Similar Risk Factors Found for Young- and Late-Onset Dementia

Health and lifestyle influence the risk of late-onset dementia. Is this true when disease begins before age 65? Yes, according to researchers led by Stevie Hendriks and Sebastian Köhler, Maastricht University, the Netherlands. In the December 26, 2023, JAMA Neurology, they enlist 15 risk factors, many of which are modifiable, as being associated with risk for young-onset dementia (YOD). They included cardiovascular ill health, diabetes, excessive drinking, social isolation, and having two APOE4 alleles.

“This is a great step in identifying reversible risk factors of YOD that people can focus on to try to reduce their risk,” Dustin Hammers, Indiana University School of Medicine, Indianapolis, told Alzforum. Hammers collaborates on the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS). Zoe Arvanitakis of Rush University Medical Center in Chicago sees it similarly. “It gives hope to families of people with YOD that, if you live a healthy lifestyle, there is something you can do about it,” she said.

Most of the factors Hendriks and Köhler identified also contribute to risk for late-onset dementia (LOD), meaning that tackling these co-morbidities and lifestyle issues might prevent dementia across the age span. “[That] the risk factors … associated with YOD are essentially the same as those reported to be associated with LOD is reassuring,” wrote David Bennett, also at Rush U. The amount of overlap with LOD surprised Arvanitakis. “To me, it means that we need to think of early life, rather than mid-life, risk factors for dementia and move several decades earlier, from the 50s to the 20s, in terms of risk reduction research,” she said.

Scientists have produced an extensive body of research on modifiable risk factors of LOD (e.g., Aug 2020 conference news; Jan 2022 news; Aug 2020 conference news). In contrast, just a few dozen studies have tackled YOD. This is mainly because it is rare; the incidence in the current study was less than 0.2 percent.

Prior studies attributed increased risk of YOD to fewer years of formal education, poor cardiovascular health, depression, and heavy alcohol use, among other factors. Alas, associations were inconsistent and study populations small, typically only a few hundred people (reviewed by Cations et al., 2016; Cations et al., 2018; Chen et al., 2017).

In one large study of almost 489,000 Swedish men who as teens had enlisted in their country's armed services, 487 who developed YOD three decades later had modifiable risk factors similar to those identified by previous studies (Aug 2013 news).  

To test a more general population, first author Hendriks analyzed health records from 356,000 participants in the U.K. Biobank who were cognitively normal at baseline. On enrollment, their average age was 55; half were women. Over nine years of follow-up, on average, 485 were diagnosed with all-cause dementia, i.e., YOD. Hendriks correlated YOD incidence with 39 risk factors, including sociodemographic, lifestyle, cardiometabolic, psychiatric, other health factors, blood measurements, air pollution measures, and the number of APOE4 alleles.

Risk Factors. Fifteen modifiable risk factors were associated with a lower or higher risk of developing early onset AD (p-values <0.05). [Courtesy of Hendriks et al., JAMA Neurology, 2023.]

Of these 39 factors, three lowered and 12 increased risk of YOD (image above). The latter included nine known to increase LOD risk: low socioeconomic status, hearing loss, stroke, heart disease, diabetes, depression, vitamin D deficiency, social isolation, and carrying two copies of APOE4. These increased risk by 1.53- to 3.25-fold.

Two of the other three risk factors—high plasma C-reactive protein levels and orthostatic hypotension—had a weaker relationship with dementia. Elevated plasma C-reactive protein correlated with a 1.5-fold risk of YOD. Orthostatic hypotension, i.e., a drop in blood pressure when standing after sitting or lying down, correlated with a 4.2 times higher risk of YOD. The authors believe these correlations might be due to reverse causation, since the associations collapsed in people diagnosed three years or more after baseline, suggesting that baseline CRP and hypotension might be driven by impending dementia.

More dubious results emerged from analyzing drinking. Having a diagnosis of alcohol-use disorder, simply defined as being dependent on alcohol, came out as linked to double the risk of getting YOD. Strangely enough, alcohol consumption appeared protective. Compared to non-drinkers, people who drank alcohol moderately, or even heavily, had a 28 to 36 percent lower risk of dementia, respectively. Moderate drinkers consumed one or two alcoholic beverages per day, while heavy drinkers had more than two daily. This stumped Hendriks, but she suspects that moderate alcohol consumption reflects the “healthy drinker” phenomenon that has surfaced recently in the literature: Namely, that alcohol falsely seems beneficial because some avoid drinking due to their poor health or medications they take, or because they have quit after years of drinking to excess. Previous U.K. Biobank studies have debunked the idea that alcohol is protective, linking even mild drinking to increased risk for hypertension, coronary artery disease, and brain atrophy, with higher consumption having progressively worse outcomes (Biddinger et al., 2022; Daviet et al., 2022). 

The two other protective factors, one physical and one mental, namely a stronger grip and education, i.e., having a higher academic degree, reduced risk by 42 and 37 percent, respectively.

All told, most of the 15 factors that alter YOD risk echo those that contribute to LOD and are amenable to interventions. “Addressing these modifiable factors may prove effective in mitigating the risk of developing YOD and can be readily integrated in current dementia prevention initiatives,” wrote Hendriks and colleagues.—Chelsea Weidman Burke

Comments

  1. This study identified risk factors for young-onset dementia, including: lower formal education, lower socioeconomic status, carrying two apolipoprotein e4 alleles, no alcohol use, alcohol use disorder, social isolation, vitamin D deficiency, high C-reactive protein levels (women only), lower handgrip strength, hearing impairment, orthostatic hypotension, stroke, diabetes (men only), heart disease, and depression.

    The take-home message is that risk factors for young-onset dementia identified from the U.K. Biobank include many, but not all, of the same risk factors as those identified for older-onset, aka late-onset dementia. I can summarize in two words the most important thing to do to reduce your risk of dementia, whether you are young or old: Stay healthy!

    The biggest thing that surprised me were the risk factors that were missing: physical activity, diet, high blood pressure.

    To understand the risk factors, I think it is helpful to think about them in categories.

    There are risk factors that we know, or suspect, to actually cause dementia, either directly or indirectly. These include carrying two apolipoprotein e4 alleles, alcohol use disorder, social isolation, vitamin D deficiency, hearing impairment, stroke, diabetes, and heart disease.

    Other risk factors may not cause dementia but may be associated with less cognitive reserve, leading dementia symptoms to show up earlier. These include lower formal education and lower socioeconomic status.

    Some apparent risk factors may be attributable to “reverse causation.” In other words, the impending dementia may cause symptoms that, because they present before overt dementia, appear to be risk factors. These include: lower handgrip strength (a sign of frailty), no alcohol use (because once people develop memory loss they may stop drinking, also known as the “healthy drinker effect”), and depression (because many people get sad when they have trouble remembering or when they are worried about having dementia).

    Lastly, there are risk factors that could be either a contributing cause or a result of the impending dementia. These include high C-reactive protein (a sign of inflammation) and orthostatic hypotension (which can lead to brain damage and dementia but can also be a result of some types of dementia).

    Prior studies also found the following risk factors associated with young-onset dementia: stroke, depression, alcohol use disorder, vitamin D deficiency, and social isolation. There were also some risk factors found in prior studies not found in this study: height, hypertension, dementia in the father, overall cognitive function, drug use disorder, and neuroleptic use (medication used to treat agitation or psychosis).

    View all comments by Andrew E. Budson

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References

News Citations

  1. Lancet Commission’s Dementia Hit List Adds Alcohol, Pollution, TBI
  2. Stroke Severity, Recurrence Increase Dementia Risk
  3. Heart Health Is Brain Health, and It Starts in Your 20s
  4. Cognitive Function and Alcohol Major Predictors for Early Dementia

Paper Citations

  1. Cations M, Withall A, Low LF, Draper B. What is the role of modifiable environmental and lifestyle risk factors in young onset dementia?. Eur J Epidemiol. 2016 Feb;31(2):107-24. Epub 2015 Nov 30 PubMed.
  2. Cations M, Draper B, Low LF, Radford K, Trollor J, Brodaty H, Sachdev P, Gonski P, Broe GA, Withall A. Non-Genetic Risk Factors for Degenerative and Vascular Young Onset Dementia: Results from the INSPIRED and KGOW Studies. J Alzheimers Dis. 2018;62(4):1747-1758. PubMed.
  3. Chen Y, Sillaire AR, Dallongeville J, Skrobala E, Wallon D, Dubois B, Hannequin D, Pasquier F, Lille YOD study group. Low Prevalence and Clinical Effect of Vascular Risk Factors in Early-Onset Alzheimer's Disease. J Alzheimers Dis. 2017;60(3):1045-1054. PubMed.
  4. Biddinger KJ, Emdin CA, Haas ME, Wang M, Hindy G, Ellinor PT, Kathiresan S, Khera AV, Aragam KG. Association of Habitual Alcohol Intake With Risk of Cardiovascular Disease. JAMA Netw Open. 2022 Mar 1;5(3):e223849. PubMed.
  5. Daviet R, Aydogan G, Jagannathan K, Spilka N, Koellinger PD, Kranzler HR, Nave G, Wetherill RR. Associations between alcohol consumption and gray and white matter volumes in the UK Biobank. Nat Commun. 2022 Mar 4;13(1):1175. PubMed.

External Citations

  1. Longitudinal Early Onset Alzheimer’s Disease Study

Further Reading

No Available Further Reading

Primary Papers

  1. Hendriks S, Ranson JM, Peetoom K, Lourida I, Tai XY, de Vugt M, Llewellyn DJ, Köhler S. Risk Factors for Young-Onset Dementia in the UK Biobank. JAMA Neurol. 2024 Feb 1;81(2):134-142. PubMed.

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