Younger Age at AF Onset Linked to Greater Dementia Risk

Atrial fibrillation (AF) is not only linked to an increased likelihood of developing dementia, but this risk increases in people who see their AF symptoms start at a younger age, according to new prospective data.

Complications of AF, such as stroke, have previously been associated with later development of dementia, and both are generally seen as conditions of older age. Prior research has shown a direct connection between AF and dementia, including Alzheimer’s disease and vascular dementia.

Connecting earlier onset AF with an increased risk for dementia may have public health implications, senior author Fanfan Zheng, PhD (Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China), told TCTMD in an email. “Our findings demonstrated that cognitive evaluation and monitoring among AF patients, especially those younger than 65 years at diagnosis, is of paramount importance in clinical practice,” she said.

T. Jared Bunch, MD (University of Utah Hospital, Salt Lake City), who commented on the study for TCTMD, agreed. The findings bring awareness to the need for better treatment of AF in younger patients, who are not always “treated as aggressively with anticoagulation and that can impact brain health over time,” he said. Because treatments for AF are known to be more effective not only in younger people but also when started earlier in the disease course, Bunch added, “it is helpful in that regard to have these type of studies that push the focus into younger patients.”

The findings were published online yesterday in JAMA Network Open with Wenya Zhang, BS (Chinese Academy of Medical Sciences & Peking Union Medical College), as first author.

Dementia and AF Timing

For the study, the researchers analyzed data from 433,746 people (mean age 56.9 years; 54.5% female; 94.5% white) enrolled in the UK Biobank between 2006 and 2010, including 30,601 with diagnosed AF.

Compared with those without AF, those who were diagnosed with the condition had a greater risk of later developing all-cause dementia (adjusted HR 1.42; 95% CI 1.32-1.52) and vascular dementia (adjusted HR 2.06; 95% CI 1.80-2.36) over a median follow-up period of 12.6 years. However, they were no more vulnerable to Alzheimer’s disease (adjusted HR 1.08; 95% CI 0.96-1.21).

Additionally, an analysis of patients with AF showed that younger age of onset was directly related to a higher risk of developing all-cause dementia (adjusted HR per 10-year decrease 1.23; 95% CI 1.16-1.32), Alzheimer’s disease (adjusted HR per 10-year decrease 1.27; 95% CI 1.13-1.42), and vascular dementia (adjusted HR per 10-year decrease 1.35; 95% CI 1.20-1.51).

In a propensity-score-matched analysis, the highest risk of developing all-cause dementia was seen in those with AF diagnosed before age 65 (adjusted HR 1.82; 95% CI 1.54-2.15). This risk was less elevated, though still significantly higher, in those whose AF was diagnosed between age 65-74 (adjusted HR 1.47; 95% CI 1.31-1.65) and not significant in those diagnosed at 75 years or older (adjusted HR 1.11; 95% CI 0.96-1.28). Similar patterns were observed for both Alzheimer’s disease and vascular dementia.

There are several possible explanations for why younger age of AF onset would be linked with a greater risk of later dementia, according to Zheng. First, AF-related ischemic stroke “directly impairs cerebral neuron functions and then contributes the development of dementia in late-life,” she said. Additionally, “hypoperfusion, inflammation, atherosclerotic vascular damage, brain atrophy, and other [mechanisms]” might also be at play, especially when they start earlier in a person’s lifespan, according to Zheng. Lastly, “a younger onset age of AF may represent a higher burden of accumulating risk factors, which collectively exacerbate cognitive impairment.”

Potential Mechanisms

The effect of survival bias can’t be excluded here, in that patients with AF and dementia have a high risk of mortality within the first 6 months and older patients with both conditions are more likely to die before they can be studied, according to Bunch. Also, he pointed to the fact that younger patients are better at recognizing their brain abnormalities, saying, “They see it earlier and they seek evaluation.”

Another potential explanation for the relationship between the younger onset of AF and later dementia risk is that some of the genetic markers of AF are also linked with stroke, Bunch explained, noting that even “small strokes in aggregate can impact brain health.”

Lastly, he said, because younger people are often considered lower risk for brain injury and dysfunction, sometimes treatments like anticoagulation—known to be highly effective when used in first year after an AF diagnosis—are delayed. “So by the time they are started, they have already been in atrial fibrillation, or exposed to atrial fibrillation for multiple years,” Bunch said. “And those things have some consequences.”

Future research should delve further into all these potential mechanisms, he said, but also “what we really need right now is a prospective study.” Specifically, Bunch would like to see investigators seek to understand the threshold wherein AF negatively affects the brain. “Is that zero atrial fibrillation or is 3% okay? 5%? Is it minimizing episodes to less than an hour or less than 24 hours?” he asked. “We also need to understand how the brain responds and adapts and functions; what is the safe range to push to.”

Also, Bunch added, “we need to understand, in a well-studied manner, how aggressive treatments to improve the rhythm of the heart influence the brain, both short-term and long-term.” Some studies of catheter ablation have shown lower associated rates of cognitive decline and dementia, but formal, large studies of this endpoint are still needed, he argued. “That will establish if early, aggressive treatment of the rhythm can help people not only live longer, but feel better as they live longer.”

Although the current study is largely confirmatory, Bunch said, it’s important because “it just adds to the weight of evidence that the risk is real, it's significant, and it gives us an opportunity to improve that risk.”