Loneliness Linked to Alzheimer’s Disease

Nancy A. Melville

November 07, 2016

Older, cognitively normal adults with elevated levels of cortical amyloid are much more likely to report loneliness and feelings of social isolation, regardless of their social circumstances, a fact that underscores the potential role of loneliness in preclinical Alzheimer's disease.

"We report a novel association of loneliness and cortical amyloid burden in cognitively normal older adults and present evidence for loneliness as a neuropsychiatric symptom relevant to preclinical Alzheimer's disease," the authors, led by Nancy J. Donovan, MD, an associate psychiatrist at the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital, in Boston, Massachusetts, write.

"Amyloid-positive individuals were 7.5 times more likely than amyloid-negative persons to endorse any loneliness item sometimes or often."

The findings were published online November 2 in JAMA Psychiatry.

Causal Relationship?

The study included 79 cognitively normal, community-dwelling persons enrolled in the Harvard Aging Brain Study. The mean age of the participants was 76.4 years.

A total of 22 (28%) tested positive for apolipoprotein E ɛ4 (APOEε4), the genetic risk factor for Alzheimer's disease; 25 (32%) were had cortical amyloid burden, determined by Pittsburgh compound B–positron emission tomography (PiB-PET).

Self-reports of loneliness were assessed using the three-item UCLA Loneliness Scale, which asks, "How often do you feel you lack companionship?," "How often do you feel left out?," and "How often do you feel isolated from others?"

Answers were given on a four-point scale, with 1 indicating never; 2, rarely; 3, sometimes; or 4, often. The total possible scores could range from 3 to 12, with higher score indicating greater loneliness.

The overall mean loneliness score among the participants was 5.3.

After adjusting for variables that included age, sex, APOEε4 carrier status, socioeconomic status, depression, anxiety, and social networks, participants with a higher amyloid burden had a 7.5-fold greater likelihood of being classified as being lonely compared to those without that amyloid burden (odds ratio [OR], 7.5; 95% confidence interval [CI], 1.7 - 34.0; P = .01).

The link between high amyloid burden and loneliness was also significantly stronger in carriers of APOEε4 in comparison with those who were not carriers. Moreover, the link increased with higher burden ― for each 0.1 distribution volume ratio of PiB, the mean UCLA Loneliness Scale score was increased by an additional 0.5 units in APOEε4 carriers compared to noncarriers, the authors note.

The results are consistent with hypotheses concerning the effects of self-perception in preclinical Alzheimer's disease, Dr Donovan told Medscape Medical News.

"We are interested in the possibility that early brain changes due to Alzheimer's disease may be associated with subtle changes in social perception or social reward that could predispose to feelings of loneliness.

"Alternatively, social interactions may be cognitively demanding in individuals who may be experiencing mild subjective cognitive changes due to early Alzheimer's disease that might cause them restrict their social activity and feel lonely," she added.

Previous research has linked social experiences, including loneliness, with various adverse outcomes, such as depression, cognitive decline, and earlier mortality in older people. In light of this research, the authors speculate that the experience of loneliness may play a causative role in Alzheimer's disease.

"It is also possible that the subjective experience of loneliness or detachment may promote amyloid accumulation, or there may be dynamic and reciprocal effects over time," the authors note.

The researchers plan additional longitudinal studies to further evaluate whether APOEε4 influences unidirectional and/or bidirectional associations of amyloid burden and loneliness over time.

Novel Findings

The findings suggest an important role of loneliness as a symptom of mild behavioral impairment, which is gaining attention as an important concept to consider along with mild cognitive impairment, writes Paul B. Rosenberg, MD, in a commentary published concurrently with the study.

"These are novel findings, and the construct of loneliness merits a closer look," Dr Rosenberg writes.

The study is particularly important with respect to research into the earliest stage of Alzheimer's disease, Dr Rosenberg told Medscape Medical News.

"When someone walks into the clinic with their first functional problem, they've already had the disease for 20 years, so there is clearly a big window of time before that to intervene," he explained.

"We've been moving to looking at people with mild symptoms, but even they may be too far along to help, so we're trying to get to people with their first symptoms, when they are subtle, so preclinical."

Although mood changes have been among the most prominent early behavioral symptoms linked with preclinical Alzheimer's disease, loneliness appears to be another appropriate candidate, he said.

"Loneliness is fascinating as a possible symptom, for various reasons ― for one thing, it hasn't been on our list before, and the fact that in this study it wasn't actually related to the subjects' social network is very interesting."

Until more is known, the findings suggest at the very least that clinicians should not dismiss reports of loneliness, particularly when other symptoms, such as mood changes, are present.

"Right now, when older people say they're lonely, we may assume it's because they are socially isolated, as many older people are, but this study suggests that we should be listening with another ear. When a patient reports loneliness, there may be more going on than is realized," said Dr Rosenberg.

The study was supported by the National Institute of Aging; the Harvard Medical School Department of Psychiatry Dupont-Warren Fellowship and Livingston Award; the Harvard Aging Brain Study; and the Muriel Silberstein Alzheimer's Disease Research Fund. The authors and Dr Rosenberg have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online November 2, 2016. Full text, Commentary

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