A mathematical model of the impact of novel treatments on the A beta burden in the Alzheimer's brain, CSF and plasma.
With the advent of novel therapies for Alzheimer's disease, there is pressing need for biomarkers that are easy to monitor, such as the amyloid-beta (A beta) levels in the cerebrospinal fluid (CSF) and plasma. To gain a better understanding of the explanatory power of these biomarkers, we formulate and analyze a compartmental mathematical model for the A beta accumulation in the brain, CSF and plasma, throughout the course of Alzheimer's treatment. Our analysis reveals that the total A beta burden in the brain is dictated by a unitless quantity called the polymerization ratio, which is the product of the production and elongation rates divided by the product of the fragmentation and loss rates. In this ratio, the production rate and loss rate include a source and sink term, respectively, related to the intercompartmental transport. Our results suggest that production inhibitors are likely to reduce the A beta levels in all three compartments. In contrast, agents that ingest monomers off of polymers, or that increase fragmentation or block elongation, may also reduce A beta burden in the brain, but may produce little change in--or even transiently increase--CSF and plasma A beta levels. Hence, great care must be taken when interpreting these biomarkers.
Craft
David L
DL
Operations Research Center, MIT, Cambridge, MA 02139, USA.
Wein
Lawrence M
LM
Selkoe
Dennis J
DJ
D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D015415:Biomarkers / Q000032:analysis / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008954:Models, Biological
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human