A variant in PPP4R3A protects against alzheimer‐related metabolic decline

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Among the many biomarkers for Alzheimer's disease (AD), decline in glucose metabolism in the posterior cingulate cortex (PCC) is one of the earliest, occurring years before symptom onset.1 Furthermore, metabolic decline in the PCC actually predicts conversion from healthy aging to mild cognitive impairment (MCI), and from MCI to AD,2 signifying its role in AD progression. The PCC is a central and highly interconnected brain region, with a crucial role in coordinating memory and internally driven cognitive processes.4 It is also a component of the default mode network, a brain network that is particularly vulnerable in AD.6 Therefore, molecular pathways involved in declining PCC glucose metabolism may be closely associated with disease progression and worsening of symptoms. Although early decline in PCC glucose metabolism is well established in AD pathology, the genetic contribution to these changes remains unknown. Common genetic variation may influence the extent to which individuals are protected from or predisposed to hypometabolism, and as a result, their risk of developing AD and memory impairment. Genome‐wide association studies (GWAS) have identified single‐nucleotide polymorphisms (SNPs), or common genetic variants, that are associated with hallmark pathological biomarkers of AD such as beta‐amyloid plaques in the brain and phosphorylated tau in the cerebrospinal fluid (CSF).8 These studies have provided important insight into biological pathways associated with AD; however, the link between PCC metabolic decline and vulnerability to AD is poorly understood. Decline in PCC metabolism correlates well with disease progression. By contrast, amyloid deposition measured with positron emission tomography (PET), appears less sensitive to disease progression.10 As such, decline in PCC metabolism over time may provide distinct and important insights into biological mechanisms underlying the disease.
The primary aim of this study was to discover SNPs associated with longitudinal decline in PCC glucose metabolism that affect the (1) risk of developing AD and (2) progression of the disease (ie, cognitive decline). Although the pathways linking PCC glucose metabolic decline to AD remain unknown, there is substantial evidence supporting a role for abnormal glucose regulation in AD. Cellular uptake of glucose is closely regulated by oxidative stress signaling pathways.12 Furthermore, impaired oxidative stress signaling has been shown to lead to reduced glucose metabolism and the eventual development of memory impairment in AD.13 Therefore, genes involved in adaptation to oxidative stress or the regulation of glucose metabolism may contribute to PCC metabolic decline and disease vulnerability. Given that the PCC is the first and most pronounced region to undergo metabolic decline, PCC metabolism is a powerful and unexplored endophenotype for investigating unknown genetic contributions to AD. Fludeoxyglucose F 18 ([18F] FDG) PET measures the uptake of glucose into neurons and astrocytes and can be used as a proxy for neuronal activity. Thus, in order to achieve these aims, we performed a quantitative trait GWAS of longitudinal decline in PCC glucose metabolism, as measured by [18F] FDG PET imaging in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our top candidate from the GWAS was then explored further to determine its effects on AD risk, decline in cognitive performance over time, and gene expression in brain.

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