A new large genetics study has discovered new clues into how levels of a protein called apolipoprotein E (ApoE) in the blood may influence a person’s risk of developing Alzheimer’s disease.
Key facts:
- Researchers found 9 new genetic variants that influence ApoE levels in the blood. Some raise levels, while others lower levels.
- People with Alzheimer’s tend to have lower blood levels of ApoE.
- The well-known Alzheimer’s risk gene APOE comes in 3 versions – E2, E3 and E4. E4 lowers ApoE levels while E2 raises levels.
- Many of the newly found genetic variants that raise ApoE levels are associated with lower Alzheimer’s risk, while variants that lower ApoE are linked to higher risk.
- Together, all the genetic variants found explain about 25% of the differences in blood ApoE levels between people.
Source: Molecular Psychiatry (2023)
What is apolipoprotein E?
Apolipoprotein E (ApoE) is a protein involved in transporting fats and cholesterol in the bloodstream and brain.
It carries cholesterol and lipids to cells through the blood.
In the brain, it helps shuttle lipids and cholesterol to neurons, which need these fats for normal function and repair.
ApoE is made primarily by the liver, which releases it into the bloodstream.
In the brain it is made by certain support cells called astrocytes.
There are three common versions (alleles) of the ApoE gene – APOE E2, E3, and E4. These affect ApoE function.
The liver puts ApoE onto particles containing cholesterol and fats called lipoproteins.
About 50% of ApoE in the blood attaches to HDL, the “good cholesterol”.
ApoE acts as a transporter protein that docks onto cells and delivers the cholesterol and fats.
Why does ApoE matter for Alzheimer’s?
The strongest genetic risk factor for Alzheimer’s disease is having one or two copies of the APOE E4 version.
1 copy raises risk 3-fold, while 2 copies raises risk 15-fold.
E4 is believed to impair ApoE function in the brain in many ways that promote Alzheimer’s:
- E4 leads to lower overall levels of ApoE in the brain and blood. This reduces vital lipid transport to neurons.
- E4 performs lipid transport less efficiently and clears amyloid beta, a toxic Alzheimer’s protein, less effectively.
- E4 is linked to greater amyloid beta buildup, more tau tangles, and more brain inflammation.
Conversely, the E2 version lowers Alzheimer’s risk and raises ApoE levels.
So higher ApoE levels may be protective, while lower levels could contribute to risk.
Some studies have linked low blood ApoE levels to faster cognitive decline and higher dementia risk.
But it’s been unclear whether blood ApoE levels directly influence Alzheimer’s risk.
Uncovering the Genetic Basis of Blood ApoE Levels
This large genetics study aimed to uncover genetic factors that influence blood ApoE levels.
It also examined whether ApoE blood levels are linked to cognitive decline and dementia risk.
The study involved over 3,000 older adults without dementia.
Of these, about 1 in 6 developed Alzheimer’s dementia over 8 years of follow-up.
At the start, their blood ApoE levels were measured. DNA was analyzed to find genetic variants linked to ApoE levels.
Participants took thinking and memory tests at the beginning and during follow-up.
The results were used to determine if lower blood ApoE levels affected their thinking abilities or dementia risk over time.
- Lower blood ApoE levels were linked to slightly worse scores on cognitive tests, but not clearly associated with higher dementia risk.
- As expected, the E4 version lowered ApoE levels while E2 raised them compared to the common E3 version.
- The analysis uncovered 9 new genetic variants affecting blood ApoE levels. Some raised levels while others lowered levels.
- 7 of the new variants were in completely new genes outside the APOE region. The other 2 were additional variants in the APOE gene itself.
- In total, these new genetic variants together explained about 9% of the differences in blood ApoE levels between people. Known APOE variants explained about 22%.
- Many of the ApoE-raising variants were linked to lower Alzheimer’s risk, while ApoE-lowering variants were tied to higher risk. This suggests that genetically influenced blood ApoE levels contribute to Alzheimer’s risk.
Details on the Newly Uncovered Genetic Variants
The 9 new genetic variants were found in these genes or regions:
- OPRD1 gene (chromosome 1)
- GBA3 and PPARGC1A genes (chromosome 4)
- PLK2 gene (chromosome 5)
- PHF14 gene (chromosome 7)
- ZPR1/ZNF259 gene (chromosome 11)
- LINC02403 gene region (chromosome 12)
- BMP2 gene (chromosome 20)
- 2 additional variants near the APOE gene itself (chromosome 19)
The variants in OPRD1, ZPR1/ZNF259, BMP2, and the APOE region appear to raise ApoE levels.
Those in GBA3-PPARGC1A, PLK2, and LINC02403 seem to lower levels. PHF14 and ZNF259’s effects are unclear.
These genes play diverse roles, including in immune function, cholesterol metabolism, and brain cell health.
Several are involved in processes that interact with APOE pathways. The exact mechanisms of how most affect ApoE levels are still unknown.
For the two novel variants close to APOE, having one copy of each raised ApoE levels by about 30-50%.
The others had smaller effects, ranging from 7-37% increases or decreases per copy.
Having one copy of each variant would not drastically alter someone’s ApoE levels.
But together, inheriting more variants that raise levels versus lower levels starts to shift someone’s ApoE level higher or lower.
Implications of the Findings
This large analysis significantly expands our knowledge of genetic factors that influence blood ApoE levels.
The newly uncovered genes provide possible new biological targets to understand ApoE biology and how it may contribute to Alzheimer’s risk.
The findings suggest that inheriting more variants that raise ApoE levels lowers Alzheimer’s risk, while inheriting more that reduce ApoE increases risk.
This indicates that differences in blood ApoE levels influenced by genetics may contribute to a person’s risk of Alzheimer’s.
Drugs or other approaches to boost ApoE levels in the brain may therefore hold promise for lowering Alzheimer’s risk.
More studies are still needed to prove whether this is an effective prevention strategy.
While ApoE levels differed between people in this study, the differences were not dramatic.
Having more variants that raise or lower ApoE is unlikely by itself to make someone highly resistant or prone to Alzheimer’s. Many other factors come into play.
Limitations and Next Steps
- This study was in older adults of European ancestry. Findings may differ in other ethnic groups.
- It’s unknown whether effects are the same in midlife. Early influences of ApoE levels on Alzheimer’s development need study.
- It’s unclear whether blood ApoE levels directly reflect levels in the brain, where ApoE is most important for Alzheimer’s risk.
- Future research is needed confirm the 9 new genes found and uncover additional genetic factors influencing ApoE levels.
- Studies should further probe how the newly identified genes affect ApoE biology and Alzheimer’s risk using cellular and animal models.
- Clinical studies should test if therapies that increase ApoE levels in the brain can help lower dementia risk and slow cognitive decline.
In summary, this large genetics study significantly expanded our understanding of genetic factors that regulate blood ApoE levels and may therefore influence susceptibility to Alzheimer’s disease.
The findings open new avenues to explore the biology of this important Alzheimer’s risk gene.
References
- Study: Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk
- Authors: M. Muaaz Aslam et al. (2023)
