Biomarkers Track Alzheimer's Progression

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Research in 2013 offered new insights into the trajectory of the Alzheimer’s disease process. New evidence suggests that cellular changes associated with the disease begin years—even decades—before people first show clinical symptoms of memory loss or cognitive difficulties. Increasingly, researchers are employing biomarkers—specific proteins in blood or cerebrospinal fluid (CSF) or imaging of brain structure and function—to measure risk for Alzheimer’s, even in symptom-free people. Biomarkers are used in research settings to track the onset and progression of the disease as well as the effectiveness of promising interventions.

The findings described below highlight ways in which biomarkers are advancing our understanding of Alzheimer’s disease.


View a short video of NIA Division of Neuroscience Director Dr. Neil Buckholtz discussing the use of biomarkers:

An Evolving Alzheimer’s Model

In 2010, experts at the Mayo Clinic, Rochester, MN, first proposed a model suggesting that Alzheimer’s biomarkers emerge at different stages of the disease (Jack et al., 2010). The model proposed markers that tracked disease onset and progression: changes in levels of amyloid protein in the brain and CSF were the first sign of disease onset, followed by changes in the level of the protein tau in CSF, changes in brain structure, and, finally, memory loss and other clinical symptoms. Subsequent research has generally supported this model, with one key exception: the relationship of abnormal tau to other biomarkers and disease progression was puzzling. In people with Alzheimer’s disease, tau abnormalities in CSF become detectable only after brain amyloid accumulation has begun. However, autopsy analyses have detected abnormal tau in the brains of most middle-aged people, almost always before amyloid markers change.

In 2013, Jack and colleagues from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) revised the model to show that tau changes begin before amyloid changes, but that amyloid changes occur faster and are the first ones detectable (Jack, Knopman et al., 2013). Like many other researchers, they suggest that beta-amyloid accumulates due to its overproduction and/or underclearance. Jack and his team further suggest that beta-amyloid, rather than tau, may initiate disease onset. One hypothesis now being considered is that amyloid pathology exacerbates typical, age-related accumulation of abnormal tau, leading to the severe tau pathology seen in people with Alzheimer’s.

Alzheimer’s Disease Progression

This line graph illustrates how Alzheimer’s disease-related changes may occur in the brain long before symptoms of cognitive decline first appear in people with mild cognitive impairment, or MCI. The horizontal axis on the graph represents time, and the vertical axis represents the severity of disease. The graph shows six lines that curve up gradually from different points along the horizontal axis. The first four curved lines represent specific markers as they appear sequentially over time as the disease progresses. The fifth and sixth curved lines represent cognitive impairment in individuals at high and low risk of developing Alzheimer’s. In general, as time passes, the severity of disease, as detected by markers, increases. A horizontal line slightly above and parallel to the time axis shows the point in time when each marker can be initially detected. The first two curved lines, for C S F amyloid-beta 42 and amyloid P E T imaging, are adjacent, both rising slowly at first, then rapidly in the early presymptomatic stage, and then more gradually as disease severity rises. The third line, for CSF tau, is the first to appear on the time axis and crosses the first two lines early on the time axis, meaning it is detectable later than amyloid. The fourth line, for M R I plus F D G-P E T imaging, rises steadily over time as disease severity increases. The fifth and sixth lines, both of which represent cognitive impairment, also rise steadily and show that high-risk individuals become impaired sooner than low-risk individuals. The area between these two lines is shaded to show the range of impairment severity, from normal to M C I to dementia. All six lines meet at a point in the upper right corner of the diagram, representing the furthest point in time and maximum disease severity.
This diagram illustrates how Alzheimer’s disease-related changes may occur in the brain long before symptoms of cognitive decline first appear in people with mild cognitive impairment (MCI). The curves represent the sequence in which specific markers may play a role as people progress from normal cognition, to MCI, and finally, to dementia. This model suggests that in typical late-onset Alzheimer’s disease, tau changes may begin before amyloid changes, but that amyloid changes occur faster and are usually the first ones detectable. It also suggests that amyloid accumulation drives progression of tau and other downstream events in the disorder (Jack, Knopman et al., 2013).

Toxic Changes Build Slowly in Alzheimer’s

Researchers at the Mayo Clinic, Rochester, MN, identified a window of several years during which treatments targeting beta-amyloid buildup might be most effective (Jack, Wiste et al., 2013). The researchers used positron emission tomography (PET) scans to study beta-amyloid accumulation in the brains of 260 people age 70 to 92. At the start of the study, 22 percent of the volunteers had mild cognitive impairment (MCI) or Alzheimer’s, and the rest were cognitively normal. The PET images revealed that beta-amyloid levels built up slowly over an average of 15 years, then reached a plateau. These results suggest that there may be a long window of opportunity for future treatments that slow beta-amyloid buildup.

Biomarkers Predict Alzheimer’s Years in Advance

Brain imaging and CSF biomarker testing may help predict which cognitively normal older people will develop Alzheimer’s disease years before cognitive symptoms appear. Researchers at the Washington University School of Medicine in St. Louis investigated four biomarkers: beta-amyloid deposits in the brain measured by PET scans and CSF levels of beta-amyloid, tau, and phosphorylated tau (the more toxic form of tau). They determined whether or not these biomarkers influenced cognition in 201 dementia-free volunteers, ages 45 to 88, for an average of 3.7 years and in some cases as long as 7.5 years (Roe et al., 2013).

Fourteen percent of the volunteers developed memory loss and other signs of cognitive impairment during the study. Significantly, biomarker levels successfully predicted who was at risk for cognitive decline and how soon impairment would develop. The four biomarkers all performed equally well in predicting disease development, and their predictive value was improved by adding demographic data to the analysis: older participants, men, and African Americans who developed cognitive impairment did so faster than volunteers who were younger, female, or white. The findings point to the power of biomarkers as predictors of disease risk in early, symptom-free stages of Alzheimer’s disease.

Testing Brain Biomarkers in Clinical Settings

In 2011 the National Institute on Aging/Alzheimer’s Association Diagnostic Guidelines for Alzheimer’s Disease redefined the full spectrum of the disease as it gradually changes over many years, from earliest preclinical stages of the disease to MCI to dementia due to Alzheimer’s pathology. Importantly, the guidelines addressed the use in research settings of imaging and biomarkers in blood and CSF that may help determine whether changes in brain and body fluids are caused by Alzheimer’s disease.

Researchers at the Mayo Clinic, Rochester, MN, wanted to test the biomarker guidelines in a community setting to see if they can predict whether a person with MCI will progress to Alzheimer’s dementia (Petersen, 2013). They looked for beta-amyloid deposits using Pittsburgh Compound B (PiB) PET scans and Alzheimer’s-related brain neurodegenerative changes using magnetic resonance imaging or fluorodeoxyglucose PET scans. All 154 volunteers, age 70 to 89, had been diagnosed with MCI based on their cognitive symptoms.

The pattern of biomarkers in this group was similar to that previously seen in ADNI research participants: 43 percent showed both beta-amyloid accumulation and neurodegeneration, 14 percent had amyloid-beta accumulation only, 29 percent had neurodegeneration only, and 14 percent showed neither marker. This study supports the validity of using biomarkers in the clinical diagnosis of MCI.

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