Alzheimer’s Disease: Tipping the energy balance

Alzheimer’s Afternoons Seminar Series
(March 26) Lance Johnson

The Alzheimer’s Afternoons Seminar Series started off with a seminar by Dr. Lance Johnson from the University of Kentucky.  Dr. Johnson is one of the organizers of the popular online seminar series but also a guest editor (along with Allan Butterfield) for a special issue of the journal Neurobiology of Disease containing eleven articles on ApoE and Alzheimer’s.  The open access articles (technically published in June 2020, but available online in April 2020) can be accessed here:

This seminar is based in part of a recent article in this series:


Holden C. Williams, Brandon C. Farmer, Margaret A. Piron, Adeline E. Walsh, Ronald C. Bruntz, Matthew S. Gentry, Ramon C. Sun, Lance A. Johnson.  APOE alters glucose flux through central carbon pathways in astrocytes.  Neurobiology of Disease, Volume 136, 2020, 104742, ISSN 0969-9961.

Dr. Johnson opened by explaining the theory that carriers of the apoe4 risk gene, which significantly increases the incidence of late onset Alzheimer’s disease (LOAD), process metabolic “fuels” differently. Specifically, he cited increasing evidence that apoe4 astrocytes and microglia – brain cells which tend to neurons and fight infection – are less able to process sugars by the usual processes of glycoloysis, the citric acid cycle, and/or oxidative phosphorylation (OXPHOS).  He postulated that this one reason why apoe4 astrocytes fail to adequately nurture and protect neurons.

He mentioned the Randle cycle (the “glucose fatty-acid cycle”) which helps cells fine-tune fuel usage.  Normally, this cycle balances the competition of glucose and fatty acids for metabolic substrates in cells.  (If you own a plug-in hybrid car think of this as the computer which constantly balances the use of the engine vs. the battery to drive the wheels.)

In recent years the inability to use glucose effectively has become a well-recognized hallmark of the disease.

Dr. Johnson hypothesized that apoe4 brain cells process glucose mainly through glycolysis, ending in the production of lactate.

Normally, this occurs when adequate oxygen for OXPHOS is lacking.  It can also occur in cancerous tumors via the Warburg effect.  In any case, converting glucose to lactate provides only a small amount of energy and requires that lactate – which becomes toxic when it accumulates – be recycled later, at significant metabolic cost.  In short, it is a quick way to produce a bit of ATP and NAD, but quite inefficient.

His theory also predicts that apoe4 brains would use fats as an alternative fuel.

This may require some explanation for non-experts:

Fatty acids are simple chains of hydrocarbon molecules, with a small “head group”.  They vary in length from short chain (e.g., having eight carbons; C-8) to long chain (e.g., having 18 carbons; C-18) and usually have an even number of carbons in the chain.  Sometimes specific carbons are connected by double bounds, instead of single bonds; these “degrees of unsaturation” form kinks in the chain and change the molecule’s personality.

Double bond kinks can determine how fats “stack” or fit together.  Fatty acids that stack well tend to be solid at room temperature and are called “fats”, whereas those with double bond kinks tend to require more personal space, are liquids at room temperature, and are commonly called “oils”.

Examples include: saturated fats (no double bonds), unsaturated fats (one double bond), poly-unsaturated fats (multiple double bonds), and trans- and partially hydrogenated- fats (mostly commercial food products; not healthy!), as well as  omega-3 fatty acids (often anti-inflammatory) and omega-6 fatty acids (often pro-inflammatory).

For convenient storage fatty acids can be “hung” from a glycerol molecule – like belts on a clothes hanger.  These are the monoglycerides (one hanging chain), diglycerides (two hanging chains), triglycerides (three hanging chains, good for storage and transport), or phospholipids (two hanging chains and a phosphate head group).

“Lipid” is a very general term.  Lipids are, technically, anything similar that doesn’t dissolve easily in water – such as fatty acids, waxes, sterols, fat-soluble vitamins (A, D, E, and K), monoglycerides, diglycerides, triglycerides, and phospholipids.

By the way cholesterol is not a fat.  It has a basic steroid structure, and is synthesized differently.

Brain tissues usually prefer to burn sugars as fuel.  Burning fats as fuel first requires that larger triglycerides and longer chain fatty acids be trimmed to a size that can enter the mitochondria.  Then is requires beta-oxidation of shorter-chain fatty acids inside mitochondrial matrix, a process that is slower and can produce more toxic reactive oxygen species (ROS) than the burning of sugars.

You’ll recall that fatty acids can be obtained from the diet and transported in the blood as triglycerides.  Triglycerides are “oily” and not soluble in blood plasma; hence they are circulated (along with cholesterol) inside tiny lipoprotein particles.  These particles include the familiar LDL (the “bad” cholesterol carrier) and HDL (the “good” cholesterol carrier), and many others.  The liver is one of the main sources of cholesterol and lipids and acts as a distribution hub to build, export, and recycle apolipoprotein particles.

These particles contain some proteins – these serve as a scaffolding to help shape the particles into hollow spheres and also acts as an address label of sorts.  Cells hoping to import cargo carried in lipoprotein particles display receptors to these proteins on their surfaces – and snag the particles as they pass by.  ApoE (apolipoprotein E) is one of these proteins, present on the surface of many (but not all) types of lipoprotein particles.  The apoe4 version of this protein differs only by one or two amino acids, but this give the molecule a different shape and different binding tendencies.

These familiar types of lipoprotein particles produced primarily by the liver – LDL, VLDL, IDL, and HDL – do not usually penetrate the blood-brain barrier.  Thus, the brain is “cut-off” from dietary fats and lipids.  Instead the brain produces its own fats, lipids, and cholesterol and shares them among the various types of brain cells in analogous lipoprotein particles that occur only in the brain.  However, the apoe4 protein is a key component of lipoprotein particles found both inside and outside of the brain.

In some cases, brain cells that are particularly hungry for fats to burn as fuel can end up breaking down the protective myelin sheaths of neurons into free fatty acids.  This would be problematic, of course.

Dr. Johnson noted the Dr. Alois Alzheimer observed “lipid droplets” in the brain of patients in 1907. Dr. Johnson’s research group wondered if these “droplets” were accumulations of fats and they wondered if individuals carrying apoe4 genes, and having a higher risk of developing LOAD, accumulated more lipid droplets in brain tissues. By analyzing brain tissues, they found interesting differences: apoe4 brain cells accumulation more droplets, but they are also smaller in diameter compared to apoe3 brain cells.

This might be explained in part by observation that apoe4 cells have lower activity of ATP-binding cassette transporters (ABC transporters) which facilitate lipid efflux from cells.  ABC transporters load fats and lipids into lipoprotein particles for export; the presence of apoe4 reduces this, leaving apolipoproteins underinflated (or “poorly lipidated”, to use the technical term).  This could explain the group’s observation.  It would be expected that lipid droplets would accumulate inside apoe4 cells if lipids and fatty acids could not be exported as rapidly.

Dr. Johnson’s group noted that the accumulation of small lipid droplets in apoe4s worsen with age.

In another set of experiments, they fed apoe4 brain cells fatty acids labeled with radioactive carbon (14C) – a useful way to trace the path of these compounds in cells.  They found that apoe4 cells were indeed burning more fatty acids by beta-oxidation in mitochondria, supporting their hypothesis.

To explore this further they conducted metabolic experiments on 94 human subjects (all <55 years old and healthy; 33 of these carried at least one copy of the apoe4 gene).  The researchers recorded the subject’s metabolic activity – including their respiratory exchange ratio – at rest, then after consuming sugary drinks.  They found that subjects without apoe4 genes (including those with the apoe2 genes, which is protective against LOAD) burned the sugars easily.  They showed the typical increase in oxygen uptake that is expected when subjects are burning sugars as fuels.  On the other hand, subjects with apoe4 genes did not metabolize sugars as well; they exhibited no increase in oxygen uptake or usage.

Their conclusion from this collection of experiments – some of which were recently published – was that the data support the original theory: apoe4 cells process sugars poorly and seem to use more fatty acids as fuel to compensate.

Dr. Johnson compared the metabolism of apoe4 astrocyctes and microglia to the “Warburg effect” seen in cancerous tumors.  As mentioned previously many types of cancerous cells run glycolysis without the citric acid cycle and OXPHOS.  This process is fast but inefficient.  It churns out lactate acid as a waste product.  He mentioned that a “high fat diet” made this more pronounced.  NOTE: a “high-fat diet” usually refers to a poor-quality diet akin to a “Super-size Me”-type Standard American Diet, which is appropriately abbreviated as S.A.D.