Why start treatment for people at high risk of dementia aged 30-40 years old?
Dementia is often not on teens' worry lists, yet a major Alzheimer's drug trial is recruiting participants as young as 18 to answer the most pressing question facing the field: Can the devastation caused by the disease be halted by identifying those who are about to develop the disease and treating them for up to a decade before they develop symptoms?
The recent development of drugs that can slow cognitive decline in patients with Alzheimer's disease is undoubtedly a welcome breakthrough, but to date, the effectiveness of these drugs has only been proven in patients with mild symptoms. Once a patient is diagnosed, their brain has actually undergone extensive changes. However, there is growing evidence that starting these drugs long before these injuries occur may significantly slow the disease and may even stop its progression.
Now we have drugs that can slow down the disease progression by about 30% in symptomatic people, but that's not enough, we want to get to 100%, which means preventing people from developing symptoms.
In medicine, treatment is performed when a disease causes pathological changes in the body, but it is not severe enough to cause clinical symptoms, which is called secondary prevention (primary prevention is carried out before any pathological changes occur in the disease, and tertiary prevention is the management of the disease with symptoms already appearing in order to slow down the worsening of symptoms). Secondary prevention is essential to reduce the risk of death and disability in patients with early stages such as heart disease or diabetes. Doctors don't wait until people have heart disease to prescribe cholesterol-lowering statins, or wait until people have damaged arteries or kidneys to give metformin to control blood sugar.
In 2023, the results of the trial of lecanemab (brand name Leqembi) and donanemab in Alzheimer's disease patients with mild cognitive impairment suggest that the medical community may have mastered the way to apply secondary prevention to the disease. Both drugs are monoclonal antibodies that target amyloid plaques, clumps of scleroprotein that form in the brains of people with Alzheimer's disease.
Although there are still many unknowns about the mechanism of Alzheimer's disease, there is little doubt at the moment that the accumulation of plaques began many years after the onset of symptoms. In trials of lecanemab and donanemab, the earlier the patient was from the onset of plaque accumulation, the better the drug was at removing most of the plaque and slowing cognitive decline. It's only when these medications have cleared almost all of the plaque that you can see the true benefit of your symptoms.
Given that even patients with mild symptoms already have a large plaque build-up, testing anti-plaque drugs may be more effective at an earlier stage of the accumulation process means that asymptomatic patients need to be involved in the trial. Research is turning to people who are just on the verge of plaque positivity and treating them in an attempt to stop them from accumulating more plaques and avoiding symptoms.
The past three trials have focused on asymptomatic patients, but all have failed. One of them was the A4 study, led by Sperling, which ended after six years in 2020 and looked at the effects of the anti-plaque drug solanezumab in patients who did not have cognitive impairment but showed plaque accumulation on PET imaging. The other, the DIAN-TU study led by Bartman, looked at the effects of solanezumab or another anti-plaque drug, gantenerumab, in patients with a rare familial genetic mutation that puts them at high risk of developing Alzheimer's disease and onset of cognitive decline around the age of 30, 40 or 50. The third trial, the Alzheimer's Disease Prevention Initiative (ADAD) trial, also looked at asymptomatic carriers with early-onset mutations in their families, which was conducted in Colombia.
Although the three trials failed to find results with significant benefit for patients, scientists do not believe that these findings refute the idea that anti-amyloid drugs may prevent cognitive decline if given early enough. The drug mechanism tested in all three trials differed from the newer drugs lecanemab and donanemab and never reached the same stage of regulatory approval. Newer drugs are now considered more promising. In fact, the DIAN-TU trial is expanding the use of lecanemab.
With newer drugs, novel trials are underway in asymptomatic patients with proven plaque accumulation. One of them is AHEAD 3-45, also led by Sperling, which will test the efficacy of lecanemab in patients aged 55 to 80 years.
The four-year trial will actually include two sister trials, A3 and A45. A3 is a phase II trial that will focus on people with low brain amyloid levels, while A45 is a phase III trial where subjects have higher amyloid levels. In addition, A3 is designed to measure amyloid progression, while A45 will focus more on the onset of cognitive impairment. All the data point in the direction of treating patients early in the disease for better outcomes.
Therefore, if you are only between 20 and 40 years old and have many dementia patients in your family, you may have a way to prevent dementia radiation 100% in 20 years.
参考文献——THE NEW AGE OF ALZHEIMER’S，2024， Davos Alzheimer’s Collaborative (DAC)