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. 2025 Apr 22;104(8):e213377.
doi: 10.1212/WNL.0000000000213377. Epub 2025 Mar 31.

Grief and Economic Stressors by Sex, Gender, and Education: Associations With Alzheimer Disease-Related Outcomes

Eleni Palpatzis  1   2   3 , Muge Akinci  1   2   3 , Marina Garcia-Prat  3 , Kaj Blennow  4   5 , Henrik Zetterberg  4   5   6   7   8   9 , Clara Quijano-Rubio  10 , Gwendlyn Kollmorgen  11 , Norbert Wild  11 , Juan Domingo Gispert  3   12   13 , Marc Suárez-Calvet  3   12   13   14 , Oriol Grau-Rivera  3   12   13   14 , Karine Fauria  3   12   15 , Anna Brugulat-Serrat  3   12   13   16 , Gonzalo Sanchez-Benavides  3   12   13 , Eider M Arenaza-Urquijo  1   3 ; ALFA study
Collaborators, Affiliations

Grief and Economic Stressors by Sex, Gender, and Education: Associations With Alzheimer Disease-Related Outcomes

Eleni Palpatzis et al. Neurology. .

Erratum in

Abstract

Background and objectives: The prevalence and impact of stressful life events (SLEs) on age-related and Alzheimer disease (AD)-related pathways may depend on social determinants including gender and education. We investigated whether specific SLEs are associated with AD pathology and neurodegeneration and how these associations differ by gender and education.

Methods: This cross-sectional study included cognitively unimpaired participants, most with a family history of sporadic AD, from the ALzheimer's and FAmilies (ALFA) cohort, based in Barcelona, Spain. Participants had available assessments on occurrence and type of lifetime SLEs and lumbar puncture and/or structural MRI. We performed multiple regression analyses to examine the associations of specific SLE type with (1) AD pathologies (CSF phosphorylated tau 181 [p-tau181] and β-amyloid [Aβ] 42/40) and (2) neurodegeneration markers (CSF neurogranin and GM volumes voxel-wise) including interaction and stratification analyses by gender (women/men) and education.

Results: In total, 1,290 cognitively unimpaired participants (mean age = 59.4 years, range: 48-77 years, 99% White participants, 61% women) were included (393 with lumbar puncture and 1,234 with spectroscopic MRI assessments). Less educated participants and women reported more grief-related and economic-related SLEs. Furthermore, women reported more abuse and reproductive SLEs. Grief-related SLEs were associated with AD and neurodegeneration CSF outcomes while economic SLEs were associated with MRI-based GM outcomes, both in an age-independent manner. Specifically, partner's death was associated with lower Aβ42/40 (B = -5.19; 95% CI -9.61 to -0.76; p = 0.022) and higher p-tau181 (B = 0.18; 95% CI 0.05-0.32; p = 0.007) and neurogranin (B = 0.19; 95% CI 0.05-0.32; p = 0.007). The associations with Aβ42/40 were driven by less educated participants and men and associations with p-tau181 and neurogranin driven by women. Unemployment and economic loss were associated with lower GM volumes in limbic and frontal areas, driven by more educated participants and men and by women, respectively.

Discussion: Older adults at risk of cognitive decline with less education and women may be more susceptible to experience more SLEs. Men who have experienced widowhood and unemployment and women who have experienced financial difficulties may benefit from interventions.

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Conflict of interest statement

E. Palpatzis, M. Akinci, and M. Garcia-Prat report no disclosures relevant to the manuscript. K. Blennow has served as a consultant and on advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served on data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for Biogen, Eisai, and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. H. Zetterberg has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). C. Quijano-Rubio is a full-time employee of Roche Diagnostics International Ltd., Rotkreuz, Switzerland. G. Kollmorgen and N. Wild are full-time employees of Roche Diagnostics GmbH, Penzberg, Germany. J.D. Gispert has received research support from GE Healthcare, Roche Diagnostics, and F. Hoffmann-La Roche; has received speaker fees from Biogen and Philips; and has received consultant fees from Roche Diagnostics. M. Suárez-Calvet has given lectures in symposia sponsored by Almirall, Eli Lilly, Novo Nordisk, Roche Diagnostics, S.L.U., and Roche Farma, S.A.; has served as a consultant and on advisory boards for Roche Diagnostics International Ltd. and Grifols S.L; was granted with a project funded by Roche Diagnostics International Ltd.; and received in-kind support for research (to the institution) from ADx NeuroSciences, Avid Radiopharmaceuticals Inc., Eli Lilly, Janssen Research & Development, and Roche Diagnostics International Ltd. All payments were made to the institution. O. Grau-Rivera has received research support from F. Hoffmann-La Roche and speaker fees from Roche Diagnostics. K. Fauria, A. Brugulat-Serrat, G. Sánchez Benavides, and E.M. Arenaza-Urquijo report no biomedical financial interests or potential conflicts of interest. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Percentage of Participants Who Have Experienced Each SLE At Least Once in Their Lifetime Within the Whole Sample (n = 1,290)
(A) Stratified by education. Asterisks represent significant differences (p < 0.05) in prevalence between those with lower and higher educational levels. (B) Stratified by gender. Asterisks represent significant differences (p < 0.05) in prevalence between men and women. SLE = stressful life event.
Figure 2
Figure 2. Results of the Voxel-Wise Analyses Showing the Association of Specific SLEs With Reduced Regional Gray Matter Volumes Within the Whole MRI Sample
Y-axes represent the probability of gray matter within the significant clusters identified in SPM analyses. X-axes represent having experienced a stressful life event (0 = no, 1 = yes). (A) Unemployment: thresholded at p < 0.001 at voxel level and family-wise error p < 0.05 at cluster level. (B) Severe financial loss: thresholded at p < 0.001 at voxel level and family-wise error p < 0.05 at cluster level. All models were adjusted for age, gender, education, total intracranial volume, APOE ε4-carrier status, history of cardiovascular disease, history of psychiatric disease, and all other stressful life events. SLE = stressful life event.
Figure 3
Figure 3. Results of the Voxel-Wise Analyses Showing the Association of Specific SLEs With Reduced Regional Gray Matter Volumes in the Stratified Models
Y-axes represent the probability of gray matter within the significant clusters identified in SPM analyses. X-axes represent having experienced a stressful life event (0 = no, 1 = yes). (A) Unemployment among men: thresholded at uncorrected p < 0.001 at voxel level and family-wise error p < 0.05 at cluster level. Medial temporal results are shown as a binary mask overlaid into a T1 structural image. (B) Severe financial loss among women: thresholded at uncorrected p < 0.001 at voxel level and family-wise error p < 0.05 at cluster level. (C) Unemployment among those with higher education: thresholded at uncorrected p < 0.001 at voxel level and family-wise error p < 0.05 at cluster level. Medial temporal results are shown as a binary mask overlaid into a T1 structural image. All models were adjusted for age, total intracranial volume, APOE ε4-carrier status, history of cardiovascular disease, history of psychiatric disease, all other stressful life events, education (only panels A and B), and gender (only panel C). SLE = stressful life event.
See this image and copyright information in PMC

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