Early-Onset Alzheimer’s Disease Mimicking Cognitive Progression Independent of Relapse Activity in Multiple Sclerosis: A Case Report and Diagnostic Strategy

Background Cognitive impairment (CI) is a common and disabling feature of multiple sclerosis (MS) and is increasingly recognized as part of progression independent of relapse activity (PIRA). However, distinguishing MS-related cognitive PIRA from comorbid neurodegenerative disorders remains challenging, particularly in younger patients, in whom diagnostic overshadowing may delay appropriate diagnosis and management. Herein, we report a case of a patient with MS who developed rapid, memory-predominant CI. Case presentation: A 46-year-old man with long-standing MS developed rapidly progressive, memory-predominant CI that mimicked cognitive PIRA. Despite the absence of clinical relapses and limited magnetic resonance imaging (MRI) activity, cognitive decline progressed and was disproportionate to physical disability. Neuropsychological assessment revealed an early amnestic-dominant profile rather than the processing speed-predominant pattern observed in MS-related CI. Despite escalation from interferon-β1a to high-efficacy anti-CD20 therapy (ofatumumab), cognitive deterioration persisted, arguing against ongoing inflammatory disease activity as the primary cause. Longitudinal MRI showed progressive corpus callosum and parietal lobe atrophy without new white matter lesions. Single-photon emission computed tomography showed hypoperfusion in the bilateral parietal lobes, precuneus, and posterior cingulate gyrus. Cerebrospinal fluid analysis showed reduced amyloid-β1–42/1–40 with elevated phosphorylated tau levels, consistent with Alzheimer’s disease (AD) pathology. Based on the clinical course, neuropsychological profile, neuroimaging findings, and biomarker evidence, comorbid early-onset AD was identified as the predominant cause of cognitive decline. Conclusions This case highlights a critical diagnostic pitfall in MS: rapidly progressive memory-dominant CI may represent a cognitive PIRA mimic rather than MS-related progression. Therefore, clinicians should consider comorbid AD when cognitive decline is amnestic, disproportionate to physical disability, and unresponsive to high-efficacy disease-modifying therapies.