Exploring Neprilysin and Amyloid-Beta–Tau Axes in Alzheimer Disease

The development of disease-modifying therapies for Alzheimer disease (AD) has increasingly centered on targeting amyloid-beta (Aβ) pathology, but questions remain about the biological processes that follow Aβ accumulation and contribute to tau pathology and neurodegeneration. Understanding these interconnected pathways could help identify new therapeutic targets and inform strategies designed to intervene earlier in the disease course, potentially before the onset of cognitive impairment.

At the 2026 Alzheimer’s Association International Conference (AAIC), held July 12-15, in London, Takaomi Saido, PhD, principal director of RIKEN BIO in Japan, presented a talk “From Curiosity to Cure: The Neprilysin-Donanemab & Aβ-Tau Axes in Alzheimer’s Disease.” The presentationhighlighted decades of research into Aβ metabolism and the development of donanemab, alongside ongoing work investigating the mechanisms linking Aβ and tau pathology. The presentation also discussed the role of neprilysin as a major Aβ-degrading enzyme, the potential influence of somatostatin on neprilysin expression, and research using novel mouse models to investigate the relationship between Aβ deposition and tau pathology.

During the meeting, Saido sat down to discuss the evolution of this work and the potential implications for the future of AD treatment. Throughout the conversation, he highlighted the possibility of targeting neprilysin-related pathways to influence Aβ accumulation, the ongoing effort to identify the molecular mechanisms responsible for the Aβ-to-tau transition, and the potential for developing disease-modifying therapies capable of halting AD progression during its preclinical stage.

"We made a conceptual and technical basis for development of donanemab more than 30 years ago," Saido said. "We then identified the major Aβ-degrading enzyme, neprilysin, whose expression in the brain [changes] with aging, we also found that somatostatin upregulates neprilysin expression. This has opened up a new therapeutic approach to control AD development in its preclinical stage."

Neprilysin has been a longstanding focus of Saido's research because of its role in the degradation of Aβ. His presentation connected this work with the development of donanemab and broader efforts to understand how Aβ metabolism may be influenced before the accumulation of pathology leads to clinical symptoms. Saido also described research examining somatostatin as a regulator of neprilysin expression, suggesting that pathways involved in Aβ degradation may represent potential targets for therapeutic intervention during the preclinical phase of AD.

The presentation also highlighted the development of second-generation mouse models of Aβ and tau pathology designed to address some of the limitations associated with traditional transgenic overexpression models. Among the concerns raised were the use of artificial promoters, overexpression-related artifacts, the lack of relevant negative controls, and other processes that may produce pathology that does not accurately reflect the biology of AD. The presentation also cited issues including artificial endoplasmic reticulum stress, artificial calpain activation, and neurodegeneration occurring without tau pathology.

Using alternative models, Saido and colleagues examined the relationship between Aβ deposition and tau pathology, including how aging and different tau mutations may influence the timing and progression of pathology. The presentation included analyses of S305N and P301S MAPT models, which demonstrated differences in tau pathology and its progression over time.

In S305N double-mutant mice, tau pathology was first detectable at 6 months, followed by a modest increase at 15 months, after which the distribution remained relatively consistent through 30 months. In this model, Aβ was associated with a slow progression of tau pathology. By comparison, P301S double-mutant mice showed no detectable pathology until 24 months. By 30 months, sparse neuronal tau staining was observed in cortical areas and the hippocampus, with stronger pathology in the thalamus and midbrain. In this model, Aβ was associated with a faster progression of tau pathology.

The findings pointed to potentially distinct pathways through which Aβ pathology may influence the development and progression of tau pathology. Saido said researchers are now working to identify the molecules responsible for the Aβ-to-tau transition, with the potential for those mechanisms to reveal new targets for therapeutic development.

"We are in the middle of identifying molecules responsible for the Aβ-tau transition," Saido said. "Some of these selectively expressed in the brain will be relevant targets without the concerns about the systemic side effects."

The presentation identified several questions that remain to be addressed, including why S305N-carrying triple-mutant mice develop brain atrophy comparable with P301S-carrying mice at 12 months despite the absence of major pathology at 6 months. One possibility raised was that S305N mice may experience accelerated pathology between 6 and 12 months. Another is that a mechanism independent of phosphorylation and seeding activity may contribute to the observed brain atrophy.

More broadly, Saido's presentation emphasized the need to define the cellular and molecular phases involved in the Aβ-to-tau transition. The work proposed that microscopic omics followed by reverse genetics could help identify the mechanisms underlying this process and clarify how Aβ pathology contributes to the subsequent development of tau pathology.

For Saido, identifying these mechanisms could ultimately lead to new therapeutic strategies that target AD earlier in its course.

"These approaches will lead to generation of new medications that are much less expensive and safer, without a major side effect, such as amyloid-related imaging abnormalities (ARIA), than using therapeutic antibodies," Saido said.

The potential to intervene before the onset of cognitive impairment represents the broader goal of this research. Although current disease-modifying approaches have demonstrated the clinical relevance of targeting AD pathology, Saido said the field should continue working toward therapies capable of altering disease progression.

"I believe it will become possible to develop disease-modifying therapies that halt the progression of AD during its preclinical stage, ultimately enabling a future in which AD can be prevented before the onset of cognitive impairment," Saido said.

The work presented at AAIC underscored the continued importance of understanding the biological relationship between Aβ and tau pathology. While the mechanisms underlying the transition remain incompletely defined, identifying the cellular and molecular processes involved could provide new opportunities for therapeutic intervention. For Saido, the longer-term goal is to translate decades of research into approaches that can address AD before the disease has progressed to the point of irreversible cognitive impairment.

REFERENCES
1. Saido TC. From Curiosity to Cure: The Neprilysin-Donanemab & Aβ - Tau Axes in Alzheimer’s Disease. Presented at: Alzheimer’s Association; July 12-15, 2026; London, United Kingdom.

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