Wittrahm R, Takalo M, Kuulasmaa T, Mäkinen PM, Mäkinen P, Končarević S, Fartzdinov V, Selzer S, Kokkola T, Antikainen L, Martiskainen H, Kemppainen S, Marttinen M, Jeskanen H, Rostalski H, Rahunen E, Kivipelto M, Ngandu T, Natunen T, Lambert JC, Tanzi RE, Kim DY, Rauramaa T, Herukka SK, Soininen H, Laakso M, Pike I, Leinonen V, Haapasalo A, Hiltunen M. Protective Alzheimer's disease-associated APP A673T variant predominantly decreases sAPPβ levels in cerebrospinal fluid and 2D/3D cell culture models. Neurobiol Dis. 2023 Jun 15;182:106140. Epub 2023 Apr 28 PubMed.
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German Center for Neurodegenerative Diseases (DZNE)
This study reports a very important finding for Alzheimer's disease and specifically for the development of BACE1-targeted inhibitors. The study demonstrates that the protective Icelandic mutation—located close to the BACE1 cleavage site in APP—lowers CSF Aβ42 by nearly 30 percent. A similar reduction was previously reported by the same group, but in plasma. Importantly, this mild CSF Aβ42 reduction—which, however, occurs life-long—correlated with the absence of amyloid and tau pathology. This new data suggests that a mild inhibition of BACE1 (less than 50 percent) may be a reasonable strategy for prevention of Alzheimer's disease. Further considerations on low-level BACE1 inhibition for the prevention of AD are summarized in McDade et al., 2021.
McDade E, Voytyuk I, Aisen P, Bateman RJ, Carrillo MC, De Strooper B, Haass C, Reiman EM, Sperling R, Tariot PN, Yan R, Masters CL, Vassar R, Lichtenthaler SF. The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol. 2021 Nov;17(11):703-714. Epub 2021 Sep 21 PubMed.
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