Episode # 7
The Alzheimer's Solution Revolution
#7—Genetic Variants in the Risk for Late-onset Alzheimer’s Disease—ApoE4 and Beyond
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EPISODE 7
Summary and Audio
How does your unique genome increase the risk for Alzheimer’s disease as you age?
In today’s episode—#7, I’ll be giving a comprehensive overview on the APOE gene, the ApoE4 genetic variant, and other genes and their genetic variants that are linked to the risk for late-onset Alzheimer’s Disease (LOAD), and how, when, and why Alzheimer’s takes root in certain individuals that are carriers of these genes and the variants associated with them.
While the ApoE4 genetic risk variant is widely recognized as a risk factor for LOAD, how ApoE4 contributes to the risk for Alzheimer’s is not as so well recognized by most individuals.
Indeed, the ApoE4 genetic variant is often highlighted as the most significant risk factor for LOAD, but how often have you run across the reasons why ApoE4 raises your risk for LOAD, and how other genetic variants may similarly and synergistically increase the risk for LOAD?
Yes, many other risk variants add to the polygenic (more than one gene) disease profile of LOAD.
The known functional and structural vulnerabilities linked to the ApoE4 variant are multifaceted, and I describe these functional and structural abnormalities that are linked to ApoE4 in my book, “The Diabetic Brain in Alzheimer’s Disease”.
However, since the mechanisms that underlie the link between ApoE4 in LOAD are a vast topic, I focus on two key points—cholesterol and fat binding and transport, and beta-amyloid deposition and clearance from the brain.
ApoE4, APOJ, ABCA1 and ABCA7, and TREM2 variants greatly determine how these two key mechanisms—cholesterol and beta-amyloid metabolism are factored into the risk for LOAD.
Additionally, I briefly describe another very common variant—MTHFR 677T, that is a critical risk variant in methylation and homocysteine metabolism—yet another pathway that links the heart-brain axis in the risk for Alzheimer’s disease.
Please listen in and get ready for about 35 minutes of a revealing overview on the genes and their variants that are widely available in genetic profiling tests, and they are major risk factors in late-onset Alzheimer’s disease.
Top Takeaways
- The ApoE genetic variant, ApoE4, is the most well-known genetic risk factor for late-onset Alzheimer’s disease (LOAD). However, LOAD is a polygenic (more than one gene) and several other genes and genetic variants such as Clusterin (APOJ), ABCA1, ABCA7, TREM2, and MTHFR 677T—also are associated with an increased risk for LOAD.
- Several unfavorable diet and lifestyle risk factors in turn affects how ApoE4 is expressed in terms of cholesterol, glucose, and insulin dysmetabolism. ApoE4 is also associated with driving inflammation, the increased processing and aggregation of beta-amyloid protein, and brain shrinkage (atrophy) in regions of the brain tied to memory.
- The brain comprises about 2% of our total body weight, yet it contains about 25% of the human body’s cholesterol. The brain’s structure is highly dependent on cholesterol in maintaining healthy cell membranes, signal transmission between neurons, and in the recovery from injuries.
- Clusterin, or APOJ, is the second most common apolipoprotein in the brain after APOE. APOJ is an essential apolipoprotein in fat transport, mitochondrial integrity, and in the clearance of harmful beta-amyloid buildup. However, certain apolipoprotein variants weaken these beneficial effects.
- ABCA1 and ABCA7 genes which encode for ABCA1 and ABCA7 proteins are critical in the transport and metabolism of lipids (fats) such as cholesterol and phospholipids, and also support the clearance (phagocytosis) of beta-amyloid by immune cells (macrophages and microglia).
- The TREM2 gene is another key factor with regard to brain’s immune cells (microglia) regulatory role of inflammatory responses and clearance of damaged proteins. A rare TREM2 mutation (R47H) is associated with dysregulated microglial inflammation responses, and the reduced capacity of microglia in beta-amyloid and other debris clearance.
- Carriers of both the ApoE4 and MTHFR 677T gene variants are at an increased higher risk for Alzheimer’s and heart disease. Both risk variants are linked to high homocysteine levels, inflammation, and poor blood vessel health.
- High levels of homocysteine (hyperhomocysteinemia)—a byproduct of protein metabolism—are toxic to the brain and blood vessels. Hyperhomocysteinemia is associated by vitamin B deficiencies and is more common in people with the MTHFR 677T gene variant which is linked to folate dysmetabolism.
- Genetic testing for key variants like ApoE4 and MTHFR 677T are inavluable risk assessments. Both genetic variants are modifiable risk factors which may shed priceless insights that can be leveraged in the prevention of dementia and LOAD through diet and lifestyle interventions.
Epidsode 7
Timestamp Highlights
In this Episode
[1:01] Late-onset Alzheimer’s disease (LOAD) as a polygenic disorder — a preview of the ApoE4 genetic risk variant of the APOE gene, and other genetic variants associated with an increased risk for LOAD.
[2:08] LOAD is a polygenic (more than one gene) disorder—many genetic risk variants are associated with an increased risk for LOAD.
[2:57] The link between ApoE4 and cholesterol metabolism in the body (e.g., atherosclrosis, coronary heart disease).
[3:46] The APOE gene encodes for ApoE4—a lipoprotein—which along with other lipoproteins (e.g., HDL, LDL) perform important cholesterol and fat transport functions in the body and brain.
[7:40] Brain cholesterol synthesis and metabolism—why it is such an important topic associated with brain health and the risk for LOAD
[8:42] Review of findings of recent studies (2020, 2022) with regard to ApoE4 and HDL cholesterol.
[10:00] Why ApoE4 is linked to an increased risk for LOAD.
[12:24] ApoE4’s role in transport of cholesterol, vitamins E & K, and its effect on neuroplasticity.
[15:10] Other key risk genes associated with Alzheimer’s disease: APOJ (Clusterin), ABCA1, ABCA7, TREM2.
[17:20] Clusterin’s functions and role in cholesterol/fat transport, mitochondrial function, synaptic plasticity and beta-amyloid clearance from the brain.
[19:08] ABCA1’s role in cholesterol/fat transport into the cell, interactions with APOE lipoprotein, and the role of ABCA1 variant’s associated with a four-fold increased risk for LOAD.
[23:14] ABCA7’s impact on lipid (fat) equilibrium and beta-amyloid clearance.
[24:59] TREM2 interaction with lipoproteins (APOE, ABCA) in the uptake of fats into the cell. Additionally, variants of TREM2 (e.g., R47H variant) are associated with microglial inflammation responses, and impairment of microglial phagocytosis (engulfment) of beta-amyloid and tau proteins—an important constituent in their degradation and clearance.
[30:00] MTHFR 677T variant is a genetic risk variant associated with the risk for elevated homocysteine, cardiovascular disease, stroke, vascular dementia, and LOAD, and that risk (polygenic) is increases when combined with ApoE4.
[34:04] Importance of testing for the ApoE4 and MTHFR 677T variants and other genetic variants—especially if you have a family history of Alzheimer’s.
Please listen in!
Ralph Sanchez, MTCM, CNS, D.Hom
BrainDefend®
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