The First Discovery

In 1906, the German psychiatrist Dr. Alois Alzheimer described the case of Auguste D., a woman of fifty-one who had been admitted to the hospital five years before her death with a series of symptoms that included problems with memory and comprehension, an inability to speak, disorientation and hallucinations, and behavioral issues. After she died, Dr. Alzheimer performed an autopsy. Examining her brain tissue under a microscope, he found two unusual pathologies. One of these was a massive amount of sticky, insoluble proteins lodged in the spaces between nerve cells. Today these are called beta-amyloid plaques. The other was tangled bundles of protein threads within the neurons themselves, now called neurofibrillary tangles. Plaques and tangles are now considered the hallmarks of AD.

When Dr. Alzheimer made his seminal discovery, few took notice. At that time, the most common cause of dementia was syphilis. In his day, he was much better known for his studies of this type of dementia than for the relatively infrequent Alzheimer's disease. Also, Alzheimer's disease was not as common then, because few people lived to seventy-five, the average age of onset. People only lived to forty-seven or forty-eight in 1900. (The top ten killers were infectious disease like pneumonia, small pox, influenza, and venereal diseases.)

In 1910, the condition characterized by plaques, tangles, and accompanying symptoms was first called "Alzheimer's disease" by Dr. Alzheimer's supervisor at the Royal Psychiatric Clinic in Germany. However, for fifty years following Dr. Alzheimer's discoveries, knowledge about the disease grew slowly. Continuing improvements in scientific instruments and methods allowed scientists to conduct more sophisticated studies of the biological structure of plaques and tangles. They began to recognize that the "Alzheimer's disease" defined as plaques and tangles occurring in the brains of relatively young adults were, in fact, the same structures they saw at autopsy in the brains of older people who had "senile dementia," the result of what was then called "hardening of the arteries."

The common assumption was that forgetfulness was a normal part of old age. Most people thought, "Uncle Fred is going through his second childhood," or "Grandma just can't remember where she puts things, but it's no big deal." During the 1960s, though, there was growing recognition that dementia was not, in fact, a normal part of aging but was often caused by a disease of the brain, Alzheimer's disease.

Since then, discoveries in Alzheimer's disease have come increasingly rapidly. We know now that, in most cases, symptoms of the disease emerge after age sixty-five; this is called late-onset AD. In a small number of cases, people develop the disease in their thirties, forties or fifties; this is called early-onset AD. Breakthroughs in the field of genetics have shown that early-onset cases run in families and are the result of particular genetic mutations. Late-onset AD probably results from a combination of genetic, environmental, and lifestyle factors. In both forms, the disease has the same pathology—the accumulation of beta-amyloid in plaques and neurofibrillary tangles that disrupt communication among neurons, ultimately leading to cell death.

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Excerpted from THE ALZHEIMER'S PROJECT: MOMENTUM IN SCIENCE, published by Public Affairs, www.publicaffairsbooks.com.

Alzheimer's Disease (AD)

A progressive degenerative disease of the brain that causes impairment of memory and other cognitive abilities.

Amyloid Precursor Protein (APP)

The larger protein from which beta-amyloid is formed.

ApoE Gene

A gene that codes for a protein that carries cholesterol to and within cells; different forms of the ApoE gene are associated with differing risks for late-onset Alzheimer's disease. This gene may be referred to as a risk factor gene or a "susceptibility gene" because one form of the gene, called APOE4, is associated with the risk of developing late onset AD.

Beta-Amyloid

Derived from the amyloid precursor protein and found in plaques, the insoluble deposits outside neurons. May also be called A-beta.

Beta-Amyloid Plaque

A largely insoluble deposit found in the space between nerve cells in the brain. The plaques in Alzheimer's disease are made of beta-amyloid and other molecules, surrounded by non-nerve cells (glia) and damaged axons and dendrites from nearby neurons.

Cognitive Reserve

The brain's ability to operate effectively even when some damage to cells or brain cell communications has occurred.

Dementia

A broad term referring to a decline in cognitive function that interferes with daily life and activities. Alzheimer's disease is one form of dementia.

Functional MRI (fMRI)

An adaptation of an MRI (see magnetic resonance imaging) technique that measures brain activity during a mental task, such as one involving memory, language, or attention.

Hippocampal Formation

A structure in the brain that plays a major role in learning and memory and is involved in converting short-term to long-term memory. Also called the hippocampus.

Inflammation

The process by which the body responds to cellular injury by attempting to eliminate foreign matter and damaged tissue.

Insulin Resistance

A condition in which the pancreas makes enough insulin, but the cells do not respond properly to it; characterizes and precedes type 2 diabetes.

Magnetic Resonance Imaging (MRI)

A diagnostic and research technique that uses magnetic fields to generate a computer image of internal structures in the body.

Mild Cognitive Impairment (MCI)

A condition in which a person has cognitive problems greater than those expected for his or her age. Amnestic MCI includes memory problems, but not the personality or other cognitive problems that characterize AD.

Neurodegenerative Disease

A disease characterized by a progressive decline in the structure and function of brain tissue. These diseases include AD, Parkinson's disease, frontotemporal lobar degeneration, and dementia with Lewy bodies. They are usually more common in older people.

Oligomers

Clusters of a small number of beta-amyloid peptides.

Oxidative Damage

Damage that can occur to cells when they are exposed to too many free radicals.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Synapse

The tiny gap between nerve cells across which neurotransmitters and nerve signals pass.

Tau

A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.

Tangles

A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.

Memory

Normal Aging

Genetic Risk Factor

Dominant and Recessive Genes

Genes and Proteins

Protein-Misfolding Disease

Cholesterol

Biomarkers

Disease-Modifying Drug

Transgenic Mice

An animal that has had a gene (such as the human APP gene) inserted into its chromosomes for the purpose of research. Mice carrying a mutated human APP gene often develop plaques in their brains as they age.

Pathology

Microglia

Insulin & Insulin Resistance

Susceptibility Gene

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Susceptibility Genes

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Genome-Wide Association Study

Vascular Disease

Genetics

Genetics

Normal Aging