Frailty and Alzheimer’s Disease Related Plasma Biomarkers in Men from Midlife to Early Old Age

Abstract Background About 7 million older American adults are affected by frailty (Bandeen‐Roche et al., 2015). Frailty places older adults at an increased risk of adverse physical and mental health outcomes, including Alzheimer’s Disease (AD). However, prior to old age, frailty or its relationship to AD biomarkers such as beta‐amyloid 40 and 42 (Aβ40, Aβ42), tau, and neurofilament light (NfL) are understudied. Method Participants in this prospective longitudinal observational study were community‐based men of predominantly European ancestry. Data were collected across 3 waves at average ages 56 (2002‐08), 62 (2009‐14), and 68 (2016‐19). We calculated frailty index (FI) scores using 37 out of 49 items from an index previously validated in the UK Biobank (Williams et al. 2019; Jiang et al. 2017) which assesses health deficits across multiple physiological systems. FI is calculated as a proportion of deficits out of the total, with scores ranging from 0 (no deficits) to 1 (all deficits present). AD‐related plasma biomarkers for Aβ40,and Aβ42, total tau, and NfL were assayed at average ages 56 and 68. Biomarker values were adjusted for study site and storage time. Result Average FI score at age 56 was .2, equivalent to having about 7 health deficits. Frailty was significantly correlated (rs=.67‐.74) over time. Higher frailty at both age 56 and 62 doubled the risk for mortality across the 12 years of the study. Age 56 frailty was significantly associated with age 56 tau. Age 68 frailty was significantly associated with age 68 NfL, tau, Aβ40 and Aβ42. In models adjusted for age, education, and ethnicity, age 56 frailty predicted age 68 NfL (B=0.64, t=2.72, p=0.007); associations with age 68 Aβ40 (B=0.39, t=1.96, p=0.0513) and Aβ42 were attenuated (B=0.27, t=1.79, p=0.0743). Age 62 frailty mediated associations between age 56 tau and age 68 tau and NfL, but not other biomarkers. Conclusion The results are striking given the relatively young age of the sample. Even as early as one’s 50s, links between frailty and increased risk for AD emerged. Public health groups have recommended routine frailty screening in adults over 65, but it may be important to start screenings earlier.