Alzheimer’s Disease and Insulin Resistance: Can Metabolic Engineering Help?

Key Takeaways

  • Alzheimer’s may be a metabolic disorder: Growing evidence suggests Alzheimer’s disease is linked to insulin resistance and impaired cellular energy regulation in the brain.
  • AMPK plays a key role in brain health: AMPK is a master metabolic regulator that improves energy balance, reduces inflammation, and may help protect neurons from degeneration.
  • Lithium may work by activating AMPK: Research indicates that lithium can inhibit GSK3β, which increases AMPK activity and may reduce amyloid plaque formation associated with Alzheimer’s.
  • Diet can activate AMPK naturally: The Zone Diet, omega-3 fatty acids, and polyphenols—all core elements of Metabolic Engineering®—work together to increase AMPK activity.
  • Reducing insulin resistance may lower Alzheimer’s risk: Metabolic Engineering® targets the underlying metabolic dysfunction that contributes to Alzheimer’s and other chronic diseases.

Effectively treating Alzheimer’s disease has been one of the most significant failures of the pharmacological industry.  Yet Alzheimer’s can be viewed as a metabolic disorder driven by increasing insulin resistance (1).  Thus, it seems intuitive that reducing insulin resistance should be the primary tool to both prevent and treat the symptoms of Alzheimer’s. So, where to start?  The most likely candidate is increasing AMPK activity (2).  As to why it works is a little more complicated. 

It starts with the approval in 2002 for using lithium salts to treat bipolar depression and especially manic episodes of bipolar depression (3).  As to why it worked, no one seemed to know at the time.  Now it appears that lithium activates AMPK.  In particular, lithium inhibits the key enzyme (GSK3β) that inhibits AMPK activity (4).  It makes more sense to me to activate AMPK directly and bypass using the lithium.   

A recent article from Harvard Medical School confirms the potential benefits of lithium for treating Alzheimer’s (5).  This new publication indicates that the earliest changes in patients with mild cognitive impairment, the precursor condition to Alzheimer’s, are related to low levels of lithium in the brain. 

In animal models prone to developing Alzheimer’s, adding lithium to their drinking water dramatically reduced the development of amyloid plaques in their brains.  Of course, these benefits were strongly influenced by the type of lithium salt given to the animals, meaning there is a lot of work to do before such a drug will ever get clinical approval.  

So why not start activating AMPK and not have to wait for some drug approval far in the future?  You can start by using Metabolic Engineering® to begin activating AMPK with your next meal.  

The foundation of Metabolic Engineering® is the calorie-restricted Zone diet, which continually activates AMPK and keeps it in a therapeutic zone.  Adding high-dose omega-3 fatty acids to the Zone diet will further reduce neuroinflammation, another key component in the development of Alzheimer’s disease.  Not surprisingly, it was found in 1999 that taking 9.6 grams of EPA and DHA daily had significant benefits in treating bipolar depression (6). 

In my book, The OmegaRx Zone, I reported some of my early experiences using even higher doses with Alzheimer’s patients (7).  Finally, add some polyphenols that indirectly activate AMPK, and you have the appropriate dietary system that reduces the likelihood of developing any chronic disease associated with insulin resistance.  What are some of those chronic conditions?  They include obesity, type 2 diabetes, cardiovascular disease, polycystic ovary syndrome (the primary cause of infertility), and neurological conditions such as Alzheimer’s, Parkinson’s, and depression.  

How do you know if Metabolic Engineering® is working?  The blood markers of Zone will tell you within a short period of time (one to three months).  Your goal is to get to Zone and stay there for the rest of your life.  The appropriate time to treat these chronic conditions associated with insulin resistance is years before they develop their clinical symptoms.  Metabolic Engineering® provides the dietary pathway to change your future starting today.


FAQ

Is Alzheimer’s disease related to insulin resistance?

Yes. Many researchers now view Alzheimer’s as a metabolic disorder of the brain. Insulin resistance reduces the brain’s ability to efficiently use glucose for energy, which may contribute to cognitive decline.

What role does AMPK play in Alzheimer’s disease?

AMPK is a cellular energy regulator. Higher AMPK activity improves metabolic efficiency, reduces inflammation, and may help protect brain cells from damage linked to Alzheimer’s.

Why is lithium being studied for Alzheimer’s?

Lithium appears to activate AMPK by inhibiting the enzyme GSK3β. Some research suggests lithium may reduce amyloid plaque formation in the brain, although more clinical trials are needed.

Can diet help reduce the risk of Alzheimer’s?

Diet may play a significant role. An anti-inflammatory dietary approach that improves metabolic control—such as the Zone Diet combined with omega-3 fatty acids and polyphenols—may support brain health.

What is Metabolic Engineering® and how does it affect brain health?

Metabolic Engineering® is a dietary system combining the Zone Diet, omega-3 fatty acids, and polyphenols. Together these nutrients activate AMPK, reduce inflammation, and improve metabolic balance throughout the body, including the brain.

References:

  • 1.  Yoon JH, Hwang J, Son SU, Choi J, You SW, Park H, Cha SY, Maeng S.  How Can Insulin Resistance Cause Alzheimer’s Disease?  Int J Mol Sci. 2023; 24:3506. doi: 10.3390/ijms24043506. 
  • 2.  Chen M, Huang M, Liu J, Huang J, Shi J, Jin F  AMPK: A Bridge Between Diabetes Mellitus and Alzheimer’s Disease.  Behavioral Brain Research. 2021; 400:113043. doi.org/10.1016/j.bbr.2020.113043.
  • 3.  Goodwin FK. Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment.  J Clin Psychiatry.  2002; 63 Suppl 10:5-12. PMID: 12392347.
  • 4.  Gherardelli C, Cisternas P, Inestrosa NC.  Lithium Enhances Hippocampal Glucose Metabolism in an In Vitro Mice Model of Alzheimer’s Disease.  Int J Mol Sci. 2022; 23:8733. doi: 10.3390/ijms23158733. 
  • 5.  Aron L, Ngian ZK, Qiu C, Choi J, Liang M, Drake DM, Hamplova SE, Lacey EK, Roche P, Yuan M, Hazaveh SS, Lee EA, Bennett DA, Yankner BA.  Lithium Deficiency and the Onset of Alzheimer’s Disease.  Nature. 2025; 645:712-721. doi: 10.1038/s41586-025-09335-x. 
  • 6.  Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB.  Omega-3 Fatty Acids in Bipolar Disorder:  A Preliminary Double-Blind, Placebo-Controlled Trial.  Arch Gen Psychiatry. 1999; 56:407-12. doi: 10.1001/archpsyc.56.5.407. 
  • 7.  Sears B.  The OmegaRx Zone.  Regan Books. New York, NY (2001)

Key Takeaways:

  • Allulose may naturally stimulate GLP-1 release, helping regulate appetite and fat metabolism without the need for injectable drugs. 
  • Early research suggests greater fat loss and less rebound weight gain compared to semaglutide in animal studies. 
  • Unlike traditional sugar, allulose is minimally absorbed and not counted as sugar, making it easier to incorporate into daily nutrition. 
  • Long-term success depends on body composition—not just weight, with diet (like the Zone Diet) helping preserve lean mass while reducing body fat.  

What if there were a simple sugar that was more powerful than GLP-1 drugs in terms of fat loss?  What if that simple sugar were already approved as a food additive so it could be added to food products like shakes, bars, oatmeal, and granola, making it realistic to take it for a lifetime? 

And of course, what if that simple sugar were less expensive than any GLP-1 drug?  If so, it could be a radical change in obesity treatment.  

The first injectable GLP-1 drug (semaglutide) was introduced in 2017 for treating diabetes under the tradename Ozempic.  The oral version of semaglutide for treating diabetes, under the trademark Rybelsus, was introduced in 2019, but you had to take it daily rather than a weekly injection.  Not surprisingly, patient compliance was less than with a weekly injection. 

Once injectable semaglutide was approved for weight loss in 2021 (under the trademark of Wegovy), TV advertising took off, and the world never looked back.  A slightly altered form of Wegovy for oral use was approved in December 2025, but it has similar side effects to the injectable form[‘;;;.  

Unfortunately, more than 50 percent of people who start GLP-1 drugs quit after one year most likely due to its side effects (1).  Once you stop taking the GLP-1 drugs, the lost weight rapidly returns, and the metabolic benefits of the initial weight loss quickly erode (2).   

Ok, what about that simple sugar?  Its name is allulose.  It has GRAS status as a food additive since 2012.  What makes allulose unique is that it triggers the natural release of GLP-1 from the gut upon ingestion (3).  Although 70% as sweet as sugar, allulose is rapidly excreted from the body, so the FDA doesn’t consider it sugar for labeling purposes.  Its only drawback is that it can cause potential gut issues when consumed in high amounts. 

The simple solution to that problem is to consume it in smaller amounts, three times a day, so you can enhance the release of GLP-1 from the gut each time you eat.  The easiest way to do that is to incorporate it into food products that can be consumed at every meal. 

Now what about the scientific data?  A recent article compared oral semaglutide with allulose for weight loss in diet-induced obese mice (4).  Although obese mice are not identical to obese humans, the results are highly suggestive.  The appetite suppression in mice receiving allulose was greater, weight loss was greater, and the regain of lost weight after stopping supplementation was slower with allulose than with semaglutide. 

A preliminary study in humans indicates that allulose has a dose-dependent effect on fat loss without any decrease in calorie intake (5).   Although a direct comparison of high-dose oral allulose with injectable GLP-1 drugs remains to be done, the preliminary data suggests that adding allulose to your diet (or better yet including it in food products that are easily integrated into any diet) may provide a more natural alternative to achieving long-term weight loss than to use of chemically modified hormones (i.e., GLP-1 drugs) with their significant side effects. 

However, it’s not just weight loss you want to achieve.  Your primary goal if you want to live longer is to lose excess body fat, not just weight.  A recent study suggested that your body fat percent is a better predictor of longevity than is your BMI (6). 

Using GLP-1 drugs, there is a considerable loss of lean body mass along with the overall weight loss.  The result is that your body fat percentage changes more slowly.  Thus, your real goal is to lose excess fat and maintain lean body mass.  

Published data demonstrate that when type 2 diabetics are put on the a dietary program that was consistent with the Zone diet in both the levels of calorie restriction (1,200 to 1,500 calories per day) and a macronutrient composition (40% carbohydrates, 30% protein, and 30% fat) the result was not only is there complete remission of their diabetes, but also an increase in their lean body mass (7).  

So, what does this suggest for the future of obesity treatment?  First, incorporating more allulose into your diet makes it far easier to achieve the real goal of changing your body composition to live longer than taking GLP-1 drugs.  Second, incorporating allulose into a new generation of ZoneRx® Foods can make it easier to add it to your diet.  Third, if you follow a Metabolic Engineering® dietary system using the Zone diet guidelines and incorporating ZoneRx® Foods as a source of allulose, coupled with adequate levels of omega-3 fatty acids and polyphenols, you will likely lose fat, gain lean body mass, and probably live longer.


  • References
  • 1. Rodriguez PJ, Zhang V, Gratzl S et al. Discontinuation and reinitiation of dual-labeled GLP-1 receptor agonists among US adults with overweight or obesity. JAMA Netw Open. 2025 Jan 2;8(1):e2457349. doi: 10.1001/jamanetworkopen.2024.57349. 
  • 2.  Tzang CC, Wu PH, Luo CA et al. Metabolic rebound after GLP-1 receptor agonist discontinuation: a systematic review and meta-analysis. EClinicalMedicine. 2025 Nov 28;90:103680. doi: 10.1016/j.eclinm.2025.103680. 
  • 3.  Iwasaki Y, Sendo M, Dezaki K et al.  GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose. Nat Commun. 2018 Jan 9;9(1):113. doi: 10.1038/s41467-017-02488-y. 
  • 4. Rakhat Y, Banno S, Zhantleu D et al.  D-Allulose reduces weight more persistently than oral semaglutide while both equally elevate grip strength in diet-induced obese mice. Nutrients. 2026 Feb 23;18(4):707. doi: 10.3390/nu18040707. 
  • 5.  Han Y, Kwon EY, Yu MK et al.  A preliminary study for evaluating the dose-dependent effect of d-Allulose for fat mass reduction in adult humans: A randomized, double-blind, placebo-controlled trial. Nutrients. 2018 Jan 31;10(2):160. doi: 10.3390/nu10020160. 
  • 6.  Mainous AG, Yin L, Wu V et al.  Body mass index vs. body fat percentage as a predictor of mortality in adults aged 20-49 years.  Ann Fam Med. 2025 Jul 28;23(4):337-343. doi: 10.1370/afm. 240330. 
  • 7.    Stentz FB, Lawson D, Tucker S et al.  Decreased cardiovascular risk factors and inflammation with remission of type 2 diabetes in adults with obesity using a high protein diet:  Randomized control trial. Obes Pillars. 2022 Dec 1;4:100047. doi: 10.1016/j.obpill.2022.100047.

This podcast covers these topics. Click to see more related podcasts:

Alzheimer’s Disease and Insulin Resistance: Can Metabolic Engineering Help?

Dr. Barry Sears

Barry Sears

Founder & President, Zone Labs

October 31, 2025

Read Time: 10 minutes

Key Takeaways:

  • Alzheimer’s may be a metabolic disorder: Growing evidence suggests Alzheimer’s disease is linked to insulin resistance and impaired cellular energy regulation in the brain.
  • AMPK plays a key role in brain health: AMPK is a master metabolic regulator that improves energy balance, reduces inflammation, and may help protect neurons from degeneration.
  • Lithium may work by activating AMPK: Research indicates that lithium can inhibit GSK3β, which increases AMPK activity and may reduce amyloid plaque formation associated with Alzheimer’s.
  • Diet can activate AMPK naturally: The Zone Diet, omega-3 fatty acids, and polyphenols—all core elements of Metabolic Engineering®—work together to increase AMPK activity.
  • Reducing insulin resistance may lower Alzheimer’s risk: Metabolic Engineering® targets the underlying metabolic dysfunction that contributes to Alzheimer’s and other chronic diseases.

Effectively treating Alzheimer’s disease has been one of the most significant failures of the pharmacological industry.  Yet Alzheimer’s can be viewed as a metabolic disorder driven by increasing insulin resistance (1).  Thus, it seems intuitive that reducing insulin resistance should be the primary tool to both prevent and treat the symptoms of Alzheimer’s. So, where to start?  The most likely candidate is increasing AMPK activity (2).  As to why it works is a little more complicated. 

It starts with the approval in 2002 for using lithium salts to treat bipolar depression and especially manic episodes of bipolar depression (3).  As to why it worked, no one seemed to know at the time.  Now it appears that lithium activates AMPK.  In particular, lithium inhibits the key enzyme (GSK3β) that inhibits AMPK activity (4).  It makes more sense to me to activate AMPK directly and bypass using the lithium.   

A recent article from Harvard Medical School confirms the potential benefits of lithium for treating Alzheimer’s (5).  This new publication indicates that the earliest changes in patients with mild cognitive impairment, the precursor condition to Alzheimer’s, are related to low levels of lithium in the brain. 

In animal models prone to developing Alzheimer’s, adding lithium to their drinking water dramatically reduced the development of amyloid plaques in their brains.  Of course, these benefits were strongly influenced by the type of lithium salt given to the animals, meaning there is a lot of work to do before such a drug will ever get clinical approval.  

So why not start activating AMPK and not have to wait for some drug approval far in the future?  You can start by using Metabolic Engineering® to begin activating AMPK with your next meal.  

The foundation of Metabolic Engineering® is the calorie-restricted Zone diet, which continually activates AMPK and keeps it in a therapeutic zone.  Adding high-dose omega-3 fatty acids to the Zone diet will further reduce neuroinflammation, another key component in the development of Alzheimer’s disease.  Not surprisingly, it was found in 1999 that taking 9.6 grams of EPA and DHA daily had significant benefits in treating bipolar depression (6). 

In my book, The OmegaRx Zone, I reported some of my early experiences using even higher doses with Alzheimer’s patients (7).  Finally, add some polyphenols that indirectly activate AMPK, and you have the appropriate dietary system that reduces the likelihood of developing any chronic disease associated with insulin resistance.  What are some of those chronic conditions?  They include obesity, type 2 diabetes, cardiovascular disease, polycystic ovary syndrome (the primary cause of infertility), and neurological conditions such as Alzheimer’s, Parkinson’s, and depression.  

How do you know if Metabolic Engineering® is working?  The blood markers of Zone will tell you within a short period of time (one to three months).  Your goal is to get to Zone and stay there for the rest of your life.  The appropriate time to treat these chronic conditions associated with insulin resistance is years before they develop their clinical symptoms.  Metabolic Engineering® provides the dietary pathway to change your future starting today.

FAQ

Is Alzheimer’s disease related to insulin resistance?

Yes. Many researchers now view Alzheimer’s as a metabolic disorder of the brain. Insulin resistance reduces the brain’s ability to efficiently use glucose for energy, which may contribute to cognitive decline.

What role does AMPK play in Alzheimer’s disease?

AMPK is a cellular energy regulator. Higher AMPK activity improves metabolic efficiency, reduces inflammation, and may help protect brain cells from damage linked to Alzheimer’s.

Why is lithium being studied for Alzheimer’s?

Lithium appears to activate AMPK by inhibiting the enzyme GSK3β. Some research suggests lithium may reduce amyloid plaque formation in the brain, although more clinical trials are needed.

Can diet help reduce the risk of Alzheimer’s?

Diet may play a significant role. An anti-inflammatory dietary approach that improves metabolic control—such as the Zone Diet combined with omega-3 fatty acids and polyphenols—may support brain health.

What is Metabolic Engineering® and how does it affect brain health?

Metabolic Engineering® is a dietary system combining the Zone Diet, omega-3 fatty acids, and polyphenols. Together these nutrients activate AMPK, reduce inflammation, and improve metabolic balance throughout the body, including the brain.

ZoneLiving

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  1. Yoon JH, Hwang J, Son SU, Choi J, You SW, Park H, Cha SY, Maeng S.  How Can Insulin Resistance Cause Alzheimer’s Disease?  Int J Mol Sci. 2023; 24:3506. doi: 10.3390/ijms24043506. 
  2. Chen M, Huang M, Liu J, Huang J, Shi J, Jin F  AMPK: A Bridge Between Diabetes Mellitus and Alzheimer’s Disease.  Behavioral Brain Research. 2021; 400:113043. doi.org/10.1016/j.bbr.2020.113043.
  3. Goodwin FK. Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment.  J Clin Psychiatry.  2002; 63 Suppl 10:5-12. PMID: 12392347.
  4. Gherardelli C, Cisternas P, Inestrosa NC.  Lithium Enhances Hippocampal Glucose Metabolism in an In Vitro Mice Model of Alzheimer’s Disease.  Int J Mol Sci. 2022; 23:8733. doi: 10.3390/ijms23158733. 
  5. Aron L, Ngian ZK, Qiu C, Choi J, Liang M, Drake DM, Hamplova SE, Lacey EK, Roche P, Yuan M, Hazaveh SS, Lee EA, Bennett DA, Yankner BA.  Lithium Deficiency and the Onset of Alzheimer’s Disease.  Nature. 2025; 645:712-721. doi: 10.1038/s41586-025-09335-x. 
  6. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB.  Omega-3 Fatty Acids in Bipolar Disorder:  A Preliminary Double-Blind, Placebo-Controlled Trial.  Arch Gen Psychiatry. 1999; 56:407-12. doi: 10.1001/archpsyc.56.5.407. 
  7. Sears B.  The OmegaRx Zone.  Regan Books. New York, NY (2001)

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1 comment

Caledonia says:

And mercury is behind all of it. The good news is, it can be safely chelated out. There is a free Facebook group run by volunteers who can help you find out if mercury is your issue, and if so, how to chelate. It’s called Andy Cutler Chelation: Safe Mercury and Heavy Metal Detox.

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