Since the discovery of the beta-amyloid peptide in 1984, the amyloid cascade hypothesis has been the primary focus of research surrounding Alzheimer’s disease treatment and is more or less dominating the Alzheimer’s research space. The hypothesis states that the deposition of beta-amyloid protein, the primary component of the plaques, is the causative agent of Alzheimer’s disease pathology and that hallmarks, such as neurofibrillary tangles, cell loss, vascular damage, and dementia, directly result from this deposition.
However, in the past decade, after countless failed clinical trials targeting beta-amyloid plaques, this school of thought is rapidly changing. While beta-amyloid deposition is certainly still a neuropathological hallmark of Alzheimer’s disease and plays a role in the development and progression of Alzheimer’s, it is not the only factor driving Alzheimer’s disease progression. Effective treatment of Alzheimer’s disease will likely rely on a combination of multiple effective therapies targeting different pathological mechanisms. Consequently, a vast range of new novel targets, including neuroinflammation, have entered the clinical research pipeline.
Below, we take a closer look at Alzheimer’s disease neuropathology, the role of neuroinflammation in Alzheimer’s disease, neuroinflammation as a target for treatment, and the shift towards combination treatments for Alzheimer’s.
Neuropathological hallmarks of Alzheimer’s disease consist of positive and negative lesions. Positive lesions include tau hyperphosphorylation, neurofibrillary tangles, beta-amyloid plaques, cerebral amyloid angiopathy, and glial responses, while negative lesions include neuronal and synaptic loss. However, Alzheimer's is most commonly characterized by two core characteristics: beta-amyloid plaques and neurofibrillary tangles resulting from abnormal tau hyperphosphorylation.
In the past decade, a third core feature of Alzheimer’s has emerged; recent research suggests that chronic neuroinflammation influences beta-amyloid deposition and tau phosphorylation and may contribute to accelerated Alzheimer’s disease progression. In several other studies, it has also been proposed that the inflammatory response may link the initial beta-amyloid pathology and the later development of neurofibrillary tangles.
Acute inflammation in the brain is a normal defense against toxins, infections, and injury; however, in Alzheimer’s disease, there is a disruption in the equilibrium of anti- and pro-inflammatory signals, which can result in chronic neuroinflammation, the hallmark of dysregulated microglia.
Consequently, chronic neuroinflammation in Alzheimer’s disease is believed to be primarily attributed to activated microglial cells and the release of cytokines. Chronic neuroinflammation was previously thought to be a result of the neuronal loss that occurs in Alzheimer’s. However, a significant amount of research suggests that this sustained immune response in the brain is an early event in the Alzheimer’s disease continuum and neuroinflammation is a central mechanism that facilitates and exacerbates beta-amyloid and tau pathologies in addition to contributing to neurodegeneration. Depending on the state of the disease, activated microglia may have diverse impacts on the progression of Alzheimer’s disease.
It should be noted that neuroinflammation is not unique to Alzheimer’s disease; numerous studies have demonstrated elevated markers of inflammation in the brains of those with Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. Additionally, inflammatory pathways for Alzheimer’s are quite similar to those for diabetes. This is why drugs like semaglutide are often repurposed for Alzheimer’s disease.
As chronic neuroinflammation in Alzheimer’s disease may accelerate other core pathologies, inflammatory mechanisms appear to be viable targets for therapeutic development, alongside established targets, such as beta-amyloid and tau, and new targets, such as mitochondria and metabolic dysfunction, vascular disease, synaptic activity and neurotransmitters, and genetics and epigenetics.
The complex pathology of Alzheimer’s disease will likely necessitate combination treatments rather than monotherapy. Because every individual’s neurocognitive domain functions are affected uniquely in the presence of Alzheimer’s, the treatment pathways will also likely be unique. Utilizing multiple effective treatments tailored to an individual’s specific impairments due to their unique pathological manifestations will allow for more effective, well-rounded, and personalized treatment.
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