Interactive Transcript
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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.
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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.
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