NIA-AA Alzheimer's Disease Framework: Clinical Characterization of Stages

Abstract

Background: To operationalize the National Institute on Aging - Alzheimer's Association (NIA-AA) Research Framework for Alzheimer's Disease 6-stage continuum of clinical progression for persons with abnormal amyloid.

Methods: The Mayo Clinic Study of Aging is a population-based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross-sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months.

Results: Among 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44-59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short-term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1).

Interpretation: The frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021;89:1145-1156.

Conflict of interest statement

Nothing to report.

© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figures

FIGURE 1

Decision tree for determining National Institute on Aging – Alzheimer's Association (NIA‐AA) numeric stage. Flow chart detailing how participants are classified into the 6 numeric stages (or are indeterminate) based on the dimensions defined in Table 1: objective cognition (OBJ), functional assessment (FXN), subjective cognitive decline (SCD), and neurobehavioral symptoms (NBS). OBJ and FXN are cross‐sectional measures and SCD, ∆OBJ, and ∆NBS are measures of recent decline.

FIGURE 2

National Institute on Aging – Alzheimer's Association (NIA‐AA) numeric stage frequencies by age and sex among A+ participants. Estimated percentage in each NIA‐AA numeric stage at each age and by sex for 4 different staging definitions where the cutoff points for the cross‐sectional objective criterion (OBJ) and the longitudinal objective criterion (∆OBJ) are varied. Estimates are from cross‐sectional multinomial regression models with stage as the outcome and continuous age and sex as predictors. Solid lines represent the estimates for women and dotted lines represent the estimates for men.

FIGURE 3

Components of the stage 2 definition. Percentage of stage 2 A+ participants with each combination of decline components (subjective cognitive decline [SCD], longitudinal objective cognition criterion [∆OBJ], and neurobehavioral symptoms [∆NBS]) for 4 different staging definitions where the cutoff points for the cross‐sectional objective criterion (OBJ) and the ∆OBJ are varied. Bars within each panel may not necessarily add to 100% due to rounding.

FIGURE 4

Comparison of the numeric clinical staging and clinically defined diagnosis. Percentage of clinically defined cognitively unimpaired (CU) and mild cognitive impairment (MCI) A+ participants in each numeric clinical stage for 4 different staging definitions where the cutoff points for the cross‐sectional objective criterion (OBJ) and the longitudinal objective criterion (∆OBJ) are varied. Bars within each panel may not necessarily add to 100% due to rounding.

FIGURE 5

Stability of staging definitions. Percentage of participants that stayed in the same stage (stable; blue), moved to a lower stage (improve; green), moved to a higher stage (worsen; red), or were indeterminate (grey) between visits 3 and 4 (approximately 15 months) among 198 A+ participants with follow‐up. Percentages are shown for 4 different staging definitions where the cutoff points for the cross‐sectional objective criterion (OBJ) and the longitudinal objective criterion (∆OBJ) are varied. Stage at visit 4 (follow‐up) was defined in the same way as stage at visit 3 but used visit 4 for the cross‐sectional measures (index visit) and visits 2, 3, and 4 for the decline measures. Row percentages may not necessarily add to 100% due to rounding.

FIGURE 6

National Institute on Aging – Alzheimer's Association (NIA‐AA) numeric stage frequencies by age and sex among A+ participants, A− participants, and all participants. Sensitivity analysis showing the estimated percentage in each NIA‐AA numeric stage at each age and by sex among A+ participants, A− participants, and among all participants using the staging definition where the cutoff point for the cross‐sectional objective criterion was OBJ ≤ −1.5 and the cutoff point for the longitudinal objective criterion was ΔOBJ ≤ −0.1. Estimates are from cross‐sectional multinomial regression models with stage as the outcome and continuous age and sex as predictors. Solid lines represent the estimates for women and dotted lines represent the estimates for men.