1-2-3 stages of Alzheimer’s

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Posted: Wednesday, February 19, 2014 4:00 pm

ST. LOUIS, Mo. (Ivanhoe Newswire) – We classify cancer into different stages and now researchers are doing something similar with Alzheimer’s disease. It could mean a much earlier diagnosis for many.

Sister Barbara Schlatter has been a nun for 50 years.

“I entered the convent in 1963,” Sister Barbara told Ivanhoe.

She’s helped a lot of people during that time, but two people she couldn’t help were her parents. They both passed away with Alzheimer’s. Now, Sister Barbara worries about her aging brain.

“When I can’t get a word, I think, uh oh, is this it?” Sister Barbara said.

Recently, investigators found a way to “stage” the disease during a period they call “pre-clinical Alzheimer’s.”

“The data suggests that, the pathology starts anywhere from 10 to 20 years before any sign of clinical symptoms,” Anne Fagan, PhD, Research Professor, Washington University in St. Louis, told Ivanhoe.

Researchers divide preclinical Alzheimer’s into three stages based on results from spinal fluid and imaging tests.

They studied 311 patients. The preclinical stages are based on biomarkers that indicates how much amyloid plaque and tangle-related proteins are found in the brain and whether or not patients eventually go on to show symptoms of memory decline.

“Once you get dementia, that is actually the end stage,” Dr. Fagan said.

Sister Barbara hopes the research will one day save others from the heartache she felt watching her parents fade away.

About 31 percent of the 311 patients studied fell into one of the stages. This percentage matched findings from autopsy studies, suggesting that Alzheimer’s starts long before symptoms develop.

Researchers believe patients with preclinical Alzheimer’s could be an important target for new therapies. Interestingly, the investigators found individuals with preclinical Alzheimer’s were six times more likely to die over the next decade, but they aren’t sure why.


BACKGROUND: Alzheimer’s disease is an irreparable brain condition that slowly affects brain functioning, eventually leading to dementia. The disease is named after Dr. Alois Alzheimer, who, in 1906, while studying the brain of a recently-deceased woman, found abnormal clumps and tangled bundles of fibers in her brain. These are now called amyloid plaques and neurofibrillary tangles, respectively, and make up two of the three main features of Alzheimer’s. The other is the breakdown of neurons, or connections between nerves, in the brain. Together, these three conditions affect key areas of the brain, including the hippocampus, responsible for memories. As more neurons run less efficiently, they eventually die, and brain tissue beings to shrink. (Source: http://www.nia.nih.gov/alzheimers/topics/alzheimers-basics?utm_source=ad_fact_sheet&utm_medium=web&utm_content=basics&utm_campaign=top_promo_box)

CAUSES: There is no known cause or cure for Alzheimer’s. Despite this, the most important factor to consider with Alzheimer’s is that it is a progressive disease. The biggest risk factor for the disease is age. Every five years after the age of 65, your risk of developing the disease doubles, and after age 85 the risk of the disease is 50 percent. Another risk factor is family history. Those with family members who had the disease have a higher risk, and those with multiple family members who had it are at an even higher risk. There is also a belief that head trauma may play a role in causing the disease later in life. Research is also growing relating to heart health and the disease, perhaps linking cardiovascular health and an increased risk of the disease. (Source: http://www.alz.org/alzheimers_disease_causes_risk_factors.asp)

NEW TECHNOLOGY: Starting in 2011, the National Institute on Aging together with Alzheimer’s Association, proposed a classification system for the disease. Researchers at Washington University studied the need for such a classification, and not only validated the system, but also developed another system to define what they called preclinical Alzheimer’s. Those with preclinical Alzheimer’s may seem cognitively normal, but have certain biomarkers believed to associated with Alzheimer’s later in life. Split into three stages, preclinical Alzheimer’s is the start of a potentially decades long process that ends with the presence of symptoms of Alzheimer’s or dementia. (Source: http://news.wustl.edu/news/Pages/25876.aspx)


Anne Fagan, PhD, Research Professor, Washington University in St. Louis, talks about staging Alzheimer’s.

How early can you detect Alzheimer’s?

Dr. Fagan: That is the question of the day. We don’t know exactly, however, we estimate, and the data suggests, that the underlying brain pathology start to develop anywhere from 10 to 20 years before any sign of clinical symptoms, any sign of memory loss or thinking problems.

What’s the earliest you’ve seen it?

Dr. Fagan: We have seen biomarker evidence of pathology in people as young as in their fifties. And these changes can be seen in cognitively normal people. We don’t know if or when they’re going to develop dementia. So that’s why longitudinal biomarker studies are going to be very informative, to be able to actually look within a person over time as they progress through their disease, to see how early we can detect their pathology, and what happens to these pathologic changes over time. We will be able to compare the changes we see in their cerebrospinal fluid with the imaging changes observed in their brain as well as when they start developing symptoms.

How does the brain physically change?

Dr. Fagan: In Alzheimer’s disease, it’s a very long process. We believe that it starts with accumulation of a peptide called the amyloid-beta peptide. In particular, there is a 42 form that is 42 amino acids long, so it’s called A-beta 42; levels of this increase in Alzheimer’s disease brains. But for most cases, we don’t know why it accumulates. In a small minority of cases, those with genetic mutations, we know that they are producing more of this protein.

Do you see that increase 20 years before symptoms?

Dr. Fagan: Yes we do. In the people who have genetic mutations,we see evidence of A-beta accumulation at least 20 years before they’re expected to develop dementia, which for people with mutations, is similar to their parent’s age of dementia onset.. A-beta is one of these proteins that will come together and aggregate into blobs, if you will, that can’t be cleared from the brain. So the higher levels that you have, the more likely it is to aggregate and to form what is called amyloid plaques, one of the hallmarks of Alzheimer’s disease.

So are there specific areas in the brain where these blobs develop? Can you tell me a specific region?

Dr. Fagan: The entorhinal cortex, for example, is one of the earlier places where pathology develops.

Does everyone with Alzheimer’s and dementia have a genetic mutation?

Dr. Fagan: No, actually, quite the contrary. Only about 1% of Alzheimer’s cases are estimated to be due to mutations. These are very rare. The mutations are in one of three genes: the amyloid precursor protein, called APP, which is the protein that gets clipped to make A-beta. The other two genes, presenilin 1 and presenilin 2, encode proteins that are part of the enzyme complex that clips APP into A-beta 42. Mutations in all of these genes lead to increased production of A-beta 42, so that’s why these folks are destined to get Alzheimer’s disease.

There are three stages that you talk about in your paper?

Dr. Fagan: Yes, a few years ago the Alzheimer’s Association in collaboration with the National Institute of Health put together three working groups of experts in the field, with the goal of making recommendations for better defining the various stages of Alzheimer’s disease as can be identified with biomarkers. After several conference calls and meetings to discuss the topic, each group wrote a paper to outline the various recommendations. I was a member of the working group on what is termed “preclinical” Alzheimer’s disease. Our paper focused on the hypothesized sequence of events that are taking place in the brain before any cognitive changes have developed. The paper that you’re talking about is the first test of the hypothesized stages, using biomarkers in cerebrospinal fluid.

So, do all three of these stages happen before?

Dr. Fagan: Yes, that’s why we call it the preclinical stage, meaning before clinical symptoms. These individuals do not have any symptoms. If they were to go to a neurologist and undergo all the usual cognitive testing, they would be defined as cognitively normal, not demented. However, individuals who are in this preclinical stage actually already have underlying Alzheimer’s pathology that we can detect by analyzing their cerebrospinal fluid or with specific neuroimaging tests. Post-mortem studies have shown that roughly 30% of cognitively normal individuals over the age of 65 who died from other causes and came to autopsy have enough Alzheimer’s pathology in their brain to warrant an AD diagnosis. When we evaluate biomarkers in cognitively normal elders while they’re still alive, we see the same percentage who have underlying pathology.

Why is it that those people don’t show the symptoms, and other people with probably less do show them?

Dr. Fagan: Well that’s a really good question. One possibility is that that these people who die with an abundance of Alzheimer’s pathology would have gone on to develop dementia had they lived long enough. That, obviously, is a hypothesis that we can never test. However, another possibility is that some people have protective factors that allow their brains to function normally even though they have abundant pathology. Scientists talk about brain reserve and cognitive reserve to describe such possible protective factors; brain reserve meaning their brain physiology itself is somehow “stronger”, perhaps having more or stronger connections between nerve cells that can withstand the damage caused by the Alzheimer’s plaques and tangles. Cognitive reserve, on the other hand, refers more to the ability to use what one has more efficiently and effectively. Lots of research is being conducted to find such protective factors. What we know for sure, though, is that the brain pathology of Alzheimer’s starts many years prior to any symptoms. In this way it’s similar to cancer. One can have a cancerous tumor that develops and grows over many years before any symptoms are noticed. When someone is found to have a cancerous tumor, they are diagnosed with cancer, regardless of whether they show symptoms yet. The Alzheimer’s field is evolving in a similar way with the acknowledgement of the underlying pathology as evidence of the presence of disease, the symptoms of which, namely dementia, may not develop for many years.

So these stages essentially happen like the higher the stage, the faster the disease progresses?

Dr. Fagan: Yes, if you define disease as the appearance of dementia symptoms. We hypothesize that in the first stage, aptly called Stage One, folks have biomarker evidence of amyloid pathology, plaques, in their brain. This evidence could be defined by amyloid imaging using PET scan, or quantification of A-beta 42 in the cerebrospinal fluid. People in Stage Two would have evidence of amyloid pathology, and also evidence of neurofibrillary tangles and neurodegeneration, as viewed by MRI or measurement of the tau protein, the major component of tangles, in cerebrospinal fluid, In both Stage One and Two, people show no signs of cognitive problems. Stage Three, however, is defined by the presence of amyloid plaques, tangles and neurodegeneration, and now also subtle cognitive impairments. People who are in Stage Three are likely to develop dementia sooner than those in Stages One or Two, which makes sense because the stages reflect a continuum.

If you have this evidence, is it sure that you’re going to get it?

Dr. Fagan: Another good question. We don’t know yet. That’s why these longitudinal studies, in which we are able to collect CSF and perform scans on individual people as they get older, are so important. Before these longitudinal studies started, all we could do was compare the biomarker pattern in somebody who is at age 45 with somebody else who is age 55 and infer the biomarker changes based on the comparison between the people of different ages.. We know that you’re more likely to see the degenerative changes in someone older than in someone younger. But again in order to understand the precise timing of these changes and how they relate to the development of cognitive symptoms, you will have to look at a given individual over many years, and that’s what we are now doing. It will take a while since the disease process is so long, but the results from these studies will be critical for our understanding of the normal course of the disease which is then critical for developing effective treatments. The goal is to be able identify people at very early, preclinical stages, so that treatments have the best chance of preserving their normal function. To date, treating people who already have the dementia symptoms has not worked, likely because so much of their brain has already deteriorated.

But it doesn’t necessarily mean from Stage One to Stage Three, it progresses quicker?

Dr. Fagan: We don’t know that yet. If you compare different people who are at the different proposed biomarker stages, people who are in Stage Three go on to dement faster than those who are in Stage One. What we don’t know yet is the timing of progression through the various preclinical stages, from One to Two to Three. That’s where the longitudinal studies come in.

It’s just after you get to Stage Three?

Dr. Fagan: Well, we don’t know that. We are looking at the data from individuals who are in Stage One, as we’ve defined it, and actually followed them over time to see how long it takes for them to get to Stage Two. And then again how long does it take them to get to Stage Three to get into Alzheimer’s dementia.

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