Skip to content

Larger Study Confirms Loneliness as a Preclinical Symptom of Alzheimer's Disease

Key findings

  • In 117 cognitively normal adults, greater tau pathology in the right entorhinal cortex was associated with more frequent feelings of lacking companionship, feeling left out or feeling isolated
  • Greater amyloid-ß deposition was also associated with greater loneliness, particularly in carriers of the apolipoprotein e4 allele, the major genetic risk factor for late-onset Alzheimer's disease
  • Together, these findings support the hypothesis that loneliness may be a sensitive subjective marker of very early Alzheimer's disease

It's now accepted that in patients with Alzheimer's disease (AD), deposition of amyloid-β and tau in the brain precedes the symptoms of the disease. There is also increasing evidence that transitional cognitive changes or neuropsychiatric symptoms occur during this preclinical stage. If true, these symptoms might provide opportunities for intervention before cognitive and functional impairment begin.

Nancy J. Donovan, MD, of the Department of Psychiatry, and colleagues previously reported in JAMA Psychiatry that loneliness can be a preclinical symptom of AD. In a study of 79 patients, they found that greater cortical deposition of amyloid-β, imaged with positron emission tomography (PET), was associated with greater self-reported loneliness.

The association was stronger in carriers of the apolipoprotein E (APOE) ε4 allele, the major genetic risk factor for sporadic, late-onset AD.

In a new study that also included imaging of tau, Federico d'Oleire Uquillas, a researcher in the Athinoula A. Martinos Center for Biomedical Imaging at Mass General, Dr. Donovan and colleagues confirmed these results in a larger sample. The results appear in Translational Psychiatry.

Study Methods

The team studied 117 community-dwelling older adults (65–92 years old) from the Harvard Aging Brain Study who tested as cognitively normal and nondepressed. They completed three questionnaires:

  • The three-item version of the UCLA Loneliness Scale, which asks:
    • How often do you feel you lack companionship?
    • How often do you feel left out?
    • How often do you feel isolated from others?
  • The seven items from the Hospital Anxiety Depression Scale (HADS) that ask about anxiety
  • A social network questionnaire that asks whether or not the individual is:
    • Married
    • Has a total of three or more friends, children or relatives who visit monthly
    • Is a member of a community group
    • Participates in religious services or activities

The subjects also underwent two specialized types of PET, which imaged:

  • The entorhinal cortex (EC): an initial site of tau deposition in typical aging as well as in early AD
  • The inferior temporal cortex (ITC): a site where tau often progresses beyond the entorhinal cortex in AD patient and where early amyloid-β deposition occurs

Loneliness Scores

The average loneliness score for the sample was 5.2 out of 12. Overall, 21% of the sample said they feel a lack of companionship sometimes or often, 17% said they feel left out sometimes or often and 13% said they feel isolated sometimes or often.

For most subjects, loneliness scores were low or moderate. However, the researchers consider older adults with even moderate loneliness to be a clinically meaningful group. They point to a nationally representative U.S. study, carried out by researchers at the University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, and published in JAMA Internal Medicine, in which moderately and severely lonely participants had similar adverse functional outcomes and a higher risk of death than nonlonely participants.

Imaging Results

Greater tau deposition in the right EC was associated with higher loneliness scores, adjusting for age, sex and APOE ε4 carrier status. There was no association between loneliness scores and tau pathology in the left EC or the ITC.

The association of loneliness with tau in the right EC remained significant after adjustment for occupation/educational attainment, extent of social network, score on the Geriatric Depression Scale, HADS-anxiety score, memory performance and time between PET scan and neuropsychiatric visit.

Because tau pathology in the right EC was associated with a dimension of loneliness that was unrelated to psychosocial and neuropsychiatric confounders, the researchers conclude that it had a distinct underlying neural mechanism.

Greater deposition of amyloid-β was also associated with higher loneliness scores, adjusting for age, sex and APOE ε4 status, and the association was stronger in APOEε4 carriers than in non-carriers.

Brain Mapping

Whole-brain imaging was consistent with the region of interest results, showing correlations between loneliness scores and tau deposition in the right EC, adjusted for age, sex, APOEε4 carrier status, occupation/educational attainment, social network, depression, anxiety, memory performance and time between visits.

The maps also revealed clusters of tau in the right ITC and right fusiform gyrus. The researchers note that a previous study identified the EC, fusiform gyrus and posterior cingulate cortex as the regions of tau pathology that best distinguished cognitively normal participants with high levels of amyloid-β from those with low amyloid-β. That team defined these regions in combination as a meta-region of interest for early AD changes.

In this context, the researchers conclude, associations of loneliness with higher cortical amyloid-β and higher tau in the entorhinal cortex point to loneliness as a potential marker of more advanced, and possibly more active, AD pathophysiology in cognitively normal older adults.

average loneliness score for the sample (out of 12)

Learn more about the Athinoula A. Martinos Center for Biomedical Imaging

Explore psychiatry research at Mass General


Previous research has shown that diagnostic codes routinely collected in electronic health records can help predict domestic abuse an average of two years in advance. Could EHR systems also be used to predict suicidal behavior?


A consortium of psychiatry researchers from Massachusetts General Hospital has provided the first molecular genetic evidence of PTSD heritability.