Cardiometabolic disease and dementia risk : identifying compensatory factors

Specific cardiometabolic diseases (CMDs) - including type 2 diabetes, heart disease, and stroke - have been individually linked to increased risk of dementia. With population aging, a growing number of older adults are living with cardiometabolic multimorbidity - i.e., the presence of multiple, co-occurring CMDs. However, the role of cardiometabolic multimorbidity in the development of dementia is not well-understood. This thesis aimed to explore the complex interplay between cardiometabolic multimorbidity, cognitive decline, and dementia, and to identify possible compensatory factors that may attenuate the detrimental influence of CMDs on cognitive and brain health. This was carried out using data from three longitudinal studies: the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), the Screening Across the Lifespan Twin (SALT) study, and the UK Biobank (UKB).

Study I. The relationship between CMDs and cognitive phenotypes in the preclinical/prodromal phase of dementia was examined using 12y follow-up data from SNAC-K (n=2,577). Cardiometabolic multimorbidity was associated with accelerated cognitive decline (ß -0.03 [-0.04, -0.02]) and a significantly increased risk of both cognitive impairment (HR 1.73 [1.23, 2.44]) and its progression to dementia (HR 1.86 [1.17, 2.97]).

Study II. The association between cardiometabolic multimorbidity and dementia was assessed using 18y follow-up data from 17,913 twin individuals from SALT. Cardiometabolic multimorbidity was associated with a significantly increased risk of all-cause dementia (HR 1.42 [1.31, 1.53), Alzheimer's disease (HR 1.26 [1.10, 1.45]) and vascular dementia (HR 1.64 [1.42, 1.88]). Comparison of monozygotic and dizygotic twin pairs further indicated that genetic factors may underlie the association between CMDs and dementia.

Study III. Cognitive reserve (characterized by higher educational and occupational attainment, social stimulation, and engagement in leisure activities) was explored as a potential compensatory factor that might attenuate the association between CMDs and dementia using 15y follow-up data from UKB (n=216,178). People with CMDs and moderate-to-high compared to low levels of cognitive reserve had 17% lower risk of dementia (HR 0.83 [0.77, 0.91]) and significantly larger volumes of gray matter and hippocampus on brain MRI.

Study IV. The compensatory role of anti-inflammatory diet in the CMD-dementia association was examined using 15y follow-up data from UKB (n=84,342). People with CMDs and an anti-inflammatory compared to pro- inflammatory diet had 31% lower risk of dementia (HR 0.69 [0.55, 0.88]) as well as a significantly larger volume of gray matter and significantly smaller volume of white matter hyperintensities on brain MRI.

Conclusions. Together, the findings highlight cardiometabolic multimorbidity as an especially high-risk state for a continuum of cognitive phenotypes spanning from accelerated cognitive decline to cognitive impairment and dementia. This appears to involve both neurodegenerative and vascular processes in the brain. Further, genetic background may underpin the CMD-dementia association. However, modifiable factors including high levels of cognitive reserve and adherence to an anti-inflammatory diet appear to attenuate the association between CMDs, brain pathologies, and dementia.

Keywords: Cardiometabolic disease, dementia, Alzheimer's disease, vascular dementia, cognitive decline, brain MRI, cognitive reserve, anti-inflammatory diet, population-based study, twin study

List of scientific papers

This thesis is based on the following original papers, which will be referred to in the text as Studies I, II, III, and IV.

I. Dove A, Marseglia A, Shang Y, Vetrano DL, Grande G, Laukka EJ, Fratiglioni L, Xu W. Cardiometabolic multimorbidity accelerates cognitive decline and dementia progression. Alzheimer's & Dementia. 2022 Jun 16; 19(3): 821-830.
https://doi.org/10.1002/alz.12708

II. Dove A, Guo J, Marseglia A, Fastbom J, Vetrano DL, Fratiglioni L, Pedersen N, Xu W. Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry. European Heart Journal. 2023 Feb 14; 44(7): 573-582.
https://doi.org/10.1093/eurheartj/ehac744

III. Dove A, Yang W, Dekhtyar S, Guo J, Wang J, Marseglia A, Vetrano DL, Whitmer RA, Xu W. High cognitive reserve attenuates the risk of dementia associated with cardiometabolic diseases. Alzheimer's Research & https://doi.org/10.1186/s13195-024-01528-2

IV. Dove A, Dunk MM, Wang J, Guo J, Whitmer RA, Xu W. Anti- inflammatory diet and dementia in older adults with cardiometabolic diseases. JAMA Network Open. 2024 Aug 12; 7(8): e2427125.
https://doi.org/10.1001/jamanetworkopen.2024.27125