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Four new risk factors for young-onset dementia were identified in the prospective U.K. Biobank study.

Orthostatic hypotension, vitamin D deficiency, high C-reactive protein (CRP) levels, and social isolation emerged as new risk factors for dementia before age 65, reported Stevie Hendriks, PhD, of Maastricht University in the Netherlands, and co-authors in .

During 8 years of follow-up, the incidence rate of young-onset dementia was 16.8 per 100,000 person-years. Incidence increased in 5-year bands from ages 40 to 64 and was higher in men compared with women.

Many people with young-onset dementia are in their 40s and 50s. Recent estimates suggest that young-onset dementia affects about 200,000 people in the U.S.

"Young-onset dementia has a very serious impact, because the people affected usually still have a job, children, and a busy life," Hendriks told MedPage Today. "The cause is often assumed to be genetic, but for many people we don't actually know exactly what the cause is."

"We already knew from research on people who develop dementia at an older age that there are a series of modifiable risk factors," she added. "This study shows that there are several modifiable factors that are also associated with young-onset dementia."

About 40% of late-onset dementia cases may be prevented or delayed by modifying 12 risk factors, according to the Lancet Commission.

Hendriks and colleagues studied 356,052 participants younger than 65 without a dementia diagnosis at baseline. Baseline assessments occurred from 2006 through 2010. Participants were followed until 2021 or until they reached age 65.

The mean baseline age was 54.6 and 55.3% of the cohort were women. Incident young-onset dementia was identified by hospital inpatient records or death registers. Over 8.12 years of follow-up, 485 new cases of young-onset dementia were seen.

The researchers developed a list of 39 potential risk factors from systematic reviews of late-onset dementia and young-onset dementia risk factors. In a fully adjusted model, factors significantly associated with higher young-onset dementia risk were:

• Orthostatic hypotension, HR 4.20
• Depression, HR 3.25
• Alcohol use disorder, HR. 2.39
• Stroke, HR 2.07
• Carrying two APOE4 alleles, HR 1.87
• Lower socioeconomic status, HR 1.82
• Diabetes, HR 1.65
• Heart disease, HR 1.61
• Vitamin D deficiency, HR 1.59
• Hearing impairment, HR 1.56
• High CRP levels, HR 1.54
• Social isolation, HR 1.53

Higher formal education, lower physical frailty (assessed by handgrip strength), and alcohol use were associated with lower young-onset dementia risk.

Orthostatic hypotension was reported as a risk factor for late-onset dementia in a recent umbrella review, Hendriks and colleagues observed. "Additionally, orthostatic hypotension may also be an early sign of Parkinson's dementia or Lewy body dementia, sometimes occurring years or decades before diagnosis, explaining the reverse causality we found in our sensitivity analysis."

"We found both vitamin D deficiency and high CRP levels were associated with increased risk of young-onset dementia," the team added. "It has been suggested that vitamin D acts as a neurosteroid that protects against neurodegenerative processes. Notably, CRP was only significantly associated with young-onset dementia when vitamin D was included in the model."

Other findings may be influenced by reverse causality, since dementia pathology may start years before clinical symptoms, the researchers acknowledged. Some risk factors may reflect an underlying etiology, such as dementia due to stroke. In addition, the U.K. Biobank cohort is overrepresented by healthy and white individuals, and results might not apply to other populations.

"With external validation of our results, more risk factors for young-onset dementia could be incorporated in the prevention strategy communicated from the Lancet Commission," Hendriks and co-authors wrote.

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