Updated Model Of Alzheimer's Disease Biomarker Sequence Supported And Refined With Clinical Evidence

Brain imaging and biomarker studies presented at AAIC 2013 show an increasingly detailed picture of Alzheimer's progression, starting with amyloid abnormalities and leading to memory and thinking symptoms.

BOSTON, July 16, 2013 /PRNewswire-USNewswire/ -- An updated model of the sequence of changes in the brains of people with Alzheimer's disease was reported today at the Alzheimer's Association International Conference® 2013 (AAIC® 2013) in Boston.

In the hypothetical model of Alzheimer's progression over time, now refined with several years of clinical evidence, biological markers of changes in beta-amyloid protein become abnormal first, then biomarkers of the degeneration and death of brain cells, followed by dementia symptoms.

Two other studies presented today support the updated Alzheimer's model by demonstrating that abnormal changes in beta-amyloid protein precede dementia symptoms by years or even decades and then begin to plateau by the time cognitive changes are observable.

"Having a clearer and more accurate portrayal of the sequence of biomarker changes in Alzheimer's disease is extremely valuable," said Maria Carrillo, Ph.D., Alzheimer's Association vice president of medical and scientific relations. "For example, it will enable us to better design treatment studies — enhancing the selection of study participants, targeting the proper time during the disease to give the treatment and measuring treatment effects."

"These three reports underscore the importance of Alzheimer's disease biomarker studies, and also begin to show us when those biomarkers might be potential targets for therapy," said Carrillo. "It is when biomarkers are at their most dynamic and changeable that they can best be measured and perhaps modified through treatment."

Research confirms hypothesis that amyloid abnormalities precede other Alzheimer's indicators; Updated biomarker model is presented

In 2010, Clifford Jack, Jr., M.D., of the Mayo Clinic College of Medicine and colleagues proposed a hypothetical model of the sequence of change in Alzheimer's disease biomarkers and related them to each other and to the emergence and progression of outward dementia symptoms. In that model, beta-amyloid markers become abnormal first, then biomarkers of neurodegeneration, followed by clinical symptoms.

At AAIC 2013, Jack and colleagues report that they have updated the model based on research evidence that has accumulated since the original publication that supports the original model's general outlines, yet also challenges some its assumptions. In the updated model:

• Biomarkers are ordered somewhat differently.
• The curves in the chart that represent biomarker change now have different shapes.
• There is more overlap between changes in biomarkers.
• Changes in biomarkers are described in relation to time, not to severity of symptoms.
• Cognitive outcome is expressed as a range of possible values, reflecting the fact that individuals respond to Alzheimer's pathology uniquely.

"One of the most important criticisms of our original model was that it failed to account for abnormalities in tau protein in the brain that are a nearly universal feature of aging," said Jack. "Our model now distinguishes between biomarkers of Alzheimer's disease pathology and biomarkers of normal aging."

According to Jack, the updated change in biomarker ordering is as follows:

• Change in a type of beta-amyloid known as Aβ42 in cerebrospinal fluid (CSF) is now positioned slightly before images of amyloid buildup assessed by a PET scan.
• This is then followed by changes in tau measured in CSF.
• Brain volume measured by FDG PET and by MRI are drawn coincidentally to indicate that they are the last biomarkers to become abnormal but also that they track most closely with progressive cognitive impairment.

Amyloid abnormalities begin many years before clinical symptoms appear

The deposition of beta-amyloid in the brains of people with Alzheimer's begins years or even decades before cognitive changes become apparent, according to evidence from a clinical study reported at AAIC 2013 by Victor Villemagne, M.D., of the Florey Institute of Neuroscience and Mental Health at the University of Melbourne and colleagues.

Two-hundred-six (206) participants — 151 healthy controls, 36 with mild cognitive impairment (MCI) and 19 with Alzheimer's disease — in the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Ageing were evaluated at the beginning of the study and every 18 months for an average of 4.1 years.

Using data from neuropsychological examinations, MRI and PET scans, the scientists projected that, on average, it takes more than 10 years from being free of beta-amyloid to reach a level that is considered abnormal. From there they projected that it takes, on average, about 19 years to reach the levels usually found in people with Alzheimer's disease. At that point in the disease, beta amyloid deposition starts to slow, trending towards a plateau. Changes in the brain's memory center — the hippocampus — appear about five years before onset of full-blown dementia, and memory changes about three years before.

Significantly, the researchers found that amyloid deposition rates among the study participants were very similar to projected rates among patients with dominantly inherited Alzheimer's disease, a rare genetic form of the disease which usually strikes before age 60. "This suggests that similar basic mechanisms are at play, irrespective of dissimilar pathogenic pathways," Villemagne said.

"Beta-amyloid deposition in Alzheimer's disease is a slow and protracted process, likely to extend for more than two decades. The results of this and other longitudinal studies will allow us to better understand how changes in beta-amyloid in the brain relate to changes in cognition and other Alzheimer's biomarkers. This will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness," Villemagne concluded.

Study confirms that abnormal beta-amyloid begins cascade of Alzheimer's pathology

According to new NIA/Alzheimer's Association diagnostic guidelines, Alzheimer's disease can be subdivided into three stages — asymptomatic Alzheimer's, MCI due to Alzheimer's and dementia due to Alzheimer's. The rates of neuropathological, cognitive and functional decline in each of these stages is not fully understood, and this limits clinical trial design, in particular in the predementia stages.

Daniela Bertens of VU University Medical Center, Amsterdam, Netherlands, and colleagues investigated 284 subjects with abnormal beta-amyloid from the Alzheimer's Disease Neuroimaging Initiative, using amyloid levels in cerebrospinal fluid (CSF) as a diagnostic marker and followed them for four years. The study included 44 subjects with asymptomatic Alzheimer's, 148 with Alzheimer's-related MCI and 92 with Alzheimer's dementia, plus a control group of cognitively normal subjects with normal amyloid levels. Participants were measured at regular intervals for biomarkers of amyloid, neuronal dysfunction and brain atrophy using CSF tests and brain imaging, as well as for cognition, using standard clinical scales and tests.

• Participants with asymptomatic Alzheimer's started the study with impairment of beta-amyloid, tau and executive functioning. During the follow up period, ventricular volume increased and they declined on functional impairments in daily life, but not on FDG-PET imaging, other measures of brain atrophy and other cognitive measures.
• Participants with MCI-AD had impairment on all markers at the start of the study, except on whole brain volume. They showed declines in tau in CSF, FDG-PET, atrophy markers and cognition.
• Participants with dementia also had impairment on all biomarkers and cognitive markers at the start of the study. During the four years, they declined on FDG-PET, atrophy markers and cognition.

The researchers found that the rate of decline on beta-amyloid and tau decreased from the preclinical stage to the dementia stage. On the other hand, the rate of decline on FDG-PET, atrophy markers and cognition increased as Alzheimer's disease progressed.

"The observed rates of decline are in line with the amyloid cascade hypothesis," said Bertens. "Our findings give insight into the progression of Alzheimer's disease and therefore might be useful in the design of treatment studies. Some markers will be useful for the selection of study subjects, while other markers can be used to measure disease progression and treatment effects."

About AAIC
The Alzheimer's Association International Conference (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders.  As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer's Association
The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research; to provide and enhance care and support for all affected; and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800.272.3900.

SOURCE Alzheimer's Association