In Largest Study Yet, Hereditary Amyloidosis Reveals Its Hidden Impact on the Brain

Hereditary transthyretin amyloidosis has long been understood as a disease of the nerves and the heart. Caused by mutations in the gene encoding transthyretin, a transport protein produced mainly by the liver, the condition drives progressive damage to the peripheral nervous system and the cardiac muscle. But a growing body of evidence points to a quieter, more insidious process unfolding inside the skull, where the same misfolded protein slowly accumulates in the membranes and vessels surrounding the brain. Now, one of the largest studies of its kind has documented just how common these central nervous system complications are, and the findings suggest that as patients live longer thanks to modern therapies, brain involvement is becoming one of the defining challenges of the disease.

The new research, conducted at the Unidade Corino de Andrade in Porto, Portugal, one of the world’s principal referral centers for the condition, followed 151 patients carrying the V30M mutation, the variant responsible for the large endemic focus of the disease in northern Portugal. All participants were systematically evaluated for a spectrum of central nervous system manifestations, including transient focal neurological episodes, headaches, seizures, stroke, and symptoms of cranial nerve dysfunction. The results, published in the Journal of Neurology, reveal that nearly one in three patients had experienced transient focal neurological episodes, brief spells of cortical dysfunction that can mimic small strokes, while close to a quarter reported recurrent headaches and nearly seven percent had suffered seizures.

The mechanism behind these symptoms is a form of cerebral amyloid angiopathy specific to transthyretin. Although current disease-modifying therapies, from liver transplantation to tafamidis and gene-silencing drugs, act on the liver to suppress or stabilize the circulating form of the protein, the choroid plexus inside the brain continues to produce its own transthyretin, which is secreted directly into the cerebrospinal fluid. This intrathecal production is essentially untouched by liver-directed treatments. Over years, the protein deposits in the leptomeningeal membranes and arteries, particularly around the brainstem and spinal cord, gradually stiffening and damaging the vessels that bathe the brain’s surface.

The study’s most striking finding concerns the relationship between disease duration and brain symptoms. Transient focal neurological episodes were virtually absent in patients within their first five years of illness, but their prevalence climbed steadily with time, reaching more than seventy percent among those living with the disease for over two decades. When researchers dichotomized the cohort at fifteen years of disease duration, the difference was stark: fewer than eight percent of patients with shorter disease duration reported a history of these episodes, compared with just over half of those with longer disease. In statistical models, disease duration greater than fifteen years carried nearly a sixfold increase in the odds of having experienced such episodes, an association that remained robust after adjustment for age, sex, treatment category, and disease severity.

These episodes themselves are clinically distinctive and troubling. Most patients reported recurrent attacks, with a median of ten episodes per person, lasting around fifteen minutes. Language dysfunction was the most common manifestation, followed by sensory disturbances, and the majority of patients experienced more than one type of symptom. Crucially, most episodes involved a temporary loss of function, such as weakness or numbness, rather than positive phenomena like tingling or jerking. This makes them nearly impossible to distinguish from transient ischemic attacks on clinical grounds alone, a diagnostic dilemma the researchers emphasize repeatedly. Because recurrence is the main differentiating feature, the team advises that any first episode should prompt a full stroke work-up, including brain magnetic resonance imaging whenever feasible.

Yet the picture may differ from the cerebral amyloid angiopathy caused by amyloid-beta, the protein implicated in Alzheimer’s disease and sporadic cerebral amyloid angiopathy. In that condition, transient focal neurological episodes are strongly linked to superficial siderosis, a chronic accumulation of blood products on the brain’s surface, and to a high risk of devastating lobar hemorrhages. In transthyretin amyloidosis, neuropathological studies from Portugal have found superficial siderosis in only a small minority of cases, and brain imaging studies of patients with these episodes, including those from the present cohort, have frequently shown no hemorrhagic or ischemic lesions despite clear evidence of amyloid deposition on PET scans. This raises the possibility that the transient episodes arise from a different mechanism, perhaps cortical spreading depression or focal seizure activity, rather than from the vessel rupture seen in other amyloid conditions.

The study also broadened the recognized symptom spectrum beyond transient episodes. Nearly forty percent of patients reported symptoms attributable to cranial nerve dysfunction, most commonly reduced smell, followed by hearing loss and tinnitus. On bedside examination, objective hearing loss was detected in almost a quarter of participants and was associated with both older age and longer disease duration, findings that align with the dense amyloid deposition these patients often show around the brainstem, where cranial nerves exit. Headaches were also frequent, though the overall prevalence, including migraine-type headache, appeared similar to that of the general population. Symptomatic stroke, by contrast, was rare, occurring in only two patients, both with alternative explanations that may or may not have involved the underlying disease.

Therapeutic questions loom large over these findings. The researchers found that patients on tafamidis appeared less likely to report transient episodes in unadjusted analyses, but this association was heavily confounded by disease duration and treatment era, and it lost statistical significance after adjustment. Similarly, isolated case reports have described stabilization of central nervous system symptoms and improvement in leptomeningeal enhancement with gene-silencing therapies such as vutrisiran, despite the theoretical limitation of poor blood-brain barrier penetration. Notably, tafamidis has been detected in the cerebrospinal fluid at concentrations capable of partially stabilizing transthyretin, and higher doses approved for cardiac disease show stronger effects in laboratory assays. But no clinical trial has ever included central nervous system outcomes as endpoints, leaving the true effect of every available therapy on the brain essentially unknown.

The study also tested whether plasma neurofilament light chain, a widely used blood marker of axonal injury, could serve as a surrogate for brain involvement. The answer, at least for now, appears to be no. Baseline levels did not differ between patients with and without a history of transient episodes, and longitudinal measurements over twelve months showed no divergence in trajectory between the two groups. The researchers suggest that the substantial peripheral nerve damage characteristic of the disease may drown out any small central signal in the bloodstream, and they propose that cerebrospinal fluid neurofilament measurements might prove more informative. Alternatively, axonal injury may simply not be the central mechanism driving the brain complications.

The authors caution that their cohort consisted almost entirely of patients with early-onset V30M disease seen at a single center, and that survival bias cannot be excluded, since patients who died of catastrophic strokes would not have been recruited. Recall bias in self-reported transient symptoms is another limitation, though the researchers cross-checked patient accounts against medical records. Still, the consistency of the transient episode frequency with earlier studies lends credibility to the central conclusion: central nervous system assessment should become a routine component of follow-up care for patients with longstanding hereditary amyloidosis. As disease-modifying therapies extend survival, more patients are living long enough to enter the window in which brain involvement emerges, and the field urgently needs longitudinal studies, validated biomarkers, and clinical trials designed to answer whether current drugs can protect the brain as effectively as they protect the heart and the peripheral nerves.

Subject of Research: Central nervous system manifestations in hereditary transthyretin amyloidosis

Article Title: Central nervous system manifestations in hereditary transthyretin amyloidosis: a cross-sectional study with 151 patients

Article References: Sousa, L., Coelho, T., Fernandes, J., Cardoso, M., Alves, C., da Silva, A. M., Sousa, A. P., Pinto, M. M., Pereira, R. M., Ruano, L., Lemos, C., Baldeiras, I., Reis, C., & Taipa, R. (2026). Central nervous system manifestations in hereditary transthyretin amyloidosis: a cross-sectional study with 151 patients. Journal of Neurology, 273(10), Article 611. https://doi.org/10.1007/s00415-026-14146-9

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14146-9

Keywords: hereditary transthyretin amyloidosis, ATTRv amyloidosis, central nervous system, cerebral amyloid angiopathy, transient focal neurological episodes, V30M mutation, tafamidis, gene silencing therapy, neurofilament light chain, transthyretin, Journal of Neurology, Porto