In Alzheimer's disease clinical trials, can changes in Aβ levels represent cognitive changes?

*For medical professionals only

The pathologic features of Alzheimer's disease (AD) are β amyloid (Aβ) deposits, tau-containing nerve fiber tangles, neuronal damage and degeneration[1].

Clinically, it is manifested as progressive cognitive decline and behavioral changes, which increase the burden on nursing staff, families and society to a certain extent [2].

Genetic data, biomarkers, and clinical observations [3] all emphasize that reducing Aβ in the brain parenchyma is still a relevant target for delaying the progression of
AD disease.
However, previous randomized controlled trials (RCTs) targeting Aβ have produced inconsistent results, and the link between Aβ pathological changes and cognitive function of AD is still hotly debated [4].

So, can the reduction of Aβ plaques in the brain represent a delay in dementia or cognitive decline caused by AD?

The team of Ackley et al.
[5], who published a meta-analysis of instrumental variables in 2021 on the relationship between reduced Aβ levels and cognitive change, concluded that in most typical RCTs, a reduction in amyloid β did not fundamentally improve cognitive performance
.

Recently, a research team led by Menglan Pang and Changyu Shen of Biogen Biologics published important research results
in the journal Alzheimer's & Dementia.
They re-conducted a meta-analysis
after correcting the inconsistencies in the original data and adding new RCTs.
Interestingly, this updated meta-analysis concludes the opposite, with the latest results suggesting a possible causal relationship between the reduction of Aβ plaques and cognitive decline in AD patients, and Aβ is a viable biological target for the treatment and prevention of AD
.

Let's take a look at how this study is carried out
.

In the original study published by Ackley et al.
[5], 14 RCTs
up to 30 April 2020 were collected using a meta-analysis of instrumental variables 。 Search on the Alzheimer's Research Forum (alzforum.
org) to identify "amyloid-related" drugs for the treatment of "Alzheimer's disease" and "mild cognitive impairment"; Subsequently, a search on ClinicalTrials.
gov identified RCT-related drugs that were 'completed', 'terminated', or 'effective, not recruited'; In addition, the trial required a placebo-controlled group and standardized uptake ratio (SUVR) for amyloid β measured by positron emission tomography (PET) and cognitive function measured by the Dementia Severity Rating Scale (CDR-SB), Alzheimer's Disease Rating Scale-Cognitive Scale (ADAS-Cog), and the Simple Mental State Scale (MMSE) to verify the relationship between
changes in Aβ-PET SUVR and changes in cognitive function.

In this updated meta-analysis, based on the original study by Ackley et al.
[5], three authors independently reviewed source data for Aβ-PET SUVR, CDR-SB, ADAS-Cog, and MMSE on ClinicalTrials.
gov, as well as published articles and clinical studies; Another author, based on the search strategy and selection criteria used in the original paper, found four items
on the ClinicalTrials.
gov with a "last updated" date between April 30, 2020 and March 1, 2022.
TWO TRIALS OF ADUCANUMAB'S PRIME AND DONANEMAB'S TRAILBLAZER-ALZ MET THE INCLUSION CRITERIA FOR INCLUSION IN THIS UPDATED META-ANALYSIS
.

Summary of RCT characteristics

The results found that every 0.
1 decrease in Aβ-PET SUVR was associated
with a decrease of 0.
09 (95% CI: 0.
034–0.
15), 0.
33 (95% CI: 0.
12–0.
55) and 0.
13 (95% CI: 0.
017–0.
24) in CDR-SB, ADAS-Cog, and mmse scores, respectively.
This suggests that there may be a statistically significant causal relationship between the reduction of Aβ plaques and the decline in cognitive function.

Note: This forest plot represents the effect
of Aβ reduction measured by PET SUVR on changes in (A) CDR-SB, (B) ADAS-Cog, and (C) MMSE.
A positive effect estimate – 0.
1 per reduction in PET SUVR – suggests that a decrease in Aβ decreases cognitive and functional decline
.
The center and width of the diamond represent the summary estimate and the 95% confidence interval
, respectively.
In addition, the Lecanemab trial was not published and was excluded from the 'All published data' and 'All published antibody data' categories
in sensitivity analyses.
Recent Aβ-targeted antibodies include gantenerumab, aducanumab (ENGAGE, EMERGE, PRIME), lecanemab, and donanemab tests

In this study, the original pathway and retrieval strategy were meta-analyzed by Ackley's team to verify the correlation
of changes in Aβ-PET SUVR in AD-induced cognitive decline.
The advantage of instrumental variable meta-analysis is the use of randomization as an instrumental variable to eliminate potential confounders, and the integration of data from multiple RCTs makes the study quite impressive in terms of accuracy and rigor, but it still has some limitations:

First, the individuals included in this meta-analysis were at different stages of AD and failed to effectively distinguish prodromal, mild, or moderate AD
.
Biologically, different subgroups may benefit from anti-Aβ therapy to varying degrees [6].

Second, while the study considered a linear relationship between Aβ deposition and cognitive decline, the precise temporal and spatial dynamics of this relationship are unclear
.
Again, research is limited by most typical clinical trials and cannot be followed up.

In addition to this, clinical scores used in clinical trials, especially MMSE, do not accurately assess changes
in cognitive function in the early stages of AD due to their limited sensitivity.
Finally, the radiotracers used in the individual assays included in this analysis vary in sensitivity, specificity, and other performance metrics, and may also cause small differences [7].

More notably, Aβ-targeting drugs are still one of the topics of discussion in the field of AD therapy, and the conclusions of this meta-analysis suggest that there may be a causal relationship between the reduction of Aβ-PET and cognitive decline, which not only highlights the feasibility of Aβ as a viable biological target in AD, but also thoroughly understands the potential
of Aβ-targeting drugs in the treatment of AD.

In addition, the Aβ-PET SUVR value may be used as a biomarker for subsequent AD-related trials, which will be more economical and time-efficient than using cognitive function measurement as a clinical endpoint, thereby guiding future drug development and clinical application
.

References:

[1] Jack CR Jr, Bennett DA, Blennow K, et al.
NIA-AA research framework: toward a biological definition of Alzheimer’s disease.
Alzheimers Dement.
2018; 14(4):535-562.

[2] McKhann GM, Knopman DS, Chertkow H, et al.
The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.
Alzheimers Dement.
2011; 7:263-269.

[3] Karran E, De Strooper B.
The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics.
Nat Rev Drug Discov.
2022; 21:306-318.

[4] Karlawish J, Grill JD.
The approval of Aduhelm risks eroding public trust in Alzheimer research and the FDA.
Nat Rev Neurol.
2021; 17:523524.

[5] Ackley SF, Zimmerman SC, Brenowitz WD, et al.
Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis.
BMJ.
2021; 372:n156.

[6] Mangialasche F, Solomon A, Winblad B, et al.
Alzheimer’s disease: clinical trials and drug development.
Lancet Neurol.
2010; 9:702-716.

[7] Krishnadas N, Villemagne VL, Doré V, et al.
Advances in brain amyloid imaging.
Semin Nucl Med.
2021; 51:241-252.

The author of this article Xu Peiru

Responsible editorDai Siyu