DEFINING TOMORROW'S VASCULAR STRATEGIES
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22 March 2021
Triglycerides, dementia and atherosclerotic cardiovascular disease
Moderately elevated triglycerides may represent a risk factor for both dementia and atherosclerotic cardiovascular disease (ASCVD), according to this study.
Nordestgaard LT, Christoffersen M, Afzal S, et al. Triglycerides as a shared risk factor between dementia and atherosclerotic cardiovascular disease: a study of 125 727 individuals. Clin Chem 2021;67:245-255.
STUDY SUMMARY
Objective: To investigate whether hypertriglyceridaemia is associated with increased risk of non-Alzheimer dementia, Alzheimer disease, and ischaemic stroke.   
Study design: Observational analysis using longitudinal data from the Copenhagen General Population Study and the Copenhagen City Heart Study, two very large prospective observational studies.
Study population: 125,727 individuals enrolled in these two Danish studies
Main study variable:

· Plasma triglycerides (TG)

· Non-Alzheimer dementia (vascular and unspecified dementia), Alzheimer disease, and ischaemic stroke, defined according to the International Classification of Diseases.

Methods: Modelling of triglycerides as a predictor of non-Alzheimer dementia, Alzheimer disease, and ischemic stroke was made using Cox regression analysis (restricted cubic splines), with multifactorial adjustments for APOE genotype, body mass index, hypertension, diabetes, smoking, physical activity, and lipoprotein(a).
Results:

Higher plasma TG concentration was associated with increased risk of non-Alzheimer dementia and ischaemic stroke, but not with Alzheimer disease. Patients in the highest percentile for plasma TG (median 629 mg/dL or 7.1 mmol/L) had a 75% increase in the risk of non-Alzheimer dementia and 89% increase in risk for ischemic stroke, compared with those with plasma TG in the 1-50th percentile (median 89 mg/dL or 1.0 mmol/L) (age, sex and cohort adjusted models). This increased risk persisted in multifactorial adjusted models, some of which included body mass index and diabetes (Table 1).

 

Table 1. Association of elevated triglycerides with risk for study endpoints

Endpoint

Hazard ratio (95% CI)*

Age, sex and cohort adjusted

Hazard ratio (95% CI)*

Multivariable adjusted

 

 

 

Non-Alzheimer dementia

1.75 (1.17-2.63)

1.62 (1.08-2.44)

Alzheimer disease

1.18 (0.73-1.91)

1.25 (0.77-2.02)

Ischaemic stroke

1.89 (1.50-2.38)

1.57 (1.24-1.98)

 

* Comparing the highest percentile with 1-50th percentile for plasma TG

Authors’ conclusion: Moderate hypertriglyceridemia was associated with increased risk of both non-Alzheimer dementia and ischaemic stroke, highlighting plasma triglycerides as a shared risk factor between dementia and atherosclerotic cardiovascular disease (ASCVD).

COMMENT

Accumulating data support a role for elevated TG, a marker for TG-rich lipoproteins and their remnants, in the causal pathway for ASCVD.  The strongest evidence is from Mendelian randomization studies and genetic analyses, which support for a causal association between TG and ASCVD (1) 

This study adds new information indicating that elevated TG are also associated with an increased risk for non-Alzheimer’s dementia and ischaemic stroke. These associations are anticipated given that ASCVD underlies both conditions. The lack of association with Alzheimer’s disease may relate to lack of statistical power, given the low incidence of cases in the study populations, possibly due to the age range represented (45 to 67 years). The conclusions are strengthened by methodological features including well-defined study populations with long follow-up and rigorous identification of cases.  It is, however, recognised that the study populations – white, Danish individuals – may limit wider generalisability. 

In conclusion, these findings have important implications given the burden of care associated with both conditions (2); indeed, stroke is the leading cause of disability in adults in developed countries, the second major cause of dementia and the third commonest cause of death (3). Therapeutic targeting of hypertriglyceridaemia not only impacts ASCVD but has benefit in vascular dementia. Further study of a potential role of elevated TG in Alzheimer’s disease is merited, given evidence from mechanistic studies that the vast majority of plasma amyloid, implicated in the pathogenesis of the disease, is lipoprotein-bound, principally to TG-rich lipoproteins (2).

References

1. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014; 384: 626-635.

2. Editorial. The shared burden of stroke and dementia. Lancet Neurology 2016;15:891.

3. Krishnamurthi RV, Moran AE, Feigin VL, et al. Stroke prevalence, mortality and disability-adjusted life years in adults aged 20-64 years in 1990-2013: Data from the Global Burden of Disease 2013 Study. Neuroepidemiology 2015;45:190-202.

4. Mamo JC, Jian L, James AP, et al. Plasma lipoprotein beta-amyloid in subjects with Alzheimer’s disease or mild cognitive impairment. Ann Clin Biochem 2008;45:395–403.

Key words triglycerides; ischemic stroke; dementia; Alzheimer’s diseas