Associations of Widowhood and β-Amyloid With Cognitive Decline in Cognitively Unimpaired Older Adults | Dementia and Cognitive Impairment | JAMA Network Open | JAMA Network
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    1 Comment for this article
    RE: Associations of widowhood and β-amyloid with cognitive decline in cognitively unimpaired older adults
    Tomoyuki Kawada, MD | Nippon Medical School
    I have read the article by Biddle et al. (1) with great interest. The authors conducted a prospective study to determine the effect of widowhood status on the level of brain β-amyloid and cognitive decline in 257 participants. The authors concluded that being widowed was significantly associated with accelerated β-amyloid-related cognitive decline during 3 years. Namely, the rate of cognitive decline among widowed participants with high β-amyloid was nearly 3 times faster than among married participants with high β-amyloid, presenting standardized regression coefficients (95% confidence intervals [CIs]) of -0.33 (-0.46 to -0.19) and -0.12 (-0.18 to -0.01), respectively. I have a concern about their study with special reference to sex difference, because percentage of widowed women occupied 88.6% of all widowed participants (n=35).

    I previously conducted a cross-sectional study to determine whether marital status is an independent risk factor for poor self-rated health (2). Adjusted odds ratios (ORs) (95% CI) of being male, having disease, physical complaints, depressive state, having lower levels of education, and being divorced for poor self-rated health were 1.41 (1.18–1.69), 10.8 (8.62–13.7), 1.11 (1.09–1.12), 1.11 (1.08–1.13), 1.22 (1.02–1.46), and 1.53 (1.01–2.31), respectively. I presented that health status was affected especially in male divorced inhabitants, and sex difference regarding health risk should be specified by further prospective studies.

    Regarding sex difference, Cuijpers et al. (3) conducted a meta-analysis of prospective studies regarding the effect of depression on mortality, stratified by sex. Among people with depression, relative risk (RR) (95% confidence interval [CI]) of men against women for mortality was 1.97 (1.63-2.37). In addition, RRs (95% CIs) of depression for mortality in women and in men were 1.55 (1.32-1.82) and 2.04 (1.76-2.37), respectively. Trevisan e al. also conducted a prospective study to examine the association between marital status and the incidence of frailty (4). Adjusted ORs (95% CIs) of men who had never married and were widowed against married men for developing frailty were 3.84 (2.76-5.35) and 1.43 (1.06-1.95), respectively. In contrast, adjusted OR (95% CI) of widowed women against married women for developing frailty was 0.77 (0.66-0.91).

    Although the mechanism of sex difference cannot be specified, frailty is a predictor of cognitive impairment and depression (5,6). Poor self-rated health is closely related to multi-morbidity, unhealthy behaviors and frailty (7), and risk factors for the progression of cognitive decline and increased level of brain β-amyloid should be evaluated by considering sex difference.


    1. Biddle KD, Jacobs HIL, d'Oleire Uquillas F, et al. JAMA Netw Open 2020;3(2):e200121. doi:10.1001/jamanetworkopen.2020.0121

    2. Kawada T, Suzuki S. J Divorce Remarriage 2011;52(1):48-54.

    3. Cuijpers P, Vogelzangs N, Twisk J, et al. J Affect Disord 2014;161:47-54. doi:10.1016/j.jad.2014.03.003

    4. Trevisan C, Veronese N, Maggi S, et al. J Womens Health (Larchmt) 2016;25(6):630-637. doi:10.1089/jwh.2015.5592

    5. Chu NM, Bandeen-Roche K, Tian J, et al. J Gerontol A Biol Sci Med Sci 2019;74(11):1761-1770. doi:10.1093/gerona/glz134

    6. Brown PJ, Roose SP, O'Boyle KR, et al. Am J Geriatr Psychiatry 2020;28(2):145-154. doi:10.1016/j.jagp.2019.10.005

    7. Feenstra M, van Munster BC, MacNeil Vroomen JL, et al. BMJ Open 2020;10(2):e035012. doi:10.1136/bmjopen-2019-035012
    Original Investigation
    February 26, 2020

    Associations of Widowhood and β-Amyloid With Cognitive Decline in Cognitively Unimpaired Older Adults

    Author Affiliations
    • 1Division of Geriatric Psychiatry, Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
    • 2School for Mental Health and Neuroscience, Alzheimer Centre, Limburg, Maastricht University, Maastricht, the Netherlands
    • 3Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
    • 4Princeton Neuroscience Institute, Princeton, New Jersey
    • 5Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
    • 6Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts
    • 7Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
    JAMA Netw Open. 2020;3(2):e200121. doi:10.1001/jamanetworkopen.2020.0121
    Key Points español 中文 (chinese)

    Question  Is widowhood a specific risk factor associated with more rapid cognitive decline among cognitively unimpaired older adults with higher levels of brain β-amyloid, the Alzheimer disease biomarker?

    Findings  In this cohort study of 257 community-dwelling cognitively unimpaired older adults, widowhood and β-amyloid were additively and interactively associated with cognitive decline. These results were independent of demographic factors, cardiovascular disease risk, depression, health-related behaviors, and social support factors.

    Meaning  These findings suggest that widowhood may be an understudied risk factor for cognitive decline associated with Alzheimer disease and highlight the need for increased research and clinical attention to this high-risk group.


    Importance  To reduce the rising incidence of clinical impairment due to Alzheimer disease, it is essential to define older adults at highest risk. Widowhood may be an unrecognized factor contributing to accelerated clinical progression along the Alzheimer disease pathway among cognitively unimpaired older adults.

    Objective  To determine whether widowhood status and level of brain β-amyloid (ie, the Alzheimer disease pathologic protein) are additively or interactively associated with cognitive decline among cognitively unimpaired older adults.

    Design, Setting, and Participants  In this cohort study, 257 married, widowed, and unmarried (ie, never married, divorced, or separated) participants from the Harvard Aging Brain Study longitudinal cohort underwent baseline evaluation of neocortical β-amyloid levels using Pittsburgh compound B positron emission tomography and 4 annual cognitive assessments. Data were collected from September 2010 to February 2017 and analyzed from July 2018 to July 2019.

    Main Outcomes and Measures  Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite.

    Results  Of the 257 participants, 153 (59.5%) were women, and the mean (SD) age was 73.5 (6.1) years; 145 participants (56.4%) were married (66 [45.5%] women), 77 (30.0%) were unmarried (56 [72.7%] women), and 35 (13.6%) were widowed (31 [88.6%] women). Compared with married participants, widowed participants demonstrated worsening cognitive performance after adjusting for age, sex, socioeconomic status, depression, and β-amyloid levels (β = −0.11; 95% CI, −0.19 to −0.04; P = .002) with no difference observed between married and unmarried participants. Furthermore, widowed participants with higher baseline β-amyloid levels exhibited steeper cognitive decline (β = −0.22; 95% CI, −0.42 to −0.03; P = .02), indicating both independent and interactive associations of β-amyloid levels and widowhood with cognition. In a secondary model using dichotomous β-amyloid–marital status groupings, the rate of cognitive decline among widowed participants with high β-amyloid was nearly 3 times faster than among married participants with high β-amyloid (widowed, high β-amyloid: β, −0.33; 95% CI, −0.46 to −0.19; P < .001; married, high β-amyloid: β, −0.12; 95% CI, −0.18 to −0.01; P < .001).

    Conclusions and Relevance  In a sample of cognitively unimpaired older adults, being widowed was associated with accelerated β-amyloid–related cognitive decline during 3 years. Cognitively unimpaired, widowed older adults were particularly susceptible to Alzheimer disease clinical progression, emphasizing the need for increased research attention and evidenced-based interventions for this high-risk group.