Key Points:
- Having a particular DNA sequence in the gene APOE called APOE4 is associated with accelerated aging and an increased risk of developing Alzheimer’s disease in humans and mice.
- Treating mice genetically engineered to have the human APOE4 sequence with alfatradiol lowers scores on an assessment of age-related physical decline, where a lower score suggests reduced signs of physical deficits.
- In mice with the APOE4 sequence, alfatradiol reduces cognitive errors on a test of memory and lowers the abundance of neuronal plaques associated with Alzheimer’s disease.
As published in Communications Medicine, Pike and colleagues from the University of Southern California in Los Angeles find that in genetically engineered mice with the human version of a DNA sequence predisposing to dementia and accelerated aging (APOE4), treating with alfatradiol improves scores on an assessment of age-related physical decline (frailty index score). Mice with the human APOE4 sequence treated with alfatradiol also exhibited significantly reduced errors on a cognitive assessment evaluating memory. Moreover, alfatradiol lowered the abundance of neuronal plaques associated with Alzheimer’s disease (amyloid-beta [Aβ] plaques) in these mice. If translatable to humans, these findings suggest that alfatradiol could counteract the risks of age-related physiological decline and signs of dementia in the approximately 25% of the US human population who possess the APOE4 genetic sequence.
The contribution of genetic factors to human longevity has received substantial attention, with some estimates suggesting that it accounts for approximately 20% to 30% of the variance in longevity. To confirm this percentage, researchers will need to perform additional studies evaluating the lifespans of large numbers of people to uncover how much genetics influences lifespan.
However, for some people who have at least one copy of the APOE4 genetic sequence, about 25% of the US population and about 40% to 65% of patients with Alzheimer’s disease, genetics could play a more significant role. For example, some research has associated having a copy of the APOE4 genetic sequence with a shortening of lifespan by about 1.2 years. Not only that but having a copy of this genetic sequence has also been associated with a two to three times increased risk of developing Alzheimer’s disease. Thus, a significant portion of the population has the APOE4-associated genetic predisposition linked to accelerated aging and increased risk of developing Alzheimer’s disease.
This raises the question of whether any available drugs could counteract the potential accelerated aging and increased risk of developing Alzheimer’s disease in those with the APOE4 sequence. With this question in mind, Pike and colleagues genetically engineered mice to have the human version of the APOE4 sequence, which more accurately models this genetic risk factor in mice. Seeking to test an FDA-approved drug that has been shown to extend mouse lifespan and promote longevity, the California-based researchers turned to alfatradiol, which extended male mouse average lifespan by about 12%. Accordingly, Pike and colleagues administered alfatradiol to middle-aged male mice carrying the human version of the APOE4 sequence, since conducting preclinical mouse studies serves as one of the first steps in finding if a drug works for people.
Alfatradiol Improves Frailty, Lowers Cognitive Errors, and Reduces Neuronal Plaques Associated with Alzheimer’s Disease
To begin their experimentation with alfatradiol, Pike and colleagues sought to find whether mice with the APOE4 sequence exhibit accelerated age-related physical decline and, if so, whether alfatradiol could alleviate it. To assess age-related physical decline, a condition known as frailty, Pike and colleagues assessed visible markers of aging in bones and skeletal muscles, the eyes and nose, the respiratory system, and the digestive system, as well as any observable signs of discomfort. As such, the researchers found that mice with the APOE4 genetic sequence exhibited significantly more frailty compared to mice with the human version of this sequence that is most commonly present in humans (APOE3). This finding suggests that the APOE4 genetic sequence, believed to accelerate aging, increases measurements of frailty in mice.
To test whether alfatradiol treatment affects frailty in mice with the APOE4 sequence, Pike and colleagues treated middle-aged mice (roughly equivalent to 40-year-old humans) with alfatradiol. Interestingly, the research team found that treating the APOE4 mice with alfatradiol for five months significantly lowered frailty so that their frailty index scores were not significantly different from those of mice with the more common APOE3 genetic sequence. This finding supports that alfatradiol improves signs of age-related frailty.
To find whether alfatradiol can counteract signs of cognitive decline in mice with the APOE4 sequence, Pike and colleagues used a test of spatial memory called the Barnes maze. For the Barnes maze, mice are placed on a round surface with holes at the outer edges. One of the holes has an escape box, which typical mice learn to identify during training so that the number of errors they commit in finding the escape box declines. Intriguingly, untreated mice with the APOE4 sequence exhibited more errors in locating the escape box during four days of training, suggesting impaired learning and memory.
When mice with the APOE4 sequence received alfatradiol, the number of errors they committed in the Barnes maze over the four days of training declined, suggesting that alfatradiol restored learning and memory in these mice. Furthermore, untreated and treated mice with the common APOE3 genetic sequence exhibited lower numbers of errors over four days of training, suggesting no learning and memory impairments and little or no effect of alfatradiol in these mice. These findings suggest that alfatradiol may prevent cognitive decline in mice with the APOE4 genetic sequence.
Since the APOE4 genetic sequence has been associated with accelerated aging and an increased risk of developing Alzheimer’s disease, Pike and colleagues tested whether alfatradiol reduces levels of neuronal plaques (Aβ plaques)—a hallmark of Alzheimer’s disease—in APOE4 mice. Interestingly, alfatradiol nearly cut the abundance of Aβ plaques in half in these mice. On the other hand, alfatradiol had no significant effects on Aβ plaque levels in mice with the more common APOE3 sequence. This data suggests that in mice with the APOE4 sequence, alfatradiol substantially reduces Aβ plaque levels in the brain.
Human Trials Necessary to Confirm Alfatradiol’s Effects in Humans Carrying the APOE4 Sequence
One limitation of Pike and colleagues’ study was that middle-aged mice with the APOE4 sequence were used to assess alfatradiol’s effects. In that regard, the APOE4 sequence has been associated with cognitive decline and Aβ plaques that worsen with age. As such, performing similar experiments in older mice with this genetic predisposition may yield more significant results with alfatradiol treatment.
Another limitation of the study was that only male mice were tested. The authors said in their publication that only male mice were included because alfatradiol was shown to extend lifespan only in male mice. All the same, it remains possible that alfatradiol could improve signs of frailty, cognition, and Aβ plaque levels in female mice. Due to this possibility, future studies should include female mice to determine whether alfatradiol’s effects are specific to males or if the drug also confers benefits in females.
Collectively, the study’s findings suggest that alfatradiol may work against accelerated aging and cognitive decline associated with having the APOE4 genetic sequence. Accordingly, anyone interested in finding whether they are among the approximately 25% of the US population carrying this genetic sequence can have a test done. Such a genetic test involves providing a sample of genetic material via a cheek swab or having blood drawn. Costs for this kind of test usually range from $100 to $150.
Also, Pike and colleagues’ study constitutes preclinical evidence in a mouse model, suggesting alfatradiol counteracts an APOE4 genetic sequence-related predisposition to accelerated aging and Alzheimer’s disease. As with any preclinical study, human trials testing alfatradiol in carriers of the APOE4 sequence are necessary to determine if these findings apply to people.
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