About Alzheimer's Disease

Alzheimer's disease (AD) is the most common dementia that occurs in humans as they age. AD disrupts communication in areas of the brain by causing neurons to dysfunction and to die. AD is characterized by progressive loss of memory and cognitive faculties, including memory loss, language deterioration, impaired visuospatial skills, poor judgment, and an attitude of indifference. Motor function is preserved. Current estimates are that 6-10% of adults over 65 have AD, and this figure is expected to double every five years. For the population of 85 and older, estimates of the prevalence of AD have been as high as 30-47%. As the proportion of AD patients increases with age, and as the average for human life expectancy also increases, the treatment of AD is becoming a major public health priority.

Unfortunately, currently available therapeutic interventions are far from satisfactory. Even though there has been substantial scientific research on AD, as yet, there is still a lack of understanding of the cause and progression of AD, which has resulted in no clear approach to adequately treat, prevent, or delay the progression of the disease. The increase in the public's concern over AD is well founded and requires the public to become more fully informed about the latest research on AD.

This website is designed to assist you - the public and researchers - in locating information on AD, to help you understand the research on AD that is being conducted at OHSU's Neurological Sciences Institute in the Reddy laboratory, and how our research results can ultimately contribute to the goals of treating, preventing, and delaying the progression of the disease.

We begin with summaries of the 2 types of AD and its characteristics, followed by a more technical discussion of AD and of the research being conducted in the Reddy laboratory.

Types of Alzheimer's Disease: A Summary

AD occurs in two forms: familial (typically abbreviated as FAD) and sporadic (SAD). Familial AD is hereditary and runs in families. About 10-15% of all AD patients have the familial form of AD. It has a known genetic causal link, which has been identified as a relatively few mutations in the following genes:

amyloid precursor protein, located on human chromosome 21,
presenilin 1, located on human chromosome 14, and
presenilin 2, a homologue (similar) to presenilin 1 and located on human chromosome 1.

The onset of familial AD occurs earlier than the onset of sporadic AD, sometimes with symptoms becoming evident as early as age 28 when there is a mutation at presenilin 1.

In contrast to familial AD, symptoms of sporadic AD are not typically observed until after age 65. There is no known genetic link with sporadic AD, although a risk factor (the apolipoprotein E with isoform 4/4 [ApoE 4/4]) has been identified.

Despite the age difference in onset for both types of AD, they are clinically nearly identical, and as such are treated as one in research.

Characteristics of Alzheimer's Disease: A Summary

Characteristics of neurons affected by AD have been identified through autopsies of different areas of the brain. Two distinct abnormalities have been found in the hippocampus, the entorhinal cortex, the basal forebrain, and the associated cortices of the basal forebrain. Researchers believe that these abnormalities precede neuronal dysfunction and death. These 2 distinct abnormalities are: (1) senile plaques and (2) neurofibrillary tangles.

Senile plaques.

Senile plaques are found in the brain neurons of AD patients, but they are also found in cognitively normal, but remarkably older, people. However, they are not in as high concentrations in normal older people as they are in AD patients. Senile plaques are outside of the cells (extracellular) and are primarily composed of the protein amyloid-beta40-42. This protein is not common, but it is also not necessarily pathological. Research thus far suggests that senile plaques accumulate in AD patients and disrupt the ability of the neurons to transmit electrical signals, and thus, senile plaques interfere with how neurons communicate with each other.

Neurofibrillary tangles.

Neurofibrillary tangles are an array of protein fibers within cells (intracellular). They are primarily composed of a hyper-phosphorylated tau protein, and may interfere with axonal transport in the cells. They are found in a few other diseases of the brain besides AD, such as progressive supranuclear palsy. Senile plaques and neurofibrillary tangles do not necessarily occur together, and only one is sufficient for AD-like symptoms to develop.

A More Technical Look at Alzheimer's Disease

AD occurs in two forms, so-called familial Alzheimer's disease (FAD) and sporadic Alzheimer's disease (SAD). Whereas FAD has known genetic links, for which a patient can be tested and which ultimately leads to AD when present, sporadic AD - as its name indicates - does not allow for such predictability. Furthermore, patients with FAD usually begin exhibiting symptoms earlier than do those with SAD, even as early as age 28. However, FAD is far less common than is SAD, with all the types of FAD together making up only about 10-15% of all AD patients. SAD, which has a symptomatic onset anywhere from 65 years of age up to the end of life, comprises the remaining 85-90% of those suffering from AD.

FAD is associated with specific mutations of 3 particular genes: the amyloid precursor protein (APP) gene, presenilin 1 (PS1), and presenilin 2 (PS2). It is important to note that the genes themselves do not cause the disease, but are normal and possibly very important to the healthy functioning of the body. Rather, it is the specific mutations of these genes that appear to spark the disease. PS 1 and PS 2 are similar in name, due to their association with AD: PS2 was found only after PS1 had been associated with AD. These 2 genes are so similar in structure that when researchers tried to isolate PS1, they found 2 genes rather than one!

As for SAD, no gene or genetic combination has been seen to be determinant in the eventual development of AD, but one gene has been seen to be a risk factor for AD, meaning that many people with a particular genotype more likely acquire the disease. This gene is apolipoprotein E (ApoE) and risk factor genotype is 4/4. However, except for the consideration of age, FAD and SAD are similar enough to be considered identical in terms of disease effects. Therefore, researchers assume that both types of AD progress identically, and so research methods to research of FAD are identical to those used to research SAD; and findings from the research of each have been applied to our understanding of both.

AD affects those areas of the brain in which higher thought processes are carried out, which leads to failure of reasoning, delusions, and hallucination--in a word, dementia. However, AD does not affect other processes, such as motor coordination or automatic responses. Two hallmarks are seen in the brain of a late AD patient, which are thought to be intimately involved in neuronal dysfunction and death: senile plaques (SPs) and neurofibrillary tangles (NFTs).

The SPs are primarily made up of a protein called amyloid-beta, which is an infrequent but not necessarily undesirable protein. You might recognize 'amyloid,' from the APP gene which produces it. The amyloid precursor protein is processed into the more common amyloid-alpha or the amyloid-beta form, the latter which is of concern in AD, depending on other proteins that process this protein. Note that mutations in PS1 or PS2 appear to change how the APP protein is processed into either amyloid-alpha or amyloid-beta, whereas mutations in the APP gene change the APP-protein itself and therefore how it is processed. SPs form around the outside of a neuron where electrical signals are normally transmitted - a function that SPs may likely interrupt. SPs are an alternate cleavage of a normal protein (amyloid-alpha) that is highly insoluble. The mutations in the amyloid precursor protein change the protein so that it tends to be cleaved in favor of the beta form in the brain; the mutations of presenilin 1 and presenilin 2 modify the cleavage process to achieve the same result.

An NFT is a pathological hall-mark of AD that consists of tau protein. An NFT occurs intracellularyand is thought to interfere with the functioning of the cell. NFTs may interfere with axonal transport and/or action potentials.

Interestingly, while SPs have been found, albeit rather diffusely, in healthy but very elderly individuals, NFTs have been found in the brains of patients with other neurological disorders, such as progressive supranuclear palsy. To add an additional layer of complexity, it appears that both SP and NFT are not needed to develop AD, and neither SP nor NFT is needed to develop AD. In other words, AD has been found in patients with neither SP or NFT.

Research on Alzheimer's Disease in the Reddy Laboratory

Since AD is a late-onset disease, not affecting the majority of patients before the age of 65 and clearly fatally damaging a previously healthy brain, it is important to understand what events occur before neurons are irreversibly damaged. We need to study the brain, to learn what happens to neurons as AD progresses.

The Reddy laboratory has 2 primary purposes to its research: (1) to identify genetic characteristics of brain cells affected by AD, at different stages of disease progression, and (2) to determine the role of genetic component in sporadic AD patients.

For the research dealing with disease progression, the Reddy laboratory is investigating messenger RNA (mRNA) expression for thousands of genes in the brains of AD transgenic mouse models by using modern molecular biology techniques, such as gene chip (or DNA chip or cDNA microarray). The Reddy laboratory is studying mRNA expressions at different time points, starting from 15 days and 2-3 months (before formation of amyloid plaques), 8-9 months (during the formation of amyloid plaques), and 18-20 months (end stage of animal's life). This would allow us to understand the genes responsible for early cellular changes in AD, and also genes responsible for progression of the disease. More details of this project are given in the section Alzheimer's Disease Progression in Mouse Models.

The second aspect of our research involves examining how genes vary in late-onset sporadic AD patients. It is known that nearly 85-90% of total AD patients are sporadic cases without any known genetic basis. Sporadic AD patients manifest clinical symptoms very late in life. Therefore, there is a strong possibility of the presence of a genetic factor that predisposes some people to AD. With this hypothesis in mind, the Reddy laboratory is examining nucleotide changes in the genomes of sporadic AD patients using single-strand confirmation polymorphism (SSCP) and DNA sequencing analysis. The SSCP techniques identify nucleotide changes in the gene, based on the mobility shift of a single strand of DNA. We verify these DNA changes via sequencing analysis (arrangement of nucleotides in a DNA strand). In addition, the Reddy laboratory is studying how altered nucleotide changes lead to symptoms of AD by using conventional molecular and biochemical methods.

We invite you to read further about the different avenues researchers in the Reddy laboratory are pursuing, in the study of genetic variants relating to AD, to help further our understanding of Alzheimer's disease.

This document was created for the neurogenetics laboratory run by P. H. Reddy, Ph.D. in the NSI of OHSU. Page last updated: 28 Sept 2001.