R3i Editorials

March 2021
Elevated triglyceride: linking ASCVD and dementia
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

The connection between the heart and brain has been long recognised. Epidemiological studies show that an adverse profile of cardiovascular risk factors, including hypercholesterolaemia, hypertension, hyperglycaemia and smoking, from midlife onwards is implicated in the development and onset of cognitive decline and dementia 1. Indeed, up to one-third of global dementia cases might be attributable to these modifiable risk factors 2. This has led some to propose an algorithm-based risk score to identify high-risk individuals most likely to benefit from early intervention against the major cardiovascular risk factors to prevent dementia 3. Added to this, cardiometabolic conditions such as metabolic syndrome, obesity and type 2 diabetes mellitus – the other pandemics -are also associated with an increased risk for dementia 4. All three conditions are commonly associated with atherogenic dyslipidaemia, characterised by elevated triglycerides (TG) and decreased high-density lipoprotein cholesterol. The increasing population prevalence of hypertriglyceridaemia, as well as accumulating evidence for a causal role of TG-rich lipoproteins – typified by the biomarker plasma TG – in atherosclerotic cardiovascular disease (ASCVD), suggest a plausible rationale to investigate potential associations between TG and different dementia types. This was the aim of the study by Nordestgaard and colleagues 5, discussed in this month’s Focus.

Briefly, the authors used longitudinal data from over 125,000 individuals enrolled in the Copenhagen General Population Study and the Copenhagen City Heart Study to study this question. While they demonstrated an association between higher TG and risk for non-Alzheimer’s dementia or ischaemic stroke, there was no significant association for risk for Alzheimer’s disease. This finding, however, does not exclude an association, given the age range of individuals in the studies (45 to 67 years) and the limited number of cases of Alzheimer’s disease 5.

In an accompanying editorial 6, evidence for a possible link between TG and Alzheimer’s disease was discussed. Other cohort studies have suggested an association, although it must be acknowledged that in a recent study from Korea, evidence suggesting that hypertriglyceridaemia was predictive of Alzheimer’s disease and vascular dementia may more likely relate to the prevalence of hypertension in the study cohort 7. On the other hand, there is evidence that beta-amyloid, a defining marker of Alzheimer’s disease, is largely lipoprotein-bound, principally to TG-rich lipoproteins 8,9. Studies in an amyloid-transgenic mouse model for Alzheimer’s disease also implicate amyloid bound to TG-rich lipoproteins in disease progression (10). Questions about a potential association between TG-rich lipoproteins and Alzheimer’s disease have yet to be resolved.

It should be noted that associations between modestly elevated TG and risk for non-Alzheimer’s dementia and ischaemic stroke demonstrated by Nordestgaard et al 5 are anticipated given evidence supporting TG-rich lipoproteins in the causal pathway of ASCVD 11.

Taken together, the ensuing question is: Should TG be a therapeutic target to prevent both ASCVD and dementia? Certainly, lowering elevated TG to desirable levels (<1.7 mmol/L or <150 mg/dL) is recommended by guidelines to prevent ASCVD, of which ischaemic stroke and vascular dementia are related complications. The jury is still out on a link between elevated TG and Alzheimer’s disease. Resolving such uncertainties is critical given that, globally, the number of individuals living with dementia has more than doubled between 1990 and 2016 12. The burden on individuals, carers and healthcare providers is already substantial and escalating, as populations age. Clearly, more needs to be done to manage known risk factors, as well as identify emerging risk factors, possibly elevated TG, a feature of type 2 diabetes, metabolic and obesity.

References

  1. Qiu C, Fratiglioni L. A major role for cardiovascular burden in age-related cognitive decline. Nat Rev Cardiol 2015;12:267–277.
    2. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet 2017;390:2673-2734.
    3. Rasmussen IJ, Rasmussen KL, Nordestgaard BG et al. Impact of cardiovascular risk factors and genetics on 10-year absolute risk of dementia: risk charts for targeted prevention. Eur Heart J 2020;41:4024-4033.
    4. Beeri MS, Bendlin BB. The link between type 2 diabetes and dementia: from biomarkers to treatment. Lancet Diabetes Endocrinol 2020;8:736-738.
    5. 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.
    6. Watts GF, Mamo JCL. Hypertriglyceridemia and Alzheimer Disease: opening the mind to new therapeutic opportunities. Clin Chem 2021;67:6-8.
    7. Lee JY, Han K, Han E, et al. Risk of incident dementia according to metabolic health and obesity status in late life: a population-based cohort study. J Clin Endocrinol Metab 2019;104:2942–2952.
    8. Takechi R, Galloway S, Pallebage-Gamarallage MM, Mamo JC. Chylomicron amyloid beta in the aetiology of Alzheimer’s disease. Atheroscler Suppl 2008;9:19–25.
    9. 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.
    10. Burgess BL, McIsaac SA, Naus KE, et al. Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer’s disease mouse models with abundant A beta in plasma. Neurobiol Dis 2006;24:114–127.
    11. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease. New insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-563.
    12. GBD 2016 Dementia Collaborators. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18:88-106.