Failed amyloid clearance may be cause of AD
Defective mechanisms for removing amyloid-beta protein from the brain, rather than excessive production, may be the root cause of Alzheimer's disease, researchers said.
Rates of amyloid-beta production appeared similar in 12 patients with late-onset Alzheimer's disease relative to 12 cognitively healthy controls, but clearance rates were lower by about 30%, according to Randall J. Bateman, MD, of Washington University in St. Louis, and colleagues.
Writing online in Science, the researchers concluded that "the common late-onset form of Alzheimer's disease is characterized by an overall impairment in amyloid-beta clearance."
The findings were based on measurements of metabolically labeled amyloid-beta protein in cerebrospinal fluid samples. The 40- and 42-amino acid forms of the protein were analyzed separately.
Numerous potential therapies for Alzheimer's disease have been developed that seek to limit amyloid-beta production, such as by inhibiting enzymes that cleave the protein from a larger precursor sequence.
However, those that have reached advanced clinical testing have yielded disappointing results, , fueling doubts about amyloid-beta's contribution to Alzheimer symptoms in the first place.
The findings by Bateman and colleagues suggest that amyloid deposits may indeed be important in Alzheimer pathology, but not because of excessive production.
The researchers recruited 12 patients older than 60 diagnosed with early-stage Alzheimer's disease (Clinical Dementia Rating scores of 0.5 to 1.0) and no other known possible explanation for their symptoms.
Patients' average age was 77. Two were homozygous for the epsilon-4 apolipoprotein E allele and four were heterozygous for it and the epsilon-3 allele.
Control participants were somewhat younger, with a mean age of 71. None were homozygous for apoE epsilon-4 but six showed type 3/4 heterozygosity.
During lumbar puncture, participants received an infusion of 13C-leucine, which attaches to amyloid-beta and serves as a radiolabel. CSF and blood samples were taken over a 36-hour period.
Rates of amyloid-beta production and clearance could be inferred from the respective levels of labeled and unlabeled proteins in serial samples.
"The increase in labeled amyloid-beta during the production phase and the removal of labeled amyloid-beta during the clearance phase reflects the relative production and clearance of amyloid-beta in the central nervous system," Bateman and colleagues explained.
They found that production rates were virtually identical in patients and controls -- averaging 6.6% and 6.8% per hour for the AB-42 and AB-40 forms of the protein in patients, respectively, versus 6.7% and 6.8% per hour, respectively, in the controls.
Clearance rates, on the other hand, were clearly different: 5.3% per hour in patients compared with 7.6% per hour in controls for AB-42 (P=0.03). Results were similar for AB-40, with clearance rates of 5.2% per hour in patients and 7.0% per hour in controls (P=0.01).
Although the findings "suggest impaired metabolism of amyloid beta in Alzheimer's disease compared to controls," Bateman and colleagues wrote, they noted that alternative explanations were possible because of the small sample size and limitations to their measurements.
For example, they noted, pools of amyloid proteins in CSF could have escaped detection with their methods.
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