Brain atrophy in ageing: Estimating effects of blood glucose levels vs. other type 2 diabetes effects.

It is now well documented that ageing is associated with brain shrinkage, particularly in late adulthood [1,2]. From age 60 onwards, the average adult brain atrophies 0.5%/yr for the whole brain, 0.33%/yr for grey matter and 0.62–0.68%/yr for white matter [3–5]. This may seem small, but cumulatively adds up to substantial volume losses over decades: between the ages of 60 and 70, approximately 54 mL (5%) of total brain volume is lost, a substantial amount when coupled with cumulative atrophy across the lifespan. Type two diabetes mellitus (T2D) is associated with the development of structural brain abnormalities, including increased cerebral atrophy over time [2]. Individuals with T2D have a significantly lower total brain volume (0.1–1.5%), grey matter volume ( 1%), and WMV (< 1%) than those with normal fasting glucose (NFG), corresponding to between one and three years of age-associated atrophy [1]. There is mounting evidence that variation of blood glucose in the normal fasting glucose (NFG) range may also impact on brain structure and be associated with cognitive impairment [1,2,6]. Blood glucose levels and T2D are typically related, but it does not follow that an individual with T2D necessarily has high blood glucose levels. Successful glycaemic control following diagnosis can return blood glucose levels to normal. However, glycaemic control is not synonymous with addressing T2D comorbidities, such as obesity or pre-existing vascular damage, which mechanistically link T2D to cerebral atrophy. For example, while blood glucose is associated with both grey and white matter atrophy, obesity has differential effects on grey and white matter in otherwise healthy overweight and obese individuals [7,8]. The current study examined the overlap in the association between blood glucose levels (across the whole range, and in NFG only), T2D and longitudinal brain volumes (total, white matter, and grey matter) in a healthy, community-living ageing population (see Fig. S1, Supplementary material).