The scientific community is engaged in a vigorous debate regarding the underlying cause of Alzheimer's disease (AD), specifically questioning the long-held belief that extracellular amyloid plaques are the primary driver of neurodegeneration. This debate has been fueled by recent clinical trial results and a re-evaluation of genetic and pathological evidence.
Challenging the Amyloid Cascade Hypothesis
Scott A. Small, Director of the Alzheimer’s Disease Research Center at Columbia University, penned an open letter to Dennis J. Selkoe, a leading Alzheimer's researcher at Harvard Medical School, published on Alzforum. In the letter, Small challenges the conclusion that extracellular amyloid aggregates are a definitive cause of AD. He argues that while amyloid-clearing drugs have demonstrated the ability to remove amyloid plaques from the brain, clinical trials have not consistently shown a corresponding reduction in neurodegeneration.
"The trials clearly establish that aggregates are mildly detrimental to our cognition, but there are many mechanisms by which extracellular aggregates of any kind can mildly impair neuronal function without necessarily triggering neurodegeneration. And in fact, as well known, the trials have failed on readouts of neurodegeneration," Small stated.
The Case for Intracellular Pathology
Small's argument centers on the significance of intracellular pathology, particularly endosomal enlargement, as a potential initiator of neurodegeneration. He points to genetic studies involving causal genes such as APP, PSEN1, PSEN2, and SORL1, which induce both extracellular amyloid plaques and intracellular endosomal enlargement. Notably, the intracellular pathology can occur before and independently of extracellular amyloid pathology.
"In model systems, all the causal genes induce amyloid-free endosomal enlargement, an intracellular pathology first established in 'sporadic' AD brains. This amyloid-free intracellular pathology localizes to the entorhinal cortex/hippocampus, precisely where the neurogenerative process and its associated cognitive impairment occurs first and foremost," Small explained.
Mechanistically, endosomal enlargement appears to be driven by blockage of the endosomal recycling pathway, leading to "endosomal traffic jams." This disruption impairs the recycling of glutamate receptors and other critical proteins, ultimately triggering neurodegeneration.
The Need for Experimental Medicine
Small emphasizes the importance of experimental medicine, specifically clinical trials, to resolve the debate. He advocates for future trials that test drugs targeting both amyloid plaques and intracellular traffic jams, particularly early in the disease process.
"Future trials testing drugs that either clear out amyloid or clear up traffic jams, early in the disease process, are required to resolve whether it is AD’s extracellular or intracellular pathologies that is the prime driver of neurodegeneration," Small concluded.
The ongoing debate highlights the complexity of Alzheimer's disease and the need for a more nuanced understanding of its underlying mechanisms. While amyloid plaques remain a key pathological feature, the focus is shifting towards exploring the role of intracellular processes in driving neurodegeneration and cognitive decline. Future research and clinical trials will be crucial in determining the most effective therapeutic strategies for this devastating disease.
