Loneliness May Be a Precursor to Alzheimer's Disease

Recognition of self-reported symptoms that may appear at early onset of amyloid accumulation, such as loneliness, point to opportunities for preventive therapies.
Recognition of self-reported symptoms that may appear at early onset of amyloid accumulation, such as loneliness, point to opportunities for preventive therapies.

Researchers from Brigham and Women's Hospital in Boston, led by Nancy Donovan, MD, director of the Center for Alzheimer Research and Treatment, have identified loneliness as a precursor to clinical Alzheimer's disease (AD) in a study published in JAMA Psychiatry.1

Using a community-dwelling cohort of 79 participants (43 women, 36 men) between the ages of 65 and 90 who were cognitively normal at the outset, the investigators found that increased amyloid burden  was up to 7.5 times more likely to be associated with reports of loneliness in these individuals. The association between loneliness and amyloid burden was highest among those who carried the genetic risk factor for AD, apoliprotein E ε4 (APOE ε4).

Quantification of loneliness was assessed using The UCLA Loneliness Scale, which requires participants to rate the occurrence of lack of companionship, feeling left out, and feeling isolated from 1-4 (ranging from never to often). The participants also all underwent positron emission tomography (PET) scans, assessed according to Pittsburgh Compound B (PiB) criteria, to quantify amyloid burden in the brain. Higher PiB-PET scores corresponded to higher loneliness scores.

The construct recognized as “loneliness” features a combination of social and emotional isolation. What makes loneliness a good marker is the fact that it is quantifiable by a number of measures, the authors argued, and may be readily distinguished from other mental states including depression, anxiety, and social isolation due to other causes.

The association between loneliness and cognitive and functional decline has been previously documented, but without directly linking it to the risk of developing AD.2-6 Dr Donovan and colleagues were able to demonstrate a clear link between loneliness and in vivo measurements of amyloid burden in the brain that marks the development of cognitive decline.

The Brigham and Women's study indicates that amyloid accumulation may exert influence on social behaviors that lead to greater isolation — loneliness — and that these behavioral changes may be rooted in cognitive changes occurring at very early stages of cognitive decline. "People who are starting to accumulate amyloid may not be as well-functioning in terms of perceiving, understanding, or responding to social stimuli or interactions," Dr Donovan reported, adding that, "This could be an early social signal of cognitive change."

The significance of this study, as reported in the accompanying editorial by Paul Rosenberg, MD, of Johns Hopkins University in Baltimore, Maryland,7 is that it moves potential detection of AD — and the possibility of intervention — up to a much earlier point in the disease process than even the current threshold of preclinical disease identified by biomarkers such as PiB-PET measurements of amyloid burden. “One can imagine a future landscape of treatment in which older persons are screened for AD risk with a mix of self-report measures,” Dr Rosenberg suggested, noting that further investigations should look at other neuropsychiatric symptoms as potential additional markers.

Clinical Implications

Current therapies are aimed at slowing disease progression in patients already showing clinical signs of AD. Recognition of self-reported symptoms, such as loneliness, that may appear at early onset of amyloid accumulation points to opportunities for preventive therapies or those that may at least arrest disease progression at much earlier stages. The study also suggests potential of other changes in behavioral and social status that may provide very early signs of impending cognitive decline.

References

  1. Donovan NJ, Okereke OI, Vannini P, et al. Association of Higher Cortical Amyloid Burden With Loneliness in Cognitively Normal Older Adults. JAMA Psychiatry. 2016; doi:10.1001/jamapsychiatry.2016.2657.
  2. Wilson RS, Krueger KR, Arnold SE, et al. Loneliness and risk of Alzheimer disease. Arch Gen Psychiatry. 2007;64:234-240.
  3. Deary IJ, Gow AJ, Taylor MD, et al. The Lothian Birth Cohort 1936: a study to examine influences on cognitive ageing from age 11 to age 70 and beyond. BMC Geriatr. 2007;7:28.
  4. Tilvis RS, K.h.nen-V.re MH, Jolkkonen J,et al. Predictors ofcognitive decline and mortality of aged people over a 10-year period. J Gerontol A Biol Sci Med Sci. 2004;59:268-274.
  5. Shankar A, Hamer M, McMunn A, et al. Social isolation and loneliness: relationships with cognitive function during 4 years of follow-up in the English Longitudinal Study of Ageing. Psychosom Med. 2013;75:161-170.
  6. Donovan NJ,Wu Q, Rentz DM, et al. Loneliness, depression and cognitive function in older U.S. adults. Int J Geriatr Psychiatry. 2016.
  7. Rosenberg PB. Loneliness as a Marker of Brain Amyloid Burden and Preclinical Alzheimer Disease. JAMA Psychiatry. 2016; doi:10.1001/jamapsychiatry.2016.2688.
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