A full list of >120 Penn BiND Lab publications is available here.
Genotype differences between primary age-related tauopathy (PART) and Alzheimer disease (AD). Adapted from McMillan et al., 2018
Alzheimer genetic risk is reduced in primary age-related tauopathy: a potential model of resistance?
Nearly all adults >50 years of age have evidence for neurofibrillary tau tangles (NFTs) and a significant proportion of individuals additionally develop amyloid plaques (Aβ) consistent with Alzheimer's disease (AD). In an effort to identify the independent genetic risk factors for NFTs and Aβ, we investigated genotypic frequencies of AD susceptibility loci between autopsy-confirmed AD and primary age-related tauopathy (PART), a neuropathological condition defined by characteristic neurofibrillary tau tangles (NFTs) with minimal or absent Aβ. General linear models assessed the odds of AD (N = 1190) relative to PART (N = 376) neuropathologically confirmed cases from two independent series: the Penn Brain Bank (PENN; AD N = 312; PART N = 65) and National Alzheimer's Coordinating Center (NACC; AD N = 878; PART N = 311). We also evaluated the odds of Braak stage NFT burden. Three genotypes significantly associated with reduced AD risk relative to PART in the PENN (N = 377) and NACC (N = 1189) cohorts including APOE ε4, APOE ε2, and rs6656401 in the CR1 gene. The genotypes rs6733839 in the BIN1 gene and rs28834970 in the PTK2B gene approached significance in the PENN cohort and were significantly associated with reduced AD risk in the NACC cohort. In a combined cohort analysis (N = 1566), APOE ε4 dosage was highly associated with higher Braak stage of NFT burden in Probable PART and AD, but not Definite PART. The presence of genotypic differences between PART and AD suggest that PART can provide a genetic model of NFT risk and potential Aβ resistance to inform disease-modifying therapies.
McMillan, C. T., Lee, E. B., Jefferson-George, K. S., Naj, A. C., Van Deerlin, V. M., Trojanowksi, J. Q., & Wolk, D. A. (2018). Alzheimer genetic risk is reduced in primary age-related tauopathy: a potential model of resistance? Annals of Clinical and Translational Neurology, 5(8), 927-934. PubMed
Increased copies of risk alleles in rs12608932 in the UNC13A gene are associated with increased TDP-43 pathological burden. Adapted from Placek et al., 2019
UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis
The majority (90%-95%) of amyotrophic lateral sclerosis (ALS) is sporadic, and ∼50% of patients develop symptoms of frontotemporal degeneration (FTD) associated with shorter survival. The genetic polymorphism rs12608932 in UNC13A confers increased risk of sporadic ALS and sporadic FTD and modifies survival in ALS. Here, we evaluate whether rs12608932 is also associated with frontotemporal disease in sporadic ALS. We identified reduced cortical thickness in sporadic ALS with T1-weighted magnetic resonance imaging (N = 109) relative to controls (N = 113), and observed that minor allele (C) carriers exhibited greater reduction of cortical thickness in the dorsal prefrontal, ventromedial prefrontal, anterior temporal, and middle temporal cortices and worse performance on a frontal lobe-mediated cognitive test (reverse digit span). In sporadic ALS with autopsy data (N = 102), minor allele homozygotes exhibited greater burden of phosphorylated tar DNA-binding protein-43 kda (TDP-43) pathology in the middle frontal, middle temporal, and motor cortices. Our findings demonstrate converging evidence that rs12608932 may modify frontotemporal disease in sporadic ALS and suggest that rs12608932 may function as a prognostic indicator and could be used to define patient endophenotypes in clinical trials.
Placek, K., Baer, G. M., Elman, L., McCluskey, L., Hennessy, L., Ferraro, P. M., Lee, E. B., Lee, V. M.-Y., Trojanowski, J. Q., Van Deerlin, V. M., Grossman, M., Irwin, D. J., & McMillan, C. T. (2019). UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis. Neurobiology of Aging, 73, 190–199. PubMed
Converging evidence suggests that C9orf72 promoter hypermethylation is neuroprotective including evidence for higher cortical thickness in hippocampus, thalamus and frontal cortex measured with MRI and less neuronal loss measured in frontal cortex and hippocampus in brain tissue (thalamus not available). Adapted from McMillan et al., 2015
C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging & neuropathological evidence
To use in vivo neuroimaging and postmortem neuropathologic analysis in C9orf72 repeat expansion patients to investigate the hypothesis that C9orf72 promoter hypermethylation is neuroprotective and regionally selective. Twenty patients with a C9orf72 repeat expansion participating in a high-resolution MRI scan and a clinical examination and a subset of patients (n = 11) were followed longitudinally with these measures. Gray matter (GM) density was related to C9orf72 promoter hypermethylation using permutation-based testing. Regional neuronal loss was measured in an independent autopsy series (n = 35) of C9orf72 repeat expansion patients. GM analysis revealed that hippocampus, frontal cortex, and thalamus are associated with hypermethylation and thus appear to be relatively protected from mutant C9orf72. Neuropathologic analysis demonstrated an association between reduced neuronal loss and hypermethylation in hippocampus and frontal cortex. Longitudinal neuroimaging revealed that hypermethylation is associated with reduced longitudinal decline in GM regions protected by hypermethylation and longitudinal neuropsychological assessment demonstrated that longitudinal decline in verbal recall is protected by hypermethylation. These cross-sectional and longitudinal neuroimaging studies, along with neuropathologic validation studies, provide converging evidence for neuroprotective properties of C9orf72 promoter hypermethylation. These findings converge with prior postmortem studies suggesting that C9orf72 promoter hypermethylation may be a neuroprotective target for drug discovery.
McMillan, C. T., Russ, J., Wood, E. M., Irwin, D. J., Grossman, M., McCluskey, L., Elman, L., Van Deerlin, V. M., & Lee, E. B. (2015). C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging & neuropathological evidence Neurology 84(16): 1622-1630. PubMed