Utility of an Alzheimer’s Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer’s Disease: A Prospective Longitudinal Study

Porter, Tenielle; Burnham, Samantha; Milicic, Lidija; Savage, Greg; Maruff, Paul; Lim, Yen Ying; Li, Qiao Xin; Ames, David; Masters, Colin L.; Rainey-Smith, Stephanie R.; Rowe, Christopher C.; Salvado, Olivier; Groth, David; Verdile, Giuseppe; Villemagne, Victor L.

doi:10.3233/jad-180713

Cited by 33 publications

(39 citation statements)

References 63 publications

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“…Further, these associations have been reported in both cognitively normal individuals (Sabuncu et al, 2012; Andrews et al, 2016; Marden et al, 2016) and those who had already developed AD (Carrasquillo et al, 2015). Few studies have investigated the utility of PRSs independent of APOE genotype or have reported no associations when APOE was excluded, similar to our previous study (Porter et al, 2018b). However, two studies have observed significant associations between clinical and cognitive outcomes and PRS independent of APOE (Mormino et al, 2016; Desikan et al, 2017).…”

Section: Discussionsupporting

confidence: 83%

“…Individual sample em PRSs were then calculated by summing the effect sizes if the assigned risk genotypes were present. We have previously reported that the utility of PRSs for prediction of cognitive decline are dependent on the inclusion of APOE genotype in their construction (Porter et al, 2018b). As such we wished to determine whether the utility of the em PRS defined in this study was likewise dependent on the inclusion of APOE .…”

Section: Methodsmentioning

confidence: 99%

“…We have previously reported that while an AD risk weighted PRS was associated with cognitive decline (Porter et al, 2018b), the association was only observed in carriers of the apolipoprotein E ( APOE ) ε4 allele. This is consistent with other studies which have reported no association with cognition when APOE was removed from the calculation of a PRS (Carrasquillo et al, 2015; Andrews et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer’s Disease

Porter

Burnham

Savage

et al. 2018

Front. Aging Neurosci.

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Studies of Alzheimer’s disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRStruec¯APOE) or excluding APOE (emPRStrues¯APOE). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer’s cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRStruec¯APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRStrues¯APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development.

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Section: Discussionsupporting

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer’s Disease

Porter

Burnham

Savage

et al. 2018

Front. Aging Neurosci.

Self Cite

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“…Previous studies have examined genetic predictors of cognitive decline primarily in individuals in a preclinical stage of Alzheimer’s disease, defined from the occurrence of brain atrophy or abnormal CSF biomarkers of Alzheimer’s disease, and found significant effects of APOE ɛ4 35 and polygenic scores weighted on association to Alzheimer’s disease 35 , 36 , on episodic memory 37 . However, two previous studies based on the Lothian birth cohort also focused on genetic predictors of normal cognitive aging, but failed to identify an effect of polygenic risk for Alzheimer’s disease on age-related cognitive decline 38 , 39 , although a significant effect of APOE ɛ4 was observed on cognitive slope 39 .…”

Section: Discussionmentioning

confidence: 99%

Effects of polygenic risk for Alzheimer’s disease on rate of cognitive decline in normal aging

et al. 2020

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Most people’s cognitive abilities decline with age, with significant and partly genetically driven, individual differences in rate of change. Although APOE ɛ4 and genetic scores for late-onset Alzheimer’s disease (LOAD) have been related to cognitive decline during preclinical stages of dementia, there is limited knowledge concerning genetic factors implied in normal cognitive aging. In the present study, we examined three potential genetic predictors of age-related cognitive decline as follows: (1) the APOE ɛ4 allele, (2) a polygenic score for general cognitive ability (PGS-cog), and (3) a polygenic risk score for late-onset AD (PRS-LOAD). We examined up to six time points of cognitive measurements in the longitudinal population-based Betula study, covering a 25-year follow-up period. Only participants that remained alive and non-demented until the most recent dementia screening (1–3 years after the last test occasion) were included ( n = 1087). Individual differences in rate of cognitive change (composite score) were predicted by the PRS-LOAD and APOE ɛ4, but not by PGS-cog. To control for the possibility that the results reflected a preclinical state of Alzheimer’s disease in some participants, we re-ran the analyses excluding cognitive data from the last test occasion to model cognitive change up-until a minimum of 6 years before potential onset of clinical Alzheimers. Strikingly, the association of PRS-LOAD, but not APOE ɛ4, with cognitive change remained. The results indicate that PRS-LOAD predicts individual difference in rate of cognitive decline in normal aging, but it remains to be determined to what extent this reflects preclinical Alzheimer’s disease brain pathophysiology and subsequent risk to develop the disease.

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“…3,4 Similarly, it is broadly agreed that the earliest signs of dementia in AD are preceded by a preclinical period of a decade or longer. 5 The risk of progression to AD can be accurately determined during the preclinical period by bioimaging methods and quantification of specific proteins in blood and cerebrospinal fluid. 6,7 Despite this diagnostically and prognostically actionable base of knowledge as well as a long preclinical period perfectly suited to preventative medicine, no effective means of prevention or therapy have emerged.…”

Section: Introductionmentioning

confidence: 99%

Advancing medicine for Alzheimer’s disease: A plasma neural exosome platform

Goetzl

2020

FASEB j.

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Enrichment of neurally derived extracellular vesicles of several cell‐types from plasma for protein quantification longitudinally in living patients with Alzheimer’s disease has permitted the development of a tentative temporal framework of initiating events, progression mechanisms, and amplification processes. Interactions of beta‐amyloid peptides with an elevated level of their normal prion protein dendritic receptor and of phospho‐tau species with their synaptogyrin‐3 synaptic vesicle receptor replace excessive production and accumulation of neuropathic proteins as the major initiating events. Synaptic dysfunction and microvascular angiopathy are confirmed as early progression mechanisms of decreased neuronal network connectivity, hypoxia, altered blood‐brain barrier, and neurocellular degeneration. Neurally derived extracellular vesicle protein abnormalities also reveal a range of later amplification processes that encompasses insulin resistance, lysosomal defects, decreased survival factors, increased reactive oxygen species, and excessive neuroinflammation. New potential therapeutic targets also are suggested as well as the likely timing of their pathogenic engagement.

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Utility of an Alzheimer’s Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer’s Disease: A Prospective Longitudinal Study

Cited by 33 publications

References 63 publications

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer’s Disease

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer’s Disease

Effects of polygenic risk for Alzheimer’s disease on rate of cognitive decline in normal aging

Advancing medicine for Alzheimer’s disease: A plasma neural exosome platform

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