Dementia with Lewy bodies in women: combating misdiagnosis through sex-specific biomarkers of disease risk and progression

Dementia with Lewy Bodies (DLB) is difficult to diagnose clinically, particularly in women, and our new genome-wide association study may explain why this is true; Males and females have different signatures of genetic risk for DLB. This may explain why DLB is less prevalent in woman and presents with a more Alzheimer’s disease-like clinical profile, thus making DLB in woman more likely to be mis-diagnosed as AD clinically. Early misdiagnosis and non-diagnosis are common, especially in women, and clinicians need objective biomarkers to support their initial DLB diagnosis. In this project, we will examine the effects of different risk genes in DLB on new biomarkers in blood and cerebrospinal fluid in women compared to men, and how they relate to the clinical characteristics of DLB, with a particular focus on woman. We will further identify possible sex-specific responses to treatment with Ambroxol in DLB in persons participating in a clinical drug trial.

Dementia with Lewy Bodies (DLB) is difficult to diagnose, particularly in women, and our new DLB genome-wide association study (GWAS) may explain why this is true; Males and females have different signatures of genetic risk for DLB. Notably, APOE was the only significant genetic hit for women diagnosed with DLB whilst the known PD-risk loci at SNCA and GBA increased the risk of DLB only in males. This may explain why DLB is less prevalent in woman and presents with a more AD-like clinical profile, thus making DLB in woman more likely to be mis-diagnosed as AD clinically. Early misdiagnosis and non-diagnosis are common, especially in women, and clinicians need objective biomarkers to support their initial DLB diagnosis. We have validated genetic sex-specific differences in DLB by executing a new, larger GWAS. We will extend this to understand the impact of these differences on disease severity and progression. To understand how the sex-specific genetic signatures impact disease risk, we will use a panel of cutting-edge biofluid biomarkers to assess how SNCA variants impact misfolded and aggregated forms of alpha-synuclein, how GBA variants impact GCase (dys)function, and how ApoE variants reflect Alzheimer’s disease co-pathology in DLB with a particular focus on woman. These data will be combined to update current thinking on sex-specific protocols for the diagnosis of DLB and to combat the unacceptable rates of misdiagnosis of women with DLB. We will identify possible sex-specific responses to treatment of Ambroxol in DLB in the ANeED Study. For this call we apply for funding to perform the science work and costs related to the new biomarkers defined above with a particular focus on woman. We expect to find new biomarkers for diagnosing DLB with higher precision in woman than the clinical diagnostic workup we rely on today.