Decline in cognitively complex everyday activities accelerates along the Alzheimer’s disease continuum

Abstract

Background Impairment in daily functioning is a clinical hallmark of dementia. Difficulties with “instrumental activities of daily living” (IADL) seem to increase gradually over the course of Alzheimer’s disease (AD), before dementia onset. However, it is currently not well established how difficulties develop along the preclinical and prodromal stages of AD. We aimed to investigate the trajectories of decline in IADL performance, as reported by a study partner, along the early stages of AD. Methods In a longitudinal multicenter study, combining data from community-based and memory clinic cohorts, we included 1555 individuals (mean age 72.5 ± 7.8 years; 50% female) based on availability of amyloid biomarkers, longitudinal IADL data, and clinical information at baseline. Median follow-up duration was 2.1 years. All amyloid-positive participants (n = 982) were classified into the National Institute on Aging–Alzheimer’s Association (NIA-AA) clinical stages ranging from preclinical AD (1) to overt dementia (4+). Cognitively normal amyloid-negative individuals (n = 573) served as a comparison group. The total scores of three study-partner reported IADL questionnaires were standardized. Results The rate of decline in cognitively normal (stage 1) individuals with and without abnormal amyloid did not differ (p = .453). However, from stage 2 onwards, decline was significantly faster in individuals on the AD continuum (B [95%CI] = − 0.32 [− 0.55, − 0.09], p = .007). The rate of decline increased with each successive stage: one standard deviation (SD) unit per year in stage 3 (− 1.06 [− 1.27, − 0.85], p < .001) and nearly two SD units per year in stage 4+ (1.93 [− 2.19, − 1.67], p < .001). Overall, results were similar between community-based and memory clinic study cohorts. Conclusions Our results suggest that the rate of functional decline accelerates along the AD continuum, as shown by steeper rates of decline in each successive NIA-AA clinical stage. These results imply that incremental changes in function are a meaningful measure for early disease monitoring. Combined with the low-cost assessment, this advocates the use of these functional questionnaires for capturing the effects of early AD-related cognitive decline on daily life.

Why a clinical trial is as good as its outcome measure: A framework for the selection and use of cognitive outcome measures for clinical trials of Alzheimer's disease

“…Previous studies have shown the added clinical value of combining cognitive with IADL measures, as illustrated by the fact that associations between the overall composite combining cognitive and functional abilities and other clinical measures such as quality of life and caregiver burden were mostly driven by the functional component of the composite in individuals with MCI and mild AD dementia 17 ; likewise the detection of change over time in individuals with MCI on the composite was most apparent on the instrumental ADL (IADL) component 34 . Together, these and other findings emphasize the importance of the inclusion of a sensitive IADL measure to capture clinically meaningful decline in prodromal stages of AD 102 . Thus, outcome measures that combine cognitive and functional items may be useful for measuring the totality of disease progression in Stage 3 participants.…”

“…For trials targeting Stage 3 individuals, combining cognitive with functional outcome measures may provide an effective approach to establish the meaningfulness of treatments, and this has been recommended by regulatory agencies 4,89 . Accumulating evidence indicates that instrumental activities of daily living (IADL) begin to deteriorate before the onset of dementia, 102 and that an MCI diagnosis accompanied by more IADL problems leads to increased risk of developing dementia 103 . Previous studies have shown the added clinical value of combining cognitive with IADL measures, as illustrated by the fact that associations between the overall composite combining cognitive and functional abilities and other clinical measures such as quality of life and caregiver burden were mostly driven by the functional component of the composite in individuals with MCI and mild AD dementia 17 ; likewise the detection of change over time in individuals with MCI on the composite was most apparent on the instrumental ADL (IADL) component 34 .…”

“…before the onset of dementia,102 and that an MCI diagnosis accompanied by more IADL problems leads to increased risk of developing dementia 103. Previous studies have shown the added clinical value of combining cognitive with IADL measures, as illustrated by the fact that associations between the overall composite combining cognitive and functional abilities and other clinical measures such as quality of life and caregiver burden were mostly driven by the functional component of the composite in individuals with MCI and mild AD dementia17 ; likewise the detection of change over time in individuals with MCI on the composite was most apparent on the instrumental ADL (IADL) component 34.…”

Determining the Minimal Important Change of Everyday Functioning in Dementia

“…These findings provide further evidence that biological and cognitive factors underlie changes in IADL functioning: We previously found that any decline in IADL functioning was associated with disease severity, i.e., that patients with dementia declined faster than patients with subjective cognitive complaints, 18 and that worse IADL performance was associated with atrophy in the medial temporal lobe. 48 Studies with other IADL measures related changes in IADL to disease stage, 3 amyloid burden, 49 and executive functioning, 50 irrespective of the clinical meaningfulness of changes. In the present work, we show that disease stage, atrophy, and caregiver burden are associated with clinically meaningful changes in everyday functioning.…”

Does psychological resilience mediate the relation between daily functioning and prefrailty status?

“…In early disease monitoring, incremental changes in function are already seen as a meaningful measure. For example, in Alzheimer's disease, the more complex activities, such as managing paperwork, are specifically sensitive to the earliest cognitive changes (Dubbelman et al, 2020) and may be an indicator of cognitive decline when limited. Also, Wilkins et al (2021) support this by showing that everyday preferences are important predictors for older adults with cognitive impairment.…”