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Randomized Controlled Trial
. 2025 Jul;41(5):e70053.
doi: 10.1002/dmrr.70053.

Associations of Prediabetes, Diabetes and Glucose-Related Markers With Cognition and Neuroimaging in a 2-Year Multidomain Lifestyle Randomised Controlled Trial

Thais Lorenzo  1   2   3   4 , Tiia Ngandu  2   5 , Jenni Lehtisalo  5   6 , Riitta Antikainen  7   8 , Juan Domingo Gispert  1   3   9 , Nina Kemppainen  10   11 , Tiina Laatikainen  5   6   12   13 , Jaana Lindström  5 , Juha Rinne  10   11 , Hilkka Soininen  13 , Timo Strandberg  7   14 , Rafael de la Torre  15   16 , Jaakko Tuomilehto  5   17   18   19   20 , Alina Solomon  2   6   21 , Miia Kivipelto  2   6   13   21
Affiliations
Randomized Controlled Trial

Associations of Prediabetes, Diabetes and Glucose-Related Markers With Cognition and Neuroimaging in a 2-Year Multidomain Lifestyle Randomised Controlled Trial

Thais Lorenzo et al. Diabetes Metab Res Rev. 2025 Jul.

Abstract

Aims: Few longitudinal studies have explored Oral Glucose Tolerance Test markers (OGTT) and both cognitive and brain changes. We investigated OGTT and other glycaemia and insulin resistance markers, and cognitive and neuroimaging changes in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER).

Materials and methods: At-risk individuals aged 60-77 years without dementia (N = 1259) were randomly enrolled in a 2-year multidomain lifestyle intervention or regular health advice program. 1025 participants without previously diagnosed diabetes underwent OGTT. Brain MRI scans were available for 132 participants and amyloid (PiB)-PET and FDG-PET scans for 47. Cognition was assessed using the modified Neuropsychological Test Battery (mNTB).

Results: Higher baseline dysglycaemia measures, particularly those from the OGTT, were connected to less favourable changes in multiple cognitive measures and hippocampal volume. Higher baseline triglyceride-glucose (TyG) index was associated with higher amyloid accumulation and decline in brain glucose metabolism. Higher baseline glycated haemoglobin (HbA1c) was related to favourable changes in processing speed and cortical thickness. There were no significant intervention-control differences in the change in glycaemia markers. Baseline dysglycaemia and glycaemia-related markers did not modify the previously reported intervention benefits on cognition.

Conclusions: Higher baseline dysglycaemia measures are linked to more deleterious changes in cognition. Specifically, OGTT measures may be the most sensitive for detecting subtle glycaemic abnormalities associated with both unfavourable cognitive and neuroimaging changes. However, HbA1c shows mixed associations with cognition and neuroimaging in people at risk of dementia without previously diagnosed diabetes. This study emphasises the importance of more accurate glucose-related markers when investigating early stages of glucose metabolism abnormalities and their relationship to subtle cognitive impairment and its structural brain correlates.

Trial registration: ID NCT01041989 https://clinicaltrials.gov.

Keywords: HbA1c; clinical trial; cognition; dementia; dysglycaemia; neuroimaging; oral glucose tolerance test; prediabetes; prevention; risk factors.

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Conflict of interest statement

J.D.G. has received research support from GE HealthCare, Roche Diagnostics and Hoffmann—La Roche, speaker/consulting fees from Biogen, Philips Netherlands, Roche Diagnostics, Esteve and Life‐MI and serves on the Molecular Neuroimaging Advisory Board of Prothena Biosciences; he is the inventor, founder and co‐owner of Betascreen SL. JT owns shares in Orion Pharma, Aktivolabs LTD and Digostics LTD.

Figures

FIGURE 1
FIGURE 1
Associations between baseline glucose markers and change in cognition over 2 years. Estimates (95% CIs) are shown from linear mixed models. Negative estimates indicate that higher baseline glucose markers were related to less favourable cognitive changes. Positive estimates indicate that higher baseline glucose markers were related to cognitive improvement. Estimates with 95% CIs that do not cross the dotted reference line are statistically significant. *Dysglycaemia is defined as having either prediabetes or diabetes.
See this image and copyright information in PMC

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