Mixed neuropathologies and estimated rates of clinical progression in a large autopsy sample

Abstract

Introduction: Whether co-occurring neuropathologies interact or independently affect clinical disease progression is uncertain. We estimated rates of clinical progression and tested whether associations between clinical progression and Alzheimer's disease neuropathology (ADNP) were modified by co-occurring Lewy body disease (LBD) or vascular brain injury (VBI).

Methods: Linear mixed effects models evaluated longitudinal trends in the Clinical Dementia Rating Scale Sum of Boxes on 2046 autopsied participants seen at a U.S. Alzheimer's Disease Center.

Results: Annual clinical progression was slightly faster for ADNP + LBD compared with ADNP only (P = .06) and slightly slower for ADNP + VBI (P = .003). Differences in progression were less than expected if each neuropathology independently contributed to progression; ADNP interacted with LBD (P = .002) and VBI (P = .003). In secondary models, the effect of additional pathologies on clinical progression was greater in those with intermediate compared with high levels of ADNP.

Discussion: The impact of co-occurring pathologies on progression may depend on severity of ADNP.

Keywords: Alzheimer's disease neuropathology; Cerebrovascular disease; Clinical progression; Lewy body disease; Mixed neuropathology.

Figure 1. Co-occurrence of Alzheimer’s disease neuropathology (ADNP), Lewy body disease (LBD), and vascular brain injury (VBI)

ADNP = moderate/frequent neuritic plaques & Braak stage III–VI; LBD = Lewy bodies in any brain region examined; VBI = gross infarcts and cortical microinfarcts.

Figure 2. Model based population mean trajectories of clinical impairment (CDR-SB) prior to death

ADNP, Alzheimer’s disease neuropathology = moderate/frequent neuritic plaques & Braak III–VI; CDR-SB, Clinical Dementia Rating Sum of Boxes; LBD, Lewy body disease = Lewy bodies in any brain region examined; low NP, low neuropathology = no ADNP, no VBI, no LBD, and no other major pathologies; VBI, vascular brain injury = any gross infarcts or cortical microscopic infarcts. Progression was faster for those with LDB only (p=0.002) and ADNP only (p=0.002) but not VBI only (p=0.2) compared to those with low NP. Compared to ADNP only progression for ADNP+LBD was borderline faster (p=0.06) while progression was slower for ADNP+VBI (p=0.003). Significant negative interactions were present between ADNP and LBD (p=0.002) and between ADNP and VBI (p=0.003), such that participants with ADNP and co-occurring LBD or VBI had a lower rate of progression than would be expected if each pathology independently contributed to progression.

Figure 3. Model based population mean trajectories of clinical impairment (CDR-SB) prior to death associated with intermediate and high ADNP with and without co-occurring cortical LBD

ADNP, Alzheimer’s disease neuropathology; CDR-SB, Clinical Dementia Rating Sum of Boxes; cLBD, cortical Lewy body disease. Intermediate ADNP = moderate/frequent neuritic plaques & Braak III–IV; high ADNP= moderate or frequent plaques & Braak V–VI. Trajectories for ADNP+VBI were similar to ADNP only and are not shown. Compared to high ADNP, progression in intermediate ADNP+cLBD was significantly faster (p=0.04), but progression in high ADNP+cLBD was not significantly different (p=0.2). Significant negative interactions were present between high ADNP and cLBD (p=0.003) such that participants with ADNP and co-occurring LBD or VBI had a lower rate of progression than would be expected if each pathology independently contributed to progression.