Alzheimer's prevention initiative: a proposal to evaluate presymptomatic treatments as quickly as possible

Abstract

Now is the time to launch the era of Alzheimer's disease (AD) prevention research, establish the methods and infrastructure to rapidly evaluate presymptomatic AD treatments and evaluate them rigorously and rapidly in randomized clinical trials. This article is a call to arms. It contends that the evaluation of presymptomatic AD treatments must become an urgent priority, it identifies what is holding us back and proposes new public policies and scientific strategies to overcome these roadblocks. It defines the term 'presymptomatic AD treatment', notes the best established biomarkers of AD progression and pathology and suggests how they could be used to rapidly evaluate presymptomatic AD treatments in the people at risk. It introduces an approach to evaluate presymptomatic AD treatments in asymptomatic people at the highest risk of imminent clinical onset and determines the extent to which the treatment's biomarker predicts a clinical outcome. We propose an Alzheimer's Prevention Initiative, which is now being reviewed and refined in partnership with leading academic and industry investigators. It is intended to evaluate the most promising presymptomatic AD treatments, help develop a regulatory pathway for their accelerated approval using reasonably likely surrogate end points and find demonstrably effective presymptomatic AD treatments as quickly as possible.

Keywords: MRI; PET; amyloid; apolipoprotein; biomarker; clinical trial; genetics; presenilin; public policy; surrogate marker.

Figure 1. The best established brain imaging biomarkers of Alzheimer’s disease progression and pathology

(A) Fluorodeoxyglucose-PET studies find characteristic and progressive declines in regional cerebral metabolic rate for glucose in people with Alzheimer’s disease (AD), as illustrated in this statistical brain map, comparing symptomatic AD patients and controls. (B) Structural MRI studies find brain shrinkage in people with AD, including (i) accelerated rates of atrophy in the Hi and ERC regions-of-interest; (ii) accelerated rates of whole brain atrophy using sequential MRIs, as shown in red in a symptomatic AD patient; (iii) a characteristic and progressive loss of gray matter, as shown in this statistical brain map comparing symptomatic AD patients and controls; and (iv) characteristic and progressive cortical thinning, as shown in this statistical brain map comparing symptomatic AD patients and controls. (C) PET studies of fibrillar amyloid-β (Aβ), as illustrated in this statistical comparison of Pittsburgh Compound-B PET measurements of fibrillar Aβ in symptomatic AD patients and controls; fibrillar Aβ PET studies using other radioligands are now under investigation. Several of the brain imaging measurements shown in this figure have been used to detect and track presymptomatic AD, and other brain imaging techniques are contributing to the early detection, tracking and scientific study of AD. ERC: Entorhinal cortex; Hi: Hippocampus; Pa: Parietal; PF: Prefrontal; Te: Temporal. Reproduced with permission from [26].

Figure 2. Correlations between APOE ε4 gene dose (the number of ε4 alleles in a person’s APOE genotype, reflecting three levels of genetic risk for late-onset Alzheimer’s disease [AD]) in 160 cognitively normal late-middle-aged persons and reduced CMRgl in posterior cingulate, precuneus, parieto-temporal and frontal preferentially affected by AD

This study and others have demonstrated the ability of FDG PET to detect and track characteristic CMRgl reductions in people at risk for late-onset and early-onset AD. Adapted with permission from [40].

Figure 3. Annual rates of whole brain atrophy in cognitively normal late-middle-aged people with two copies, one copy and no copies of the APOE ε4 allele, reflecting three levels of genetic risk for late-onset Alzheimer’s disease

Rates are reflected in terms of their means and SD. Other studies have demonstrated the ability to track rates of whole brain atrophy prior to symptomatic Alzheimer’s disease in early-onset Alzheimer’s disease-causing mutation carriers. SD: Standard deviation. Adapted with permission from [27].

Figure 4. Increases in Pittsburgh Compound-B PET measurements of fibrillar amyloid-β burden in cognitively normal adults (average age 63) with two copies, one copy or no copies of the APOE ε4 allele, reflecting three levels of genetic risk for late-onset Alzheimer’s disease, and in symptomatic Alzheimer’s disease patients

The statistical maps show no increases in ε4 noncarriers in comparison to the ε4 carriers, as well as increases in ε4 heterozygotes, ε4 homozygotes and symptomatic AD patients in comparison to the ε4 noncarriers. While longitudinal assessment is needed, the cross-sectional data shown here suggests that PET will be able to track progressive increases in fibrillar amyloid-β during this presymptomatic stage of AD, in contrast to the symptomatic stages of AD when fibrillar amyloid-β may have plateaued. AD: Alzheimer’s disease. Adapted with permission from [31].

Figure 5. Pittsburgh Compound-B PET measurements of fibrillar amyloid-β burden in a presymptomatic carrier of an early-onset Alzheimer’s disease-causing presenilin 1 mutation

As illustrated in this image, presymptomatic patients with several early-onset Alzheimer’s disease-causing mutations appear to have unusually high levels of fibrillar amyloid-β in the striatum, as well as increased levels in cerebral cortex. Reproduced with permission from [33].