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.
Self-help fails because people are sold one universal cure by the hyper-responders who had a transformative result from it. The real problem is context: every method works for the right person at the right time, which is almost never you just because the author says so.
Spencer Greenberg was once so socially anxious his heart pounded just approaching a stranger. His therapist gave him homework: go to a bar alone, talk to 5 strangers. Starting with asking for the time, he worked up to asking men for hugs — and his anxiety fell dramatically in 6 months.
A person who flies regularly but obsessively checks weather forecasts before every flight is not doing exposure therapy — they're teaching their brain that flying is only safe with the ritual. Safety behaviors prevent the brain from ever learning that the feared thing is actually fine.
The worry-time technique assigns all worries to one scheduled slot (e.g. 5 PM). Every time a worry surfaces, you write it down and ban yourself from engaging with it until that time. When 5 PM arrives, most worries feel trivial and the act of batch-worrying exposes how little it actually accomplishes.
In a randomized study of 20 habit techniques, 'habit reflection' stood out: recall a past habit you successfully built, write down what helped you succeed, then apply those same strategies to your new habit. It works because it's self-adapting — it uses whatever worked for YOU.
The tiny habits technique — always having a minimal version of your habit you can do when life gets in the way — keeps the mental machinery of habit formation from breaking. Paradoxically, people given a tiny-habit fallback option were MORE successful at the full habit, not less.
Fears and worries act like playground bullies — they want to ambush you. But when you deliberately seek them out and choose the time of engagement, they lose their power. The volitional act of starting the fight on your own terms is one of CBT's most underappreciated insights.
Most downtime defaults are things you regret immediately after — phone scrolling, binge TV. 'Glad you did it' activities meet the same need for rest but leave you feeling like you spent your time well. The switch from a bad screen to a documentary, a book, or a walk costs almost no extra effort but compounds into identity over time.
You rarely control your first reactive thought. But you can train your second thought — the response to the trigger — by asking whether your initial reaction is the most helpful one and replacing it with something equally true but more constructive. Over time, that second thought becomes automatic.
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