Genetic effects on longitudinal cognitive decline during the early stages of Alzheimer\u2019s disease

Atul Kumar,Oskar Hansson,Maryam Shoai,Sebastian Palmqvist,Erik Stomrud,Niklas Mattsson-Carlgren,John Hardy

doi:10.1038/s41598-021-99310-z

Abstract

Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence, and educational attainment) to predict longitudinal cognitive change (measured by mini-mental state examination (MMSE) [primary outcome] and other cognitive tests) over a mean of 4.2 years. We included 260 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 121 Aβ-positive CU (preclinical AD), 50 Aβ-negative mild cognitive impairment (MCI) patients, and 127 Aβ-positive MCI patients (prodromal AD). Statistical significance was determined at Bonferroni corrected p value < 0.05. The PGS for intelligence (beta = 0.1, p = 2.9e−02) was protective against decline in MMSE in CU and MCI participants regardless of Aβ status. The polygenic risk score for AD (beta = − 0.12, p = 9.4e−03) was correlated with the rate of change in MMSE and was partially mediated by Aβ-pathology (mediation effect 20%). There was no effect of education PGS on cognitive measures. Genetic variants associated with intelligence mitigate cognitive decline independent of Aβ-pathology, while effects of genetic variants associated with AD are partly mediated by Aβ-pathology.

Highlights

Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability
None of the polygenic risk score (PRS)-Alz or APOE models showed any significant association with the random intercept after Bonferroni correction (Fig. 2b, supplementary table S11). These results suggests that the effect of APOE on cognitive decline largely depends on Aβ status
In this study of genetic contributions to cognitive decline in the earliest stages of AD, we investigated whether a priori defined PRS/polygenic scores (PGS) for AD, intelligence and educational attainment were associated with cognitive decline in cognitively unimpaired (CU) and mild cognitive impairment (MCI) individuals depending upon their Aβ status

Summary

Introduction

Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. Abbreviations AD Alzheimer’s disease PGS Polygenic scores GWAS Genome-wide association study MMSE Mini-mental state examination Aβ β-Amyloid CU Cognitively unimpaired MCI Mild cognitive impairment PRS Polygenic risk score SCD Subjective cognitive decline QC Quality control HWE Hardy–Weinberg equilibrium MAF Minor allele frequency LD Linkage disequilibrium CSF Cerebrospinal fluid GO Gene ontology PPI Protein–Protein interaction. It is unclear if genetic variants that are associated with AD d iagnosis[12], as well as with intelligence[13] and education a ttainment[14], may modulate cognitive decline during the earliest stages of AD This is especially relevant given the increased focus on early disease stages (including preclinical AD) for potential disease-modifying treatments. We used longitudinal cognitive data from the BioFINDER study and utilized three polygenic predictors: (1) a PRS for AD (PRS-Alz), (2) a PGS for intelligence (PGS-Int) and (3) a PGS for educational attainment (PGSEdu) to ascertain the role of genetic variants that contribute to AD, intelligence and educational attainment as predictors of cognitive decline

Methods

Results

Conclusion