Response to the letter titled “Targeting dementia prevention with semaglutide: the case for APOE4 homozygotes”

1.

To the Editor,

We appreciate the opportunity to address Dr. Daly and colleagues’ comments regarding our study. ¹ The author raised an interesting question that future studies shall focus on testing semaglutide, on Alzheimer's disease (AD) in high‐risk patients with a nondiabetic genetic risk profile—those with apolipoprotein (APOE) ε4 homozygotes. The APOE ε4 allele remains the strongest genetic risk factor for sporadic AD ² ; however, ≈ 45% of dementia cases have been linked to 14 modifiable non‐genetic risk factors, including diet, physical inactivity, diabetes, obesity, hypertension, high low‐density lipoprotein cholesterol, smoking, alcohol drinking, sleep disorders, and depression. ³ Semaglutide has benefits in treating multiple modifiable AD risk factors, including obesity, type 2 diabetes, and cardiovascular and chronic kidney diseases, and appears to be promising for treating smoking and alcohol drinking ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ . Emerging research suggests that semaglutide has anti‐inflammatory and immunological properties ¹⁰ , ¹¹ and that it improves vascular function. ⁵ , ¹² Given its ability to target multiple non‐genetic risk factors and proximal mechanisms of AD, focusing exclusively on individuals with APOE ε4 homozygotes may overlook important opportunities in other high‐risk populations. However, we agree that the benefit and risk profiles of semaglutide may differ in people with different clinical and genetic characteristics, including APOE genotypes; therefore, a precision medicine approach is warranted.

CONFLICT OF INTEREST STATEMENT

The author declares no conflicts of interest. Author disclosures are available in the supporting information.

Supporting information

Supporting information