MAPT rs242557 variant: a driver from early to late mild cognitive impairment

The rs242557 variant of the microtubule-associated protein tau (MAPT) gene has been associated with a variety of tauopathies and dementias. This study comprehensively evaluated the effects of the rs242557 variant on AD as well as other stages. 856 human subjects were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. The effect of the rs242557 variant on cognitive impairment was first assessed. Subjects with the variant had more severe cognitive impairment than subjects without the variant in early mild cognitive impairment (EMCI). We then analyzed neuronal loss and tau aggregation by comparing hippocampal volume and standardised uptake value ratios (SUVRs) of the tau PET tracer 18F-AV1451 in the hippocampus between rs242557 variant carriers and non‐carriers. The results suggest that rs242557 variant accelerates the progression of EMCI (hippocampal volume: left β: -0.107, p = 0.218; right β: -0.121, p = 0.145) (hippocampal 18F-AV1451: left β: 0.186, p = 0.036; right β: 0.198, p = 0.022) to late mild cognitive impairment (LMCI) (hippocampal volume: left β: -0.296, p = 0.002; right β: -0.264, p = 0.004) (hippocampal 18F-AV1451: left β: 0.358, p = 0.000; right β: 0.343, p = 0.000). Hippocampal glucose metabolism was assessed with similar results (left β: -0.369, p = 0.000; right β: -0.403, p = 0.000). We further found that F18-AV1451 signals were higher in male subjects carrying the rs242557 variant in the LMCI subjects (left β: 0.337, p = 0.02; right β:0.288, p = 0.059). Finally, lower Aβ42/Aβ40 levels (β: -0.277, p = 0.001) and higher p-tau181 levels (β: 0.492, p = 0.011) were found in the plasma of rs242557 variant carriers. The above results suggest that the rs242557 variant is associated with accelerated MCI progression and that the development of drugs targeting rs242557 variant may be a potential strategy to halt the progression of MCI to AD.