APOE and Alzheimer’s Disease
Our circulatory system is a vast transit system that allows for the movement of molecules like nutrients and hormones between various tissues of interest. The blood, being mostly water soluble, is the perfect highway for electrolytes, proteins, cells and nutrients which can easily move along this route.
Fatty substances, called lipids, however, are less readily able to travel through this medium, as they don’t blend seamlessly into the water-soluble blood. For this reason, our body has a complex system of proteins called lipoproteins that exist for the purpose of carrying these fat-soluble molecules.
There are a number of types of lipoproteins, each with a distinct lipoprotein “tag” and a specific form and function. Those you may be most familiar are the ones found on a standard lipid panel:
Chylomicrons: These lipoproteins transport dietary lipids (triglycerides and cholesterol) from the small intestine to the liver and other tissues. Apolipoprotein B-48 (apoB-48) is the protein “tag” associated with this molecule. Fun fact, chylomicrons are the reason we ask you to complete your lipid panel fasting, as they can overinflate a triglyceride measure.
Very low-density lipoproteins (VLDL): ApoB-100. These triglyceride-rich lipoproteins transport lipids synthesized in the liver to extra hepatic tissues like adipose (fat) tissue and muscle.
Low-density lipoproteins (LDL): ApoB-100 and small amounts of apoE (the focus of this post). These lipoproteins transport cholesterol from the liver to various tissues in the body. High levels of LDL’s apolipoprotein ApoB in the blood are associated with an increased risk of cardiovascular disease.
High-density lipoproteins (HDL): These lipoproteins transport cholesterol from the tissues back to the liver for processing and elimination. HDL contains several different apolipoproteins, including apoA-I, apoA-II, and apoE. ApoA-I is the primary apolipoprotein associated with HDL serves in the process of reverse cholesterol transport (RCT) pathway, which helps to remove excess cholesterol from peripheral tissues and transport it back to the liver for processing and elimination.
APOE
Apolipoprotein E (ApoE), is coded by the APOE gene found on chromosome 19 in humans. It has several functions in lipid metabolism, its primary being to serve as a ligand for receptors on various cell types, including hepatocytes and macrophages. When apoE binds to these receptors, it facilitates the uptake and clearance of lipoproteins from the bloodstream and helps to regulate plasma lipid levels.
Unlike other apolipoproteins, ApoE is a particularly complex one in that it serves a dual purpose of interfacing with lipids in the serum, as well as those in the central nervous system. This is where ApoE’s relevance in Alzheimer’s Disease (AD) enters.
There are three common variants of the APOE gene: ε2, ε3 (the most common), and ε4. These numbers define the APOE subtypes. As with any gene, every individual has two copies, thus two subtypes which can be any of six combinations.
Those with APOe3/e4 have an estimated 2-3 times increased risk of AD, and those with e4/e4 are about an 8-12x increase. But, these variants, unlike other genes, are not deterministic, meaning those with two copies of e4 can still live a long life without ever developing AD.
Though the exact mechanism of ApoE’s role in AD development has not been identified, there are several theories.
We know ApoE assists clearance of beta-amyloid, a protein that is associated with Alzheimer's disease. This process may help to prevent the accumulation of beta-amyloid and the development of Alzheimer's disease.
But, a study published in Nature (Blanchard, et al., 2022) found that APOe4 has an additional non-amyloid association. The team found that APOe4 triggers insulation-making brain cells known as oligodendrocytes to accumulate cholesterol in the wrong place.
It was identified that mice with the APOE4 variant had a tendency to aberrantly collect cholesterol inside the cell.
Ultimately, these cells were particularly bad at a process called cholesterol efflux, in which a cell transports cholesterol to the outside. This correlated with reduced myelination, the process by which a nerve becomes insulated, a function that allows for successful conduction.
As it stands, it appears that APOe4 increase AD risk in both amyloid and non-amyloid manners. Interestingly, there are additional genetic associations that can further modify AD risk, such as TOMM40, which further increases risk, and KL-VS (Klotho modifier) which, in the presence of APOE4, appears to reduce risk to that of an e3/e3.
For those with one or two copies of e4, the primary strategy is prevention, through the following:
Cardiovascular Exercise: in addition to strength-training, which carries benefits in other areas of preventive medicine, cardiovascular exercise exhibits neuroprotective activity by promoting the production of BDNF, brain-derived neurotrophic factor. This protein acts on the hippocampus, cortex, and basal forebrain areas of the brain to promote learning, memory, and higher-order thinking by facilitating the growth and differentiation of new neurons and connections amongst them. In addition, CV exercise benefits overall cardiovascular health and reduces risk of cardiovascular disease, which has its own AD associations.
Omega 3 Fatty Acids, particularly the long-chain polyunsaturated fatty acids (LCPUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to have many positive effects on brain health and cognitive function. Rhonda Patrick, PhD published a paper (Patrick, 2018) that posits that the phospholipid (fish-derived) form of omega-3 fatty acid docosahexaenoic acid (DHA) reduces the risk of AD due to an impaired brain transport of free DHA in APOE4 carriers. Much of her work theorizes that APOE4 presence in the brain is associated with a degradation in blood brain barrier integrity, which is evidence by the disruption of the vascularization of this area of the brain.
Blood glucose control: Alzheimer’s disease is referred to some as “Type 3 Diabetes” due to its close connection to this common metabolic derangement. A 2021 JAMA study (Amidei, et al.,) found that amongst 10,095 participants, a younger age of Type 2 Diabetes onset was associated with a higher risk for incident dementia. This may be due to the association chronically elevated blood glucose has with small vessel dysfunction, a common finding in post-mortem brain tissue of those with AD.
What’s on the horizon?
As we’re only at the tip of the iceberg when it comes to identifying the associating between both lipid and glucose metabolism in the pathogenesis of AD, we can expect to see an uptick of discoveries in the coming decade.
Folks may be curious to know if there will be a blood test to measure ApoE activity in the serum, however, it’s important to consider that it’s the central nervous system ApoE activity that bears association with AD. Therefore, if we are to test ApoE (concentration, not genotype) this test would best be done with a cerebrospinal fluid (CSF) draw. This metric, which is not without its risks (a lumbar puncture isn’t a simple visit to Quest) would allow us to visualize gene expression in vivo.
Dr. Emily D’Adamo, ND
@emilydadamo.nd on Instagram