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The Nose Knows: Altered Sense of Smell as Early Warning Sign of Neurodegeneration

The fact that the olfactory bulb has the highest concentration of insulin and insulin receptors in the brain is worth looking at more closely. Alterations to the senses of taste and smell are recognized as potential early warning signs of Alzheimer’s disease (AD) and Parkinson’s disease (PD). And AD and PD both have strong mechanistic links to chronic hyperinsulinemia or insulin resistance.

Problems with insulin signaling are a new frontier for research into the etiology of various neurodegenerative diseases. With regard to PD:

“…there is growing evidence that a process analogous to peripheral insulin resistance occurs in the brains of Parkinson’s disease patients, even in those without diabetes. This raises the possibility that defective insulin signalling pathways may contribute to the development of the pathological features of Parkinson’s disease, and thereby suggests that the insulin signalling pathway may potentially be a novel target for disease modification.” (Athauda & Foltynie, 2016)

And with regard to Alzheimer’s:

“Insulin resistance is usually at or near the top of the list of known lifestyle-related factors heightening the risk of declining cognition in the elderly.” (Cunnane et al., 2010)

“…targeting the insulin signaling pathway during early AD cognitive impairment represents a viable therapeutic opportunity based upon solid empirical evidence that insulin resistance, AD pathology and related cognitive decline are mechanistically interrelated.” (Dineley, Jahrling, Denner, 2014)

Considering that conventional therapies for these devastating neurodegenerative illnesses offer lackluster results at best, and that pharmaceutical treatments bring undesirable and sometimes dangerous side-effects (such as compulsive gambling, in the case of Parkinson’s), it’s long past time to begin exploring alternative therapies and acknowledge the possibility that research efforts have been focused on the wrong targets. For example, anti-amyloid drugs developed for Alzheimer’s disease have all shown no beneficial impact on disease progression, so it may be time to move on from the failed amyloid hypothesis.

Much is still unknown about the roles of insulin in the brain. Glucose uptake into the brain isn’t insulin-dependent: the endothelial cells comprising blood brain barrier (BBB) express GLUT-1, neurons express GLUT-3, and microglia express GLUT-5. None of these glucose transporters is insulin-sensitive. But insulin crosses the BBB, and insulin receptors are laced throughout the brain, with different regions having different concentrations of these. So clearly, insulin is doing something in the brain, and it might be entirely unrelated to glucose metabolism.

Interestingly, compared to healthy age-matched individuals, patients with Alzheimer’s have been shown to have higher plasma insulin levels, but lower insulin levels in cerebrospinal fluid, which is taken to be a measure of insulin in brain interstitial fluid. So if less insulin is getting into the brain, it makes sense that the olfactory bulb—which appears to be highly regulated by insulin—would be affected. And the fact that it’s affected very early in the disease process suggests that reductions or alterations in olfactory function could tip people off to peripheral insulin resistance they might not have even been aware of, mostly because measures of insulin are not standard parts of routine bloodwork the way glucose testing is.

And if insulin resistance increases risk for Alzheimer’s and Parkinson’s, and exacerbates complications of multiple sclerosis, then targeting insulin regulation might be a useful addition to the otherwise disappointing treatments for these conditions. Low-carb and ketogenic diets are known to improve several markers of metabolic syndrome and insulin resistance. Preliminary research is already being done exploring ketogenic diets or the use of exogenous ketones for all three of these conditions. (See here for examples of such research for Alzheimer’s, Parkinson’s, and multiple sclerosis.)

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