Insights: APOE, Klotho, and the Risk of Alzheimer’s Disease

It is extremely exciting that so much research is coming out on Alzheimer’s Disease and Dementia at the moment.  The Lancet just published their 2024 report on Dementia prevention, intervention and care.  The report identifies 14 modifiable risk factors, including new additions such as untreated vision loss and high LDL cholesterol, that could prevent or delay nearly half of dementia cases if addressed effectively. The Commission also underscores the importance of personalized approaches to dementia prevention, advocating for actions like improving air quality, reducing social isolation, and ensuring access to education, hearing aids, and depression treatment.

For this blog, I wanted to dig deeper into two genetic factors – the apolipoprotein E (APOE) gene as well as the Klotho gene – both of which may influence Alzheimer’s risk and progression.

The Role of APOE in Alzheimer’s Disease

The APOE gene encodes apolipoprotein E, a protein involved in lipid metabolism, including the transport and redistribution of cholesterol and other lipids in the brain. There are three common alleles of the APOE gene: ε2, ε3, and ε4. Each individual inherits one allele from each parent, resulting in one of the six possible genotypes (e.g., ε2/ε3, ε3/ε4).  Most nutrigenomic tests these days run the APOE gene.

• APOE ε4: The presence of the APOE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer’s disease. Individuals with one copy of the ε4 allele have an increased risk of developing AD, while those with two copies have an even higher risk. Studies show that ε4 carriers have a higher propensity for amyloid-beta plaque formation, a hallmark of Alzheimer’s pathology .
• APOE ε3: This is the most common allele and is considered neutral in terms of Alzheimer’s risk. Individuals with the ε3/ε3 genotype have a baseline risk of developing AD.
• APOE ε2: The ε2 allele is considered protective against Alzheimer’s, with carriers having a lower risk of developing the disease compared to ε3 or ε4 carriers.

While APOE ε4 increases the risk of developing Alzheimer’s, the extent of this risk can vary depending on several factors, including age, gender, ethnicity, and overall lifestyle. For example, women with the APOE ε4 allele tend to have a higher risk of developing AD compared to men with the same allele. Additionally, the impact of APOE ε4 may differ across ethnic groups.

Recent studies have shown that lifestyle factors, such as diet, exercise, cognitive engagement, and cardiovascular health, can significantly influence the risk associated with APOE ε4. For instance, individuals with APOE ε4 who maintain a healthy lifestyle may reduce their risk of developing AD compared to those with less healthy habits.

Diet-related factors that increase the risk associated with APOE ε4 carriers are:

1. High saturated fat intake alongside a low omega-3 fatty acid intake.
2. High carbohydrate and sugar intake – Insulin resistance has been linked to increased amyloid-beta accumulation and inflammation, both of which are associated with cognitive decline.
3. Low phytonutrient intake – phytonutrients can protect against oxidative stress, which is a significant factor in the progression of AD. APOE ε4 carriers may have increased oxidative stress and thus a higher requirement for phytonutrients in their diet.
4. High alcohol consumption – excessive alcohol intake is associated with an increased risk of dementia, especially in APOE ε4 carriers. Alcohol can exacerbate brain atrophy and cognitive decline.

Klotho: A Protective Gene Against Cognitive Decline

The Klotho gene is definitely less well-known than APOE but is gaining attention for its potential protective effects against cognitive decline. Klotho encodes a protein that has multiple functions, including the regulation of aging processes and protection against oxidative stress.

• Klotho and Longevity: The Klotho protein is associated with increased lifespan and improved cognitive function. Higher levels of Klotho have been linked to better cognitive performance and a reduced risk of age-related diseases, including Alzheimer’s.  Klotho has been shown to enhance cognitive function independently of its effects on aging. Animal studies have demonstrated that increasing Klotho levels can improve cognitive performance, even in the absence of AD pathology.

Klotho also enhances synaptic plasticity, which is crucial for learning and memory. It has been found to protect against synaptic loss, which is a hallmark of AD. Klotho also influences signaling pathways like IGF-1 and Wnt that are important for maintaining synaptic health.

Klotho acts as an antioxidant, reducing oxidative stress in neurons. This is particularly important in AD, where oxidative damage is a major factor contributing to neuronal loss.

• Klotho Variants: The KL-VS variant of the Klotho gene has been associated with enhanced cognitive abilities and may confer protection against the development of AD. Research suggests that individuals with higher Klotho levels may experience slower cognitive decline, even in the presence of the APOE ε4 allele .  As far as I know, it is not possible to test for the KL-VS variant in South Africa but please correct me if I am wrong.  I believe it does form part of the 23andMe profile as well as some other US direct-to-consumer testing.

Potential Interplay between Klotho and APOE ε4

Research suggests that Klotho may modulate the risk of AD in individuals carrying the APOE ε4 allele. For example, high levels of Klotho may mitigate the increased risk of AD conferred by the APOE ε4 genotype. This interaction is still under investigation, but it holds promise for understanding how Klotho could be used therapeutically.

Potential way to increase Klotho and address APOE at the same time

1. Aerobic Exercise: Regular physical activity, particularly aerobic exercise, has been shown to increase Klotho levels. For APOE ε4 carriers, regular physical activity may delay the onset of Alzheimer’s symptoms. Some studies suggest that the cognitive benefits of exercise are even more pronounced in APOE ε4 carriers than in non-carriers. Exercise has anti-inflammatory effects, which can counteract the chronic neuroinflammation observed in Alzheimer’s disease. Since APOE ε4 carriers are more susceptible to inflammation-related cognitive decline, regular physical activity can be especially protective.
2. Caloric Restriction: Some studies indicate that caloric restriction, which is known to extend lifespan in various organisms, may also increase Klotho levels. Caloric restriction has been shown to increase the production of brain-derived neurotrophic factor (BDNF), a protein that supports neuron survival and cognitive function. Since APOE ε4 carriers often exhibit lower BDNF levels, caloric restriction may help counteract this deficiency, supporting cognitive health.
3. Resveratrol: Some studies suggest that resveratrol, a polyphenol found in grapes and red wine, might have a positive impact on Klotho levels. Resveratrol is believed to mimic the effects of caloric restriction and may upregulate Klotho expression. Resveratrol has been shown to promote the clearance of amyloid-beta, a protein that aggregates to form plaques in the brains of Alzheimer’s patients. APOE ε4 carriers are particularly prone to amyloid-beta deposition, so resveratrol’s ability to enhance clearance could be significant for this population.  Additionally, resveratrol is known to activate sirtuins, particularly SIRT1, which are enzymes involved in cellular stress resistance and longevity. Sirtuins have been implicated in neuroprotection and may play a role in reducing the progression of neurodegenerative diseases.

Klotho’s ability to enhance synaptic plasticity, reduce neuroinflammation, and mitigate oxidative stress provides an exciting avenue for therapeutic strategies aimed at those most vulnerable to Alzheimer’s disease. The discovery that higher levels of Klotho can potentially offset the increased risk conferred by APOE ε4 underscores the importance of exploring genetic and lifestyle interventions that can boost Klotho expression.

As research continues to unravel the mechanisms by which Klotho interacts with APOE ε4, it becomes increasingly clear that a multifaceted approach – combining genetic insights, lifestyle modifications, and targeted therapies – could be key to preventing or delaying the onset of Alzheimer’s in high-risk populations.