Loneliness is associated with an increased 10-year incidence of all-cause dementia in adults aged 80 years or younger without an apolipoprotein E4 allele (APOE ε4), a known genetic risk factor for Alzheimer disease (AD). These are the findings of a study published in Neurology.

The prevalence of loneliness is rising from 11% to 14% over a 2-year period extending early into the COVID-19 pandemic, the researchers noted. Among US and international adults aged 60 years and older, the estimated prevalence of loneliness ranges higher from 13% to 43%. Previous research has found loneliness is associated with an increased risk of cognitive decline, dementia, and AD and related dementia (ADRD) neuropathologic changes. However, other studies have reported inconsistent findings.

The objective of the current study was to determine the association of loneliness with 10-year all-cause dementia risk and the cross-sectional association of loneliness with early markers of ADRD vulnerability.


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The analysis included original participants from the Framingham Study who were attending their 25th biennial examination (1997-1999) and offspring participants who were attending their seventh quadrennial examination (1998-2001). In the primary dementia analysis, eligible participants had a loneliness assessment and were aged 60 years or older.

Loneliness was quantified with use of the Center for Epidemiologic Studies Depression Scale (CES-D). Participants were classified as “lonely” (3-7 days) or “not lonely” (0-2 days) according to the number of days they felt lonely within the past week. The primary outcome was clinical diagnosis of incident all-cause dementia in the 10-year follow-up. Researchers also screened participants for APOE ε4 allele.

In the dementia analytic cohort, 2308 participants were included (576 original and 1732 offspring members), with a mean age of 73 years (SD, 9 years) and 56% were women. Of this group, 144 (6%) participants felt lonely 3 days or more within the past week.

In the follow-up (median 10.00 [interquartile range, 5.50-10.00] years), 329 (14%) participants were diagnosed with dementia (189 original and 140 offspring members). Among the lonely participants, 31 of 144 (22%) developed dementia. After adjustment for age, sex, and education level in the overall dementia group, loneliness was significantly associated with a higher incidence of dementia (hazard ratio, 1.54; 95% CI, 1.06-2.24).

In participants aged 80 years or younger, those who were lonely were more than twice as likely to develop dementia (hazard ratio, 2.27; 95% CI, 1.32-3.91). Loneliness was associated with a 3-fold increased hazard of incident dementia in younger participants who did not have an APOE ε4 allele (hazard ratio, 3.03; 95% CI, 1.63-5.62).

The cognition sample included 1875 participants without dementia (41 original and 1834 offspring members), with a mean age of 62 years (SD, 9 years) and 54% were women. Loneliness was associated with poorer cognition in executive function, as lonely participants had a score of 0.23 standard deviation units (SDU) lower vs participants who were not lonely.

In a subset of the cognition group used to assess the relationship between loneliness and neuroanatomic measures, baseline brain magnetic resonance imaging was obtained for 1643 of 1875 (88%) participants. Lonely participants had total cerebral volumes that were 0.25 SDU lower and white-matter hyperintensity volumes that were 0.28 SDU greater than participants who were not lonely.

In sensitivity analysis, primary findings in the dementia analysis remained after exclusion of 88 participants with baseline mild cognitive impairment (hazard ratio, 1.92; 95% CI, 1.29-2.85) and after advancing follow-up by 5 years (hazard ratio, 1.83; 95% CI, 1.08-3.12).

Among several limitations, the researchers noted that their study included mostly White individuals. Also, it is possible that “depression without loneliness” had a more influential role than “loneliness without depression” in the older age group.

“This association between loneliness and 10-year dementia risk may be at least partly due to the involvement of loneliness in the earliest stages of ADRD neuropathogenesis, as suggested by our subsequent findings characterizing how loneliness in dementia-free adults relates with early cognitive and imaging measures of ADRD vulnerability,” the researchers stated.

Reference

Salinas J, Beiser AS, Samra JK, et al. Association of loneliness with 10-year dementia risk and early markers of vulnerability for neurocognitive decline. Neurology. Published online February 7, 2022. doi:10.1212/WNL.0000000000200039