Biomarkers.

Area of Science:

• Neurology
• Biomarkers
• Cognitive Science

Background:

• Alzheimer's disease (AD) clinical trials often use preclinical Alzheimer's disease cognitive composite (PACC) scores, combining memory, executive function, and mental status measures.
• The sensitivity of cognitive measures during the emergent AD stage, characterized by rising amyloid-beta (Aβ) levels within normal limits, remains unevaluated.

Purpose of the Study:

• To compare the sensitivity of different cognitive composite scores in detecting Aβ-related cognitive decline in initially cognitively unimpaired (CU) individuals.
• To evaluate cognitive changes associated with increasing Aβ levels indicative of emergent AD.

Main Methods:

• Utilized data from 611 CU individuals in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, initially Aβ-negative.
• Assessed cognitive changes using four composite scores: PACC, PACC5 (including Semantic Fluency), PACC5 without MMSE, and a memory-only composite.
• Employed linear mixed-effects models (LMM) to compare cognitive change rates between individuals who became Aβ-positive (emergent AD) and those who remained Aβ-negative (stable CU Aβ-).

Main Results:

• 86 out of 611 CU participants developed emergent AD, characterized by faster Aβ accumulation.
• A statistically significant group-by-time interaction was observed for PACC, PACC5 (excluding MMSE), and memory composites.
• The memory composite demonstrated the strongest effect, indicating the highest sensitivity to Aβ-related cognitive changes (β[SE] = -0.089[0.029], p = 0.003).

Conclusions:

• The memory composite is the most sensitive cognitive measure for detecting Aβ-related changes in individuals with increasing Aβ levels during the emergent AD stage.
• Clinical trials targeting emergent AD should incorporate memory assessments to effectively capture AD-related cognitive changes.