Association between the LRP1B and APOE loci and the development of Parkinson's disease dementia

Abstract

Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson's disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson's disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson's disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson's disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson's disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson's disease dementia [hazard ratio = 2.41 (1.94-3.00), P = 2.32 × 10-15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17-4.81), P = 7.07 × 10-09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21-3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson's disease dementia, with significantly reduced levels of amyloid β42 (P = 0.0012) in Parkinson's disease dementia compared to Parkinson's disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson's disease dementia.

Keywords: Parkinson’s disease; dementia; genome-wide; survival.

Figure 1

Manhattan plot representing the results of the GWSS meta-analysis. The GWSS was conducted using a CPH model in each cohort separately, and results were meta-analysed (PDD: n = 265; PD: n = 3658). The gene closest to the top variant is indicated at each genome-wide significant locus. Genome-wide significance was set at 5 × 10⁻⁸ and is indicated by the dashed line.

Figure 2

Interaction between APOE and LRP1B rs80306347 signals. (A) Kaplan–Meier curve for dementia-free survival based on APOE ɛ4 and LRP1B rs80306347 carrier status of PD patients. Compared to non-carriers of either allele, LRP1B rs80306347 carriers had an HR of progression to PDD of 2.33 (95% CI = 1.34–4.05; P = 0.00273), while APOE ɛ4 carriers had an HR of 2.48 (95% CI = 1.91–3.21; P = 9.67 × 10⁻¹²). Carriers of both alleles had the most significant increase in the hazards ratio of progressing to PDD (HR = 8.08; 95% CI = 4.64–14.06; P = 1.55 × 10⁻¹³). (B) Kaplan–Meier curve for dementia-free survival based on LRP1B rs80306347 carrier status in PD APOE ɛ4 carriers. (C) Kaplan–Meier curve for dementia-free survival based on LRP1B rs80306347 carrier status in PD APOE ɛ4 non-carriers. Statistical analysis was conducted using CPH models in the combined cohorts (n = 3923 individuals) at the specified loci.

Figure 3

Survival curves of candidate gene analysis. (A) Kaplan–Meier curve for dementia-free survival based on GBA E365K (E362K) and N409S (N370S) carrier status of PD patients. (B) Kaplan–Meier curve for dementia-free survival based on APOE ɛ4 carrier status of PD patients. (C) Kaplan–Meier curve for dementia-free survival on the basis of LRP1B rs80306347 carrier status of PD patients. Statistical analysis was conducted per locus using CPH models in the combined cohorts (n = 3923 individuals).

Figure 4

Alzheimer’s disease and PD-GRS. (A and B) Violin plots depicting the distribution of the meta-analysis of z-transformed Alzheimer’s disease (A) and PD GRSs (B) in PD and PDD. The central line of the boxplots indicates the median, the box limits indicate the first and third quartiles, the whiskers indicate ±1.5 × IQR, and the data points indicate the outliers. (C and D) Survival Kaplan–Meier curves for dementia-free survival of PD patients based on the stratification of Alzheimer's disease-GRS into low-, middle- and high-risk tertiles, either including (C) or excluding APOE (D).

Figure 5

CSF measurements of Alzheimer's disease biomarkers. Box plots representing the measurements (in pg/ml) of the CSF biomarkers Aβ42, p-Tau181 and total Tau in a subset of individuals from the AMP-PD cohort (n = 352) across time (M0 = study baseline, M12 = 12 months, M24 = 24 months, M36 = 36 months). (A) CSF biomarker levels by phenotype (n = 28 PDD and n = 324 PD cases). (B) CSF biomarker levels by APOE ɛ4 allele carrier status (n = 86 APOE ɛ4 allele carriers and n = 266 APOE ɛ4 allele non-carriers). Box plots display a median line, the box limits indicate the first and third quartiles, the whiskers indicate ±1.5 × IQR, and the data points indicate the outliers. The Wilcoxon rank-sum test was used to compare medians across phenotypic groups. Significance threshold: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.