Baseline amyloid spatial extent in combination with tau burden captures cognitive decline, measured digital clock drawing test and PACC5, in preclinical Alzheimer's disease

BACKGROUND: Digital cognitive assessments have potential to improve detection of early cognitive changes in emerging Alzheimer's disease (AD) pathology in preclinical AD. Spatial extent (EXT) measures the spread of amyloid-b (Ab) and is potentially more sensitive to early Ab burden than the traditional measure of neocortical Ab level. Previously, we observed that worsening digital clock drawing test (DCTclock) performance was cross-sectionally associated with spreading amyloid and greater entorhinal tau in cognitively normal (CN) participants. We sought to evaluate these relationships longitudinally. METHOD: 195 CN older adults from the Harvard Aging Brain Study were included with annual DCTclock and PACC5 assessments for up to 6 years (Table 1). DCTclock measures included a composite summary score (DCT) and 4 subscores (information processing, spatial reasoning, simple motor, drawing efficiency) for both command and copy versions. Baseline amyloid ([11C]Pittsburgh Compound B) and entorhinal tau (Flortaucipir SUVR, n = 174) PET were measured. Abspread was estimated as the neocortical spatial extent (EXT, %PiB+ using region-specific thresholds) and grouped into 3 EXT stages: EXT- (EXT<7.2%, no Ab), EXT+ (7.2%EXT<95.6%, spreading Ab), EXT++ (EXT95.6%, widespread Ab). A series of linear mixed effect models assessed the effects of EXT group and entorhinal tau on PACC5 and DCTclock over time, corrected for age, sex, and education. RESULT: Individuals in the EXT+ and EXT++ groups showed a significantly faster cognitive decline on PACC5 and DCTclock command information processing subscore (DCT-IP) compared to EXT- (Figure 1). When including ERC tau, elevated ERC tau burden and EXT+/EXT++ independently contributed to a faster decline in PACC5, whereas faster decline in DCT-IP was significant in the EXT+ group only (Figure 2). CONCLUSION: Longitudinal assessment with DCTclock captured unique information about cognitive decline in the early stages of the spread of amyloid. However, the PACC remained a superior measure of the more severe cognitive decline associated with amyloid and tau pathology in later stages of preclinical AD.