Thyroid Hormones, Genes and APOE4

How DIO1 and DIO2 SNPs can quietly sabotage T4→T3 conversion, cognitive health, and sleep

Most people assume that thyroid issues—especially hypothyroidism—are as simple as taking a daily pill and getting on with life. I wish that had been true for me. It wasn’t. I learned this the hard way.

Thirty-five years ago, I was diagnosed with Hashimoto’s Thyroiditis. The next decade was the most miserable period of my life. I was building a career, raising four children, and burning the candle at both ends. I battled intense anxiety, waves of physical symptoms, aches and pains, dry skin, brain fog, hair loss, brittle nails, constipation, poor sleep, and mood swings…to name just a few.

Fast forward to New Year’s Eve, 2000. I had just received the results of a fine-needle biopsy for a nodule on my right thyroid lobe. The letter from my endocrinologist said the biopsy was “inconclusive”…possible papillary thyroid cancer…and that surgery was recommended. Not exactly the way you want to ring in the 21st century.

Six weeks after surgery (the nodule was benign), I woke up in the middle of the night with the sensation of a frog leaping around in my chest. The next day my doctor confirmed new-onset atrial fibrillation. A same-day referral to a cardiologist ended with a beta blocker and blood thinner prescription, and the warning that I might need to take these for life. Diagnosis: “Lone Atrial Fibrillation,” meaning no known cause. I had absolutely no doubt it was tied to my thyroid lobectomy and thyroid status. My cardiologist vehemently disagreed.

The minute I arrived home, I searched for a functional medicine doctor. Until I could see her, I took a daily aspirin to reduce clot risk. When I told her I was on Synthroid (T4-only medication), she immediately switched me to NDT—natural desiccated thyroid, which contains both T4 and active T3. Within two weeks, my Afib episodes disappeared. They never returned.

This was my first lesson that taking T4 alone (an inert storage hormone until it’s converted into T3) doesn’t guarantee your body will convert it into the active hormone your brain actually needs: T3 and it was also my introduction to functional medicine….aimed at fixing problems instead of patching them. T4/T3 a bit like having a box of spaghetti in the cupboard (T4) which are unusable until they’re cooked (i.e. converted to T3).

Today I want to shine a light on the genetic variants that determine how efficiently you convert T4 to T3—and why this matters profoundly for anyone, but especially for those of us with APOE4. These genes are a reason we often see clusters of thyroid dysfunction within families and even multiple generations.

If you aren’t converting well, your labs may look “normal” while your brain, mood, energy, sleep, and metabolism pay the price.

The Two Genes That Control T4 → T3 Conversion

Two deiodinase enzymes activate thyroid hormone:

1. DIO1 — converts T4 → T3 in the liver, kidneys, and thyroid

2. DIO2 — converts T4 → T3 inside the cells, especially in the brain

Think of them as the body’s hormone-processing plant.

If you have variants in either of these genes, you may have plenty of circulating T4 but still experience:

• Low intracellular T3

• Low brain T3

• High reverse T3

• Anxiety

• Brain fog

• Depression

• Poor sleep

• Feeling hypothyroid despite normal labs

• Needing T3 (Cytomel) to feel normal

DIO2 rs225014 (Thr92Ala): The Game-Changer for APOE4

Risk allele: A

• CA = moderate reduction

• AA = most impaired

This variant:

• Reduces T4→T3 conversion inside the brain

• Is linked to depression, cognitive slowing, and memory issues

• Predicts poor response to T4-only therapy

• Strongly predicts who thrives on combination therapy (T4 + T3)

For APOE4s—who already have:

• reduced brain glucose metabolism

• higher neuroinflammation

• greater mitochondrial strain

—adding low brain T3 on top of that is a perfect storm.

If a tiny bit of Cytomel feels transformative, this SNP is often the reason.

DIO1: Lower T3, Higher Reverse T3

Key SNP: DIO1 rs2235544
Risk allele: A

Effects:

• Lower T3

• Higher reverse T3

• Sluggish peripheral conversion

• Difficulty clearing excess T4

This explains why many APOE4s struggle on:

• high-dose T4

• T4-only therapy

• generic levothyroxine

• slow-titration approaches

Why APOE4 Brains Are Especially Sensitive to Low T3

This is the part an endocrinologist rarely discusses—yet it’s critical.

APOE4 brains naturally have:

• reduced glucose uptake

• increased oxidative stress

• higher neuroinflammation

• impaired lipid transport

• greater mitochondrial burden

T3 is the hormone that:

• boosts mitochondrial energy

• supports synaptic formation

• regulates myelination

• enhances memory and mood

• increases neuroplasticity

• modulates inflammation

• supports temperature and metabolism

If your brain can’t convert T4 to T3 efficiently?

Cognition suffers silently—even when labs look perfect.

For an APOE4 carrier, this is the last thing we need.

The Thyroid Pattern: A Signature Profile

Across the thyroid dysfunction community, we see the same story:

• Normal TSH

• Normal T4

• Low-normal T3

• Ongoing symptoms

• Dramatic improvement with a small dose of T3

Endocrinologists often dismiss this as psychological.
Mine did too—25 years ago.

It wasn’t psychological.
It was genetics + brain energy biology.

Common symptoms when DIO1/DIO2 are impaired:

• Waking at 2–3 AM (very typical)

• Palpitations from low intracellular T3

• Cold intolerance

• Anxiety

• Slow gut motility

• Poor exercise tolerance

• Low deep sleep

• Needing T3 at bedtime to sleep (extremely common in DIO2 variants)

Does this sound familiar?
It’s almost a clinical fingerprint.

Why This Matters for Alzheimer’s Prevention

For APOE4 carriers, thyroid optimization is brain optimization.

T3 supports:

• neuronal energy

• cognition and memory

• mood

• amyloid clearance

• synaptic repair

• mitochondrial efficiency

• BDNF

• microglial function

Low T3 is not just a thyroid issue—it is a brain energy crisis.

And conversion naturally worsens with age.

Important SNPs to Know

DIO2 rs225014 (Thr92Ala) * the big one!
Risk allele: C (or G, depending on the lab report)
TC (Thr/Ala) = moderate reduction
CC (Ala/Ala) = most impaired

On most consumer reports, T = normal and C = risk at rs225014.

DIO2 rs12885300
Risk allele: C (or G)

DIO1 rs2235544
Risk allele: T (or A)

DIO1 rs11206244
Risk allele: T (or A)

Any of these—especially DIO2 variants—can make T4-only therapy ineffective.

What APOE4s Should Consider

1. Check your genetics

If you have your DNA data, check your genetics!

2. If you have symptoms + a DIO2 variant → consider combination therapy

Many APOE4s thrive on:

• T4 + low-dose T3

• NP Thyroid + Cytomel

• Time-released T3

• Split dosing

• Bedtime T3 for sleep regulation

3. Watch reverse T3

High rT3 = impaired conversion.

4. Track your deep sleep

Low T3 often appears as:

• Low deep and REM

• Middle-of-the-night waking

5. Avoid high-dose T4 if DIO1/DIO2 are impaired

Increasing T4 can worsen symptoms.

6. Work with someone who understands genetics

Most endocrinologists do not.
Good functional providers often do.

Final Thoughts

For APOE4 carriers, optimal thyroid function is non-negotiable.
If you don’t convert T4 into T3 efficiently—due to genetics, age, inflammation, or stress—your brain feels it long before your labs do.

Understanding your DIO1 and DIO2 status can explain years or decades of mysterious symptoms and transform:

• cognition

• sleep

• energy

• mood

• metabolism

• long-term brain resilience

This is one of the most overlooked tools in the APOE4 prevention toolkit.

My own thyroid has been optimized for years now.
I owe that to the late Dr. Christine Gustafson in Alpharetta, GA—a compassionate, brilliant functional medicine trailblazer who gave me my life back. She’s been gone for over 13 years, but I think of her often and remain forever grateful.

Today, I take enough NDT to keep my T4 in range—but at the very low end.
Keeping T4 low also keeps reverse T3 low, since rT3 is made from excess T4.
I take Cytomel (T3), splitting my dose: T3 in the morning and my NDT (which also contains some T3) at bedtime.

For me—and for many APOE4s—this has been life-changing.