Blood Biomarkers for AD Detected Years Before Symptoms

June 26, 2015

Abnormal levels of several proteins thought to play a role in Alzheimer's disease have been detected in blood samples from individuals that were taken many years before they developed symptoms of the condition.

This observation has led to suggestions that these proteins could be useful biomarkers to identify people at risk for Alzheimer's and also as surrogate markers of positive responses to drug therapy for the condition.

"We retrospectively looked back and found blood samples for patients with Alzheimer's from many years previously, and we have found raised levels of several proteins implicated in Alzheimer's in these samples taken many years before the patient developed symptoms," lead author, Edward J. Goetzl, MD, UCSF Medical Center, San Francisco, commented to Medscape Medical News.

The findings are reported in a study published online in Neurology on June 10.


The hope is that these findings will lead to biomarkers for Alzheimer's that can be detected many years before the disease develops. Dr Goetzl explains: "If we screen people in their 50s we should be able to pick out the ones with abnormal levels of these proteins and we believe these individuals are at high risk of developing Alzheimer's. We could then try to intervene at this very early stage before symptoms have started to see if we can prevent or delay the onset of the condition."

"Our results also show us that there are major abnormalities in how these proteins function in brain cells, which could potentially provide a new target for treatments," he added.

For the study, the researchers analyzed levels of several key proteins in exosomes contained in blood samples taken from patients with Alzheimer's disease and controls.

Dr Goetzl explained that some of the toxic proteins involved in Alzheimer's disease are taken into lysosomes in the central nervous system, but often they cannot be degraded and are eventually secreted into exosomes found in the blood. "We therefore tested the levels of these proteins in the exosomes in plasma taken from blood samples of patients with Alzheimer's disease."

The current Neurology paper describes two studies. The first had a cross-sectional design in which levels of these proteins were analyzed from blood samples from 26 patients with Alzheimer's disease and 16 patients with frontotemporal dementia and compared with samples from controls. In the second study, blood samples taken from 20 patients with Alzheimer's up 10 years before they developed symptoms were analyzed and compared with samples from controls.

Results showed that for the cross sectional study, mean exosomal levels of three proteins — cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated protein — were significantly higher in patients with Alzheimer's than in controls.

Levels of heat-shock protein 70 were significantly lower in patients with Alzheimer's disease than in controls. Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with Alzheimer's than for patients with frontotemporal dementia. Stepwise discriminant modeling of the protein levels correctly classified 100% of patients with Alzheimer's.

In the longitudinal study, exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of Alzheimer's disease.

Dr Goetzl commented: "We decided to look at functional clusters of proteins rather than the proteonomic approach, which simply identifies proteins which may be increased in Alzheimer's but do not have a clear relationship to the pathophysiology of the condition. We wanted to look at proteins we knew about — those that we think have a directly pathogenic role. All these proteins have been implicated in Alzheimer's in animal studies and/or postmortem analyses."

He added that they now have data on around 100 patients, with some samples taken up to 20 years before Alzheimer's symptoms developed. "The ability to detect abnormal levels of these proteins in patients with Alzheimer's is close to 100%," he said.

Dr Goetzl noted that prospective studies are now underway to try to confirm these results. "These involve taking blood samples and testing for these proteins and then following individuals for several years to see whether the blood tests can predict who goes on to develop Alzheimer's."

Two such studies are underway: one involving cognitively normal individuals in their 70s at the time of initial blood testing and the other focusing on patients with mild cognitive impairment at baseline.

Other studies are underway to evaluate whether these blood tests could be a surrogate marker for response to new Alzheimer's drug therapies.

The current study was supported by the National Institute on Aging and NanoSomiX Inc, a California-based biotechnology company that provided a grant for method development. Dr Goetzl has filed a provisional application with the US Patent Office for the platform and methods described in this report; he was a founder of NanoSomiX but now only receives support from them for purchasing laboratory supplies.

Neurology. Published online June 10, 2015. Abstract


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