Pathophysiology of Alzheimer Dementia

00:00 Now, let's talk about Alzheimer's disease pathology. When you think about Alzheimer's disease, I want you to think about 2 proteins that are developing and depositing on the brain. The first is beta-amyloid. Beta-amyloid is a protein that's involved in Alzheimer's disease as well as other disorders, diseases, and pathology. It's formed from the breakdown of larger proteins and the most predominant large protein is called amyloid precursor protein. This is a normal protein in the brain and neurons and breakdown of that protein to beta-amyloid is a normal process. In Alzheimer's disease, there are abnormal levels of this naturally occurring protein that clump together and form plaques, neuritic plaques, that collect between neurons and disrupt cell function. So this is one of the contributors to the cogntive dysfunction in patients with dementia. Importantly, some of the mutations that we talked about like the presenilin 1 and 2 increase the production of amyloid and the neurotoxic forms of beta-amyloid, those beta-amyloid plaques that develop outside of neurons and that's how they predispose to early development of Alzheimer's disease. So beta-amyloid is an important component of the underlying pathology in Alzheimer's disease.

01:19 In addition, I want you to think of tau and the tau protein. This is the second important brain pathology and protein involved in Alzheimer's disease. Healthy neurons in part are supported internally by structures called microtubules. They keep the neurons together and help propagate information from 1 part of the neuron down the axon to the other part. They help guide nutrients and molecules from the cell bodies to the axon and dendrites. And in healthy neurons, tau normally binds to and stabilizes those microtubules assisting in microtubule assembly and stabilization.

01:57 So tau is critically important in the maintenance of normal function of the neuron and specifically the microtubule. Neurofibrillary tangles are abnormal accumulations of this protein tau that collects inside of neurons in patients with dementia including Alzheimer's disease. In Alzheimer's disease, we see abnormal functioning of tau.

02:22 Abnormal chemical changes within the nerve cause tau to detach from the microtubules and stick together to other tau molecules forming threads that eventually join to form a tangle inside the neuron. These tangles are neurofibrillary tangles, block the neuron's transport system resulting in harm to the neuron, decrease function at the synapse (synaptic discommunication) and abnormal function of the neuron.

02:49 And so the second brain pathology that contributes to symptoms in Alzheimer's disease is the development of neurofibrillary tangles which is a result of abnormal tau processing. So if we put this together, Alzheimer's disease is really a combination of the development of beta-amyloid plaques and the development of neurofibrillary tangles which contributes to underlying brain pathology. Alzheimer's disease brain changes result from this complex interplay between tau and beta-amyloid proteins and several other factors as well. It does appear that abnormal tau accumulates in specific brain regions involved in memory and so some of those early changes that we see in brain pathology occur in areas that control memory and visuospatial dysfunction. Beta-amyloid clumps into plaques between neurons. As the level of beta-amyloid reaches a tipping point, we see rapid spread of tau throughout the brain. And that interplay between these 2 contributes to development of symptoms and progression over time in Alzheimer's disease. So let's look at some of the histopathologic findings that we see. Here, we're looking at a neuritic plaque. Again, the neuritic plaque is the development of beta-amyloid in between neurons and we can see that in each of these slides here, this build-up and clumping of proteins around the neurons. The neurons are these satellite cells that have small projections outside of them and so you can see the size and severity of deposits in between neurons. Similarly here, we can see the neurofibrillary tangles. On the top, we're looking at a normal preclinical Alzheimer's disease brain where there is really a paucity of neurofibrillary tangles. As clinical symptoms develop, we see a substantial increase in the number of tangles that occur within and between neurons contributing to Alzheimer's disease pathology and symptoms. So let's talk about the amyloid hypothesis which is one of the most prominent hypothesis for why dementia develops.

04:52 And let's walk through what's happening in the brain. First, there's an increase in amyloid beta production and accumulation. This amyloid beta oligo-dimerizes and plaques deposit. The plaques contribute to 2 things going on in the brain. The first is microglia activation. The microglia are the immune cells within the brain and activation sets off an inflammatory response that contributes to degeneration. In addition, we see altered neuronal homeostasis. The neurons don't work right. This increases oxidative stress and injury ultimately progressing to neuritic injury. As amyloid beta accumulates and reaches a tipping point, there's a dramatic increase in tau deposition that also occurs in the brain, ultimately resulting in the development of Alzheimer's dementia.