The main cause of amyloidosis is protein misfolding. Normally, your body produces proteins that fold into precise shapes to do their jobs. In amyloidosis, certain proteins fold incorrectly, clump together into stiff fibers called amyloid fibrils, and deposit in organs and tissues where they cause damage. The specific protein that misfolds determines the type of amyloidosis you have, and each type has a different underlying trigger.
How Protein Misfolding Leads to Amyloid Deposits
Your cells have a built-in quality control system that catches and clears misfolded proteins. In amyloidosis, that system gets overwhelmed. The misfolded proteins escape, and once they’re free, they act as templates: each misfolded protein encourages more proteins to misfold in the same way. This chain reaction produces small clusters called oligomers, which grow into thread-like structures called protofilaments, and those eventually bundle into the dense, insoluble amyloid fibrils that accumulate in tissue.
What makes these fibrils so stubborn is their structure. The misfolded proteins stack together in rigid sheets stabilized by hydrogen bonds and other chemical forces. Once formed, your body has no effective way to break them down. They build up gradually in organs like the heart, kidneys, liver, or nerves, interfering with normal function over months or years.
AL Amyloidosis: Abnormal Immune Cells
AL amyloidosis (sometimes called primary amyloidosis) is one of the most commonly diagnosed forms, with a global incidence of roughly 1 in 100,000 people per year. It’s caused by a disorder in plasma cells, the immune cells in your bone marrow that produce antibodies. In AL amyloidosis, a small clone of abnormal plasma cells churns out misfolded fragments of antibodies called light chains. These light chains circulate through the bloodstream and deposit as amyloid in organs throughout the body.
The abnormal plasma cell clone in AL amyloidosis sits on a spectrum between a harmless condition called monoclonal gammopathy and a full-blown blood cancer called multiple myeloma. It typically has fewer genetic mutations and grows more slowly than myeloma, but the light chains it produces are directly toxic to tissue. Heart involvement is particularly dangerous. Patients who achieve a complete cardiac response to treatment have a five-year survival rate around 93%, nearly matching the general population. Without that response, outcomes are significantly worse, especially when heart damage is advanced.
ATTR Amyloidosis: A Transport Protein Gone Wrong
ATTR amyloidosis involves transthyretin, a protein made by the liver that carries vitamin A and thyroid hormone through the blood. There are two forms, and they have different causes.
Hereditary ATTR
Over 120 different gene mutations can cause hereditary ATTR amyloidosis. These mutations destabilize the transthyretin protein, making it more likely to break apart and misfold. The condition follows an autosomal dominant inheritance pattern, meaning you only need to inherit the gene change from one parent to be at risk. Hereditary ATTR is rare, affecting roughly 1 in 450,000 people globally, though certain populations carry specific mutations at higher rates.
Wild-Type ATTR
In wild-type ATTR, there’s no genetic mutation involved. The transthyretin protein is structurally normal but begins misfolding on its own as part of aging. This form typically affects people over 65 and primarily targets the heart. It’s more common than hereditary ATTR. A study in Tuscany found an incidence of about 1 in 37,500, and many experts believe it remains widely underdiagnosed in elderly patients with heart failure.
AA Amyloidosis: Chronic Inflammation
AA amyloidosis (sometimes called secondary amyloidosis) is triggered by long-term inflammation. When your body fights a chronic infection or autoimmune disease, the liver produces an inflammatory protein called serum amyloid A. If inflammation persists for years, this protein accumulates to levels where it begins misfolding and depositing as amyloid, most often in the kidneys.
The list of conditions that can lead to AA amyloidosis is long:
- Autoimmune diseases: rheumatoid arthritis, lupus, psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease
- Chronic infections: tuberculosis, bronchiectasis, chronic bone infections (osteomyelitis)
- Inherited inflammatory conditions: familial Mediterranean fever, cystic fibrosis
- Certain cancers: Hodgkin lymphoma, hairy cell leukemia
AA amyloidosis is the rarest systemic form, occurring in roughly 1 to 2 per million people. The key to preventing and managing it is controlling the underlying inflammatory disease.
Dialysis-Related Amyloidosis
People on long-term dialysis face a unique form of amyloidosis caused by a protein called beta-2 microglobulin. This small protein sits on the surface of most cells and is normally filtered out by the kidneys. When kidney function fails, beta-2 microglobulin accumulates in the blood because even modern dialysis machines can’t clear it efficiently. Over time, the excess protein misfolds and deposits as amyloid, typically in joints and bones, causing pain and stiffness.
Rare Hereditary Forms
Beyond transthyretin, mutations in several other genes can cause hereditary amyloidosis. These include genes responsible for producing apolipoprotein AI, gelsolin, lysozyme, cystatin C, fibrinogen, and apolipoprotein AII. Each mutation leads to a different misfolded protein and tends to affect specific organs. Like hereditary ATTR, most of these follow an autosomal dominant inheritance pattern. They are extremely rare, and diagnosis often requires specialized testing.
Localized Amyloidosis
Not all amyloidosis is systemic. In some cases, amyloid deposits form in a single organ without spreading. Localized amyloid in the airway, eye, or bladder is often caused by light chains produced locally by immune cells in that tissue, not by a bone marrow disorder. Other localized forms involve proteins produced by hormone-secreting glands or cells in the skin and heart. These tend to be less dangerous than systemic amyloidosis because they don’t affect multiple organs.
How Amyloidosis Is Confirmed
Because different types of amyloidosis require completely different treatments, identifying the exact protein involved is critical. Diagnosis starts with a tissue biopsy, which is stained with a dye called Congo red. Under polarized light, amyloid deposits stained with Congo red glow with a distinctive apple-green color. Once amyloid is confirmed, the tissue undergoes mass spectrometry, a technique that identifies the precise proteins present in the deposit. This two-step process, staining followed by protein identification, is the gold standard for diagnosis and ensures patients receive the right treatment for their specific type.