Subjective Cognitive Decline Plus and Longitudinal Assessment and Risk for Cognitive Impairment

Abstract

Importance: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting.

Objective: To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults.

Design, setting, and participants: The Framingham Heart Study, a community-based prospective cohort study, assessed SCD between 2005 and 2019, with up to 12 years of follow-up. Participants 60 years and older with normal cognition at analytic baseline were included. Cox proportional hazards (CPH) models were adjusted for baseline age, sex, education, APOE ε4 status, and tertiles of AD polygenic risk score (PRS), excluding the APOE region. Data were analyzed from May 2021 to November 2023.

Exposure: SCD was assessed longitudinally using a single question and considered present if endorsed at the last cognitively normal visit. It was treated as a time-varying variable, beginning at the first of consecutive, cognitively normal visits, including the last, at which it was endorsed.

Main outcomes and measures: Consensus-diagnosed MCI, AD, and all-cause dementia.

Results: This study included 3585 participants (mean [SD] baseline age, 68.0 [7.7] years; 1975 female [55.1%]). A total of 1596 participants (44.5%) had SCD, and 770 (21.5%) were carriers of APOE ε4. APOE ε4 and tertiles of AD PRS status did not significantly differ between the SCD and non-SCD groups. MCI, AD, and all-cause dementia were diagnosed in 236 participants (6.6%), 73 participants (2.0%), and 89 participants (2.5%), respectively, during follow-up. On average, SCD preceded MCI by 4.4 years, AD by 6.8 years, and all-cause dementia by 6.9 years. SCD was significantly associated with survival time to MCI (hazard ratio [HR], 1.57; 95% CI, 1.22-2.03; P <.001), AD (HR, 2.98; 95% CI, 1.89-4.70; P <.001), and all-cause dementia (HR, 2.14; 95% CI, 1.44-3.18; P <.001). After adjustment for APOE and AD PRS, the hazards of SCD were largely unchanged.

Conclusions and relevance: Results of this cohort study suggest that in a community setting, SCD reflecting SCD+ features was associated with an increased risk of future MCI, AD, and all-cause dementia with similar hazards estimated in clinic-based settings. SCD may be an independent risk factor for AD and other dementias beyond the risk incurred by APOE ε4 and AD PRS.

Figure 1.. Description and Exemplar Participants Demonstrating How Survival Time Was Calculated for Those in the Subjective Cognitive Decline (SCD) and Non-SCD Groups

A visit was considered valid if the participant was cognitively normal at the time of the visit and the question about SCD was administered. SCD was treated as time-varying; therefore, some participants may have contributed time to both the SCD and non-SCD groups. Participants were considered to have SCD beginning at their baseline visit and for all time subsequently if they met 1 of the following criteria: (1) SCD was endorsed at the baseline visit and all subsequent valid visits or (2) participants had only 1 valid visit during which SCD was endorsed. For participants who changed their responses across valid visits, SCD was considered present if endorsed at the last valid visit. If SCD was endorsed during consecutive valid visits, including the last, the participant was considered to have SCD beginning at the first of these consecutive visits—prior visits counted toward time without SCD. Participants were not considered to have SCD at the baseline visit and for all time subsequently if SCD was not endorsed at the last valid visit. We defined 4 time periods to calculate the survival time for SCD and non-SCD groups: (1) SCD time in red was the time from the first to the last consecutive valid visit during which SCD was endorsed, provided it was endorsed at the last valid visit, (2) cognitively normal time in blue was the time from the first to the last valid visit, (3) occurring time in orange was the time from the last valid visit to the onset of mild cognitive impairment (MCI) or dementia (depending on which analysis), and (4) contacted time in green was the time from the last valid visit to the last contact or death for participants who did not develop MCI or dementia. For participants who contributed time to the SCD group (regardless of whether they also contributed time to the non-SCD group), the survival time was calculated in the following ways: (1) the sum of SCD time and occurring time for those who developed MCI or dementia (eg, participants A and D), (2) the sum of SCD time and contacted time for those who did not develop MCI or dementia (eg, participant B). For participants who only contributed time to the non-SCD group, the survival time was calculated in the following ways: (1) the sum of cognitively normal time and occurring time for those who developed MCI or dementia (eg, participant C), (2) the sum of cognitively normal time and contacted time for those who did not develop MCI or dementia (eg, participant E). For participants who contributed time to both the non-SCD and SCD groups, time contributed to the non-SCD group was calculated as the difference between cognitively normal time and SCD time (eg, participants B and D).

Figure 2.. Flowchart of the Study Sample Selection

A, Among 3735 participants from the hybrid set of visits, 1651 and 2663 participants were classified into the subjective cognitive decline (SCD) and non-SCD groups, respectively—579 participants (15.5%) who changed their SCD status contributed time to both groups. A total of 3585 participants (96.0%) had available information for the APOE genotypes, and among those with APOE genotypes, 3057 (81.8%) had available data to derive an Alzheimer disease (AD) polygenic risk score (PRS). B, Among 2692 participants from the set of neuropsychological (NP) visits, 1194 and 1740 participants were classified into the SCD and non-SCD groups, respectively—242 participants (9.0%) who answered inconsistently contributed time to both groups. A total of 2581 participants (95.9%) had available information for the APOE genotypes, and among those with APOE genotypes, 2207 (82.0%) had available data to derive an AD PRS.

Figure 3.. Kaplan-Meier Curves for Mild Cognitive Impairment (MCI), Alzheimer Disease (AD), and All-Cause Dementia in Survival Models With APOE Adjustment

We used Cox proportional hazards models adjusted for age, sex, educational level, APOE ε4 status, and APOE ε2 status to plot the Kaplan-Meier curve for MCI, AD, and all-cause dementia in the participants from the hybrid set of visits. Compared with the non-SCD group, the SCD group had significantly higher hazards of conversion to MCI, AD, or all-cause dementia.