scholarly journals Genetic risk for Alzheimer’s disease predicts hippocampal volume through the lifespan

2019 ◽  
Author(s):  
Kristine B Walhovd ◽  
Anders M. Fjell ◽  
Øystein Sørensen ◽  
Athanasia Monica Mowinckel ◽  
Céline Sonja Reinbold ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Hippocampal Volume ◽  
Polygenic Risk Score ◽  
List Type ◽  
Polygenic Risk ◽  
Negative Effect ◽  
Mri Scans ◽  
Healthy Persons

AbstractINTRODUCTIONIt is unknown whether genetic risk for Alzheimer’s disease (AD) represents a stable influence on the brain from early in life, or whether effects are age-dependent. It is critical to characterize the effects of genetic risk factors on the primary neural substrate of AD, the hippocampus, throughout life.METHODSRelations of polygenic risk score (PGS) for AD, including variants in Apolipoprotein E (APOE) with hippocampal volume and its change were assessed in a healthy longitudinal lifespan sample (n = 1181, 4-95 years), followed for up to 11 years with a total of 2690 MRI scans.RESULTSAD-PGS showed a significant negative effect on hippocampal volume. Offset effects of AD-PGS and APOE ε4 were present in hippocampal development, and interactions between age and genetic risk on volume change were not consistently observed. DISCUSSION: Endophenotypic manifestation of polygenic risk for AD may be seen across the lifespan in healthy persons.HighlightsGenetic risk for AD affects the hippocampus throughout the lifespanAPOE ε4 carriers have smaller hippocampi in developmentDifferent effects of genetic risk at different ages were not consistently observedGenetic factors increasing risk for AD impact healthy persons throughout lifeA broader population and age range are relevant targets for attempts to prevent AD

scholarly journals Genetic risk for Alzheimer disease predicts hippocampal volume through the human lifespan

2020 ◽  
Vol 6 (5) ◽  
pp. e506 ◽  
Author(s):  
Kristine B. Walhovd ◽  
Anders M. Fjell ◽  
Øystein Sørensen ◽  
Athanasia Monika Mowinckel ◽  
Céline Sonja Reinbold ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Genetic Risk ◽  
Hippocampal Volume ◽  
Older Age ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Human Lifespan ◽  
Negative Effect ◽  
Additive Mixed Models ◽  
Age Range

ObjectiveTo test the hypothesis that genetic risk for Alzheimer disease (AD) may represent a stable influence on the brain from early in life, rather than being primarily age dependent, we investigated in a lifespan sample of 1,181 persons with a total of 2,690 brain scans, whether higher polygenic risk score (PGS) for AD and presence of APOE ε4 was associated with lower hippocampal volumes to begin with, as an offset effect, or possibly faster decline in older age.MethodsUsing general additive mixed models, we assessed the relations of PGS for AD, including variants in APOE with hippocampal volume and its change in a cognitively healthy longitudinal lifespan sample (age range: 4–95 years, mean visit age 39.7 years, SD 26.9 years), followed for up to 11 years.ResultsAD-PGS and APOE ε4 in isolation showed a significant negative effect on hippocampal volume. The effect of a 1 sample SD increase in AD-PGS on hippocampal volume was estimated to –36.4 mm3 (confidence interval [CI]: –71.8, –1.04) and the effect of carrying ε4 allele(s) –107.0 mm3 (CI: –182.0, –31.5). Offset effects of AD-PGS and APOE ε4 were present in hippocampal development, and interactions between age and genetic risk on volume change were not consistently observed.ConclusionsEndophenotypic manifestation of polygenic risk for AD may be seen across the lifespan in cognitively healthy persons, not being confined to clinical populations or older age. This emphasizes that a broader population and age range may be relevant targets for attempts to prevent AD.

scholarly journals Genetic risk for Alzheimer's disease influences neuropathology via multiple biological pathways

2020 ◽  
Author(s):  
Eilis Hannon ◽  
Gemma L Shireby ◽  
Keeley Brookes ◽  
Johannes Attems ◽  
Rebecca Sims ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Cognitive Assessment ◽  
Apoe Genotype ◽  
Amyloid Plaques ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Β Amyloid

Alzheimer's disease is a highly heritable, common neurodegenerative disease characterised neuropathologically by the accumulation of β-amyloid plaques and tau-containing neurofibrillary tangles. In addition to the well-established risk associated with the APOE locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer's disease. Major challenges in understanding how genetic risk influences the development of Alzheimer's disease are clinical and neuropathological heterogeneity, and the high level of accompanying comorbidities. We report a multimodal analysis integrating longitudinal clinical and cognitive assessment with neuropathological data collected as part of the Brains for Dementia Research (BDR) study to understand how genetic risk factors for Alzheimer's disease influence the development of neuropathology and clinical performance. 693 donors in the BDR cohort with genetic data, semi-quantitative neuropathology measurements, cognitive assessments and established diagnostic criteria were included in this study. We tested the association of APOE genotype and Alzheimer's disease polygenic risk score - a quantitative measure of genetic burden - with survival, four common neuropathological features in Alzheimer's disease brains (neurofibrillary tangles, β-amyloid plaques, Lewy bodies and TDP-43 proteinopathy), clinical status (clinical dementia rating) and cognitive performance (Mini-Mental State Exam, Montreal Cognitive Assessment). The APOE ϵ4 allele was significantly associated with younger age of death in the BDR cohort. Our analyses of neuropathology highlighted two independent pathways from APOE ϵ4, one where β-amyloid accumulation mediates the development of tauopathy, and a second characterized by direct effects on tauopathy independent of β-amyloidosis. Although we also detected association between APOE ϵ4 and dementia status and cognitive performance, these were all mediated by tauopathy, highlighting that they are a consequence of the neuropathological changes. Analyses of polygenic risk score identified associations with tauopathy and β-amyloidosis, which appeared to have both shared and unique contributions, suggesting that different genetic variants associated with Alzheimer's disease affect different features of neuropathology to different degrees. Taken together, our results provide insight into how genetic risk for Alzheimer's disease influences both the clinical and pathological features of dementia, increasing our understanding about the interplay between APOE genotype and other genetic risk factors.

P4-240: Using polygenic risk score to predict Alzheimer's disease

2015 ◽  
Vol 11 (7S_Part_19) ◽  
pp. P872-P872 ◽  
Author(s):  
Valentina Escott-Price ◽  
Rebecca Sims ◽  
Denise Harold ◽  
Maria Vronskaya ◽  
Peter Holmans ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Polygenic Risk

P3-077: ALZHEIMER'S DISEASE (AD) POLYGENIC RISK SCORE (PRS) AS A PREDICTOR OF CONVERSION FROM MILD COGNITIVE IMPAIRMENT (MCI)

2006 ◽  
Vol 14 (7S_Part_20) ◽  
pp. P1094-P1094
Author(s):  
Sultan Raja Chaudhury ◽  
Tulsi Patel ◽  
Abigail Fallows ◽  
Keeley J. Brookes ◽  
Tamar Guetta-Baranes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Polygenic Risk

scholarly journals POLYGENIC RISK SCORE ANALYSIS OF ALZHEIMER’S DISEASE IN CASES WITHOUT APOE4 OR APOE2 ALLELES

2018 ◽  
pp. 1-4
Author(s):  
V. Escott-Price ◽  
A. Myers ◽  
M. Huentelman ◽  
M. Shoai ◽  
J. Hardy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Score ◽  
Clinical Trial Design ◽  
Polygenic Risk Score ◽  
Carrier Status ◽  
Predictive Utility ◽  
Polygenic Risk ◽  
Score Analysis ◽  
E4 Allele

The We and others have previously shown that polygenic risk score analysis (PRS) has considerable predictive utility for identifying those at high risk of developing Alzheimer’s disease (AD) with an area under the curve (AUC) of >0.8. However, by far the greatest determinant of this risk is the apolipoprotein E locus with the E4 allele alone giving an AUC of ~0.68 and the inclusion of the protective E2 allele increasing this to ~0.69 in a clinical cohort. An important question is to determine how good PRS is at predicting risk in those who do not carry the E4 allele (E3 homozygotes, E3E2 and E2E2) and in those who carry neither the E4 or E2 allele (i.e. E3 homozygotes). Previous studies have shown that PRS remains a significant predictor of AD risk in clinical cohorts after controlling for APOE ε4 carrier status. In this study we assess the accuracy of PRS prediction in a cohort of pathologically confirmed AD cases and controls. The exclusion of APOE4 carriers has surprisingly little effect on the PRS prediction accuracy (AUC ~0.83 [95% CI: 0.80-0.86]), and the accuracy remained higher than that in clinical cohorts with APOE included as a predictor. From a practical perspective this suggests that PRS analysis will have predictive utility even in E4 negative individuals and may be useful in clinical trial design.

scholarly journals Use of an Alzheimer’s disease polygenic risk score to identify mild cognitive impairment in adults in their 50s

2018 ◽  
Vol 24 (3) ◽  
pp. 421-430 ◽  
Author(s):  
Mark W. Logue ◽  
Matthew S. Panizzon ◽  
Jeremy A. Elman ◽  
Nathan A. Gillespie ◽  
Sean N. Hatton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Polygenic Risk
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