SEQUENCE OF COGNITIVE DECLINE IN ADULTS WITH DOWN SYNDROME DURING PROGRESSION FROM PRECLINICAL TO PRODROMAL ALZHEIMER'S DISEASE

Abstract

Down syndrome (DS, trisomy 21) is associated with a high risk of Alzheimer's disease (AD) due to triplication of the APP gene on chromosome 21. DS is therefore an important population in which to test the efficacy of drugs aimed at preventing or delaying onset of disease, before neurodegeneration occurs. However, there is lack of data on the early progression of AD in DS. We aimed to define the progression of aging-related decline associated with AD in DS using detailed cognitive phenotyping in a large cohort of older individuals with DS to identify tests that could be used as outcome measures, and to understand the sequence of cognitive decline, as well as effect of the APOE gene. Using cognitive test data and informant-rated questionnaires from 316 adults with DS aged 16 and older, we firstly compared individuals in the preclinical, prodromal and dementia stage of AD to identify cognitive domains most affected in each group and to estimate effect sizes of potential cognitive outcome measures for trials. We also used a data-driven approach, the Event-Based Model (EBM), to estimate the sequence of AD-related cognitive decline and assign participants to a disease stage. We demonstrated that individuals with DS experience significant cognitive decline before the onset of clinical dementia, with large effect sizes on several cognitive measures for the transition from preclinical to prodromal, and from prodromal to dementia stages. Decline in visuospatial memory and sustained attention are implicated as early events in AD in DS; informant measures defined later events. A staging model was identified, with older adults with an AD diagnosis and those with APOE e4 status being more likely to be staged later. We estimated sample sizes required for clinical trials to prevent or delay decline. Significant cognitive change occurs during the prodromal stages of AD in DS, highlighting the necessity for early assessment. Sample size calculations suggest that trials of treatment to prevent or delay dementia are feasible in DS individuals.