Romano (DeMuro) C, Novak G, Choi J, Qin S, Henley D, Donohue M, Romano G, Raman R, Amariglio R, Aisen P, Sperling R. Assessing clinically meaningful functional outcomes in preclinical alzheimer's disease. Poster presented at the 15th Conference Clinical Trials Alzheimer's Disease 2022; November 29, 2022. San Francisco, CA. [abstract] J Prev Alzheimers Dis. 2022 Dec 3; 9(Supplement 1):S186-7.

BACKGROUND: Rigorously developed and highly sensitive composite neurocognitive measures have been created to assess very subtle changes in cognition related to preclinical Alzheimer’s Disease (AD). An example of these instruments includes the Preclinical Alzheimer Cognitive Composite (PACC) which is comprised of four scales that assess episodic memory, executive function and global cognition. Similar to cognition, subtle functional decline occurs in cognitively unimpaired individuals who later progress to MCI or AD dementia. Highly sensitive functional measures may capture these subtle changes and may help to define clinically meaningful clinical trial outcomes in preclinical AD. Janssen Research & Development LLC and Shionogi and Co Ltd were developing atabecestat, a nonselective oral BACE-1 and BACE-2 inhibitor. A phase 2b/3 confirmatory registration trial (the EARLY trial) was conducted to evaluate efficacy and safety of atabecestat for slowing cognitive decline in preclinical AD and was terminated prior to completion. This study included several functional measures: the Cognitive Function Index (CFI), the Cognitive Function Index Acute (CFIa), the Alzheimer’s Disease Cooperative Study Activities of Daily Living Prevention Instrument (ADCS-ADL-PI), the State-Trait Anxiety Inventory-6 item version (STAI-6) and the Geriatric Depression Scale (GDS), in addition to neurocognitive assessments; the PACC and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

OBJECTIVES: Objectives of this research were to interrogate screening data collected in the EARLY trial to examine the relationship between functional measures and amyloid status, and to examine the relationship between functional and cognitive measures. These data will be useful to guide selection of clinically meaningful functional endpoints in future clinical trials.

METHODS: The analysis population included any participant screened for the EARLY study with amyloid status, based on either PET or CSF, and with any one of the following assessments: the self and study partner versions of the CFI (14 items to assess change over past 1 year across a 3 point scale), the CFIa (a modified version of the CFI with an expanded Likert scale and current recall period), the ADCS-ADL-PI (18 items across a 4 point scale, including 3 high-level function items), STAI-6 (6 items assessed with a 4 point scale) and the GDS-short form (15 items with a dichotomous response scale), in addition to the PACC and RBANS. Screening demographics were summarized by amyloid eligibility group, with frequencies and percentages for categorical variables, and mean and standard deviation for continuous data. Comparisons between groups (where sufficient data) were performed using t-tests for continuous variables, and Pearson’s chi-squared test for categorical data. Analysis of covariance (ANCOVA) models were used to examine the difference in functional measures between amyloid groups controlling for pre-specified covariates of age, gender and education. Pearson correlation coefficients were used to examine the cross-sectional relationship between the functional and cognitive measures.

RESULTS: The analysis sample included a total of 3,686 participants. Of these, 756 (21%) were Aβ+, 2182 (59%) were female, 2721 (74%) were married, and 3472 (94%) had a high school or greater education; 1154 (32%) were identified as APOE e4 carriers. Controlling for age, sex and education, scores were significantly higher (worse) for Aβ+ than Aβ- on the CFIa self [2.09 (CI 1.28 – 2.91), p<0.001] and study partner [1.91 (CI 1.09 – 2.73), p < 0.001], and on the CFI self [0.74 (CI 0.27 – 1.21), p=0.002] and study partner [0.56 (CI 0.13 – 0.99), p=0.011], but not for the ADCS-ADL-PI, GDS, or STAI. In Aβ+ participants, Pearson correlations to the PACC were moderate with the CFI (self and study partner, −0.31 and −0.34 respectively), moderate to small with the ADCS-ADL-PI (self and study partner, 0.33 and 0.25 respectively), and small with the CFIa (self and study partner, −0.20 and −0.28, respectively). Correlations of the RBANS were small with the CFI, CFIa, ADCS-ADL-PI and the STAI (range r= 0.10 — 0.23). The corresponding correlations were generally smaller among Aβ- individuals, except for a moderate correlation between the PACC and the ADCS-ADL-PI (0.34 for both self and study partner). Correlations between the CFI and CFIa were strong (ranging 0.59 to 0.67) and were similar between participant and study partner.

CONCLUSIONS: In this cross-sectional assessment, self and study partner rated versions of the CFI and CFIa were sensitive to amyloid status, and the CFI and ADCS-ADL-PI-self demonstrated generally moderate relationships (Irl ≥ 0.30) to the PACC. While CFI and CFIa were well-correlated, the level of correlation did not indicate a redundancy between measures indicating these tools may measure different aspects of function. Results of this analysis provide important information on the sensitivity of these functional assessments to amyloid pathology and to neurocognitive assessment. Exploration of these relationships may provide valuable insight into clinically meaningful interpretation of clinical trial study endpoints. Longitudinal assessment of these measures will provide further discernment as to whether these functional measures may detect change over time.

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