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Preface

This Practical Guide is part of Forever Healthy's "Maximizing Health" initiative that seeks to review the world's leading medical knowledge on various health-related topics and turn it into actionable information.

Section 1: Overview 

Motivation

APOE is the gene responsible for coding Apolipoprotein E, a key player in our lipid metabolism. APOE comes in 3 significant variants: ε2, ε3 & ε4. Since humans carry two copies of the gene, there are six possible permutations: APOE 2/2, 2/3, 2/4, 3/3, 3/4 & 4/4. In Europe / USA, roughly 75% of people are APOE3/3, and the APOE3/4 or 4/4 variants are present in 20 - 25 %.

The ε4 variant is well known for its association with a significantly higher risk of Alzheimer's disease. Numerous other conditions have been linked to it including different forms of dementia, cardiovascular disease (CVD), and decreased longevity. There are several important implications for carriers of one or two copies of the ε4 variant, particularly concerning saturated fat and heavy metal detox.

Key Questions 

This analysis seeks to answer the following questions:

• Which risks are involved in carrying one or two ε4 alleles?

• What are the potential risk mitigation strategies?

• Who should be tested for APOE4?

Impatient readers may choose to skip directly to Section 4 for the summary of findings and tips on risk management. 

Section 2: Methods

Literature search

A literature search was conducted on PubMed, Google, Google Scholar, and SNPedia using the search terms shown in Table 1. Titles and abstracts of the resulting studies were screened and relevant articles downloaded in full text. The references of the full-text articles were manually searched to identify additional trials that may have been missed by the search terms.

Table 1: Literature Search (as of Jul 27, 2020 )

Recommended Reading/Viewing

The following sites and documents offer information on APOE4 at a consumer level and are useful as an introduction to the topic. However, sometimes they are not entirely accurate or specific in every detail.

•  

  • High cholesterol and the APOE gene - gbhealthwatch.com
    
    
    

  • Reducing Risk For APOE4 Genotypes (pdf) 

    A brief overview and links to some relevant studies
    
    
    

  • The straight dope on cholesterol - Peter Attia

    Since APOE has such a strong impact on lipid metabolism, cholesterol profile, and our CVD risk profile we have included this reference. A good introduction to cholesterol and the significance of the individual markers for CVD.

Abbreviation list

Section 3: Review of APOE4's influence on metabolism & disease

Saturated Fat & LDL-C

There is a correlation between APOE4, the amount of fat consumed, and low-density lipoprotein cholesterol (LDL-C). It appears that it is primarily the amount of saturated fatty acids (SFA) that drives total LDL-C and not monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA).

Interview with Joe D. Goldstrich, MD (Goldstrich, 2011)

An anecdotal example of severely elevated LDL on saturated fat consumption due to the bulletproof diet (bayesianinvestor.com)

Saturated Fat: Healthful, Harmful, or Somewhere In Between? (thepaleomom.com)

Gene-nutrient interactions: dietary behavior associated with high coronary heart disease risk particularly affects serum LDL cholesterol in apolipoprotein E epsilon4-carrying free-living individuals (Loktionov et al., 2000)

• Alcohol intake was positively correlated with triacylglycerol concentration.

• Positive correlations between diet and blood lipids were found for total fat intake and total and LDL cholesterol and for saturated fat intake and total and LDL cholesterol.

• Monounsaturated fat consumption was also positively correlated with total and LDL cholesterol concentrations, whereas it was inversely related to HDL cholesterol. There were also inverse associations between HDL cholesterol and polyunsaturated fat. However, when energy was controlled for by expressing intakes as a percentage of total energy, only the relation between saturated fat and LDL cholesterol remained significant.

Saturated Fat & LDL Particle Size

The increase of LDL-C observed in APOE4 carriers when consuming saturated fat seems to result from an increase in both the size and number of LDL particles (LDL-P).

Gene-diet interactions and plasma lipoproteins: Role of apolipoprotein E and habitual saturated fat intake (Campos et al., 2001)

Saturated Fat & CRP 

There is evidence that consuming saturated fat increases C-reactive protein (CRP), a marker of systemic inflammation, in APOE4 carriers. Multiple studies have reported a lower baseline CRP in APOE4 carriers. 

APOE genotype influences triglyceride and C-reactive protein responses to altered dietary fat intake in UK adults (Carvalho-Wells et al., 2012)

Impact of the Apolipoprotein E (epsilon) Genotype on Cardiometabolic Risk Markers and Responsiveness to Acute and Chronic Dietary Fat Manipulation (Rathnayake et al, 2019)

Mono-unsaturated Fat, Carbohydrates, LDL Particle Size & Particle Count

Elevated LDL particle number (LDL-P) and decreased LDL particle size are both significant CVD risk factors.

There is evidence that MUFA decrease both LDL particle number (good) and LDL particle size (problematic) in APOE4 carriers.

Reduced-fat (particularly saturated fat) diets with low glycemic index carbohydrates appear to have positive effects on the metabolic profile. However, this is probably very individual, and studies can only give us a general hint on ways to try to optimize our diet to lower our CVD risk factors. On a personal level, it is important to experiment with different macro ratios and retest frequently.

Apolipoprotein E isoform phenotype and LDL subclass response to a reduced-fat diet (Dreon et al.,1994)

The Effect of Dietary Fat on LDL Size Is Influenced by Apolipoprotein E Genotype in Healthy Subjects (Moreno et al., 2004)

Moreno shows that for APOE3/4, a MUFA based diet produces a greater increase in HDL-C and a reduction in triglycerides, LDL-C, and ApoB (a proxy for LDL-P) than a carbohydrate (CHO) based diet.

APOE4 Genotype Exerts Greater Benefit in Lowering Plasma Cholesterol and Apolipoprotein B Than Wild Type (E3/E3), After Replacement of Dietary Saturated Fats With Low Glycaemic Index Carbohydrates (Griffin et al., 2018)

Dietary Cholesterol

APOE4 carriers seem to have a higher uptake of dietary cholesterol than APOE 2 & 3. There is evidence that they also experience greater decreases in total cholesterol and apo B when saturated fats are replaced with low GI carbohydrates on a lower-fat diet. 
 

Apolipoprotein E polymorphism and atherosclerosis (Davignon et al.,1988)

APOE4 Genotype Exerts Greater Benefit in Lowering Plasma Cholesterol and Apolipoprotein B than Wild Type (E3/E3), after Replacement of Dietary Saturated Fats with Low Glycaemic Index Carbohydrates (Griffin et al., 2018)

Fish Oil & LDL / HDL

Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) are the main omega-3 essential fatty acids in fish oil and are generally considered to have a number of important health benefits. However, there is some evidence that for APOE4 carriers, DHA supplementation may be less effective and can substantially increase LDL-C, reduce LDL particle size, and increase LDL-P. Additionally, EPA may also lower HDL-C and HDL-P.

APOE4 carriers exhibit disturbances in DHA metabolism. This results in an inability to maintain an appropriate balance between the arachidonic acid and DHA/EPA content in phospholipids that the body creates or modifies. This imbalance leads to an inflammatory state that may contribute to the development of several diseases. 

DHA and EPA clearance from plasma is also faster than in non-carriers. Lower levels of DHA (baseline and post-supplementation) in APOE4 carriers have been reported by several studies. 

There is, however, also a significant amount of evidence that APOE4 carriers do profit from anti-inflammatory effects, and lowering of triglycerides (TG) & very-low-density LDL (VLDL) following DHA supplementation and that the negative effects may be dose-dependent.

Consumption of DHA/EPA between the amount of 700 - 1,800 mg/day appears to have net positive effects.

Disturbance in uniformly 13C-labelled DHA metabolism in elderly human subjects carrying the apoE e4 allele (Chouinard-Watkins et al., 2013)

Effect of APOE Genotype on Plasma Docosahexaenoic Acid (DHA), Eicosapentaenoic Acid, Arachidonic Acid, and Hippocampal Volume in the Alzheimer’s Disease Cooperative Study-Sponsored DHA Clinical Trial (Tomaszewski et al., 2020)

ApoE Polymorphism and Fish Oil Supplementation in Subjects With an Atherogenic Lipoprotein Phenotype (Minihane et al., 2000)

Contribution of apolipoprotein E genotype and docosahexaenoic acid to the LDL-cholesterol response to fish oil (Olano-Martin et al., 2009)

APOE genotype modifies the association between plasma measured omega-3 fatty acids and plasma lipids in the Multi-Ethnic Study of Atherosclerosis (MESA) (Liang et al., 2013)

Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study (Caslake et al., 2008)

APOE genotype influences triglyceride and C-reactive protein responses to altered dietary fat intake in UK adults (Carvalho-Wells, 2012)

Disrupted fatty acid distribution in HDL and LDL according to apolipoprotein E allele (Dang et al., 2015)

Interaction between BMI and APOE genotype is associated with changes in the plasma long-chain–PUFA response to a fish-oil supplement in healthy participants (Chouinard-Watkins et al., 2013)

The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease (Yassine et al., 2016)

Apolipoprotein E genotype status affects habitual human blood mononuclear cell gene expression and its response to fish oil intervention (Matualatupauw et al., 2016)

Motor Function

There is inconclusive evidence on a correlation between APOE4 and motor function. Some studies have reported a relationship between the presence of an APOE4 allele and the decrease of motor function in healthy adults while others found no such association.

The Association of APOE Ε4 Status with Lower Limb Function and Handgrip strength in older Adults (Maltais et al., 2019)

Exercise 

There is lots of evidence that regular exercise can counter the risk posed by carrying APOE4. A sedentary lifestyle increases the risk of cognitive decline and Alzheimer's. However, a study has also shown that exercise is less effective in improving brain function in APOE4 carrying individuals than in those carrying APOE2 or E3 alleles.

Exercise, APOE genotype, and the evolution of the human lifespan (Raichlen et al., 2014) 

Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition (Neurol et al., 2012)

Physical Activity May Modulate Effects of ApoE Genotype on Lipid Profile (Bernstein et al., 2002)

Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease (Smith et al., 2014)

Effect of aerobic exercise on cognition in younger adults A randomized clinical trial (Stern et al., 2019)

Neurodegeneration & Multiple Sclerosis

A correlation between APOE4 and increased risk of various types of neurodegeneration and other diseases of the CNS has been shown in several studies. There is also evidence that ApoE isoforms control Aβ production (a key pathological finding in AD). 

APOE and Alzheimer’s Disease: Evidence Mounts that Targeting APOE4 may Combat Alzheimer’s Pathogenesis (Uddin et al., 2018)

Relative effect of APOE e4 on neuroimaging biomarker changes across the lifespan (Gonneaud et al., 2016)

Apolipoprotein E e4 allele frequency in patients with Lewy body dementia, Alzheimer's disease and age-matched controls (St Clair et al., 1994)

Apolipoprotein E 4 is associated with rapid progression of multiple sclerosis (Fazekas et al., 2001)

Apolipoprotein E ε4 Is Associated with Neuronal Loss in the Substantia nigra in Alzheimer’s Disease (Camicioli et al., 1999)

Regional brain atrophy in cognitively intact adults with a single APOE 4 allele (Wishart et al., 2006)

White Matter Lesions in Alzheimer Patients Are Influenced by Apolipoprotein E Genotype (Bronge et al.,1999) 

Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer’s disease: lessons from ApoE mouse models (Huang et al., 2011)

Traumatic Brain Injury 

There is some evidence that APOE4 carriers have enhanced EEG abnormalities and worse functional outcomes following traumatic brain injury (TBI).

Different quantitative EEG alterations induced by TBI among patients with different APOE genotypes (Jiang et al., 2011)

Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury (Friedman et al., 1999)

Telomeres

There is evidence that APOE4 carriers may have an accelerated rate of telomere shortening.

Accelerated Cell Aging in Female APOE-e4 Carriers: Implications for Hormone Therapy Use (Jacobs et al., 2013)

...the odds of an APOE-ε4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR = 6.26, 95% CI = 1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-ε4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers.

Heavy Metal Toxicity

APOE4 carriers have a substantially reduced capacity for heavy metal detox (both mercury and lead) which might be a primary reason for the higher Alzheimer's risk since they are both highly neurotoxic.

• APOE2 can transport two atoms of mercury out of the brain

• APOE3 can transport one atom of mercury out of the brain

• APOE4 cannot transport mercury out of the brain

Amalgam fillings (which should be removed anyhow) in combination with periodontitis and anaerobic bacterially infected teeth (teeth with root canals) pose an even higher health risk due to the toxic mercury compounds that are created by simple chemical reactions directly in the mouth and then absorbed by the body. This is especially so for APOE4 carriers.

Apolipoprotein E genotyping as a potential biomarker for mercury neurotoxicity (Godfrey et al., 2003)

Susceptibility Factors in Mercury Toxicity: Immune Reactivity, Detoxification System Function, Enzymatic Blockages, Synergistic Exposures (Windham)

The relationship of the toxic effects of mercury to exacerbation of the medical condition classified as Alzheimer’s disease (Haley, 2007)

Cardiovascular Disease

APOE4 is associated with an increased risk of CVD including coronary heart disease, intracerebral hemorrhage, and atherosclerotic cerebral infarction.

APOE Gene Polymorphism and Risk of Coronary Stenosis in Pakistani Population (Cheema et al., 2015)

APOE genotype, ethnicity, and the risk of cerebral hemorrhage (Tzourio et al., 2008)

Apolipoprotein E Epsilon 4 Enhances the Association between the rs2910164 Polymorphism of miR-146a and Risk of Atherosclerotic Cerebral Infarction (Zhong et al., 2016)

Polymorphism of the apolipoprotein E gene and early carotid atherosclerosis defined by ultrasonography in asymptomatic adults (Cattin et al., 1997)

Insulin Resistance

There is evidence that APOE4 carriers with metabolic syndrome and a high intake of SFA have a significantly increased risk of developing type 2 diabetes. 

APOE Genotype Influences Insulin Resistance, Apolipoprotein CII and CIII According to Plasma Fatty Acid Profile in the Metabolic Syndrome (Fallaize et al, 2017)

Glucose

A correlation between APOE4 and an accelerated rate of increasing plasma glucose has been demonstrated.

apoE4 allele and the natural history of cardiovascular risk factors (Scuteri et al., 2005)

Metabolic Phenotype & Increased Disease Risk

There is evidence that APOE4 carrying women with poor metabolic phenotype are more likely to have higher levels of subclinical atherosclerosis compared with ApoE4- women.

Effect of ApoE4 Genotype on the Association Between Metabolic Phenotype and Subclinical Atherosclerosis in Postmenopausal Women (Sriprasert et al., 2019)

Toward a personalized lifestyle intervention approach to prevent Alzheimer’s disease (Maki, 2018)

Sex

There is evidence of sex-related differences in carriers of APOE4. Women carrying one APOE4 allele had reduced hippocampal volume whereas men only showed a reduction when they were carrying two copies of APOE4. Statistically significant age-associated memory impairment was only observed in women carrying APOE4. 

Sex, Apolipoprotein E 4 Status, and Hippocampal Volume in Mild Cognitive Impairment (Fleisher et al., 2005)

Apolipoprotein E Gender Effects on Cognitive Performance in Age-Associated Memory Impairment (Bartrés-Faz et al., 2002)

Longevity

Carriage of the APOE4 allele is the only major genetic determinant of survival into old age.

A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals (Nebel et al., 2011)

Bone Mineral Density

There is evidence that post-menopausal APOE4 carrying women have decreased spinal mineral bone density, with a 2-fold higher rate of bone loss. 

Apolipoprotein E Gene Polymorphism and Bone Loss: Estrogen Status Modifies the Influence of Apolipoprotein E on Bone Loss (Salamone et al., 2000)

Apolipoprotein E 4 allele is associated with low bone density in postmenopausal women (Zajícˇková et al., 2003)

Gut Microbiome

Several studies have implicated a link between the gut microbiome, short-chain fatty acids (SCFA), and the development of AD. There is evidence that gut microbiota composition in humans differs by APOE genotype. This results in a changed production of amino acids and SCFA, potentially contributing to Alzheimer's pathology. 

APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer’s disease pathophysiology (Tran et al., 2019)

Alcohol

There is evidence that APOE4 carriers do not profit from the protective effect of a small amount of alcohol like APOE2 carriers do. Consuming alcohol can increase triglycerides for APOE4. APOE4 carriers probably do best without alcohol.

Gene-nutrient interactions: dietary behaviour associated with high coronary heart disease risk particularly affects serum LDL cholesterol in apolipoprotein E epsilon4-carrying free-living individuals (Loktionov et al., 2000)

Saturated fat intake and alcohol consumption modulate the association between the APOE polymorphism and risk of future coronary heart disease: a nested case-control study in the Spanish EPIC cohort (Corella et al., 2011)

Apolipoprotein E, alcohol consumption, and risk of ischemic stroke: The Framingham Heart Study revisited (Djoussé et al., 2009)

Quercetin & HDL

There is inconclusive evidence regarding the effect of Quercetin on HDL-C in APOE4 carriers. One study reported that quercetin lowered HDL-C, while a more recent study reported that quercetin increased HDL-C. There is, however, also evidence that Quercetin's beneficial effects of lowering oxLDL and TNFa also extend to APOE4 carriers.

Serum Lipid and Blood Pressure Responses to Quercetin Vary in Overweight Patients by Apolipoprotein E Genotype (Egert et al., 2009)

Effect of quercetin on traits of the metabolic syndrome, endothelial function, and inflammation in men with different APOE isoforms (Pfeuffer et al., 2011)

Cholesterol-lowering Substances

There is conflicting evidence on the effects of consuming plant sterols in APOE4 carriers with one study reporting increased cholesterol-lowering effects, and another studying reporting decreased effects. Varying responses to statins have also been reported.

CYP7A1-rs3808607 and APOE isoform associate with LDL cholesterol lowering after plant sterol consumption in a randomized clinical trial (Mackay at al., 2015)

Serum Lipid and Antioxidant Responses in Hypercholesterolemic Men and Women Receiving Plant Sterol Esters Vary by Apolipoprotein E Genotype (Sanchez-Muniz et al., 2008)

Apolipoprotein-E polymorphism and response to pravastatin in men with coronary artery disease (REGRESS) (Maitland-Van Der Zee et al., 2006)

Evolutionary / Ancestral / Paleo Style Diets

These diets often emphasize liberally consuming saturated fat from coconut oil, palm oil, butter, ghee, fatty meat, dark chocolate, etc. which are nowadays deemed safe for consumption. 

Viewing the population as a whole, switching from an unhealthy diet to a clean ancestral diet lowers the risk for CVD, even if it is high in saturated fat. Unfortunately, if broken down according to APOE status, this remains true only for those that don't carry the APOE4 variant.

For carriers of the APOE4 variant, consuming saturated fatty acids can substantially raise the risk of CVD.

Sadly, most of the proponents of this lifestyle have not yet realized this critical fact and still promote the consumption of saturated fat to everyone, putting a significant percentage of the population in harm's way.

However, these diets at their core are not about saturated fat but about eating clean and healthy food. A modified variant of these diets that is low in saturated fat is easily achievable.

Section 4: Summary of Findings

There are multiple, mostly adverse effects associated with carrying one or two copies of APOE4:

• Decreased longevity
  
  
  

• A substantially higher risk of late-onset AD and other forms of dementia, worse outcomes following traumatic brain injury, & accelerated progression of MS
  
  
  

• A substantially higher risk of CVD including coronary heart disease, intracerebral hemorrhage, and atherosclerotic cerebral infarction
  
  
  

• Severely impaired heavy metal detoxification capabilities, particularly for lead and mercury
  
  
  

• Increased susceptibility to the detrimental effects of a sedentary lifestyle regarding increased AD risk
  
  
  

• Accelerated telomere shortening
  
  
  

• Greater risk of disease when found in combination with a poor metabolic profile
  
  
  

• Reduced hippocampal volume and increased age-related memory impairment (females)
  
  
  

• Lower bone density (females)
  
  
  

• Consuming saturated fats can:

  • substantially raise LDL-P which is a major risk factor for CVD

  • raise CRP, which is a risk factor for CVD, however, APOE4 carriers have lower baseline levels of CRP

  • increase LDL particle size, which in itself, is cardioprotective. However, this may be outweighed by the rise in LDL-P

  • substantially raise LDL-C

  • result in insulin resistance & an increased risk of diabetes
    
    
    

• Consuming MUFA found in olive oil, avocados, etc. can:

  • decrease LDL-P which is cardioprotective

  • decrease LDL particle size, which is a risk factor for CVD. However, this may be outweighed by the decrease in LDL-P

  • decrease LDL-C 
    
    
    

• Consuming DHA & EPA (e.g., from fish oil) produces many health benefits but can also result in adverse health effects if consumed in high doses
  
  
  

• Consuming DHA can 

  • increase LDL-P (bad)

  • reduce LDL particle size (bad)

  • increase LDL-C (bad)

  • decrease inflammatory gene expression (good)

  • decrease triglycerides (good)
    
    
    

• Consuming EPA can 

  • lower HDL-C (bad)

  • lower HDL-P (bad)
    
    
    
    

• Consuming alcohol can increase triglycerides

• Consuming small amounts of alcohol has no cardioprotective effect (only works for APOE2)

• Consuming plant sterols may result in a greater LDL-C lowering effect (good)

• Pravastatin may be less effective in lowering cholesterol

Section 5: Risk Management 

Testing APOE Status

Regarding the high probability of being an APOE4 carrier and its far-reaching consequences, everybody should have their APOE status checked (e.g., using 23andme.com).

The good news is that once APOE status is known, diet and lifestyle can be modified in order to counter the risk factors that come with the E4 variant.

Basic Risk Management for APOE4 Carriers

• Closely monitor levels of mercury, lead and heavy metal toxicity in general

• Take appropriate measures to detox mercury and other heavy metals
  
  

• Carefully monitor the cholesterol profile, particularly LDL-P measured with NMR, which is strongly correlated with increased CVD risk
  
  
  

• APOE4 carriers usually do better on a diet low in SFA, low in PUFA, low but sufficient protein with a focus on moderate amounts of MUFA and low GI carbohydrates
  
  
  

• Keep saturated fat intake as low as possible

• Avoid palm oil, coconut oil, coconut milk, butter and ghee

• Avoid bulletproof coffee
  
  
  

• Consume nuts with care. Of all nuts, almonds are the lowest in SFA (3.7%)

• Unfortunately, dark chocolate and raw cacao nibs are high in saturated fat (up to 40%)
  
  
  

• Since 50% of fat in animal meat is saturated, avoid fatty animal meats like bacon

• If consuming animal meat, go for the lowest fat option like lean chicken

• If possible, go for fish or crustaceans which are low in saturated fat
  
  
  

• Limit EPA + DHA to a max. of 1800 mg/day

• consume EHA & DHA in their natural form by eating fatty fish
  
  
  

• Keep the intake of PUFA on the lower side. Unfortunately, there is not much research on the effect on PUFA in general for APOE4, but the research on EHA and DHA (both PUFA) shows that more might not be better
  
  
  

• Good sources of MUFA are avocados and olive oil

• Good sources of low GI carbs are lentils & sweet potatoes
  
  With all general guidelines and medical research on APOE4 and nutrition, keep in mind that the reaction of the metabolism to dietary changes is highly individual. Determining the right balance of macronutrients, especially balancing MUFA and carbohydrates for an optimal cholesterol profile, requires personal experimentation and frequent retesting.
   

• Take care to get appropriate amounts of exercise to counter the adverse effects of a sedentary lifestyle for APOE4 carriers 
  
  It is hard to say what a sufficient amount of training should be since all studies just correlate the amount of physical activity (mostly self-reported) and the occurrence of AD. As much physical activity as possible, such as daily walking, using a standing/walking desk, regular yoga, and stretching, is a good place to start. 

• Oral supplementation of anserine/carnosine may help preserve cognitive functions in APOE4-carrying older adults (Masuoka et al., 2019).