The Role of apoE4 in Alzheimer's Disease

Alzheimer’s Disease (AD) is perhaps the first thing that jumps into people’s minds when they hear the word “dementia,” a classification of diseases that interfere with patients’ cognitive function enough to affect their daily lives. Indeed, it is the most common dementia, accounting for well over half of all dementia cases (Alzheimer's Association, n.d.). Alzheimer’s manifests itself as irreversible and progressive cognitive impairment, typically beginning with amnesia and gradually worsening until the patient meets serious challenges responding to their environment (Alzheimer's Association, n.d.). Perhaps, then, it would produce a sense of doom in those who learn that the particular alleles they inherited from their parents could become strong predictors of AD occurrence. Our main character, apoE ε4, is one such allele (Serrano-Pozo et al., 2021).

I. ApoE & Isoforms Overview

Apolipoprotein E (apoE) is a protein particle that binds to lipids and some cell receptors to facilitate lipid clearance from the blood (Huang & Mahley, 2014). In the brain, it helps transport proteins as it moves around the brain in cerebrospinal fluid (Huang & Mahley, 2014). However, varieties in the apoE gene can produce different isoforms, or manifestations of the same complex, of apoE. The most common isoforms are apoE2, apoE3, and apoE4. ApoE3 is the most common isoform, with apoE2 a major protector against and apoE4 a big risk factor for Alzheimer’s Disease (Serrano-Pozo et al., 2021). However, apoE2 presents its own host of problems – with its lower binding affinity to some receptors, it presents worse levels of blood lipid regulation, leading to type III hyperlipoproteinemia (Mahley & Huang, 1999).

II. ApoE4 Overview

ApoE4 differs from apoE3 in the 112th amino acid in their peptide chain, but because proteins have extremely complex structures that require very little error in every amino acid in the chain, this singular difference causes a major distinction in their 3D structure (Huang & Mahley, 2014).

As such, apoE4 has a preference to bind to different lipids and lipoproteins compared to apoE3 and apoE2. This difference leads to lower LDL (“bad” cholesterol) levels in the body, leading to increased risk of cardiovascular diseases like atherosclerosis (Mahley, 2016).

While AD is typically caused by amyloid-beta plaques and tau neurofibrillary tangles (NFTs), ApoE4 has also been shown to have an amyloid-beta-independent mechanism for AD development. More atherosclerosis means less effective blood flow to the brain, affecting the nutrients and oxygen levels in the brain and leading to neuronal death, among other negative effects.

III. ApoE4’s Role in Plaques & Tangles

“Plaques and tangles” are what neuroscientists refer to as the two main disease mechanisms of AD. “Plaques” refer to amyloid-beta plaques, the deposition of which around (not inside) brain neurons is strongly associated with AD symptoms. The amyloid cascade hypothesis, which puts amyloid deposits at the center of AD pathology, is currently the most widely accepted hypothesis for AD development and has guided scientists to find two drugs that slow the progression of the disease. “Tangles” refer to hyperphosphorylated tau proteins, which aggregate inside the neuron to form NFTs and cause neuronal death. Note that the toxicity of amyloid-beta may be associated with the formation of tau tangles (Zheng et al., 2002). Note also that tau-related pathological features can often be found in many other brain diseases while amyloid-beta plaque deposition is much more signature of AD (although it can also be found in a handful of other diseases).

Plaques

ApoE4 has long been shown to facilitate amyloid plaque formation, In 1993, Strittmatter et al. compared how well apoE4 and apoE3 bound to synthetic amyloid-beta. They discovered that, while both proteins bound amyloid-beta, apoE3 took hours to bind while apoE4 took merely minutes. Moreover, a transgenic mouse study revealed that expression of apoE4 resulted in markedly more amyloid-beta deposits than when apoE3 is expressed and that expression of apoE2 resulted in much less amyloid-beta deposition (Dodart et al., 2005). Not only does amyloid-beta increase plaque formation, it decreases amyloid clearance as well. In a study of mice expressing human apoE isoforms, the authors discovered that not only concentration but also clearance of amyloid-beta depended on the apoE isoform, with the half-life of A-beta in apoE4 mice much longer than those in apoE3 and apoE2 mice (Castellano et al., 2011). Thus, apoE4 likely becomes an AD risk factor by promoting deposition and obstructing clearance of amyloid-beta.

Tangles

ApoE4 has also been suggested to increase tau hyperphosphorylation, leading to the formation of NFTs. Firstly, mice with the human apoE4 gene display higher levels of tau phosphorylation than those with the apoE3 gene (Kobayashi et al., 2003; Chan et al., 2009), suggesting that human apoE4 carriers are more prone to this disease mechanism than noncarriers. Secondly, current findings suggest that carriers of the apoE4 gene are also more affected by some bad lifestyle choices than noncarriers. A pro-oxidative stress diet, consisting of folate and vitamin E deficiency and iron-rich food (pro-oxidant), raised phospho-tau levels in apoE4-expressing mice but not apoE-expressing ones over the period of a month (Chan et al., 2009). Note that this increase is on top of the already-higher phospho-tau concentration in apoE4-expressing mice. While mice and humans have many biological differences, these findings in mice can reveal the extent of NFT promulgation in apoE4 carriers compared to noncarriers.

The cause of this promulgation seems to come from apoE4 fragments: in a study examining the postmortem brain tissues of three AD patients and two non-AD normal subjects, researchers discovered that apoE4 fragments seemed to induce NFTs in neurons (Huang et al., 2001). Researchers have also learned that apoE4 is more prone to fragmentation than apoE3, amplifying the neurotoxic effect of its fragments on the neurons of carriers (Huang, 2010).

IV. Promises & Challenges

Carrying apoE4 significantly increases one’s risk for late-onset Alzheimer’s disease (LOAD) and lowers the starting age of pathology. Thus, patients carrying the allele should pay special care to their daily habits and make sure they don’t increase their AD risk even more. That said, the overrepresentation of apoE4 carriers in those with LOAD means that targeting apoE4 for AD treatment can be useful for many inflicted with the disease. Researchers have explored various options, and upregulation (producing more) of specific lipid receptors called LDLRs seem promising because it is relatively straightforward with fewer side effects than other options (Li et al., 2022). Combined with genetic tests, apoE4 carriers may see a unique treatment option due to their special disease mechanism.

On the other hand, even though two new drugs have recently been approved by the FDA for the slowing of AD progression, both seem to have significant safety issues for those carrying the apoE4 allele (Sims et al., 2023; Cummings et al., 2023). Specifically, ARIA-E, a type of edema, seems to occur more frequently as the number of carried apoE4 copies increases. In other words, someone who has both copies of apoE4 are more likely to experience edema than someone with one copy, who would nevertheless still be more likely to have the side effect than a noncarrier AD patient. For now, then, AD treatment for apoE4 patients remains limited.