Effects of amyloid pathology and neurodegeneration on cognitive change in cognitively normal adults

Understanding short-term cognitive decline in relation to Alzheimer's neuroimaging biomarkers in early stages of the development of neuropathology and neurodegeneration will inform participant recruitment and monitoring strategies in clinical trials aimed at prevention of cognitive impairment and dementia. We assessed associations among neuroimaging measures of cerebral amyloid pathology, a hallmark Alzheimer's neuropathology, hippocampal atrophy, and prospective cognition among 171 cognitively normal Baltimore Longitudinal Study of Aging participants (baseline age 56-95 years, 48% female, 562 cognitive assessments, 3.7 years follow-up). We categorized each individual based on dichotomous amyloid pathology (A) and hippocampal neurodegeneration (N) status at baseline: A-N-, A+N-, A-N+, A+N+. We conducted linear mixed effects analyses to assess cross-sectional and longitudinal trends in cognitive test z-scores by amyloid and neurodegeneration group. To investigate the effects of amyloid dose and degree of hippocampal atrophy, we assessed the associations of continuous mean cortical amyloid level and hippocampal volume with cognitive performance among individuals with detectable amyloid pathology at baseline. Individuals with amyloidosis or hippocampal atrophy had steeper longitudinal declines in verbal episodic memory and learning compared to those with neither condition (A+N- versus A-N-: β = - 0.069, P = 0.017; A-N+ versus A-N-: β = - 0.081, P = 0.025). Among individuals with hippocampal atrophy, amyloid positivity was associated with steeper declines in verbal memory (β = - 0.123, P = 0.015), visual memory (β = - 0.121, P = 0.036), language (β = - 0.144, P = 0.0004), and mental status (β = - 0.242, P = 0.002). Similarly, among individuals with amyloidosis, hippocampal atrophy was associated with steeper declines in verbal memory (β = - 0.135, P = 0.004), visual memory (β = - 0.141, P = 0.010), language (β = - 0.108, P = 0.006), and mental status (β = - 0.165, P = 0.022). Presence of both amyloidosis and hippocampal atrophy was associated with greater declines than would be expected by their additive contributions in visual memory (β = - 0.139, P = 0.036), language (β = - 0.132, P = 0.005), and mental status (β = - 0.170, P = 0.049). Neither amyloidosis nor hippocampal atrophy was predictive of declines in executive function, processing speed, or visuospatial ability. Among individuals with amyloidosis, higher baseline amyloid level was associated with lower concurrent visual memory, steeper declines in language, visuospatial ability, and mental status, whereas greater hippocampal atrophy was associated with steeper declines in category fluency. Our results suggest that both amyloid pathology and neurodegeneration have disadvantageous, in part synergistic, effects on prospective cognition. These cognitive effects are detectable early among cognitively normal individuals with amyloidosis, who are in preclinical stages of Alzheimer's disease according to research criteria. Our findings highlight the importance of early intervention to target both amyloidosis and atrophy to preserve cognitive function before further damage occurs.