New studies on preventing Alzheimer's

Two interesting new studies came out in the past few weeks on preventing or reversing Alzheimer’s disease. It seems that the field of Alzheimer's research has taken big steps forward recently, with a lot of out-of-the-box thinking and new avenues of study.

Dopamine, neprilysin, and reversal of Alzheimer’s (in mice)

First up is a new study published in the journal Science Signaling. (Here’s a more readable article about the study.) The research was done by a group of Japanese researchers at the RIKEN Center for Brain Science.

The researchers looked at an enzyme called neprilysin, which breaks down amyloid-beta in areas of the brain that are important for working memory. In mice, increasing dopamine by giving them levodopa increased neprilysin and reversed some of the Alzheimer's symptoms.

First, reversing symptoms is important because most interventions only seem to stop Alzheimer's from getting worse.

The study is important because it shows that neprilysin is probably a good target for reversing the pathology. However, simply increasing overall dopamine levels is probably not the answer in humans. Excess dopamine can be harmful to nerve cells (or cause psychosis). Levodopa is a precursor to dopamine used in Parkinson's disease, but it has some serious side effects. In the mouse study, researchers were able to target specific regions of the brain for treatment. Hopefully, this will lead to more targeted ways to increase neprilysin in humans.

Boosting electrical oscillations in the brain:

The other study published this week in PNAS takes a completely different approach than reducing amyloid-beta plaque. It builds on earlier research showing that gamma wave oscillations are reduced in Alzheimer's brains.

First, a little background:
Gamma oscillations are the electrical fluctuations in the brain's cortex that show up on an EEG. They have a specific frequency (about 30-100 Hz) and are the rhythmic pattern of firing and synaptic inhibition in the brain. Here's a more detailed explanation:

In many cases, γ oscillations reflect interactions between excitatory neurons and inhibitory interneurons in which excitatory neurons fire, triggering the synchronized discharge of many inhibitory interneurons, which deliver feedback inhibition to excitatory neurons, transiently silencing them. When this inhibition wears off, excitatory neurons fire again, triggering a new cycle of the γ oscillation. In other cases, interactions between inhibitory neurons themselves may suffice to generate γ oscillations, and the relative contributions of these two mechanisms to various forms of γ oscillations remain unclear.[ref]

In people with Alzheimer's disease or even early mild cognitive impairment, gamma oscillations in the brain are reduced. There have been a number of studies over the past 10 years that show that listening to gamma waves or looking at light that oscillates at the right frequency may make some difference (but isn't a cure for Alzheimer's). Here’s an overview of some of the external stimuli gamma oscillation studies. While interesting, the external gamma approach doesn't seem to match what the brain needs at the right time, as gamma oscillations change with brain tasks.

This new study in PNAS took a different approach. The researchers looked at pharmacological ways of enhancing gamma oscillations by reducing the inhibitory side of the equation.

GABA is the inhibitory neurotransmitter. Without inhibition, neurons would be overexcited and fire constantly. (Epileptic seizures can be caused by a lack of GABA inhibition or by a GABA/glutamate imbalance).

Within the brain, there are different regions with several different variations of GABA receptors on neurons. The researchers first identified the specific GABA receptor subtypes in the region of the brain involved in episodic memory. They then looked at different drugs that target the specific receptors and developed a negative allosteric modulator compound that could target the receptors and reduce the inhibition of gamma oscillations. Testing the compound in a mouse model of Alzheimer's disease showed that the novel compound could reach the brain and alter the amplitude of gamma oscillations. The researchers then tested oral administration of the compound to Alzheimer's mice for two weeks. The mice showed a reversal of cognitive impairment and recovery of working memory.

Conclusion:

While both of these new studies are early stage and in animal models, I’m encouraged by the different avenues researchers are taking toward finding a cure for Alzheimer’s. The recent genetic study on the role that fibronectin plays in amyloid-beta plaque and neuroinflammation in people with APOE4 is also exciting. Together, these three new studies illustrate totally different paths involved in neuroinflammatory diseases — with multiple ways to approach prevention.