Loneliness leads to first stages of dementia

In apparently healthy over 65s, loneliness can have a potentially disastrous effect on the brain. Neurologists at the University of Harvard published about this in JAMA Psychiatry. The researchers discovered that loneliness stimulates the accumulation of amyloid plaques, and these amyloid plaques cause dementia.

The researchers did scans of the brains of 79 healthy men and women aged between 65 and 90, which enabled them to see the extent of amyloid plaque accumulation in their brain cells. In people who have Alzheimer’s – which is the cause of dementia in 60-70 percent of all cases – brain cells die off because there are too many of the amyloid plaques.

The researchers also got the participants to fill out standard questionnaires on loneliness, depression and anxiety.

The lonelier the participants were, the more plaques the researchers found in their brains. Even when the researchers had filtered out the effects of other factors such as age, income, social network, depression and anxiety, the relationship was still there.

Brain cells make apolipoprotein E, a protein that transports cholesterol into brain cells. Quite a few people have genes that predispose them to making an over enthusiastic variant of apolipoprotein E. It’s called ApoE4, and this variant increases the likelihood of developing Alzheimer’s. The likelihood of loneliness leading to dementia was even higher in this group than in the people with better genes.

The researchers are aware that the relationship they discovered could be interpreted in various ways. “Loneliness or other subtle impairments in social-emotional perception or behavior could arise in preclinical Alzheimer’s disease due to amyloid-related alterations in neural activity at a local or network level,” they wrote. The plaques they found could actually be the cause of the feelings of loneliness. The researchers are more in favour of the alternative explanation – that loneliness speeds up the formation of plaques.

“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,” they wrote. “Numerous epidemiological studies have established that antecedent social and psychosocial factors, including loneliness, are related to adverse outcomes such as depression, cognitive decline, functional impairment, and earlier mortality in older people.”

“Social disengagement, manifesting as low numbers of social ties, contacts, and group activities, has been associated with cognitive decline in population-based studies of older people, even in those individuals with relatively high baseline cognitive and functional status.”

“Many studies have also found independent effects on long-term cognition for more qualitative social and socio-emotional constructs such as emotional support, negative social interactions, and loneliness.”

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


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.

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).

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.


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