Cerebral amyloid angiopathy and neuritic plaques impact tangle burden and cognitive decline in a heterogeneous clinical population

Abstract

AbstractBackgroundAlzheimer disease (AD) presents with two primary pathologies: neurofibrillary tangles (NFT) and neuritic plaques (NP). However, these hallmark pathologies typically co‐occur with pathologies from AD‐related dementias like cerebral amyloid angiopathy (CAA) [Godrich, 2022; PMID: 35142102]. While CAA is known to impact cognitive impairment, the role of CAA in AD dementia is still not well described [Rabin, 2022; PMID: 35759327]. Here we present an analysis of CAA, NP, and NFT to assess the interplay of these pathologies with cognitive decline and genetic risk factors for AD.MethodData come from 4,915 autopsied individuals from the National Alzheimer’s Coordinating Centers (NACC). NFT, NP, and CAA were measured ordinally. We used ordinal logistic regression to model and compare independent and interactive effects of CAA and NP on NFT and cognitive decline while adjusting for sex, AAD, and APOE. We also evaluate models with an APOE and NP interaction as a comparison to gauge whether it is more informative than CAA. Finally, we replicate causal mediation analysis from Rabin et al. and extend the path model to include APOE, stratifying both models by NP severity (Fig.1).ResultThe model with CAA and NP interactions best explained NFT burden outcome (per AIC, pseudo‐R2, and F‐test), even when compared to models with APOE. We replicated Rabin et al. findings that CAA does not directly affect cognitive decline but rather indirectly via NFT mediation, but only in individuals in the high NP group. We saw this in a larger clinical cohort with ordinal measures of neuropathology, which are more commonly obtained than linear ones. We also extended the mediation analysis to include APOE and findings held.ConclusionWe replicated the relationship between CAA, AD pathologies, and cognitive decline [Rabin, 2022] and extend the findings to a more heterogeneous clinical population. Even when accounting for APOE, CAA still had an indirect effect on cognitive decline in the high NP group as mediated by NFT severity, showing that the findings are likely not due to APOE confounding. These findings continue to underscore the importance of the consideration of co‐occurring neuropathologies like CAA when developing novel AD therapeutics.