A new review of processes underlying Alzheimer’s disease by Dr. Karl Herrup presents a new synthesis and framework to view this debilitating illness. The current standard view of the cause of Alzheimer’s disease is known as the Amyloid Cascade Hypothesis. The existence of amyloid beta plaques in the brains of Alzheimer’s disease patients lead to the idea that the plaques may be the cause of the disease (see my earlier blog post “Wrong Idea for Cause of Alzheimer’s Disease?“).
The review paper titled “Reimagining Alzheimer’s Disease—An Age-Based Hypothesis” by Karl Herrup was published December 15, 2010 in the Journal of Neuroscience.
Dr. Herrup presents a compelling argument for an Age-Based Hypothesis to explain the cause of Alzheimer’s disease. This hypothesis takes into account a lot of new data that the Amyloid Cascade Hypothesis does not. In addition, the amyloid deposition cycle is taken into account and fits in naturally within the larger framework of the Age-Based Hypothesis.
Age, of course, is considered a fundamental factor in the Age-Based Hypothesis. You may break your hip at any age but as you age a broken hip is made more likely (due to poor balance at an advanced age, for instance) and more serious because of age related changes in the healing power of the body among other factors. The brain in the aged is different in many ways from the youthful brain. The Age-Based Hypothesis states that, given an elderly brain, the process leading to the expression of Alzheimer’s disease follows three important steps. Each step is highlighted in a light blue bubble in Figure 1 (above) and sequentially numbered in purple.
First an initiating injury transforms an elderly brain into an elderly brain on a trajectory towards expressing Alzheimer’s disease. The injury could be anything from a serious bump on the head to a highly traumatic event such as the loss of a spouse. The initiating injury leads to the second step which is chronic nervous tissue inflammation. This is where the Age-Based Hypothesis encompasses amyloid beta deposition since inflammation of brain tissue activates the amyloid deposition cycle. In the third step, the chronically inflamed brain tissue moves into a new state (change-of-state) that may kick off any of several intracellular molecular cascades that lead to synaptic dysfunction and neuronal death. It’s synaptic dysfunction and neuronal death that result in dementia.
The Age-Based Hypothesis makes a lot of sense and may lead to new insights including new ways of treating the disease. There may be many changes to this hypothesis over the coming months and years but I think it’ll prove to be a productive hypothesis.
