No sooner had Biogen reported on the encouraging results of its Phase 1 clinical trials last week , than the Mayo Clinic published the results of its brain bank analyses.  The Mayo Clinic paper calls into question some fundamental assumptions of researchers who are focused on reducing Abeta protein in the brain as a means of slowing or stopping the progression of Alzheimer’s disease.

 

The Back Story

 

There has long been a divide within the research community, reported before in the blog, as to which protein played the more important role in the development of Alzheimer’s disease: Abeta proteins which form plaques outside of the brain cells, or Tau, which cause tangles inside the cell that lead to its death.  Both proteins accumulate abnormally in the brains of those diagnosed with Alzheimer’s, but no one yet understands why these proteins build up, nor the interplay between these two proteins.

Pharmaceutical companies have targeted Abeta proteins for therapeutic intervention, since they appear before Tau tangles form.  Their hypothesis is that the Abeta proteins trigger the development of Tau.  Since Abeta proteins appear before Tau proteins, the assumption is that the cascade of damaging protein accumulation might be prevented if drugs successfully eliminate the build up of Abeta proteins.

 

Mayo Clinic Findings

 

The Mayo Clinic research first reviewed 3600 brains in its brain bank for the presence of Abeta and Tau.  The researchers then reviewed the PET scans and diagnostic testing of the 35 people who were followed by Mayo during their illness and who subsequently donated their brains to the brain bank after death.

 

The Mayo researchers determined that:

• Although Abeta accumulates in the brain first, the diagnosis of Alzheimer’s disease is linked to the emergence of Tau protein build- up.
• Even if people have significant Abeta build-up in their brains, their cognitive functioning is not impaired.
• The onset of the disease, its duration and a person’s final mini-mental test scores are all correlated to the date Tau starts to accumulate, and amount of Tau in a person’s brain.
• Tau proteins initially form in the hippocampus, the area of the brain which processes short-term memory, and which is the first cognitive deficit associated with Alzheimer’s.  In contrast, Abeta first accumulates in the cortex, whose function is not initially affected in Alzheimer’s disease.

 

Implications of this Study

 

A Screening Test to Detect Tau.  If other scientists corroborate the findings of the Mayo Clinic researchers, researchers will shift focus to finding subjects with Tau deposits, not Abeta deposits.  Since there is no technology yet that images Tau in a living person, the development of this capability takes on new urgency.  In the meantime, researchers may need to determine the level of Abeta in a person’s brain that is predictive of the formation of Tau for purposes of selecting subjects for clinical trials.  Otherwise, trials are likely to include a number of subjects who may never develop Alzheimer’s disease.

 

Review of Clinical Data.  Biogen and Eli Lilly are developing drugs based on the theory that Abeta initiates the disease process.  Their trials include people who have no symptoms of the disease, but who do have Abeta accumulations.  If these people are not susceptible to Alzheimer’s, their inclusion in the trial will distort the results, and the data may overstate a drug’s effectiveness.  It may be worthwhile to review the statistical analyses once subjects with low levels of Abeta are eliminated from database.

Discovering what causes diseases and how to treat them is not a straight-forward endeavor.  Although some will see the Mayo research as a setback to a specific drug trial, the new knowledge gained will lead to a better understanding of the disease process, and ultimately, a more effective treatment.