Polygenic hazard scores in preclinical Alzheimer disease

Tan, Chin Hong; Hyman, Bradley T.; Tan, Jacinth J. X.; Hess, Christopher P.; Dillon, William P.; Schellenberg, Gerard D.; Besser, Lilah M.; Kukull, Walter A.; Kauppi, Karolina; McEvoy, Linda K.; Andreassen, Ole A.; Dale, Anders M.; Fan, Chun Chieh; Desikan, Rahul S.

doi:10.1002/ana.25029

Cited by 60 publications

(65 citation statements)

References 17 publications

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“…In the current study, we investigated the clinical utility of PHS for individual assessment of risk for clinical progression to AD over time among older individuals with MCI, a critical question for most patients admitted to memory clinics. Whereas prior work from our group has shown the value of PHS for predicting AD-associated clinical and cognitive decline among non-demented elderly individuals (Tan et al, 2017 ), a critical next step in assessing the potential clinical utility of PHS is to examine the extent to which PHS provides independent information beyond other commonly used predictors, such as brain atrophy levels and baseline cognitive function, and to determine whether combinations of these measures improve prediction of clinical decline and progression to dementia. To this end, we used survival analyses (Klein et al, 2013 ) to compare single-, two-, and three-factor models of PHS, atrophy score, and MMSE for prediction of time to progression from MCI to AD over 120 months of follow-up.…”

Section: Introductionmentioning

confidence: 70%

Combining Polygenic Hazard Score With Volumetric MRI and Cognitive Measures Improves Prediction of Progression From Mild Cognitive Impairment to Alzheimer's Disease

et al. 2018

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Improved prediction of progression to Alzheimer's Disease (AD) among older individuals with mild cognitive impairment (MCI) is of high clinical and societal importance. We recently developed a polygenic hazard score (PHS) that predicted age of AD onset above and beyond APOE. Here, we used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to further explore the potential clinical utility of PHS for predicting AD development in older adults with MCI. We examined the predictive value of PHS alone and in combination with baseline structural magnetic resonance imaging (MRI) data on performance on the Mini-Mental State Exam (MMSE). In survival analyses, PHS significantly predicted time to progression from MCI to AD over 120 months (p = 1.07e-5), and PHS was significantly more predictive than APOE alone (p = 0.015). Combining PHS with baseline brain atrophy score and/or MMSE score significantly improved prediction compared to models without PHS (three-factor model p = 4.28e-17). Prediction model accuracies, sensitivities and area under the curve were also improved by including PHS in the model, compared to only using atrophy score and MMSE. Further, using linear mixed-effect modeling, PHS improved the prediction of change in the Clinical Dementia Rating—Sum of Boxes (CDR-SB) score and MMSE over 36 months in patients with MCI at baseline, beyond both APOE and baseline levels of brain atrophy. These results illustrate the potential clinical utility of PHS for assessment of risk for AD progression among individuals with MCI both alone, or in conjunction with clinical measures of prodromal disease including measures of cognitive function and regional brain atrophy.

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Section: Introductionmentioning

confidence: 70%

Combining Polygenic Hazard Score With Volumetric MRI and Cognitive Measures Improves Prediction of Progression From Mild Cognitive Impairment to Alzheimer's Disease

et al. 2018

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“…We resolved ‘ties’ using the Breslow method. We covaried for sex, education, APOE ε4 status, age at baseline, and also age at baseline stratified into quintiles to adjust for violations of Cox proportional hazards assumptions by baseline age [27]. We restricted survival analyses, which involves AD dementia censoring, as well as the PPV/NPV analyses (see above) to the combined CN and MCI groups only as the CN individuals had low conversion rates during the observation period (< 5%).…”

Section: Methodsmentioning

confidence: 99%

“…Importantly, PHS was associated with in vivo biomarkers of AD pathology such as reduced CSF Aβ 1–42 and elevated CSF total tau across the AD spectrum (in older controls, MCI and AD dementia individuals). Further, using a large prospective clinical cohort, we have recently shown that PHS predicts time to AD dementia and longitudinal multi-domain cognitive decline in cognitively normal older (CN) individuals and in patients with mild cognitive impairment (MCI) [27]. …”

Section: Introductionmentioning

confidence: 99%

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

et al. 2017

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There is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer’s disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical decline in 347 cognitive normal (CN; baseline age range = 59.7–90.1, 98.85% white) and 599 mild cognitively impaired (MCI; baseline age range = 54.4–91.4, 98.83% white) individuals from the Alzheimer’s Disease Neuroimaging Initiative 1, GO, and 2. We further investigated the association of PHS with post-mortem amyloid load and neurofibrillary tangles in the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 485, age at death range = 71.3–108.3). In CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%; for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. High PHS individuals with amyloid and tau pathology showed the steepest longitudinal cognitive and clinical decline, even among APOE ε4 noncarriers. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression. In the ROSMAP cohort, higher PHS was associated with higher post-mortem amyloid load and neurofibrillary tangles, even in APOE ε4 noncarriers. Together, our results show that even after accounting for APOE ε4 effects, PHS may be useful in MCI and preclinical AD therapeutic trials to enrich for biomarker-positive individuals at highest risk for short-term clinical progression.

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“…The PRS has also been used to detect individuals at greater risk for developing AD, and proved to be successful, even in those individuals that were noncarriers of the APOE ε4 allele. The PRS predicted longitudinal clinical decline in older individuals that showed moderate to high depositions of amyloid beta and or tau [62] and in clinically diagnosed AD individuals [63]. Moreover, the AD PRS was found to predict the level and rate of memory loss in a sample of non-Hispanic whites from the Health and Retirement Study [64] and in the ADNI (Alzheimer's Disease Neuroimaging Initiative) cohort [65].…”

Section: Genetic Overlap Within Characteristics Of the Same Diseasementioning

confidence: 98%

Polygenic Risk Scores in Neurodegenerative Diseases: a Review

et al. 2019

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Purpose of the Review This review summarizes the current state of the art of polygenic risk scores (PRSs) in the assessment of risk for neurodegenerative diseases. Recent Findings Polygenic risk scores have been used to identify the shared genetic architecture between comorbid complex traits, disease presentations, and disease endophenotypes. Summary The pathological and symptomatologic overlap between neurodegenerative diseases is strikingly high. In some cases, the diagnostic decision is arbitrary depending on the first appearance of symptomatology. Genetic studies have demonstrated that the genetic architecture of each of these diseases is different, but has a high degree of overlap. The creation of polygenic risk scores has allowed a more accurate calculation of this overlap. However, the power of the PRS is dependent on the power of the genome-wide association studies (GWAS) used to describe the genetic architecture. Even though not all neurodegenerative disease GWAS have the same sample size, and thus the same power, the use of polygenic risk scores has been successful in demonstrating the genetic overlap that has been observed phenotypically.

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Polygenic hazard scores in preclinical Alzheimer disease

Cited by 60 publications

References 17 publications

Combining Polygenic Hazard Score With Volumetric MRI and Cognitive Measures Improves Prediction of Progression From Mild Cognitive Impairment to Alzheimer's Disease

Combining Polygenic Hazard Score With Volumetric MRI and Cognitive Measures Improves Prediction of Progression From Mild Cognitive Impairment to Alzheimer's Disease

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

Polygenic Risk Scores in Neurodegenerative Diseases: a Review

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