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Dementia incidence tripled in lonely older adults who otherwise would be expected to have relatively low risk based on age and genes, researchers found.

Lonely older people under age 80 without an APOE4 allele had a threefold greater risk of dementia (adjusted HR 3.03, 95% CI 1.63-5.62) over 10 years than similar people who weren't lonely, reported Joel Salinas, MD, MBA, MSc, of NYU Grossman School of Medicine in New York City, and colleagues.

Regardless of age or APOE4 status, lonely older adults had a higher 10-year dementia risk compared with those who weren't lonely (adjusted HR 1.54, 95% CI 1.06-2.24).

Among people without dementia, loneliness was associated with poorer executive function, lower total cerebral volume, and greater white matter injury, the researchers wrote in

The study provides that loneliness increases the 10-year risk of developing dementia. "This magnifies the population health implications of observed trends in the growing prevalence of loneliness," Salinas said.

"These findings not only establish the link between loneliness and dementia risk much more firmly, but also have implications for how we think about risk factors for dementia, the relevance of basic loneliness screening in assessing individuals at greater risk, and how there is a potential to underestimate this risk in lonely adults, especially if they don't have any known genetic risk factors like the APOE4 allele," Salinas told MedPage Today.

"Future studies need to clarify the underlying biological pathways involved, but there is much individuals can do now to help address loneliness in themselves, their friends and families, and their communities," he added.

Health risks associated with social isolation and loneliness shifted to the forefront during the COVID-19 pandemic, but the biology of loneliness has been investigated for many years.

"The body treats loneliness as a state of threat and responds by activating defensive systems like the sympathetic nervous system, which in turn prompts the immune system to enhance inflammation," observed Steve Cole, PhD, of the University of California Los Angeles, who wasn't part of the study. "That's one pathway by which social isolation could accelerate the progression of Alzheimer's disease and other inflammation-related chronic diseases," he told MedPage Today.

"However, it's difficult to sort out the mechanisms involved in correlational studies such as this," Cole pointed out. "We also know that inflammation alters brain function and social motivation, raising the possibility that early Alzheimer's-related biological processes might actually promote loneliness and social isolation."

"Regardless of the causal directions involved, this study adds to the growing body of evidence that social process and cognitive health are deeply linked and may open novel opportunities for maintaining cognitive health as we age," Cole said.

Using prospectively collected data from the population-based , Salinas and colleagues assessed 2,308 participants who were dementia-free at baseline with an average age of 73. More than half (56%) were women and 80% of the cohort did not have an APOE4 allele.

Loneliness was recorded at baseline using the Center for Epidemiologic Studies Depression Scale () and was defined as feeling lonely 3 or more days in the past week. Models were adjusted for age, sex, and educational level.

A total of 144 people (6%) were lonely. Over 10-year follow-up, incident dementia occurred in 14% of all participants and in 22% of lonely people.

There was no significant association between loneliness and dementia in people 80 or older, but lonely people who were younger -- ages 60 to 79 -- were more than twice as likely to develop dementia (adjusted HR 2.27, 95% CI 1.32-3.91).

In a second sample of 1,875 dementia-free, stroke-free Framingham Study participants with a mean age of 62, loneliness was associated with poorer cognition in the executive function domain. Of 1,611 people in this sample who had imaging, lonely participants had total cerebral volumes that were 0.25 standard deviation units (SDU) lower and white matter hyperintensity volumes that were 0.28 SDU greater.

These findings suggest that loneliness may be involved in the earliest stages of Alzheimer's or dementia neuropathogenesis, Salinas and colleagues noted.

Like most Framingham Study cohorts, the ones used in this analysis included mainly people who were white. The possibility of reverse causality in this study cannot be ruled out, Salinas' group acknowledged. Loneliness was slightly more prevalent among the oldest participants, but "it remains possible that 'depression without loneliness' had a more influential role than 'loneliness without depression' in this age group," the researchers wrote.

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