Impact of Common Variations in PLD3 on Neuroimaging Phenotypes in Non-demented Elders

Abstract

Rare variants of phospholipase D3 (PLD3) have been identified as Alzheimer's disease (AD) susceptibility loci, whereas little is known about the potential role of common variants in the progression of AD. To examine the impact of genetic variations in PLD3 on neuroimaging phenotypes in a large non-demented population. A total of 261 normal cognition (NC) and 456 mild cognitive impairment (MCI) individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database are included in our analysis. Multiple linear regression models were applied to examine the association between four single-nucleotide polymorphisms (SNPs; rs7249146, rs4490097, rs12151243, and rs10407447) with the florbetapir retention on florbetapir 18F amyloid positron emission tomography (AV45-PET), the cerebral metabolic rate for glucose (CMRgl) on 18F-fluorodeoxyglucose PET (FDG-PET), and regional volume on magnetic resonance imaging (MRI) at baseline and in the cohort study. We did not detect any significant associations of PLD3 SNPs with florbetapir retention on AV45-PET. In the analysis of FDG-PET, rs10407447 was associated with the CMRgl in the left angular gyrus and bilateral posterior cingulate cortex in the MCI group. Regarding the MRI analysis, rs10407447 was also associated with bilateral inferior lateral ventricle and lateral ventricle volume in MCI group. The main findings of our study provide evidence that support the possible role of PLD3 common variants in influencing AD-related neuroimaging phenotypes. Nevertheless, further work is necessary to explain the functional mechanisms of differences and confirm the causal variants.

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials

“…Rare variants of PLD3 are confirmed AD susceptibility loci; phospholipase D3 modulates APP processing. However, a common variant in the same gene, rs10407447, was associated with regional metabolism and lateral ventricular volume in CN and MCI subjects [190]. A study of SNPs found in genes preferentially expressed in the hippocampus identified a novel locus, NAV2 (neuron navigator 2), associated with episodic memory scores [191].…”

Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes

“…Several variations in the PLD3 gene increase the risk to develop late-onset Alzheimer's disease (LOAD), and particularly one variant (Val232Met) doubles the risk of developing the disease (Cruchaga et al, 2014). However, more recent studies reproduced the association only in part or did not even find an association at all (Heilmann et al, 2015;Hooli et al, 2015;Lambert et al, 2015; van der Lee et al, 2015;Wang et al, 2015Wang et al, , 2016Zhang et al, 2016). Overexpression of PLD3 decreases the levels of both full-length APP and extracellular amyloid b (Ab) under conditions of high overexpression, whereas PLD3 knockdown increases extracellular Ab levels (Cruchaga et al, 2014).…”

Phospholipase D3 contributes to Alzheimer’s disease risk via disruption of Aβ clearance and microglia response to amyloid plaques

“…PLD3 is expressed in pyramidal neurons within the brain, and in AD brains, PLD3 co-localizes with amyloid plaques [8, 9]. Common variants in PLD3 are associated with CSF Aβ levels, an AD biomarker [10]. In vitro , PLD3 expression is correlated with extracellular Aβ levels: Pld3 silencing is associated with increased Aβ levels, and PLD3 overexpression is associated with reduced Aβ levels [4].…”