In this educational video, Dr. David Perlmutter reviews a Neurology journal study titled “Midlife Insulin Resistance, APOE Genotype, and Late‑Life Brain Amyloid Accumulation.” The study followed over 6,000 middle‑aged adults (average age ~55) who were cognitively normal at baseline, measured their insulin resistance using HOMA‑IR, and performed amyloid PET scans about 15 years later. Participants were stratified by APOE4 status (carriers vs. non‑carriers) and by insulin resistance (low vs. high). Findings showed that: - The lowest amyloid positivity occurred in individuals who were both insulin‑sensitive and APOE4‑negative. - Insulin‑resistant participants without APOE4 still had a markedly higher amyloid rate. - APOE4 carriers who were insulin‑sensitive also showed increased amyloid, but less than those who were insulin‑resistant. - The combination of APOE4 carriage and insulin resistance yielded the highest amyloid positivity (~90%). The key conclusion is that midlife insulin resistance is an independent, modifiable risk factor for later‑life brain amyloid accumulation, even among those without the APOE4 allele. Dr. Perlmutter emphasizes that while genetic risk (APOE4) cannot be changed, insulin resistance can be mitigated through lifestyle interventions—diet low in refined carbs and sugars, regular physical activity, adequate sleep, and stress management. By controlling insulin resistance, individuals may lower their risk of amyloid buildup and, consequently, Alzheimer’s disease.
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Well, hello everyone. Dr. David Perlmutter here. Today we're going to talk about your brain. We're going to talk about the relationship between carrying a certain genetic predisposition, the accumulation of amyloid, a sticky protein within the brain that's been associated with Alzheimer's disease, and some modifiable risk factors. We're going to look at a study. That understands that yes, carrying the APOE4 allele, the gene that is associated with increased risk for Alzheimer's, that is carried by 20 to 25% of Americans, is associated with an increased risk of having higher levels of this beta amyloid protein in the brain. But what the study looks at, which is really quite fascinating, is that there is also a relationship between insulin resistance, and the accumulation of beta amyloid in the brain. And what we're going to look at is how do these 2 things play against each other or for each other. And with the understanding that indeed we don't change our genetic makeup, but we certainly have a huge role to play in terms of insulin resistance. Let's look at the study. It's called Midlife Insulin Resistance, APOE Genotype, and Late-Life brain amyloid accumulation, and this occurred, or was published rather, in the journal, again one of our most well-respected neurology journals, the journal Neurology. Now this study looked at over 6,000 individuals whose average age was 55 years of age and looked at something called their HOMA-IR score. That's a marker of insulin resistance. And compared the lowest insulin resistance to the highest insulin resistance, and this started off in individuals who were not demented, and then did some screening of their brains using a new type of PET scan that actually looks at amyloid within the brain. They did this scan 15 years later. Now again, these individuals were studied to determine whether or not they were resistant to insulin and then had brain scans 50 years later. They wanted to look at whether these individuals were ApoE4 positive or ApoE4 negative. ApoE4 positive means they were either 4/4 or 3/4, they had at least one copy of the ApoE4 allele, an allele that is associated with increased risk for Alzheimer's disease. APOE4 negative was 2/3 or 3/3, in other words they don't carry the APOE4 allele. Now this next slide is a bit complicated, but on the very left of your screen the percentage of people who had brain scans that showed amyloid accumulation was lowest in those people who had neither insulin resistance nor did they carry the APOE4 gene. Moving next, we see those who are insulin resistant and still do not carry the APOE4 gene. So a dramatic increase without any change in genetics, a dramatic increase in percentage of people who have amyloid-positive brain scans simply because we've gone from insulin sensitive to insulin resistant. The next group shows the effect of only carrying the APOE4 gene in insulin resistant Negative people, they don't have insulin resistance, but now they are the ones that have the APOE4 gene, a significant percentage of participants having amyloid in their brains. And finally, the scenario of having insulin resistance and carrying the gene, having 90% of these individuals having risk for having amyloid-positive brain scans. When we look just at those individuals who carry the APOE4 allele, in other words, these are all— these people do not have insulin resistance, they likely have lower blood sugars, here is the increased risk of carrying, rather of demonstrating a positive amyloid scan, but I think the difference between these individuals on this slide is even more compelling. This is the individuals, all of the people in the study, and simply asking the question whether or not these folks are insulin resistant. My point is that you're not going to change, again, your genes, whether you carry the APOE4 gene or not, or allele or not, but what you are going to look at in this study, this slide rather, is whether or not you are insulin resistant. If you're not, you're on the left side of the slide. If you are, you have a dramatic increased risk, it looks like from this report, of having a positive beta amyloid scan. My point is that you can control to a significant degree whether or not you are insulin resistant Based upon your diet. These results indicate that midlife insulin resistance is an independent risk factor for brain amyloid accumulation in elderly individuals without dementia. So they, again, at the beginning of the study, these were not demented people, but then look at their risk of developing amyloid in the brain, which is indeed associated with dementia. So what do we learn from this? We ultimately learn that our diet and other lifestyle choices like sedentarity, in other words being sedentary, sleep, stress, which play a role in insulin activity, in blood sugar balance, affect the risk of developing insulin resistance, and that this does appear, according to these researchers, to be associated with risk for accumulation of amyloid. This is a really interesting study. Again, you do see a higher risk of beta amyloid accumulation in individuals who are carrying the APOE4 allele, but keep in mind that there's a dramatic increased risk as well if you happen to be also insulin resistant, or even if you don't carry the APOE4 allele and you're insulin resistant. The point is you're not going to change whether or not you carry carry the APOE4 allele, something you can learn about by doing a gene analysis like 23andMe, but you absolutely can play a huge role in determining whether or not you are insulin resistant. Insulin resistance is a consequence of perpetually having a higher and higher blood sugar, and guess what? That's related to diet, a diet that's higher in refined carbohydrates and sugars is a diet that's going to continually challenge the insulin system and ultimately pave the way for becoming insulin resistant, the harbinger for type 2 diabetes, but as we see here, associated with increased risk for accumulation of beta amyloid within the brain. Thanks for watching. I'll see you next time. I'm Dr. David Perlmutter. Bye for now.
