Possible Reason Behind Alzheimer's Disease Immunotherapy Failure Discovered
New research may have discovered why anti-amyloid beta immunotherapy fails in many patients.
Investigators in a recent study may have discovered why a certain type of immunotherapy is ineffective in certain patients with Alzheimer’s disease.
These immunotherapy treatments showed promising results in animal studies, but the clinical trials have not shown the same response in humans with Alzheimer’s disease, vascular cognitive impairment and dementia, according to a study published by the Journal of Neuroscience.
Vascular cognitive impairment and dementia is characterized by inadequate blood flow to the brain from micro infarcts, mini-strokes, or strokes. While the 2 diseases may be mutually exclusive, approximately 40% to 60% of patients with Alzheimer’s disease (AD) also have vascular cognitive impairment and dementia (VCID).
In these patients, anti-Aβ immunotherapy is typically unsuccessful.
“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,” said Donna Wilcock, PhD. “If up to 40% 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.”
It has been shown numerous times that the formation of brain plaques containing amyloid β (Aβ) peptides is the first sign of Alzheimer’s disease. Another recent study found that the formation of the initial amyloid fibrils, which make up the amyloid plaques, can take decades, but the process is much more rapid following the initial formation.
Inhibiting the creation of amyloid β plaques has been the focus of many researchers working towards the goal of a treatment for Alzheimer’s disease. Novel anti-Aβ immunotherapy uses antibodies to clear Aβ from the brain has been the leading treatment approach, according to the current study.
Unfortunately, the findings in preclinical studies have not translated to humans.
“There has been 1 failure after another in clinical trials, which has been really disheartening for the scientific community and for patients,” Dr Wilcock said. “My work might shed some early light on why they failed and eventually open the door for a combination treatment for VCID and AD.”
Investigators used a mouse model of combined Alzheimer’s disease and vascular cognitive impairment and dementia, along with a mouse model of Alzheimer’s disease, to examine the ability of anti-Aβ immunotherapy in each. They discovered that Aβ levels were reduced in both, but the groups with Alzheimer’s disease and vascular cognitive impairment and dementia did not have improved cognitive function.
Their findings suggest that this type of immunotherapy may be failing in patients because of the presence of both diseases. A promising strategy may be to target both diseases.
“The failure of anti-Ab 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 1 disease, which has led to failure of successful translation to clinic,” Dr Wilcock said. “By developing a model that more accurately reflects the brain changes we see in the human brain with dementia, we can better develop our treatment approaches and increase our chances of successful translation. Our next step is to add a treatment for VCID on top of the Aβ immunotherapy to try to overcome the inability to produce a meaningful improvement in learning and memory.”