Mixed neuropathologies and associations with domain-specific cognitive decline

Area of Science:

• Neuropathology
• Cognitive Neuroscience
• Geriatric Medicine

Background:

• Alzheimer disease neuropathologic change (ADNC) is a primary driver of cognitive decline.
• The impact of co-occurring pathologies like Lewy body disease (LBD) and vascular brain injury (VBI) on cognitive trajectories in the presence of ADNC is not fully understood.

Purpose of the Study:

• To investigate how the presence of LBD or VBI modifies cognitive decline in individuals with ADNC.
• To determine if the interaction between ADNC and other pathologies affects specific cognitive domains.

Main Methods:

• Analysis of autopsy data from 1,603 participants from US Alzheimer's Disease Centers.
• Derivation of standardized cognitive domain scores (memory, attention, language, executive function) from longitudinal neuropsychological testing.
• Application of multivariable linear mixed-effects models to assess neuropathology-cognition associations.

Main Results:

• ADNC combined with LBD was associated with worse cognitive trajectories, particularly in executive function and attention.
• ADNC combined with VBI showed less cognitive impairment and slower decline compared to other groups.
• Significant interactions between LBD and ADNC for memory, and VBI and ADNC for language, indicated non-additive effects on decline, especially in high ADNC cases.
• Microinfarcts were linked to cognitive decline in non-ADNC individuals, but this association was reduced in those with ADNC.

Conclusions:

• Co-occurrence of LBD with ADNC is linked to poorer executive function and attention.
• The influence of co-pathologies on cognitive decline may be modulated by the severity of underlying ADNC.
• Further research with antemortem biomarkers is recommended to validate these neuropathological findings.