Swank Center for Memory Care and Geriatric Consultation, ChristianaCare
Learn about how Alzheimer’s disease was discovered, the search for the cause of this brain disease, and the future of Alzheimer’s treatment.
When Alois Alzheimer met Auguste Deter in 1901, he could not have suspected that her sad story would make his name a household word throughout the world. Dr. Alzheimer was a young psychiatrist in his late 30s, a hard-working clinician committed to understanding the relationship between brain disease and mental illness. Following the death of his wife earlier that year, he had buried himself in his clinical work, caring for psychiatric patients at the Community Hospital for Mental and Epileptic Patients in Frankfurt, Germany.
Auguste Deter (whom we would learn about as “Auguste D”) was only 50 years old when her husband noticed her increasing memory problems. She soon became more fearful, paranoid, and aggressive, making it necessary to admit her to the psychiatric hospital at age 51. She remained an inpatient there until her death in 1906, although by then she was no longer under Dr. Alzheimer’s care. He had since moved on to a research position at the Munich Hospital under the leadership of Dr. Emil Kraepelin, one of the most influential psychiatrists of his era.
Alzheimer’s former boss from Frankfurt, Dr. Emil Sioli, informed Dr. Alzheimer of his former patient’s death. He sent her brain material to Alzheimer, who examined Ms. Deter’s brain microscopically using new stains that revealed the presence of what we now call amyloid plaques and neurofibrillary tangles. Though it seems odd now, Alzheimer’s initial 1906 presentation linking this specific brain pathology to a clinical syndrome was met with limited enthusiasm by his peers.
Alzheimer later published his descriptions of several similar patients in 1909 and Kraepelin included Ms. Deter’s case in the 1910 edition of his widely respected psychiatry textbook. It was Kraepelin who named this dementia after his junior colleague.
Auguste Deter was not an elderly woman at the onset of her illness, and Alzheimer’s disease (AD) was therefore regarded as a “presenile dementia” to distinguish it from the familiar “senile dementia” thought to result from aging-related vascular disease. Further investigation, however, showed that plaques and tangles were present in the brains of the majority of older adults with symptoms of dementia.
In the late 1960’s, the British psychiatrists Tomlinson and Roth described the importance of these plaques in older adults, and in 1970 Dr. Roth questioned the meaningfulness of the age criterion that distinguished AD from “senile dementia of the Alzheimer’s type.”
The American neurologist, Robert Katzman, suggested in 1976 that we should do away with the age distinction that separated pre-senile from senile dementia of the Alzheimer’s type and by the early 1980’s AD was widely recognized as the most common cause of dementia in older adults.
The search for AD’s causes began with Dr. Alzheimer and continues today in full force. In the late 1970’s, researchers described a “cholinergic hypothesis” of AD. This theory attributed AD symptoms to a deficit of the neurotransmitter acetylcholine, a small chemical messenger that is essential for proper memory function. This theory encouraged the testing of medications that increased brain levels of acetylcholine by either increasing its production or blocking its destruction. One class of these experimental medications, the cholinesterase inhibitors, was approved by the FDA and remains in common use today. Donepezil, rivastigmine, and galantamine are examples of cholinesterase inhibitors.
We can thank the cholinergic hypothesis for providing us with medicine that has mild symptom-reducing effects. Unfortunately, this class of medication has no real effect on disease progression. Researchers now consider the changes in the cholinergic system to be downstream of more basic disease mechanisms.
Memantine, the other FDA-approved medication for AD treatment, is thought to work differently, by stabilizing functioning of the glutamate system. Like the cholinesterase inhibitors, memantine is a symptom-alleviating, rather than disease-modifying, medication.
In 1984, the identification of the beta-amyloid protein in the blood vessels of patients with Down syndrome and AD suggested that the 21st chromosome (present in an extra copy in people with Down syndrome), might hold clues to understanding AD’s pathology.
This proved true when beta amyloid was identified in 1987 as an important component of senile plaques and was linked to a gene located on chromosome 21. Soon after, in the early 1990s, the discovery of mutations that promoted excessive production of beta-amyloid protein with AD added evidence to what became the “amyloid cascade” hypothesis, which is the theory that AD pathology results from accumulation of amyloid plaques in the brain leading to an inflammatory response and brain cell destruction. These mutations, each in their own way, raised levels of beta amyloid and increased the risk for developing clinical AD.
Much, but not all, of the international research effort in AD in recent years has been driven by the amyloid cascade hypothesis. Competing or complementary theories, however, have also urged consideration of the importance of tau protein abnormalities, which lead to the formation of neurofibrillary tangles (the insoluble twisted fibers found inside the brain's cells). The tau protein forms part of a structure called a microtubule, which helps transport nutrients and other important substances from one part of the nerve cell to another. In Alzheimer's disease, however, the tau protein is abnormal and the microtubule structures collapse.
Pathological changes in tau protein, as supporters of the tau theory point out, closely parallel the clinical changes that occur later in AD.
Other researchers have focused on the importance of lifestyle factors, changes in the blood-brain barrier, improper metabolism of metals such as copper or iron or zinc, systemic inflammation, or inflammation-inducing infections with bacteria or fungi as potential pathways to the development of AD.
In 2011, AD clinical detection and treatment research took a major step forward when a joint committee of experts reviewed earlier studies and reached a groundbreaking conclusion .
Based on decades of evidence with biomarkers and neuroimaging, the experts on this committee recommended that we redefine what we consider AD. No longer should it be regarded as simply a clinical syndrome of dementia, but instead it should be understood as a pathological process that develops into a clinical disease over the course of decades.
Before cognitive decline steals away a person’s independence, the disease must simmer during an initial, asymptomatic clinical phase that can persist for years. During this period, amyloid accumulation can be demonstrated using advanced neuroimaging techniques or examination of cerebrospinal fluid.
In this new model of AD, symptoms begin to appear during the second, mildly symptomatic pre-dementia stage which is called mild cognitive impairment or mild neurocognitive disorder. During this phase of AD, the pathology continues to progress, but clinical symptoms remain limited. Performance of more complex tasks is affected, but general independence is preserved.
Only in the third phase of AD, the phase of dementia (now called “major neurocognitive disorder”) do we see the characteristic independence-destroying changes in cognitive and behavioral functioning.
This reframing of the nature of AD, focusing on its pathology rather than its symptoms, has nurtured research into techniques for earlier detection and promoted the idea that intervention in the earliest stages of AD, even before disease symptoms are present, may offer more hope than efforts to reverse the destructive effects of the disease’s third stage.
Furthermore, the recognition of AD’s pre-symptomatic phase encourages greater attention to preventive interventions such as management of chronic medical illnesses that impact brain health, attention to brain-healthy nutrition, increased aerobic activity, restorative sleep, and other brain healthy lifestyle interventions.
Although the number of people with AD continues to increase daily, our time is a brighter era in the history of AD and other dementias. More than a hundred new medications are now being tested and many nonpharmacologic interventions, some of them preventive, are being explored. Even if the damage of later stages of AD are impossible to cure or reverse, current investigations offer the hope of arresting or slowing the disease’s effects – and perhaps identifying and preventing progression at an earlier, even asymptomatic stage.
As Yogi Berra is supposed to have said, “The future ain’t what it used to be.” And with respect to dementia treatment, we can hope the future will bring greater help for people with dementia and those who care for them.
James Ellison, MD received his medical degree from UCSF in 1978 and trained in psychiatry at the Massachusetts General Hospital (1979-1982).
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