BACKGROUND:
There is a need for sensitive cognitive measures that can detect subtle cognitive decline in the preclinical stages of Alzheimer’s disease (AD). The ‘Insight 46’ study provides an opportunity to investigate longitudinal associations between biomarkers of preclinical AD and early cognitive decline in a British cohort of identical age (all born in the same week in 1946).
METHODS:
Participants were assessed at ages ~70, ~73, and ~77 years (max n=702). Cognitive tests included the Preclinical Alzheimer Cognitive Composite (PACC), 7-day ‘accelerated forgetting’, Addenbrookes Cognitive Exam (ACE-III), Digit Symbol Substitution test (enhanced at age 77 with smartpens to capture novel process metrics including “think time vs. ink time”), and (at age 77) unsupervised remote digital testing using the Cognitron platform. Biomarker measures included β-amyloid-PET, plasma phosphorylated tau-217 (p-tau-217) and brain MRI. Linear regression models were used to investigate associations between cognitive outcomes and biomarker predictors including amyloid status (positive/negative), p-tau-217 status (low/intermediate/positive) and rates of whole-brain and hippocampal atrophy between ages ~70-73 and ~70-77, adjusting for relevant covariates.
RESULTS:
Between ages 70-73, there was little cognitive change overall, but we observed practice effects on memory tests and age-related declines on speed measures. Among amyloid-positive participants, faster rates of whole-brain and hippocampal atrophy between ages 70-73 were associated with reduced practice effects on memory measures. By age 77, there was clear divergence in cognitive trajectories with poorer performance among those with elevated amyloid and ptau-217 on a range of measures including PACC, ACE-III and Cognitron ‘delayed visual memory’ accuracy and speed (effect sizes d≈0.30-0.55), and associations between rates of atrophy and cognitive decline. At age ~73 amyloid-positive participants showed accelerated forgetting after 7 days, but at age ~77 even their immediate recall was poorer. DSST “think time” was sensitive to rates of atrophy whereas the standard ‘total score’ was not, suggesting that neurodegeneration initially comprises strategic efficiency on this task.
CONCLUSION:
Subtle cognitive decline is detectable among clinically-normal adults with evidence of preclinical AD pathology in their 70s, particularly in the memory domain. Speed and process metrics hold promise for enhancing detection of early deficits.