Biomarkers Offer Clues For Earlier Alzheimer's Diagnosis

PARIS – Two studies highlighted at the Alzheimer’s Association International Conference 2011 underscored the increasing focus on improving and promoting early diagnosis of Alzheimer’s disease using biomarkers.

One study focused on a potential blood-based predictor of neocortical amyloid burden – a known predictor of progression to Alzheimer’s disease – and suggests there is hope for the development of a low-cost and noninvasive screening tool.

The other study delved deeper into the value of cerebrospinal fluid biomarkers, which are already known to be associated with mild cognitive impairment leading to Alzheimer’s disease. In it, researchers analyzed just how early those markers – including amyloid beta 42, total tau, and phosphorylated tau (p-tau) – become useful as predictors of disease onset, which have particular implications for patient selection in ongoing and future clinical trials.

In the blood biomarker study, a panel of nine known blood-based markers of Alzheimer’s disease was found to have high sensitivity and specificity for identifying key levels of amyloid in the brain, suggesting that an effective and economical screening test for early identification of individuals at risk for the disease is within reach, Samantha Burnham, Ph.D., reported during a press briefing at the conference.

Currently, neocortical amyloid burden is assessable only by expensive positron emission tomography, which requires radiotracers such as Pittsburgh Compound B (PiB) that are not widely available, and by invasive cerebrospinal fluid (CSF) evaluation for markers that have been shown to correlate with neocortical amyloid burden, said Dr. Burnham of the Commonwealth Scientific and Industrial Research Organization (CSIRO), Perth, Australia.

She and her colleagues used 273 samples from patients with baseline blood and PiB-PET measurements from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study to build a model based on the nine blood-based markers (including amyloid beta 42, apolipoprotein E gene status, and cortisol levels) to estimate the amount of deposited amyloid in the brain. The panel of markers had 83% sensitivity and 85% specificity for identifying the level of amyloid deemed to indicate the risk of Alzheimer’s, she said.

In 817 nonimaged AIBL study participants, the researchers used the panel to predict if the percentage of patients with a high neocortical amyloid burden matched prior findings in the literature in regard to clinical diagnosis. Overall, 34% of healthy controls, 87% of individuals with mild cognitive impairment, and 100% of Alzheimer’s disease patients had a high burden, Dr. Burnham said.

Additionally, the investigators sought to validate the panel of markers in 74 subjects from the Alzheimer’s Disease Neuroimaging Initiative. In this validation study, measurements for two of the markers from the panel were unavailable, and the sensitivity and specificity were slightly lower, but still impressive at 76% for both. Furthermore, when the samples from the AIBL study were reassessed without the two missing markers, the sensitivity and specificity dropped to 74%, a level comparable to that seen in the validation study, suggesting that the accuracy in the validation study might have been even greater if all nine markers were available, she noted.

Because neocortical amyloid burden predicts progression to Alzheimer’s disease, and because the model used in this study accurately predicts neocortical amyloid burden, it appears likely that the findings will lead to the development of a useful, affordable screening test for the early identification of individuals at risk for developing Alzheimer’s disease, she concluded.

"This is a good start toward having a blood-based diagnosis," she said.

The development of such a diagnostic test is a long sought after goal among Alzheimer’s researchers and clinicians, which is why Dr. Burnham’s data were among the findings highlighted at the conference, according to Dr. Reisa Sperling of the department of neurology at Harvard Medical School, Boston, and a member of the panel of investigators at the press briefing.

"We all want a simpler test – we all want a blood test, an eye test, a skin test – something where it would be less expensive and less invasive," she said, commenting on the value of the findings.

The role of amyloid load is established, and using PiB-PET imaging as a marker of amyloid as the new gold standard with which to evaluate the usefulness of biomarkers, as was done in this study, is "really a wonderful way to use these biomarkers to look for simpler tests such as a blood test," she said.

In the study of cerebrospinal fluid biomarkers, Dr. Henrik Zetterberg presented data indicating that baseline levels of amyloid beta 42 and tau (both total and phosphorylated) are highly predictive of Alzheimer’s disease at up to 10 years prior to the onset of dementia.

"These are by far the best-studied [biomarkers], and show the greatest differences with regard to Alzheimer’s disease, and also they have the most direct link to the neuropathology of Alzheimer’s disease," said Dr. Zetterberg, professor and group leader of the research team on neurochemical pathogenesis and diagnostics at the University of Gothenburg (Sweden).

Although more biomarkers will most likely be identified in the future, these CSF proteins have shown the most consistent results across studies thus far, and they have high sensitivity and specificity for Alzheimer’s disease.

"The basic question we were trying to address is actually, ‘When do these biomarkers turn positive? When can we detect Alzheimer’s disease by measuring these proteins?’ " he said.

In his study of 137 patients with mild cognitive impairment, the levels of amyloid beta 42 were already fully decreased to levels that indicate a high risk of developing Alzheimer’s dementia in 5-10 years.

During nearly 10 years of follow-up, 54% of subjects developed Alzheimer’s disease and 16% developed other forms of dementia. Baseline amyloid beta 42 levels in those who developed Alzheimer’s disease were significantly reduced, compared with nonconverters, and total and p-tau levels were elevated, Dr. Zetterberg said.

Furthermore, the amyloid beta 42 levels were equally reduced at baseline in early and later converters (those who converted within 0-5 years, and those who converted between 5 and 10 years, respectively), while CSF levels of total and p-tau were significantly higher in the early converters, compared with the later converters.

A ratio of baseline levels of amyloid beta 42 to p-tau predicted development of Alzheimer’s disease within the study period with a sensitivity of 88% and a specificity of 90%, he said.

"So the conclusion might be that Alzheimer’s disease can actually be accurately diagnosed 5-10 years before onset of dementia," he said.

The findings support the hypothesis that altered amyloid beta metabolism precedes tau-related pathology and neuronal degeneration. These CSF biomarkers may be useful for selecting patients for early intervention in clinical trials, as well as for monitoring treatment effects, Dr. Zetterberg concluded.

Dr. Burnham and Dr. Zetterberg said they had no relevant financial disclosures.

PARIS – Two studies highlighted at the Alzheimer’s Association International Conference 2011 underscored the increasing focus on improving and promoting early diagnosis of Alzheimer’s disease using biomarkers.

One study focused on a potential blood-based predictor of neocortical amyloid burden – a known predictor of progression to Alzheimer’s disease – and suggests there is hope for the development of a low-cost and noninvasive screening tool.

The other study delved deeper into the value of cerebrospinal fluid biomarkers, which are already known to be associated with mild cognitive impairment leading to Alzheimer’s disease. In it, researchers analyzed just how early those markers – including amyloid beta 42, total tau, and phosphorylated tau (p-tau) – become useful as predictors of disease onset, which have particular implications for patient selection in ongoing and future clinical trials.

In the blood biomarker study, a panel of nine known blood-based markers of Alzheimer’s disease was found to have high sensitivity and specificity for identifying key levels of amyloid in the brain, suggesting that an effective and economical screening test for early identification of individuals at risk for the disease is within reach, Samantha Burnham, Ph.D., reported during a press briefing at the conference.

Currently, neocortical amyloid burden is assessable only by expensive positron emission tomography, which requires radiotracers such as Pittsburgh Compound B (PiB) that are not widely available, and by invasive cerebrospinal fluid (CSF) evaluation for markers that have been shown to correlate with neocortical amyloid burden, said Dr. Burnham of the Commonwealth Scientific and Industrial Research Organization (CSIRO), Perth, Australia.

She and her colleagues used 273 samples from patients with baseline blood and PiB-PET measurements from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study to build a model based on the nine blood-based markers (including amyloid beta 42, apolipoprotein E gene status, and cortisol levels) to estimate the amount of deposited amyloid in the brain. The panel of markers had 83% sensitivity and 85% specificity for identifying the level of amyloid deemed to indicate the risk of Alzheimer’s, she said.

In 817 nonimaged AIBL study participants, the researchers used the panel to predict if the percentage of patients with a high neocortical amyloid burden matched prior findings in the literature in regard to clinical diagnosis. Overall, 34% of healthy controls, 87% of individuals with mild cognitive impairment, and 100% of Alzheimer’s disease patients had a high burden, Dr. Burnham said.

Additionally, the investigators sought to validate the panel of markers in 74 subjects from the Alzheimer’s Disease Neuroimaging Initiative. In this validation study, measurements for two of the markers from the panel were unavailable, and the sensitivity and specificity were slightly lower, but still impressive at 76% for both. Furthermore, when the samples from the AIBL study were reassessed without the two missing markers, the sensitivity and specificity dropped to 74%, a level comparable to that seen in the validation study, suggesting that the accuracy in the validation study might have been even greater if all nine markers were available, she noted.

Because neocortical amyloid burden predicts progression to Alzheimer’s disease, and because the model used in this study accurately predicts neocortical amyloid burden, it appears likely that the findings will lead to the development of a useful, affordable screening test for the early identification of individuals at risk for developing Alzheimer’s disease, she concluded.

"This is a good start toward having a blood-based diagnosis," she said.

The development of such a diagnostic test is a long sought after goal among Alzheimer’s researchers and clinicians, which is why Dr. Burnham’s data were among the findings highlighted at the conference, according to Dr. Reisa Sperling of the department of neurology at Harvard Medical School, Boston, and a member of the panel of investigators at the press briefing.

"We all want a simpler test – we all want a blood test, an eye test, a skin test – something where it would be less expensive and less invasive," she said, commenting on the value of the findings.

The role of amyloid load is established, and using PiB-PET imaging as a marker of amyloid as the new gold standard with which to evaluate the usefulness of biomarkers, as was done in this study, is "really a wonderful way to use these biomarkers to look for simpler tests such as a blood test," she said.

In the study of cerebrospinal fluid biomarkers, Dr. Henrik Zetterberg presented data indicating that baseline levels of amyloid beta 42 and tau (both total and phosphorylated) are highly predictive of Alzheimer’s disease at up to 10 years prior to the onset of dementia.

"These are by far the best-studied [biomarkers], and show the greatest differences with regard to Alzheimer’s disease, and also they have the most direct link to the neuropathology of Alzheimer’s disease," said Dr. Zetterberg, professor and group leader of the research team on neurochemical pathogenesis and diagnostics at the University of Gothenburg (Sweden).

Although more biomarkers will most likely be identified in the future, these CSF proteins have shown the most consistent results across studies thus far, and they have high sensitivity and specificity for Alzheimer’s disease.

"The basic question we were trying to address is actually, ‘When do these biomarkers turn positive? When can we detect Alzheimer’s disease by measuring these proteins?’ " he said.

In his study of 137 patients with mild cognitive impairment, the levels of amyloid beta 42 were already fully decreased to levels that indicate a high risk of developing Alzheimer’s dementia in 5-10 years.

During nearly 10 years of follow-up, 54% of subjects developed Alzheimer’s disease and 16% developed other forms of dementia. Baseline amyloid beta 42 levels in those who developed Alzheimer’s disease were significantly reduced, compared with nonconverters, and total and p-tau levels were elevated, Dr. Zetterberg said.

Furthermore, the amyloid beta 42 levels were equally reduced at baseline in early and later converters (those who converted within 0-5 years, and those who converted between 5 and 10 years, respectively), while CSF levels of total and p-tau were significantly higher in the early converters, compared with the later converters.

A ratio of baseline levels of amyloid beta 42 to p-tau predicted development of Alzheimer’s disease within the study period with a sensitivity of 88% and a specificity of 90%, he said.

"So the conclusion might be that Alzheimer’s disease can actually be accurately diagnosed 5-10 years before onset of dementia," he said.

The findings support the hypothesis that altered amyloid beta metabolism precedes tau-related pathology and neuronal degeneration. These CSF biomarkers may be useful for selecting patients for early intervention in clinical trials, as well as for monitoring treatment effects, Dr. Zetterberg concluded.

Dr. Burnham and Dr. Zetterberg said they had no relevant financial disclosures.

PARIS – Two studies highlighted at the Alzheimer’s Association International Conference 2011 underscored the increasing focus on improving and promoting early diagnosis of Alzheimer’s disease using biomarkers.

One study focused on a potential blood-based predictor of neocortical amyloid burden – a known predictor of progression to Alzheimer’s disease – and suggests there is hope for the development of a low-cost and noninvasive screening tool.

The other study delved deeper into the value of cerebrospinal fluid biomarkers, which are already known to be associated with mild cognitive impairment leading to Alzheimer’s disease. In it, researchers analyzed just how early those markers – including amyloid beta 42, total tau, and phosphorylated tau (p-tau) – become useful as predictors of disease onset, which have particular implications for patient selection in ongoing and future clinical trials.

In the blood biomarker study, a panel of nine known blood-based markers of Alzheimer’s disease was found to have high sensitivity and specificity for identifying key levels of amyloid in the brain, suggesting that an effective and economical screening test for early identification of individuals at risk for the disease is within reach, Samantha Burnham, Ph.D., reported during a press briefing at the conference.

Currently, neocortical amyloid burden is assessable only by expensive positron emission tomography, which requires radiotracers such as Pittsburgh Compound B (PiB) that are not widely available, and by invasive cerebrospinal fluid (CSF) evaluation for markers that have been shown to correlate with neocortical amyloid burden, said Dr. Burnham of the Commonwealth Scientific and Industrial Research Organization (CSIRO), Perth, Australia.

She and her colleagues used 273 samples from patients with baseline blood and PiB-PET measurements from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study to build a model based on the nine blood-based markers (including amyloid beta 42, apolipoprotein E gene status, and cortisol levels) to estimate the amount of deposited amyloid in the brain. The panel of markers had 83% sensitivity and 85% specificity for identifying the level of amyloid deemed to indicate the risk of Alzheimer’s, she said.

In 817 nonimaged AIBL study participants, the researchers used the panel to predict if the percentage of patients with a high neocortical amyloid burden matched prior findings in the literature in regard to clinical diagnosis. Overall, 34% of healthy controls, 87% of individuals with mild cognitive impairment, and 100% of Alzheimer’s disease patients had a high burden, Dr. Burnham said.

Additionally, the investigators sought to validate the panel of markers in 74 subjects from the Alzheimer’s Disease Neuroimaging Initiative. In this validation study, measurements for two of the markers from the panel were unavailable, and the sensitivity and specificity were slightly lower, but still impressive at 76% for both. Furthermore, when the samples from the AIBL study were reassessed without the two missing markers, the sensitivity and specificity dropped to 74%, a level comparable to that seen in the validation study, suggesting that the accuracy in the validation study might have been even greater if all nine markers were available, she noted.

Because neocortical amyloid burden predicts progression to Alzheimer’s disease, and because the model used in this study accurately predicts neocortical amyloid burden, it appears likely that the findings will lead to the development of a useful, affordable screening test for the early identification of individuals at risk for developing Alzheimer’s disease, she concluded.

"This is a good start toward having a blood-based diagnosis," she said.

The development of such a diagnostic test is a long sought after goal among Alzheimer’s researchers and clinicians, which is why Dr. Burnham’s data were among the findings highlighted at the conference, according to Dr. Reisa Sperling of the department of neurology at Harvard Medical School, Boston, and a member of the panel of investigators at the press briefing.

"We all want a simpler test – we all want a blood test, an eye test, a skin test – something where it would be less expensive and less invasive," she said, commenting on the value of the findings.

The role of amyloid load is established, and using PiB-PET imaging as a marker of amyloid as the new gold standard with which to evaluate the usefulness of biomarkers, as was done in this study, is "really a wonderful way to use these biomarkers to look for simpler tests such as a blood test," she said.

In the study of cerebrospinal fluid biomarkers, Dr. Henrik Zetterberg presented data indicating that baseline levels of amyloid beta 42 and tau (both total and phosphorylated) are highly predictive of Alzheimer’s disease at up to 10 years prior to the onset of dementia.

"These are by far the best-studied [biomarkers], and show the greatest differences with regard to Alzheimer’s disease, and also they have the most direct link to the neuropathology of Alzheimer’s disease," said Dr. Zetterberg, professor and group leader of the research team on neurochemical pathogenesis and diagnostics at the University of Gothenburg (Sweden).

Although more biomarkers will most likely be identified in the future, these CSF proteins have shown the most consistent results across studies thus far, and they have high sensitivity and specificity for Alzheimer’s disease.

"The basic question we were trying to address is actually, ‘When do these biomarkers turn positive? When can we detect Alzheimer’s disease by measuring these proteins?’ " he said.

In his study of 137 patients with mild cognitive impairment, the levels of amyloid beta 42 were already fully decreased to levels that indicate a high risk of developing Alzheimer’s dementia in 5-10 years.

During nearly 10 years of follow-up, 54% of subjects developed Alzheimer’s disease and 16% developed other forms of dementia. Baseline amyloid beta 42 levels in those who developed Alzheimer’s disease were significantly reduced, compared with nonconverters, and total and p-tau levels were elevated, Dr. Zetterberg said.

Furthermore, the amyloid beta 42 levels were equally reduced at baseline in early and later converters (those who converted within 0-5 years, and those who converted between 5 and 10 years, respectively), while CSF levels of total and p-tau were significantly higher in the early converters, compared with the later converters.

A ratio of baseline levels of amyloid beta 42 to p-tau predicted development of Alzheimer’s disease within the study period with a sensitivity of 88% and a specificity of 90%, he said.

"So the conclusion might be that Alzheimer’s disease can actually be accurately diagnosed 5-10 years before onset of dementia," he said.

The findings support the hypothesis that altered amyloid beta metabolism precedes tau-related pathology and neuronal degeneration. These CSF biomarkers may be useful for selecting patients for early intervention in clinical trials, as well as for monitoring treatment effects, Dr. Zetterberg concluded.

Dr. Burnham and Dr. Zetterberg said they had no relevant financial disclosures.