Importance of ApoE4 status and gut microbiota status in treatment with Lecanemab for early Alzheimer's disease

Recent research demonstrates that Apolipoprotein-E (ApoE) isoforms (ApoE3 and ApoE4), the strongest genetic risk factor for Alzheimer’s disease, regulates brain inflammation and tau-mediated brain damage, however, the gut microbiota also regulates brain inflammation. Seo et al. reported that manipulation of the gut microbiota resulted in a strong reduction of inflammation, tau pathology, and brain damage in a sex- and ApoE-dependent manner. Therefore, ApoE-associated gut microbiota targeting may provide an avenue to further explore the prevention or treatment of Alzheimer’s disease.

On January 6, 2023, a treatment with lecanemab, which may moderately slow mild cognitive decline and reduce amyloid-β plaques in patients with early Alzheimer disease, gained accelerated approval from the US Food and Drug Administration (FDA). On January 16, 2023, in Japan, Eisai announced that it had submitted a new drug application to the Ministry of Health, Labor and Welfare for a new drug for Alzheimer's disease, lecanemab (US brand name: LEQEMBI), which is being jointly developed with Biogen.

However, in a nod to safety concerns, the lecanemab’s label will include a warning about developing a type of brain swelling or bleeding called Amyloid-related imaging abnormalities (ARIA), which stands for amyloid-related imaging abnormalities. It recommends that anyone taking lecanemab have three MRIs in roughly the first 6 months of treatment to watch for those side effects.

In lecanemab’s large clinical trial, 9.2% of people with two copies of the gene variant had symptomatic brain swelling, i.e., ARIA, compared with 1.4% of people with no copies. In short, people with two copies of the ApoE4 gene, which predisposes to Alzheimer’s, may be at higher risk of ARIA.

Alzheimer’s patients aren’t routinely tested for ApoE4 because it hasn’t traditionally affected diagnosis or treatment. In Japan, there is concern about the problem of excessive medical treatment, such as the frequent use of PET scans (currently about 100,000 yen) for the diagnosis of early Alzheimer's disease and for follow-up during the course of treatment with lecanemab. When deciding to initiate treatment with lecanemab, people should preferably be tested for ApoE4 status to inform their risk of developing ARIA. In addition, further studies are required to clarify the effects of lecanemab administration on the gut microbiota.

We do not have potential conflicts of interest.

Doctor specializing in cancer care.
Doctor specializing in emerging infectious diseases.

Report Published in Science, on Jan. 25 2023 by Kyoto@takumaH