A chance to prevent Alzheimer’s disease sooner than you think

Alzheimer’s disease is the most common form of cognitive impairment. With increasing longevity, its prevalence continues to grow, and treatments that prevent its clinical onset would have a profound effect. Characterised by amyloid plaques, tau tangles, and neuronal loss, Alzheimer’s pathology is already extensive and hard to stop by the time cognitive impairment is detected. Secondary prevention therapies have the potential to avert further disease progression and to stop or delay cognitive impairment in people with biomarker evidence of the disease. Primary prevention therapies have the potential to avert the disease itself in people without cognitive impairment. Based on developments from the past 3 years, there is a realistic chance to develop, secure regulatory approval of, and implement widespread accessibility to effective preventive therapies in the next few years. We believe that intravenously administered anti-amyloid antibodies for secondary prevention of Alzheimer’s disease can be available within 3 years, and subcutaneously self-administered therapies soon thereafter. We also think that subcutaneous antibody therapies for primary prevention can be developed within 5 years. In this Insight, we consider the reasons why we have this chance and the steps to achieve these audacious goals.

The antibodies lecanemab and donanemab dramatically reduce PET and blood biomarker measures of amyloid, and they partly slow clinical decline in people with Alzheimer’s disease who are mildly impaired. These findings support the role of amyloid in the development and potential prevention of Alzheimer’s disease, and they increase the chance to find effective prevention therapies in the next few years. We postulate that these treatments will be more effective in amyloid-positive people without cognitive impairment (ie, secondary prevention, when the disease is less extensive) than in those who have cognitive impairment. If these drugs remove the earliest forming plaques (and soluble amyloid aggregates in and around plaques) in people who are not yet amyloid-positive (ie, primary prevention), they have the potential to prevent Alzheimer’s disease completely. Their main adverse effects, amyloid-related imaging abnormalities (ARIA), are thought to be due to effects on cerebrovascular amyloid plaques, causing leaky blood vessels. We postulate that treatment-related ARIA will be less frequent and severe in amyloid-positive people who are cognitively unimpaired, compared with those who have cognitive impairment, and rare in people who are not yet amyloid-positive. Prevention trials will have to clarify the benefits and risks of these drugs.

Two secondary prevention trials (AHEAD, NCT04468659; and TRAILBLAZER-ALZ 3, NCT05026866) are evaluating lecanemab and donanemab in cognitively unimpaired people with biomarker evidence of amyloid. If these therapies safely avert the onset of cognitive impairment, they could be considered for full regulatory approval within 3 years. If their plaque-clearing biomarker effects are associated with a clinical benefit, regulatory agencies (eg, the US Food and Drug Administration [FDA]) could use these measures as surrogate endpoints that are reasonably likely to predict a clinical benefit in other prevention trials.

Surrogate biomarker endpoints can be used in trials to support conditional regulatory approval of drug treatments for serious medical disorders that fill an unmet need. Such endpoints have sometimes failed to predict a clinical benefit, but they have also accelerated development of life-changing treatments. If the AHEAD and TRAILBLAZER-ALZ 3 trials are successful, amyloid biomarkers could be used as surrogate endpoints in ensuing prevention trials and provide evidence to support conditional regulatory approval of self-administered secondary prevention drugs within 4 years. Surrogate endpoints could also be used to evaluate the ability of the treatments to avert the onset of amyloid plaques in people at genetic risk of Alzheimer’s disease and provide evidence to support conditional regulatory approval of the first primary prevention therapy within 5 years. These trials will need a sufficiently large number of participants to inform the safety of the treatment.

For primary prevention, drug doses might be administered infrequently (eg, every 6–24 months), depending on the extent to which each dose can clear the earliest forming plaques. We see value in conducting the first of these primary prevention trials in amyloid-negative, cognitively unimpaired individuals who are carriers of the APOE ε4 allele, the major susceptibility gene for Alzheimer’s disease. Such trials could lead to the approval of a primary prevention therapy for many people at risk within 5 years and set the stage for other trials in cognitively unimpaired, amyloid-negative people with other genetic or non-genetic risk factors. By the time the first primary prevention trial is completed, it might be possible for regulatory agencies to consider full rather than conditional approval, based on the surrogate endpoint effects of the treatment. In our opinion, this possibility would require several developments: demonstration of a clinical benefit in the secondary prevention trials; additional evidence that people who are positive for amyloid PET or fluid biomarkers are at high risk for cognitive impairment; and the support of the research community for the proposal to base the diagnosis of Alzheimer’s disease on a suitable amyloid test.

Prevention therapies and the screening programmes needed to inform their use should be cost-effective, convenient, covered by health insurance, and widely accessible as soon as possible after their full or conditional regulatory approval. It will be important to show that the treatment is cost-effective and that the number of individuals needing treatment to avert one bad outcome is acceptable. In the USA, Medicare should cover the cost of prevention therapies that are reasonably likely to have a clinical benefit, get conditional regulatory approval, and are subject to further evaluation in suitable post-marketing studies. Rational drug pricing by the pharmaceutical industry must complement other efforts to support the widespread accessibility of prevention therapies.

Post-marketing evaluation strategies are needed to demonstrate comparable surrogate biomarker effects in under-represented populations and the clinical value of screening programmes and prevention therapies in larger populations over longer treatment durations than those in the original trials. For instance, randomised delayed-start trials, which compare longer versus shorter treatment durations in participants who initially receive either drug or placebo, before all receive the experimental drug treatment, could be used to confirm the clinical benefit of a prevention therapy following conditional approval, but avoiding the requirement for some of the participants to receive placebo for many years.

A blood test screening programme will be needed to identify and treat people who would benefit from prevention therapy. Screening programme recommendations are typically made by institutions such as the US Preventive Services Task Force (USPSTF) or the German Joint Federal Committee, which commonly require data from multiple large and lengthy screening-and-treatment trials. We would like to ask these organisations to consider what would be needed to make a conditional recommendation for a blood test screening programme by the time the first prevention therapy is approved by regulatory agencies, and to subsequently confirm that the benefits of the programme outweigh the risks.

We hope that our proposal contributes to the development, regulatory approval, and widespread access of Alzheimer’s disease prevention therapies. In the panel, we offer a six-part plan to evaluate and prepare for the regulatory approval and widespread accessibility of effective prevention therapies, and the screening programmes to inform their use, as soon as possible. Some of our predictions, proposed trials, recommendations, and timelines will need adjustment depending on new developments and input from all stakeholders and policy institutions. While the scientific, infrastructure-related, and socioeconomic challenges are formidable, they can be addressed if all stakeholders start working together now. Can we find reasonably safe and effective prevention therapies for Alzheimer’s disease and address the challenges needed to support their approval, affordability, and widespread accessibility within the next few years? We have an unprecedented opportunity and shared responsibility to find out.

Panel: A proposal to accelerate the development and widespread access to prevention therapies for Alzheimer’s disease within 3–5 years.

Full regulatory approval of the first secondary prevention therapies within 3 years

In ongoing secondary prevention trials, demonstrate that lecanemab and donanemab safely reduce the rate of progression to cognitive impairment in amyloid-positive participants. Show that amyloid PET and plasma biomarker effects of treatment are associated with a clinical benefit, supporting their potential use as surrogate endpoints that are at least reasonably likely to predict a clinical benefit in other prevention trials.

Accelerated approval of accessible secondary prevention therapies soon after

Use surrogate endpoints to demonstrate that self-administered subcutaneous anti-amyloid therapies are safe and efficient in cognitively unimpaired, amyloid-positive individuals. Start the trials as soon as possible, use amyloid blood tests to complete enrollment within 12 months, and aim for trial completion within 1 year.

Accelerated or full approval of the first primary prevention therapies within 5 years

Use surrogate endpoints and adequate safety data to demonstrate that infrequently administered subcutaneous antibody therapies safely prevent amyloid plaques in cognitively unimpaired carriers of the APOE ε4 allele. Start the trials as soon as possible, complete enrolment within 12 months, and aim for trial completion within 36 months.

Extend this approach to other prevention therapies and other people at genetic risk

Prepare for regulatory approval, health insurance coverage, and accessibility

Address issues related with regulatory approval, appropriate use, and widespread accessibility of primary and secondary Alzheimer’s disease prevention therapies, and the screening programmes needed to inform their use. Capitalise on the use of blood tests, scalable genetic and biomarker risk disclosure and treatment management programmes, accessible drugs and dosing strategies, and appropriate pricing. Implement insurance coverage and post-marketing strategies to optimise accessibility, further inform biomarker and clinical effects, and clarify their relevance in under-represented groups.

Chart the path to address these goals, including all stakeholders, and starting now