Our goal is to examine whether mutations in the glucocerebrosidase (GBA) gene are a risk factor and biomarker for Dementia with Lewy Bodies (DLB). GBA has recently been demonstrated to be a risk factor for Parkinson disease (PD). In a recent autopsy study of patients with DLB, PD, Alzheimer disease (AD), and without dementia, we sequenced the GBA gene in each of 187 brains. Carriers of GBA mutations were more likely to have DLB (with findings of cortical Lewy bodies), even in the presence of AD pathology (plaques and tangles), although they were less likely to have such AD pathology. Conversely, those with AP0E-?4 were more likely to have AD pathological findings, and less likely to have DLB pathology. Thus, just as AP0E-?4 is a risk factor for AD, it is possible that GBA is a risk factor and marker for DLB. Here we propose to further study the relation of GBA to DLB in living ADRC subjects by sequencing the GBA gene in 800 consecutive well-characterized ADRC subjects with full UDS data, and available DNA, and APOE genotype. We will: (1) compare carriers and non-carriers for disease diagnosis and severity, for clinical symptoms common in DLB including hallucinations, parkinsonism, and fluctuations, and for neuropsychological test characteristics of DLB, such as relative preservation of memory, but impaired subcortical and visuospatial function;(2) compare disease, symptoms, and neuropsychological test characteristics, in carriers who have GBA mutations thought to be of """"""""mild"""""""" phenotype even when homozygous, to those carrying mutations known to be of """"""""severe"""""""" phenotype when homozygous;(3) determine in the collected cerebrospinal fluid (CSF) of 100 ADRC subjects whether there is decreased GBA enzymatic activity in CSF of patients who are GBA mutation carriers of mild type or severe type, versus noncarriers, and in unaffected individuals. We hypothesize that GBA mutations may be a marker for DLB, and that decreased GBA activity may predispose to DLB. Our results may allow improved accuracy of diagnosis of DLB during life, and may have related implications on making prognostic statements and treatment plans for patients with dementia.

Public Health Relevance

Dementia with Lewy Bodies (DLB) is the second most common (after Alzheimer disease, AD) neurodegenerative pathology. However, it is difficult to diagnose DLB accurately during life, and distinguish it from AD. The results of these studies may improve diagnosis, suggest a mechanism in which GBA may relate to development of DLB, and improve the ability to prognosticate and treat persons with DLB.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University
New York
United States
Zip Code
Besser, Lilah M; Alosco, Michael L; Ramirez Gomez, Liliana et al. (2016) Late-Life Vascular Risk Factors and Alzheimer Disease Neuropathology in Individuals with Normal Cognition. J Neuropathol Exp Neurol 75:955-962
Burke, Shanna L; Maramaldi, Peter; Cadet, Tamara et al. (2016) Neuropsychiatric symptoms and Apolipoprotein E: Associations with eventual Alzheimer's disease development. Arch Gerontol Geriatr 65:231-8
John, Samantha E; Gurnani, Ashita S; Bussell, Cara et al. (2016) The effectiveness and unique contribution of neuropsychological tests and the δ latent phenotype in the differential diagnosis of dementia in the uniform data set. Neuropsychology 30:946-960
Hur, Jang Ho; Park, Shi-Young; Dall'Armi, Claudia et al. (2016) Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect. Sci Rep 6:39170
Bonham, Luke W; Geier, Ethan G; Fan, Chun C et al. (2016) Age-dependent effects of APOE ε4 in preclinical Alzheimer's disease. Ann Clin Transl Neurol 3:668-77
Ting, Simon Kang Seng; Hao, Ying; Chia, Pei Shi et al. (2016) Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer's disease. Sci Rep 6:20858
Fischer, Corinne E; Qian, Winnie; Schweizer, Tom A et al. (2016) Lewy Bodies, Vascular Risk Factors, and Subcortical Arteriosclerotic Leukoencephalopathy, but not Alzheimer Pathology, are Associated with Development of Psychosis in Alzheimer's Disease. J Alzheimers Dis 50:283-95
Karch, Celeste M; Ezerskiy, Lubov A; Bertelsen, Sarah et al. (2016) Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One 11:e0148717
McCutcheon, Sarah T; Han, Dingfen; Troncoso, Juan et al. (2016) Clinicopathological correlates of depression in early Alzheimer's disease in the NACC. Int J Geriatr Psychiatry 31:1301-1311
Ebbert, Mark T W; Boehme, Kevin L; Wadsworth, Mark E et al. (2016) Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk. Alzheimers Dement 12:121-9

Showing the most recent 10 out of 536 publications