Ep155: Valerie Daggett on Early Detection, and Treatment, of Alzheimer's

Episode Summary

Executive Summary: Valerie Daggett traces the scientific path that led from protein-folding research to AltPep’s Alzheimer’s and Parkinson’s programs: computational discovery of a toxic “alpha sheet” structure in amyloid oligomers, validation with biophysics, and translation into a blood/CSF diagnostic plus a therapeutic peptide that binds and helps clear toxic species early in disease.

Main Topics: Daggett’s scientific origins and path to protein folding (Priority: 5/5): She grew up in Portland, followed a math-first path through Reed, UCSF, Stanford postdoc work, and became drawn to biochemistry because it let her see mechanisms rather than just outcomes. Computational biology as a tool to map protein misfolding (Priority: 5/5): Daggett argues that simulations reveal the intermediate steps of folding/unfolding that experiments alone often miss, and that these methods became central to understanding disease-associated misfolding. Discovery and validation of alpha sheet (Priority: 5/5): Her group found that multiple amyloidogenic proteins funnel through a novel secondary structure, alpha sheet, which appears associated with toxic oligomers and can be used as a biomarker/target. From academic discovery to AltPep formation (Priority: 4/5): The move to bioengineering enabled in-house wet-lab work, peptide synthesis, structural validation, and a translation path that academia alone could not support at the necessary speed and scale. SOBA-AD diagnostic and retrospective clinical validation (Priority: 5/5): AltPep’s assay detected toxic oligomers in CSF and plasma, including in samples from people who later converted to cognitive impairment, supporting early diagnosis before symptoms. Therapeutic strategy and disease-stage focus (Priority: 4/5): The company’s peptide therapeutics are designed to bind toxic oligomers, stimulate clearance, and intervene earlier than plaque-focused approaches; clinical trials will likely target mild cognitive impairment first. Company-building, FDA path, and expansion beyond Alzheimer’s (Priority: 4/5): Daggett describes fundraising, regulatory strategy, and a platform approach extending to Parkinson’s and other amyloid diseases, with support from investors, UW, and clinical collaborators.

Key Arguments: Protein misfolding is not just a structural curiosity; it is a mechanistic driver of many diseases, especially amyloid disorders. Computational simulation can discover intermediates in folding/unfolding that are hard or impossible to infer directly from experiments. Alpha sheet is a non-native structure associated with toxic amyloid oligomers, not with normal protein forms, making it valuable for both detection and targeting. The industry’s historical focus on plaques missed the earlier toxic oligomer stage that likely initiates disease. A combined diagnostic-therapeutic platform is more powerful than treating symptoms late: detect early, then clear toxic species before irreversible neurodegeneration. Academic translation alone is too slow and under-resourced for this problem; a company can move faster, fund development, and reach patients. Biomarkers now make Alzheimer’s trials more tractable because waiting 20 years for clinical endpoints is impractical. The same conceptual platform can be adapted to Parkinson’s and other amyloid diseases by changing the target peptide and assay conditions.

Data Points: Series B financing: $53 million - AltPep raised this amount in June 2023, with investors including Section 32, Alexandria Real Estate Equities, and Eli Lilly. Years in faculty role: 30 years - Daggett said she has been on the University of Washington faculty for three decades. Graduation year: 1979 - She graduated high school in 1979 after accelerated math training. Approximate time to scientific inflection: ~15 years ago - She described a major expansion in protein-folding and amyloid work around that time. Number of amyloid diseases: Over 50 - Daggett said more than 50 diseases are caused by proteins/peptides that undergo similar misfolding pathways. Sample set size: 379 - The retrospective clinical study analyzed 379 samples. Diagnostic performance: 99% sensitivity and 99% specificity - She cited the PNAS-associated results for the assay detecting toxic oligomers. False positives that later converted: 12 of 13 - Among apparent false positives in controls, 12 later progressed to mild cognitive impairment. Banked plasma lag time: Up to 20 years - The assay detected toxic oligomers in plasma samples banked long before symptoms fully emerged. FDA product status: Breakthrough status planned - Daggett said AltPep hopes to obtain FDA breakthrough status for the Alzheimer’s diagnostic. Pipeline milestone: Clinical entry expected this year - She said the Alzheimer’s therapeutic, alt 100, was expected to enter the clinic after GMP and GLP/IND-enabling work.

Pivotal Quotes: "What if you could screen everyone at age 40 with a simple blood test that could detect trace amounts of the toxic forms of amyloid beta protein..." — Luke Timmerman: Opening framing of AltPep’s diagnostic/therapeutic concept and why the company is notable. "We discovered a new secondary structure, which we call alpha sheet." — Valerie Daggett: Explaining the computational and structural finding at the center of AltPep’s platform. "It takes a village." — Valerie Daggett: Describing the collaborative ecosystem needed to translate academic discovery into a company and clinical program.

Implications: If validated broadly, AltPep could shift Alzheimer’s care from late-stage symptom management to early detection and prevention, and create a platform for other amyloid diseases. It also signals that biomarker-enabled trials and academic founders can accelerate translational biotech.