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Ann Clin Transl Neurol. 2018 Apr 2;5(5):616-629. doi: 10.1002/acn3.560. eCollection 2018 May.

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment.

Author information

1
Human Genetics and Genomics Graduate Program University of California Los Angeles Los Angeles California.
2
Medical Scientist Training Program David Geffen School of Medicine at the University of California Los Angeles Los Angeles California.
3
Department of Psychiatry Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles California.
4
Memory and Aging Center Department of Neurology University of California San Francisco San Francisco California.
5
A&G Pharmaceutical, Inc. 9130 Red Branch Rd Columbia Maryland 21045.
6
Greenebaum Cancer Center University of Maryland Baltimore Maryland 21201.
7
Department of Neurology University of California Los Angeles Los Angeles California.

Abstract

Objective:

Changes in progranulin (GRN) expression have been hypothesized to alter risk for Alzheimer's disease (AD). We investigated the relationship between GRN expression in peripheral blood and clinical diagnosis of AD and mild cognitive impairment (MCI).

Methods:

Peripheral blood progranulin gene expression was measured, using microarrays from Alzheimer's (n = 186), MCI (n = 118), and control (n = 204) subjects from the University of California San Francisco Memory and Aging Center (UCSF-MAC) and two independent published series (AddNeuroMed and ADNI). GRN gene expression was correlated with clinical, demographic, and genetic data, including APOE haplotype and the GRN rs5848 single-nucleotide polymorphism. Finally, we assessed progranulin protein levels, using enzyme-linked immunosorbent assay, and methylation status using methylation microarrays.

Results:

We observed an increase in blood progranulin gene expression and a decrease in GRN promoter methylation in males (P = 0.007). Progranulin expression was 13% higher in AD and MCI patients compared with controls in the UCSF-MAC cohort (F2,505 = 10.41, P = 3.72*10-5). This finding was replicated in the AddNeuroMed (F2,271 = 17.9, P = 4.83*10-8) but not the ADNI series. The rs5848 SNP (T-allele) predicted decreased blood progranulin gene expression (P = 0.03). The APOE4 haplotype was positively associated with progranulin expression independent of diagnosis (P = 0.04). Finally, we did not identify differences in plasma progranulin protein levels or gene methylation between diagnostic categories.

Interpretation:

Progranulin mRNA is elevated in peripheral blood of patients with AD and MCI and its expression is associated with numerous genetic and demographic factors. These data suggest a role in the pathogenesis of neurodegenerative dementias besides frontotemporal dementia.

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