Work

P3‐457: Combined Neuropathological Pathways Account for Age‐related Increases in Risk of Dementia

Year: 2018

Type: article

Abstract: Our objectives were to characterize the interrelationship of known dementia-related neuropathologies in one comprehensive model and to quantify the extent to which the accumulation of neuropathologies accounts for the association between age and dementia. We used data from 1,362 autopsied participants of three community-based clinico-pathologic cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively. At the time of death (mean age: 89 years), 44% of our sample had a clinical dementia diagnosis. Of those with a clinical dementia diagnosis, 85% were diagnosed with Alzheimer's disease dementia without a second cause of cognitive impairment. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, as amyloid beta plaques were important in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, while the remaining three interrelated pathways together accounted for 68% (amyloid/tau: 24%, Lewy body: 1%, and TDP-43/hippocampal sclerosis: 43%). Age-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which independently contributes to dementia risk. Multi-pronged approaches may be necessary if we are to develop effective therapies. This finding may also have implications for the traditional notions of “normal” cognitive aging . Results of path analysis of combined pathologic pathways mediating the effect of age on dementia risk. Numbers are standardized coefficients or factor loadings. denotes non-significant paths. Abbreviations: Arter. Scler: arteriolosclerosis, CAA: cerebral amyloid angiopathy; CVDA: atherosclerosis, Gross: gross infarcts, Hippo. Sclerosis: hippocampal sclerosis; Micro: microinfarcts; Mesio. Tangles: mesiotemporal neurofibrilary tangles; Neocort Tangles: neocortical neurofibrilary tangles, TDP: TAR DNA- binding protein 43, T-EC: neurofibrillary tangles in the entorhinal cortex, T-Hip: neurofibrillary tangles in the hippocampus, T-IP: neurofibrillary tangles in the inferior parietal cortex, T-MF: neurofibrillary tangles in the midfrontal cortex, T-MT: neurofibrillary tangles in the midtemporal cortex.

Source: Alzheimer s & Dementia

DOI: 10.1016/j.jalz.2018.06.1821