Alzheimer's Association: International Conference on Alzheimer's Disease (ICAD 2011)

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.

PARIS – Concerns that individuals with early symptoms of Alzheimer’s disease may avoid or delay seeking medical care because of a perceived lack of effective therapies or other worries may be largely unfounded.

In fact, expectations about just what can be done for those who receive an Alzheimer’s disease diagnosis may be too high, according to the findings of a recent five-country telephone survey presented at the Alzheimer’s Association International Conference.

In all, 85%-95% of the 2,678 adults aged 18 and older from France, Germany, Poland, Spain, and the United States said they would see a doctor if they were experiencing confusion or memory loss, 52%-71% said they believe that an effective treatment currently exists or will soon be available, and 38%-59% said they believe a reliable test for early Alzheimer’s disease currently exists, Robert Blendon, Sc.D., reported during a press briefing at the conference.

If anything, the findings suggest that clinicians will have to temper the expectations of those who come in seeking answers about their symptoms, said Dr. Blendon, professor of health policy and political analysis at the Harvard School of Public Health, Boston.

Alzheimer’s disease organizations in many countries, including the United States, are working to promote early diagnosis. One purpose of this random telephone survey, which was a joint project of the Harvard School of Public Health and Alzheimer Europe, was to determine if the public would respond to such campaigns. The investigators also wanted to elucidate cultural differences regarding views on Alzheimer’s disease, he said.

In addition to the somewhat surprising responses regarding whether or not they would seek a diagnosis, the majority (51%-78%) of respondents from each country also said that if an accurate preclinical diagnostic test existed, they would seek a diagnosis.

Respondents expressed deep overall concerns about developing Alzheimer’s disease. In four of the five countries, Alzheimer’s ranked second after cancer as the most feared disease. In Poland, it ranked third after cancer and heart disease.

More than half of the respondents from each of the countries (54%-77%) said they had known someone with the disease, and nearly 30% said they had personal experience with a family member who had Alzheimer’s disease.

The findings suggest that if educational campaigns were undertaken to persuade the public about seeking care for symptoms that might be associated with Alzheimer’s disease, a large proportion would do so, Dr. Blendon said.

It would be important, however, to address what appear to be unrealistic expectations about the availability of diagnostic testing and effective therapies at this time. A particular leadership challenge for any public education campaign would be to promote early diagnosis while providing positive reasons for seeking a diagnosis (such as allowing those with early Alzheimer’s disease to be involved in planning their long-term care), given the current absence of disease-modifying treatment, he said.

The level of fear about Alzheimer’s disease that is apparent from this survey is evidence of the urgency with which the public wants the matter addressed through research and government support, Dr. Blendon noted.

The majority of respondents (86% from France, 68% from Germany, 75% from Poland, 83% from Spain, and 67% from the United States) expressed strong support for increasing government spending for research on new treatments, he said.

The study was supported by a grant from Bayer Corp. to Alzheimer Europe. Dr. Blendon did not report any disclosures.

PARIS – Concerns that individuals with early symptoms of Alzheimer’s disease may avoid or delay seeking medical care because of a perceived lack of effective therapies or other worries may be largely unfounded.

In fact, expectations about just what can be done for those who receive an Alzheimer’s disease diagnosis may be too high, according to the findings of a recent five-country telephone survey presented at the Alzheimer’s Association International Conference.

In all, 85%-95% of the 2,678 adults aged 18 and older from France, Germany, Poland, Spain, and the United States said they would see a doctor if they were experiencing confusion or memory loss, 52%-71% said they believe that an effective treatment currently exists or will soon be available, and 38%-59% said they believe a reliable test for early Alzheimer’s disease currently exists, Robert Blendon, Sc.D., reported during a press briefing at the conference.

If anything, the findings suggest that clinicians will have to temper the expectations of those who come in seeking answers about their symptoms, said Dr. Blendon, professor of health policy and political analysis at the Harvard School of Public Health, Boston.

Alzheimer’s disease organizations in many countries, including the United States, are working to promote early diagnosis. One purpose of this random telephone survey, which was a joint project of the Harvard School of Public Health and Alzheimer Europe, was to determine if the public would respond to such campaigns. The investigators also wanted to elucidate cultural differences regarding views on Alzheimer’s disease, he said.

In addition to the somewhat surprising responses regarding whether or not they would seek a diagnosis, the majority (51%-78%) of respondents from each country also said that if an accurate preclinical diagnostic test existed, they would seek a diagnosis.

Respondents expressed deep overall concerns about developing Alzheimer’s disease. In four of the five countries, Alzheimer’s ranked second after cancer as the most feared disease. In Poland, it ranked third after cancer and heart disease.

More than half of the respondents from each of the countries (54%-77%) said they had known someone with the disease, and nearly 30% said they had personal experience with a family member who had Alzheimer’s disease.

The findings suggest that if educational campaigns were undertaken to persuade the public about seeking care for symptoms that might be associated with Alzheimer’s disease, a large proportion would do so, Dr. Blendon said.

It would be important, however, to address what appear to be unrealistic expectations about the availability of diagnostic testing and effective therapies at this time. A particular leadership challenge for any public education campaign would be to promote early diagnosis while providing positive reasons for seeking a diagnosis (such as allowing those with early Alzheimer’s disease to be involved in planning their long-term care), given the current absence of disease-modifying treatment, he said.

The level of fear about Alzheimer’s disease that is apparent from this survey is evidence of the urgency with which the public wants the matter addressed through research and government support, Dr. Blendon noted.

The majority of respondents (86% from France, 68% from Germany, 75% from Poland, 83% from Spain, and 67% from the United States) expressed strong support for increasing government spending for research on new treatments, he said.

The study was supported by a grant from Bayer Corp. to Alzheimer Europe. Dr. Blendon did not report any disclosures.

PARIS – Concerns that individuals with early symptoms of Alzheimer’s disease may avoid or delay seeking medical care because of a perceived lack of effective therapies or other worries may be largely unfounded.

In fact, expectations about just what can be done for those who receive an Alzheimer’s disease diagnosis may be too high, according to the findings of a recent five-country telephone survey presented at the Alzheimer’s Association International Conference.

In all, 85%-95% of the 2,678 adults aged 18 and older from France, Germany, Poland, Spain, and the United States said they would see a doctor if they were experiencing confusion or memory loss, 52%-71% said they believe that an effective treatment currently exists or will soon be available, and 38%-59% said they believe a reliable test for early Alzheimer’s disease currently exists, Robert Blendon, Sc.D., reported during a press briefing at the conference.

If anything, the findings suggest that clinicians will have to temper the expectations of those who come in seeking answers about their symptoms, said Dr. Blendon, professor of health policy and political analysis at the Harvard School of Public Health, Boston.

Alzheimer’s disease organizations in many countries, including the United States, are working to promote early diagnosis. One purpose of this random telephone survey, which was a joint project of the Harvard School of Public Health and Alzheimer Europe, was to determine if the public would respond to such campaigns. The investigators also wanted to elucidate cultural differences regarding views on Alzheimer’s disease, he said.

In addition to the somewhat surprising responses regarding whether or not they would seek a diagnosis, the majority (51%-78%) of respondents from each country also said that if an accurate preclinical diagnostic test existed, they would seek a diagnosis.

Respondents expressed deep overall concerns about developing Alzheimer’s disease. In four of the five countries, Alzheimer’s ranked second after cancer as the most feared disease. In Poland, it ranked third after cancer and heart disease.

More than half of the respondents from each of the countries (54%-77%) said they had known someone with the disease, and nearly 30% said they had personal experience with a family member who had Alzheimer’s disease.

The findings suggest that if educational campaigns were undertaken to persuade the public about seeking care for symptoms that might be associated with Alzheimer’s disease, a large proportion would do so, Dr. Blendon said.

It would be important, however, to address what appear to be unrealistic expectations about the availability of diagnostic testing and effective therapies at this time. A particular leadership challenge for any public education campaign would be to promote early diagnosis while providing positive reasons for seeking a diagnosis (such as allowing those with early Alzheimer’s disease to be involved in planning their long-term care), given the current absence of disease-modifying treatment, he said.

The level of fear about Alzheimer’s disease that is apparent from this survey is evidence of the urgency with which the public wants the matter addressed through research and government support, Dr. Blendon noted.

The majority of respondents (86% from France, 68% from Germany, 75% from Poland, 83% from Spain, and 67% from the United States) expressed strong support for increasing government spending for research on new treatments, he said.

The study was supported by a grant from Bayer Corp. to Alzheimer Europe. Dr. Blendon did not report any disclosures.

PARIS – Falls occur significantly more often among cognitively normal older adults with evidence of preclinical Alzheimer’s disease on positron emission tomography than among those with no signs of Alzheimer’s, according to findings from an ongoing prospective cohort study.

If the findings hold up, they suggest that falls could prove to be an early signal of the disease, Susan Stark, Ph.D., said at the Alzheimer’s Association International Conference.

Her study involved 119 adults from longitudinal studies of memory and aging at Washington University’s Knight Alzheimer's Disease Research Center in St. Louis who underwent amyloid imaging via Pittsburgh compound-B PET scanning (PIB PET). A total of 18 had a positive scan, indicating amyloid plaque burden in the brain consistent with preclinical Alzheimer’s disease, Dr. Stark reported in a poster.

Of those 18 subjects, 12 (67%) experienced at least one fall during the first 8 months of the study, compared with only 36 of 101 (36%) patients with a negative PIB PET, indicating low amyloid plaque burden. The rate of falls among those in the latter group is about what would be expected among healthy adults in this age group, said Dr. Stark of the occupational therapy program in the department of neurology at Washington University.

Participants had a mean age of 74.5 years, were mostly female (64%), and reported falls monthly by mail. All underwent clinical evaluation and a PET scan with PIB PET. They also provided cerebrospinal fluid for biomarker analysis.

The findings point to the importance of understanding not only the cognitive impairments associated with Alzheimer’s disease but also the motor changes that appear to precede cognitive changes, Dr. Stark noted.

In a written statement highlighting the research, Maria Carrillo, Ph.D., agreed that the findings "illustrate the significance of understanding that, in some people, changes in gait and balance may appear before cognitive impairment."

Evidence increasingly suggests that "silent" biological brain changes may be occurring a decade or more before outward symptoms of Alzheimer’s can be seen, said Dr. Carrillo, senior director of medical and scientific relations for the Alzheimer’s Association.

"According to this study, a fall by an older adult who otherwise has a low risk of falling may signal a need for diagnostic evaluation for Alzheimer’s," she said.

Dr. Stark added that while her study is the first she knows of that has identified a risk of increased falls related to a diagnosis of preclinical Alzheimer’s disease, the findings are consistent with those from previous studies of mobility problems in those with very early symptomatic disease or mild cognitive impairment.

Dr. Carrillo said additional research is urgently needed to further explore the connection between motor deficits and falls as an early sign of disease.

Not only will such research elucidate such connections, it might also help prevent falls and the multiple problems associated with them in older adults, Dr. Carrillo added.

"In the near future, with continued research, we will improve our ability to detect and intervene early in Alzheimer’s disease. With earlier detection, perhaps we can also lower the risk of falls, which can be disabling, expensive, and even deadly in older adults," she said.

This study was funded by the National Institute on Aging. Neither Dr. Stark nor Dr. Carrillo had disclosures to report.

PARIS – Falls occur significantly more often among cognitively normal older adults with evidence of preclinical Alzheimer’s disease on positron emission tomography than among those with no signs of Alzheimer’s, according to findings from an ongoing prospective cohort study.

If the findings hold up, they suggest that falls could prove to be an early signal of the disease, Susan Stark, Ph.D., said at the Alzheimer’s Association International Conference.

Her study involved 119 adults from longitudinal studies of memory and aging at Washington University’s Knight Alzheimer's Disease Research Center in St. Louis who underwent amyloid imaging via Pittsburgh compound-B PET scanning (PIB PET). A total of 18 had a positive scan, indicating amyloid plaque burden in the brain consistent with preclinical Alzheimer’s disease, Dr. Stark reported in a poster.

Of those 18 subjects, 12 (67%) experienced at least one fall during the first 8 months of the study, compared with only 36 of 101 (36%) patients with a negative PIB PET, indicating low amyloid plaque burden. The rate of falls among those in the latter group is about what would be expected among healthy adults in this age group, said Dr. Stark of the occupational therapy program in the department of neurology at Washington University.

Participants had a mean age of 74.5 years, were mostly female (64%), and reported falls monthly by mail. All underwent clinical evaluation and a PET scan with PIB PET. They also provided cerebrospinal fluid for biomarker analysis.

The findings point to the importance of understanding not only the cognitive impairments associated with Alzheimer’s disease but also the motor changes that appear to precede cognitive changes, Dr. Stark noted.

In a written statement highlighting the research, Maria Carrillo, Ph.D., agreed that the findings "illustrate the significance of understanding that, in some people, changes in gait and balance may appear before cognitive impairment."

Evidence increasingly suggests that "silent" biological brain changes may be occurring a decade or more before outward symptoms of Alzheimer’s can be seen, said Dr. Carrillo, senior director of medical and scientific relations for the Alzheimer’s Association.

"According to this study, a fall by an older adult who otherwise has a low risk of falling may signal a need for diagnostic evaluation for Alzheimer’s," she said.

Dr. Stark added that while her study is the first she knows of that has identified a risk of increased falls related to a diagnosis of preclinical Alzheimer’s disease, the findings are consistent with those from previous studies of mobility problems in those with very early symptomatic disease or mild cognitive impairment.

Dr. Carrillo said additional research is urgently needed to further explore the connection between motor deficits and falls as an early sign of disease.

Not only will such research elucidate such connections, it might also help prevent falls and the multiple problems associated with them in older adults, Dr. Carrillo added.

"In the near future, with continued research, we will improve our ability to detect and intervene early in Alzheimer’s disease. With earlier detection, perhaps we can also lower the risk of falls, which can be disabling, expensive, and even deadly in older adults," she said.

This study was funded by the National Institute on Aging. Neither Dr. Stark nor Dr. Carrillo had disclosures to report.

PARIS – Falls occur significantly more often among cognitively normal older adults with evidence of preclinical Alzheimer’s disease on positron emission tomography than among those with no signs of Alzheimer’s, according to findings from an ongoing prospective cohort study.

If the findings hold up, they suggest that falls could prove to be an early signal of the disease, Susan Stark, Ph.D., said at the Alzheimer’s Association International Conference.

Her study involved 119 adults from longitudinal studies of memory and aging at Washington University’s Knight Alzheimer's Disease Research Center in St. Louis who underwent amyloid imaging via Pittsburgh compound-B PET scanning (PIB PET). A total of 18 had a positive scan, indicating amyloid plaque burden in the brain consistent with preclinical Alzheimer’s disease, Dr. Stark reported in a poster.

Of those 18 subjects, 12 (67%) experienced at least one fall during the first 8 months of the study, compared with only 36 of 101 (36%) patients with a negative PIB PET, indicating low amyloid plaque burden. The rate of falls among those in the latter group is about what would be expected among healthy adults in this age group, said Dr. Stark of the occupational therapy program in the department of neurology at Washington University.

Participants had a mean age of 74.5 years, were mostly female (64%), and reported falls monthly by mail. All underwent clinical evaluation and a PET scan with PIB PET. They also provided cerebrospinal fluid for biomarker analysis.

The findings point to the importance of understanding not only the cognitive impairments associated with Alzheimer’s disease but also the motor changes that appear to precede cognitive changes, Dr. Stark noted.

In a written statement highlighting the research, Maria Carrillo, Ph.D., agreed that the findings "illustrate the significance of understanding that, in some people, changes in gait and balance may appear before cognitive impairment."

Evidence increasingly suggests that "silent" biological brain changes may be occurring a decade or more before outward symptoms of Alzheimer’s can be seen, said Dr. Carrillo, senior director of medical and scientific relations for the Alzheimer’s Association.

"According to this study, a fall by an older adult who otherwise has a low risk of falling may signal a need for diagnostic evaluation for Alzheimer’s," she said.

Dr. Stark added that while her study is the first she knows of that has identified a risk of increased falls related to a diagnosis of preclinical Alzheimer’s disease, the findings are consistent with those from previous studies of mobility problems in those with very early symptomatic disease or mild cognitive impairment.

Dr. Carrillo said additional research is urgently needed to further explore the connection between motor deficits and falls as an early sign of disease.

Not only will such research elucidate such connections, it might also help prevent falls and the multiple problems associated with them in older adults, Dr. Carrillo added.

"In the near future, with continued research, we will improve our ability to detect and intervene early in Alzheimer’s disease. With earlier detection, perhaps we can also lower the risk of falls, which can be disabling, expensive, and even deadly in older adults," she said.

This study was funded by the National Institute on Aging. Neither Dr. Stark nor Dr. Carrillo had disclosures to report.

PARIS – Interim findings from the Dominantly Inherited Alzheimer Network study provide encouraging insights about the potential for preclinical detection of Alzheimer’s disease and are setting the stage for prevention trials to begin as early as 2012.

Specifically, the findings from the Dominantly Inherited Alzheimer Network (DIAN) suggest that measurable changes in brain chemistry are apparent at up to 20 or more years before the onset of dementia in Alzheimer’s disease patients, DIAN investigators reported at the Alzheimer’s Association International Conference.

DIAN, an international collaboration involving 11 leading Alzheimer’s research centers in the United States, the United Kingdom, and Australia, was established in 2008 to investigate an autosomal dominant form of Alzheimer’s disease caused by rare genetic mutations in either amyloid precursor protein (APP), or presenilin 1 (PSEN1) or 2 (PSEN2) that virtually ensure a carrier will develop the disease before they reach their 50s – and perhaps as early as their 20s or 30s. The network aims to enroll 200 mutation carriers and 200 noncarrier siblings to evaluate the sequence and rate of biomarker abnormalities that develop prior to the onset of detectable cognitive changes associated with the disease.

The approximately 1% of Alzheimer’s disease patients who have the genetic form of the disease are believed to comprise an ideal study population for this purpose. The findings presented at the conference indicate that autosomal dominant Alzheimer’s disease is quite similar to the far more common later-onset, sporadic form of the disease, and that the two forms of the disease share pathophysiological mechanisms, according to Dr. Randall Bateman, assistant director of DIAN and professor of neurology at Washington University in St. Louis, which serves as the coordinating center for the network.

Findings from the initial 195 patients enrolled in DIAN for whom cerebrospinal fluid and plasma samples were available indicate that patterns of biomarker changes observed in prior studies of sporadic Alzheimer’s patients are also seen in the DIAN cohort. These changes include increased levels of amyloid-beta42 in the blood and decreased levels in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of amyloid plaques in the brain) and elevated levels of tau and phosphorylated tau in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of neurofibrillary tangles and/or brain cell death). The presence of both amyloid plaques and neurofibrillary tangles is characteristic of Alzheimer’s disease, said Anne M. Fagan, Ph.D., a research professor in the department of neurology at Washington University and the DIAN Biomarker Core director. 

"What’s really important is that we see these changes even before the onset of symptoms," Dr. Fagan said, adding that the levels of amyloid-beta42 in CSF decrease with increasing dementia severity.

The opposite is seen with tau, with levels in the CSF increasing with the progression of dementia symptoms, and this is also consistent with what is seen in sporadic Alzheimer’s disease, she said.

"Importantly, changes can be detected many years prior to the appearance of cognitive symptoms. We have some people who are 30 years prior to their estimated age of onset (based on family history, which is a reasonably accurate predictor of carrier age of onset) and we’re already starting to see some changes and some differences in these people that early," she said.

The findings suggest that these changes represent a potential target for treatments and preventive measures, Dr. Bateman said.

"This group provides several unique insights into the process of Alzheimer’s disease ... we think the DIAN network represents an ideal cohort to bring forth treatment trials and prevention trials," he said, explaining that the cohort is particularly well-suited for proof-of-concept studies of the effects of drugs on biomarkers, and for primary and secondary prevention studies in asymptomatic carriers.

Several factors provide the rationale for conducting such trials, he said.

For one thing, current therapeutic trials may be too late.

"We may be trying to treat the disease in its latest stage of development with treatments that may be ideally suited for some of the earlier stages of development," he said.

Since amyloid plaques can develop 15-20 years prior to symptom development, applying therapeutics that target the amyloid protein at the earlier signs of damage may prevent dementia, he explained.

Also, the risk-benefit ratio in this population is clear given that 100% of carriers are destined to develop Alzheimer’s – and the timing of that development can be estimated with reasonable certainty.

"If we can offer them treatment before they develop dementia, it offers them a chance of hope," he said.

Furthermore, since many of the agents currently in trials were developed based on information derived from the genetic mutations seen in the DIAN cohort, and since that information informed one of the major hypotheses (the amyloid hypothesis) about Alzheimer’s disease, it seems likely that these individuals are the most likely to respond to the treatments, he said, adding that if they are successful, these studies could bridge prevention trials between the genetic and sporadic forms of the disease.

Based on this rationale, DIAN is moving forward with the development of additional trials within the network, he said.

To date, a clinical trials committee has been formed and is charged with designing and managing the most effective trials through interactions with pharmaceutical sponsors, the National Institute on Aging, and the U.S. Food and Drug Administration. The committee has completed its scientific review and vetting of the rational for trials in this cohort, formed a "Pharma Consortium" with members from 12 pharmaceutical companies, and started the DIAN Therapeutic Trials Unit to implement the trials.

Multiple meetings have been held, and DIAN has obtained the support of regulatory agencies, including the FDA and the European Medicines Agency, Dr. Bateman noted.

Additionally, 11 therapeutic nomination packets have been received from pharmaceutical companies and are under consideration for use in the trials. He declined to identify the candidate drugs but said most are anti-amyloid agents.

The first trials should begin in early 2012, he said.

The hope is that these trials will lead to the same kind of success seen with statin drugs, which were initially tested in patients with an aggressive genetic form of hypercholesterolemia that struck people early in life, increasing their risk for heart attack and stroke.

The treatment was found to be effective in this population, and the findings translated into a highly effective therapy for the population at large, Dr. Bateman said, noting that millions of people around the world have benefited from treatment with those drugs.

The findings from DIAN, and the future directions of the network represent "a very exciting and new style of a collaborative type of multinational research, which is going to allow us to understand things in a way that couldn’t be done before by targeting populations at very high risk, and which allows us for the first time to really approach the problem of preventing Alzheimer’s rather than intervening after it’s developed, " said Dr. Ralph Nixon, professor of psychiatry and cell biology at New York University and moderator of a press briefing about the findings.

The approach is one that the Alzheimer’s Association has encouraged in recent years because "it cuts across a number of missions of the association, which are to underscore the importance of early detection so we can be in a position to treat these individuals when therapies are available for them," said Dr. Nixon, who also is vice chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

"But I think the most important message really is that we now have from this study the validation that it really is possible to detect changes at such an early stage that we are going to enhance the chances of administering therapies that will be more effective, even retesting therapies that might have failed in interventional trials ... as well as testing new innovative therapies that come along," he said.

DIAN is supported by a National Institutes of Health grant, as well as by grants from an anonymous foundation. The presenters had no conflicts of interest to report. 

PARIS – Interim findings from the Dominantly Inherited Alzheimer Network study provide encouraging insights about the potential for preclinical detection of Alzheimer’s disease and are setting the stage for prevention trials to begin as early as 2012.

Specifically, the findings from the Dominantly Inherited Alzheimer Network (DIAN) suggest that measurable changes in brain chemistry are apparent at up to 20 or more years before the onset of dementia in Alzheimer’s disease patients, DIAN investigators reported at the Alzheimer’s Association International Conference.

DIAN, an international collaboration involving 11 leading Alzheimer’s research centers in the United States, the United Kingdom, and Australia, was established in 2008 to investigate an autosomal dominant form of Alzheimer’s disease caused by rare genetic mutations in either amyloid precursor protein (APP), or presenilin 1 (PSEN1) or 2 (PSEN2) that virtually ensure a carrier will develop the disease before they reach their 50s – and perhaps as early as their 20s or 30s. The network aims to enroll 200 mutation carriers and 200 noncarrier siblings to evaluate the sequence and rate of biomarker abnormalities that develop prior to the onset of detectable cognitive changes associated with the disease.

The approximately 1% of Alzheimer’s disease patients who have the genetic form of the disease are believed to comprise an ideal study population for this purpose. The findings presented at the conference indicate that autosomal dominant Alzheimer’s disease is quite similar to the far more common later-onset, sporadic form of the disease, and that the two forms of the disease share pathophysiological mechanisms, according to Dr. Randall Bateman, assistant director of DIAN and professor of neurology at Washington University in St. Louis, which serves as the coordinating center for the network.

Findings from the initial 195 patients enrolled in DIAN for whom cerebrospinal fluid and plasma samples were available indicate that patterns of biomarker changes observed in prior studies of sporadic Alzheimer’s patients are also seen in the DIAN cohort. These changes include increased levels of amyloid-beta42 in the blood and decreased levels in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of amyloid plaques in the brain) and elevated levels of tau and phosphorylated tau in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of neurofibrillary tangles and/or brain cell death). The presence of both amyloid plaques and neurofibrillary tangles is characteristic of Alzheimer’s disease, said Anne M. Fagan, Ph.D., a research professor in the department of neurology at Washington University and the DIAN Biomarker Core director. 

"What’s really important is that we see these changes even before the onset of symptoms," Dr. Fagan said, adding that the levels of amyloid-beta42 in CSF decrease with increasing dementia severity.

The opposite is seen with tau, with levels in the CSF increasing with the progression of dementia symptoms, and this is also consistent with what is seen in sporadic Alzheimer’s disease, she said.

"Importantly, changes can be detected many years prior to the appearance of cognitive symptoms. We have some people who are 30 years prior to their estimated age of onset (based on family history, which is a reasonably accurate predictor of carrier age of onset) and we’re already starting to see some changes and some differences in these people that early," she said.

The findings suggest that these changes represent a potential target for treatments and preventive measures, Dr. Bateman said.

"This group provides several unique insights into the process of Alzheimer’s disease ... we think the DIAN network represents an ideal cohort to bring forth treatment trials and prevention trials," he said, explaining that the cohort is particularly well-suited for proof-of-concept studies of the effects of drugs on biomarkers, and for primary and secondary prevention studies in asymptomatic carriers.

Several factors provide the rationale for conducting such trials, he said.

For one thing, current therapeutic trials may be too late.

"We may be trying to treat the disease in its latest stage of development with treatments that may be ideally suited for some of the earlier stages of development," he said.

Since amyloid plaques can develop 15-20 years prior to symptom development, applying therapeutics that target the amyloid protein at the earlier signs of damage may prevent dementia, he explained.

Also, the risk-benefit ratio in this population is clear given that 100% of carriers are destined to develop Alzheimer’s – and the timing of that development can be estimated with reasonable certainty.

"If we can offer them treatment before they develop dementia, it offers them a chance of hope," he said.

Furthermore, since many of the agents currently in trials were developed based on information derived from the genetic mutations seen in the DIAN cohort, and since that information informed one of the major hypotheses (the amyloid hypothesis) about Alzheimer’s disease, it seems likely that these individuals are the most likely to respond to the treatments, he said, adding that if they are successful, these studies could bridge prevention trials between the genetic and sporadic forms of the disease.

Based on this rationale, DIAN is moving forward with the development of additional trials within the network, he said.

To date, a clinical trials committee has been formed and is charged with designing and managing the most effective trials through interactions with pharmaceutical sponsors, the National Institute on Aging, and the U.S. Food and Drug Administration. The committee has completed its scientific review and vetting of the rational for trials in this cohort, formed a "Pharma Consortium" with members from 12 pharmaceutical companies, and started the DIAN Therapeutic Trials Unit to implement the trials.

Multiple meetings have been held, and DIAN has obtained the support of regulatory agencies, including the FDA and the European Medicines Agency, Dr. Bateman noted.

Additionally, 11 therapeutic nomination packets have been received from pharmaceutical companies and are under consideration for use in the trials. He declined to identify the candidate drugs but said most are anti-amyloid agents.

The first trials should begin in early 2012, he said.

The hope is that these trials will lead to the same kind of success seen with statin drugs, which were initially tested in patients with an aggressive genetic form of hypercholesterolemia that struck people early in life, increasing their risk for heart attack and stroke.

The treatment was found to be effective in this population, and the findings translated into a highly effective therapy for the population at large, Dr. Bateman said, noting that millions of people around the world have benefited from treatment with those drugs.

The findings from DIAN, and the future directions of the network represent "a very exciting and new style of a collaborative type of multinational research, which is going to allow us to understand things in a way that couldn’t be done before by targeting populations at very high risk, and which allows us for the first time to really approach the problem of preventing Alzheimer’s rather than intervening after it’s developed, " said Dr. Ralph Nixon, professor of psychiatry and cell biology at New York University and moderator of a press briefing about the findings.

The approach is one that the Alzheimer’s Association has encouraged in recent years because "it cuts across a number of missions of the association, which are to underscore the importance of early detection so we can be in a position to treat these individuals when therapies are available for them," said Dr. Nixon, who also is vice chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

"But I think the most important message really is that we now have from this study the validation that it really is possible to detect changes at such an early stage that we are going to enhance the chances of administering therapies that will be more effective, even retesting therapies that might have failed in interventional trials ... as well as testing new innovative therapies that come along," he said.

DIAN is supported by a National Institutes of Health grant, as well as by grants from an anonymous foundation. The presenters had no conflicts of interest to report. 

PARIS – Interim findings from the Dominantly Inherited Alzheimer Network study provide encouraging insights about the potential for preclinical detection of Alzheimer’s disease and are setting the stage for prevention trials to begin as early as 2012.

Specifically, the findings from the Dominantly Inherited Alzheimer Network (DIAN) suggest that measurable changes in brain chemistry are apparent at up to 20 or more years before the onset of dementia in Alzheimer’s disease patients, DIAN investigators reported at the Alzheimer’s Association International Conference.

DIAN, an international collaboration involving 11 leading Alzheimer’s research centers in the United States, the United Kingdom, and Australia, was established in 2008 to investigate an autosomal dominant form of Alzheimer’s disease caused by rare genetic mutations in either amyloid precursor protein (APP), or presenilin 1 (PSEN1) or 2 (PSEN2) that virtually ensure a carrier will develop the disease before they reach their 50s – and perhaps as early as their 20s or 30s. The network aims to enroll 200 mutation carriers and 200 noncarrier siblings to evaluate the sequence and rate of biomarker abnormalities that develop prior to the onset of detectable cognitive changes associated with the disease.

The approximately 1% of Alzheimer’s disease patients who have the genetic form of the disease are believed to comprise an ideal study population for this purpose. The findings presented at the conference indicate that autosomal dominant Alzheimer’s disease is quite similar to the far more common later-onset, sporadic form of the disease, and that the two forms of the disease share pathophysiological mechanisms, according to Dr. Randall Bateman, assistant director of DIAN and professor of neurology at Washington University in St. Louis, which serves as the coordinating center for the network.

Findings from the initial 195 patients enrolled in DIAN for whom cerebrospinal fluid and plasma samples were available indicate that patterns of biomarker changes observed in prior studies of sporadic Alzheimer’s patients are also seen in the DIAN cohort. These changes include increased levels of amyloid-beta42 in the blood and decreased levels in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of amyloid plaques in the brain) and elevated levels of tau and phosphorylated tau in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of neurofibrillary tangles and/or brain cell death). The presence of both amyloid plaques and neurofibrillary tangles is characteristic of Alzheimer’s disease, said Anne M. Fagan, Ph.D., a research professor in the department of neurology at Washington University and the DIAN Biomarker Core director. 

"What’s really important is that we see these changes even before the onset of symptoms," Dr. Fagan said, adding that the levels of amyloid-beta42 in CSF decrease with increasing dementia severity.

The opposite is seen with tau, with levels in the CSF increasing with the progression of dementia symptoms, and this is also consistent with what is seen in sporadic Alzheimer’s disease, she said.

"Importantly, changes can be detected many years prior to the appearance of cognitive symptoms. We have some people who are 30 years prior to their estimated age of onset (based on family history, which is a reasonably accurate predictor of carrier age of onset) and we’re already starting to see some changes and some differences in these people that early," she said.

The findings suggest that these changes represent a potential target for treatments and preventive measures, Dr. Bateman said.

"This group provides several unique insights into the process of Alzheimer’s disease ... we think the DIAN network represents an ideal cohort to bring forth treatment trials and prevention trials," he said, explaining that the cohort is particularly well-suited for proof-of-concept studies of the effects of drugs on biomarkers, and for primary and secondary prevention studies in asymptomatic carriers.

Several factors provide the rationale for conducting such trials, he said.

For one thing, current therapeutic trials may be too late.

"We may be trying to treat the disease in its latest stage of development with treatments that may be ideally suited for some of the earlier stages of development," he said.

Since amyloid plaques can develop 15-20 years prior to symptom development, applying therapeutics that target the amyloid protein at the earlier signs of damage may prevent dementia, he explained.

Also, the risk-benefit ratio in this population is clear given that 100% of carriers are destined to develop Alzheimer’s – and the timing of that development can be estimated with reasonable certainty.

"If we can offer them treatment before they develop dementia, it offers them a chance of hope," he said.

Furthermore, since many of the agents currently in trials were developed based on information derived from the genetic mutations seen in the DIAN cohort, and since that information informed one of the major hypotheses (the amyloid hypothesis) about Alzheimer’s disease, it seems likely that these individuals are the most likely to respond to the treatments, he said, adding that if they are successful, these studies could bridge prevention trials between the genetic and sporadic forms of the disease.

Based on this rationale, DIAN is moving forward with the development of additional trials within the network, he said.

To date, a clinical trials committee has been formed and is charged with designing and managing the most effective trials through interactions with pharmaceutical sponsors, the National Institute on Aging, and the U.S. Food and Drug Administration. The committee has completed its scientific review and vetting of the rational for trials in this cohort, formed a "Pharma Consortium" with members from 12 pharmaceutical companies, and started the DIAN Therapeutic Trials Unit to implement the trials.

Multiple meetings have been held, and DIAN has obtained the support of regulatory agencies, including the FDA and the European Medicines Agency, Dr. Bateman noted.

Additionally, 11 therapeutic nomination packets have been received from pharmaceutical companies and are under consideration for use in the trials. He declined to identify the candidate drugs but said most are anti-amyloid agents.

The first trials should begin in early 2012, he said.

The hope is that these trials will lead to the same kind of success seen with statin drugs, which were initially tested in patients with an aggressive genetic form of hypercholesterolemia that struck people early in life, increasing their risk for heart attack and stroke.

The treatment was found to be effective in this population, and the findings translated into a highly effective therapy for the population at large, Dr. Bateman said, noting that millions of people around the world have benefited from treatment with those drugs.

The findings from DIAN, and the future directions of the network represent "a very exciting and new style of a collaborative type of multinational research, which is going to allow us to understand things in a way that couldn’t be done before by targeting populations at very high risk, and which allows us for the first time to really approach the problem of preventing Alzheimer’s rather than intervening after it’s developed, " said Dr. Ralph Nixon, professor of psychiatry and cell biology at New York University and moderator of a press briefing about the findings.

The approach is one that the Alzheimer’s Association has encouraged in recent years because "it cuts across a number of missions of the association, which are to underscore the importance of early detection so we can be in a position to treat these individuals when therapies are available for them," said Dr. Nixon, who also is vice chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

"But I think the most important message really is that we now have from this study the validation that it really is possible to detect changes at such an early stage that we are going to enhance the chances of administering therapies that will be more effective, even retesting therapies that might have failed in interventional trials ... as well as testing new innovative therapies that come along," he said.

DIAN is supported by a National Institutes of Health grant, as well as by grants from an anonymous foundation. The presenters had no conflicts of interest to report. 

PARIS – A panel of blood-based biomarkers for neocortical amyloid burden – a known predictor of progression to Alzheimer’s disease – shows promise as an effective and economical screening test for early identification of individuals at risk for the disease, according to findings from an Australian study highlighted at an international conference on Alzheimer’s disease.

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, or by invasive cerebrospinal fluid evaluation, Samantha Burnham, Ph.D., reported at an international conference on Alzheimer’s disease.

After analyzing 273 samples from patients with baseline blood and PiB-PET measurements from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, the researchers developed a model using 9 blood-based markers (including A beta 1-42, ApoE, and cortisol) to estimate the amount of deposited amyloid in the brain.

That panel of markers had 83% sensitivity and 85% specificity for identifying the level of amyloid deemed to indicate risk of Alzheimer’s, said Dr. Burnham of the Commonwealth Scientific and Industrial Research Organization (CSIRO), Perth, Australia.

Predictions using the panel were also made in 817 nonimaged AIBL study participants. When those participants were grouped according to clinical diagnosis, the percentages of high neocortical amyloid burden were consistent with prior findings in the literature, with 34% of healthy controls, 87% of mild cognitively impaired individuals, and 100% of Alzheimer’s disease patients having a high burden, Dr. Burnham said.

In addition, the panel of markers was assessed in 74 subjects from the Alzheimer’s Disease Neuroimaging Initiative for validation. In that validation study, measurements for two of the markers from the panel were unavailable, and the sensitivity and specificity were slightly lower, at 76%.

Furthermore, when the samples from the AIBL study were reassessed without the two missing markers, the sensitivity and specificity dropped to a level comparable to that seen in the validation study (74%), 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 given that the model used in the study accurately predicts neocortical amyloid burden, Dr. Burnham said, it appears likely that the findings will lead to development of a useful, affordable screening test for the early identification of individuals at risk for developing Alzheimer’s disease.

While it is impossible to provide a timeline for development of such a test, as further validation is needed, she added, these findings are indeed a "first stepping stone toward early diagnosis.

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

The conference was sponsored by the Alzheimer’s Association. Dr. Burnham had no disclosures relevant to her presentation.

PARIS – A panel of blood-based biomarkers for neocortical amyloid burden – a known predictor of progression to Alzheimer’s disease – shows promise as an effective and economical screening test for early identification of individuals at risk for the disease, according to findings from an Australian study highlighted at an international conference on Alzheimer’s disease.

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, or by invasive cerebrospinal fluid evaluation, Samantha Burnham, Ph.D., reported at an international conference on Alzheimer’s disease.

After analyzing 273 samples from patients with baseline blood and PiB-PET measurements from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, the researchers developed a model using 9 blood-based markers (including A beta 1-42, ApoE, and cortisol) to estimate the amount of deposited amyloid in the brain.

That panel of markers had 83% sensitivity and 85% specificity for identifying the level of amyloid deemed to indicate risk of Alzheimer’s, said Dr. Burnham of the Commonwealth Scientific and Industrial Research Organization (CSIRO), Perth, Australia.

Predictions using the panel were also made in 817 nonimaged AIBL study participants. When those participants were grouped according to clinical diagnosis, the percentages of high neocortical amyloid burden were consistent with prior findings in the literature, with 34% of healthy controls, 87% of mild cognitively impaired individuals, and 100% of Alzheimer’s disease patients having a high burden, Dr. Burnham said.

In addition, the panel of markers was assessed in 74 subjects from the Alzheimer’s Disease Neuroimaging Initiative for validation. In that validation study, measurements for two of the markers from the panel were unavailable, and the sensitivity and specificity were slightly lower, at 76%.

Furthermore, when the samples from the AIBL study were reassessed without the two missing markers, the sensitivity and specificity dropped to a level comparable to that seen in the validation study (74%), 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 given that the model used in the study accurately predicts neocortical amyloid burden, Dr. Burnham said, it appears likely that the findings will lead to development of a useful, affordable screening test for the early identification of individuals at risk for developing Alzheimer’s disease.

While it is impossible to provide a timeline for development of such a test, as further validation is needed, she added, these findings are indeed a "first stepping stone toward early diagnosis.

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

The conference was sponsored by the Alzheimer’s Association. Dr. Burnham had no disclosures relevant to her presentation.

PARIS – A panel of blood-based biomarkers for neocortical amyloid burden – a known predictor of progression to Alzheimer’s disease – shows promise as an effective and economical screening test for early identification of individuals at risk for the disease, according to findings from an Australian study highlighted at an international conference on Alzheimer’s disease.

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, or by invasive cerebrospinal fluid evaluation, Samantha Burnham, Ph.D., reported at an international conference on Alzheimer’s disease.

After analyzing 273 samples from patients with baseline blood and PiB-PET measurements from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, the researchers developed a model using 9 blood-based markers (including A beta 1-42, ApoE, and cortisol) to estimate the amount of deposited amyloid in the brain.

That panel of markers had 83% sensitivity and 85% specificity for identifying the level of amyloid deemed to indicate risk of Alzheimer’s, said Dr. Burnham of the Commonwealth Scientific and Industrial Research Organization (CSIRO), Perth, Australia.

Predictions using the panel were also made in 817 nonimaged AIBL study participants. When those participants were grouped according to clinical diagnosis, the percentages of high neocortical amyloid burden were consistent with prior findings in the literature, with 34% of healthy controls, 87% of mild cognitively impaired individuals, and 100% of Alzheimer’s disease patients having a high burden, Dr. Burnham said.

In addition, the panel of markers was assessed in 74 subjects from the Alzheimer’s Disease Neuroimaging Initiative for validation. In that validation study, measurements for two of the markers from the panel were unavailable, and the sensitivity and specificity were slightly lower, at 76%.

Furthermore, when the samples from the AIBL study were reassessed without the two missing markers, the sensitivity and specificity dropped to a level comparable to that seen in the validation study (74%), 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 given that the model used in the study accurately predicts neocortical amyloid burden, Dr. Burnham said, it appears likely that the findings will lead to development of a useful, affordable screening test for the early identification of individuals at risk for developing Alzheimer’s disease.

While it is impossible to provide a timeline for development of such a test, as further validation is needed, she added, these findings are indeed a "first stepping stone toward early diagnosis.

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

The conference was sponsored by the Alzheimer’s Association. Dr. Burnham had no disclosures relevant to her presentation.

PARIS – Traumatic brain injury may double the risk of developing dementia, according to findings from a study of more than 280,000 U.S. veterans.

The risk of dementia over 7 years was 15.3% in 4,902 veterans who had a traumatic brain injury (TBI) diagnosis in 1997-2000, compared with 6.8% in those without a TBI diagnosis. The comparison yielded a hazard ratio of 2.3 for those with any TBI diagnosis after adjustment for age, sex, race, and multiple medical and psychiatric conditions.

The difference was statistically significant for all TBI types, including intracranial injury (the most common form, which accounted for 40% of the injuries among the veterans) as well as for concussion, postconcussion syndrome, head fracture, and unspecified head injury, Dr. Kristine Yaffe and her colleagues reported in a poster on July 18 at the International Conference on Alzheimer’s Disease.

The findings also offer some hope that early treatment and rehabilitation after TBI could help ward off dementia, and they underscore the need for monitoring affected older adults for signs of cognitive impairment following a TBI, Dr. Yaffe said at the conference.

"The issue is important because TBI is very common," according to Dr. Yaffe, professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco, who noted that the condition is common in the general population as well as among veterans.

About 1.7 million people experience a TBI each year in the United States, most often as a result of falls and car crashes, according to data from the U.S. Centers for Disease Control and Prevention. About 2% of the veterans included in this study had a TBI diagnosis during the study period.

In fact, TBI is known as the "signature wound" incurred by soldiers involved in conflicts in Iraq and Afghanistan, because it accounts for 22% of casualties and 59% of blast-related injuries. Findings from this and prior studies that suggest an association between such injuries and the development of symptomatic dementia raise concern about potential long-term consequences for affected veterans, as well as for older adults in the general population who experience a TBI, said Dr. Yaffe, who is also director of the memory disorders clinic at the San Francisco VA Medical Center.

That is particularly true because amyloid plaques similar to those seen in the brains of Alzheimer’s patients are also present in nearly a third of TBI patients who don’t survive their injuries.

"It is possible that these injuries result in the death of axons and neurons, even after a single TBI. Loss of axons and neurons could result in earlier manifestation of Alzheimer’s symptoms," the researchers said in a statement regarding the findings.

Veterans included in the study were aged 55 years or older with no dementia diagnosis at baseline. Each veteran had received care through the Veterans Health Administration, had at least one visit during 1997-2000, and had a follow-up visit from 2001-2007.

Dr. Yaffe’s research was funded by the U.S. Department of Defense. She had no other relevant disclosures.

PARIS – Traumatic brain injury may double the risk of developing dementia, according to findings from a study of more than 280,000 U.S. veterans.

The risk of dementia over 7 years was 15.3% in 4,902 veterans who had a traumatic brain injury (TBI) diagnosis in 1997-2000, compared with 6.8% in those without a TBI diagnosis. The comparison yielded a hazard ratio of 2.3 for those with any TBI diagnosis after adjustment for age, sex, race, and multiple medical and psychiatric conditions.

The difference was statistically significant for all TBI types, including intracranial injury (the most common form, which accounted for 40% of the injuries among the veterans) as well as for concussion, postconcussion syndrome, head fracture, and unspecified head injury, Dr. Kristine Yaffe and her colleagues reported in a poster on July 18 at the International Conference on Alzheimer’s Disease.

The findings also offer some hope that early treatment and rehabilitation after TBI could help ward off dementia, and they underscore the need for monitoring affected older adults for signs of cognitive impairment following a TBI, Dr. Yaffe said at the conference.

"The issue is important because TBI is very common," according to Dr. Yaffe, professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco, who noted that the condition is common in the general population as well as among veterans.

About 1.7 million people experience a TBI each year in the United States, most often as a result of falls and car crashes, according to data from the U.S. Centers for Disease Control and Prevention. About 2% of the veterans included in this study had a TBI diagnosis during the study period.

In fact, TBI is known as the "signature wound" incurred by soldiers involved in conflicts in Iraq and Afghanistan, because it accounts for 22% of casualties and 59% of blast-related injuries. Findings from this and prior studies that suggest an association between such injuries and the development of symptomatic dementia raise concern about potential long-term consequences for affected veterans, as well as for older adults in the general population who experience a TBI, said Dr. Yaffe, who is also director of the memory disorders clinic at the San Francisco VA Medical Center.

That is particularly true because amyloid plaques similar to those seen in the brains of Alzheimer’s patients are also present in nearly a third of TBI patients who don’t survive their injuries.

"It is possible that these injuries result in the death of axons and neurons, even after a single TBI. Loss of axons and neurons could result in earlier manifestation of Alzheimer’s symptoms," the researchers said in a statement regarding the findings.

Veterans included in the study were aged 55 years or older with no dementia diagnosis at baseline. Each veteran had received care through the Veterans Health Administration, had at least one visit during 1997-2000, and had a follow-up visit from 2001-2007.

Dr. Yaffe’s research was funded by the U.S. Department of Defense. She had no other relevant disclosures.

PARIS – Traumatic brain injury may double the risk of developing dementia, according to findings from a study of more than 280,000 U.S. veterans.

The risk of dementia over 7 years was 15.3% in 4,902 veterans who had a traumatic brain injury (TBI) diagnosis in 1997-2000, compared with 6.8% in those without a TBI diagnosis. The comparison yielded a hazard ratio of 2.3 for those with any TBI diagnosis after adjustment for age, sex, race, and multiple medical and psychiatric conditions.

The difference was statistically significant for all TBI types, including intracranial injury (the most common form, which accounted for 40% of the injuries among the veterans) as well as for concussion, postconcussion syndrome, head fracture, and unspecified head injury, Dr. Kristine Yaffe and her colleagues reported in a poster on July 18 at the International Conference on Alzheimer’s Disease.

The findings also offer some hope that early treatment and rehabilitation after TBI could help ward off dementia, and they underscore the need for monitoring affected older adults for signs of cognitive impairment following a TBI, Dr. Yaffe said at the conference.

"The issue is important because TBI is very common," according to Dr. Yaffe, professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco, who noted that the condition is common in the general population as well as among veterans.

About 1.7 million people experience a TBI each year in the United States, most often as a result of falls and car crashes, according to data from the U.S. Centers for Disease Control and Prevention. About 2% of the veterans included in this study had a TBI diagnosis during the study period.

In fact, TBI is known as the "signature wound" incurred by soldiers involved in conflicts in Iraq and Afghanistan, because it accounts for 22% of casualties and 59% of blast-related injuries. Findings from this and prior studies that suggest an association between such injuries and the development of symptomatic dementia raise concern about potential long-term consequences for affected veterans, as well as for older adults in the general population who experience a TBI, said Dr. Yaffe, who is also director of the memory disorders clinic at the San Francisco VA Medical Center.

That is particularly true because amyloid plaques similar to those seen in the brains of Alzheimer’s patients are also present in nearly a third of TBI patients who don’t survive their injuries.

"It is possible that these injuries result in the death of axons and neurons, even after a single TBI. Loss of axons and neurons could result in earlier manifestation of Alzheimer’s symptoms," the researchers said in a statement regarding the findings.

Veterans included in the study were aged 55 years or older with no dementia diagnosis at baseline. Each veteran had received care through the Veterans Health Administration, had at least one visit during 1997-2000, and had a follow-up visit from 2001-2007.

Dr. Yaffe’s research was funded by the U.S. Department of Defense. She had no other relevant disclosures.