Incremental declines in independence associated with disease progression in early symptomatic Alzheimer’s disease (AD)

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Abstract Background Associations between disease progression (DP) and health outcomes are poorly characterized in mild cognitive impairment (MCI) and mild AD (MILD). To address this, we examined the impact of DP on incremental changes in independent functioning over 18 months; baseline factors associated with DP were also explored. Methods Participants included amyloid‐positive participants assigned to placebo in EXPEDITION‐1/2/3 (solanezumab) and AMARANTH (lanabecestat) studies. DP defined as worsening ³5 (MCI1) or ³9 (MILD2) points on the Integrated Alzheimer’s Disease Rating Scale (iADRS). Endpoints included proportions of participants requiring home supervision (³1 hour) or unable to leave home independently (score <3) and change in total care partner time. Machine learning methods using penalized logistic regression and random forest identified factors associated with DP. Least squares mean change (LSMC) was estimated from mixed‐model repeated measures. Results Of 1884 participants (274 MCI, 1610 MILD), 56% of MCI and 63% of MILD participants met DP criteria over 18 months. Baseline AD medication use, greater care partner time, worse functional activities questionnaire (FAQ) score and CDR‐SB, higher iADRS, and lower BMI and MMSE increased odds of DP for MILD (Figure 1) but not for MCI. Proportion of participants with DP requiring home supervision (p<0.001; MILD only) and not leaving home independently (p<0.05; MCI&MILD) increased significantly at each post‐baseline visit over 18 months (Figure 2). DP in MILD only had significantly higher proportions of participants who could not be left home alone or travel outside of home independently vs no DP (p<0.05). In those with DP, total care partner time increased significantly from baseline to 18 months (LSMC: 46.0±12.5 hours/month for MCI and 73.2±5.5 for MILD) (Figure 3). For DP vs no DP, increased care partner time at 18 months was significantly higher for MILD (LSMC difference, 66.0±9.3 hours/month; p<0.001) but not for MCI. Conclusions Early symptomatic AD participants who progressed over 18 months had reduced independence and required more care partner time. Treatments that slow DP may preserve independence and reduce overall health care burden. References 1. Wessels AM, et al. J Prev Alzheimers Dis. 2015;2:227‐241 2. Wessels AM, et al. J Alzheimers Dis. 2022;88:577‐588.

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