Possible iatrogenic cerebral amyloid angiopathy in the elderly: a diagnostic dilemma – a case report and considerations to inform future revisions of diagnostic criteria

Abstract Background Iatrogenic cerebral amyloid angiopathy (iCAA) has recently emerged as a distinct entity within the CAA spectrum, defined by prior medical interventions capable of transmitting exogenous amyloid-β seeds to the brain, followed decades later by the development of CAA-related clinical and radiological manifestations via proposed prion-like mechanisms. Unlike sporadic CAA, which is strongly age-associated, iCAA typically presents in young or middle-aged adults, depending on the age at exposure. However, presentation in older adults remains pathomechanistically plausible. Here, we report and discuss the diagnostic and classification dilemma of an elderly patient who meets the Queen Square criteria for possible iCAA. Case presentation A 68-year-old male patient with a history of untreated hypertension, recent cognitive decline, and resection of a frontobasal meningioma two decades earlier presented with small lobar haemorrhages following blunt head trauma. Magnetic resonance imaging revealed innumerable lobar cerebral microbleeds (CMBs) with multifocal cortical superficial siderosis (cSS) suggestive of CAA, in association with two deep CMBs. Cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker analysis showed severe amyloid-β pathology with normal phosphorylated tau levels, consistent with CAA without AD. Whole-exome sequencing did not reveal variants consistent with hereditary CAA. The apolipoprotein E genotype was ε4/ε4. Retrospective neuropathological evaluation of the resection material showed no evidence of pre-existing amyloid-β pathology in the cortex. Conclusion This case represents a multifaceted diagnostic dilemma. It fulfils all criteria for probable iCAA except for age, thereby currently qualifying as possible iCAA (age ≥ 55 years), reflecting an increasing possibility of sporadic CAA with advancing age. Despite this, it does not fulfil possible/probable sporadic CAA according to the Boston criteria due to the presence of deep CMBs, which are characteristic of hypertensive arteriopathy but are also well-recognised in iCAA. The absence of full AD CSF profile, despite ε4 homozygosity, is consistent with iCAA, in which marked phosphorylated tau pathology is atypical. Among previously reported elderly possible iCAA cases in the literature, we are aware of only three with a similarly detailed diagnostic work-up, and none with retrospective evaluation of pre-existing amyloid-β pathology. The classification challenges are discussed, and recommendations are provided to inform future updates of diagnostic criteria.