Insulin and Alzheimer’s Disease

Posted on October 9, 2020March 4, 2021 by Michael Mega

Insulin is typically associated with regulating blood glucose levels and diabetes, but it also serves as a crucial signaling molecule throughout the body, including the central nervous system (CNS). In fact, there is evidence that insulin may play a role in the development of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). Dysregulation of insulin signaling negatively impacts cognition and increases deposition of amyloid plaques and tau tangles. Luckily, there are also mechanisms that can upregulate insulin sensitivity and these treatments have potential to reduce or alleviate AD symptoms.

Insulin is a hormone released primarily by the pancreas. It can cross the blood-brain barrier (BBB) to have CNS effects. However, if one develops insulin resistance, which is correlated with AD, normal tissues fail to sufficiently respond to the presence of insulin. In these cases, insulin dysregulation induces hyperglycemia, too much sugar in the blood, which leads to glucose neurotoxicity, reduced cerebral blood flow, and accumulation of toxic byproducts in the brain, all of which can lead to cognitive impairment.

There are several ways to test insulin resistance but they all follow a basic method of administering insulin and monitoring the response of the target tissue, whether peripheral or in the CNS. There is a close bi-directional relationship between insulin functioning in the body and the brain. For patients with AD there is a trend towards insulin insensitivity and hyperinsulinemia (too much insulin in the blood). Excess insulin downregulates the receptors that move insulin through the BBB into the CNS, meaning less insulin in the brain.

A reduction in CNS insulin is significant because insulin in the brain protects against amyloid-beta synaptotoxicity and promotes clearance of plaques. AD patients with peripheral insulin resistance have increased amyloid deposition compared to healthy controls. Tests of peripheral insulin resistance successfully predict amyloid deposition in the brain 15 years later, as confirmed by an amyloid PET scan. Furthermore, patients with altered insulin signaling from diabetes have increased tau levels in cerebrospinal fluid. A final additive risk factor is that excess insulin acts as a vasoconstrictor limiting blood flow to the brain and decreasing amyloid and tau clearance. Dysfunctional insulin signaling may be a risk factor for AD.

Understanding how insulin resistance impacts AD risk has improved our range of potential treatments. Intranasal insulin administration allows it to bypass the BBB and enter the CNS, reducing AD pathology and improving memory in rats after long-term administration. In humans, twenty-one days of treatment enhanced episodic memory. However, clinical trials testing intranasal insulin show mixed results indicating the need for further research. One can also increase insulin sensitivity with “insulin sensitizers”, such as Metformin, but evidence for these treatments in AD is limited. In mice and primates a GLP-1 agonist, which stimulates insulin production and regulates glucostasis, called liraglutide preserved memory and increased hippocampal neuronal density. Liraglutide is currently in a Phase II clinical trial for use in humans with AD.

Although these potential treatments are promising there are proven ways to enhance insulin sensitivity and reduce AD risk right now and without a prescription. Consuming a diet of primarily polyunsaturated fatty acids, nuts, and plant-based foods correlates with increased insulin sensitivity and decreased risk of AD-related cognitive decline compared to diets containing higher saturated fats, animal proteins, and refined sugars. Additionally, regular exercise is a powerful modulator of insulin sensitivity and has also been shown to reduce risk of AD. In the meantime, while we wait for the aforementioned therapies to be approved, a lifestyle and diet change is not only protective against AD, but can also improve your overall general health.

Sources:

Kellar, D. & Craft, S. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches [Internet]. The Lancet Neurology. 2020. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1474442220302313

Learning Impairment in Preclinical AD

Posted on September 25, 2020March 4, 2021 by Michael Mega

Memory impairment is often the hallmark symptom of Alzheimer’s disease (AD). However, research recently discovered a trend suggesting that decreased learning may preface memory loss in the preclinical phase of AD. Amyloid-positive patients in the preclinical stage of AD first experience a decline in learning ability while their memory is still comparable to amyloid-negative healthy controls. This discovery, much like the blood test we discussed a few blogs ago, may become a means of determining whether someone is going to develop AD well before memory impairment ensues.

During the preclinical stage of AD both amyloid-positive and amyloid-negative participants score equivalently on episodic memory tests. Over several years of repeat testing the amyloid-negative group improved their scores as a product of practice while amyloid-positive participants stagnated. This suggests that an impairment of learning precedes an impairment of episodic memory in the preclinical stage of AD.

Investigating further, scientists developed a test called the Online Repeated Cognitive Assessment (ORCA) where participants spend 30 minutes a day viewing Chinese characters paired with a correct or incorrect English word. After each session, patients reviewed their scores to see what pairings correctly matched, allowing them to learn from their previous mistakes. After several days participants began learning which Chinese characters represented the correct English words and which were incorrect. A previous study using this same paradigm found that amyloid-positive participants made more mistakes than the amyloid-negative group by the second session, and the gap continued to widen over the following days.

A more recent study tested 80 cognitively normal participants, 38 of whom were amyloid positive, on the ORCA along with other cognitive tests and neuroimaging. The amyloid-positive group showed learning deficits in the first session and the reduced learning compared to amyloid-negative individuals continued to grow over 6 days. After 6 days, the average ORCA scores of the two groups differed significantly, with amyloid-positive individuals showing reduced learning abilities compared to amyloid-negative patients. However, on episodic memory tests, both groups scored similarly, supporting the hypothesis that learning deficits may establish before memory impairment begins in amyloid-positive patients.

A well-designed learning test may be more useful for testing in the early stages of AD than the current standard measures of delayed recall. Generally, this type of “practice effect” learning, is avoided in clinical trials as it can confound memory test scores. Although, some experts who promote practice effect testing feel that decreased learning of new information echoes patient complaints of those that notice dysfunction but score normally on memory tests. This provides a means of testing the longitudinal progression of AD prior to the onset of memory impairment. Unfortunately, the test is not yet ready for use in clinical trials. Hopefully in the future this improved testing will translate to improved therapies for AD but only time will tell.

Sources:

In Preclinical Alzheimer’s, Learning Falters Before Memory [Internet]. Alzforum. 2020. Available from: https://www.alzforum.org/news/research-news/preclinical-alzheimers-learning-falters-memory

New Discovery in Tau Pathology

Posted on September 17, 2020March 4, 2021 by Michael Mega

We frequently discuss what factors increase or reduce risk for Alzheimer’s disease (AD) and other memory-impairing disorders. However, with research constantly ongoing there is always more to learn. Recently, researchers discovered an important impact of misfolded tau protein in rat brains with AD that sheds some light on how tau increases risk, providing an important window into the mechanism of AD progression. Once researchers understand how tau impacts the brain, it will be much easier to discover ways to combat the process.

Many theories exist as to how misfolded tau protein impacts neuronal communication and promotes degeneration, but few have been empirically proven or replicated. Without this key factor, researchers only know what biomarker causes the degeneration (tau) and what impairment it causes, but not how. Unfortunately, without understanding how misfolded tau leads to impairment, it’s difficult to counteract the mechanism causing the impairment. Luckily, a recent study discovered a unique relationship between tau, nitric oxide (NO), and cerebral vasculature that occurs even before tau forms neurofibrillary tangles (NFTs).

Specifically, in rats with overexpression of mutant tau proteins, the tau can be translocated to the dendrite where it displaces an important protein called neuronal nitric oxide synthase (nNOS) involved in the production of NO in the brain. Under normal circumstances NO is a product of neural activity, signaling blood vessels in the area to expand increasing oxygen to support the increase in activity. This process is called neurovascular coupling. Neurovascular uncoupling occurs in disease models when tau proteins bind to the receptor on neurons that nNOS would normally bind to, thereby preventing NO production and transmission of the signal to expand blood vessels. Reduced blood flow to areas of high activity in the brain prevents many cellular processes that allow for optimal cognition. This is why vascular complications can induce cognitive impairment even without AD.

Increased blood flow not only provides oxygen and nutrients to neurons, but also serves as a garbageman, taking away unnecessary or toxic proteins. Without clearance of these waste products, they build up much more quickly and induce dysfunction. Mutant tau proteins are one of these toxic molecules that would normally be cleared from the brain by the blood. When not cleared, the tau proteins can aggregate into NFTs inducing further dysfunction and even cell death.

These findings indicate that tauopathy development supports the progression of its own NFT buildup, through reduction of vascular waste clearance, creating a cycle of impairment and degeneration. If we can find a way to override nNOS silencing by tau, we would expect cognition to improve with further clearance of tau tangles and Aꞵ due to increased blood flow, in turn slowing or halting disease progression.

Sources:

With Tau in Synapses, NO Neurovascular Coupling [Internet]. Alzforum. 2020. Available from: https://www.alzforum.org/news/research-news/tau-synapses-no-neurovascular-coupling.

Park, L., et al. Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration [Internet]. Nature Neuroscience. 2020. Available from: https://www.nature.com/articles/s41593-020-0686-7.