Genetic Determinants of Disease Progression in Alzheimer's Disease

Abstract

There is a strong genetic basis for late-onset of Alzheimer’s disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer’s Disease Research Center. Patients were classified as “rapid progressors” if the MMSE changed ≥3 points in 12 months and “slow progressors” if the MMSE changed ≤2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between SNPs and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p=0.94) or APOE*2 (p=0.33) with AD progression, we found multiple nominally significant associations (p<0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2 and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ and ADAM19) at p<1E-05. Our data suggest that short-term clinical disease progression in AD has genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies.

Evaluation of gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer disease

“…70 71 PTK2B, was described as a GWAs hit locus in the largest GWAs meta-analysis conducted to date (Lambert et 72 al. 2013), and later corroborated by others (Wang et al 2015;Beecham et al 2014). The protein encoded by 73…”

Positional effects revealed in Illumina Methylation Array and the impact on analysis

“…There are 145 CpG loci that were detected in the Batch_data, but not in the PosBatch(ComBat)_data, and 152 CpG loci detected in the PosBatch(ComBat)_data, but not the Batch_data. One of 152 CpG loci named cg24519157 is located in gene CASS4, which is an AD significant signal studied in several studies [39][40][41][42][43][44] . Therefore the positional effects could have confounded the methylation comparisons between case and control if the positional effects were not peer-reviewed) is the author/funder.…”

Late Onset Alzheimer’s disease risk variants in cognitive decline: The PATH Through Life Study

“…Therefore, the lack of associations with cognitive performance with the majority of the LOAD risk loci in this study could indicate that they exert their pathological effects at latter stages. Associations have been reported between LOAD risk loci CD2AP, CLU, MS4A6A and INPP5D and progression from normal cognition to dementia [72]; between CLU, CR1, and NME8 and progression from MCI to dementia [72][73][74]; between INPP5D, MEFC2, EPHA1, PT2KB, FERMT2, CASS4 and rate of progression in AD [75]; and between PICALM and MS4A6A and progression to MCI/Dementia from normal cognition normal [21].…”