Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study

Tai, Xin You; Veldsman, Michele; Lyall, Donald M.; Littlejohns, Thomas J.; Langa, Kenneth M.; Ranson, Janice M; Llewellyn, David J.

doi:10.1016/s2666-7568(22)00117-9

Cited by 44 publications

(45 citation statements)

References 47 publications

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“…In line with this, a recent study using data from the UK Biobank also reported a monotonic increase in dementia risk with one, two, and three co-morbid CMDs (including T2D, myocardial infarction, and stroke). 9 …”

Section: Discussionmentioning

confidence: 99%

“…A UK Biobank study showed a strong association between cardiometabolic multimorbidity and dementia, regardless of an individual’s AD-related polygenic risk. 9 On the other hand, a Danish population-based study reported that 10-year dementia risk among people with vascular risk factors like T2D or hypertension can vary substantially according to their APOE genotype and dementia-related polygenic risk score. 43 Future studies are needed to identify which genes are involved in the CMD–dementia association and whether these could point to common biological pathways implicated in both CMDs and dementia.…”

Section: Discussionmentioning

confidence: 99%

“…CMDs were defined as T2D, HD, and stroke, following previous studies examining the impact of cardiometabolic multimorbidity on health outcomes. 1 , 2 , 4 , 7 , 9 , 22–24 CMDs were assessed at baseline using data from multiple sources. T2D was identified based on self-reported histories of diabetes, records from the NPR, and use of glucose-lowering medications according to the Swedish Prescribed Drug Register.…”

Section: Methodsmentioning

confidence: 99%

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Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry

Dove

Guo

Marseglia

et al. 2022

European Heart Journal

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Aims Cardiometabolic diseases (CMDs), including diabetes, heart disease, and stroke, are established risk factors for dementia, but their combined impact has been investigated only recently. This study aimed to examine the association between mid- and late-life cardiometabolic multimorbidity and dementia and explore the role of genetic background in this association. Methods and results Within the Swedish Twin Registry, 17 913 dementia-free individuals aged ≥60 were followed for 18 years. CMDs [including age of onset in mid (60) or late (≥60) life] and dementia were ascertained from medical records. Cardiometabolic multimorbidity was defined as having ≥2 CMDs. Cox regression was used to estimate the CMD–dementia association in (i) a classical cohort study design and (ii) a co-twin study design involving 356 monozygotic and dizygotic pairs. By comparing the strength of the association in the two designs, the contribution of genetic background was estimated. At baseline, 3,312 (18.5%) participants had 1 CMD and 839 (4.7%) had ≥2 CMDs. Over the follow-up period, 3,020 participants developed dementia. In the classic cohort design, the hazard ratio (95% confidence interval) of dementia was 1.42 (1.27–1.58) for 1 CMD and 2.10 (1.73–2.57) for ≥2 CMDs. Dementia risk was stronger with mid-life as opposed to late-life CMDs. In the co-twin design, the CMD–dementia association was attenuated among monozygotic [0.99 (0.50–1.98)] but not dizygotic [1.55 (1.15–2.09)] twins, suggesting that the association was in part due to genetic factors common to both CMDs and dementia. Conclusion Cardiometabolic multimorbidity, particularly in mid-life, is associated with an increased risk of dementia. Genetic background may underpin this association.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry

Dove

Guo

Marseglia

et al. 2022

European Heart Journal

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“…While recent evidence has highlighted a shared pathology link of tau accumulation in epilepsy and dementia, another intriguing line of inquiry is the role of modifiable cardiovascular risk factors that contribute to dementia risk in the general aging population . Established stroke is a risk factor for developing epilepsy in older adults; however, the effect of upstream cardiovascular risk factors is less clear with conflicting findings .…”

Section: Introductionmentioning

confidence: 99%

Association of Dementia Risk With Focal Epilepsy and Modifiable Cardiovascular Risk Factors

et al. 2023

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ImportanceEpilepsy has been associated with cognitive impairment and potentially dementia in older individuals. However, the extent to which epilepsy may increase dementia risk, how this compares with other neurological conditions, and how modifiable cardiovascular risk factors may affect this risk remain unclear.ObjectiveTo compare the differential risks of subsequent dementia for focal epilepsy compared with stroke and migraine as well as healthy controls, stratified by cardiovascular risk.Design, Setting, and ParticipantsThis cross-sectional study is based on data from the UK Biobank, a population-based cohort of more than 500 000 participants aged 38 to 72 years who underwent physiological measurements and cognitive testing and provided biological samples at 1 of 22 centers across the United Kingdom. Participants were eligible for this study if they were without dementia at baseline and had clinical data pertaining to a history of focal epilepsy, stroke, or migraine. The baseline assessment was performed from 2006 to 2010, and participants were followed up until 2021.ExposuresMutually exclusive groups of participants with epilepsy, stroke, and migraine at baseline assessment and controls (who had none of these conditions). Individuals were divided into low, moderate, or high cardiovascular risk groups based on factors that included waist to hip ratio, history of hypertension, hypercholesterolemia, diabetes, and smoking pack-years.Main Outcomes and MeasuresIncident all-cause dementia; measures of executive function; and brain total hippocampal, gray matter, and white matter hyperintensity volumes.ResultsOf 495 149 participants (225 481 [45.5%] men; mean [SD] age, 57.5 [8.1] years), 3864 had a diagnosis of focal epilepsy only, 6397 had a history of stroke only, and 14 518 had migraine only. Executive function was comparable between participants with epilepsy and stroke and worse than the control and migraine group. Focal epilepsy was associated with a higher risk of developing dementia (hazard ratio [HR], 4.02; 95% CI, 3.45 to 4.68; P &lt; .001), compared with stroke (HR, 2.56; 95% CI, 2.28 to 2.87; P &lt; .001), or migraine (HR, 1.02; 95% CI, 0.85 to 1.21; P = .94). Participants with focal epilepsy and high cardiovascular risk were more than 13 times more likely to develop dementia (HR, 13.66; 95% CI, 10.61 to 17.60; P &lt; .001) compared with controls with low cardiovascular risk. The imaging subsample included 42 353 participants. Focal epilepsy was associated with lower hippocampal volume (mean difference, −0.17; 95% CI, −0.02 to −0.32; t = −2.18; P = .03) and lower total gray matter volume (mean difference, −0.33; 95% CI, −0.18 to −0.48; t = −4.29; P &lt; .001) compared with controls. There was no significant difference in white matter hyperintensity volume (mean difference, 0.10; 95% CI, −0.07 to 0.26; t = 1.14; P = .26).Conclusions and RelevanceIn this study, focal epilepsy was associated with a significant risk of developing dementia, to a greater extent than stroke, which was magnified substantially in individuals with high cardiovascular risk. Further findings suggest that targeting modifiable cardiovascular risk factors may be an effective intervention to reduce dementia risk in individuals with epilepsy.

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“…Although the causality between ARHL and/or tinnitus and the above-mentioned comorbidities and frailty phenotypes has been poorly established, accumulative epidemiological studies suggest that ARHL and/or tinnitus are closely related to these comorbidities and frailty phenotypes ( Panza et al, 2015 ; Wayne and Johnsrude, 2015 ; Yoo et al, 2019 ; Ruan et al, 2021 ). Moreover, some comorbidities, such as cardiometabolic multimorbidity ( Tai et al, 2022 ), and psychological disorders ( Price and Duman, 2020 ) have been independently associated with the risk of dementia.…”

Section: Introductionmentioning

confidence: 99%

Vulnerability to chronic stress and the phenotypic heterogeneity of presbycusis with subjective tinnitus

Ruan

Liu

et al. 2022

Front. Neurosci.

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Age-related functional reserve decline and vulnerability of multiple physiological systems and organs, as well as at the cellular and molecular levels, result in different frailty phenotypes, such as physical, cognitive, and psychosocial frailty, and multiple comorbidities, including age-related hearing loss (ARHL) and/or tinnitus due to the decline in auditory reserve. However, the contributions of chronic non-audiogenic cumulative exposure, and chronic audiogenic stress to phenotypic heterogeneity of presbycusis and/or tinnitus remain elusive. Because of the cumulative environmental stressors throughout life, allostasis systems, the hypothalamus-pituitary-adrenal (HPA) and the sympathetic adrenal–medullary (SAM) axes become dysregulated and less able to maintain homeostasis, which leads to allostatic load and maladaptation. Brain–body communication via the neuroendocrine system promotes systemic chronic inflammation, overmobilization of energetic substances (glucose and lipids), and neuroplastic changes via the non-genomic and genomic actions of glucocorticoids, catecholamines, and their receptors. These systemic maladaptive alterations might lead to different frailty phenotypes and physical, cognitive, and psychological comorbidities, which, in turn, cause and exacerbate ARHL and/or tinnitus with phenotypic heterogeneity. Chronic audiogenic stressors, including aging accompanying ontological diseases, cumulative noise exposure, and ototoxic drugs as well as tinnitus, activate the HPA axis and SAM directly and indirectly by the amygdala, promoting allostatic load and maladaptive neuroplasticity in the auditory system and other vulnerable brain regions, such as the hippocampus, amygdala, and medial prefrontal cortex (mPFC). In the auditory system, peripheral deafferentation, central disinhibition, and tonotopic map reorganization may trigger tinnitus. Cross-modal maladaptive neuroplasticity between the auditory and other sensory systems is involved in tinnitus modulation. Persistent dendritic growth and formation, reduction in GABAergic inhibitory synaptic inputs induced by chronic audiogenic stresses in the amygdala, and increased dendritic atrophy in the hippocampus and mPFC, might involve the enhancement of attentional processing and long-term memory storage of chronic subjective tinnitus, accompanied by cognitive impairments and emotional comorbidities. Therefore, presbycusis and tinnitus are multisystem disorders with phenotypic heterogeneity. Stressors play a critical role in the phenotypic heterogeneity of presbycusis. Differential diagnosis based on biomarkers of metabonomics study, and interventions tailored to different ARHL phenotypes and/or tinnitus will contribute to healthy aging and improvement in the quality of life.

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Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study

Cited by 44 publications

References 47 publications

Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry

Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry

Association of Dementia Risk With Focal Epilepsy and Modifiable Cardiovascular Risk Factors

Vulnerability to chronic stress and the phenotypic heterogeneity of presbycusis with subjective tinnitus

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