Assessment of genetic risk for improved clinical-neuropathological correlations
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RESEARCH
Assessment of genetic risk for improved clinical‑neuropathological correlations Barbara E. Spencer1, Robin G. Jennings1, Chun C. Fan2,3 and James B. Brewer1,3*
Abstract In the clinical diagnosis of dementia with Lewy bodies, distinction from Alzheimer’s disease is suboptimal and complicated by shared genetic risk factors and frequent co-pathology. In the present study we tested the ability of polygenic scores for Alzheimer’s disease, dementia with Lewy bodies, and Parkinson’s disease to differentiate individuals in a 2713-participant, pathologically defined sample. A dementia with Lewy bodies polygenic score that excluded apolipoprotein E due to its overlap with Alzheimer’s disease risk was specifically associated with at least limbic (transitional) Lewy-related pathology and a pathological diagnosis of dementia with Lewy bodies. An Alzheimer’s disease polygenic score was associated with neuritic plaques and neurofibrillary tangles but not Lewy-related pathology, and was most strongly associated with an Alzheimer’s pathological diagnosis. Our results indicate that an assessment of genetic risk may be useful to clinically distinguish between Alzheimer’s disease and dementia with Lewy bodies. Notably, we found no association with a Parkinson’s disease polygenic score, which aligns with evidence that dementia with Lewy bodies has a distinct genetic signature that can be exploited to improve clinical diagnoses. Keywords: Alzheimer’s disease, Dementia with Lewy bodies, Parkinson’s disease, Polygenic risk, Diagnosis Introduction In heterogeneous disease cohorts, accurate distinctions between Alzheimer’s disease (AD) and related dementias may improve precision in care delivery and thus lead to better outcomes. In the diagnosis of dementia with Lewy bodies (DLB), distinction from AD is suboptimal and complicated by the frequent co-occurrence of AD neuropathologic changes (NC) with Lewy body (LB) pathology. Patients clinically diagnosed with AD often present with concurrent LB pathology at autopsy, though many studies have attempted to tease apart the differences in clinical presentations to better reflect underlying pathology [2, 6, 9, 14, 21, 25]. Incorporating information about genetic risk into a difficult differential diagnosis may improve clinicalneuropathological correlations. A recently developed *Correspondence: [email protected] 1 Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, Mail Code 0949, La Jolla, CA 92093, USA Full list of author information is available at the end of the article
AD polygenic hazard score (PHS) is associated with the hallmark Alzheimer’s disease neuropathologic changes (ADNC), neuritic plaques and neurofibrillary tangles. However, the large-scale genetic studies that identify such risk typically rely on clinical diagnoses, which are imperfect proxies for the often mixed underlying pathologies [5, 20]. While the AD PHS has reported associations with LBs [22], it is unclear whether this reflects a shared genetic risk between patholo
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