Summary: A new study reveals how certain genes and education levels impact Alzheimer’s disease risk, even in individuals destined to develop dementia.
Key facts:
- The APOE gene influences Alzheimer’s onset in people with a genetic mutation causing early-onset Alzheimer’s.
- Having APOE e4 accelerates onset of decline while APOE e2 delays it.
- More years of education protects against cognitive decline in mutation carriers.
- Education seems to offset the harmful effect of APOE e4 on cognition.
Source: Nature Communications
Inherited Alzheimer’s Risk Modified by Other Factors
Individuals who inherit rare mutations causing early-onset Alzheimer’s dementia are destined to develop the disease due to their genes.
However, new research shows other genetic and environmental factors like education can modify the course, accelerating or slowing onset of decline.
The study, published in Nature Communications, involved people in Colombia belonging to the world’s largest family lineage carrying a single mutation that causes Alzheimer’s dementia around age 45, on average.
Researchers found that in these mutation carriers, having one copy of the APOE e4 gene variant sped up impairment by about 5 years compared to not having this variant.
Yet having one copy of the APOE e2 variant delayed decline by about 4 years.
More years spent in school also protected cognition despite participants’ inherited mutation.
Additionally, more education seemed to offset APOE e4’s harmful effects on thinking abilities – good news for the possibility of mitigating genetic risk through lifestyle factors like schooling.
APOE e4, e2, and Alzheimer’s Risk
The APOE gene has long been connected to Alzheimer’s disease risk.
People with one copy of the e4 variant have a higher chance of developing Alzheimer’s.
Those with two copies have an even greater risk of earlier onset.
The e4 variant is believed to promote a buildup of amyloid protein plaques in the brain, a hallmark of Alzheimer’s.
In contrast, having one or two copies of the e2 variant lowers Alzheimer’s risk and delays onset.
E2 seems to be protective, though exactly how requires more research.
However, previous evidence for how e4 and e2 influence early-onset Alzheimer’s caused by rare mutations has been mixed.
The new study helped clarify the role of these APOE variants in inherited Alzheimer’s using a large family sample to boost statistical power.
The PSEN1 Mutation and Colombian Family
The study involved 1,269 people belonging to an extended family in Colombia.
About half carry an Alzheimer’s-causing mutation in the PSEN1 gene called E280A. This mutation leads to early onset dementia around age 45 on average.
The Colombian family represents the world’s largest kindred with inherited Alzheimer’s tied to a single mutation.
Studying them provides a unique window into genetic risks unleashing disease earlier than typical late-onset Alzheimer’s developing after age 65.
All family members inherited the same cultural and environmental factors growing up. This reduces variability so researchers can better isolate genetic effects on cognitive decline.
APOE e4 Accelerates, e2 Delays Onset of Decline
The study first compared Alzheimer’s markers between PSEN1 mutation carriers and non-carriers. As expected, mutation carriers showed cognitive impairment on tests as they aged.
Researchers next looked at whether having the APOE e4 variant made impairment strike earlier in mutation carriers.
It did – their cognitive test scores started declining 5 years faster if they had one e4 copy versus no e4 copies.
In contrast, having one APOE e2 copy delayed onset of thinking problems by about 4 years compared to not having this protective variant.
These results confirm APOE modifies Alzheimer’s onset even in mutation carriers destined to develop dementia due to their genes. E4 isn’t deterministic but does significantly move up disease onset.
How Education Protects the Brain
Higher education levels also benefited cognition in mutation carriers. Each additional year of schooling correlated with higher scores on cognitive testing.
This protective effect of education held even accounting for APOE status. And education seemed to mitigate e4’s harmful effects. Among mutation carriers with the e4 variant, more years of schooling buffered cognitive decline.
Exactly why education protects against cognitive impairment isn’t fully understood yet.
The leading theory is that education builds up “cognitive reserve” – a buffer protecting the brain against damage.
People with more reserve can endure more Alzheimer’s pathology before it impairs cognition.
In the general population, higher education reduces dementia risk by up to 30% on average. But evidence in inherited Alzheimer’s has been mixed.
This study helps confirm education’s benefits persist despite mutations causing aggressive brain disease.
While e4 risk can’t be changed, education levels can, making it a potential target for dementia prevention. More research is needed to pin down what types or durations of schooling build the most cognitive reserve.
Hope for Offsetting Genetic Risk Factors
Taken together, these findings demonstrate that although genes largely determine Alzheimer’s risk, other modifying factors like APOE status and education still significantly influence when symptoms manifest.
Lifestyle interventions that increase reserve may help offset genetic risks, both in inherited and more common late-onset Alzheimer’s.
Education is likely not the only factor that matters – adequate sleep, exercise, social and cognitive activity are also hypothesized to strengthen resilience.
While more research is required, the study provides hope that it may be possible to delay dementia onset through modifiable risk factors – even in mutation carriers whose genetic hand deals them an early Alzheimer’s fate.
References
- Study: Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease
- Authors: Langella et al. (2023)
