New drugs are linked to slower cognitive decline in Alzheimer’s, suggesting a potential mechanism of benefit for monoclonal antibodies.
Researchers at the University of Cincinnati discovered that new monoclonal antibody drugs may slow cognitive decline by increasing levels of a critical brain protein, amyloid-beta 42 (Aβ42), rather than solely focusing on reducing amyloid plaques in the brain. This finding shifts attention from plaque accumulation to the potential role of Aβ42 in supporting brain health.
Alzheimer’s disease, the most common form of dementia, is characterized by progressive memory loss, cognitive decline, and behavioral changes. The condition gradually impairs daily functioning and quality of life, impacting millions globally. At a biological level, Alzheimer’s is marked by two primary features: the buildup of amyloid plaques outside neurons and the formation of neurofibrillary tangles composed of tau protein inside neurons.
Amyloid-beta, a protein fragment naturally produced in the brain during normal cellular processes, exists in several forms. Among these, two variants—Aβ40 and Aβ42—are of particular interest in Alzheimer’s research. Aβ40, the more common form, constitutes approximately 90% of all amyloid-beta produced and is generally considered benign under normal conditions. In contrast, Aβ42, though less abundant, is more prone to clumping and forming plaques. This increased tendency to aggregate has made Aβ42 a central focus in theories about Alzheimer’s pathology.
The amyloid cascade hypothesis, first proposed in the early 1990s, has dominated the field for decades. According to this theory, Alzheimer’s begins when Aβ42 molecules aggregate to form clumps known as oligomers. These oligomers further accumulate into amyloid plaques, which are believed to disrupt neuronal communication, trigger inflammation, and eventually lead to the widespread damage observed in Alzheimer’s. Support for this hypothesis stems from genetic studies linking mutations in genes affecting amyloid production to rare, inherited forms of the disease.
Despite the widespread acceptance of the amyloid cascade hypothesis, treatments targeting amyloid plaque removal have largely been unsuccessful. Over 30 clinical trials focusing on amyloid have either shown no significant cognitive benefits or, in some cases, exacerbated symptoms. This has raised questions about whether plaques are the primary cause of Alzheimer’s or merely a secondary byproduct of the disease. Observations that many older individuals with amyloid plaques do not develop dementia have further complicated this debate.
“The discovery of Aβ42’s potential role in maintaining brain health represents a significant shift in Alzheimer’s research, opening new avenues for therapeutic development.”
Neurology professor Alberto J. Espay and his team proposed a hypothesis suggesting that the loss of normal, soluble Aβ42 in the brain, rather than the accumulation of amyloid plaques, might be the driving force behind Alzheimer’s pathology. Research supporting this idea indicates that Aβ42 plays a vital role in maintaining neuronal health and synaptic function. It is suggested that its depletion, rather than its aggregation, could be the primary factor leading to cognitive decline.
It was observed that some newly approved monoclonal antibody treatments, such as aducanumab, lecanemab, and donanemab, inadvertently increased Aβ42 levels in cerebrospinal fluid, which was correlated with cognitive improvements. These findings led to further investigation into whether elevating Aβ42 levels might explain the therapeutic benefits of these treatments, providing a new perspective on the disease’s underlying mechanisms.
“Most anti-Aβ interventions had succeeded in clearing the brain from amyloid plaques, yet they were either futile or statistically favored the placebo group,” explained Espay, the director and endowed chair of the Gardner Family Center for Parkinson’s Disease and Movement Disorders and co-author of Brain Fables, the Hidden History of Neurodegenerative Diseases and a Blueprint to Conquer Them.
>“It was of interest to determine what made aducanumab, lecanemab, and donanemab unique. Along the way, it was discovered that, in addition to removing amyloid, virtually all monoclonal anti-Aβ antibodies also increase Aβ42 in cerebrospinal fluid.”
“The focus shifted to exploring whether cognitive outcomes could be explained from the opposite end of protein homeostasis—by the increases in Aβ42. This lies at the heart of two opposing hypotheses in neurodegeneration, particularly in Alzheimer’s disease: one posits that the disease is caused by the accumulation of amyloid plaques (the amyloid cascade hypothesis); the other suggests that the disease is caused by the loss of Aβ42 as it transforms into amyloid plaques (the proteinopenia hypothesis). Evidence has been reviewed in favor of the latter.”
This perspective highlights the importance of understanding the role of Aβ42 in brain health and opens new avenues for exploring therapeutic strategies that focus on preserving or enhancing its levels, rather than solely targeting plaque removal.
In a recent study, Espay and colleagues analyzed data from 24 randomized clinical trials involving monoclonal antibody drugs designed to target amyloid plaques. These trials included nearly 26,000 patients diagnosed with early or moderate Alzheimer’s disease. The analysis focused on changes in two key biomarkers: amyloid plaque levels, measured through imaging, and cerebrospinal fluid levels of Aβ42. Cognitive performance was also evaluated using standardized tests such as the Alzheimer’s Disease Assessment Scale and the Clinical Dementia Rating.
Statistical methods were employed to compare cognitive outcomes in patients treated with monoclonal antibodies against changes in amyloid plaques and Aβ42 levels. By examining the relationship between these biomarkers and cognitive improvement, the researchers sought to identify which factor was more closely associated with slowing cognitive decline.
The findings revealed that increases in Aβ42 levels were just as strongly linked to cognitive improvement as the reduction of amyloid plaques. Treatments that elevated Aβ42 levels consistently correlated with better cognitive outcomes. Conversely, interventions that reduced Aβ42 levels—such as certain enzyme inhibitors—were associated with worsened cognitive performance.
A hypothesis was proposed suggesting that amyloid plaques might not directly cause Alzheimer’s symptoms. Instead, plaques could represent a protective response by the brain to stress or injury. The real issue, it was suggested, might be the depletion of soluble Aβ42, which plays a critical role in neuron health and synaptic function. When Aβ42 levels fall below a critical threshold, cognitive decline appears to accelerate.
“There are two sides to any story. It has been assumed that the only explanation for any potential benefit of the newly approved monoclonal antibodies for Alzheimer’s is their ability to remove amyloid plaques from the brain. Yet many other interventions have achieved this in the past, without success. The alternative explanation for any benefit is the increase in Aβ42 levels in cerebrospinal fluid, which most antibodies accomplish—though such data is often confined to the supplementary materials of trial reports.”
However, the study has limitations. The analysis relied on aggregated data from clinical trials, which may reduce the precision of the findings.
“Individual-level data were not available, as these are not shared by the companies that own the data. This meant the analysis was conducted with reduced power to detect significant differences,” Espay noted.
This limitation required conclusions to be drawn from group-level trends rather than detailed, individualized data, potentially obscuring important nuances in how different patients respond to treatments.
The study also highlights practical challenges. While monoclonal antibody treatments effectively increase Aβ42 levels, they carry risks such as brain inflammation and shrinkage. Moving forward, there is interest in exploring the potential benefits of directly increasing Aβ42 levels without the toxic effects associated with amyloid removal.
“There is resistance to viewing Alzheimer’s as a loss, which is paradoxical,” Espay added. “The field has long been comfortable with the idea that Alzheimer’s is about a ‘gain’—of amyloid plaques. However, amyloid forms as a reaction to various stressors. If too much amyloid is produced in this process, less of the normal protein from which it originates—Aβ42—remains.”
This research underscores the importance of reevaluating long-standing assumptions about Alzheimer’s disease and exploring new therapeutic approaches that prioritize the preservation or enhancement of Aβ42 levels, offering hope for more effective treatments in the future.
https://doi.org/10.1093/brain/awae216
Abstract
Positive effects of new anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer’s disease (AD) have been attributed to brain amyloid reduction. However, most anti-Aβ antibodies also increase the CSF levels of the 42-amino acid isoform (Aβ42). We evaluated the associations of changes in CSF Aβ42 and brain Aβ-PET with cognitive and clinical end points in randomized trials of anti-Aβ drugs that lowered (β- and γ-secretase inhibitors) or increased CSF Aβ42 levels (anti-Aβ monoclonal antibodies) to test the hypothesis that post-treatment increases in CSF Aβ42 levels are independently associated with cognitive and clinical outcomes.
From long-term (≥12 months) randomized placebo-controlled clinical trials of anti-Aβ drugs published until November 2023, we calculated the post-treatment versus baseline difference in ADAS-Cog (cognitive subscale of the Alzheimer’s Disease Assessment Scale) and CDR-SB (Clinical Dementia Rate-Sum of Boxes) and z-standardized changes in CSF Aβ42 and Aβ-PET Centiloids (CL). We estimated the effect size [regression coefficients (RCs) and confidence intervals (CIs)] and the heterogeneity (I2) of the associations between AD biomarkers and cognitive and clinical end points using random-effects meta-regression models.
We included 25 966 subjects with AD from 24 trials. In random-effects analysis, increases in CSF Aβ42 were associated with slower decline in ADAS-Cog (RC: −0.55; 95% CI: −0.89, −0.21, P = 0.003, I2 = 61.4%) and CDR-SB (RC: −0.16; 95% CI: −0.26, −0.06, P = 0.002, I2 = 34.5%). Similarly, decreases in Aβ–PET were associated with slower decline in ADAS-Cog (RC: 0.69; 95% CI: 0.48, 0.89, P < 0.001, I2 = 0%) and CDR-SB (RC: 0.26; 95% CI: 0.18, 0.33, P < 0.001, I2 = 0%). Sensitivity analyses yielded similar results.
Higher CSF Aβ42 levels after exposure to anti-Aβ drugs are independently associated with slowing cognitive impairment and clinical decline. Increases in Aβ42 may represent a mechanism of potential benefit of anti-Aβ monoclonal antibodies in AD.