A new study led by researchers from University College London (UCL) has identified that more than 90% of Alzheimer’s cases may be significantly influenced by variations in a single gene known as APOE. This breakthrough suggests that therapies targeting this gene could potentially prevent the disease in a majority of cases.
Historically, the APOE gene has been associated with the risk of developing Alzheimer’s, but the recent analysis has brought to light a more nuanced understanding of its variations. The study examined the three primary variations of the APOE gene: ε2, ε3, and ε4. While ε4 is recognized for its strong link to increased Alzheimer’s risk, the research indicates that ε3 may also be a critical factor in the disease’s development.
Researchers analyzed data from nearly 470,000 individuals, revealing that ε3 is not a neutral variant as previously thought. Instead, it can be seen as a significant risk factor. According to Dylan Williams, a genetic epidemiologist at UCL, “When we consider the contributions of ε3 and ε4, we can see that APOE potentially has a role in almost all Alzheimer’s disease.”
Individuals inherit two copies of the APOE gene, leading to six possible combinations. The ε2/ε2 combination is the most protective against Alzheimer’s, while ε4/ε4 poses the highest risk. Most individuals fall somewhere in between, and the specific combination inherited can alter the structure and function of the protein produced by the gene. This protein plays a vital role in brain functions linked to Alzheimer’s, including neuron repair, inflammation control, and the removal of amyloid-beta protein plaques.
The findings open up new avenues for potential treatments. The researchers suggest that targeting the APOE gene or its protein products could significantly reduce the likelihood of developing Alzheimer’s, potentially bringing more individuals down to the risk level associated with the ε2/ε2 combination. “Intervening on the APOE gene specifically, or the molecular pathway between the gene and the disease, could have great, and probably under-appreciated, potential for preventing or treating a large majority of Alzheimer’s disease,” Williams stated.
Moreover, the implications of this study could extend beyond Alzheimer’s. The research indicates that nearly half of all dementia cases might be attributed to the APOE gene. Nevertheless, genetic risks do not operate in isolation. Environmental and lifestyle factors, such as obesity, social isolation, and sleep deprivation, likely interact with genetic predispositions, although the nature of these interactions is not yet fully understood.
Williams emphasized, “Without the contributions of APOE ε3 and ε4, most Alzheimer’s disease cases would not occur, irrespective of what other factors are inherited or experienced by carriers of these variants throughout life.”
Despite the promising nature of these findings, the path forward is complex. Developing treatments that effectively target genes and proteins poses significant challenges, and any gene therapy would require careful evaluation and regulation. Nonetheless, this research could signal a pivotal shift in the approach to Alzheimer’s research, which has faced difficulties in identifying effective treatments.
“Complex diseases like Alzheimer’s will require multiple strategies to reduce disease occurrence,” Williams noted. This comprehensive understanding of the APOE gene is a vital step in exploring various methods to mitigate Alzheimer’s and dementia risk. The research has been published in the journal NPJ Dementia.
