Genetic Risk Scores for Alzheimer Disease May Have Implications for Parkinson Disease

Researchers from a new study have found that genetic risk scores (GRS) and cerebral spinal fluid (CSF) biomarkers of Alzheimer disease have implications for outcomes of patients with Parkinson disease (PD).

The findings from the study, published in npj Parkinson's Disease, indicate that higher GRS for AD are associated with cognitive declines in patients with PD, while higher genetic risk scores for PD signify an increased risk of PD, albeit with slower clinical progression after diagnosis.

“Coexisting Alzheimer’s disease (AD) pathology is observed in approximately 30% of autopsy-confirmed Parkinson’s disease (PD) patients, and mixed AD pathology is associated with more α-synuclein (αSyn)-positive Lewy body disease (LBD) pathology and faster cognitive decline,” explained the researchers. “Accordingly, multiple studies have focused on predicting AD pathology using cerebrospinal fluid (CSF) biomarkers, such as phosphorylated-tau, total-tau, and β-amyloid (Aβ), or apolipoprotein E ε4 allele (APOE4) in PD However, the contribution of CSF biomarkers on clinical progression in PD patients is conflicting.”

The researchers relied on data from 400 patients with de novo PD and 195 healthy controls from the Parkinson’s Progression Marker Initiative database.

First exploring factors associated with the risk of PD, the researchers found that higher GRS-PD and lower baseline CSF αSyn were both independently associated with an increased risk of disease. According to the researchers, previous studies have demonstrated that CSF αSyn is decreased at baseline in PD and GRS-PD is associated with the diagnosis and symptom onset of disease.

The group also assessed the association between GRS and CSF biomarkers, finding that higher GRS-AD was associated with higher of CSF p-tau/Aβ and was associated with a faster increase in CSF p-tau/Aβ. They also found that higher GRS-AD was associated with lower CSF αSyn but with a slower decline in CSF αSyn. Higher GRS-PD was associated with faster CSF p-tau/Aβ increase, and both GRS-AD and GRS-PD interactively associated with higher CSF αSyn.

“Taken together, our data suggest that higher GRS-AD and higher CSF p-tau/Aβ reflect AD-related pathophysiology in PD, while higher GRS-PD and lower CSF αSyn could reflect PD-related pathophysiology leading to the occurrence of PD,” commented the researchers. “There may be a complex interplay between AD- and PD-related pathophysiology, which supports the view that mixed AD pathology needs to be considered in PD patients.”

Having higher baseline CSF p-tau/Aβ and GRS-AD were associated with cognitive decline in patients. Higher GRS-PD was associated with better semantic fluency domain, lower decline in frontal-related cognitive function, and better motor symptoms, given the same level of CSF biomarkers and dopamine transporter uptake.

Notably, this finding was not consistent with previous findings, which have indicated faster cognitive decline and motor progression in patients with PD who had higher GRS-PD. The researchers note that these conflicting findings could be a result of different single nucleotide polymorphisms used for GRS, differences in patient demographics, and further consideration of CSF biomarkers and AD-GRS in the current study.

Reference

Lee Y, Jeong S, Park M, et al. Effects of Alzheimer’s genetic risk scores and CSF biomarkers in de novo Parkinson’s Disease. npj Parkinsons Dis. Published online May 11, 2022. doi:10.1038/s41531-022-00317-8