Sex Differences in the Associations of Obesity with Tau, Amyloid PET, and Cognitive Outcomes in Preclinical Alzheimer’s Disease: Cross-Sectional A4 Study

Article type: Research Article

Authors: Wang, Xin^a | Sundermann, Erin E.^b | Buckley, Rachel F.^c | Reas, Emilie T.^a | McEvoy, Linda K.^{d; e} | Banks, Sarah J.^{a; b; *} | on behalf of the A4 Study Team¹

Affiliations: [a] Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA | [b] Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA | [c] Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA | [d] Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA | [e] Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA

Correspondence: [*] Correspondence to: Sarah J. Banks, University of California San Diego, 9500 Gilman Drive, m/c 0841, La Jolla, CA 92093, USA. Tel.: +1 858 246 1466; E-mail: [email protected].

Note: [1] Full listing of A4 Study team and site personnel available at A4STUDY.org.

Abstract: Background:The association between obesity and Alzheimer’s disease (AD) is complex. Recent studies indicated the relationships between obesity and AD may differ by sex, and women may benefit from being overweight in terms of AD risk. Objective:We investigated whether sex modifies the associations of obesity with tau positron emission tomography (PET), amyloid PET, and cognition in preclinical AD. Methods:We included 387 cognitively-unimpaired amyloid-positive participants (221 women, 166 men, 87.6% non-Hispanic White) with available 18F-flortaucipir PET, 18F-florbetapir PET, and completed the Preclinical Alzheimer Cognitive Composite (PACC) tests from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study. Participants were categorized based on body mass index (BMI: kg/m2): normal-weight (BMI: 18.5-25), overweight (BMI: 25-30), and obese (BMI≥30). Results:Significant sex by BMI category interactions on PACC and its components: Mini-Mental State Examination (MMSE) and Reminding Test–Free+Total Recall (FCSRT96) revealed that overweight and obese women outperformed normal-weight women on FCSRT96, while obese men showed poorer MMSE performance than normal-weight men. These interactions were independent of APOE4. There were no significant interactions of sex by BMI category on tau and amyloid PET. However, sex-stratified analyses observed obesity was associated with less regional tau and mean cortical amyloid in women, not in men. Conclusion:This study found that in preclinical AD, overweight and obesity were associated with better verbal memory in women, whereas obesity was associated with worse global cognition among men. Future studies focusing on the mechanism for this relationship may inform sex-specific interventions for AD prevention.

Keywords: Alzheimer’s disease, cognition, obesity, overweight, sex differences

DOI: 10.3233/JAD-230466

Journal: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 615-624, 2023