prediction in asymptomatic individuals. Currently, two types of genetic tests are marketed for Alzheimer's. However, both are of limited value. In this review, we present an overview of the complex genetic profile of Alzheimer's disease and discuss the utility of the available genetic tests, including the limits of their diagnostic and predictive value. We also provide recommendations for genetic testing for Alzheimer's and consider future prospects for performing genetic profiling as a component of treatment for this highly prevalent neurological disorder.


Alzheimer's disease is a genetically complex and heterogeneous disorder. The roughly five percent of it that develops prior to age 60, referred to as early onset Alzheimer's disease, often displays autosomal-dominant inheritance, which means that only one mutant allele need be inherited to develop the trait or disease. Thus, a parent with an autosomal-dominant disease will transmit the disease to roughly 50 percent of offspring. Defects in three genes are known to cause early onset Alzheimer's in families,

Late-onset Alzheimer's, developing beyond age 60, has been associated with genetic risk factors rather than causative genes, notably the apolipoprotein E gene (APOE) on chromosome 19. Genetic studies of the disease originally used relatively rare families with several generations afflicted with early onset Alzheimer's and eventually led to the identification of the amyloid precursor protein (APP) gene on chromosome 21 (Goate et al., 1991) as the first Alzheimer's disease gene. Six different pathogenic mutations have been found in this gene in roughly twentyfive families worldwide, causing Alzheimer's between the ages of 39 and 67 (Tanzi, 1999).

The second early-onset gene identified was presenilin-I (PSENI) on chromosome 14. PSENI accounts for up to 40 percent of early-onset cases, especially those occurring before age So. To date, this gene has been reported to contain more than seventy mutations in more than iro families, with an age-of onset range of 23 to 64 years (average age of onset, 45). Shortly after PSEm was identified, presenilin-a (PSEN2) on chromosome r was discovered to contain a mutation causing Alzheimer's disease in a series of related families of Volga German descent (Tanzi, 1999). The age-of onset range in the Volga German patients is 44 to 85 years, with an average age of onset of 52. To date, only five different mutations have been reported in PSEN2.

In contrast to the relatively simple profile of early onset Alzheimer's genetics, late-onset Alzheimer's is genetically very complex, with early epidemiological studies showing that genetic factors play a significant role in the etiology of late-onset (Blacker and Tanzi, 1998). The most well-established gene for late-onset Alzheimer's disease is apolipoprotein E (APOE) on chromosome 19. The APOE gene has three major alleles (variant forms), designated epsilon-a, 3, and 4 (Saunders et al., 1993; Strittmatter et al., 1993). Numerous population-based studies have documented that the APOE-4 allele confers increased risk and susceptibility for Alzheimer's but is not determinative for the disease. In contrast, weaker evidence implicates the APOE-a allele as a protective factor (Farrer et al., r997). Carriers of two APOE-4 alleles have a five-to-eight fold increased risk for getting the disease; however, many such people escape the disease (Breitner et al.

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Genetic Screening in Alzheimer's Disease


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