Chromosomes & Alzheimer's Disease

When scientists talk about the genetics of Alzheimer's disease, they are referring to sequences of DNA at specific loci, or locations, on several chromosomes. While four mutations, one each on human chromosomes 1, 14, 19, and 21, have been known to be associated with the disease for 15 years, investigators now have elucidated three more such genetic links.

What is Alzheimer's Disease?

• A growing public health problem in the U.S. and other industrialized nations, Alzheimer's Disease (AD) is an acquired condition, manifesting in cognitive and behavioral impairment. Generally, patients present with progressive memory loss, complemented by impairment of other cognitive functions such as language disorders, and impairment of visuospatial skills. Diagnosis of AD is made if the severity of symptoms interferes noticeably with an individual's social and occupational function.

Statistics of Alzheimer's Disease

• The most common cause of dementia and fourthth (in some studies the third) leading cause of death in adults, AD has been on the rise in recent years. While on-set of AD is most common above age 60, a small fraction of cases (less than 10 percent) can begin as early as the third decade of life. Prevalence increases to about 40 percent above age 80 but, interestingly, the risk of new on-set of AD may decrease somewhere beyond age 90. In the U.S., AD affects approximately 5.2 million people, resulting in a wide range of cognitive and physical impairments.

Future Trends

• According to estimates, 7.7 million Americans will have AD by 2030 and 11 to 16 million by 2050. Rates and trends in other industrialized countries are similar to those of the U.S.

Pathology

• Since the publication of Alois Alzheimer's manuscripts describing AD as cerebrocortical atrophy in the early 20th century, investigators have elucidated various histopathological phenomena suggestive of the disease. These include neurofibrillary tangles (NFTs); senile plaques (SPs), granulovacuolar degeneration, neuropil threads, synaptic degeneration, neuropil threads and neuronal loss. Since such findings occur in various other neurodegenerative disorders, no lesion has been discovered thus far that is pathognomonic for AD.

Etiology and genetics

• While the cause of AD is unknown and while less than seven percent of all cases are familial (linked specifically to heredity), investigators have undertaken a number of genetic studies relating AD to chromosomal factors. Thus, while the disease does not manifest from specific Alzheimer genes, it does seem to result from a combination of converging risk factors. For this reason, it is important to understand what genes are and how they affect human health.

Chromosomes and Genes

• Chromosomes are long strands of deoxyribonucleic acid (DNA), held together, shaped, and organized with proteins called histones. Humans have 46 chromosomes, 23 pairs, each with a multitude of genes. While small chromosomes, like the Y chromosome in males, can have only a handful of genes, most hold many thousands. Known mutations of genes connected with AD are spread among various chromosomes.

Gene Mutations Associated with Alzheimer's Disease

• Mutations in genes for amyloid precursor protein (APP) on chromosome 21, presenilin I on chromosome 14, presenilin II on chromosome 1 all lead to a relative excess in the production of beta-amyloid peptide found in nerve cells of the brain on autopsy in association with AD. Another gene associated with AD is called apolipoprotein E (APOE), found on chromosome 19. Recently, Philippe Amouyel and colleagues at the Pasteur Institute, in Paris, found a connection with the genes CR1 and CLU, the latter which Julie Williams and colleagues in Wales have demonstrated as well. Additionally, Williams and colleagues discovered an association between AD and a gene called Picalm.