What’s Next in Neurodegeneration?

Photo by Milad Fakurian on Unsplash

TL;DR

• With an aging global population, the prevalence of Alzheimer’s and Parkinson’s is rising.

• The financial burden on US healthcare systems today is $200 billion, estimated to exceed $1 trillion by 2060.

• However, both diseases lack curative options or truly disease-modifying therapies.

• This is largely driven by limited disease understanding: cause vs. correlation.

• Initial excitement on targeting toxic protein aggregates did not lead to expected clinical success.

• The next breakthrough will likely come from addressing truly causative pathways as upstream as possible, early before irreversible damage is done, combined with early disease detection catching the patient early before full blown disease onset.

• Today, more than 75% of Alzheimer’s treatments in the pipeline are positioned as potentially disease-modifying.

What are Neurodegenerative Diseases?

Neurodegenerative diseases impact all age groups, from childhood leukodystrophies to age-related conditions like Alzheimer’s (AD), Parkinson’s (PD), and macular degeneration (AMD). Neurodegenerative diseases are incurable and often arise from complex genetic and environmental interactions. While current treatments manage symptoms, none halt disease progression.

Ageing Population, Increase in Patient Numbers & Costs

With an aging global population, the prevalence of Alzheimer’s and Parkinson’s is rising, placing immense pressure on healthcare systems. Alzheimer’s will impact about 20% of Americans aged 65+ by 2050, while Parkinson’s cases have more than doubled since the 1990s, highlighting the urgent need for innovative treatments. Recent estimates have reported the financial burden to be around $200 billion for the US healthcare system alone, expected to increase to $1.4 trillion by 2060.

Complex Multiple Drivers of Disease

Research into Alzheimer's and Parkinson’s reveals complex, multifactorial disease mechanisms. These diverse origins suggest that targeting a single pathway might not be sufficient to get to clinically relevant outcomes. See below for an overview of molecular pathways involved in pathogenesis.

A Timeline of Progress in Neurodegenerative Therapeutics

Our understanding of neurodegenerative disorders has come a long way, from pure symptom management to first small successes in disease modification.

How Do We Treat Neurodegeneration Today?

Nevertheless, due to the lack of disease understanding, current treatments still primarily manage symptoms, without truly game-changers in disease-modifying options.

Novel Approaches: Next-Gen Breakthrough in the Pipeline?

Scraping through the pipelines of pharma and biotech players in the neurodegeneration space shows quite some activity with several late-stage assets. Below, we move through the low-hanging fruits of toxic aggregates and synaptic protection, towards riskier but potentially curable approaches as stem cell therapies for Parkinson’s.

The Low-Hanging Fruit: Next-Gen of Protein-Aggregation

Amyloid antibodies saw modest success, but novel approaches focus on toxic Aβ oligomers (e.g., Alzheon’s ALZ-801, Phase 3) and tau aggregation (J&J’s Posdinemab, Phase 2). In Parkinson’s, Roche’s Prasinezumab (Phase 2) leads alpha-synuclein targeting, though efficacy concerns persist. The question remains: can these strategies meaningfully slow disease progression?

Synaptic Protection & Repair: Next-Gen Symptom Modifiers

Cholinergic and dopaminergic system-targeting drugs are evolving. Ladostigil (Phase 2) and AlzeCure’s ACD856 (Phase 1) aim to enhance cognition in Alzheimer’s. In Parkinson’s, Cerevance’s Solengepras and AbbVie’s Tavapadon (Phase 3, positive data) may improve disease progression, but they remain symptomatic rather than curative.

Neuroinflammation: A Key Driver, but How Much Impact?

Late-stage assets targeting brain inflammation (BioVie’s NE3107, AB Science’s Masitinib, both Phase 3) show promise in slowing cognitive decline, with Sargramostim (Phase 2) focusing on microglial repair. While inflammation is a major disease driver, early data suggests only some smaller benefits over existing therapies.

Mitochondrial & Lysosomal Function: Stabilizing Cellular Health

Targeting energy production and waste clearance is gaining traction. Biogen’s BIIB122 (Phase 2) and early-stage drugs like AbbVie’s ABBV-1008 and Mission Tx’s MTX325 suggest potential. While these strategies may slow cellular dysfunction, the challenge is addressing disease progression at its core.

Cell & Gene Therapies: Restorative Potential, But Still Early

Gene therapies focus on rare mutations (Lexeo Tx’s LX1001, Biogen’s BIIB080, Prevail’s PR001), but limitations remain in regenerating degenerated neurons. While cell therapies in Alzheimer’s are still very early, stem cell-based approaches in Parkinson’s (BlueRock’s Bemdaneprocel, Phase 3; Aspen’s ANPD001, Phase 1/2) aim to replace lost neurons. These could be the first curative therapies, but challenges remain in requiring transplantation of cells into the brain.

Looking Ahead: What Will Truly Move the Needle?

The field is shifting beyond traditional targets, with major efforts in neuroinflammation, mitochondrial health, and gene therapy. The key to real breakthroughs lies in targeting upstream disease mechanisms, but a truly game-changing therapy is yet to emerge.

Key Investment Trends in Alzheimer’s & Parkinson’s

Increased Funding for Early Diagnostics: Investors are backing AI-driven and biomarker-based diagnostics for early detection, which is key in neurodegeneration.

Key Deals:

• RetiSpec ($10M Series A, led by iGan Partners, with Eli Lilly participation) – AI-driven retinal imaging for Alzheimer’s.

• BeauBrain Healthcare ($3M Series A, led by Lotte Ventures) – ATN biomarker-based Alzheimer’s detection.

• ESP Diagnostics (£1M Pre-Seed) – Liquid biopsy for Parkinson’s and Lewy Body Dementia.

Strong Interest in Gene Therapies: Investors are increasingly funding gene therapy approaches, including antisense oligos.

Key Deals:

• Trace Neuroscience ($101M Series A, led by Third Rock Ventures) – Antisense oligonucleotide therapy targeting UNC13A in ALS and Alzheimer’s.

• Celosia Therapeutics ($16.75M Series A, led by Uniseed) – Gene therapy targeting TDP-43 in ALS.

• Amlogenyx ($14M Seed, led by GordonMD Global Investments) – Gene therapy targeting amyloid-beta plaques in Alzheimer’s.

Neuromodulation: Non-invasive neuromodulation approaches are attracting investment.

Key Deals:

• Grey Matter Neurosciences ($14M Seed, led by Wittington Ventures) – Focused ultrasound therapy for Alzheimer’s.

• Nuuron (€3.5M Seed, led by High-Tech Gründerfonds) – Digital-photonic stimulation for Alzheimer’s therapy.

Protein Clearance Strategies: Companies are focusing on protein degradation and neuroprotection mechanisms.

Key Deals:

• Asceneuron ($100M Series C, led by Novo Holdings) – OGA inhibitor ASN51 for tau protein clearance in Alzheimer’s.

• Vanqua Bio ($45M Series B extension) – GCase activator for Parkinson’s.

• Booster Therapeutics ($15M Seed, led by Apollo Health Ventures & Novo Holdings) – Small molecules activating proteasomes for neurodegeneration.

AI-Driven Care & Monitoring Solutions: AI-based solutions for caregiving and fall prevention are gaining traction.

Key Deals:

• SafelyYou ($43M Series C, led by Touring Capital) – AI fall detection for Alzheimer’s patients.

• Rippl ($23M Series A, led by Kin Ventures) – Virtual dementia care navigation.

• dannce.ai ($2.6M Pre-Seed, led by LDV Capital) – AI-powered 3D motor impairment tracking for Parkinson’s.

Overall, the investment landscape for Alzheimer's and Parkinson’s is shifting toward earlier diagnosis, neuromodulation, gene therapy, and AI-driven care solutions, with big-ticket Series A & C rounds showing investor confidence in potentially disease-modifying approaches. It is a challenging space, with setbacks just this week. Asceneuron halted its clinical trial for the OGA inhibitor. This comes after Biogen and Eli Lilly saw their OGA inhibitors fail recently. This highlights the challenges of identifying novel targets for Alzheimer’s and Parkinson’s. As early-stage investors, we are looking for truly causative pathways as targets, as upstream as possible, with potential to halt disease progression completely instead of minor slowing down.

Outlook: Early Detection & Intervention are the Holy Grail

The future of managing neurodegenerative disorders depends on gaining a deeper understanding of truly causative disease-drivers. Recent failures taught us that targeting toxic aggregates alone has major limitations and that we need to interfere at an earlier stage. In a nutshell, the holy grail here is i) to catch the patient as early as possible before full blown disease, and ii) to target causative upstream molecular pathways that drive disease, instead of end-stage products as protein aggregates. Therefore, combination of early detection technologies by AI-powered diagnostics and novel treatment angles through upcoming modalities might bring new hope to the field. Eventually, we might have to explore multi-target approaches, addressing several pathways combined to slow or prevent the degeneration of neurons.