History of Alzheimer's disease

A unique case
Interpreting the disease
What's in a name?
Not uncommon anymore
Making strides
Where is research headed?
Further reading
Timeline

In 1901, a 51-year-old woman (Auguste D) sought help in the psychiatric hospital in Frankfurt. Her family was worried because she had become paranoid and forgetful. Auguste D was placed in the care of the physician Alois Alzheimer. Born in 1864 near Würzberg, Germany, the son of a notary, Alzheimer studied medicine in Berlin and other cities and began his medical career as an internist in Frankfurt. He had a particular interest in nervous disorders, and learned special techniques for studying them from a colleague. One of his early contributions, in 1894, was to describe the changes in the brain caused by vascular disease such as stroke.

A unique case

Alzheimer's original notes from his observation of Auguste D were misplaced after 1909. Recently, however, they were recovered and published. In them, Alzheimer reports that Auguste D's earliest symptom was jealousy toward her husband. Soon after, she began to lose her memory. She became more and more disoriented, and began to exhibit peculiar behavior, for example carrying objects to and fro and hiding them. During her first days in the hospital, Alzheimer documented his patient's symptoms. She could not remember her husband's name, and even seemed confused by the question. She could identify the proper colours of things like snow and soot, but was unable to name common objects. She complained of anxiousness. She needed help to write, and Alzheimer noted that she seemed to read without understanding.

With time, Auguste D became increasingly immobile and uncommunicative. She died in 1906 of multiple causes, including pneumonia and nephritis.

Alzheimer had moved to Munich in 1903 to work with the renowned psychiatrist Emil Kraepelin. But when Auguste D died, he had her brain sent to him for examination. He reported his findings to a conference in Tübingen in November of that year, and published them in 1907 under the title "A unique illness involving the cerebral cortex".

Auguste D's brain was full of surprises. It showed marked signs of atrophy in the cortical region, the area of the brain that governs memory and thinking. Alzheimer also remarked odd structural changes-twisted bands of fibres inside brain cells and dense deposits around them. We now know these structures as neurofibrillary tangles and amyloid plaques, the hallmarks of AD. Several years later, Alzheimer published a second case for which he supplied drawings of fibrillary tangles.

Interpreting the disease

In the two years following Auguste D's death, cases similar to the one reported by Alzheimer were described by his Italian colleagues Francesco Bonfiglio and Gaetano Perusini. Perusini also reexamined Auguste D's brain, and made his own evaluation of it, which agreed with Alzheimer's. All three physicians classified what they were seeing as senile dementia (dementia that occurs after age 65). But Auguste D's case was unusual owing to her young age and the speed with which her condition degenerated. Although the senile plaques Alzheimer noted were known, neurofibrillary tangles were not. It took three years for Alzheimer's discovery to be recognized.

The term dementia had been known since Roman times, but it was used as a general term for insanity. Dementia in the elderly in the sense we know it was first described in a book about mental illness in 1838. Until Alzheimer's time, senile dementia was believed to be due to a disease of the arteries in the brain. The basis for our current understanding about dementia was largely established after 1850 and before 1910, including the discovery of plaques in the cortex of senile patients.

Kraepelin introduced the term Alzheimer's disease (AD) in the 8th edition of his textbook Compendium der Psychiatrie (1910). He reported that autopsy showed changes typical of "the most serious form of senile dementia". One-third of the cells in the cortex were destroyed. But there was some confusion about how to interpret the disease. Although the changes in the brain did indeed suggest senile dementia, the relative youth of the patient argued that the disease was a new one. For that reason, Kraepelin characterized it as presenile dementia. Thus began a lasting argument about AD that was only recently resolved. Was Alzheimer's disease senile dementia or something else? And was it part of the normal aging process?

What's in a name?

The way doctors define disorders is based on their clinical experience and what that experience leads them to expect. When dementia was first defined as a disorder, it was considered a problem of the elderly. It was not expected that such symptoms would commonly affect people who were younger. When that proved to be the case, the condition was considered exceptional or atypical. Because it was unexpected and atypical, this suggested that the disease process might be a different one.

Why does the name you give to something matter? It matters because failing to realize that you are looking at a single disease process instead of two unrelated ones has implications for how you investigate and treat a disease. In the case of AD, better understanding of the underlying disease process showed that even though the disorder progressed with age, when it began at a younger age, it was still the same disease as the disorder affecting the elderly. A better idea of the disease process reshaped prior understanding, based on clinical patterns, with a new understanding based on observable changes in the cells of the central nervous system.

Although AD gained acceptance as a disease state, it did not attract much attention at first. One reason was the emphasis on a psychological explanation for the symptoms of dementia that resulted from the influence of Sigmund Freud. A second reason was that Kraepelin's description of the disease did not offer much hope for treatment.

Until 1936, AD was commonly diagnosed based both on the pattern of symptoms observed by the doctor, and by examination of brain tissue after death. But when it became clear that many nondemented people also showed plaques and tangles, diagnosis began to be made on the basis of clinical criteria alone.

In recent years, AD has burst to the forefront of public consciousness. For one thing, people are now living longer than ever before, and AD is a disease primarily of old age. Also, the surge in population following the Second World War has contributed to an increasingly older population worldwide. Finally, most people with AD do not die of the disease but of complications from it, such as pneumonia. For a long time, owing to a lack of awareness about AD, someone who contracted pneumonia as a complication of AD would have their cause of death listed as pneumonia. Better diagnosis of AD has led to greater recognition of the impact of the disease.

Not uncommon anymore

In the 1960s, people began to realize that AD was not rare, as previously thought, but indeed the predominant cause of dementia and a common illness. Senility, which was considered to be a normal part of aging was now seen as abnormal, the result of disease or other illness, and possibly treatable.

One of the effects of AD is that the synaptic connections in the brain-the spaces between brain cells where communication takes place-are lost. Some of the cells that are destroyed supply a chemical substance called acetylcholine to portions of the brain concerned with memory. So the first drugs developed for AD were aimed at boosting the action of acetylcholine, or preventing it from breaking down in the first place. In 1993, the US Food and Drug Administration approved the first drug to treat AD. This drug, and two others that have been approved since, may relieve some of the symptoms of AD. But to the extent that they work, they work only in the early stages of the disease. And they are temporary solutions at best. Thus far, no treatment has been found to cure the disease or to slow its progression.

Making strides

In the last two decades criteria for diagnosing AD have become stricter, and ways of imaging the brain hold out the promise of even more accurate diagnoses. Furthermore, researchers have made progress in understanding the genetic basis of AD. Between 1991 and 1995, new molecular cloning techniques made it possible to identify defects called mutations associated with AD in four genes.

Genes exist to make proteins, which direct all of the workings of the body. The first finding in AD genetics was the discovery that a mutation in the gene that makes the so-called amyloid precursor protein results in overproduction of the protein. Research in the 1980s on families in which AD struck at an early age helped to locate this gene on chromosome 21 in 1991. But these mutations are extremely rare, and worldwide they account for less than 5% of all cases of AD.

In 1995, researchers identified mutations in genes called presenilin 1 and 2 that cause 50% of early onset cases of AD. Genes to account for the remaining cases of early-onset AD remain to be identified. One form of a fourth gene, called ApoE, does not always cause AD but can increase a person's chance of getting the common version of the disease that occurs in people over 65. Research continues into other genes involved in both early- and late-onset AD.

All people with Down's syndrome develop plaques and tangles by their 40s, which puts them at increased risk of developing dementia as their life expectancy increases. So findings in AD genetics are also being used to help understand how Down's works.

Where is research headed?

Other research on AD has focused on a number of different factors that may put people at risk for developing AD, such as lower education, aluminium poisoning and weakened immunity. But none of these findings is conclusive. Race, culture, environment and lifestyle do not appear to have any effect on a person's risk of development AD. Conversely, there is some evidence that a severe blow to the head can cause the disease. But injury alone is not sufficient, and many people who develop AD have never sustained a blow to the head.

Research is also continuing into developing mouse and rat models that will reproduce every htmect of AD. Although mice with the same mutations found in humans do develop amyloid plaques, they do not lose neurons anywhere near the extent that humans do, nor do their brains form neurofibrillary tangles. Development of an appropriate animal model is not only critical for finding drugs to treat the disease, but also other treatments, such as implanting healthy cells into the brain to replace damaged ones.

Perhaps the most important finding to come from research over the years is to recognize that AD is not part of normal aging but a real disease. In other words, AD is primarily a disease of old age, but simply living a long time is not enough to cause it. AD appears to have many causes, which makes it complicated. But that also opens up the possibility of different therapeutic approaches, as well as different ways of preventing the disease.

Timeline

1907	Dr. Alois Alzheimer describes two cases of "presenile" dementia with extensive plaques and neurofibrillary tangles.
1968	Researchers show that the severity of dementia in AD seems more closely related to the density of plaques and tangles and not to cerebrovascular changes.
1984	Researchers at the University of California at San Diego discover that amyloid plaques consist largely of peptide fragments.
1991	Mutations in gene for amyloid precursor protein discovered in several families with early-onset AD.
1992	Tacrine is approved by the US Food and Drug Administration (FDA) as the first treatment for mild-to-moderate AD.
1993	Discovery of gene (ApoE4) that increases the risk of the more typical form of AD, which appears late in life.
1995	Mutations in presenilin genes found to cause an aggressive form of early-onset AD.
1996	Donepezil hydrochloride is the second drug approved by the FDA to treat early-stageAD.
1997	Research suggests vitamin E may slow the progression of AD.
1999	An experimental vaccine is shown to reverse AD-like symptoms in mice.
2000	FDA approves third drug (rivastigmine) for treatment of early-stage AD. Phase I clinical trials begun in US and UK to test the safety of an amyloid vaccine in human subjects.

Giselle Weiss
2 December 2000