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Original Investigation
December 2016

Association of Higher Cortical Amyloid Burden With Loneliness in Cognitively Normal Older Adults

Author Affiliations
  • 1Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 4Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
  • 5Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 6Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
JAMA Psychiatry. 2016;73(12):1230-1237. doi:10.1001/jamapsychiatry.2016.2657
Key Points

Question  Is higher cortical amyloid burden, a marker of preclinical Alzheimer disease, associated with greater self-reported loneliness in older adults with normal cognition?

Findings  In a cross-sectional study of 79 community-dwelling older adults, higher brain amyloid burden was associated with more frequent feelings of isolation, being left out, and lacking companionship, independent of sociodemographic factors, objective measures of social network, depressive and anxiety symptoms.

Meaning  Loneliness, characterized by subtle feelings of social detachment, may be associated with early brain changes in preclinical Alzheimer disease, prior to mild cognitive impairment.


Importance  Emotional and behavioral symptoms in cognitively normal older people may be direct manifestations of Alzheimer disease (AD) pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment. Loneliness is a perceived state of social and emotional isolation that has been associated with cognitive and functional decline and an increased risk of incident AD dementia. We hypothesized that loneliness might occur in association with elevated cortical amyloid burden, an in vivo research biomarker of AD.

Objective  To determine whether cortical amyloid burden is associated with greater loneliness in cognitively normal older adults.

Design, Setting, and Participants  Cross-sectional analyses using data from the Harvard Aging Brain Study of 79 cognitively normal, community-dwelling participants. A continuous, aggregate measure of cortical amyloid burden, determined by Pittsburgh Compound B–positron emission tomography (PiB-PET), was examined in association with loneliness in linear regression models adjusting for age, sex, apolipoprotein E ε4 (APOEε4), socioeconomic status, depression, anxiety, and social network (without and with the interaction of amyloid and APOEε4). We also quantified the association of high amyloid burden (amyloid-positive group) to loneliness (lonely group) using logistic regression, controlling for the same covariates, with the amyloid-positive group and the lonely group, each composing 32% of the sample (n = 25).

Main Outcomes and Measures  Loneliness, as determined by the 3-item UCLA Loneliness Scale (possible range, 3-12, with higher score indicating greater loneliness).

Results  The 79 participants included 43 women and 36 men with a mean (SD) age of 76.4 (6.2) years. Mean (SD) cortical amyloid burden via PiB-PET was 1.230 (0.209), and the mean (SD) UCLA-3 loneliness score was 5.3 (1.8). Twenty-two (28%) had positive APOEε4 carrier status, and 25 (32%) were in the amyloid-positive group with cortical PiB distribution volume ratio greater than 1.2. Controlling for age, sex, APOEε4, socioeconomic status, depression, anxiety, and social network, we found that higher amyloid burden was significantly associated with greater loneliness: compared with individuals in the amyloid-negative group, those in the amyloid-positive group were 7.5-fold (95% CI, 1.7-fold to 34.0-fold) more likely to be classified as lonely than nonlonely (β = 3.3, partial r = 0.4, P = .002). Furthermore, the association of high amyloid burden and loneliness was stronger in APOEε4 carriers than in noncarriers.

Conclusions and Relevance  We report a novel association of loneliness with cortical amyloid burden in cognitively normal older adults, suggesting that loneliness is a neuropsychiatric symptom relevant to preclinical AD. This work will inform new research into the neural underpinnings and disease mechanisms involved in loneliness and may enhance early detection and intervention research in AD.