Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative

Zettergren, Anna; Lord, Jodie; Ashton, Nicholas J.; Benedet, Andréa Lessa; Karikari, Thomas K.; Lantero‐Rodriguez, Juan; Snellman, Anniina; Suárez‐Calvet, Marc; Proitsi, Petroula; Zetterberg, Henrik; Blennow, Kaj

doi:10.1186/s13195-020-00754-8

Cited by 42 publications

(47 citation statements)

References 34 publications

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“…In patients with familial AD, the level of plasma p-tau181 was comparable among APP and PSEN1 mutation carriers ( 20 ). Though plasma p-tau181 changed without a specific gene, it was associated with APOE ε4 ( 36 ). The association between tau and APOE ε4 was also independent of Aβ, primarily mediated by activated microglia ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Plasma p-tau181 Level Predicts Neurodegeneration and Progression to Alzheimer's Dementia: A Longitudinal Study

Wang

Chen

et al. 2021

Front. Neurol.

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Background: Plasma-based biomarkers would be potential biomarkers for early diagnosis of Alzheimer's disease (AD) because they are more available and cost-effective than cerebrospinal fluid (CSF) or neuroimaging. Therefore, we aimed to evaluate whether phosphorylated tau181 (p-tau181) in plasma could be an accurate AD predictor.Methods: Participants from the ADNI database included 185 cognitively unimpaired subjects with negative Aβ (CU–), 66 subjects with pre-clinical AD (CU with positive Aβ), 164 subjects with mild cognitive impairment with negative Aβ (MCI–), 254 subjects with prodromal AD (MCI with positive Aβ), and 98 subjects with dementia. Multiple linear regression models, linear mixed-effects models, and local regression were used to explore cross-sectional and longitudinal associations of plasma p-tau181 with cognition, neuroimaging, or CSF biomarkers adjusted for age, sex, education, and APOE genotype. Besides, Kaplan–Meier and adjusted Cox-regression model were performed to predict the risk of progression to dementia. Receiver operating characteristic analyses were performed to evaluate the predictive value of p-tau181.Results: Plasma p-tau181 level was highest in AD dementia, followed by prodromal AD and pre-clinical AD. In pre-clinical AD, plasma p-tau181 was negatively associated with hippocampal volume (β = −0.031, p-value = 0.017). In prodromal AD, plasma p-tau181 was associated with decreased global cognition, executive function, memory, language, and visuospatial functioning (β range −0.119 to −0.273, p-value < 0.05) and correlated with hippocampal volume (β = −0.028, p-value < 0.005) and white matter hyperintensity volume (WMH) volume (β = 0.02, p-value = 0.01). In AD dementia, increased plasma p-tau181 was associated with worse memory. In the whole group, baseline plasma p-tau181 was significantly associated with longitudinal increases in multiple neuropsychological test z-scores and correlated with AD-related CSF biomarkers and hippocampal volume (p-value < 0.05). Meanwhile, CU or MCI with high plasma p-tau181 carried a higher risk of progression to dementia. The area under the curve (AUC) of the adjusted model (age, sex, education, APOE genotype, and plasma p-tau181) was 0.78; that of additionally included CSF biomarkers was 0.84.Conclusions: Plasma p-tau181 level is related to multiple AD-associated cognitive domains and AD-related CSF biomarkers at the clinical stages of AD. Moreover, plasma p-tau181 level is related to the change rates of cognitive decline and hippocampal atrophy. Thus, this study confirms the utility of plasma p-tau181 as a non-invasive biomarker for early detection and prediction of AD.

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Section: Discussionmentioning

confidence: 99%

Plasma p-tau181 Level Predicts Neurodegeneration and Progression to Alzheimer's Dementia: A Longitudinal Study

Wang

Chen

et al. 2021

Front. Neurol.

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“…We demonstrate that the predictive power of the present PGS is dependent on the effect of tau-PET changes. Overall, the current study substantially adds to previous studies that used a lower number of genome-wide significant SNPs for construing a PGS and were confined to cross-sectional analyses of pathologic tau 15,16, for review see: 18,44 .…”

Section: Discussionmentioning

confidence: 99%

“…It also remains unclear whether a PGS is predictive of the progression of tau pathology, which underlies cognitive decline. So far, studies examining the value of a PGS for predicting tau pathology have been limited to cross-sectional assessments 13,[15][16][17] , leaving the question unaddressed whether a PGS is associated with faster rates of fibrillar tau progression 18 .…”

Section: Introductionmentioning

confidence: 99%

Polygenic effect on accelerated tau pathology accumulation in Alzheimer’s disease: implications for patient selection in clinical trials

Rubinski¹,

Frerich²,

Malik³

et al. 2021

Preprint

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Progression of fibrillar tau is a key driver of dementia symptoms in Alzheimer’s disease (AD), but predictors of the rate of tau accumulation at patient-level are missing. Here we combined the to-date largest number of genetic risk variants of AD (n=85 lead SNPs) from recent GWAS to generate a polygenic score (PGS) predicting the rate of change in fibrillar tau. We found that a higher PGS was associated with higher rates of PET-assessed fibrillar-tau accumulation over a mean of 1.8 yrs (range = 0.6 – 4 yrs). This, in turn, mediated effects of the PGS on faster rates of cognitive decline. Sensitivity analysis showed that the effects were similar for men and women but pronounced in individuals with elevated levels of beta-amyloid and strongest for lead SNPs expressed in microglia. Together, our results demonstrate that the PGS predicts tau progression in Alzheimer’s disease, which could afford sample size savings by up to 34% when used alone and up to 61% when combined with APOE ε4 genotype in clinical trials targeting tau pathology.

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“…PRS represent aggregate genetic propensity for a trait and so if associated with another trait imply a degree of shared genetics influences both traits. For example, a higher AD PRS has been associated with lower cognitive ability in individuals without dementia [20] and with increased levels of the promising AD biomarker p-tau181 [21]. If a protein PRS is associated with AD, this provides a genetic signal linked to a specific, modifiable biological risk factor, something which remains a challenge for genome wide association studies (GWAS) [22].…”

Section: Introductionmentioning

confidence: 99%

Assessing genetic overlap and causality between blood plasma proteins and Alzheimer’s Disease

Handy

Lord

Green

et al. 2021

Preprint

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Background Blood plasma proteins are modifiable and have been associated with Alzheimer’s disease (AD), but understanding which proteins are on the causal pathway remains challenging.ObjectiveInvestigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian Randomization (MR).MethodsFollowing a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritised proteins with and without the apolipoprotein E region (APOE+/- PRS) and tested for association with AD status across three cohorts (n=6244). An AD PRS was also tested for association with protein levels in one cohort (n=410). Proteins showing association with AD were taken forward for MR.ResultsFor APOE e3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p-value <0.00017). No protein APOE-PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p-value=0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p-value=0.025, protein APOE-PRS p-value=0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the 5 proteins demonstrated a causal association (p-value<0.05) in either direction.ConclusionApolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, modifiable risk factor. Whilst evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.

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Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative

Cited by 42 publications

References 34 publications

Plasma p-tau181 Level Predicts Neurodegeneration and Progression to Alzheimer's Dementia: A Longitudinal Study

Plasma p-tau181 Level Predicts Neurodegeneration and Progression to Alzheimer's Dementia: A Longitudinal Study

Polygenic effect on accelerated tau pathology accumulation in Alzheimer’s disease: implications for patient selection in clinical trials

Assessing genetic overlap and causality between blood plasma proteins and Alzheimer’s Disease

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