Regenerating Synapses Might Assist Deal with Neurodegenerative Illnesses

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March 3, 2026

Neurodegenerative diseases rank among the most profound tragedies of the human condition, capable in various forms of robbing the afflicted of a lifetime of memories, basic comprehension, sense of self, the ability to move and communicate, and the comfort of social bonds and shared reality. Yet, despite their devastating impact and long history of study, effective therapies remain elusive, leaving the vast majority of patients on a path of inexorable decline and mortality. This impasse derives in large part from the complexity and multiplicity of pathogenic mechanisms, their heterogeneous manifestation across individuals, and unique vulnerabilities of affected neural populations. Among the core challenges in developing new treatments is finding points of convergence among diverse etiologic factors that can be targeted to slow or reverse disease progression.

Synaptopathy: A Fundamental Convergence Point in Neurodegenerative Diseases

It is increasingly recognized that synapse loss is an early and nodal event in the pathogenesis of diverse neurodegenerative diseases, including dementias, motor disorders, neuropsychiatric conditions, and many others. In these conditions, collectively referred to as the synaptopathies, loss of excitatory glutamatergic synapses in particular is a key driver of symptoms.^1,2

Numbering up to 1,000 trillion in the human brain, glutamatergic synapses establish an indispensable neural framework for cognition, emotion, sensation, perception, language, and movement. They are also the locus of several forms of plasticity (i.e. functional and structural change) underlying learning and memory. In considering how glutamatergic synapses are affected by disease, their microanatomy and composition are critical. Dendritic spines, the small protrusions of dendritic membrane that constitute the postsynaptic element at the majority of glutamatergic synapses, are among the most functionally and molecularly complex subcellular specializations in all of biology. It is perhaps owing to their finely tuned complexity that dendritic spine synapses are particularly sensitive to disease mechanisms and among the first dominos to fall.

The Convergence of Pathology

The impact of synapse loss in neurodegenerative diseases and how it arises from convergent pathogenic mechanisms is evident when comparing distinct mechanisms within and across Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and schizophrenia (SCZ). This trio represents the most common forms of dementia, adult-onset motor neuron disease, and psychosis, respectively.

Researchers have linked synapse loss in AD to the effects of neuroinflammation—particularly, active elimination of synapses by microglia—cytoskeletal disruption, impaired energy metabolism and proteostasis, excitotoxicity, and the synaptotoxic effects of beta amyloid and phosphorylated tau. An early and progressive loss of glutamatergic synapses essentially uncouples the cortical and limbic networks in the brain, which are involved in memory formation and cognition. Accordingly, synapse loss is highly correlated with cognitive decline.^3,4 Moreover, clinical evidence suggests that retention of normal synaptic density supports cognitive resilience.⁵ Individuals with high levels of amyloid pathology consistent with AD can nevertheless exhibit normal cognition if their synaptic networks remain robust.

In ALS, histological studies in postmortem patient specimens and diverse genetic models of ALS indicate that synapse loss on upper motor neurons occurs at early, presymptomatic stages of disease.⁶ It has also been observed in motor subcircuits and cognitive centers, including the prefrontal cortices of ALS patients who exhibit cognitive decline.⁷ In the spinal cord, synapse loss appears to manifest about the time of motor symptom onset.

The case for synapse loss as a key etiologic factor in ALS is bolstered by work on the most common molecular pathology of ALS, transactive response DNA binding protein 43 (TDP-43) mislocalization to the cytoplasm, and the most common genetic cause of ALS, the chromosome 9 open reading frame 72 (C9orf72) repeat expansion. TDP-43 is normally found in the nucleus where it regulates RNA processing and transcription. Its mislocalization alone is sufficient to drive large reductions in dendritic spine synapses.⁸ Remarkably, the corresponding loss of nuclear TDP-43 has been shown to synergize with ALS risk SNPs in UNC13A, a gene critical for presynaptic function.^9,10 This disrupts splicing of UNC13A, leading to reduced protein expression and synaptic failure.

The C9orf72 repeat expansion has multiple deleterious effects on the glutamatergic synapses, including impairing glutamate release and both the formation and maturation of dendritic spines, in addition to synaptotoxic influences mediated by TDP-43 pathology present in C9orf72 mutation carriers.^11,12 The early loss of synapses in ALS may contribute to other pathological features of the disease, such as cortical hyperexcitability, and to a “dying forward” propagation of pathology implicated in ALS progression. Interestingly, TDP-43 mislocalization and downstream synaptic impairment also occur in AD and the oft-comorbid pathology, Limbic-predominant Age-related TDP-43 Encephalopathy.

In SCZ, synapse loss is a critical point of convergence for genetic and environmental factors.¹³ Large reductions in glutamatergic synapses in the frontal cortical and other regions may result in a hyperactive state of midbrain dopaminergic neurons that promotes psychotic (positive) symptoms. Synapse loss in other regions including the hippocampus and prefrontal cortex likely contribute to negative symptoms (e.g. anhedonia) and cognitive deficits of SCZ. Mechanistically, SCZ appears to involve deficits in synaptic homeostasis set in motion by genetic factors and in utero environmental factors that summate in late adolescence to early adulthood with exaggerated synaptic pruning by microglia, a mechanism heavily influenced by genetic and environmental SCZ risk factors.¹³ Interestingly, synapse loss in SCZ does not appear to be accompanied by extensive neuron loss, making it a potentially “purer” synaptopathy.

AD, ALS, and SCZ can be thought of as a basis set of a much broader domain of conditions involving cognitive, motor, and psychiatric symptoms in which synapse loss has been implicated as a major driver. The clear message from data across the synaptopathies is that therapeutics capable of regenerating glutamatergic synapses may be transformative—with the potential to slow or even reverse symptom progression. However, while this potential has been long recognized for diseases like AD and SCZ, pharmacological tools to achieve synaptic regeneration have until recently been lacking.

The Regenerative Turn in Therapeutic Development

Therapeutic development in neurodegenerative disease has historically been dominated by efforts to ameliorate symptoms or slow progression by targeting putative molecular pathways and known genetic drivers. However, such efforts have rarely achieved more than a modest slowing of the decline in conditions such as AD and ALS, and they have left many symptoms inadequately controlled in SCZ.

Novel “neuroplastogens” are being developed that have the potential to regenerate what has been lost at the synaptic level—and on time scales far shorter than the 12–18-month regimens that have been necessary to observe slowing of disease by recently approved therapeutics. This advance may require a reset in thinking about clinical trial design and what is possible in terms of therapeutic benefit. Therapeutic outcomes including rapid improvements in cognition, memory, and psychiatric symptoms can only be regarded as bold and high-reaching given the history of neurodegenerative disease, but they are nevertheless prompted by sound preclinical data.

Emerging Clinical Data and the Therapeutic Horizon

Data from Phase 2a clinical trials of a novel synaptogenic small molecule therapeutic have demonstrated potential to slow disease progression in ALS and rapidly improve cognition in AD. If replicated in larger trials, the clinical goal may shift from merely slowing the rate of decline to actively halting disease progression and even reclaiming lost function. For ALS patients, this could mean maintaining motor control and autonomy for significantly longer. For AD patients, it may be possible to restore memory faculties and functional independence.

The horizon for a safe and effective synaptic regenerative therapeutic is filled with opportunities. Frontotemporal dementia and a broad set of neuropsychiatric conditions are potential indications, including depression for which the synaptogenic drug esketamine has already been FDA approved. Aging, the biggest risk factor for dementias, is itself associated with synapse loss, and neuroplastogens may offset the aging component of synaptic compromise and attendant cognitive dysfunction.¹⁴

Leading causes of blindness may also be a target. The retina, an extension of the central nervous system, harbors glutamatergic circuitry that degenerates in glaucoma, diabetic retinopathy, and age-related macular degeneration. In a preclinical glaucoma study, the same small molecule that has shown encouraging signs of efficacy in AD and ALS protected retinal projection neurons and partially preserved retinal function.¹⁵ Such benefits of synaptic regeneration on the neural machinery of vision may extend to diabetic retinopathy, another major cause of blindness.

Can Regeneration Modify Disease?

In general, restoration of synapses can be viewed as disease modifying given the critical role of synapse loss in the genesis of symptoms. However, several fundamental questions remain that bear on the potential to modify underlying disease processes.

Is synapse loss part of a domino effect in disease progression, or is it one of many parallel pathogenic mechanisms that must be independently targeted? Both are likely, as is the expectation that synaptic regenerative compounds will find synergies with other targeted approaches.
In diseases where significant neuron loss is also observed, how much benefit can be realized by restoring synapses on the neurons that remain? In light of the primary nature of synapse loss in neurodegeneration, we can expect that some function can be restored without addressing neuron loss as well. This idea is supported by work in an AD mouse model where reversal of large deficits in dendritic spines restored memory.¹⁶
Can regenerating synapses using disease agnostic therapeutics be disease-modifying at the molecular level? Neurobiology is replete with examples of bidirectional or retrograde signaling events linking synaptic activity to alterations in gene expression and the activity of signaling events and cellular processes implicated in neurodegenerative disease. For instance, it is reasonable to propose that pharmacological normalization of synaptic density can restore activity-dependent neurotrophic mechanisms that antagonize disease processes.

A New Era for Synaptic Regenerative Therapeutics

Multiple programs are under way to develop synaptic regenerative therapeutics. Success in any one of them may redefine what is therapeutically possible in diseases that to this day remorselessly strip patients of their function, independence, and dignity. Much like transformative therapies in inflammatory disease (e.g. tumor necrosis factor blockers) and oncology (e.g. checkpoint inhibitors), they could see broad use as a means to target a key tipping point common to diverse diseases. But in synaptic regenerative drugs’ capacity to regenerate neural architecture, there is the potential for something entirely unique: the spark of renewal of mind, sensation, and action of self. The next few years will begin to reveal how far that spark can go in improving people’s lives.