A New Explanation For Why So Many Alzheimer’s Trials Fail

Around 40-60% of Alzheimer’s patients also have Vascular Cognitive Impairment and Dementia (VCID), which may explain why so many trials have failed

Alzheimer’s disease (AD) is actually comparatively well funded, with a US federal budget of $936 million in 2016. Despite the significant research efforts ongoing across the globe however, and a vastly improved understanding in Alzheimer’s pathology, the vast majority of trials have failed and those that have ‘succeeded’ have shown disappointing results – with many patients finding no benefit at all. This has confounded scientists for some time and led to a great debate over exactly what causes the disease. 

“These findings are important in that they provide a possible explanation for why clinical trials of anti-Aβ immunotherapy for Alzheimer’s disease have been historically unsuccessful. If up to 40 percent of people with Alzheimer’s also have VCID, treatment candidates that target only the AD physiology won’t be effective in those patients. It’s like treating only half the disease”

Could VCID be behind the failure?

Vascular Cognitive Impairment and Dementia is characterised by an inadequate supply of blood to the brain as a result of stroke events and vascular problems in the brain. The dominant pathology in Alzheimer’s disease is the famous amyloid beta (Aβ) plaques. There are also other features such as tau tangles within cells, but the majority of the scientific community believes that Aβ are the primary cause of neural decline (regardless of how and why Aβ starts to become a problem). 

One promising therapy that emerged was therefore to target Aβ with antibodies or immunotherapy; clearing the toxic peptides from the brain. 

“There has been one failure after another in clinical trials, which has been really disheartening for the scientific community and for patients. This work might shed some early light on why they failed and eventually open the door for a combination treatment for VCID and AD”

Why is VCID a problem when it comes to targeting Aβ?

A recent paper explored the problem of VCID by developing a mouse model combining both VCID and AD. When this model was compared to those mice with only one of the two, it revealed that Aβ targeting therapies showed no effect in the combination mice. VCID was somehow preventing any cognitive benefit from the treatment that was seen in the model with only AD. This means that in order to see benefits in humans it may be necessary to remove patients with VCID from trials, as well as treating VCID in those patients with both diseases. It should be said that Aβ may well not be the best therapy route for Alzheimer’s disease, but this is certainly a fresh explanation of why trials have largely failed in humans thus far after indicating good results in animals. 

“The failure of anti-Aβ immunotherapy in the mixed AD-VCID model suggests that both disease processes have to be treated to have a successful outcome. The missing link has been that our animal models usually possess the hallmarks of only one disease, which has led to failure of successful translation to clinic”

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