scholarly journals Polygenic effect on accelerated tau pathology accumulation in Alzheimer's disease: Implications for patient selection in clinical trials

2021 ◽  
Author(s):  
Anna Rubinski ◽  
Simon Frerich ◽  
Rainer Malik ◽  
Nicolai Franzmeier ◽  
Alfredo Ramirez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Genetic Risk ◽  
Rate Of Change ◽  
Polygenic Effect ◽  
Tau Pathology ◽  
Patient Level ◽  
Risk Variants ◽  
Key Driver

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 the 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.

scholarly journals Translating genetic risk variants in disease‐associated enhancers into novel mouse models of Alzheimer’s disease

2020 ◽  
Vol 16 (S2) ◽  
Author(s):  
Christoph Preuss ◽  
Xi Chen ◽  
Kathleen Chen ◽  
Chandra Theesfeld ◽  
Evan Cofer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Genetic Risk ◽  
Risk Variants ◽  
Genetic Risk Variants

scholarly journals Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 359-373 ◽  
Author(s):  
Christopher D Morrone ◽  
Paolo Bazzigaluppi ◽  
Tina L Beckett ◽  
Mary E Hill ◽  
Margaret M Koletar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Function ◽  
Spatial Memory ◽  
Regional Differences ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Barnes Maze ◽  
Tau Pathology

Abstract Failure of Alzheimer’s disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer’s disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

P4-239: ASSOCIATION OF ALZHEIMER'S DISEASE GENETIC RISK VARIANTS WITH PATHOLOGY ENDOPHENOTYPES

2006 ◽  
Vol 14 (7S_Part_29) ◽  
pp. P1534-P1534
Author(s):  
Julia Kofler ◽  
Kang-Hsien Fan ◽  
Qi Yan ◽  
Robert A. Sweet ◽  
Eleanor Feingold ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Risk Variants ◽  
Genetic Risk Variants

P2-076: Alzheimer’s Disease Genetic Risk Variants Beyond Apoe ε4 Predict Mortality in The Adult Changes in Thought (ACT) Study

2016 ◽  
Vol 12 ◽  
pp. P637-P638
Author(s):  
Jesse Mez ◽  
Jessica R. Marden ◽  
Shubhabrata Mukherjee ◽  
Paul Brewster ◽  
Jamie L. Hamilton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Apoe Ε4 ◽  
Risk Variants ◽  
Genetic Risk Variants

scholarly journals Manifestations of genetic risk for Alzheimer’s Disease in the blood: a cross-sectional multi-omic analysis in healthy adults aged 18-90+

2021 ◽  
Author(s):  
Laura Heath ◽  
John C. Earls ◽  
Andrew T. Magis ◽  
Sergey A. Kornilov ◽  
Jennifer C. Lovejoy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Study ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Multiple Testing ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Cross Sectional ◽  
Risk Variants

AbstractDeeply phenotyped cohort data can elucidate differences associated with genetic risk for common complex diseases across an age spectrum. Previous work has identified genetic variants associated with Alzheimer’s disease (AD) risk from large-scale genome-wide association study meta-analyses. To explore effects of known AD-risk variants, we performed a phenome-wide association study on ~2000 clinical, proteomic, and metabolic blood-based analytes obtained from 2,831 cognitively normal adult clients of a consumer-based scientific wellness company. Results uncovered statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE). These effects were detectable from early adulthood. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. Sex-stratified GWAS results from an independent AD case-control meta-analysis supported sexspecific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. These analyses support evidence from previous functional genomics studies in the identification of a causal variant within the PILRA gene. Taken together, this study highlights clues to the earliest effects of AD genetic risk variants in individuals where disease symptoms have not (yet) arisen.

scholarly journals Alzheimer's disease genetic risk variants beyond APOE ε4 predict mortality

2017 ◽  
Vol 8 (1) ◽  
pp. 188-195 ◽  
Author(s):  
Jesse Mez ◽  
Jessica R. Marden ◽  
Shubhabrata Mukherjee ◽  
Stefan Walter ◽  
Laura E. Gibbons ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Apoe Ε4 ◽  
Risk Variants ◽  
Genetic Risk Variants
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