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So, why do we talk so much about

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Alzheimer's disease?

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Well, it's because of all the different dementias,

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it makes up the largest proportion.

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So, about 60% by autopsy series compared

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to the other dementias.

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Alzheimer's disease doubles in frequency

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every five years after the age of 60,

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it is the most common.

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So 6 million Americans are suffering with

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Alzheimer's disease right now. In 2021,

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it cost our nation $355,000,000,000.01 in

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three seniors will die of dementia.

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So this is a huge health population issue.

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Alzheimer's kills more patients than even

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breast and prostate cancer combined.

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And to give you some kind of idea of what's been

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happening with Alzheimer's, since the year 2000,

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death rates from heart disease have gone down 7%,

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but have gone up in Alzheimer's disease by 145%.

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So the hallmarks of Alzheimer's disease are beta

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amyloid plaques and neurofibrillary tangles.

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These beta amyloid plaques are extracellular in

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location and can be directly imaged with amyloid

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PET. Again, here is a positive amyloid PET.

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Amyloid PET becomes positive at the preclinical

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stage of Alzheimer's disease,

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actually up to 20 years before the

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patient becomes symptomatic.

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So it's really incredible how early it can pick

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this up. Amyloid plaque deposition by disease.

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You'll see a lot of amyloid plaque deposition

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in Alzheimer's disease.

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You can see some in dementia with Lewy bodies,

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and you shouldn't see any amyloid plaque

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in frontotemporal dementia.

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This happens to be an amyloid-laden cell.

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Here's the beta amyloid plaque in the

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extracellular space, and this is a normal,

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healthy cell for comparison. Now,

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neurofibrillary tangles are intracellular in

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location, so they're intracellular tau,

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notably in the hippocampi,

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and they can be directly imaged by Tau PET.

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This is again a Tau PET example with tau

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deposition here in the bilateral temporal lobes.

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So let's talk a little bit more

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about beta amyloid plaques.

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So beta amyloid proteins of 40 and 42 are

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generated or produced from amyloid

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precursor protein. Now,

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beta amyloid 40 is associated with

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cerebral amyloid angiopathy,

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and beta amyloid 42 is associated with Alzheimer's

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disease. After these proteins are made,

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they're transported across

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the blood-brain barrier,

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and then they are degraded by certain proteins

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and enzymes, such as APOE and MMPs.

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Now, after that,

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if there is any kind of disruption

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at any point of this pathway,

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either at the production stage or at the transport

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stage or at the degradation stage,

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these amyloid plaques can deposit in small to

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medium-sized arterial blood vessels

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and capillaries in the cortex.

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So this helps explain the mechanism

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for Alzheimer's disease.

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And this AD barrier pathway also helps explain the

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mechanism for cerebral amyloid angiopathy,

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which is known to cause spontaneous hemorrhages as

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well as cognitive decline and

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acute neurologic events.

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Now,

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we're now starting to realize the importance of

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the glymphatic system and the role it plays in the

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clearance of these beta amyloid

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plaques and other toxins.

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So the glymphatic system denotes a perivascular

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pathway whereby CSF enters the brain parenchyma

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via the perioral space and then goes through,

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in a convective flow pattern into the interstitial

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space and then joins the perivenous space after it

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sort of sweeps with them these toxins and plaques,

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etc.

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And then it exits the brain in the perivenous

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space and then out into the lymphatic system.

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Now,

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these aquaporin-4 receptors are located

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on both the arteries and the veins,

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and they help decrease the resistance of CSF flow

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into the interstitial space. And as we age,

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this lymphatic system pathway,

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this clearance pathway, actually slows down.

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But interestingly, while we sleep,

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the interstitial space expands.

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So good sleep patterns are actually felt to be

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protective for Alzheimer's disease because, again,

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it helps our bodies sort of clear the plaques from

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the brain out of the interstitial space.

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Now,

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tau is a protein that's normally found in axons.

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In a healthy brain,

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it helps form and strengthen the microtubules,

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which transport nutrients along the axon.

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But in the disease brain,

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there's an imbalance of the protein

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kinases and phosphatases,

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and it causes Tau to become hyperphosphorylated,

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resulting in the disassembly of these

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microtubules. So this impairs cellular signaling,

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and free tau molecules aggregate into insoluble

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paired helical fragments and straight filaments

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which accumulate in the cells as neurofibrillary

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tangles in Alzheimer's disease and other related

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tauopathies. Now, some of the other tauopathies,

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other than just Alzheimer's disease,

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are behavioral variant frontotemporal dementia,

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chronic traumatic encephalopathy, Down's,

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progressive supranuclear palsy,

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and corticobasal degeneration.

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Now, Tau PET,

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one of the interesting things about this is it can

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accurately predict the location of future atrophy,

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unlike the amyloid,

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which is again a diffuse pattern.

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So Tau is actually a better predictor of the

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timing of imminent cognitive decline.

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So you see here on Tau PET,

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here's the Tau deposition in the temporal lobes,

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and it perfectly matches the area of

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atrophy that you see on brain MRI.

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This is a look at Alzheimer's disease across a

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time spectrum. Here's the presymptomatic stage,

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early and late,

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mild cognitive impairment and dementia.

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So mild cognitive impairment is memory loss,

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but with preservation of the activities

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of daily living and the.

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Conversion rate from MCI to Alzheimer's

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disease is 40%.

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So everyone who develops Alzheimer's disease will

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pass through a stage of mild cognitive impairment.

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But not everyone with mild cognitive

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impairment will develop dementia.

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Here's a look at what some of the different

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modalities are in screening.

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The brown is the activities of daily living.

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The green is cognitive decline.

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So you see the activities of daily living are

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pretty well preserved in the MCI stage,

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and then they start to go up.

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The blue is Tau PET,

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the pink is quantitative volumetric imaging.

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Here.

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The orange line is an FDG PET.

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And then you see a very different curve

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for amyloid PET, because, again,

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it detects it in the early clinical stage.

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Now,

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some of the CSF biomarkers can also detect

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amyloid earlier, like CSF beta amyloid.

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42 CSF markers do have greater than

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80% sensitivity and specificity,

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but there's still a lot of interlab variability

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at this point in stage.

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At this point in time,

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you can also try to detect amyloid in the blood,

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such. There's a test such as precipitate Aβ,

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that will look for beta amyloid

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fibrils in the blood,

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as it will also tell you your APOE4 status.

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And so again,

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the genetic marker would be APOE4.

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Now, there are two types of Alzheimer's.

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There's an early-onset type, which is familial,

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less than 5% of the cases of Alzheimer's,

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and then the late-onset,

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which is much more common.

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It's sporadic,

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and that's 95% of Alzheimer's cases are sporadic.

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There are risk factors,

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there are certain non-modifiable risk factors,

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such as age. The older we are,

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the more at risk gender.

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Alzheimer's disease is more common in women than

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in men, and then genetics are non-modifiable.

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There are actually several genes that

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are linked to Alzheimer's disease,

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but APOE4 is the most common genetic risk

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factor for Alzheimer's disease. Now,

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there also are a lot of modifiable risk factors,

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things that we can do to help prevent Alzheimer's.

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So some of the modifiable risk factors are

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hypertension, diabetes, smoking, alcohol, obesity,

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poor diet, poor exercise patterns,

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a lack of cognitive engagement or social

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isolation, depression, traumatic brain injury,

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and again, poor sleep patterns,

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as we mentioned when we talked

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about the lymphatic system.

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So I want to spend a little time talking about

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APOE because it's quite important.

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So apolipoproteins play a role in lipid and

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cholesterol homeostasis in the bloodstream.

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There are three ApoE gene alleles.

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So E2, E3, and E4.

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E3 is actually the most common.

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So over 50% of the population is E3.

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But the one we worry about is APOE4.

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And that's the one with the strongest genetic

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risk factor for Alzheimer's disease.

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It is involved in the clearance of those beta amyloid

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plaques. So you may be wondering how common this.

9:00

Is 25% of the population carries one APOE

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four allele, so they're heterozygous.

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And if you carry that,

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you have a three times risk of developing

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Alzheimer's disease over the general population.

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Now,

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two to 3% of the population carries two APOE

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four alleles, so they're homozygous.

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And if you are homozygous,

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you have a twelve times risk of developing

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Alzheimer's disease over the

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general old population.

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APOE4 is a risk factor not

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just for Alzheimer's disease.

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It's also a risk factor for cerebral amyloid

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angiopathy, CAA-related inflammation,

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dementia with Lewy bodies, cowopathy,

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microvascular ischemic disease,

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and vascular dementia, multiple sclerosis,

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poor outcome following traumatic brain injury,

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and amyloid-related imaging abnormalities,

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which we'll talk about a little bit later.