Dataset Information

Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.

ABSTRACT:

Objective

To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD).

Methods

Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.

Results

We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10^-7) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10^-7) and sLOAD (OR = 1.40; P = 1.21 × 10^-3). The PRS was associated with cerebrospinal fluid ptau₁₈₁-Aβ₄₂ on eADAD (P = 4.36 × 10^-2).

Conclusion

Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.

SUBMITTER: Cruchaga C

PROVIDER: S-EPMC5803427 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.

Cruchaga Carlos C Del-Aguila Jorge L JL Saef Benjamin B Black Kathleen K Fernandez Maria Victoria MV Budde John J Ibanez Laura L Deming Yuetiva Y Kapoor Manav M Tosto Giuseppe G Mayeux Richard P RP Holtzman David M DM Fagan Anne M AM Morris John C JC Bateman Randall J RJ Bateman Randall J RJ Goate Alison M AM Harari Oscar O

Alzheimer's & dementia : the journal of the Alzheimer's Association 20170921 2

<h4>Objective</h4>To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD).<h4>Methods</h4>Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.<h4>Results</h4>We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLO ...[more]

PMID: 28943286

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Project description:BackgroundDegradation of white matter microstructure has been demonstrated in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). In preparation for clinical trials, ongoing studies are investigating the utility of longitudinal brain imaging for quantification of disease progression. To date only one study has examined sample size calculations based on longitudinal changes in white matter integrity in FTLD.ObjectiveTo quantify longitudinal changes in white matter microstructural integrity in the three canonical subtypes of frontotemporal dementia (FTD) and AD using diffusion tensor imaging (DTI).Methods60 patients with clinical diagnoses of FTD, including 27 with behavioral variant frontotemporal dementia (bvFTD), 14 with non-fluent variant primary progressive aphasia (nfvPPA), and 19 with semantic variant PPA (svPPA), as well as 19 patients with AD and 69 healthy controls were studied. We used a voxel-wise approach to calculate annual rate of change in fractional anisotropy (FA) and mean diffusivity (MD) in each group using two time points approximately one year apart. Mean rates of change in FA and MD in 48 atlas-based regions-of-interest, as well as global measures of cognitive function were used to calculate sample sizes for clinical trials (80% power, alpha of 5%).ResultsAll FTD groups showed statistically significant baseline and longitudinal white matter degeneration, with predominant involvement of frontal tracts in the bvFTD group, frontal and temporal tracts in the PPA groups and posterior tracts in the AD group. Longitudinal change in MD yielded a larger number of regions with sample sizes below 100 participants per therapeutic arm in comparison with FA. SvPPA had the smallest sample size based on change in MD in the fornix (n = 41 participants per study arm to detect a 40% effect of drug), and nfvPPA and AD had their smallest sample sizes based on rate of change in MD within the left superior longitudinal fasciculus (n = 49 for nfvPPA, and n = 23 for AD). BvFTD generally showed the largest sample size estimates (minimum n = 140 based on MD in the corpus callosum). The corpus callosum appeared to be the best region for a potential study that would include all FTD subtypes. Change in global measure of functional status (CDR box score) yielded the smallest sample size for bvFTD (n = 71), but clinical measures were inferior to white matter change for the other groups.ConclusionsAll three of the canonical subtypes of FTD are associated with significant change in white matter integrity over one year. These changes are consistent enough that drug effects in future clinical trials could be detected with relatively small numbers of participants. While there are some differences in regions of change across groups, the genu of the corpus callosum is a region that could be used to track progression in studies that include all subtypes.

Dataset Information

Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.

Objective

Methods

Results

Conclusion

Publications

Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.

Similar Datasets

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