Nov 15, 2011

The Promises and the Perils of the End of Alzheimers Disease

I am witnessing the dawn of a new age of Alzheimers disease, an age that will be marked by the end of Alzheimers disease.

By Jason Karlawish

Jason Karlawish
University of Pennsylvania
When I was in medical school, we spoke of senility. Alzheimers disease was an uncommon cause of dementia.

When I started practicing geriatric medicine at the end of the 20th century, Alzheimers disease was established as the most common cause of dementia.

Now, I am witnessing the dawn of a new age of Alzheimers disease, an age that will be marked by the end of Alzheimers disease. A world without Alzheimers disease holds great promise to reduce the suffering of millions of patients and their families, but it also presents perils.

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The end of Alzheimers disease

Unlike infectious diseases that plagued the U.S. until the middle of the 20th century, and still plague developing nations, Alzheimers is, like most diseases of the developed world, a disease of an aging world. Its pathology takes many years to accumulate and then many years to subtly unfold.

The beginning of the end of Alzheimers disease started last summer when researchers proposed new diagnostic criteria for Alzheimers disease. These criteria put together some thirty years of research showing that by the time a person has dementia with symptoms of memory loss and day-to-day problems such as disorganized finances, the changes in brain structure and function typically have been present for ten or more years.

The criteria capture a change in our values about what is a disease. Why wait to diagnose Alzheimers disease until a person is disabled? At the same time as a person has only an annoying memory problem that, while requiring extra time to finish a task, does not require someone else to help her complete that task, we can also see Alzheimers pathology in images of her brain and measures of body fluids such as the fluid that surrounds the brain.

This condition, called mild cognitive impairment due to Alzheimers disease, means physicians can diagnose Alzheimers disease before a patient is demented.

But even more revolutionary than extending the diagnosis to persons with mild cognitive problems, is the proposal that Alzheimers disease can be diagnosed prior to the onset of any symptoms. This idea of “pre-clinical Alzheimers disease” has rightly captured the energy and imagination of researchers across the globe. The prospect of diagnosis prior to disability promises a public health triumph.

The triumph of the biomarker

Central to this pre-clinical Alzheimers disease concept is a word that is relatively new to medicine. That word is “biomarker,” describing a measure such as a protein or other molecules, or imaging such as an MRI scan, that correlates disease with its clinical expression.

Biomarkers have experienced a viral spread in the scientific literature. Over the last ten years, citations for biomarker-based research have risen from a trivial few hundred to many thousands of publications. Medicine is undergoing a “biomarkerization,” a term that describes how biomarkers are becoming more and more the central focus of how we think about health, disease and treatment. Biomarkers have given birth to novel terms such as “theranostics,” to describe biomarkers that both identify a person who needs a treatment and monitor the success of that person’s treatment.

Working models exist for this biomarker driven diagnosis of Alzheimer disease.

Cardiology and endocrinology have seen their diseases transform from clinical syndromes into biomarker-driven measures of risk states. When I trained in medical school, heart disease focused on the evaluation of chest pain and the treatment of a heart attack and the years of disability that followed. It was classic bedside medicine. Now, heart disease is a numbers game: physicians and patients chart the levels of the good and bad cholesterols as well as other risk factors, while experts debate “how low should we go?” with risk reduction. The field of endocrinology has experienced a similar transformation when osteoporosis transformed into measures of bone mineral density and other measures of the risk of a fracture.

In Philadelphia, posters in public transit terminals depict an ambulance crashing through a living room wall where a man and a woman sit in matched easy chairs. The vehicle’s side panel reads “Hank, diabetes complications are coming to get you.” Beneath this image of domestic catastrophe is this plain message “Know your numbers. Know your A1C.” The A1C is a numeric measure of blood glucose metabolism. It has become diabetes.

The operative concept in this new biomarker driven world is risk. Disease is not so much about signs and symptoms but instead, it is about measures that describe risk of future health events such as a stroke, hip fracture or diabetes complications. Pre-clinical Alzheimers disease will mark the arrival of the brain at risk of dementia. Imagine a poster that warns Hank “Alzheimers disease is coming to get you.”

Moving pre-clinical Alzheimers disease into clinical practice

Right now, the concept is not ready for clinical practice. Among the important research studies that will make it ready are clinical trials that test interventions that attack the biomarkers of disease. At present, the most promising biomarker target is amyloid protein. The logic of these experiments is elegant. Show that asymptomatic persons who receive an anti-amyloid agent decline slower than persons who do not receive the agent, and you have gold standard proof of concept that the marker amyloid is the gateway to cognitive decline. Amyloid becomes the “bad cholesterol” of the brain and “Alzheimers disease” will end because we will start talking about attacking amyloid on the brain.

The promises of this new world of diagnosis and treatment before disability are evident. Persons will not have to develop disability before they are treated. Instead, we will delay the time to disability. We will treat time.

But this pre-clinical diagnosis also has challenges. Our experiences of being on drugs for heart disease or osteoporosis have not prepared us for living with a “brain at risk” of decline and taking daily medication to reduce that risk.

Persons on treatment will need monitoring of their cognitive abilities. The professionals who perform this monitoring will need to be skilled in assessing capacity so that they respect that the person at risk is still capable of working, driving and managing their finances. We must respect privacy while at the same time engage in public and honest discussion of being at risk so that having brain amyloid does not repeat the discrimination and stigma seen in the early years of the HIV epidemic.

The brain at risk also presents policy challenges. Broadly, these challenges are captured with questions that engage our values. How much risk reduction is worth the costs of diagnosis and treatment? A disease that starts out as a clinical problem in desperate need of treatment can easy become lost debates over cost-effectiveness.

These issues warrant the need for a National Alzheimers Education Program, a federal program that will develop guidelines and recommendations on how to translate pre-clinical Alzheimers disease into our day-to-day lives.

A national and public Program is essential because pre-clinical Alzheimers disease, like heart disease and diabetes, engages millions of people and it is intimately wrapped up in the pharmaceutical and biotechnology companies that own the drugs and biomarkers that define diseases.

Private interests must not trump the public good of reducing the burden of disability caused by cognitive impairment.

Jason Karlawish is a Professor of Medicine and Medical Ethics at the University of Pennsylvania and the associate director of the Penn Memory Center.

He is the author of the recently published book “Open Wound: The Tragic Obsession of Dr. William Beaumont.” He can be reached at

Open Wound: The Tragic Obsession
of Dr. William Beaumont

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Original content Jason Karlawish, the Alzheimer's Reading Room