Type 2 diabetes mellitus and biomarkers of neurodegeneration

Significance Statement

Australian researchers looked at the relationship between type 2 diabetes, the loss of brain cells and their connections, beta amyloid levels and tau protein. The study was conducted in 816 people (average age= 74 years). Of those, mild cognitive impairment (n= 397), Alzheimer’s disease dementia (n=191) and no memory and thinking problems (n=228). A total of 124 of the study patients had diabetes. Diabetic patients had on average 16 pg/ml higher levels of tau protein in the spinal and brain fluid irrespective of the diagnosis of dementia. Higher levels of tau in spinal fluid may eventually contribute to the development of dementia. Diabetic patients had also reduced cortex thickness (0.03 mm less than control).

Journal Reference

Neurology. 2015 Sep 2. pii: 10.1212/WNL.0000000000001982.

Moran C¹, Beare R¹, Phan TG¹, Bruce DG¹, Callisaya ML¹, Srikanth V²; Alzheimer’s Disease Neuroimaging Initiative (ADNI).

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¹From the Stroke and Ageing Research Group (C.M., T.G.P., V.S.), Vascular Brain Ageing Division, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne; Neurosciences (C.M., T.G.P., V.S.), Monash Medical Centre, Monash Health, Melbourne; Caulfield General Medical Centre (C.M.), Alfred Health, Melbourne; Developmental Imaging (R.B.), Murdoch Children’s Research Institute, Melbourne; School of Medicine and Pharmacology (D.G.B.), Fremantle Hospital, University of Western Australia; and Menzies Research Institute Tasmania (M.L.C., V.S.), University of Tasmania, Hobart, Australia.

²From the Stroke and Ageing Research Group (C.M., T.G.P., V.S.), Vascular Brain Ageing Division, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne; Neurosciences (C.M., T.G.P., V.S.), Monash Medical Centre, Monash Health, Melbourne; Caulfield General Medical Centre (C.M.), Alfred Health, Melbourne; Developmental Imaging (R.B.), Murdoch Children’s Research Institute, Melbourne; School of Medicine and Pharmacology (D.G.B.), Fremantle Hospital, University of Western Australia; and Menzies Research Institute Tasmania (M.L.C., V.S.), University of Tasmania, Hobart, Australia. [email protected].

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Abstract

OBJECTIVE:

Our objective was to investigate whether type 2 diabetes mellitus (T2DM) influences neurodegeneration in a manner similar to Alzheimer disease (AD), by promoting brain β-amyloid (Aβ) or tau.

METHODS:

We studied the cross-sectional associations of type 2 diabetes mellitus with cortical thickness, brain Aβ load, and CSF levels of Aβ and tau in a sample of people from the Alzheimer’s Disease Neuroimaging Initiative with diagnoses of AD dementia, mild cognitive impairment, and normal cognition. All (n = 816) received MRI, and a subsample underwent brain amyloid imaging (n = 102) and CSF Aβ and tau measurements (n = 415). Analyses were performed across and within cognitive diagnostic strata.

RESULTS:

There were 124 people with type 2 diabetes mellitus (mean age 75.5 years) and 692 without type 2 diabetes mellitus (mean age 74.1 years). After adjusting for age, sex, total intracranial volume, APO ε4 status, and cognitive diagnosis, T2DM was associated with lower bilateral frontal and parietal cortical thickness (mL) (β = -0.03, p = 0.01). Type 2 diabetes mellitus was not associated with ¹¹C Pittsburgh compound B standardized uptake value ratio (AU) in any brain region or with CSF Aβ₄₂ levels (pg/mL). T2DM was associated with greater CSF total tau (pg/mL) (β = 16.06, p = 0.04) and phosphorylated tau (β = 5.84, p = 0.02). The association between type 2 diabetes mellitus and cortical thickness was attenuated by 15% by the inclusion of phosphorylated tau.

CONCLUSIONS:

Type 2 diabetes mellitus may promote neurodegeneration independent of AD dementia diagnosis, and its effect may be driven by tau phosphorylation. The mechanisms through which type 2 diabetes mellitus may promote tau phosphorylation deserve further study.

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