Spinal Fluid Proteins may Signal Alzheimer's.
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Decreases with age in the cerebrospinal fluid concentrations of a specific amyloid-beta protein may help identify the early signs of Alzheimer's disease.
Older cognitively normal patients with the apolipoprotein E 4 (ApoE4) genetic variant, which confers increased risk for Alzheimer's, had significantly greater decreases in levels of amyloid-beta42 protein in their CNS fluid than did older people with low-risk alleles, reported Elaine R. Peskind, M.D., of the VA Puget Sound Health Care System, and colleagues.
Among volunteers in a community-based study who were negative for the ApoE4 allele, mean amyloid-beta42 levels in CSF rose slightly until about age 50, then fell slightly with increasing age.
Among ApoE4 carriers, however, amyloid-beta42 concentrations declined slightly in the younger participants, then dropped off rapidly beginning between the ages of 50 and 60 years, the investigators reported in the July issue of the Archives of Neurology.
The investigators did a single spinal tap for each of 184 volunteers who were from 21 to 88 years old.
These findings have implications for the preclinical diagnosis of Alzheimer's, as well as for treatment," Dr. Peskind and colleagues wrote. "Follow-up of cohorts such as ours will be important to affirm our cross-sectional findings and to assess whether subjects who fall in the lowest part of the age- and ApoE-adjusted range for CSF amyloid-beta42 concentration have the highest risk of developing Alzheimer's."
In an accompanying editorial, Archives of Neurology editor Roger N. Rosenberg, M.D., a neurologist at the University of Texas Southwestern Medical Center in Dallas, wrote that the data "provide the means to identify patients who have the apolipoprotein E 4 allele, potentially have asymptomatic Alzheimer disease, are acquiring the neuropathologic abnormalities of the disease as indicated by abnormal cerebrospinal fluid levels of ab42, and would be ideal candidates for therapeutic intervention."
The amyloid-beta peptide is cleaved by the amyloid precursor protein into fragments ranging between 38 and 42 amino acids in length, hence the amyloid-beta42 designation. Previous studies have shown that decreased levels of amyloid-beta42, but not amyloid-beta4o in CSF is a biomarker for Alzheimer's.
Amyloid-beta42 concentrations may be lower in patients with AD because the protein fragment is taken up by amyloid-beta plaques in the brain, presumably years before symptoms of the neurodegenerative disease develop, the authors suggested.
To get a handle on the interactive effects of normal aging and the presence of the ApoE4 allele on levels of amyloid-beta42 in CNS fluid, the authors recruited 184 volunteers who were from 21 to 88 years old.
The participants, 94 men and 90 women, all underwent detailed clinical and laboratory evaluations and were found to be cognitively normal on the Mini-Mental State Examination and Clinical Dementia Rating Scale, and had no clinical evidence or history of cognitive or functional decline.
Cerebrospinal fluid was collected by spinal tap in the morning following an overnight fast, and concentrations of amyloid-beta42 and amyloid-beta40 were measured by sandwich enzyme-linked immunosorbent assay. The investigators also used restriction digest techniques to determine ApoE genotypes in the volunteers.
They found that concentration of amyloid-beta42, but not amyloid-beta40 decreased significantly with age in all participants.
There was a sharp decrease in CSF amyloid-beta42 concentrations beginning in the 60s in participants who were positive for the ApoE4 allele. The age-associated decrease was significantly greater, and the effect was larger, in those participants who were ApoE4 carriers than among those who did not have the high-risk allele.
"Our results are therefore consistent with differential aggregation and deposition in the brain, clearance, or binding to carrier molecules that selectively affects amyloid-beta42," they wrote.
"These results do suggest that sequestration of amyloid-beta42 in the brain occurs early in ApoE4 allele carriers, bolstering evidence for this as a key initiating factor in AD pathogenesis. Measuring amyloid-beta concentration in CSF provides an indirect estimation of the net effect of production, clearance, aggregation, and deposition; therefore, we cannot determine which of these factors is most important."
Their findings support the results of a recent study which found that asymptomatic adults who were carriers of mutations in the genes encoding for presenilin complexes involved in amyloid-beta precursor-protein cleavage also had low levels of amyloid-beta42 in CSF, "lending further support to a decrease in CSF ab42 concentration as a preclinical biomarker for AD," they added.
Older cognitively normal patients with the apolipoprotein E 4 (ApoE4) genetic variant, which confers increased risk for Alzheimer's, had significantly greater decreases in levels of amyloid-beta42 protein in their CNS fluid than did older people with low-risk alleles, reported Elaine R. Peskind, M.D., of the VA Puget Sound Health Care System, and colleagues.
Among volunteers in a community-based study who were negative for the ApoE4 allele, mean amyloid-beta42 levels in CSF rose slightly until about age 50, then fell slightly with increasing age.
Among ApoE4 carriers, however, amyloid-beta42 concentrations declined slightly in the younger participants, then dropped off rapidly beginning between the ages of 50 and 60 years, the investigators reported in the July issue of the Archives of Neurology.
The investigators did a single spinal tap for each of 184 volunteers who were from 21 to 88 years old.
These findings have implications for the preclinical diagnosis of Alzheimer's, as well as for treatment," Dr. Peskind and colleagues wrote. "Follow-up of cohorts such as ours will be important to affirm our cross-sectional findings and to assess whether subjects who fall in the lowest part of the age- and ApoE-adjusted range for CSF amyloid-beta42 concentration have the highest risk of developing Alzheimer's."
In an accompanying editorial, Archives of Neurology editor Roger N. Rosenberg, M.D., a neurologist at the University of Texas Southwestern Medical Center in Dallas, wrote that the data "provide the means to identify patients who have the apolipoprotein E 4 allele, potentially have asymptomatic Alzheimer disease, are acquiring the neuropathologic abnormalities of the disease as indicated by abnormal cerebrospinal fluid levels of ab42, and would be ideal candidates for therapeutic intervention."
The amyloid-beta peptide is cleaved by the amyloid precursor protein into fragments ranging between 38 and 42 amino acids in length, hence the amyloid-beta42 designation. Previous studies have shown that decreased levels of amyloid-beta42, but not amyloid-beta4o in CSF is a biomarker for Alzheimer's.
Amyloid-beta42 concentrations may be lower in patients with AD because the protein fragment is taken up by amyloid-beta plaques in the brain, presumably years before symptoms of the neurodegenerative disease develop, the authors suggested.
To get a handle on the interactive effects of normal aging and the presence of the ApoE4 allele on levels of amyloid-beta42 in CNS fluid, the authors recruited 184 volunteers who were from 21 to 88 years old.
The participants, 94 men and 90 women, all underwent detailed clinical and laboratory evaluations and were found to be cognitively normal on the Mini-Mental State Examination and Clinical Dementia Rating Scale, and had no clinical evidence or history of cognitive or functional decline.
Cerebrospinal fluid was collected by spinal tap in the morning following an overnight fast, and concentrations of amyloid-beta42 and amyloid-beta40 were measured by sandwich enzyme-linked immunosorbent assay. The investigators also used restriction digest techniques to determine ApoE genotypes in the volunteers.
They found that concentration of amyloid-beta42, but not amyloid-beta40 decreased significantly with age in all participants.
There was a sharp decrease in CSF amyloid-beta42 concentrations beginning in the 60s in participants who were positive for the ApoE4 allele. The age-associated decrease was significantly greater, and the effect was larger, in those participants who were ApoE4 carriers than among those who did not have the high-risk allele.
"Our results are therefore consistent with differential aggregation and deposition in the brain, clearance, or binding to carrier molecules that selectively affects amyloid-beta42," they wrote.
"These results do suggest that sequestration of amyloid-beta42 in the brain occurs early in ApoE4 allele carriers, bolstering evidence for this as a key initiating factor in AD pathogenesis. Measuring amyloid-beta concentration in CSF provides an indirect estimation of the net effect of production, clearance, aggregation, and deposition; therefore, we cannot determine which of these factors is most important."
Their findings support the results of a recent study which found that asymptomatic adults who were carriers of mutations in the genes encoding for presenilin complexes involved in amyloid-beta precursor-protein cleavage also had low levels of amyloid-beta42 in CSF, "lending further support to a decrease in CSF ab42 concentration as a preclinical biomarker for AD," they added.
posted by Valery Yermalitsky at
6:28 AM
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