Abstract
We report a case of dual amyloidosis with Alzheimer's disease and wild-type transthyretin (ATTRwt) amyloidosis. A 76-year-old man with Alzheimer's disease was referred for anti-amyloid-β therapy with lecanemab. He also had symptoms of congestive heart failure and a history of carpal tunnel syndrome, cubital tunnel syndrome, and lumbar spinal stenosis; raising Technetium-99m pyrophosphate myocardial scintigraphy showed abnormal uptake, and histopathologic examination revealed transthyretin (TTR) amyloid deposition in both myocardial and gastrointestinal biopsy specimens. Genetic testing for the TTR gene revealed no variants. The diagnosis of ATTRwt amyloidosis was confirmed, and treatment with a TTR tetramer stabilizer, tafamidis, was initiated. Alzheimer's disease of the brain and ATTRwt amyloidosis of the heart are both representative amyloidoses associated with aging. To date, there are no reported cases of dual amyloidosis other than autopsy cases, but considering the high prevalence of both diseases, it is plausible that a significant number of elderly individuals may suffer from both diseases simultaneously but are underdiagnosed. In recent years, disease-modifying drugs effective against both diseases have become available, making early diagnosis increasingly important.
Introduction
Wild-type transthyretin (ATTRwt) amyloidosis is a major systemic amyloidosis characterized by the aggregation of misfolded wild-type transthyretin (TTR) proteins to form amyloid fibrils. Amyloid deposition in tendon and ligament tissue causes entrapment neuropathy, while amyloid deposition in myocardial tissue causes restrictive cardiomyopathy and arrhythmias. In particular, cardiac involvement is a critical determinant of life expectancy, and the median survival time after diagnosis is three to five years without disease-modifying therapies (DMTs) [1]. ATTRwt amyloidosis predominantly affects older individuals, and its prevalence increases with age [2]. Although its prevalence has been underestimated, autopsy studies have shown that ATTRwt amyloid deposits are present in 25% of Western individuals and 12% of Japanese individuals aged 80 years or older [3,4]. Therefore, the actual number of cases may be significantly high.
Alzheimer's disease (AD), classified as localized amyloidosis in which amyloid β (Aβ) forms senile plaques in the brain, is the most common cause of dementia, accounting for over 60% of cases. According to the World Alzheimer Report 2021, the global prevalence of dementia exceeded 55 million people [5]. AD is a prototypical aging-associated disease, with incidence increasing significantly with age. The life expectancy of individuals with AD is reported to be around eight years [6], during which the associated social and economic burden is substantial.
Given the prevalence of these two forms of amyloidosis (AD in the brain and ATTRwt amyloidosis in the heart), it is plausible that a significant number of elderly individuals may suffer from both diseases simultaneously. However, such cases of dual amyloidosis have rarely been documented in the literature.
Here, we report a case of dual amyloidosis with AD and ATTRwt amyloidosis, a condition that may have been overlooked despite its potential frequency.
Case Presentation
The patient was a 76-year-old Japanese man. He had a history of type Ⅱ diabetes mellitus, hypertension, myocardial infarction, and atrial fibrillation. Twenty years prior, he had undergone surgery for bilateral carpal tunnel syndrome, followed by surgery for right cubital tunnel syndrome 15 years ago and lumbar spinal canal stenosis 10 years ago. Since the age of 66, he has occasionally exhibited repetitive speech and questioning behaviors. His recent memory impairment progressed very slowly, and at the age of 70, he visited a psychiatrist and was diagnosed with AD. At the age of 76, he was referred to our hospital for treatment with the newly approved anti-Aβ antibody lecanemab. Cognitive impairment was characterized mainly by recent memory impairment, with a Mini-Mental State Examination score of 23 and a Clinical Dementia Rating of 1.0. 18F-flutemetamol amyloid PET imaging showed significant accumulation in the bilateral frontal, parietal, basal ganglia, and posterior cingulate gyrus-precuneus areas (Figure 1A), indicating the presence of AD pathology. Additionally, a brain MRI revealed mild hippocampal atrophy, supporting the diagnosis of AD. Clinically silent multiple lacunar infarcts were identified in the basal ganglia region, but there were no significant microbleeds on susceptibility-weighted imaging. Treatment with lecanemab was initiated.