Is a marker of preclinical Alzheimer’s associated with loneliness?

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Loneliness may be a neuropsychiatric symptom relevant to preclinical Alzheimer’s disease, found a small Harvard study that examined the association of loneliness with cortical amyloid burden in cognitively normal older adults.

Alzheimer’s disease (AD) is a process that moves through pre-clinical, mild cognitive impairment and dementia stages before it leads to progressive neuropsychiatric, cognitive and functional declines. Loneliness has been associated with cognitive and functional decline and an increased risk of AD dementia.

Dr Nancy J Donovan, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and co-authors used imaging as a measure of cortical amyloid levels in the brain and a loneliness scale to indicate levels of loneliness. The study included 43 women and 36 men with an average age of about 76.

Of the participants, 22 (28%) were carriers of the genetic risk factor apolipoprotein E ɛ4 (APOEɛ4) and 25 (32%) were in the amyloid-positive group based on volume in imaging. The participants’ average loneliness score was 5.3 on a scale of 3 to 12.

The authors report higher cortical amyloid levels were associated with greater loneliness after controlling for age, sex, APOEɛ4, socioeconomic status, depression, anxiety and social network. Participants in the amyloid-positive group were 7.5 times more likely to be classified as lonely then non-lonely compared with individuals in the amyloid-negative group. The association between high amyloid levels and loneliness also was stronger in APOEɛ4 carriers than in non-carriers, according to the results.

Limitations of the study include the demographic profile of the participants who had high intelligence and educational attainment but limited racial and socioeconomic diversity. The participants also had better mental and physical health.

“We report a novel association of loneliness and cortical amyloid burden in cognitively normal adults and present evidence for loneliness as a neuropsychiatric symptom relevant to preclinical AD. This work will inform new research into the neurobiology of loneliness and other socioemotional changes in late life and may enhance early detection and intervention research in AD,” the study concludes.

Abstract
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.

Authors
Nancy J Donovan, Olivia I Okereke, Patrizia Vannini, Rebecca E Amariglio, Dorene M Rentz, Gad A Marshall, Keith A Johnson, Reisa A Sperling

JAMA material
JAMA Psychiatry abstract
JAMA Psychiatry invited comment


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