Neuroscience is rapidly advancing disease-modifying therapies (DMTs) for Alzheimer's and Parkinson's. New treatments like Lecanemab and Donanemab for AD, and alpha-synuclein/LRRK2 inhibitors for PD, alongside gene and oligonucleotide therapies, are transforming the fight against neurodegeneration, moving beyond symptomatic relief to target underlying pathology.

The global burden of neurodegenerative conditions such as Alzheimer's disease (AD) and Parkinson's disease (PD) is escalating rapidly with the development of aging populations. Despite the availability of symptomatic treatments, the ultimate goal of neuroscience research has been to design disease-modifying therapies (DMTs)—drugs that can decrease, reverse, or prevent the underlying pathological processes leading to neuronal loss and cumulative degeneration.

Alzheimer's Disease: Overturning the Amyloid Paradigm and Beyond

Alzheimer's disease research has long focused on the "amyloid hypothesis"—that amyloid-beta plaque deposition in the brain is central to the disorder. Although this hypothesis has faced several setbacks, recent successes with amyloid-targeting monoclonal antibodies (mAbs) have partially validated its premise, at least for mild-stage AD.

Amyloid-Targeting Monoclonal Antibodies

  • Lecanemab: Granted full FDA approval in July 2023, Lecanemab demonstrated a 27% reduction in cognitive decline (measured by the Clinical Dementia Rating-Sum of Boxes, CDR-SB) over 18 months compared to placebo in individuals with early AD. It functions by reducing amyloid plaques. Side effects, predominantly Amyloid-Related Imaging Abnormalities (ARIA), including brain edema (ARIA-E) and microhemorrhages (ARIA-H), occurred in 12.6% and 17.3% of treated participants, respectively, and were typically asymptomatic.
  • Donanemab: Following FDA approval in July 2024, Donanemab also showed a more significant retardation of clinical decline, with a 36% slowing of decline on CDR-SB at 18 months in symptomatic early AD patients. Donanemab specifically targets an N3pG-modified amyloid-beta species. ARIA cases with Donanemab were comparable to Lecanemab, with ARIA-E in 24% and ARIA-H in 19.7% of clinical trial participants.

Outside Amyloid: Tau and Neuroinflammation

While amyloid is a significant early driver, tau protein tangles are most strongly linked to the progression of dementia and neurodegeneration. Treatments targeting tau pathology, such as tau aggregation inhibitors and anti-tau mAbs, are currently in clinical development. Moreover, increasing evidence suggests that neuroinflammation—the chronic activation of the brain's immune cells (microglia and astrocytes)—is a critical driver of AD progression.

  • TREM2 Pathway Modulation: TREM2 is a microglial receptor that plays a central role in clearing disease-causing proteins and regulating inflammation. Although a recent Phase II trial (INVOKE-2) of the TREM2-targeting antibody AL002 reported an adverse effect, research continues to investigate how to optimally modulate TREM2 for therapeutic benefit.

Parkinson's Disease: Targeting Alpha-Synuclein and Genetic Drivers

Parkinson's disease is characterized by the deposition of aggregated, misfolded alpha-synuclein (α-syn) protein as Lewy bodies and the progressive loss of dopamine-producing neurons. The majority of DMTs for PD are primarily aimed at preventing α-syn aggregation, facilitating its clearance, or specifically targeting genetic mutations.

Alpha-Synuclein Inhibitors

Targeting α-syn aggregation or promoting its clearance is a major area of research interest:

  • Monoclonal antibodies like Prasinezumab (Roche/Prothena) and Cinpanemab (Biogen) focus on removing α-syn aggregates. Initial trials were not entirely reassuring, but the process is still being refined, with more than 22 α-synuclein inhibitor drugs in preclinical and clinical development stages as of February 2025, according to DelveInsight.
  • Small molecules such as Buntanetap (Annovis Bio) are also being investigated for their potential to disperse multiple neurotoxic proteins, including α-synuclein and tau.

Targeting Genetic Mutations (e.g., LRRK2)

Approximately 10-15% of PD cases have a genetic etiology. The Leucine-Rich Repeat Kinase 2 (LRRK2) gene mutation is a significant genetic risk factor.

  • LRRK2 Inhibitors: Blocking LRRK2 protein hyperactivity represents a promising therapeutic direction. Denali and Biogen have LRRK2 inhibitors, such as BIIB122, in advanced Phase II (LUMA) and Phase III (LIGHTHOUSE) trials. The LUMA trial includes 640 early-stage PD patients (with and without the LRRK2 mutation) to assess the rate of disease worsening.

Additional New Therapeutic Modalities

Beyond disease-specific targets, several other novel therapeutic modalities are being explored for both AD and PD:

  • Gene Therapy: This approach aims to introduce genetic material into neurons to correct pathogenic mutations or introduce genes that code for therapeutic proteins (e.g., neurotrophic factors such as GDNF for PD). Development has been slow due to challenges in delivery (e.g., blood-brain barrier penetration) and potential off-target toxicity. However, improved viral vectors (i.e., AAVs) and delivery methods are now offering renewed hope. Well over 100 gene therapy trials have been initiated for various neurological disorders, including AD and PD.
  • Oligonucleotide Therapies (ASOs and siRNAs): These utilize short synthetic DNA or RNA strands that selectively repress or regulate gene expression to reduce levels of disease-provoking proteins. ASOs show promise in Huntington's disease and ALS. For AD and PD, ASOs are under investigation to target tau, α-synuclein, and other genetic risk genes. Intrathecal (spinal fluid) delivery is an option, despite ongoing difficulties in direct brain delivery.
  • Neuroinflammation Modulators: Recognizing neuroinflammation as a common driver, medications that modulate microglial function and inhibit chronic neuroinflammation are in development. These range from small molecules to biologics targeting specific inflammatory pathways.

The treatment paradigm for neurodegenerative diseases is undeniably being transformed. The success with amyloid-targeting therapeutics in Alzheimer's has infused new vitality and enthusiasm for tackling other complex mechanisms. These ongoing advancements offer significant hope for patients and families affected by these debilitating conditions.