T14 modulates calcium influx via the α-7 nicotinic acetylcholine receptor to regulate cell growth. Inappropriate triggering of this process has been implicated in Alzheimer’s disease (AD) and cancer, whereas T14 blockade has proven therapeutic potential in in vitro, ex vivo and in vivo models of these pathologies. Mammalian target of rapamycin complex 1 (mTORC1) is critical for growth, however its hyperactivation is implicated in AD and cancer. T14 is a product of the longer 30mer-T30. Recent work shows that T30 drives neurite growth in the human SH-SY5Y cell line via the mTOR pathway. Here, we demonstrate that T30 induces an increase in mTORC1 in PC12 cells, and ex vivo rat brain slices containing substantia nigra, but not mTORC2. The increase in mTORC1 by T30 in PC12 cells is attenuated by its blocker, NBP14. Moreover, in post-mortem human midbrain, T14 levels correlate significantly with mTORC1. Silencing mTORC1 reverses the effects of T30 on PC12 cells measured via AChE release in undifferentiated PC12 cells, whilst silencing mTORC2 does not. This suggests that T14 acts selectively via mTORC1. T14 blockade offers a preferable alternative to currently available blockers of mTOR as it would enable selective blockade of mTORC1, thereby reducing side effects associated with generalised mTOR blockade.

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Objective: Type-2 diabetes (T2D) has been associated with poorer brain health, and glycated haemoglobin (HbA1c) levels is a diagnostic test for diabetes. The aim of this study was to investigate whether continuous HbA1c levels, and HbA1c polygenic risk scores (HbA1c-PRS) significantly associate with worse brain health independent of T2D diagnosis (vs. not), by examining brain structure and cognitive test scores phenotypes.Methods: Using cross-sectional UK Biobank data (n=39,283), we tested whether HbA1c and/or HbA1c-PRS were significantly associated with multiple cognitive test scores. We also assessed associations with brain imaging phenotypes including grey matter (GM), white matter (WM), whole brain volume, hippocampal volume, white matter hyperintensity (WMH) volumes, white matter tract integrity and frontal lobe GM. We adjusted for potential confounders of age (at MRI), sex, deprivation, education, genotyping chip, 8 genetic principal components for population stratification, smoking, alcohol intake, cholesterol medication, body mass index (BMI), T2D, and APOE e4 dosage. Results: We found an association between higher HbA1c levels and poorer performance on symbol digit substitution scores (standardised beta [β] = -0.022 p = 0.001) in the fully adjusted model. We also found an association between higher HbA1c levels and worse brain MRI phenotypes of GM (β = -0.026, p < 0.001), whole brain volume (β = -0.072, p = 0.0113), and general factor for frontal lobe of GM (β = -0.022, p < 0.001) in fully adjusted models. HbA1c-PRS score was significantly associated with GM volume in the fully adjusted model (β = -0.010, p = 0.0113), however when adjusted for HbA1c levels the association was not significant.Conclusion: Our findings suggest that measured HbA1c correlates to some extent with poorer cognitive and structural brain health, and HbA1c-PRS does not add significant information to this, however further studies in diverse populations are needed to confirm these results.

AimTo investigate whether continuous HbA1c levels and HbA1c‐polygenic risk scores (HbA1c‐PRS) are significantly associated with worse brain health independent of type 2 diabetes (T2D) diagnosis (vs. not), by examining brain structure and cognitive test score phenotypes.MethodsUsing UK Biobank data (n = 39 283), we tested whether HbA1c levels and/or HbA1c‐PRS were associated with cognitive test scores and brain imaging phenotypes. We adjusted for confounders of age, sex, Townsend deprivation score, level of education, genotyping chip, eight genetic principal components, smoking, alcohol intake frequency, cholesterol medication, body mass index, T2D and apolipoprotein (APOE) e4 dosage.ResultsWe found an association between higher HbA1c levels and poorer performance on symbol digit substitution scores (standardized beta [β] = −0.022, P = .001) in the fully adjusted model. We also found an association between higher HbA1c levels and worse brain MRI phenotypes of grey matter (GM; fully‐adjusted β = −0.026, P < .001), whole brain volume (β = −0.072, P = .0113) and a general factor of frontal lobe GM (β = −0.022, P < .001) in partially and fully adjusted models. HbA1c‐PRS were significantly associated with GM volume in the fully adjusted model (β = −0.010, P = .0113); however, when adjusted for HbA1c levels, the association was not significant.ConclusionsOur findings suggest that measured HbA1c is associated with poorer cognitive health, and that HbA1c‐PRS do not add significant information to this.