Alzheimer’s – good, bad and more news

There is no still no scientific consensus on the causal mechanism of Alzheimer’s disease, or at least on the correct target for medicinal intervention – the four main contenders are:

(a) build-up of amyloid-beta fibrils

(b) build-up of tau protein tangles

(c) inflammation in the brain

(d) reaction to a virus infection

The Bad News: Last week the antibody drug “aducanumab” was withdrawn from clinical trials because of poor results – this was an anti-amyloid-beta drug. This follows other disappointing drugs aimed at amyloid-beta.

The Good News: However today there has been more positive news – a drug which has already been approved for clinical use against Hepatitis-D, called Lonafarnib, has been found to dramatically ameliorate the progress of dementia in a mouse model of the disease. The drug seems to block an enzyme (called farnesyltransferase) that facilitates the activity of the protein Rhes ultimately enhancing lysosome activity. Lysosomes are cellular waste-clearance systems that break down the toxic proteins, including tau. Research into this pathway and mechanism may open the door on further possible drugs.

Scientific American article

Update 29th May 2019:  Research published today seems to have established the mechanism by which the Herpes virus can facilitate Alzheimers. Essentially proteins from fluids within the body tend to stick to the virus surface, comprising what is termed a protein corona. It seems that there is enzymatic activity within that corona that facilitates the aggregation of amyloid plaques. It is suggested that this may not be the only causal factor leading to Alzheimers but certainly is capable of speeding up the disease process.

New Atlas article

Nature article

Update 16th Jan 2020: Research published today has shed some light on the possible mechanism leading to Alzheimers. It seems that even a little beta-amyloid will bind receptors fpr norepinephrine, a neuro-transmitter. This triggers the GSK3-beta enzyme which causes the tau tangles to become toxic, killing brain cells. This explains why the drug trials that aim to clear beta-amyloid have failed – there will always be a little left which is sufficient to trigger the critical link – GSK3-beta. The epinephrine receptor can be blocked by drugs such as idazoxan (which is already approved, but failed its clinical trials for depression treatment). Tests in mice have shown that tau build-up is indeed blocked by that drug. Independent work on blocking kinases has also implicated GSK3-beta. This holds great promise for a treatment at long last.

Herpes virus implicated in Alzheimers

Research published today in the journal “Neuron”, from analysis of DNA and RNA in Alzheimer brains, shows that Herpes virus HHV-6A and 7 (as well as the cold sore  Herpes HSV-1) are present at higher levels in Alzheimer brains than normal brains, and that the level is associated with severity.

It is posited that the virus suppresses a microRNA which usually turns off a specific gene. Indeed when they bred mice deficient in that mRNA, they found the mice developed abundant amyloid plaques – the hallmark of Alzheimers.

Alternatively it may be that amyloid plaque is generated as a defence by the brain against the virus, but that the immune response cascades out of control.

A lot more research is needed to clarify, and unfortunately the Alzheimer research community is currently rather hostile to the idea that microbes are involved in the disease process. (Interestingly the researchers were not looking for viral implication, it just showed up in the data.)

Scientific American article