Objective Criteria for Subtle Cognitive Decline in Aging and Preclinical Alzheimer Disease: A Systematic Review

Although the Alzheimer's Association (AA) biomarker-only Alzheimer disease (AD) criteria and the International Working Group clinical-pathologic AD criteria differ, both approaches appreciate the need for early detection efforts. Within the AA approach, clinical stage 2 recognizes that someone can be cognitively unimpaired but still experience "subtle cognitive decline" (SCD) measured by subjective report or objective decline using neuropsychological measures. While significant attention has been given to subjective cognitive decline methods, there are no systematic examinations of the operational definition of SCD using objective neuropsychological measures. Therefore, the primary aim of this review was to identify and describe the approaches used to classify objective SCD.

A systematic literature search was performed using PubMed/MEDLINE, Web of Science, and PsycInfo databases for articles with dates ranging from the start of the database through November 1, 2023. Included studies were peer-reviewed, described a discrete objective SCD category, included participants aged 50+ without mild cognitive impairment (MCI) or dementia, and focused on aging or AD. A modified Newcastle-Ottawa Scale was used to assess the quality of included studies. Data were extracted by the 2 authors who then categorized and described the classification approaches.

Of the 1,361 publications initially identified, 70 case-control studies met criteria for inclusion. SCD definitions generally fell into 6 categories based on using similar methodology: (1) SCD based on a specified cutoff on a single cognitive test (n = 6); (2) SCD based on a cutoff (e.g., 10th percentile) on a cognitive composite score (n = 9); (3) objectively defined SCD (Obj-SCD) using cutoffs (e.g., -1 SD) on multiple individual neuropsychological measures (n = 24); (4) "Pre-MCI" criteria defined using a Clinical Dementia Rating of 0.5 but normal performance on neuropsychological testing (n = 12); (5) cutoff based on longitudinal rate of cognitive decline (e.g., over 1 year) (n = 13); and (6) data-driven/clustering approach to classification (n = 8). Two studies used multiple classification approaches.

Six promising classification approaches were identified in the existing literature, with the Obj-SCD and Pre-MCI approaches being the most commonly applied. Additional work is needed to compare SCD approaches head-to-head to identify the most prognostically useful, particularly within racially/ethnically diverse older adults.