Assessing Risk of Incident Cognitive Impairment Using Stages of Objective Memory Impairment (SOMI) and Cerebrospinal Fluid

Background: The asymptomatic period for persons with preclinical Alzheimer’s disease (AD) lasts for several years despite the presence of AD biomarkers. These biomarkers are critical for disease detection and monitoring, but collection is burdensome and costly. Sensitive cognitive measures such as Stages of Objective Memory Impairment (SOMI) may be a low-cost alternative or adjunctive marker of disease-progression risk. Here, we used longitudinal data from the Knight Alzheimer’s Disease Research Center to investigate the odds of disease progression associated with baseline SOMI stage and cerebrospinal fluid (CSF) biomarkers of Aβ₄₂/Aβ₄₀ ratio, p-tau₁₈₁, and t-tau. Methods: We used data from 617 cognitively unimpaired participants with baseline Clinical Dementia Rating (CDR) of 0, CSF measures, and longitudinal Free and Cued Selective Reminding Test (FCSRT) scores used to classify participants into different SOMI stages (Table 1). We examined the association between SOMI stage, CSF biomarkers, and incident cognitive impairment based on time to conversion from CDR of 0 to CDR>0 (incident cognitive impairment) using Cox Models. Results: Participants, at enrollment (Table 2), were on average 67.2 (SD = 9.4) years old, 56.6% were female, and had average 7.5 years of follow-up (range 1-18). At baseline, 325 (52.7%) were SOMI-0, 206 (33.4%) were SOMI-1, 64 (10.4%) were SOMI-2, and 22 (3.6%) were SOMI-3 or -4 (merged groups). A total of 127 (20.6%) individuals converted to CDR>0. The Cox proportional hazards regression models indicated that in comparison with individuals in SOMI-0 stage, those in SOMI-3/4 stage were more than twice as likely to show disease progression (HR=2.43 (95% CI, 1.21-4.89, p=0.013)) (Table 3). Adding individual CSF biomarkers to the models did not affect the association of SOMI-3/4 with incident cognitive impairment (p<0.05 for all). In models that included SOMI stages and all CSF biomarkers, SOMI-3/4 (HR=2.13, 95% CI 1.07-4.12, p=0.033) Aβ₄₂/Aβ₄₀ (HR=9.76e-6, 95% CI=2.70e-10 - 0.35, p=0.031) and t-tau (HR=1.001, 95% CI=1.000-1.002, p=0.018), but not p-tau (p=0.645), showed significant association with incident cognitive impairment. Conclusions: SOMI-3/4 predicts incident cognitive impairment (change in CDR) independently from CSF AD biomarkers. These results support the utility of SOMI stage as an early marker of incident cognitive impairment.