World Brain Day 2022 - Lipid Metabolism and Alzheimer's Disease

Posted on July 15, 2022

Website Brain Day Image 2022

July 22nd is annual World Brain Day!

Why July 22nd? The World Federation of Neurology (WFN) was founded on July 22, 1957. The them for this year’s World Brain Day is Brain Health for All and stands on these primary pillars: Awareness, Prevention, Advocacy, Education, and Access.

We support World Brain Day, and our lipids are integral to research aimed at diagnosing and preventing brain diseases. Let’s take a look at a State-of the-Art Review discussing Alzheimer’s disease and its link to lipid metabolism published in The Federation of European Biochemical Societies (FEBS) Journal earlier this year.

First, here are a few facts and stats about AD:

  • AD is the most prevalent form of dementia.
  • Approx. 50 million people suffer from AD globally.
  • The number of people suffering from AD globally by year 2030 is 82 million and 152 million by 2050.
  • AD is characterized by memory deficits, cognitive impairment, and other behavioral changes.
  • AD develops along a continuum while progressively accumulating biomarkers, neural damage, and cognitive decline.

And a few more facts about lipids in the brain:

  • 10-12% of the wet weight of the brain is made up of lipids, and over 50% of the dry weight.
  • Major lipid species in the brain are phospholipids, sphingolipids, glycerolipids, fatty acids, and sterols.
  • These lipids are key components of synapses and the myelin sheath.
  • They are also involved in signal transduction agents regulating biological processes and as bioenergy.

Research linking lipid metabolism to AD has been accumulating for years. Lipid-targeting therapeutics have even shown efficacy in treating/preventing AD pathologies. The review takes an in-depth dive into lipids linked to AD and the opportunity that these mechanisms offer for therapeutics.

Lipid Metabolism Alterations in AD Pathologies compared to Healthy Brain

Therapeutic Opportunities by Targeting Lipid Metabolism

  1. Activation of lipid-sensitive nuclear receptors - Retinoid X Receptors (RXR), Liver X Receptors (LXR), and Peroxisome Proliferator-Activated Receptor (PPAR). These receptors are part of the nuclear receptor superfamily and are master regulators of lipid homeostasis. LXRβ is the major form of LXR in the brain, and LXRβ knockout mice exhibit neuronal loss and impaired motor function, as well as lipid accumulation. PPARγ agonists have been studied and found to have anti-inflammatory effects but PPARα could be an even more interesting target in a different therapeutic method.
  2. Reducing lipid accumulations. Activating PPARα promotes lipid degradation and reduces the accumulation of lipids. PPARα is found predominantly in astrocytes in the brain and modulates amyloid metabolism. Agonists of PPARα alleviate AD-like pathologies in mice.
  3. Boosting lipid transporters. The brain has two major regulators of lipid transport - ApoE and ABCA1. ApoE4 structure correctors are being investigated to reduce pathological effects. Other strategies include reducing the expression of ApoE4 or increasing ABCA1 activity via injection of an ABCA1 agonist.
  4. Supplementing PUFAs. Increasing the intake of ω-3 PUFAs has been proven to lower the risk of developing AD while a lower intake of these PUFAs shows an increased risk of developing AD.
  5. Replenishing ketogenic fuels. Ketone bodies represent the major non-glucose fuel source of the brain. A hallmark in AD models is hypometabolism of glucose and causes a metabolic switch from glucose to ketone bodies as the fuel source for the brain. It is hypothesized that a ketogenic diet high in saturated fats and low in carbohydrates could supply a sufficient supplement of ketone bodies to resist the bioenergetic deficits present due to glucose hypometabolism.
  6. Restricting cholesterol levels. There are a couple methods that lower cholesterol levels in the brain that have been investigated. One is the use of statins. Statins have had varying levels of success in improving AD pathologies by lowering cholesterol. These studies showed that it is dependent on the patients age, sex, and ApoE4 status, as well as the dose of statin. Lower doses of statins were more effective than higher doses in most cases. Another method for lowering cholesterol is to increase the amount of cholesterol that is metabolized into a derivative that can be exported from the brain. Increasing the conversion rate of cholesterol to 24S-hydroxycholesterol reduces Aβ pathology and improves spatial memory.

The more we understand about the brain's lipidome and its lipid metabolism, the better chance we have at diagnosing AD earlier, preventing its onset, and treating late-stage cases of AD. If you're interested to read the full review of lipid metabolism linked to Alzheimer's disease, click HERE! And remember, today is World Brain Day so promote brain health for all - including yourself!