A growing body of evidence supports an intriguing clinical/epidemiological connection between Alzheimer disease (AD) and type 2 diabetes (T2D). T2D patients have significantly increased risk of developing AD and vice versa. Recent studies have begun to reveal common pathogenic mechanisms shared by AD and metabolic disorders, notably obesity and T2D. In T2D and obesity, low-grade chronic inflammation is a key mechanism leading to peripheral insulin resistance, which progressively causes tissue deterioration and overall health decline. In the brain, proinflammatory signaling was recently found to mediate impaired neuronal insulin signaling, synapse deterioration, and memory loss. Here, we review evidence indicating that inflammation, insulin resistance, and mitochondrial dysfunction are common features in AD and T2D. We further propose the hypothesis that dementia and its underlying neuronal dysfunction are exacerbated or driven by peripheral inflammation. Identification of central and peripheral inflammation as potential mediators of brain dysfunction in AD may lead to the development of effective treatments for this devastating disease.
Alex’s Notes: Have you ever heard of Alzheimer’s disease (AD) referred to as “type-3 diabetes” or “diabetes of the brain”. I have, although I’m not sure where it first originated. When you think about it, it does make sense. The risk of developing dementia and AD is almost double in diabetic persons, and the defining metabolic parameters of type-2 diabetes (T2D) – hyperglycemia & hyperinsulinemia – are also associated with the development of AD. The strong associations between T2D and dementia have led some researchers to speculate that AD is a form of dementia caused metabolic dyshomeostasis that manifests itself in the elderly as a result of cumulative (lifelong) damage to the body and the brain. If this holds true, then you don’t even need to have reached full-blown diabetes to be at risk, since the prediabetic hyperglycemia and low-grade chronic inflammation directly impact the brain. One thing is for certain, however; the connection between AD and T2D comprises both inflammatory and metabolic parameters, making a healthy lifestyle full of exercise, generic activity, and blood sugar control crucial.
Insulin resistance is the hallmark of metabolic dysregulation that impairs the ability of cells to maintain energy balance. Interestingly, the brains of those with AD show defects similar to the body tissues of those with T2D, including metabolic stress and neuroinflammation. One of the toxins that accumulate in the AD brain is amyloid plaques (ABOs), which are thought to underpin the synaptic failure and memory loss. However, these plaques exist in everyone, including persons without cognitive impairment, and more recent evidence suggests that it is not the plaques per se that determine the extent of dementia, but rather it is the extent of synaptic deterioration caused by something other than ABOs. This isn’t saying that ABOs don’t play a role, it is merely suggesting they aren’t the only piece of the puzzle and that healthy brains are able to “deal” with them appropriately, whereas those with AD could not.
In support of the above, AD brains exhibit impaired insulin sensitivity and this is due in part from the ability of ABOs to remove insulin receptors from the brain tissue. Not surprisingly, insulin has been shown to be neuroprotective and animal studies have further demonstrated that insulin regulates brain function by controlling synapse density and plasticity. Inflammation is another keystone feature thought to play a critical role in both AD and T2D. Indeed, the brain of AD persons does show elevated markers of inflammation that are similar to those found in the chronically inflamed obese person, which just like in the body will ultimately lead to progressive tissue damage and AD. When it’s all said and done, this inflammation further induces insulin resistance of the brain, which leads to more inflammation, creating a viscous cycle. Of course, now the challenge is to understand how insulin stimulation in the brain may confer cognitive benefits. Impaired insulin sensitivity has been linked to cognitive deficits and structural/functional brain deficits in the elderly, and oddly enough, intranasal insulin spray improves memory in at-risk persons without affecting systemic insulin or glucose levels.
So up to now we have established that insulin resistance and inflammation within the brain are critical factors in the development of AD, while these traits in the peripheral (everything outside the brain) are critical for T2D. However, the single most important determinant of AD is age. Aging is associated with increased levels of inflammatory markers, but are these markers a result of aging? Or are they the predecessors that lead to aging? This alludes to another link between AD and T2D. T2D changes the blood brain barrier’s permeability, making the brain more susceptible to peripheral inflammation. In fact, diabetic AD brains show increased levels of inflammatory markers than nondiabetic AD brains. Thus, fat-derived inflammatory mediators could be an important addition to generate a state of brain inflammation.
Finally, we must address the energy-producing work horses of the body, the mitochondria. They use oxygen to produce energy and a completely normal but toxic byproduct, reactive oxygen species (ROS). Excessive ROS levels are implicated in the molecular cause of AD, with elevated levels of oxidative stress present in AD brains. Coming full circle, brain insulin signaling blocks ABO-induced neuronal oxidative stress, and interestingly, mitochondrial dysfunction and increased ROS generation were recently found to lead to insulin resistance in skeletal muscle and the liver. It appears that a complex signaling network closely connects mitochondrial dysfunction to impaired insulin signaling in both AD and T2D.
The bottom line is this. AD and T2D are linked. Exactly how they are linked has only partially been resolved, but there is a connection. This may open doors for AD treatment options based off those currently in use for diabetes. However, the best medicine is the preventive medicine. Exercise hard, exercise smart, stay active, get plenty of sleep, and eat a quality diet. This way, you won’t have to worry about either disease.