Alzheimer’s disease features the build-up of two distinct proteins in the brain: beta-amyloid, which accumulates in clumps, and tau, in tangles. But how exactly they relate to each other and the death of neurons has remained a mystery – perhaps until now.

Alzheimer's Missing Link
Are we closer to finding the Alzheimer’s Disease cure?

The role of beta-amyloid

A key conundrum is the role of beta-amyloid. Pathologists examining the brain of an Alzheimer’s patient can see it everywhere, and it appears to go hand-in-hand with the destruction of brain tissue that leads to dementia. Problem is, lab studies have shown that beta-amyloid only kills neurons in very high doses, and the beta-amyloid observed in post-mortem brains is simply not enough to account for the damage.

What’s more, drugs that successfully target beta-amyloid just don’t seem to work.

The role of tau

Then there is tau, which could either be a cause or an effect. The situation is puzzle in plain sight, akin to finding Colonel Mustard and Miss Scarlett laid out in the Billiard Room, the candlestick and lead pipe lying nearby, but without knowing who did what, and why. Until we know the correct sequence of events, our attempts to treat Alzheimer’s will continue to fail.

A missing link?

A paper in Alzheimer’s & Dementia (Dec 7, 2020) claims to have found the missing link. The author, Qin Wang, names the surprising culprit as noradrenaline: a key hormone in our flight or fight response which primes body and brain for action.

Wang argues that noradrenaline works with beta-amyloid to boost an enzyme that both activates tau and makes brain cells more vulnerable to it. In other words, noradrenaline is like a potent whiskey imbibed by Colonel Mustard and Miss Scarlett, which makes them more likely to slug each other with household implements, and more likely to die when they do.

With noradrenaline, it takes only 1-2% as much beta-amyloid to kill brain cells. Conversely, drugs might slash beta-amyloid levels, but even the small amount left behind will be enough to wreak havoc.

Noradrenaline is particularly intriguing because it makes sense of another curious element of dementia: the role of stress. Doctors have long noticed that patients with Alzheimer’s often decline more quickly amidst emotional turmoil, but have never had a precise mechanism to explain why. The usual explanation is that Alzheimer’s leads to depression, which places further strain on cognitive reserves, triggering a steeper decline.

Now we can hypothesise that the raised levels of noradrenaline in stress hastens the destructive effect of beta-amyloid and tau. Their build-up then catalyses further damage: a vicious circle indeed.

Yet this discovery also brings hope. Wang is now testing a discarded antidepressant, idazoxan, that acts against noradrenaline.

Studying mice, she and her colleagues have found that idazoxan blocked a key noradrenaline receptor, and thus deactivated the enzyme that made tau toxic.

Are we on the right path?

While this result is very promising, idazoxan alone is unlikely to halt Alzheimer’s because there remains the issue of beta-amyloid. Yet perhaps a drug like idazoxan could be part of combination treatment that involves beta-amyloid blockers, and such a multi-faceted approach could begin to make headway.

Worldwide there are dozens of drugs under study that aim to stop beta-amyloid triggering tau, so the prospect of a cocktail against early Alzheimer’s might not be too far away.

References

Qin Wang, Amyloid β redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade. Alzheimer’s and Dementia Volume16, Issue S6, 07 December 2020 https://doi.org/10.1002/alz.044769

Hammond, T.C., Xing, X., Wang, C. et al. β-amyloid and tau drive early Alzheimer’s disease decline while glucose hypometabolism drives late decline. Commun Biol 3, 352 (2020). https://doi.org/10.1038/s42003-020-1079-x

Zhang, F. et al. β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade. Science Translational Medicine 15 Jan 2020: Vol. 12, Issue 526, eaay6931 DOI: 10.1126/scitranslmed.aay6931

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