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Loneliness Increases Risk of Alzheimer Disease, New Study Finds

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Although prior research has linked social isolation with an increased risk of dementia, there has been little attention paid to emotional isolation or perceived social isolation – until this new study in Archives of General Psychiatry.

An ongoing study of elderly seniors found that loneliness significantly increases the risk of Alzheimer disease. Postmortem examination of subjects who died over the course of the four-year study, however, revealed no association between loneliness or dementia and the typical pathological signs of the disease.

Among more than 800 seniors whose average age was 80 years, those scoring highest on a standardized “loneliness” test scale had more than twice the risk of dementia than subjects with the lowest scores, according to a report published in the February issue of Archives of General Psychiatry (2007;64:234–240).

The association between self-perceived loneliness and dementia was independent of cognitive function at the study's outset, social isolation, depression, vascular burden, or level of mental or physical activity, according to lead author Robert S. Wilson, PhD, professor of neurological sciences and senior neuropsychologist at the Rush University Alzheimer's Disease Center, in Chicago.

Although prior research has linked social isolation with an increased risk of dementia, there has been little attention paid to emotional isolation or perceived social isolation, Dr. Wilson told Neurology Today in a telephone interview.

“The results suggest that loneliness contributes to risk of Alzheimer disease, and it does so through some mechanism other than typical disease pathology or cerebral infarction,” he said.

STUDY PROTOCOLS

The subjects in the study, who lived independently, were evaluated using the de Jong-Gierveld Loneliness Scale, a standardized test developed in the mid-1980s that evaluates loneliness on a scale of one to five, with higher scores indicating more loneliness. Subjects also underwent standard dementia and Alzheimer disease testing, and functional measurement of learning and memory, at the study's outset and annually.

A total of 76 seniors developed Alzheimer disease dementia over the four-year study. The average loneliness score for all patients was 2.3, and dementia risk increased by about 50 percent for each point rise on the loneliness scale. For example, a subject with high loneliness score (3.2) had about 2.1 times the risk of developing Alzheimer disease than a person with a low score (1.4).

Autopsies on 90 of the volunteers who died during the study failed to find any association between loneliness or dementia scores and any of the characteristic pathological changes associated with Alzheimer disease, such as amyloid plaques and neurofibrillary tangles, or with tissue damage due to blockage of blood flow to parts of the brain.

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Dr. Robert S. Wilson: “The results suggest that loneliness contributes to risk of Alzheimer disease, and it does so through some mechanism other than typical disease pathology or cerebral infarction.”

If there is a biological process or mechanism responsible for the association, it remains unclear, and because loneliness levels remained relatively stable, even in subjects who developed dementia, it seems unlikely that loneliness was caused by dementia, he said.

“The findings weren't a complete surprise because there is evidence that social isolation and connectedness are predictors of cognitive decline in seniors,” Dr. Wilson said, “but there hasn't been much research on what I call emotional isolation, or loneliness. We were able to show with the brain autopsies that dementia and rapid cognitive decline in these patients were not related to amyloid plaques or neurofibrillary tangles, so it isn't simply an early sign of underlying pathology that we know about.”

He noted that social isolation is associated with stress and depression, and both have been linked to elevated risk of cognitive decline.

“There is a substantial body of research on the effects of isolation and stress in animals and the biological changes in the nervous system that can result from long-term stress. These animals have elevated stress hormones and lower levels of neurotrophic factors suggesting that the long-term burden of stress alters brain function over time.”

But depression is “a special case,” he added, noting that when the researchers controlled for depression, it did not reduce loneliness, whereas controlling for loneliness decreased depression substantially, suggesting that loneliness might be one of the drivers of depression, not vice versa.

The researchers will continue to follow and evaluate the subjects, conducting autopsies on the brains of those who die and looking at other biological and neurological aspects, including possible biological pathways that might explain the changes taking place, he said.

COGNITIVE RESERVE

Nikolaos Scarmeas, MD, assistant professor of neurology at Columbia University Medical Center in New York City, said the lack of pathological correlates might be explained by cognitive reserve — the ability of healthy areas of the brain to compensate for those affected by disease — or by earlier, as-yet undetected manifestations of the disease process.

“This is a very good study by a group of researchers with significant experience in this field,” he commented in a telephone interview. “The authors indicate that a possible explanation for the lack of an association between Alzheimer's pathology and dementia in these subjects might be cognitive reserve, but there could also be some other type of biological process going on or brain dysfunction that is not detected by the presence of plaques.”

Brain autopsies show that the extent of plaques does not necessarily correlate with dementia, he noted.

“We can count plaques, but the propensity toward dementia could be due to synaptic problems and neuronal loss before plaques ever appear, but we just don't know. Synaptic and neuronal loss, perhaps caused by amyloid oligomers, might be a better measure than amyloid plaques and neurofibrillary tangles, but even then you will have variations depending on cognitive reserves.”

He also noted that loneliness, as an aspect of the depression, may best capture that part of the depressive domain most relative to cognitive performance and risk of dementia. “This is very important. It's hard to disentangle the whole range of behavior manifestations involved in stress, anxiety, other mood disorders, and the multiple elements of depression, but it was loneliness they found most relevant to dementia — loneliness could be considered a final manifestation of all of these,” he said.

SOCIAL ISOLATION AND STRESS

Social isolation, however, also plays a role in dementia, added Laura Fratiglioni, MD, PhD, professor of epidemiology in the department of neurobiology at the Karolinska Institute and the Stockholm Gerontology Research Centre in Stockholm, Sweden.

In 2002, she published a study of 1,200 elderly Swedes showing that the incidence of dementia, primarily Alzheimer disease, was highest among those seniors with the least social contact and lowest in persons with extensive social contacts with family and friends (Am J Epidemiol 2002;155:1081–1087). None of the seniors exhibited signs of dementia at the outset of the study and all scored well on standarized mental functioning tests, yet the association was true regardless of gender or depressive symptoms, she said.

“A poor social network may act as a precipitating factor for dementia, whereas an extensive social network can delay such an [outcome] by providing emotional and intellectual stimulation,” she told Neurology Today in a telephone interview.

“The Rush study is a step forward in this field and adds to it significantly by incorporating the loneliness scale. We've never had data differentiated like this before. They not only consider social networks but also the individual's feeling of being alone, independent of social contacts. In this sense the study is really elegant.”

She has a different hypothesis, however, as to why the phenomenon exists. “Dr. Roberts and his colleagues hypothesize that loneliness and limited social networking might make these seniors more vulnerable to vascular problems and other detrimental effects on the brain that decrease cognitive reserve. But my hypothesis is that feelings of loneliness increase stress, and stress has been linked to dementia in a number of studies. Loneliness is just one of the factors that increases stress in these seniors – they also have health problems and other negative events in their lives, including the death of spouses, friends, and family members.”

“There's something going on here, but we don't have all the answers yet,” she said.

ARTICLE IN BRIEF

✓ Among more than 800 seniors whose average age was 80 years, those scoring highest on a standardized “loneliness” test scale had more than twice the risk of dementia than subjects with the lowest scores, according to a new study.

REFERENCES

• Wilson RS, Krueger KR, Bennett DA, et al. Loneliness and risk of Alzheimer disease. Arch Gen Psychiatry 2007;64:234–240.
• Wang HX, Karp A, Fratiglioni L, et al. Late-life engagement in social and leisure activities is associated with a drecreased risk of dementia: a longitudinal study from the Kungsholmen project. Am J Epidemiol 2002;155:1081–1087.