ProdromeNeuro™
ProdromeNeuro™ is a precision-targeted plasmalogen precursor compound designed to investigate the restoration of deficient plasmalogen levels in the brain and body. It represents the culmination of over 20 years of research into the biochemical mechanisms underlying neurodegenerative diseases, particularly Alzheimer’s disease and dementia.
At its core, ProdromeNeuro is a 1-O-alkyl-2-acyl-glycerol (AAG) plasmalogen precursor containing docosahexaenoic acid (DHA) at the sn-2 position. This sophisticated molecular design allows it to directly enter the natural plasmalogen biosynthesis pathway and precisely target and elevate specific plasmalogens that are critically deficient in neurodegenerative conditions.
When peroxisomal function declines, plasmalogen biosynthesis is compromised at the source
Plasmalogen synthesis begins in peroxisomes – organelles whose function declines naturally with age. After 60, the brain and liver progressively lose their ability to produce adequate levels. Blood plasmalogen deficiency at this stage predicts low brain plasmalogens, lower cognitive scores, and higher neurofibrillary tangle density in post-mortem confirmed Alzheimer’s brains.
In Alzheimer’s disease, peroxisomal function is further impaired, meaning the biosynthetic pathway itself is compromised. Restoring plasmalogen levels requires a precursor molecule that enters the pathway downstream of the damaged peroxisomal steps. ProdromeNeuro™ is designed to do exactly that: bypass peroxisomal synthesis and deliver precursors directly into the body’s phospholipid remodeling pathway.
ProdromeNeuro™ is designed to address the four functions plasmalogens perform in neurons:
Research suggests that when plasmalogen levels decline, these protective and functional systems may become compromised.
From discovery to ProdromeNeuro™
ProdromeNeuro™ is the result of over two decades of plasmalogen research, each generation of molecules building on the science of the previous generation.
2005-2007 — Landmark publication
Plasmalogen deficiency as a causative factor in Alzheimer’s disease published.
Dr. Dayan Goodenowe and colleagues published landmark research demonstrating that circulating DHA-plasmalogen levels were significantly decreased in Alzheimer’s patients at all stages of dementia, and that this decrease correlated with dementia severity, and Alzheimer’s pathology. Blood plasmalogen levels were found to decline years before clinical symptoms appear. These findings were subsequently replicated by independent researchers in multiple countries.
2008 — Proof of Concept
PPI-1011: oral bioavailability of a plasmalogen precursor established.
PPI-1011 was engineered – an alkyl-diacyl glycerol with palmitic acid at sn-1, DHA at sn-2, and lipoic acid at sn-3. The lipoic acid modification enabled a composition-of-matter patent. Animal studies confirmed absorption, bioconversion to target DHA-plasmalogens, and crossing of both the blood-retinal and blood-brain barriers. The central pharmacokinetic question was answered. But PPI-1011 covered only C16 precursors and carried formulation constraints from the patent modification.
2019 — Complete Redesign
ProdromeNeuro: naturally occurring precursors, without compromise.
The entire PPI-1011 series was redesigned using naturally occurring precursors, analogs of those found in breast milk and shark liver oil, sourced from all-vegan materials. No lipoic acid modification required, eliminating the stabilizer, increasing the dose ceiling, and eliminating the carrier oil.
The result: a pure oil containing both C16 and C18 precursors, with twice the DHA content of PPI-1011.
ProdromeNeuro vs. PPI-1011: what changed and why
PPI-1011 answered the central question: can an oral plasmalogen precursor be absorbed, converted to target plasmalogens, and cross the blood-brain barrier? It could. ProdromeNeuro™ is built on that established answer – with broader plasmalogen coverage, twice the DHA, and none of the formulation constraints the original molecule required.
Note on PPI-1011: PPI-1011’s lipoic acid modification, thioglycerol stabilizer, and C16-only backbone were engineering constraints imposed by the patent strategy, not therapeutic choices. ProdromeNeuro™ eliminates all three.
How ProdromeNeuro™ Works
ProdromeNeuro™ delivers plasmalogen precursors that bypass the impaired peroxisomal steps of biosynthesis, entering the phospholipid remodeling pathway directly.
ProdromeNeuro is formulated as a pure oil and designed for stability in the gastrointestinal tract. The 1-alkyl ether bond is acid-stable and not acid-sensitive, ensuring the molecule survives gastric acid and is absorbed intact.
Upon absorption, the sn-3 position is cleaved, releasing free DHA into the bloodstream — an additional systemic benefit. The remaining 1-O-alkyl-2-acyl glycerol structure enters the natural plasmalogen biosynthesis pathway directly.
The molecule is converted to the target plasmalogens: specifically 16:0/22:6 and 18:0/22:6 plasmalenylethanolamine (PlsEtn) — the exact species deficient in Alzheimer’s disease. ProdromeNeuro™ provides both C16 and C18 precursors, covering the full spectrum of brain plasmalogens.
Plasmalogens are understood to play roles in protection against oxidative stress, membrane fluidity and fusion, membrane cholesterol regulation, and neurotransmitter release. In our proof-of-concept study, improvements in catalase, superoxide dismutase, and malondialdehyde levels were observed.
The Santa Monica Clinical Trial
In collaboration with Dr. Sheldon Jordan’s team in Santa Monica, California, a comprehensive investigational clinical trial was conducted to evaluate ProdromeNeuro™ in 22 cognitively impaired persons. The study was partially funded by the Alzheimer’s Association and presented at the 2022 International Alzheimer’s Association Conference in Denver.
KEY CLINICAL FINDINGS
DETAILED RESULTS
Pharmacokinetic Results (Blood Plasmalogen Levels)
- DHA plasmalogen levels increased significantly and dose-dependently with ProdromeNeuro supplementation
- Over two-fold elevation in DHA plasmalogen concentration relative to baseline was observed
- Both absolute and relative DHA plasmalogen levels increased, indicating stronger membrane concentration and enhanced cellular penetration capability
- Benefits were observed in both participants with low baseline plasmalogen levels and those with higher baseline levels
Oxidative Stress Biomarker Results
- Malondialdehyde (MDA) levels: Robust decrease observed, with preferential benefit in those with high baseline MDA levels
- Catalase activity: Normalized in persons with low baseline catalase activity, confirming reduced peroxide load
- Superoxide dismutase (SOD): Statistically significant recovery in persons with low baseline SOD levels
- C-reactive protein (CRP): All four participants with high baseline CRP showed improvement, with half reducing to very low levels
- Higher DHA plasmalogen levels were positively associated with catalase activity and negatively associated with MDA levels
Cognitive Results
- 9 participants (41%) showed significant cognitive improvement
- 9 participants (41%) remained cognitively stable
- 4 participants (18%) showed cognitive decline
- Cognitive improvements were statistically significant versus random outcome (p<0.05)
- Notably: 62% of participants with CDR scores of 1 or 2 (definitive dementia) showed improvements
- No relationship between baseline DHA plasmalogen levels and response, indicating broad applicability
Mobility Results
- 12 participants (55%) showed mobility improvement
- 5 participants (23%) remained stable
- 4 participants (18%) showed decline
- Mobility improvements were highly statistically significant versus random outcome (p<0.001)
Safety and Tolerability
- ProdromeNeuro was well tolerated at all dosages tested
- No adverse reactions were observed, even at the highest dose of 3,600 mg/day
- Excellent safety profile confirmed across diverse age range and cognitive impairment levels
Development Timeline
ProdromeNeuro™ is the lead investigational candidate being developed by Dr. Goodenowe Dietary Therapeutics, with the goal of pursuing FDA New Drug Approval.
Regulatory disclosure: ProdromeNeuro™ is an investigational compound and has not been approved by the U.S. Food and Drug Administration or any other regulatory authority. No claims regarding safety or efficacy are made outside of published research findings. ProdromeNeuro™ is not currently available as a commercial therapeutic.
References
- Goodenowe DB, Haroon J, Kling MA, Zielinski M, Mahdavi K, Habelhah B, Shtilkind L, Jordan S. Targeted Plasmalogen Supplementation: Effects on Blood Plasmalogens, Oxidative Stress Biomarkers, Cognition, and Mobility in Cognitively Impaired Persons. Front Cell Dev Biol. 2022 Jul 6;10:864842. doi: 10.3389/fcell.2022.864842
- Goodenowe DB. Breaking Alzheimer’s: A 15-Year Crusade to Expose the Cause and Deliver the Cure. Prodrome Sciences, 2021.
- Goodenowe DB. Compositions and methods for the treatment and prevention of disease. US Patent 9,334,235 B2.
- Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, Ahiahonu PW, Heath D, Yamazaki Y, Flax J, Krenitsky KF, Sparks DL, Lerner A, Friedland RP, Kudo T, Kamino K, Morihara T, Takeda M, Wood PL. Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer’s disease and dementia. J Lipid Res. 2007 Nov;48(11):2485-98.
- 5.Dorninger F, Forss-Petter S, Berger J. From Peroxisomal Disorders to Common Neurodegenerative Diseases – the Role of Ether Phospholipids in the Nervous System. FEBS Lett. 2017 Sep;591(18):2761-2788.
- 6.Goodenowe DB. Methods for the diagnosis of dementia and dementia-related conditions. US Patent Application.
- 7.Goodenowe DB. Plasmalogen deficiency as a causal mechanism for diseases of aging. US Patent 9,034,923 B2.