"How Not to Study a Disease The Story of Alzheimer's" by Karl Herrup

Recently, I have finished reading a book titled "How Not to Study a Disease The Story of Alzheimer's" by Karl Herrup, the professor in Neurobiology at Pittsburgh University. A traslated version into Japanese. Since the end of last century, he seems to have been involved in research of Alzheimer's disease;abbreviated as AD. A well known neurologist has introduced this book as a work overturning our common sense in AD. AD is not only an interesting subject in medical science but also a topic for myself in the age group favorably affected by AD. At age 85 years, one out of 3 persons could be affected by this malicious illness.

He emphasizes two point. First, the research has been occupied by a dogma of beta amyloid cascade. Historically, this disease was found as a type of early onset dementia pathologically featured with plaque in brain. The plaque was revealed later to be beta amyloid with neurofibrillary tangle. This pathological findings have been regarded as the basic pathogenesis of this disease. That has often excluded the other hypotheses of etiology. Beta amyloid accumulation in brain is found some 30% of intellectually normal elderly whilt 15% of AD won't show its accumulation compared with the age matched control. Both in human and animal models, antibody against beta amyloid could successfully get rid of beta amyloid. In human study, the symptoms have not been improved with that treatment whild it has caused fatal complications. 

There have been the non beta amyloid hypotheses investigated which could co exist the beta amyloid cascade hypothesis. Such as brain chronic inflammation, cholesterol metabolism abnormality related with APOE protein, abnormal myelin sheath, lysosomal dysfunction, mithochodrial dysfunction resulting oxygenation damage and so forth. The mainstream in research has firmly based on the beta amyloid cascade theory and has not valued the other hypotheses even though the latter should have been seriously considered.

The other point the author emphasized is the problem of the research fund. It is handled by National Institute of Aging, NIA, which is rather new division of medical science institute in the US and the top of NIA used to try to get more funds advertizing AD was a disease of the people. It was successful and enabled NIA collect much more funds in behalf of AD research. But their advertisement was based on the beta amyloid cascade hypothesis and the definition of the disease was too broad and ambiguous. It has caused, as the authoer says, further confusion. 

The author's view is that the etiology of AD is closely related with aging process itself. Hyperalimentation with too much glucose intake causes oxygenation in mithochondria through TCA cycle. That oxygenation is closely related with aging. As we get older, there is more unrepairable DNA accumulated, which, in brain, activates microglia in brain and results in chronic inflammation. It is another phenomenon of aging maybe related with AD. 

The author's hypothesis of AD's etiology is dysfunction of the combination composed of neuron, astrocyte, oligodendrocyte, microglia and vessel. This 5 cellular and vascular structure work in combination. When each of them deteriorates, it could cause the dysfunction of the network system. Honestly, this hypothesis was a bit difficult for me to understand. It seemed still premature as a definite etiological hypothesis of AD. Even to me, the etiology research seemed not making much progress since finding of beta amyloid as well as genes responsible for familiar AD. The author's view against binding only to the dogma of beta amyloid seems to be on the right point. I surely hope they would carry on investigation without prejudice or biases. Since AD seems closely related with aging, it may not be easy to understand the whole phenomenon but, as the authoer emphasizes, the other treatments other than beta amyloid related ones could and should be tried even without understanding it.