Tau Protein in Normal Older Adults Is Linked to Memory Decline

COPENHAGEN—Among cognitively normal seniors, PET scans showed that memory decline was linked with higher levels of tau buildup in several brain regions, according to researchers.

Keith Johnson, MD, and colleagues, using an imaging agent (F18 T807) that binds with tau in the brain, conducted PET scans of 56 cognitively normal living individuals. Participants had a median age of 72 and had undergone annual memory testing during the previous three years.

Dr. Johnson’s group found that higher levels of tau in areas of the brain important to memory (ie, entorhinal cortex and temporal neocortex) were associated with worsening on the memory test.

“These preliminary data suggest that tau in these brain areas is related to memory decline in normal older individuals,” said Dr. Johnson, Director of Molecular Neuroimaging in the Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, in Boston. “This study demonstrates the potential for PET technology to be used for early detection and to help pick participants for prevention trials and treatment trials that target tau.”

In previous research, levels of tau in the brain were more closely associated with cognitive decline in Alzheimer’s disease than were levels of beta-amyloid. Identifying the early buildup of these proteins in the brain, even before memory and thinking symptoms are present, is considered a strong candidate for early detection and diagnosis of Alzheimer’s disease and for identifying volunteers for prevention studies.

Subjective Memory Complaints in Midlife May Be Linked to Risk for Alzheimer’s Disease
Middle-aged persons with subjective memory complaints have a thinner cortex in brain regions that are vulnerable to Alzheimer’s disease and perform worse on objective cognitive tests that suggest Alzheimer’s disease, compared with middle-aged persons without subjective memory complaints, according to research presented at the 2014 Alzheimer’s Association International Conference.

“These findings suggest that some persons who endorse subjective memory complaints in midlife might be at increased risk of progression to Alzheimer’s disease in the future,” reported Stephanie Schultz, a research specialist at the Wisconsin Alzheimer’s Disease Research Center in Madison. “Therefore, such individuals might be prime candidates for clinical trials aimed at retarding the evolution of the Alzheimer’s disease pathophysiologic process.”

Subjective memory complaints are subtle changes in memory that fall below detection thresholds of common cognitive tests. “However, it is not fully known whether persons with subjective memory complaints have Alzheimer’s disease–related brain alterations or whether they indeed demonstrate poorer cognitive performance,” noted Ms. Schultz.

The researchers sought to determine whether subjective memory complaints were associated with the thinning of cortical regions involved in Alzheimer’s disease and worse performance on objective cognitive tests. Analysis was based on 216 middle-aged persons with risk factors for Alzheimer’s disease who were enrolled in the Wisconsin Registry for Alzheimer’s Prevention (median age, 54; 67% women). Forty-two percent of subjects tested positive for APOE ε4, and 71% had a family history of Alzheimer’s disease.

All participants completed a questionnaire that included the following item pertaining to subjective memory difficulties: “Do you think you have a problem with your memory?” A total of 77 persons said “yes,” and 184 said “no.” During the same visit, the participants also underwent a comprehensive neuropsychologic examination. After a mean of 5.48 years, the subjects underwent a 3D T1 MRI scan.

The researchers observed no significant differences regarding age, sex, APOE ε4 status, family history of Alzheimer’s disease, education, or score on the Mini-Mental Status Examination between persons who reported subjective memory problems and those who did not.

Compared with those who did not report a subjective memory problem, persons with a subjective memory problem had “significant cortical thinning in the entorhinal, fusiform, posterior cingulate, and inferior parietal cortices, as well as significantly reduced amygdala volume,” stated Ms. Schultz.

In addition, compared with the group who did not report a subjective memory problem, the group with a subjective memory problem had “significantly lower test scores—albeit within normal limits—on measures of immediate memory, verbal learning and memory, and verbal ability,” Ms. Schultz concluded.

—Colby Stong

Phase II Clinical Trial Results of Crenezumab for Alzheimer’s Disease
At the 2014 Alzheimer’s Association International Conference, Roche presented data from two phase II studies investigating whether crenezumab can delay cognitive and functional decline in patients with mild to moderate Alzheimer’s disease.

Although the larger study, known as ABBY, did not meet its primary end points in patients with mild to moderate Alzheimer’s disease, it provided initial evidence of a treatment effect in patients with mild Alzheimer’s disease. Similar effects on clinical decline were observed in BLAZE, a smaller biomarker study.

In the ABBY study, crenezumab treatment in patients with mild to moderate Alzheimer’s disease tended to slow the decline of cognitive abilities, as measured by the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12), but had no effect on global functioning, as measured by Clinical Dementia Rating-Sum of Boxes. These outcomes were the study’s primary end points. In an exploratory analysis of patients with milder disease treated with IV crenezumab, the researchers observed a positive trend toward greater reduction in cognitive decline in progressively milder subsets of patients, relative to placebo.

In the BLAZE study, which enrolled people who tested positive for an amyloid imaging biomarker, the primary end point was a change in brain amyloid load. In a secondary end point analysis, treatment with IV crenezumab was associated with a trend toward slowing cognitive decline in patients with mild disease (as measured by ADAS-cog12). Biomarker results from the ABBY and BLAZE studies will be presented at an upcoming meeting.

“Data from these phase II studies provide valuable information about crenezumab’s potential clinical activity in people with Alzheimer’s disease, where there is a great need for treatment options,” said Richard Scheller, PhD, Executive Vice President and Head of Genentech Research and Early Development. “These findings support the importance of testing potential disease-modifying agents, such as beta-amyloid antibodies, early in the course of the disease.”

COPENHAGEN—Among cognitively normal seniors, PET scans showed that memory decline was linked with higher levels of tau buildup in several brain regions, according to researchers.

Keith Johnson, MD, and colleagues, using an imaging agent (F18 T807) that binds with tau in the brain, conducted PET scans of 56 cognitively normal living individuals. Participants had a median age of 72 and had undergone annual memory testing during the previous three years.

Dr. Johnson’s group found that higher levels of tau in areas of the brain important to memory (ie, entorhinal cortex and temporal neocortex) were associated with worsening on the memory test.

“These preliminary data suggest that tau in these brain areas is related to memory decline in normal older individuals,” said Dr. Johnson, Director of Molecular Neuroimaging in the Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, in Boston. “This study demonstrates the potential for PET technology to be used for early detection and to help pick participants for prevention trials and treatment trials that target tau.”

In previous research, levels of tau in the brain were more closely associated with cognitive decline in Alzheimer’s disease than were levels of beta-amyloid. Identifying the early buildup of these proteins in the brain, even before memory and thinking symptoms are present, is considered a strong candidate for early detection and diagnosis of Alzheimer’s disease and for identifying volunteers for prevention studies.

Subjective Memory Complaints in Midlife May Be Linked to Risk for Alzheimer’s Disease
Middle-aged persons with subjective memory complaints have a thinner cortex in brain regions that are vulnerable to Alzheimer’s disease and perform worse on objective cognitive tests that suggest Alzheimer’s disease, compared with middle-aged persons without subjective memory complaints, according to research presented at the 2014 Alzheimer’s Association International Conference.

“These findings suggest that some persons who endorse subjective memory complaints in midlife might be at increased risk of progression to Alzheimer’s disease in the future,” reported Stephanie Schultz, a research specialist at the Wisconsin Alzheimer’s Disease Research Center in Madison. “Therefore, such individuals might be prime candidates for clinical trials aimed at retarding the evolution of the Alzheimer’s disease pathophysiologic process.”

Subjective memory complaints are subtle changes in memory that fall below detection thresholds of common cognitive tests. “However, it is not fully known whether persons with subjective memory complaints have Alzheimer’s disease–related brain alterations or whether they indeed demonstrate poorer cognitive performance,” noted Ms. Schultz.

The researchers sought to determine whether subjective memory complaints were associated with the thinning of cortical regions involved in Alzheimer’s disease and worse performance on objective cognitive tests. Analysis was based on 216 middle-aged persons with risk factors for Alzheimer’s disease who were enrolled in the Wisconsin Registry for Alzheimer’s Prevention (median age, 54; 67% women). Forty-two percent of subjects tested positive for APOE ε4, and 71% had a family history of Alzheimer’s disease.

All participants completed a questionnaire that included the following item pertaining to subjective memory difficulties: “Do you think you have a problem with your memory?” A total of 77 persons said “yes,” and 184 said “no.” During the same visit, the participants also underwent a comprehensive neuropsychologic examination. After a mean of 5.48 years, the subjects underwent a 3D T1 MRI scan.

The researchers observed no significant differences regarding age, sex, APOE ε4 status, family history of Alzheimer’s disease, education, or score on the Mini-Mental Status Examination between persons who reported subjective memory problems and those who did not.

Compared with those who did not report a subjective memory problem, persons with a subjective memory problem had “significant cortical thinning in the entorhinal, fusiform, posterior cingulate, and inferior parietal cortices, as well as significantly reduced amygdala volume,” stated Ms. Schultz.

In addition, compared with the group who did not report a subjective memory problem, the group with a subjective memory problem had “significantly lower test scores—albeit within normal limits—on measures of immediate memory, verbal learning and memory, and verbal ability,” Ms. Schultz concluded.

—Colby Stong

Phase II Clinical Trial Results of Crenezumab for Alzheimer’s Disease
At the 2014 Alzheimer’s Association International Conference, Roche presented data from two phase II studies investigating whether crenezumab can delay cognitive and functional decline in patients with mild to moderate Alzheimer’s disease.

Although the larger study, known as ABBY, did not meet its primary end points in patients with mild to moderate Alzheimer’s disease, it provided initial evidence of a treatment effect in patients with mild Alzheimer’s disease. Similar effects on clinical decline were observed in BLAZE, a smaller biomarker study.

In the ABBY study, crenezumab treatment in patients with mild to moderate Alzheimer’s disease tended to slow the decline of cognitive abilities, as measured by the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12), but had no effect on global functioning, as measured by Clinical Dementia Rating-Sum of Boxes. These outcomes were the study’s primary end points. In an exploratory analysis of patients with milder disease treated with IV crenezumab, the researchers observed a positive trend toward greater reduction in cognitive decline in progressively milder subsets of patients, relative to placebo.

In the BLAZE study, which enrolled people who tested positive for an amyloid imaging biomarker, the primary end point was a change in brain amyloid load. In a secondary end point analysis, treatment with IV crenezumab was associated with a trend toward slowing cognitive decline in patients with mild disease (as measured by ADAS-cog12). Biomarker results from the ABBY and BLAZE studies will be presented at an upcoming meeting.

“Data from these phase II studies provide valuable information about crenezumab’s potential clinical activity in people with Alzheimer’s disease, where there is a great need for treatment options,” said Richard Scheller, PhD, Executive Vice President and Head of Genentech Research and Early Development. “These findings support the importance of testing potential disease-modifying agents, such as beta-amyloid antibodies, early in the course of the disease.”

COPENHAGEN—Among cognitively normal seniors, PET scans showed that memory decline was linked with higher levels of tau buildup in several brain regions, according to researchers.

Keith Johnson, MD, and colleagues, using an imaging agent (F18 T807) that binds with tau in the brain, conducted PET scans of 56 cognitively normal living individuals. Participants had a median age of 72 and had undergone annual memory testing during the previous three years.

Dr. Johnson’s group found that higher levels of tau in areas of the brain important to memory (ie, entorhinal cortex and temporal neocortex) were associated with worsening on the memory test.

“These preliminary data suggest that tau in these brain areas is related to memory decline in normal older individuals,” said Dr. Johnson, Director of Molecular Neuroimaging in the Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, in Boston. “This study demonstrates the potential for PET technology to be used for early detection and to help pick participants for prevention trials and treatment trials that target tau.”

In previous research, levels of tau in the brain were more closely associated with cognitive decline in Alzheimer’s disease than were levels of beta-amyloid. Identifying the early buildup of these proteins in the brain, even before memory and thinking symptoms are present, is considered a strong candidate for early detection and diagnosis of Alzheimer’s disease and for identifying volunteers for prevention studies.

Subjective Memory Complaints in Midlife May Be Linked to Risk for Alzheimer’s Disease
Middle-aged persons with subjective memory complaints have a thinner cortex in brain regions that are vulnerable to Alzheimer’s disease and perform worse on objective cognitive tests that suggest Alzheimer’s disease, compared with middle-aged persons without subjective memory complaints, according to research presented at the 2014 Alzheimer’s Association International Conference.

“These findings suggest that some persons who endorse subjective memory complaints in midlife might be at increased risk of progression to Alzheimer’s disease in the future,” reported Stephanie Schultz, a research specialist at the Wisconsin Alzheimer’s Disease Research Center in Madison. “Therefore, such individuals might be prime candidates for clinical trials aimed at retarding the evolution of the Alzheimer’s disease pathophysiologic process.”

Subjective memory complaints are subtle changes in memory that fall below detection thresholds of common cognitive tests. “However, it is not fully known whether persons with subjective memory complaints have Alzheimer’s disease–related brain alterations or whether they indeed demonstrate poorer cognitive performance,” noted Ms. Schultz.

The researchers sought to determine whether subjective memory complaints were associated with the thinning of cortical regions involved in Alzheimer’s disease and worse performance on objective cognitive tests. Analysis was based on 216 middle-aged persons with risk factors for Alzheimer’s disease who were enrolled in the Wisconsin Registry for Alzheimer’s Prevention (median age, 54; 67% women). Forty-two percent of subjects tested positive for APOE ε4, and 71% had a family history of Alzheimer’s disease.

All participants completed a questionnaire that included the following item pertaining to subjective memory difficulties: “Do you think you have a problem with your memory?” A total of 77 persons said “yes,” and 184 said “no.” During the same visit, the participants also underwent a comprehensive neuropsychologic examination. After a mean of 5.48 years, the subjects underwent a 3D T1 MRI scan.

The researchers observed no significant differences regarding age, sex, APOE ε4 status, family history of Alzheimer’s disease, education, or score on the Mini-Mental Status Examination between persons who reported subjective memory problems and those who did not.

Compared with those who did not report a subjective memory problem, persons with a subjective memory problem had “significant cortical thinning in the entorhinal, fusiform, posterior cingulate, and inferior parietal cortices, as well as significantly reduced amygdala volume,” stated Ms. Schultz.

In addition, compared with the group who did not report a subjective memory problem, the group with a subjective memory problem had “significantly lower test scores—albeit within normal limits—on measures of immediate memory, verbal learning and memory, and verbal ability,” Ms. Schultz concluded.

—Colby Stong

Phase II Clinical Trial Results of Crenezumab for Alzheimer’s Disease
At the 2014 Alzheimer’s Association International Conference, Roche presented data from two phase II studies investigating whether crenezumab can delay cognitive and functional decline in patients with mild to moderate Alzheimer’s disease.

Although the larger study, known as ABBY, did not meet its primary end points in patients with mild to moderate Alzheimer’s disease, it provided initial evidence of a treatment effect in patients with mild Alzheimer’s disease. Similar effects on clinical decline were observed in BLAZE, a smaller biomarker study.

In the ABBY study, crenezumab treatment in patients with mild to moderate Alzheimer’s disease tended to slow the decline of cognitive abilities, as measured by the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12), but had no effect on global functioning, as measured by Clinical Dementia Rating-Sum of Boxes. These outcomes were the study’s primary end points. In an exploratory analysis of patients with milder disease treated with IV crenezumab, the researchers observed a positive trend toward greater reduction in cognitive decline in progressively milder subsets of patients, relative to placebo.

In the BLAZE study, which enrolled people who tested positive for an amyloid imaging biomarker, the primary end point was a change in brain amyloid load. In a secondary end point analysis, treatment with IV crenezumab was associated with a trend toward slowing cognitive decline in patients with mild disease (as measured by ADAS-cog12). Biomarker results from the ABBY and BLAZE studies will be presented at an upcoming meeting.

“Data from these phase II studies provide valuable information about crenezumab’s potential clinical activity in people with Alzheimer’s disease, where there is a great need for treatment options,” said Richard Scheller, PhD, Executive Vice President and Head of Genentech Research and Early Development. “These findings support the importance of testing potential disease-modifying agents, such as beta-amyloid antibodies, early in the course of the disease.”