Polygenic hazard score, amyloid deposition and Alzheimer’s neurodegeneration

Abstract

Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-b protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 nondemented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.

Addition of Genetics to Quantitative MRI Facilitates Earlier Prediction of Dementia: A Non-invasive Alternative to Amyloid Measures

“…Some researchers have combined the effects of known variants into a polygenic hazard score. Such combined genetics scores have demonstrated better prediction of the age of onset for AD versus APOE status alone 15,17 and may correlate with amyloid beta and tau accumulation, and cortical volume changes 17 .…”

“…Most existing models rely heavily on cognitive test results to drive their prediction and many have focused on the progression of individuals with MCI 26,27 . Predictions have been made using genetics alone 8 , MRI alone 9,28 , and through the combination of genetics with MRI and cognitive testing 10,15,17 .…”

Sex-dependent polygenic effects on the clinical progressions of Alzheimer’s disease

“… Abstract Sex differences in the manifestations of Alzheimer’s disease (AD) are under intense investigations 1,2 . Despite the emerging importance of polygenic predictions for AD 3–8 , the sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on AD can be revealed by characterizing disease progress via the hazard function.…”

“…This sex-agnostic status quo is particularly problematic for disease prediction based on polygenic effects. By aggregating the estimated regression weights of autosomal single-nucleotide-polymorphisms (SNPs) from genome-wide association studies (GWAS), polygenic scores have been used to assist in several important clinical functions, including disease prediction 20 , risk stratification 21 , enriching clinical trials 6,22 , and facilitating disease screening 23 . However, because the standard practice in GWAS treated sex as a confounding factor for autosomal effects, the basis of polygenic scores, the estimated odds ratios, are devoid of sex-dependent effects.…”

“…Such scores could underestimate the genetic risk of AD for women, since APOE e4, one of the most well-established risk factors for AD, has stronger effects on AD onset among women than among men 19 . Given the heightened awareness of utilizing polygenic effects beyond APOE as biomarkers for AD 5,22,24–27 , understanding the sex-dependent polygenic effects for AD is imperative for their application to clinical settings.…”