From the Guidelines
ApoE2 does protect against Alzheimer's disease, as it significantly reduces the risk of developing Alzheimer's compared to the more common apoE3 variant and especially the high-risk apoE4 variant. This genetic variant of the apolipoprotein E gene has been shown to have a protective effect against Alzheimer's disease, with people who inherit two copies of apoE2 having approximately 40% lower risk of developing Alzheimer's disease than those with two copies of apoE3 1. The protective effect occurs because apoE2 binds less efficiently to amyloid-beta, the protein that forms plaques in Alzheimer's disease, which helps prevent its accumulation in the brain. Additionally, apoE2 appears to maintain better neuronal health and synaptic integrity.
Some key points to consider:
- The apoE2 variant is relatively rare in the population, with only about 8% of people carrying this variant 1.
- This genetic protection is not absolute—people with apoE2 can still develop Alzheimer's due to other risk factors—but it represents one of the strongest known genetic protections against the disease 1.
- The current evidence does not support the broad clinical utility of APOE allele genetic testing in the diagnostic evaluation of individual patients suspected of having MCI or dementia due to AD, but it may be useful in certain contexts, such as therapeutic decision making 1.
- The identification of a deterministic genetic mutation known to be associated with AD or ADRD in a patient with a cognitive–behavioral syndrome increases confidence in the etiology, and guidelines on whom to test usually emphasize the presence of a pedigree consistent with an autosomal dominant inheritance pattern of dementia or a related condition, or a young patient with dementia 1.
Overall, while apoE2 is a protective genetic variant against Alzheimer's disease, it is essential to consider the complexity of the disease and the various risk factors involved.
From the Research
ApoE2 and Alzheimer's Disease
- ApoE2 has been identified as a protective factor against Alzheimer's disease (AD) [(2,3)].
- Studies have shown that ApoE2 decreases the risk of late-onset AD compared to ApoE3 2.
- The mechanisms by which ApoE2 confers protection against AD are thought to be both amyloid-β (Aβ)-dependent and independent [(2,3)].
Molecular Mechanisms
- ApoE2 has been shown to increase amyloid-β clearance and reduce activity-dependent Aβ secretion and/or excitotoxicity 3.
- ApoE2 also upregulates extracellular matrix (ECM)/integrin-related transcripts and downregulates long-term potentiation (LTP) related transcripts 3.
Clinical Implications
- ApoE2 carriers have been found to have a unique and advantageous biomarker signature, and reduced risk of mild cognitive impairment to AD conversion 3.
- However, ApoE2 is not entirely benign, and carriers may exhibit increased risk of certain cerebrovascular diseases and neurological disorders 2.
Comparison to Other Treatments
- While ApoE2 has been shown to be protective against AD, other treatments such as donepezil, galantamine, rivastigmine, and memantine have also been found to be effective in stabilizing or slowing decline in AD patients [(4,5,6)].