Melatonin, Heart Failure, and Alzheimer’s: What This Week’s Headlines Got Wrong

Headlines screamed: “Melatonin users are more likely to develop heart failure and die.”

If you take melatonin—especially if you’re an APOE4 carrier working hard to protect your brain and heart—that’s a pretty brutal thing to wake up to.

The reality? This is a single, preliminary, observational analysis, presented as a conference abstract at the American Heart Association (AHA), using electronic health-record data from >130,000 adults with chronic insomnia. It does not show that melatonin causes heart failure.

Let’s unpack why this paper is far more hype than help.

Part 1 – Why the “Melatonin = Heart Failure” Story Is So Misleading

1. It only looked at people sick enough to be prescribed melatonin

• The study used the TriNetX research network and defined “melatonin users” as insomnia patients who had at least one melatonin prescription and ≥1 year of documented use. EurekAlert

• In the U.S., millions of relatively healthy people buy melatonin over the counter and will never appear in this dataset.

• That means:

  • Users = people whose insomnia was serious enough that a clinician prescribed melatonin and documented it in the EHR.

  • “Non-users” = everyone with insomnia who didn’t have a prescription on file, including:

    • people using OTC melatonin the record never sees

    • people whose insomnia was milder

    • people whose clinicians chose other treatments

So the groups are apples vs. a fruit salad.

2. Severe insomnia and comorbidities are doing a lot of the talking

Chronic insomnia itself is a strong risk factor for cardiometabolic disease, hypertension, arrhythmias, and heart failure. People with worse insomnia, more psychiatric disease, more pain, and more cardiovascular risk are more likely to end up on prescriptions of any kind, including melatonin.

Even the AHA news release and independent cardiologists emphasized:

• This is an observational association, not proof of cause and effect.

• Residual confounding is highly likely (untreated sleep apnea, shift work, depression, polypharmacy, underlying heart disease, etc.).

In plainer language:

People whose hearts are at higher risk are also more likely to have serious sleep problems and to be given melatonin. That doesn’t mean the melatonin is what damaged the heart.

3. It’s a conference abstract with crude exposure data, not a finished, peer-reviewed trial

Important limitations that the authors and experts themselves call out:

• No dose information: we don’t know if people took 1 mg occasionally or 20 mg nightly.

• No real capture of OTC use in the “non-user” group → massive exposure misclassification.

• No granular control for:

  • sleep apnea

  • sleep duration / circadian disruption

  • shift work

  • use of other sedatives or psychiatric meds

• It’s not a randomized controlled trial and not yet peer-reviewed. It was presented as an abstract at AHA 2025 to generate hypotheses and more research, not to declare melatonin “guilty.”

So yes: interesting signal, worth following up. But absolutely not a reason to panic or throw away your melatonin bottle.

Part 2 – Why Melatonin Still Matters, Especially for APOE4 Brains and Hearts

Now, the part the headlines never mention: why melatonin is so important in the first place, particularly for APOE4 carriers.

Melatonin basics (non-nerdy version)

Melatonin is:

• Your body’s night-signal: it tells every cell, “It’s dark, it’s repair time.”

• A mitochondria-targeted antioxidant, concentrating where free-radical damage is highest.

• A regulator of blood pressure dipping, autonomic tone, and metabolic rhythms.

In APOE4 carriers, we see:

• More sleep disruption and insomnia risk.

• Evidence that circadian rhythm instability is linked to higher amyloid-β and tau levels in humans.

So, supporting healthy melatonin signaling—via light hygiene, timing, and potentially supplements—is plausibly more important, not less, in this group.

Heart & vascular angle (quickly)

Pre-clinical and early human data suggest melatonin can:

• Improve endothelial function, nitric-oxide signaling, and nighttime BP patterns.

• Reduce oxidative stress and inflammation in the heart and vasculature.

• Support mitochondrial efficiency in high-energy tissues, including heart and brain.

The new heart-failure abstract doesn’t erase decades of basic and translational work; it just reminds us we should always be thoughtful with chronic pharmacologic dosing, not that melatonin is suddenly “poison.”

Part 3 – Phase Separation 101: What It Is, and How Melatonin Fits In

What is “phase separation”?

Think of proteins in your cells like people at a party:

• Normally, they self-organize into little “conversation circles” (liquid-like droplets) where the right people can find each other and get work done.

• This liquid–liquid phase separation creates temporary “droplets” that are reversible—they form, do a job (like processing RNA or stress responses), and then dissolve.

Aberrant phase separation is what happens when:

• The room gets too hot, sticky, crowded, and smoky.

• Those flexible little circles harden into rigid clumps—like everyone freezing in awkward statues.

• In biology, that means proteins that should stay in a fluid, dynamic droplet start forming solid aggregates and fibrils.

In the brain, those pathological “hard clumps” are exactly what we see with:

• Amyloid-β plaques

• Tau tangles

• TDP-43 aggregates, etc.

Doris Loh & Russell Reiter’s work pulls this together beautifully:

• Light, water, and melatonin act together to keep proteins properly hydrated and mobile, preventing that pathological hardening process—i.e., preventing aberrant phase separation. PubMed

• Red light (around 670 nm) and melatonin both help lower “internal viscosity” and improve mitochondrial ATP, which lets cells maintain healthy protein dynamics.

That’s the new conceptual frame:

For APOE4 carriers, melatonin is far more than a sleep aid; it supports the cellular environment that keeps proteins mobile and prevents them from hardening into the aggregates associated with Alzheimer’s.

Part 4 – Melatonin, APOE4, and Alzheimer’s: What the Research Actually Shows

A large 2024 Molecular Psychiatry review called melatonin a “potential nighttime guardian against Alzheimer’s” and summarized a lot of pre-clinical and early clinical data.

1. Amyloid-β and APOE4

ApoE4 makes amyloid-β more likely to clump and form fibrils; that’s part of why APOE4 is such a strong genetic risk factor for AD. Science Direct

One classic paper showed:

• When melatonin was added to amyloid-β in the presence of ApoE4, it reversed the profibrillogenic activity—meaning it strongly blocked ApoE4’s tendency to drive amyloid into toxic fibrils.

• This effect was not just “antioxidant stuff”; it depended on melatonin’s specific structure and wasn’t reproduced by other antioxidants. Pubmed

In animal and cell models, melatonin also:

• Reduces amyloid-β production, shifting APP processing toward less toxic fragments. Brieflands

• Enhances clearance via autophagy and improved glymphatic function during deep sleep. PubMed

For APOE4 carriers, that’s not theoretical—it is directly relevant to how our genotype drives pathology.

2. Tau and neuroinflammation

Melatonin has been shown to:

• Inhibit tau hyperphosphorylation by modulating kinases like GSK3β.

• Reduce microglial activation and astrocytic reactivity in AD-like models. Frontiers

The Zhang review highlights:

• Potential melatonin effects on both amyloid and tau burdens,

• Strong antioxidant and anti-inflammatory actions,

• A circadian component—poor sleep/circadian disruption feeds back into amyloid and tau accumulation, and melatonin is a key circadian signal. PubMed

3. Phase separation in neurodegeneration

Linking back to phase separation:

• Loh & Reiter’s work in dementia and Neuro-PASC argues that loss of melatonin and ATP, especially during deep sleep, impairs brain clearance and promotes aberrant condensate hardening—turning normally reversible droplets into permanent aggregates. PubMed

• In that model, restoring robust melatonin signaling (plus light and hydration dynamics) is part of preventing proteins from crossing the line into irreversibly aggregated, neurotoxic states.

So, viewed through this lens, melatonin is:

Less “supplement for sleep” and more “physical regulator of protein behavior, energy, and detox in the aging brain.”

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Part 5 – Where This Leaves Us (Especially as APOE4s)

• The AHA abstract does not prove that melatonin causes heart failure. It’s an observational, prescription-based analysis in a high-risk, chronically sleep-disturbed population, with big limitations in exposure and confounding.

• Headlines that imply causal harm from melatonin in the general population—let alone in carefully monitored APOE4 bio-hackers—are overstating the data.

• At the same time, the study is a useful reminder that:

  • Any long-term, high-dose pharmacologic use deserves respect and monitoring.

  • The goal should never be “just knock yourself out with pills,” but restore healthy circadian rhythm and deep sleep.

For APOE4s, the deeper literature still points in the opposite direction of those scary headlines:

• Better sleep and circadian stability = less amyloid and tau over time. PMC

• Melatonin supports mitochondria, vascular health, and anti-amyloid / anti-tau mechanisms, and appears to counteract ApoE4-driven amyloid fibrillization in vitro. PubMed

• Phase-separation work suggests melatonin is one of the key players keeping proteins from “hardening” into the aggregates that define neurodegeneration. PubMed

My personal protocol includes regular nighttime melatonin (currently 10 mg), with occasional higher doses (50–100 mg) whenever I feel a cold or sniffles coming on. With frequent exposure to my young grandchildren—and the viral surprises they love to share—melatonin has reliably helped me knock “bugs” out before they take hold. The recent headline suggesting a negative link with heart failure won’t change my regular use of it.