Amyloid beta antibody treatments address Alzheimer’s disease by targeting amyloid beta, a protein implicated in its progression. These therapies use specific proteins, engineered in laboratories, to interact with amyloid beta. Their aim is to modify the underlying biological processes associated with Alzheimer’s.
The Role of Amyloid Beta in Alzheimer’s Disease
Amyloid beta is a naturally occurring protein fragment derived from amyloid precursor protein (APP). In a healthy brain, these fragments are broken down and cleared. However, in individuals with Alzheimer’s disease, these amyloid beta fragments often misfold and aggregate.
These misfolded proteins clump together to form insoluble deposits known as amyloid plaques. These plaques accumulate outside brain cells, disrupting normal cellular communication and function. Plaque formation is a hallmark pathological feature in Alzheimer’s.
The “amyloid cascade hypothesis” suggests that this accumulation of amyloid beta plaques initiates a sequence of events. This theory proposes that plaques trigger inflammation and lead to neurofibrillary tangles, composed of tau protein. This cascade contributes to brain cell damage and the cognitive decline characteristic of Alzheimer’s disease.
Mechanism of Action for Amyloid Beta Antibodies
Amyloid beta antibodies are monoclonal antibodies that function like natural immune system antibodies. These therapeutic antibodies are administered through intravenous infusion, circulating throughout the bloodstream.
Once in the bloodstream, these antibodies traverse the blood-brain barrier, gaining access to the brain. Upon entering, they selectively recognize and bind to amyloid beta proteins, whether individual fragments or aggregated into plaques.
This binding “tags” the amyloid deposits. The brain’s immune cells, called microglia, then recognize these tagged structures. Microglia engulf and clear away the antibody-bound amyloid through phagocytosis, reducing the overall amyloid plaque burden.
Approved and Investigational Antibody Therapies
Several amyloid beta antibody therapies have emerged. Lecanemab (Leqembi) has received regulatory approval. This antibody specifically targets and binds to amyloid beta protofibrils, which are small, soluble aggregates of amyloid beta that are thought to be particularly toxic to neurons.
Donanemab is another antibody therapy showing promising results in clinical trials. This drug binds to a modified form of amyloid beta, specifically targeting established amyloid plaques rather than the smaller aggregates. Its mechanism focuses on clearing these pre-existing deposits from the brain.
Aducanumab (Aduhelm) was an earlier antibody therapy that garnered attention and controversy upon its accelerated approval. This antibody also targets amyloid beta plaques, aiming to reduce their presence. Its introduction paved the way for further research and development in the field of amyloid-targeting treatments.
Clinical Outcomes and Patient Considerations
Clinical trials for amyloid beta antibody treatments have demonstrated their ability to modestly slow the rate of cognitive and functional decline in individuals with early-stage Alzheimer’s disease. These therapies do not reverse existing brain damage or restore lost memories, but rather aim to preserve cognitive function for a longer period. The observed slowing of decline has typically been in the range of 20-35% over 18 months.
A significant consideration with these treatments is the potential for Amyloid-Related Imaging Abnormalities (ARIA). ARIA manifests as temporary brain swelling (ARIA-E) or small brain bleeds (ARIA-H), detectable through magnetic resonance imaging (MRI). These abnormalities often resolve spontaneously, but regular MRI monitoring is required during treatment to detect and manage them.
Patient eligibility for these therapies is quite specific, generally limited to individuals in the early stages of Alzheimer’s disease, including those with mild cognitive impairment due to Alzheimer’s or mild Alzheimer’s dementia. Confirmation of amyloid pathology in the brain, typically through a positive amyloid PET scan or specific cerebrospinal fluid tests, is a prerequisite for treatment. These criteria ensure that the treatment is directed at individuals where amyloid plaques are confirmed.