Can Alzheimer's Be Stopped? (NOVA, 13 April 2016)

I. Alzheimer's disease
     A. progressive, incurable brain disease
     B. most common type of dementia
     C. can take 20 or more years to run its course
     D. over 40,000,000 people worldwide
          1. 10,000 people turn 65 every day - when Alzheimer's ramps up
          2. may soon be 10 million cases in the U.S.
     E. discovered in a single patient by Alois Alzheimer in 1906
          1. found plaques and tangles in the brain tissue
          2. distinquished it from other forms of dementia
II. race to find a treatment
     A. to prevent or slow progression
     B. about 20 drugs are currently in testing - only a few have been approved
        (most trials failed so badly that many companies halted development of
        over 100 potential Alzheimer's drugs as too expensive, too risky, and
        with two little hope of payoff - not mentioned in the video)
     C. inherited forms are rare but useful for drug testing because you know
        who is at risk - in one inherited form found in S. America, the chance
        of a child getting Alzheimer's if one parent has it is 50% (the
        characteristic inheritance pattern of an autosomal dominent trait)
III. plaques
     A. made from a protein called amyloid beta
     B. normally waste amyloid is cleared away, but in Alzheimer's it is not -
        instead it clumps into plaques
     C. in a British family they found a mutation in the gene responsible for
        the production of amyloid protein
     D. theorized that the amyloid plaques trigger the degenerative process
          1. this gave the drug makers a target
          2. stop the production of plaques and get rid of the ones that have
             already formed
          3. the Genentech drug is an antibody that binds to amyloid and 
             triggers the cell to destroy it
          4. similar drugs have had side effects like brain swelling in the past
     E. clincal trials with Alzheimer's patients
          1. 1/3 get high dose, 1/3 get low dose, 1/3 get placebo
          2. double blind - nobody knows who is getting which treatment to
             eliminate possible bias in the results
          3. people getting the placebo should continue to decline
          4. people getting the drug should decline more slowly or remain stable
          5. will the drug stop plaques from forming, and if so will this
             slow the progression of the disease
          6. at the "unblinding" it was found that the low dose didn't work, but
             the high dose had some benefit in milder patients (2014)
     F. prevention trials can be done with the inherited form
          1. because they know who's going to get it (from genetic tests)
          2. plaques form long before dementia begins - perhaps 20 years or
             more before the onset of symptoms (as visualized on brain scans)
          3. results won't be available until 2020
     G. the Biogen trials used only milder patients who were scanned to confirm
        that plaques were present - also tested antibodies
          1. plaques were reduced during the trial
          2. this correlated with a slower decline in cognition
          3. headache and edema (swelling) were side effects
IV. tangles - intracellular clumps of protein called tau
     A. almost everybody has some tau build-up
     B. in some people this spreads - but it does not spread unless there are
        plaques present
          1. possible that tangles do the actual damage but are set off by
             the presence of amyloid plaques
    [not in the video]
          2. this is becoming the leading theory - even in the absence of
             amyloid plaques, abnormal tau could be disease causing
          3. abnormal tau can spread from cell to cell like a pathogen
          4. treating the plaques may prevent Alzheimer's, but for people with
             Alzheimer's it's the abnormal tau that must be treated
          5. one promising lead is to attack tangled proteins using a phage
             (a virus that normally attacks bacteria) - phages have now been
             found that attack a wide variety of misfolded proteins, not only
             plaques and tangles in Alzheimer's, but also the misfolded proteins
             that occur in Parkinson's, ALS, and even prion diseases like CJD
          6. there are now two competing theories of Alzheimer's, the old
             amyloid theory, and the newer tau theory
          7. other abnormalities have also been found in mitochondria and
             microglia (the brain's immune cells)