at the moment considering the negative results for long time-see Elan and Dale Schenk invention about monoclonal antibody in Alzheimer-is still useful to rely on neuro inflammatory hypothesis?

Alain Mititelu on Feb 09, 2016 • 2 answer
• 0
This question has no further details.

Answers

I think it's too early to abandon the neuroinflammatory hypothesis. Most trials that have failed (although not all) have been based on the proposition that if we remove amyloid from the brain, we will prevent or arrest Alzheimer's. I think we can safely abandon that idea for now. Neuroinflammation has only had a few key trials and while the data suggest that blocking inflammation may not work after the dementia has begun, the epidemiological evidence is still strong that if anti-inflammatories, in particular certain NDAIDs, are taken before disease onset there is a a significant protective effect.

Dr. Karl Herrup on Feb 10, 2016
• 1

Hi Alain

I have to confess that I'm puzzled by the framing of your question. I suspect what you mean is that given the poor results in relationship to monoclonal antibodies is is still useful to rely on the amyloid hypothesis?

The neuroinflammatory hypothesis is a somewhat different idea in which sustained inflammation is thought to be driving neurodegeneration, in contrast to traditional viewpoints that until recently considered inflammation either a benign process, or perhaps simply epiphenomenonal, or as even potentially positive as it might remove amyloid. Indeed the neuroinflammatory hypothesis originated almost 20 years ago as a reaction AGAINST the amyloid hypothesis. Its most cogent summary was the classic 2000 paper in the Neurobiology of Aging Neurobiol Aging. 2000 May-Jun; 21(3):383-421.) It's still the most exhaustive summary of the data and empirical findings supporting a neuroinflammatory hypothesis for AD.

However I suspect you are referencing the treatment failures of anti-amyloid monoclonal antibodies in clinical stages of AD. I would agree with Karl Harrup that this hypothesis has hit the proverbial wall and certainly cannot be used at this point to inform a selection of therapeutic agents to treat clinical stages of AD. Whether anti-amyloid therapies may still have some value in relationship to preclinical stages is still an open question that has yet to be supported or falsified.

On the other hand, the neuroinflammatory hypothesis has proven difficult to probe outside of NSAIDs having a role in prevention. Steroids on the other hand make Alzheimer's patients notably worse (by compounding central insulin resistance and through neurotoxic effects on hippocampal systems that are already degenerating. Cytokine blockers, polyphenols, exercise, all have evidence supporting a neuroinflammatory mechanism. I would hope from the failure of the amyloid hypothesis that we don't make the same mistake in relationship to neuroinflammatory issues, reifying a single factor explanation. Of course even if neuroinflammatory processes are centrally contributory to neurodegeneration – and I believe that's a safe and conservative that at this point – that of course begs the question as to what is creating sustained CNS inflammation, and where the inflammation does not terminate its cause. In any other organ system such a situation results eventually in organ failure. I believe that's informative.

If you're interested in this line of analysis, and wish to seek more details about this point of view, I would recommend a careful review of the classic work group paper in the Neurobiology of Aging.

Douglas F Watt on Mar 02, 2016
• 2