Clinical considerations in early-onset cerebral amyloid angiopathy

Brain · 8 authors, 12 centres

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TL;DR

This review describes the causes of early-onset cerebral amyloid angiopathy (CAA), including monogenic forms (e.g., APP, PSEN1, PSEN2 mutations) and iatrogenic CAA, and provides a structured approach to diagnosis and management. Key findings include that early-onset CAA can present with intracerebral hemorrhage or cognitive decline, and that genetic testing and careful management of antithrombotic medications are critical. Clinically, recognizing these rare forms is essential for prompt diagnosis and has implications for understanding more common late-onset CAA.

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**Background** Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by amyloid deposition in cerebral blood vessels, most commonly sporadic amyloid-β CAA in older adults. However, early-onset forms (typically before age 50) are increasingly recognized and may result from genetic or iatrogenic causes. This review aims to describe the causes of early-onset CAA, provide a structured diagnostic approach, and highlight management considerations.

**Methods** This is a narrative review summarizing the literature on early-onset CAA, including monogenic causes (amyloid-β and non-amyloid-β), iatrogenic CAA, inflammatory CAA, and other rare causes. The authors synthesize clinical, pathological, and imaging features from published case series and studies, and propose a diagnostic algorithm based on expert opinion.

**Key Results** - **Monogenic amyloid-β CAA**: Mutations in APP (e.g., Dutch, Flemish, Italian, Arctic, Iowa, Piedmont) cause severe CAA with recurrent ICH, cognitive decline, or both. Dutch-type CAA (p.Glu693Gln) presents with recurrent ICH from ~50 years (range 39–76). Flemish mutation (p.Ala692Gly) presents with ICH or dementia in mid-40s (range 35–61). Italian mutation (p.Glu693Lys) causes recurrent ICH in mid-50s (range 44–63). Arctic mutation (p.Glu693Gly) leads to memory-led cognitive impairment in 50s (range 52–62). Iowa mutation (p.Asp694Asn) presents with ICH or dementia in early 50s (range 38–67). Piedmont mutation (p.Leu705Val) causes recurrent ICH (range 45–72). APP duplications are associated with early-onset Alzheimer's disease and prominent CAA, with ICH in ~1/3 of cases. PSEN1 mutations (e.g., p.Pro264Leu, p.Leu286Pro) can cause severe CAA but ICH is rare. PSEN2 mutations (e.g., p.Asn141Ile) can cause CAA with ICH. - **Non-amyloid-β CAA**: Includes familial British dementia (ITM2B mutation, ABri amyloid), familial Danish dementia (ITM2B mutation, ADan amyloid), cystatin C amyloidosis (CST3 mutation, ACys, presenting with ICH in 20s), gelsolin amyloidosis (GSN mutation, AGel, with corneal lattice dystrophy and neuropathy), prion protein CAA (PRNP stop codon mutations, APrP, with dementia), and transthyretin amyloidosis (TTR mutations, ATTR, with leptomeningeal involvement and ICH). - **Iatrogenic CAA**: Caused by transmission of amyloid-β seeds via cadaveric human growth hormone or dura mater grafts, with latency of 2–4 decades. Presents with ICH, cognitive impairment, or seizures. - **Inflammatory CAA**: CAA-related inflammation (CAA-ri) presents with seizures, altered consciousness, and cognitive decline, often with characteristic asymmetric white matter lesions and hemorrhagic markers. Mean age >65, but younger cases occur. - **Diagnostic approach**: Recommended investigations include MRI with blood-sensitive sequences, genetic testing (APP, PSEN1, PSEN2, and others), CSF amyloid-β measures, amyloid-PET, and consideration of brain biopsy in atypical cases. - **Management**: Antiplatelet and anticoagulant use should be cautious; blood pressure target ≤130/80 mmHg; statins considered individually; symptomatic treatments for Alzheimer's disease (e.g., donepezil) may be offered; immunosuppression for inflammatory CAA; genetic counseling for families.

**Clinical Implications** Early-onset CAA is rare but important to recognize due to specific genetic and iatrogenic causes that require targeted investigation and management. Diagnosis has implications for patients and families, including genetic counseling and potential participation in trials. Understanding these forms may provide insights into the pathophysiology of more common late-onset CAA.

STUDY TYPE

narrative_review

SPECIALTY

neurology

SUMMARISED BY

AI pipeline

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ORIGINAL PAPER

PMC10545523

Clinical considerations in early-onset cerebral amyloid angiopathy

Brain

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ABSTRACT

Abstract Cerebral amyloid angiopathy (CAA) is an important cerebral small vessel disease associated with brain haemorrhage and cognitive change. The commonest form, sporadic amyloid-β CAA, usually affects people in mid- to later life. However, early-onset forms, though uncommon, are increasingly recognized and may result from genetic or iatrogenic causes that warrant specific and focused investigation and management. In this review, we firstly describe the causes of early-onset CAA, including monogenic causes of amyloid-β CAA ( APP missense mutations and copy number variants; mutations of PSEN1 and PSEN2 ) and non-amyloid-β CAA (associated with ITM2B , CST3 , GSN , PRNP and TTR mutations), and other unusual sporadic and acquired causes including the newly-recognized iatrogenic subtype. We then provide a structured approach for investigating early-onset CAA, and highlight important management considerations. Improving awareness of these unusual forms of CAA amongst healthcare professionals is essential for facilitating their prompt diagnosis, and an understanding of their underlying pathophysiology may have implications for more common, late-onset, forms of the disease.

CITATION EXPORT

Gargi Banerjee, John Collinge, Nick C Fox et al.. Clinical considerations in early-onset cerebral amyloid angiopathy. Brain. (2023). https://doi.org/10.1093/brain/awad193

AUTHORS

8 · 12 CENTRES

Gargi Banerjee, John Collinge, Nick C Fox, Tammaryn Lashley, Simon Mead, Jonathan M Schott, David J Werring, Natalie S Ryan

MRC Prion Unit at University College London (UCL), Institute of Prion Diseases, UCL, London, W1W 7FF, UK
MRC Prion Unit at University College London (UCL), Institute of Prion Diseases, UCL, London, W1W 7FF, UK
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
UK Dementia Research Institute at UCL, London, WC1E 6BT, UK
The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Disorders, UCL Queen Square Institute of Neurology, London, W1 1PJ, UK
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
MRC Prion Unit at University College London (UCL), Institute of Prion Diseases, UCL, London, W1W 7FF, UK
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
UK Dementia Research Institute at UCL, London, WC1E 6BT, UK
Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
UK Dementia Research Institute at UCL, London, WC1E 6BT, UK