Type 3 Diabetes: The Possibility of Preventing Alzheimer’s Disease with Fasting
As we progress through the 21st century, the world’s population is rapidly aging. Internationally, the number of people over the age of 60 is growing faster than all younger age groups combined. By 2100, the number of older people is expected to triple to 3.1 billion. Cognitive function plays a key role in determining the quality of life for adults in old age. For this reason, Alzheimer’s disease and related dementia disorders have received increasing attention from researchers, policy makers, and the media. But to develop an effective, preventative course for Alzheimer’s, we must first understand its causes. Continuing work from Dr. Valter Longo, Professor of Gerontology and Biology at USC, may hold the key.
Symptoms of Alzheimer’s Disease
Alzheimer’s disease is a progressive neurodegenerative disease that accounts for over half of all dementia cases. It typically manifests in people over the age of 65 with short term memory loss being a common early symptom. As the disease progresses, symptoms grow increasingly severe and place an overwhelming burden on families and communities.
Patients suffering from advanced Alzheimer’s disease often experience language problems, mood swings, disorientation, behavioral issues, loss of motivation, and the inability to manage self-care. Currently, there are no FDA-approved treatments to slow or reverse the progression of the disease.
Identifying a Cause: Biological Markers of Alzheimer’s
The biological characteristics associated with Alzheimer’s disease are numerous and complex. As a result, the cause of the disease is not well understood. Alzheimer’s is primarily characterized by atrophy in the cerebral cortex of the brain due to a loss of neurons and synapses.
Another key feature is the accumulation of protein aggregates. Dense amyloid plaques, comprised of beta-amyloid peptides, accumulate around the outside of neurons while neurofibrillary tangles, comprised of the microtubule-associated protein tau form within neurons. Current research is focused on building a disease model for Alzheimer’s that can conceptually connect this array of seemingly disparate biological events.
A growing body of literature suggests that insulin resistance could be a contributing factor to the pathogenesis of Alzheimer’s, leading to its nickname, “Type 3 diabetes.”  In fact, Type 2 diabetes is a well-known risk factor for Alzheimer’s. 
Let’s take a closer look at the evidence.
The Case for Alzheimer’s as Type 3 Diabetes
Researchers proposed the term “Type 3 diabetes” after uncovering a strong link between Alzheimer’s, insulin, and insulin-like growth factor (IGF) signaling. 
Post-mortem analysis of the brains of Alzheimer’s patients showed strikingly lowered levels of insulin and IGF-1.  The role of insulin and IGF-1 in Alzheimer’s could be causal—deficiencies were present even at early stages of the disease and became more severe as it progressed. 
Moreover, work in animal models demonstrated that neurodegeneration similar to Alzheimer’s could be prevented by early treatment with insulin-sensitizer antidiabetes agents such as peroxisome proliferator-activated receptor (PPAR) agonists. 
- Insulin Signaling - mTOR Pathway
- Type 2 Diabetes Mechanisms - AD Pathogenesis
- Neuronal Signaling Mechanisms
Insulin signaling also controls mTOR pathway that inhibits autophagy. Both insulin resistance in Type 2 Diabetes and Alzheimer’s disease impairs the formation of autophagosomes and disrupts lysosomal function. Autophagosomes fuse with lysosomes to form autolysosomes. These autolysosomes have impaired lysosomal function in AD and T2DM and accumulate Aβ and tau aggregates. Undigested toxic aggregates are secreted out of the neurons and propagate toxic oligomers in adjacent neurons. Credit: Alzheimer’s Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits [2018-06-08. Shreyasi Chatterjee, Amritpal Mudher. Frontiers in Neuroscience via NCBI]
Overview of the diverse mechanisms by which Type 2 Diabetes can cause AD pathogenesis. Type 2 Diabetes accompanied by insulin resistance and hyperglycemia gives rise to metabolic problems in the brain and other target tissues that sets off a cascade of pathogenic processes such as oxidative stress, inflammatory responses, advanced glycation products and autophagic dysfunction. The reactive oxygen species generated by these pathways expedite the process of neuronal death. At the same time, the insulin resistance impairs the downstream signaling pathways and exacerbates the formation of Aβ oligomers and aggregates of hyperphosphorylated tau. The cumulative effect of all these factors expose the neurons to a range of assaults and gradually result in the loss of synapses and neuronal death. Credit: Alzheimer’s Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits [2018-06-08. Shreyasi Chatterjee, Amritpal Mudher. Frontiers in Neuroscience via NCBI]
Neuronal signaling mechanisms in a state of insulin sensitivity and insulin resistance. In the insulin sensitive state insulin binds to the receptor and activates the insulin receptor tyrosine kinase that initiates a cascade of phosphorylation events at the IRS/PI3K/AKT and Ras/Raf/ERK pathways. AKT phosphorylates GSK-3β at the inhibitory serine 9 residue and allows tau to maintain its physiological function of binding to microtubules and facilitates normal axonal transport of neuronal vesicles. In a state of insulin resistance, GSK-3β is activated by phosphorylation at Tyrosine 216 residue and hyperphosphorylates tau at pathological epitopes. Hyperphosphorylated tau then detaches from the microtubules and aggregates to form neurofibrillary tangles. Likewise, in the presence of excess insulin, the insulin degrading enzyme (IDE) is unable to degrade and facilitate clearance of Aβ oligomers that act as a competitive substrate for insulin. Thus, insulin resistance facilitates the formation of both Aβ and tau oligomers. Credit: Alzheimer’s Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits [2018-06-08. Shreyasi Chatterjee, Amritpal Mudher. Frontiers in Neuroscience via NCBI]
Fasting as a Preventative Remedy: The Work of Dr. Valter Longo
The work of Dr. Valter Longo, Professor of Gerontology and Biology at USC, has focused intensely on the relationship between IGF-1, dietary regulation, and age-related disease, including Alzheimer’s. The ultimate goal of his research is to develop a dietary protocol that can be easily and affordably implemented to prevent or reverse the effects of Alzheimer’s and other diseases of aging. 
Earlier work by Dr. Longo showed that a low-protein diet can slow the progression of Alzheimer’s in mice by lowering circulating levels of IGF-1.  Dr. Longo also developed a novel fasting mimicking diet.  The fasting mimicking diet replicates the benefits of fasting in a protocol that is easier for patients to adhere to than a strict water fast. The diet also represents a safer alternative to strict water fasting, especially for frailer elderly patients suffering from Alzheimer’s.
The results of the fasting mimicking diet were impressive. Aged mice showed significant improvement in cognitive performance, an effect that could be relevant to Alzheimer’s disease. 
Additionally, a small pilot clinical trial in humans showed that three fasting mimicking diet cycles decreased risk factors and biomarkers for aging, diabetes (an Alzheimer’s risk factor), cardiovascular disease, and cancer without significant negative side effects.
While there is still not enough clinical evidence yet to say whether this diet could help someone suffering from Alzheimer’s, Dr. Longo is hard at work answering that question. Dr. Longo and colleagues are planning a larger clinical trial to investigate the effect of the fasting mimicking diet on patients with mild cognitive impairment who are in the early stages of Alzheimer’s. 
Dr. Longo and colleagues are planning a larger clinical trial to investigate the effect of the fasting mimicking diet on patients with mild cognitive impairment who are in the early stages of Alzheimer’s. (Credit: USC/John Skalicky)
Looking Towards the Future: A Safe and Effective Treatment for Alzheimer’s Disease
Mounting evidence suggests that Alzheimer’s disease can be accurately characterized as Type 3 diabetes. The strong link between Alzheimer’s and deficits in insulin and IGF-1 further suggest that dietary changes such as Dr. Longo’s fasting mimicking diet could offer a safe and effective protocol for preventing and reversing neurodegeneration. Changes in the diet offer a more holistic and wide-scale re-programming of the brain’s metabolism which traditional, highly targeted pharmaceuticals cannot recreate.
Dietary interventions also typically have fewer side effects and are cheaper for patients to implement than pharmaceutical treatments. Moreover, fasting can help protect against a whole host of ailments, not just Alzheimer’s. As previously mentioned, work from Dr. Longo has demonstrated the ability of the fasting mimicking diet to decrease risk factors for cardiovascular disease, diabetes, and cancer.
The National Institute of Aging appears to agree. It awarded Dr. Longo and colleagues with a $10 million grant to further study the effect of the fasting on aging and regeneration.  It will be exciting to see what future clinical trials will tell us in regards to the relationship between fasting and diseases of aging.
- Alzheimer’s Disease Is Type 3 Diabetes–Evidence Reviewed [2018-11. Suzanne M. de la Monte, MD, MPH, Jack R. Wands, MD. Journal of Diabetes Science and Technology. Volume 2, Issue 6, November 2008]
- Alzheimer’s Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits [2018-06-08. Shreyasi Chatterjee, Amritpal Mudher. Frontiers in Neuroscience via NCBI]
- Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? [2005-02. Eric Steen, Benjamin M. Terry, Enrique J. Rivera, Jennifer L. Cannon, Thomas R. Neely, Rose Tavares, Julia X. Xu, Jack R. Wands, Suzanne M. de la Monte. Alzheimers Dis. 2005 Feb;7(1):63-80]
- Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? [2005-02. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. J Alzheimers Dis. 2005 Feb;7(1):63-80]
- Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine [2005-12. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. J Alzheimers Dis. 2005 Dec;8(3):247-68]
- Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer’s disease [2006-09. de la Monte SM, Tong M, Lester-Coll N, Plater M Jr, Wands JR. J Alzheimers Dis. 2006 Sep;10(1):89-109]
- Valter Longo: Understanding the Biology of Aging [2014-12-19. Christopher Edward Jones. MMRF]
- Protein restriction cycles reduce IGF-1 and phosphorylated Tau, and improve behavioral performance in an Alzheimer’s disease mouse model [2013-03-11. Edoardo Parrella, Tom Maxim, Francesca Maialetti, Lu Zhang, Junxiang Wan, Min Wei, Pinchas Cohen, Luigi Fontana and Valter D. Longo. Aging Cell. 2013 Apr; 12(2): 257–268]
- Fasting Mimicking Diet: Calorie Restriction increases Healthspan [2015-10-07. Christopher Edward Jones. MMRF]
- A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan [2015-07-07. Sebastian Brandhorst, In Young Choi, Min Wei, Chia Wei Cheng, Sargis Sedrakyan, Gerardo Navarrete, Louis Dubeau, Li Peng Yap, Ryan Park, Manlio Vinciguerra, Stefano Di Biase, Hamed Mirzaei, Mario G. Mirisola, Patra Childress, Lingyun Ji, Susan Groshen, Fabio Penna, Patrizio Odetti, Laura Perin, Peter S. Conti, Yuji Ikeno, Brian K. Kennedy, Pinchas Cohen, Todd E. Morgan, Tanya B. Dorff, and Valter D. Longo. Cell Metabolism. Volume 22, Issue 1, 7 July 2015, Pages 86-99]
- Randomized phase i / ii study of a hypoproteic diet in patients with cognitive impairment [List of Clinical Trials. L-Nutra]
- $10 million grant supports research on disease prevention, fasting and aging [2018-04-18. Beth Newcomb. USC News]