From Rare to Recognised: Shining a Light on Amyloidosis

At Porterhouse, we are proud to support World Amyloidosis Day.  Our article shines a light on this rare condition to help drive greater understanding, improve diagnosis, treatment, and care for those affected by the disease.

Amyloid protein is well known for its association with conditions such as Alzheimer’s and Parkinson’s disease, but systemic amyloidosis is much less recognised and receives significantly less public attention [1]. An estimated one new case occurs per 100,000 individuals globally every year, with over 10,000 patients worldwide affected by hereditary forms of the disease alone [2].

After diagnosis, patients with amyloidosis typically face a limited life expectancy of 3 to 5 years, with delays in detection and treatment contributing to a poor prognosis [2]. This highlights the urgent need for greater awareness and education. In response, World Amyloidosis Day, organised by the Amyloidosis Alliance, aims to raise awareness and improve treatment quality.

What is amyloidosis?

Amyloidosis refers to a group of heterogeneous disorders, all characterised by the deposition of amyloid [1]. Subtypes are distinguished based on the affected organs, clinical manifestations and the specific precursor protein involved [3], of which 36 have been identified [4] (Table 1). The subtypes are classified into hereditary forms (caused by inherited mutations) or acquired forms (resulting from mutations that occur during a person’s lifetime). These account for approximately 20% and 80% of global cases, respectively [2].

Table 1: Characteristics of the main amyloidosis subtypes [5]

Subtype*	Cause	Hereditary/acquired	Affected organs
Immunoglobulin light chain (AL)	Misfolding of monoclonal light chains in the bone marrow	Acquired	Heart, liver, kidneys, gastrointestinal tract and autonomic nerves
Transthyretin (ATTR)	Inheritance of atypical transthyretin proteins	Hereditary	Heart, peripheral and autonomic nerves, and eyes
Wild-type transthyretin (wtATTR)	Misfolding of transthyretin with age	Acquired	Heart

AL, amyloid light chain. ATTR, amyloid transthyretin. wtATTR, wild-type amyloid transthyretin. *This does not include all amyloidosis subtypes.

The common disease mechanism involves misfolded proteins aggregating into amyloid fibrils that deposit in the extracellular space of tissues (Figure 1). These deposits disrupt normal organ function and ultimately lead to disease [6]. For example, deposition of misfolded myocardial protein causes ventricular wall thickening in the heart, which impairs contractility and cardiac output [6]. Simultaneously, these protein deposits can directly damage nearby cells, potentially accelerating disease progression [6].

Figure 1: Protein misfolding leads to amyloid production, increasing the risk of amyloidosis

Epidemiology

Amyloidosis can affect individuals of any age and sex, but men are more frequently affected than women, and certain subtypes are more prevalent in particular populations [2]. In the USA, the Mayo Clinic reports that men represent approximately 70% of AL amyloidosis cases and 80% of ATTR amyloidosis cases [7].

The risk of developing amyloidosis increases with age owing to declining physiological resilience and impaired homeostasis [6]. Comorbidities further exacerbate this risk, depending on subtype; for example, carpal tunnel syndrome and cardiovascular disease are associated with a higher likelihood of ATTR amyloidosis [7].

Although most patients present with symptoms between 30 and 90 years of age, peak diagnosis typically occurs between 50 and 75 years of age [2]. Diagnostic delays remain a significant challenge and are a key focus of World Amyloidosis Day.

Diagnosis

Accurate diagnosis requires a multidisciplinary approach, involving both clinical and laboratory specialists [4]. Initial investigations detect pathological abnormalities in tissues and may include [6]:

• Echocardiography
• Magnetic resonance imaging (MRI)
• Blood and urine tests

Once amyloidosis is suspected, subtyping is essential to identify the precursor protein and determine the disease stage [3]. The stage of disease, measured by blood protein levels, provides a prognostic indicator, with life expectancy ranging from approximately 0.5 years in Stage 4 amyloidosis to 7.8 years in Stage 1 amyloidosis [8].

Patients with amyloidosis commonly present with [2]:

• Severe fatigue
• Unintentional, significant weight loss
• Oedema (swollen ankles, feet and legs)
• Shortness of breath

However, symptoms are non-specific and vary depending on the subtype, which complicates diagnosis (Figure 2).

Figure 2: Overview of amyloidosis symptoms

As a result, the average time to diagnosis is 4 years, during which patients typically see four different specialists [3]. This delay can limit treatment options, because some therapies may no longer be effective by the time the diagnosis is made, decreasing the likelihood of a successful outcome. Increased awareness may support advancements in amyloid-specific biomarker tests and treatments. Additionally, a better understanding of symptoms and treatment options will enable patients to seek earlier medical intervention, which will reduce diagnostic delays and improve outcomes [2].

Treatments

Amyloidosis is considered a multisystemic disease, with comprehensive treatment required to optimise outcomes [9]. Although there is no cure [5], early intervention can limit amyloid formation and accumulation, thereby reducing organ damage and alleviating symptoms [10]. Treatments vary with regard to mechanism of action and therapeutic target (Table 2).

 

Table 2: Approved amyloidosis treatments [10]

Treatment	Effect
Monoclonal antibodies	Target amyloid fibrils for degradation
Small molecule stabilisers	Bind to misfolded proteins to prevent aggregation
Proteasome targeting	Increases the clearance rate of amyloid deposits
Organ transplant	Replaces affected organs to restore function
Chemotherapy	Targets plasma cells to reduce monoclonal light chain misfolding in patients with AL amyloidosis

 

Emerging treatments

Personalised medicine

Advances in medical technology and the discovery of unique molecular targets have expanded therapeutic possibilities for patients with amyloidosis [11]. With growing emphasis on personalised care, emerging strategies aim to tailor treatments to the genetic and clinical profile of each patient [11].

Preclinical studies highlight the potential of CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) gene editing for hereditary ATTR amyloidosis [12]. This technique selectively edits the mutated TTR genes, preventing the associated transthyretin production and subsequent amyloid formation. Similarly, autologous stem cell transplants show promise in patients with AL amyloidosis [13]. In this approach, stem cells are harvested, induced to specialise into plasma cells in vitro, and then reintroduced into the patient to restore a functional cell population [14, 15].

Although these methods have shown potential in early clinical studies [13], further data and improved preclinical models are needed to confirm their long-term efficacy and safety.

Combination therapies

Combination therapies target multiple pathogenic pathways simultaneously. Ideally, treatment regimens would have multiple mechanisms of action, reducing protein production, preventing misfolding and promoting amyloid reabsorption [1]. As new therapies emerge, researchers are actively investigating potential combinations [10]. For example, in younger patients with hereditary ATTR amyloidosis, combined heart and liver transplants have shown better outcomes than heart transplantation alone [11], demonstrating the advantage of combination strategies.

Amyloidosis remains an under-diagnosed disease affecting adults, with delayed diagnosis contributing to poor outcomes. Looking ahead, there is hope in the development of more precise biomarkers for earlier detection, innovative therapies, and increased awareness to support timely diagnosis and effective treatment by healthcare professionals.

The information in this article is not intended or implied to be a substitute for professional medical advice, diagnosis or treatment. All content is for general information purposes only. Always seek the guidance of your doctor or other qualified healthcare professional with any questions you may have regarding your health or medical condition.

References

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11. GRG Health. Emerging therapies for amyloidosis: A new era of hope. Available at: https://www.grgonline.com/post/emerging-therapies-for-amyloidosis-a-new-era-of-hope. Accessed October 2025.
12. Mallus MT and Rizzello V. Treatment of amyloidosis: Present and future. Eur Heart J Suppl 2023; 25 (Suppl B): B99–B103.
13. Gillmore JD, Gane E, Taubel J et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med 2021; 385 (6): 493–502.
14. Bianchi G, Zhang Y and Comenzo RL. AL amyloidosis: Current chemotherapy and immune therapy treatment strategies: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2021; 3 (4): 467–487.
15. Roy V. Autologous stem cell transplant for AL amyloidosis. Bone Marrow Res 2012; 2012: 238961.

Author: Elizabeth Webster | Porterhouse Pathfinders Intern 2025