Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis

Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synudeinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of dinical heterogeneity in synudeinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed a synudeinopathy (as of Oct 1, 2015) who were previously induded in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, alpha-synudein indusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synudeinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Levey body disorder with autopsy-confirmed a synudeinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral a-synudein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0.0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (beta -4.0, 95% CI -5.5 to -2.6; p<0.0001; R-2 0.22, p<0.0001) and with survival (-2.0, -3.2 to -0.8; 0.003; 0.15, <0.0001) in models that induded age at death, sex, cerebral neuritic plaque scores, cerebral alpha-synudein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer's disease neuropathology is common in synudeinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to a-synudein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synudeinopathies should help to identify the most appropriate patients for dinical trials of emerging therapies targeting tau, amyloid-beta or alpha synudein, and to stratify them by level of Alzheimer's disease neuropathology.