This is an extremely important paper for the Alzheimer’s field and is likely to greatly influence the way researchers think about potential Alzheimer’s treatment strategies going forward. 
 
The development of new treatments that slow or block Alzheimer’s disease has been elusive, despite decades of research worldwide. This comprehensive and elegant study from Michael Heneka’s group provides strong evidence in support of a possible new disease mechanism and a new approach for treating Alzheimer’s disease. 
 
Dementia is the second leading cause of death of Australians, contributing to 5.4% of all deaths in males and 10.6% of all deaths in females each year. Alzheimer’s is the most common form of dementia.

For decades, the field of Alzheimer’s research has considered that a substance called amyloid is the cause of Alzheimer’s disease. This is in part because plaques are often seen in the brain of people with Alzheimer’s and amyloid is found in those plaques. It is not truly known what causes the plaques or whether amyloid truly causes Alzheimer’s disease.

Despite this, there have been numerous efforts to develop drugs that block Alzheimer’s disease by trying to remove amyloid from the brain of Alzheimer’s patients. Unfortunately however, there has been a string of high profile failures of these experimental treatments. Therefore the field is looking for new approaches to both explain the disease and to block the disease. 
 
Our group has long been suggesting that inflammation is a key mediator of Alzheimer’s disease. In this exciting study, the scientists led by Michael Heneka show that inflammation leads to the formation of “ASC specks” in the brain. They show that these specks seed the spread of amyloid in the brain, showing the first direct link between inflammation and amyloid deposition.

Interestingly, blocking speck formation prevented the spread of the amyloid in the brain and also reduced the extent of Alzheimer’s-like symptoms.

The study therefore shows unequivocally that inflammation (more specifically a process called “inflammasome activation”) leads to both disease and the spread amyloid.

Whether the amyloid actually is involved in the ultimate cause of disease is not proven in this study. However, the very exciting point is that blocking ASC specks may offer an exciting approach to treating disease. 
 
Thus, in summary, the data presented in the paper from Michael Heneka’s group provide highly convincing evidence that a process called inflammation that induced ASC speck formation in the brain is associated with Alzheimer’s pathology in both humans and in animals. The paper shows that blocking ASC speck formation protects against Alzheimer’s pathology.

This paper therefore clearly shows that ASC speck formation is instrumental in disease process showing unequivocally a link between inflammation and Alzheimer’s disease. This suggests a very exciting new way of thinking about the disease and treating it.
 
NOTES

• Currently around 244 people each day are joining the population with dementia in Australia. The number of new cases of dementia will increase to 318 people per day by 2025 and over 650 people per day by 2056
• Reducing the annual age-sex specific incidence rates for dementia in people aged 65 years and above by 5% would lead to nearly 36,400 fewer people with dementia in 2025 and almost 261,000 fewer people by 2056 compared with the current projections. This could save more than $120 billion by 2056
• Worldwide, there are more than 46.8 million people with dementia today and 131.5 million predicted by 2050
• If dementia were a country, it would be the world’s 18th largest economy 5

This research confirms the role of inflammatory process in the spread of the key Alzheimer pathology, the Amyloid beta oligomers or clumps of the toxic protein that accumulate over time are harmful to nerve cells and lead to the clinical picture of Alzheimer dementia after two to three decades.

The authors showed that blocking this inflammatory process could stop this damaging spread of toxic protein.

This could herald a new therapeutic target.

One of the most impenetrable but exciting papers I have read for a long time may hold a key to the puzzle that is Alzheimer’s disease.

Alzheimer’s disease is the major dementia amongst the elderly in Australia and most of the developed world. The disease typically begins to appear after the age of 60, and is more common in older people and with an ageing population we expect the number of people with this devastating disease will increase.

We still have little idea of why Alzheimer’s disease occurs.

We know that in Alzheimer’s disease one of the key hallmarks is the accumulation of large tangles of an insoluble toxic protein called beta amyloid, and production of this protein is thought to play a major role in the disease.

However, the body normally makes a harmless, soluble form of beta amyloid. What makes this harmless form turn toxic in some (but not all) older people? This paper provides a clue.

We also know inflammation is associated with Alzheimer’s disease, but is inflammation the chicken or the egg?

We also know that the toxic insoluble amyloid is also an antibacterial, and may form part of an ancient immune response. But what makes the soluble beta amyloid turn toxic?

The current paper shows that that part of the ancient immune system, when activated, released large protein complexes that can bind the soluble beta amyloid and convert it to the toxic insoluble form. The protein complexes (called specs) act as “seeds”, and one complex can generate many molecules of toxic beta amyloid.

Mice that have been genetically engineered to develop a disease that mimics human Alzheimer’s disease, are protected by either knocking out the gene for these protein complexes or administering antibodies that inactivate the protein complexes.

While this paper is a tour-de-force of science, questions remain, such as what starts the inflammation in the brain in the first place? Why does Alzheimer’s disease take so long to develop in humans?

We have also been targeting beta amyloid (and inflammation) in Alzheimer’s disease for a while now, and virtually everything we have tried has failed. Will targeting this ancient immune system work?

It is too early to tell, but therapy may have to start decades before Alzheimer’s disease becomes apparent.

While this paper is important, a cure for Alzheimer’s disease is not around the corner.

This is an important, albeit preliminary, study that suggests that the amyloid pathology may not be the prime trigger mechanism for Alzheimer Disease, but instead the trigger is due to an inflammatory process in the brain.

It would also help explain why episodes of delirium in older people, often associated with inflammatory mechanisms, increase the risk of dementia.