Podbit · The Peter Attia Drive
Obicetrapib, a CETP inhibitor, raises ApoA-1 and generates tiny protein-rich HDL particles that can cross the blood-brain barrier. The BROADWAY trial showed movement in the right direction on phosphorylated tau, amyloid-40/42 ratios, and other Alzheimer's biomarkers — suggesting it may rescue dysfunctional APOE4 brain HDL.
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At 1:31:50 · chapter starts 1:31:00
Peter closes the pharmacology discussion with the most forward-looking topic: obicetrapib, a CETP inhibitor that inhibits the transfer of cholesterol from HDL to ApoB particles, causing HDL to enlarge and ApoA-1 to rise. The biological rationale for neuroprotection comes from genetics: people with natural CETP loss-of-function variants have lower rates of Alzheimer's disease and cognitive impairment. Pharmacologically mimicking this state could theoretically confer the same benefit [1] — Tom Dayspring "Obicetrapib, a CETP inhibitor, raises ApoA-1 and generates tiny protein-rich HDL particles that can cross the blood-brain barrier. The BROA…" 1:31:50 . Tom explains the cascade: obicetrapib enlarges HDL particles, the liver interprets the reduced free ApoA-1 as a deficiency and ramps up ApoA-1 production, and circulating ApoA-1 rises. These free ApoA-1 molecules and the tiny protein-rich HDL particles they form can cross the blood-brain barrier, fuse with brain ApoE HDL particles, and potentially convert dysfunctional APOE4 brain HDL into functional units capable of properly delivering cholesterol to neurons. The BROADWAY trial, conducted primarily for cardiovascular endpoints, measured Alzheimer's biomarkers — phosphorylated tau, amyloid-40/42 ratios, and fibrillary markers — and found movement in the right direction. New Amsterdam Pharma is now planning further trials with cognitive endpoints and possibly PET imaging. Tom and Peter are cautiously optimistic, noting that getting the timing and patient selection right — catching APOE4 carriers before irreversible pathology accumulates — will be the key challenge, citing the PREDIMED trial's early-halt success as a model for well-targeted primary prevention.
Researcher Bill Harris has concluded that an omega-3 index of 8–9% in red blood cell membranes reflects adequate omega-3 content across the body's cell membranes, though no randomized trial has proven a specific brain benefit.
People with genetic CETP loss-of-function variants have lower rates of Alzheimer's disease and cognitive impairment, providing the biological rationale for testing CETP inhibitors as a neuroprotective strategy.
AI nailed Andrew Huberman's vertigo-vs-low-blood-pressure diagnosis because that pattern has been reported millions of times. But every patient's liver is different and data on liver surgeries is scarce worldwide — making solo robot surgery dangerous. The rule is simple: data abundance means AI can help; data scarcity means keep the human in the loop.
Fei-Fei Li's father had liver surgery performed by a da Vinci robot guided by a surgeon. The result: 10 times less blood loss than a typical procedure. This isn't replacement — it's the gold standard of human-machine collaboration, where the human's judgment and the robot's precision combine.
US drug overdose deaths fell from 110,000 to roughly 70,000 — the biggest CDC-recorded single-year drop ever. Men's rates fell 27% in one year, and the steepest decline of all was among 15–24-year-olds, down 37%. The crisis narrative around young men needs to make room for signs of genuine progress.
Kessler thought his grief expertise would protect him. It didn't. When his son David died unexpectedly, he found himself on the floor — and eventually realized that acceptance alone wasn't enough. That unmet need became the sixth stage: finding meaning.
Grief isn't just death — it's any unwanted change. Kessler lectured at Coca-Cola and General Mills not because they had lots of funerals, but because change management is grief management. People who grieve well live well.
Witnessing someone's grief isn't just emotional support — it's an essential act of healing. Kessler argues grief is a severance and connection heals it. But real witnessing has two steps: seeing the pain AND affirming the person's capacity to recover.
Avoiding grief isn't free — it's exhausting. Kessler's beach ball metaphor nails it: pushing a small balloon down is easy, but holding a massive beach ball underwater takes constant, draining energy. Unattended feelings don't disappear; they just consume you.
Most people try to control their environment to avoid triggers. Kessler flips this entirely: triggers aren't problems to manage around — they're a detailed map to your pain and your healing. Every trigger points directly to what needs attention.
Running from pain doesn't leave it behind — it accelerates the chase. Whatever we run from pursues us, and whatever we face transforms us. Both Kessler and Lewis Howes testify to knowing both roads firsthand.
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