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Peptides for Alzheimer's Disease Research

Alzheimer's disease (AD) affects more than 55 million people worldwide, and that number is expected to exceed 150 million by 2050 [1].

Alzheimer's disease (AD) affects more than 55 million people worldwide, and that number is expected to exceed 150 million by 2050 [1]. The disease is defined by amyloid-beta plaque accumulation and tau protein hyperphosphorylation, along with neuroinflammation, mitochondrial dysfunction, and progressive synaptic loss.

After decades of failed drug trials, the AD treatment pipeline has shifted toward multi-mechanism strategies. Peptides sit at the center of several active research areas -- from GLP-1 receptor agonists tested in large Phase 3 trials to neuroprotective compounds targeting tau stabilization, mitochondrial health, and amyloid toxicity.

This guide covers what the research says about each peptide being studied for Alzheimer's, what worked, what failed, and where things stand.

Table of Contents

The Biology Peptides Target in Alzheimer's

Alzheimer's disease isn't one problem. It's a cascade of interconnected failures that researchers now understand as a multi-mechanism process [2]:

Amyloid-beta (A-beta) accumulation: Abnormal processing of amyloid precursor protein produces A-beta peptides that aggregate into toxic oligomers and eventually plaques. The oligomers -- not the plaques themselves -- appear to be the primary drivers of early neuronal damage [3].

Tau hyperphosphorylation: The microtubule-associated protein tau becomes abnormally phosphorylated, destabilizing the neuronal cytoskeleton and forming neurofibrillary tangles that correlate more closely with cognitive decline than amyloid load does.

Neuroinflammation: Activated microglia and astrocytes release pro-inflammatory cytokines that accelerate neuronal damage. This chronic inflammation creates a self-reinforcing loop with amyloid and tau pathology.

Mitochondrial dysfunction: Impaired energy production, excessive reactive oxygen species, and disrupted mitophagy weaken neurons and make them vulnerable to other insults. A-beta itself accumulates within mitochondria and impairs the electron transport chain [4].

Insulin resistance: Brain insulin signaling dysfunction facilitates A-beta toxicity, tau hyperphosphorylation, and neuroinflammation. This link is the biological basis for testing diabetes drugs in AD.

Peptides can target one or more of these pathways. Their small size often allows blood-brain barrier penetration, and many have favorable safety profiles compared to small-molecule drugs.

GLP-1 Receptor Agonists: The EVOKE Trial Story

The GLP-1 receptor agonist semaglutide was tested in two landmark Phase 3 trials for early-stage Alzheimer's disease. The results, released in late 2025, represent both the promise and the limitations of repurposing metabolic drugs for neurodegeneration.

The Rationale

GLP-1 receptors are found throughout the brain. Activation reduces neuroinflammation, improves insulin signaling, protects the blood-brain barrier, and promotes neuronal survival. Epidemiological data suggested GLP-1 drug users had lower dementia rates [5].

EVOKE and EVOKE+ Trial Results

The EVOKE (N=1,855) and EVOKE+ (N=1,953) trials randomized 3,808 adults with amyloid-positive MCI or mild dementia to oral semaglutide or placebo over 104 weeks [6].

Primary endpoint: Not met. Semaglutide did not slow cognitive decline as measured by CDR-SB (Clinical Dementia Rating-Sum of Boxes) scores compared to placebo.

Biomarker findings: Participants on semaglutide showed reductions of up to 10% in biomarkers linked to neuroinflammation and AD pathology. These changes were statistically significant but too small to produce clinical benefit [7].

Novo Nordisk discontinued semaglutide development for Alzheimer's, including the injectable formulation. Full results will be presented at the AD/PD conference in Copenhagen in March 2026 [8].

Why It Failed and What Comes Next

Several hypotheses exist. Oral semaglutide may not achieve sufficient brain penetration. The disease stage may have been too advanced for a metabolic intervention. The 10% biomarker reduction may simply not be enough to produce clinical benefit in a 2-year window.

Howard Fillit of the Alzheimer's Drug Discovery Foundation noted that the trials still represent "a fundamental shift in how we approach the development of new Alzheimer treatments, expanding beyond amyloid to target the complete pathobiology of the disease" [7].

Preventive trials in pre-symptomatic populations, injectable formulations with better brain penetrance, and combination approaches are logical next steps. But for now, GLP-1 drugs cannot be recommended for Alzheimer's treatment.

NAP (Davunetide): Tau Stabilization Through Microtubule Protection

NAP (davunetide) is an eight-amino-acid peptide derived from activity-dependent neuroprotective protein (ADNP). Its mechanism is distinct from most AD drug candidates: rather than targeting amyloid directly, it stabilizes microtubules and reduces tau pathology.

How It Works

NAP prevents microtubule degradation by recruiting tau and end-binding proteins to microtubules. It reduces tau hyperphosphorylation, prevents caspase-3 activation and cytochrome c release from mitochondria, and activates the PI-3K/Akt neuronal survival pathway [9]. It also protects microtubules from the severing protein katanin, which becomes problematic when tau expression is reduced [10].

Preclinical and Clinical Evidence

In transgenic mouse models, intranasal NAP reduced both amyloid accumulation and tau hyperphosphorylation at early pathological stages [11]. All NAP-like peptides protected neurons against A-beta 1-42 toxicity in cell culture.

In human trials, NAP increased memory scores in patients with amnestic mild cognitive impairment -- a precursor to AD. However, a Phase 2 trial in progressive supranuclear palsy (PSP), a different tauopathy, did not show benefit. Researchers attributed this to NAP's preferential interaction with 3-repeat tau, which is characteristic of AD, rather than the 4-repeat tau dominant in PSP [12].

NAP (as CP201) is currently in Phase 3 trials for autism spectrum disorder related to ADNP syndrome. Its tau-targeting properties remain relevant to AD research, and recent reviews suggest further clinical development for AD-related tauopathy is warranted [13].

Dihexa: HGF/c-Met Pathway and Synaptogenesis

Dihexa is a synthetic hexapeptide derived from angiotensin IV that works through a completely different mechanism than most AD drug candidates. It activates the hepatocyte growth factor (HGF)/c-Met receptor system, which promotes synaptogenesis -- the formation of new synaptic connections between neurons.

Key Research

In animal models of AD-like cognitive impairment, Dihexa restored cognitive performance, outperforming donepezil (Aricept), a standard AD medication. In neurotrophic activity assays, Dihexa was seven orders of magnitude more potent than brain-derived neurotrophic factor (BDNF) [14].

A study in APP/PS1 mice (a transgenic AD model) showed Dihexa rescued cognitive impairment and recovered memory through the PI3K/AKT signaling pathway [15]. When an HGF antagonist was delivered to block Dihexa's mechanism, the cognitive benefits disappeared -- confirming that the HGF/c-Met pathway mediates its effects.

Limitations and Safety Concerns

No human studies exist. Because HGF/c-Met activation promotes cell growth and proliferation, there are theoretical concerns about cancer risk with long-term use. Dihexa is not FDA-approved, and the gap between impressive animal data and zero human trials is significant.

A related compound, ATH-1017, which also activates HGF/c-Met, has entered clinical trials for mild-to-moderate AD and Parkinson's disease, potentially providing a more regulated path to testing this mechanism in humans [16].

GHK-Cu: Gene Expression and Neuroprotection

GHK-Cu is a naturally occurring copper-binding tripeptide present in human plasma, saliva, and urine. Plasma levels drop from about 200 ng/ml at age 20 to 80 ng/ml by age 60 -- a decline that correlates with increasing vulnerability to age-related disease [17].

Why It Matters for Alzheimer's

GHK-Cu's relevance to AD operates through several pathways:

Gene expression: Research identified nearly 4,000 genes affected by GHK-Cu. The Broad Institute's Connectivity Map identified GHK as a strong HDAC inhibitor -- and HDAC inhibition shows neuroprotective properties in animal models of brain disease [17].

Lipid peroxidation defense: GHK quenches 4-HNE and acrolein -- toxic byproducts of lipid peroxidation with documented roles in AD pathology [18].

Protein aggregation: GHK prevented copper- and zinc-induced protein aggregation and CNS cell death in vitro. A GHK-based peptidomimetic (P6) interacted directly with A-beta, preventing toxic oligomer formation and fibrillar aggregation [19].

SIRT1 activation: GHK-Cu activates SIRT1, a protein involved in DNA repair and oxidative damage protection [20].

Clinical Considerations

GHK-Cu has not been tested in AD clinical trials. The evidence is strong at the mechanistic level -- gene expression modulation, anti-aggregation properties, lipid peroxidation defense -- but remains preclinical. A 1-year placebo-controlled study of 8 mg daily copper in 68 AD patients found no negative effects, suggesting that copper supplementation through GHK-Cu is unlikely to worsen the disease [18].

BPC-157: NO System Modulation and Cytoprotection

BPC-157 has demonstrated neuroprotective effects across multiple CNS models, and its relevance to Alzheimer's research centers on its regulation of the nitric oxide system, free radical counteraction, and cytoprotective properties.

What the Research Shows

BPC-157 counteracted Alzheimer's disease-like disturbances in acknowledged animal models [21]. The peptide regulates the NO system -- not through simple activation but through controlled, context-dependent modulation of NO levels, eNOS expression, and related pathways [22].

In hippocampal ischemia/reperfusion models, BPC-157 reduced neuronal damage and attenuated or completely prevented behavioral deficits in water maze testing (a measure of spatial memory). These effects correlated with changes in gene expression including Vegfr2, Nos1-3, Akt1, Mapk1, Nfkb1, and Egr1 [23].

Limitations

All BPC-157 Alzheimer's data comes from animal models. The peptide has no human AD trial data, no FDA approval, and its CNS mechanisms involve multiple subcellular sites that remain incompletely characterized. The animal evidence is consistent, but the clinical translation gap is wide.

Humanin and MOTS-c: Mitochondrial-Derived Neuroprotection

Humanin

Humanin holds a unique place in Alzheimer's research: it was literally discovered in AD brain tissue. In 2001, Hashimoto et al. isolated humanin from cDNA extracted from relatively intact regions of postmortem AD brains. The peptide provided direct protection against AD-specific neurotoxicity, including amyloid-beta-induced cell death [24].

Since then, research has shown that humanin levels in cerebrospinal fluid decrease in AD patients, while offspring of centenarians have significantly higher humanin levels than age-matched controls [25]. Humanin inhibits oxidative stress and neuroinflammation through anti-apoptotic signaling, insulin pathway modulation, mitochondrial function preservation, and autophagy. It remains one of the strongest mechanistic candidates for AD-related neuroprotection, though it has not yet advanced to AD clinical trials.

MOTS-c

MOTS-c works primarily through AMPK activation. In neurons, this pathway reduces amyloid aggregation and tau phosphorylation [26]. Both humanin and MOTS-c levels decline with age and in neurodegenerative disease, and recent research has explored whether their blood levels could serve as biomarkers for AD -- potentially integrated with established amyloid-beta and tau measurements to improve diagnostic accuracy [27].

SS-31 (Elamipretide): Mitochondrial Membrane Protection

SS-31 binds cardiolipin in the inner mitochondrial membrane, stabilizing cristae structure and reducing oxidative stress. In Alzheimer's, where amyloid-beta accumulates within mitochondria and impairs the electron transport chain, this mechanism is directly relevant.

AD-Specific Research

In Tg2576 mice (an AD model), SS-31 treatment significantly reduced expression of mitochondrial fission genes (Drp1, Fis1) and increased expression of fusion genes, biogenesis genes, and synaptic genes. Treated mice also had lower levels of both soluble and insoluble A-beta [28].

A separate study found SS-31 upregulated neural mitochondrial biogenesis against A-beta aggregation in vitro [4]. In LPS-induced memory impairment models, SS-31 improved cognitive function through both mitochondrial antioxidant activity and BDNF/TrkB signaling modulation [29].

Clinical Status

SS-31 clinical trials have focused on heart failure and mitochondrial myopathy, with mixed results. No AD-specific human trials exist. The preclinical AD data is strong -- reduced amyloid burden, restored mitochondrial dynamics, improved synaptic gene expression -- but clinical translation for neurodegenerative disease remains a future goal.

Cerebrolysin: Neurotrophic Peptide Mixture

Cerebrolysin has actually been tested in Alzheimer's patients, making it one of the few peptides in this guide with human AD data.

The peptide mixture mimics neurotrophic factor activity, crossing the blood-brain barrier to promote neurogenesis and synaptogenesis. Multiple clinical trials in AD patients have shown improvements in cognitive function, though trial quality has varied and regulatory approval for AD has not been achieved in most countries [30].

Cerebrolysin's mechanisms -- neurotrophic support, anti-inflammatory effects, antioxidant activity, and mitochondrial protection -- overlap with several of the pathways disrupted in AD. Its combination of preclinical consistency and at least some human data places it in a different category than most peptides on this list.

Semax and Selank: BDNF and Anxiolytic Pathways

Semax rapidly upregulates BDNF expression and activates dopaminergic and serotonergic systems. BDNF deficiency is well-documented in AD brains, and restoring BDNF signaling is considered a viable therapeutic strategy [31].

Selank modulates GABA and serotonin systems, reducing anxiety without sedation. Given that anxiety and depression are common in AD and worsen cognitive outcomes, Selank's anxiolytic properties may have supporting value [32].

Neither peptide has been tested specifically in AD clinical trials. Their relevance is based on mechanism-level alignment with AD pathology (BDNF deficiency, neuroinflammation, neurotransmitter dysregulation) rather than direct disease-specific evidence. For more on their cognitive applications, see our guide on best peptides for cognitive enhancement.

Peptide Comparison Table

PeptidePrimary AD MechanismEvidence LevelKey Finding
SemaglutideGLP-1 receptor activation, anti-inflammatoryPhase 3 completedEVOKE trials failed primary endpoint; 10% biomarker reduction
NAP (Davunetide)Microtubule stabilization, tau reductionPhase 2 in MCIImproved memory in amnestic MCI; failed in PSP
DihexaHGF/c-Met activation, synaptogenesisPreclinical onlyOutperformed donepezil in AD animal models; 10^7x more potent than BDNF
GHK-CuGene expression modulation, HDAC inhibition, anti-aggregationPreclinical onlyAffected ~4,000 genes; prevented A-beta aggregation in vitro
BPC-157NO system modulation, cytoprotectionPreclinical onlyCounteracted AD-like disturbances in animal models
HumaninMitochondrial protection, anti-apoptoticPreclinical + biomarker studiesDiscovered in AD brain tissue; CSF levels reduced in AD patients
MOTS-cAMPK activation, amyloid/tau reductionPreclinical onlyReduces amyloid aggregation and tau phosphorylation via AMPK
SS-31Cardiolipin binding, mitochondrial protectionPreclinical onlyReduced A-beta levels and restored mitochondrial dynamics in AD mice
CerebrolysinNeurotrophic factor mimicryClinical trials in ADSome cognitive improvement in AD patients across multiple trials
SemaxBDNF upregulation, dopamine modulationPreclinical + stroke trialsRestores BDNF; no AD-specific trials

What This Means for Patients and Families

No peptide is currently approved for treating or preventing Alzheimer's disease. The FDA-approved AD treatments remain limited to cholinesterase inhibitors (donepezil, rivastigam, galantamine), memantine, and the newer anti-amyloid antibodies (lecanemab, donanemab) -- each with meaningful limitations.

The semaglutide EVOKE trial failure is disappointing but instructive. It shows that even biologically plausible approaches with strong preclinical backing can fail in the clinic.

Among the peptides reviewed here, cerebrolysin has the most direct human AD evidence, NAP showed cognitive benefit in MCI patients, humanin has the most compelling biological connection (discovered in AD brain tissue), and Dihexa has remarkable preclinical potency but zero human studies.

If you're caring for someone with AD or concerned about your own risk, these peptides are not yet available as treatments. Clinical trials remain the appropriate path to access experimental therapies. Talk to a neurologist about eligibility for ongoing studies. For related reading, see our guides on peptides for memory and age-related cognitive decline and peptides for depression.

FAQ

Did semaglutide work for Alzheimer's disease?

No. The Phase 3 EVOKE and EVOKE+ trials tested oral semaglutide in 3,808 patients with early-stage AD over 104 weeks. The drug did not slow cognitive decline compared to placebo, despite producing small (10%) reductions in neuroinflammatory biomarkers. Novo Nordisk has discontinued semaglutide development for Alzheimer's.

What is the most promising peptide for Alzheimer's research?

No single peptide stands out as a clear frontrunner. Humanin has the strongest biological connection to AD (discovered in AD brain tissue, with declining levels in patients). NAP has the most advanced clinical data showing cognitive benefit in MCI. Dihexa has remarkable preclinical potency. The most promising approach may ultimately combine multiple peptide mechanisms rather than relying on any single agent.

Can GHK-Cu help prevent Alzheimer's?

GHK-Cu modulates thousands of genes related to neuronal health, inhibits HDACs with neuroprotective properties, quenches toxic lipid peroxidation products implicated in AD, and prevents copper- and zinc-induced protein aggregation. These mechanisms are relevant to AD prevention, but GHK-Cu has not been tested in AD clinical trials. Its potential remains theoretical.

Is humanin a biomarker for Alzheimer's risk?

Possibly. Humanin and MOTS-c levels decline in AD patients and with aging. Combining MDP levels with established amyloid and tau biomarkers could improve diagnostic accuracy. This biomarker application may develop faster than therapeutic use.

What role do mitochondria play in Alzheimer's disease?

Mitochondrial dysfunction is now considered a core feature of AD. Amyloid-beta accumulates within mitochondria and impairs the electron transport chain. Impaired mitophagy, excess reactive oxygen species, and reduced ATP production all weaken neurons. This is why peptides like SS-31, humanin, and MOTS-c are under investigation.

Are any peptides FDA-approved for Alzheimer's?

No. All peptides discussed in this guide remain investigational for Alzheimer's disease. The approved AD treatments are cholinesterase inhibitors, memantine, and anti-amyloid antibodies.

The Bottom Line

Alzheimer's research has entered a phase where multiple peptide-based strategies are being tested against distinct mechanisms of the disease. The semaglutide EVOKE trials didn't succeed in slowing cognitive decline, but they confirmed that metabolic and inflammatory pathways can be measured and modulated in AD patients -- data that will inform the next generation of trials.

Humanin and MOTS-c address the mitochondrial dysfunction at the root of neuronal energy failure. SS-31 protects the mitochondrial membrane where amyloid-beta does some of its worst damage. NAP stabilizes the microtubule architecture that tau pathology destroys. Dihexa promotes synaptogenesis through a pathway most AD drugs don't touch. GHK-Cu modulates gene expression at a scale that could address multiple disease mechanisms simultaneously. And BPC-157 offers broad cytoprotection through NO system regulation.

None of these are treatments today. But collectively, they represent a much wider toolkit than the amyloid-centric approach that dominated AD research for decades. The field is better for that diversity -- even when individual trials fail.

For patients and families, the practical advice hasn't changed: work with your neurologist, consider clinical trial participation, and stay informed as results emerge. The science is moving. For related reading, explore our guides on best peptides for anti-aging and longevity and peptides for TBI and concussion recovery.

References

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