Patient With Mild Alzheimer's Disease Homozygous for <i>ApoE</i> ε4 Showing Improved Cognition, No Brain Volume Loss, and Complete Amyloid Clearance After Lecanemab Treatment

Monoclonal antibodies targeting β-amyloid (Aβ), including lecanemab and donanemab, have been approved for the treatment of mild dementia and mild cognitive impairment caused by Alzheimer's disease (AD). Although these antibodies reduce cognitive decline in AD patients, those who have the apolipoprotein E epsilon 4 (ApoE ε4) gene still show a high risk for amyloid-related imaging abnormalities (ARIA), such as brain edema, microhemorrhages, and superficial siderosis [1]. In fact, lecanemab has not been approved for use in AD patients homozygous for ApoE ε4 in Great Britain, owing to an unfavorable risk–benefit ratio. In addition, subgroup analysis of a lecanemab trial demonstrated that patients homozygous for ApoE ε4 show less favorable treatment effects than ApoE ε4 noncarriers [2]. We herein report a case of a patient with mild AD who was homozygous for ApoE ε4, but showed improvement in cognition, no brain volume loss on magnetic resonance imaging (MRI), and complete amyloid clearance on positron emission tomography (PET) without any adverse events after 18 months of lecanemab treatment. The patient was a 75-year-old man with 12 years of education. He had been receiving donepezil treatment from his family doctor for the past 3 years. He visited the memory clinic at our hospital to receive lecanemab treatment. His short-term memory and orientation were impaired, and his Mini-Mental State Examination (MMSE) score and the Japanese version of the Montreal Cognitive Assessment (MoCA) score were 22 and 19, respectively. The Clinical Dementia Rating (CDR) score was 0.5 (global) and 4.5 (sum of boxes [SB]). MRI (Siemens MAGNETOM Symphony, 1.5 T MRI system) displayed substantial medial temporal lobe atrophy, but no other abnormalities, except for one microbleed in the right occipital lobe, and PET (Discovery 610, GE Healthcare, 18F-flutemetamol, 185 MBq) displayed amyloid positivity. Genetic testing demonstrated that his ApoE genotype was ε4/ε4. As he was diagnosed as having mild AD, and met the eligibility criteria for lecanemab treatment according to the Japanese guidelines for its optimal use, lecanemab treatment was initiated (10 mg/kg, biweekly). No infusion-related reactions were observed. Follow-up MRI at 2, 3, 6, 12, and 18 months displayed no ARIA or other adverse findings. Figure 1 shows the changes in cognition, MRI findings, and PET scans during lecanemab treatment. After 18 months of treatment, the patient's CDR-SB score improved from 4.5 to 2.5, although his global CDR (from 0.5 to 0.5), MMSE (from 22 to 22), and MoCA (from 19 to 19) scores showed no changes. Lawton's instrumental activities of daily living score also improved from 2/5 to 3/5. Follow-up MRI displayed no significant changes, and values of both the severity of volume of interest atrophy (Z-score, from 3.28 to 3.13) and extent of gray matter (GM) atrophy (from 3.76% to 3.86%) measured using voxel-based specific regional analysis system for AD (VSRAD) [3] were stable. A second PET scan after 18 months of lecanemab treatment demonstrated complete amyloid clearance (from 51.6 centiloids to 3.6 centiloids). Compared with the phase 3 trial of lecanemab (Clarity AD), in which the mean CDR-SB score change from baseline to 18 months was 1.21 in the lecanemab group vs. 1.66 in the placebo group [1], the present patient showed an improvement in CDR-SB score (−2.0 change). Follow-up assessment using comprehensive neuropsychological tests is needed. Although lecanemab mainly binds with high affinity to soluble Aβ protofibrils, the complete clearance of amyloid deposition was observed in the present patient (93% reduction of amyloid) on PET at 18 months. Moreover, no significant brain volume loss was observed. Although accelerated brain volume loss was shown in some recent studies on amyloid-removing therapies [4], an overall association between the treatment effects on brain atrophy and clinical outcomes has been reported [5]. Although the characteristic features and backgrounds of patients who respond positively to lecanemab remain unknown at present, the amyloid burden at baseline of our present patient was not very high (51.6 centiloids). Therefore, as patients in the low amyloid subgroup (< 60 centiloids) showed continued benefit in a long-term lecanemab trial [6], patients with low amyloid accumulation, indicating the earlier stages of AD, may show greater benefit than those with high amyloid accumulation. Further research is needed to elucidate the underlying mechanism of the effects of lecanemab, to provide safer and more effective therapies for patients. Although anti-amyloid therapies for patients who are ApoE ε4 carriers must be carefully considered owing to the higher risk of ARIA, lecanemab treatment may be an option even for homozygous ApoE ε4 patients, as our present ApoE ε4 homozygous patient showed a favorable response to lecanemab. We are grateful to the medical editors of the Center for International Education and Research at Tokyo Medical University for editing and reviewing the English manuscript. The authors have nothing to report. Written consent was obtained from the patient for publication of this article. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.