By Matthew E. Fink, MD
Louis and Gertrude Feil Professor and Chair, Department of Neurology, Associate Dean for Clinical Affairs, NYP/Weill Cornell Medical College College
In this large, population-based prospective cohort study, the investigators identified 15 risk factors that have strong associations with young-onset dementia. Modifications of these risk factors might delay the onset of, or prevent the development of, young-onset dementia.
Hendriks S, Ranson JM, Peetoom K, et al. Risk factors for young-onset dementia in the UK Biobank. JAMA Neurol 2023; Dec 6:e234929. doi:10.1001/jamaneurol.2023.4929. [Online ahead of print].
The global prevalence of dementia is increasing rapidly and is expected to rise from 50 million people in 2020 to 115 million people in 2050. Dementia most commonly occurs in older people, but it also can occur at a younger age. When dementia symptoms develop before the age of 65 years, it is defined as young-onset dementia (YOD). Although the numbers for YOD (3.9 million) are considerably lower than for late-onset dementia (LOD), the effect on society and families is profound when dementia occurs at a younger age.
In recent years, there has been great interest and investigation to identify modifiable risk factors that would aid in developing a program that might delay or prevent the onset of dementia. A great deal of work has looked at genetic factors, but, so far, genetic factors have been found to account for less than 10% of all YOD cases. The major genetic risk factor is apolipoprotein E (APOE), and carrying an APOE 4 allele will increase the risk of Alzheimer’s dementia in young persons, as well as in older persons.
Recent observational studies have suggested a number of modifiable risk factors, such as smoking, alcohol intake, cardiometabolic factors, and depression. Other factors that may result in protection and delay of the onset of dementia include a healthy diet, cognitive and social activity, and regular physical activity.
The study by Hendriks et al aims to investigate a large population database of individuals younger than the age of 65 years to determine if potentially modifiable risk factors are present in a dementia population compared to a control group.
The investigators used data from the UK Biobank, an ongoing prospective cohort study in the United Kingdom that consists of more than 500,000 participants recruited between 2006 and 2010, ages 37 to 73 years at baseline. The patients underwent physical examination, completed questionnaires, and provided biological samples. The current study was conducted with all participants who were younger than age 65 years and had no evidence of dementia at the time of enrollment. They then were followed until 2021, and patients with YOD were identified from hospital inpatient registers or death registers. A diagnosis of all-cause dementia was used to identify members of this group.
At baseline, 502,536 participants were assessed and, after exclusion for age older than 65 years or presence of dementia at baseline, there remained 356,052 patients included as participants. The mean age was 54.6 years and 55.3% were women. Mean follow-up duration was 8.12 years, and 485 incident cases of YOD were identified. Incident rates of YOD increased with age and were higher in men compared with women. In this study, the incident rate of YOD was 16.8 per 100,000 person years.
The investigators then identified 39 potential risk factors based on systematic reviews on factors that might have a potential association with either YOD or LOD. These factors then were grouped into domains of sociodemographic, genetic, lifestyle, environmental, blood marker, cardiometabolic, psychiatric, and other factors. Age, sex, education, economic status, and APOE status were included in all the analyses. These risk factors then were analyzed in a manual stepwise regression with a correlation matrix.
Of the 39 factors that initially were analyzed, 15 remained and showed a significant and robust association with YOD. A higher educational level, less physical frailty, and any alcohol use (relative to abstinence) were associated with a lower incidence of YOD. Having two APOE 4 alleles, lower socioeconomic status, high C-reactive protein (CRP), orthostatic hypotension, stroke, diabetes, heart disease, depression, hearing impairment, vitamin D deficiency, alcohol use disorder, and social isolation all were associated with an increased risk for YOD.
COMMENTARY
In this robust analysis based on a prospective cohort with comprehensive data, many of the risk factors identified were consistent with other studies published prior to this paper. However, there were some unexpected findings. In this study, the association of hypertension with YOD became nonsignificant when socioeconomic status was added to the model, suggesting a confounding problem, and addressing possible causation for hypertension.
Moderate to heavy alcohol use was associated with a lower incidence of dementia in this population. The authors suggest that this may be a result of the “healthy drinker effect,” in which people who drink are healthier than those who abstain. However, alcohol use disorder is associated with a higher risk of dementia. The findings regarding alcohol use are complex and will need to be investigated further.
Diabetes, stroke, heart disease, and depression all were associated with an increased risk of dementia. However, the diagnosis of depression also may be a prodrome of dementia syndrome, which is a problem that also requires further investigation. There was an interaction between sex and diabetes, in that diabetes was a significant risk factor only in men and not women. Other risk factors reported in this study have not been identified in previous reports, including social isolation, orthostatic hypotension, vitamin D deficiency, and high CRP levels. Orthostatic hypotension may be an early sign of Lewy body dementia with or without Parkinson’s disease, or it may be a cause of dementia because of cerebral hypoperfusion. Again, more investigation is needed to fully understand the significance of these risk factors.
Overall, this study revealed significant and robust risk factors for YOD. Many of these risk factors can be modified and are appropriate for the development of clinical trials that are designed to delay the onset or prevent the development of YOD.
