Is Alzheimer’s Disease Really Type 3 Diabetes?

Researchers suggest that AD is a diabetes of the brain

Alzheimer's and Diabetes Connection

Midway through the previous century, a relationship between diabetes and dementia was noticed. In 1995, an article in Medical Hypothesis posited that diabetes and Alzheimer’s disease (AD) may have a common pathophysiological mechanism. Today, it is generally accepted that there are overlapping mechanisms that interact synergistically linking the two diseases together. Recently, researchers have gone so far as to suggest that AD is a diabetes of the brain, referring to it as Type 3 diabetes.

What is the relationship between Alzheimer's and diabetes?

In the 1990’s, the Rotterdam study, a prospective population-based cohort study, published data indicating that diabetic individuals were almost two times more likely to develop dementia than non-diabetic aged matched controls (OR1.9, 95% CI 1.2-3.1).

Diabetic patients often experience impaired cognitive function, decreased mental flexibility, cortical atrophy, and neuronal loss. That these cognitive impairments are also observed in Type 1 diabetes (T1D) patients strongly suggests that diabetes, and not a common comorbidity (age, weight, or high blood pressure) of Type 2 diabetes (T2D), is the source for dementia and a potential link to late-onset AD. It should be remembered that dementia is a descriptor for a collection of cognitive impairments and that AD is the most common type of dementia. In patients with late-onset AD, it has been observed that nearly 80% of patients have T2D or abnormal blood glucose levels.

Both diabetes and AD exhibit extracellular accumulation of insoluble amyloid proteins. In AD, amyloid-beta (Ab), a toxic peptide cleaved from the amyloid precursor protein (APP), aggregates in cortical and hippocampal areas, as well as the neurovasculature. In the majority of T2D patients, pancreatic islet cell aggregations can be found which contribute to losses in b-cell volume. These aggregations contain the islet amyloid polypeptide (IAPP) or amylin.

In this review, we look at how T2D and AD are related with the intent of examining if diabetes creates a situation where peripheral pathology can lead to CNS pathology in the form of AD, or if AD is a centralized condition that is a result of or leads to brain insulin resistance. 

Insulin and the brain

The brain has a disproportionate energy requirement which, if not met, results in neuronal loss and brain atrophy. However, the primary role of insulin in the central nervous system (CNS) may not involve energy access.

Glucose crosses the blood-brain barrier using insulin-independent GLUT1 transporters expressed on neurovascular endothelia cells and astrocytes. Neurons receive glucose from astrocytes through the actions of the GLUT3 transporters, also insulin-independent. Both GLUT1 and GLUT3 are substantially reduced in the cortex and hippocampus of AD brains. However, since these transporters work in the absence of insulin, it may have a different role in the development of dementia, even when associated with T2D.

It is unclear exactly how insulin enters the brain, but it likely follows a concentration gradient across the blood-brain barrier, where the cerebral-spinal fluid (CSF) has a 10-20 fold lower insulin concentration than plasma. Once in the brain, insulin binds to its receptor, which can be found in the highest densities in the olfactory bulb, cortex, and hippocampus. Studies of AD brains have found a deficit in insulin binding, suggesting a loss of its receptor or diminished receptor binding in these areas. The interaction between insulin and receptor activates neuroregulatory pathways which eventually contribute to synaptic plasticity, neurogenesis, and apoptosis.

Insulin and Alzheimer's neuropathology

The two hallmarks of AD neuropathology are the accumulation of extracellular amyloid plaques and the presence of intracellular neurofibrillary tangles (NFT). Toxic Ab fragments are formed through sequential cleaving by b- and g-secretase of the transmembrane protein, APP. Non-toxic cleaving of APP occurs when a-secretase cleaves the protein instead of b-secretase, at a site closer to the cell membrane. NFT are created when the tau proteins become hyperphosphorylated and are unable to stabilize microtubule alignment within the neuron, creating a tangle of microtubule and tau proteins. With this in mind, the figure below illustrates how insulin could be involved in the formation of both hallmarks of AD.

Starting with the accepted idea that there is insulin resistance in the brain, reduced insulin activity leads to the inhibition of AKT, also known as protein kinase B. Shutting down AKT allows glycogen synthase kinase 3b (GSK-3b) to remain active. GSK-3b is involved in the hyperphosphorylation of tau, facilitating NFT formation. GSK-3b can also phosphorylate APP in manner that makes if more likely to be cleaved by b-secretase than by a-secretase, increasing the presence of toxic Ab40/42 fragments. The apolipoprotein (ApoE) supports GSK-3b activity, and has an affinity for binding the Ab fragment, especially the ApoE-e4 allele.

Unaggregated Ab peptides interact with the insulin pathway in two ways. They can block insulin from binding to its receptor, and they can overwhelm the activity of the insulin degrading enzyme (IDE) which acts on both Ab and insulin. This effectively creates a state of hyperinsulinemia with reduced insulin activity or insulin resistance. The interplay between Ab and insulin creates a cycle, leaving researchers to determine which came first, insulin resistance or toxic amyloid fragments.

Insulin to Alzheimer's pathway

Endocrine Web posed this question to Huntington Potter PhD, Director of the University of Colorado Alzheimer’s and Cognition Center. This was his answer:

“It has been known for some time that type 2 diabetes is associated with an increased risk of developing Alzheimer’s disease. We believe that it is possible that the decline in insulin sensitivity and sugar metabolism in Alzheimer’s brains may be an effect of the disease, rather than a cause.”

That leaves us with the notion that dementia associated with diabetes might be a consequence of the peripheral disease, thus starting the cycle with insulin resistance, whereas AD may start the cycle when toxic Ab fragments are formed.

Insulin and ApoE alleles

Regardless of where the cycle begins, insulin plays a role in dementia and could play a role in the treatment of it. First, it should be acknowledged that long-term use of insulin to control diabetes increases the risk of developing dementia. Diabetic patients treated with insulin are twice as likely to develop dementia than diabetic patients who control their disease through diet and life-style changes.

Acute insulin treatment, though, has been shown to improve cognitive function temporarily, but there is a risk. Insulin given peripherally at a dose that pushes insulin into the CNS with the intent of improving cognition, risks a hypoglycemic event. Thus, several studies have investigated the use of acute intranasal insulin dosing which does not change blood glucose or insulin levels. These studies found that both AD and patients with mild cognitive impairment (MCI) had improved scores on delayed recall, list learning and story recall after intranasal insulin treatment (20-40 IU), however there was substantial variability in study groups. This variability is likely related to a specific genetic profile connected to late onset AD.

There are four alleles in the ApoE gene, 1e-4e. Homozygosity for ApoE-4e (4e+/+; ApoE4+) is a genetic factor for late onset AD. In T2D patients, it is another risk for developing the dementia. Reger et al. analyzed cognitive performance 45 minutes after intranasal insulin treatment as a function of ApoE alleles. In dementia patients negative for ApoE4, 20 IU of intranasal insulin improved performances on immediate story recall, and immediate and delayed list learning exercises. Insulin treatment in ApoE4+ dementia patients at best had no effect and at worst further impaired cognitive function. Insulin had no effect on cognition in non-dementia controls, regardless of ApoE allele. None of the groups experienced changes in blood glucose or insulin levels.

ApoE is involved in trafficking and processing different components of the cell membrane, including APP/Ab, cholesterol, and lipoproteins. It’s involvement in membrane function may be a mechanism behind the variable response seen with insulin treatment in ApoE4+ and ApoE4- dementia patients. It has been recorded that in ApoE4+ brains there are fewer insulin receptors, an increase in blood-brain permeability, and a thinning of the cerebral vascular walls.

AD and Type 3 Diabetes: The bottom line (for now)

Many studies confirm the observation that late-onset AD and dementia associated with diabetes are related. However, there is a caution in categorizing the two types of dementia under a single title, Type 3 Diabetes. Dr. Potter further told Endocrine Web the following:

 “Putting the facts together suggested to some researchers that Alzheimer’s should be considered a Type 3 Diabetes. That may still be correct. However, one reasonable solution—to give the brain extra insulin via a nasal spray—has been reported to be ineffective at improving or even slowing the ongoing decline of cognition. Clearly more work is needed.”

Both diseases directly tap into common pathophysiological pathways, but it is not unreasonable to speculate that other unrelated or indirect pathways are also involved. As indicated by Dr. Potter, more work needs to be done and considering the genetics involved, a pharmacogenetics approach may play a leading role in both diseases.

Doctors Bjugstad and Potter report no conflicts with regard to this article.

Continue Reading:
High Rate of Undiagnosed Prediabetes Found in Patients with Alzheimer’s Disease
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