Considering Amyloid Beta and Alzheimer's Disease

Efforts to treat Alzheimer's disease by clearing the amyloid beta (Aβ) deposits and related precursors associated with the progression of the condition have proven to be challenging, beset with failures and complications. Wherever there is slow progress in this sort of work, there is always the question of whether the problem is just hard, or whether the whole strategy is the wrong direction. Alternative hypotheses and approaches will spring up, and there is a lot of that going on in Alzheimer's research. Still, the presence of amyloids of various forms are a hallmark of aged tissues, and they should be cleared as a part of the activity of any potential rejuvenation toolkit. The work on clearing Aβ will hopefully contribute meaningfully to the development of a general technology platform to achieve this goal, even if it turns out that Aβ removal isn't the right path for Alzheimer's treatment.

Most people nowadays are familiar with the advice that "correlation does not imply causation." However, this is difficult advice to take when considering human disease where we are unable to ethically experiment on humans without exceptionally good justification. To get that justification we have to rely on studying the effects of a disease in order to make an informed guess about what causes it. The problem with this is that distinguishing the effects of a disease from its causes can get murky.

A good example of this confusion between effects and causes is Alzheimer's disease (AD). AD is defined by the presence of "amyloid plaques" (sticky globs of a protein fragment called amyloid beta or Aβ) in the brains of people with dementia. There is lots of good evidence that Aβ can cause AD. For example, there are families that inherit early-onset forms of AD, and have mutations in the protein itself or in enzymes that process the protein into sticky fragment forms. When these mutants are expressed in mice, the mice develop some (but not all) of the symptoms of AD. Additionally, there are people who naturally produce 50% more of the precursor to Aβ in their cells due to a completely different genetic disease: individuals with trisomy-21, or Down's Syndrome. Down's syndrome is cause by an extra copy of chromosome 21, which adds a whole extra copy of the Aβ precursor. An unfortunate side effect of this disease is that the majority of individuals with trisomy 21 go on to develop dementia and AD in their 30's and 40's.

So stopping Aβ formation is a good way to stop AD, right? That has been the main approach that pharmaceutical companies have taken to treat the disease in the past. Many drugs that aim to reduce Aβ levels in a variety of different ways have been tested, and have all more or less failed to show significant effects in people with mild cognitive impairment (mild memory loss that can develop into AD) or AD. These failures have been costly, surprising, and a bit disheartening.

So why does targeting Aβ fail?


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