Synaptic Regeneration And The Future Of Alzheimer's R&D

By Stella Sarraf, Ph.D., founder and CEO, Spinogenix

For too long our approach to treating Alzheimer’s disease has been a case of “managed decline,” centered on delaying the inevitable. But with almost 60 million people now living with dementia – of which up to 70% suffer from Alzheimer’s — the clinical imperative for disease modifying therapies is stronger than ever. A critical transition is beginning to take form, moving beyond merely slowing disease progression toward achieving tangible functional recovery.

Since the FDA approved tacrine (Cognex) as the first Alzheimer’s treatment in 1993, drug discovery efforts have consistently prioritized symptom management to slow the cognitive decline. More recently, the approval of antibodies targeting amyloid beta has marked the first success in attempts to develop new therapies. While these represent an advance in altering the course of disease, they require extensive and often invasive diagnostic testing and 18 month-long administration periods before any measurable benefits can be observed relative to untreated controls. They also carry safety risks, including amyloid-related imaging abnormalities (ARIA), which require thorough and resource-heavy monitoring protocols.

Building on these initial successes, there is more we can do to alter the trajectory of Alzheimer’s, like expanding our strategic focus to prioritize therapies that directly address the structural damage caused by the disease. Synaptic regeneration offers a highly promising, yet often overlooked, actionable path. If we can restore the neural connections lost at the initial stages of onset, we can look forward to a new class of treatments capable of reversing cognitive decline and restoring function in people with Alzheimer’s and other dementias.

Alzheimer’s As A Synaptopathy

If we’re to successfully advance drug discovery efforts in synaptic regenerative treatments, R&D teams should evaluate Alzheimer’s as, fundamentally, a synaptopathy. While amyloid plaques and tau tangles represent the pathological hallmarks of the disease, post-mortem tissue analysis and more recent advanced neuroimaging studies have shown synapse loss to be the major biological correlate with cognitive decline. The loss of synapses — the critical neural connections that enable neuron communication, form memories, and accomplish complex cognitive tasks — occurs at the earliest stages of disease onset.

Clearing amyloid or tau aggregates may help address the toxic buildup in the brain. Yet this alone cannot rebuild the fundamental communication networks that have already been damaged. As drug developers, we should investigate mechanisms that stimulate synaptic regrowth.

Recent clinical advances have demonstrated the viability of this approach. An investigational small molecule designed to restore synapses has shown promise in Phase 2a clinical trials. During a four-week placebo-controlled period, rapid improvements in cognition were observed in Alzheimer’s participants receiving a synaptic regenerative therapy that, in preclinical work, was found to normalize synaptic density without modifying the buildup of amyloid beta or phosphorylated tau proteins. The rapid nature of these effects, and their durability through six months of treatment, support the idea that synaptic regeneration can fundamentally change the Alzheimer’s treatment paradigm.

Overcoming Bottlenecks

The current standard for Alzheimer’s trials, as seen in anti-amyloid and anti-tau studies, requires large patient cohorts and lengthy observation periods — often of 18 months or more — to demonstrate statistically significant results in slowing cognitive decline. While late-stage clinical trials for synaptic regeneration will likely still require extensive observation periods, this novel approach to treatment may address some of the more persistent bottlenecks in clinical trial design.

Current persistent bottlenecks stem from delivery and administration challenges, as large biologic therapies struggle to cross the blood-brain barrier and require costly, time-consuming IV infusions in specialized clinical settings. Formulating synaptic regenerators as orally administered small molecules overcomes these hurdles, readily crossing the blood-brain barrier and moving treatment to a once-daily pill.

While clinical trials to support regulatory approval remain lengthy, early-phase development can be optimized. Synaptic regenerative therapies are demonstrating the potential to produce more rapid benefits, including actual improvements in cognition, as opposed to a slowing of cognitive decline. Data from early-phase clinical studies have demonstrated measurable improvements in standard cognitive assessments within just a few weeks of commencing treatment.

Additionally, integrating objective neurophysiological biomarkers like quantitative electroencephalography (qEEG) into trial protocols can offer a method to measure synaptic activity and provide evidence of pharmacodynamic activity. EEG recordings of Alzheimer’s patients typically reveal a clear pattern of reduced electrical activity across different brainwave frequencies, which has been interpreted as “cortical slowing.” The same synaptic regenerative drug that showed evidence of rapidly improving cognition in a Phase 2a trial also reversed this cortical slowing measure, providing additional support for drug activity in the form of an objective and quantitative neurophysiological readout. Thus, incorporating these rapid physiological measurements may enable sponsors to make faster data-driven decisions in early-phase development.

Addressing Patient Stratification And Diagnostics

Monoclonal antibody treatments like lecanemab and donanemab require strict patient stratification based on amyloid positivity, the gold standard for which remains positron emission tomography (PET) scans. Additionally, patients need to be assessed for APOE4 status due to the risk of ARIA. This limits the pool of eligible patients, creating logistical and financial challenges for both clinical trials and eventual commercialization.

Synaptic Regeneration As A Combination Therapy

As clinical development continues to advance, synaptic regeneration is positioned to act as both a stand-alone therapy and in combination with current standard-of-care treatments. The future of Alzheimer’s treatment will likely mirror that of other fields like oncology, where combination therapies address multiple aspects of a complex disease. Drug discovery pipelines should therefore actively explore clinical models that combine synaptic regeneration with existing modalities like amyloid-clearing therapies.

Best Practices For Biopharma

If we are to fully capitalize on emerging synaptic regenerative therapies, life sciences organizations should implement two key strategies in neurodegenerative pipelines:

1. Prioritize scalable, noninvasive biomarkers to quantify synaptic regeneration without increasing patient burden. Building on the utility of quantitative EEG, the industry should prioritize the integration of additional noninvasive biomarkers that can provide robust objective evidence of disease modification and target engagement without subjecting patients to invasive CSF analyses or costly PET imaging.
2. Prioritize patient centricity and access to increase the reach and reduce the burden. Focusing development on a once-daily oral medication can significantly improve patient compliance and ease the strain on caregivers and providers. Doing so with therapies that in principle can provide benefit despite heterogeneity in disease processes and biomarkers offers the best chance to address Alzheimer’s at scale.

Charting A New Path

We are at a critical juncture in the fight against Alzheimer’s. While slowing disease progression has long been the extent of our therapeutic capabilities, the development of synaptic regenerative therapies brings the possibility of regaining lost cognitive function. Synaptic regeneration will be a critical part of efforts to move beyond symptom management to fundamentally alter the trajectory of the disease and the prospects for millions of patients.

About The Author

Stella Sarraf, Ph.D., is the founder and CEO of Spinogenix and Amydis, where she is pioneering precision synaptogenesis with the development of first-in-class small molecules for neurological diseases and ocular tracers for neurodegenerative diseases, respectively. She spent a decade in venture capital at Foresite Capital and Prospect Venture Partners, following a tenure as a senior research chemist at Merck Research Laboratories. Sarraf holds a Ph.D. in organic chemistry from Columbia University and a BA from UC Berkeley.