Deciphering Dementia in the Cardiometabolic Continuum

Gian Paolo Fadini; Mario Luca Morieri


Eur Heart J. 2023;44(7):583-585. 

Graphical Abstract

Figure 1.

Deciphering the genetic and environmental drivers of dementia in the cardiometabolic continuum. According to Dove et al., a common genetic background drives the predisposition to both multiple and early-onset cardiometabolic diseases and dementia. Thus, the study challenges the possibility of reducing dementia risk by acting on cardiometabolic event incidence (?). At the same time, genetics can prime response to several environmental factors, especially those that become unmodifiable later in life, but are profoundly affecting both cardiometabolic multimorbidity and dementia risk. Arrows in sandy brown indicate effects of genetics, whereas grey arrows indicate non-genetic effectors. Boxes in blue are conditions considered in the paper, whereas those in grey are still neglected components of this complex interplay.

Several studies in the literature enable a modern view of dementia within the cardiometabolic continuum. Cardiometabolic diseases represent a major burden to healthcare systems and a threat to global health. Effective preventive strategies and novel pharmacotherapies are now helping to reduce this burden. Dementia, instead, is a disease with no cure, immensely impacting the quality of life of affected individuals, their families, and caregivers. It is still a nightmare without ever waking up, given that no effective therapy is available.

The existence of a cardiometabolic continuum is supported by evidence that traditional cardiovascular risk factors, along with metabolic diseases, associate, interact, and potentiate each other to drive the appearance and worsening of cardiovascular complications, such as myocardial infarction, heart failure, and stroke. Within this family of disorders, many pathophysiological links develop bidirectionally. For example, not only is diabetes a risk factor for heart failure, but heart failure can also precipitate diabetes diagnosis and progression.[1] Notably, bidirectional interactions have been demonstrated between diabetes and Alzheimer's disease.[2] Diabetes accelerates neurodegeneration by promoting dysfunction and damage to the cerebral microcirculation, altering glucose metabolism and insulin signalling, as well as by modifying amyloid plaque deposition. In turn, Alzheimer's disease can worsen glucose control through behavioural changes, memory disturbances, hypothalamic dysfunction, and by inducing frailty. Hypoglycaemia contributes to this network of interactions, as shown in a 12-year follow-up study of older patients with diabetes:[3] those who experienced hypoglycaemia had a two-fold increased risk of future dementia, and those who developed dementia had a greater risk for having a subsequent hypoglycaemic event. Distinct patterns may operate for vascular dementia vs. Alzheimer's disease, but studies are often unable to differentiate these two entities.

Available data support similar links between individual cardiometabolic traits and dementia, but few studies examined how the risk changes with the combination of multiple comorbidities in the same individuals. A 'dose–response' relationship between cardiometabolic conditions and dementia should incorporate the duration of exposure, with earlier onset of cardiometabolic diseases arguably being more detrimental to the future risk of dementia. Finally, while it is well known that the apolipoprotein E4 gene variant is associated with Alzheimer's disease, a more general common genetic background may be shared by cardiometabolic diseases and dementia.

In their study published in this issue of the European Heart Journal, Dove et al. examined the association between cardiometabolic multimorbidity and the onset of dementia in a cohort of ~18 000 twin individuals followed for >15 years.[4] They report that the risk of dementia increased stepwise in participants with an increasing number of cardiometabolic comorbidities. The risk of dementia was also positively correlated with the duration of exposure to cardiometabolic diseases. Indeed, cardiometabolic multimorbidities exerted weaker enhancement of dementia risk when they developed or worsened later in life, thereby reinforcing a putative causal association. The study had the outstanding opportunity to distinguish between Alzheimer's disease and vascular dementia, showing similar results for both. The link between cardiometabolic conditions and vascular dementia is intuitively attributable to common risk factors as well as to the systemic nature of vascular disease, with concomitant or ongoing damage to the brain vasculature. It is therefore not surprising that the risk of vascular dementia increased with more severe and earlier onset cardiometabolic diseases. The link with Alzheimer's disease seems less straightforward if one does not consider the wealth of data on insulin resistance being a common denominator of both the cardiometabolic syndrome and Alzheimer's disease,[5] with brain insulin resistance preceding and predicting cognitive impairment.[6] Then, it becomes reasonable to see dementia within the spectrum of the cardiometabolic continuum. Hyperglycaemia has been repeatedly shown to entail risk of cognitive impairment, but the underlying causal relationship is not entirely clear. A Mendelian randomization study performed on the UK Biobank found little evidence for a causal association between genetic determinants of type 2 diabetes or HbA1c and measures of cognitive function and brain structure.[7]

Here comes the most intriguing part of the study by Dove et al., involving dementia-discordant twins. While twin studies had been used before to dissect the genetic and environmental drivers of dementia, this new analysis took advantage of the world's largest population-based twin registry established since the late 1800s. The registry has already contributed to our understanding of the genetic contribution to the onset of Alzheimer's disease.[8] It now shows that the impact of cardiometabolic multimorbidity observed in the entire population [hazard ratio (HR) = 1.51] was unchanged in dizygote twins (HR = 1.55) but was completely abolished in monozygote twins (HR = 0.99). The relatively small number of monozygote twins warrants caution, but, if holding true, this intriguing finding leads to the conclusion that most of the association between cardiometabolic multimorbidity and subsequent dementia risk is due to a shared genetic background rather than to the detrimental effects exerted by cardiometabolic conditions themselves.

This represent the major novelty of the study. Previous studies with a similar approach, focusing on non-stroke cardiovascular disease or coronary artery disease alone, failed to identify a genetic background shared with dementia.[9,10] Conversely, when combining type 2 diabetes, heart disease, and stroke, the authors now found evidence of a common ground. Speculatively, insulin resistance may be a strong denominator, as an underlying feature well known to be involved in the pathogenesis of each of these four conditions.

Previous studies on genetic predisposition to diabetes or HbA1c levels could have failed to identify a causal link with dementia because they included all known variants associated with these traits. However, these are complex disease traits, and their genetic determinants go far beyond insulin resistance. Conversely, Mendelian randomization studies focusing on insulin resistance alone supported the causal relationship with Alzheimer's disease.[11] Moreover, in the light of a shared genetic background, one may also reinterpret the association between mid- and late-life cardiometabolic diseases and dementia risk beyond that of solely the duration of exposure. In fact, the larger impact of mid-life cardiometabolic diseases on dementia may be driven by a stronger genetic predisposition. Data from the same registry showed that the risk of dementia associated with cardiovascular disease was greater among those with a higher genetic risk score for coronary artery disease, who are expected to develop coronary disease earlier in life.[9]

It should be noted that the authors' definition of cardiometabolic diseases included diabetes, heart disease, and stroke, but disregarded other conditions such as hypertension, dyslipidaemia, and obesity. Though such a simplified triad was used in prior studies, it can be criticized as not fully capturing the entire spectrum of the cardiometabolic continuum. Furthermore, a cardiometabolic–renal continuum is now postulated, and the association between chronic kidney disease and dementia is well documented.[12] Whether genetics would explain the impact on dementia risk of a much broader spectrum of conditions within the cardiometabolic–renal continuum needs to be confirmed. To expand this further, there is great interest today in non-traditional risk factors for cardiometabolic diseases, including environmental, psychological, reproductive, and societal factors,[13,14] that could profoundly affect dementia development. Dove et al. took into account some important aspects, such as education, marital status, and lifestyle, but others continue to be overlooked in the vast majority of the literature: income, air pollution, noise, temperature, exposure to light/darkness, and psychological distress. Other remarkable factors driving cognitive decline in the elderly are sensory deprivation statuses, such as vision and hearing loss, which are more common in people with diabetes. All these conditions are confounders in the association between cardiometabolic comorbidities and dementia risk, and should be taken into account in future studies, also when weighting the impact of a shared genetic background.

Some of those factors remain modifiable (i.e. diabetes, lifestyle, environment, education, and deprivation), while others are no longer modifiable later in life (i.e. reproductive and antenatal history, past cardiovascular events). Studies on the common genetic origin of cardiometabolic multimorbidity and dementia inform us on how much should we control cardiometabolic risk factors with the aim of preventing dementia. Of interest is the recent demonstration that the antidiabetic GLP-1 receptor agonist dulaglutide may prevent both cardiovascular events and cognitive decline,[15] but incident dementia is rarely captured by cardiovascular outcome trials and solid data on this point are still scant. New findings on monozygote twins presented by Dove et al. seems to argue against the opportunity of lowering dementia risk by preventing or delaying the summoning of cardiometabolic multimorbidity. Rather, individuals who develop multiple cardiometabolic conditions early in their lives should probably be spotlighted as those who are genetically predisposed to dementia. However, that trajectory is not necessarily going to be inescapable. There is still a chance of slowing down cognitive decline by taking care of the environment that pervades a persons' life in the broader sense and actively tackling all deprivation statuses.

Deciphering dementia in the cardiometabolic continuum remains a challenge (Graphical Abstract), but we are now understanding better the relative contribution of genetic and environmental drivers. Still much has to be done to unravel how the cardiometabolic–renal network operates on top of our genetics and interacts with established, as well as newly recognized, environmental pressures. Hitherto neglected in such a continuum, dementia is earning a prominent role and, due to population ageing, will deserve more attention by the cardiology community, even as an outcome of cardiometabolic interventions.