Assessment of the Genetic Architecture of Alzheimer’s Disease Risk in Rate of Memory Decline

Abstract

Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

Polygenic risk for Alzheimer's disease shapes hippocampal scene-selectivity

“…We sought to explore whether common AD risk alleles (identified via GWAS) contribute to variation in HC BOLD during scene encoding in young healthy individuals. While several studies have linked AD-PRS to memory [49][50][51] and structural brain changes across the lifespan [52][53][54], this work is amongst the first to quantify the relationships between AD-PRS and functional brain activity, specifically via task-based fMRI in AD vulnerable regions. More specifically, we used an embedded category localiser to target HC function in a large sample (N = 608), powered to detect relatively small effects.…”

From Polygenic Scores to Precision Medicine in Alzheimer’s Disease: A Systematic Review

“…Most studies were in healthy older adults, although two studies included participants with established AD/MCI [11,26], two studies had young adult participants [51,57], one study had adolescent participants [40] and one included longitudinal data from children aged 11 [59]. There were some cross-sectional studies that only reported associations with AD polygenic risk and cognition at one timepoint [40, 50-52, 54, 55, 57, 68], whereas longitudinal studies were able to report the correlations with change in cognition over time [11,26,31,33,36,44,45,56,60,[62][63][64]. As expected, most studies reported that the effects attenuated or were no longer significant when APOE was excluded from the PRS.…”

“…Of these, cognition has been the most widely investigated. While the methodology and samples were diverse, the vast majority of studies reported significant associations [11,26,31,33,36,40,44,45,50,52,54,56,60,63,64,68,69]. Of the negative studies, one used a threshold-based PRS [59] and another used a PRS including 15 Bonferronisignificant risk SNPs [39] but both excluded APOE entirely.…”

Genome‐wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways

“…Several studies have examined factors associated with cognitive decline in non-demented adults, [1][2][3][4][5][6][7][8][9] conversion from mild cognitive impairment (MCI) to AD, [10][11][12][13][14][15][16][17][18] and rate of cognitive decline (ROD) after AD diagnosis. [19][20][21][22][23][24][25][26] Several nongenetic determinants of decline, including lifestyle factors, biomarkers and biometric variables, and co-morbid diagnoses have also been reported. [26][27][28][29][30][31][32][33][34][35][36][37][38] Several genetic and epigenetic factors that may contribute to ROD in AD cases have also been identified.…”

“…[19][20][21][22][23][24][25][26] Several nongenetic determinants of decline, including lifestyle factors, biomarkers and biometric variables, and co-morbid diagnoses have also been reported. [26][27][28][29][30][31][32][33][34][35][36][37][38] Several genetic and epigenetic factors that may contribute to ROD in AD cases have also been identified. Expression levels of leucine rich repeat and fibronectin type III domain containing 2 (LRFN2), 39 beta-nerve growth factor and its receptors, 40 myocyte-enhancer factor 2C, 41 and inositol polyphosphate-5-phosphatase 42 have been associated with ROD in the brains of people with AD.…”