Abstract
Background:
Genome-wide association studies demonstrate that Alzheimer’s disease (AD) has a highly polygenic architecture, where thousands of independent genetic variants explain risk with high classification accuracy. This AD polygenic risk score (AD-PRS) has been previously linked to preclinical cognitive and neuroimaging features observed in asymptomatic individuals. However, shared variance between AD-PRS and neurocognitive features are small, suggesting limited preclinical utility.
Methods:
Here, we recruited sixteen clinically asymptomatic individuals (mean age 67; range 58–76) with either extremely low / high AD-PRS (defined as at least 2 standard deviations from the wider sample mean (N = 4504; N EFFECTIVE = 90)) with comparable age sex and education level. We assessed group differences in autobiographical memory and T1-weighted structural neuroimaging features.
Results:
We observed marked reductions in autobiographical recollection (Cohen’s d = − 1.66; P FDR = 0.014) and midline structure (cingulate) thickness (Cohen’s d = − 1.55, P FDR = 0.05), with no difference in hippocampal volume (P > 0.3). We further confirm the negative association between AD-PRS and cingulate thickness in a larger study with a comparable age (N = 31,966, β = − 0.002, P = 0.011), supporting the validity of our approach.
Conclusions:
These observations conform with multiple streams of prior evidence suggesting alterations in cingulate structures may occur in individuals with higher AD genetic risk. We were able to use a genetically informed research design strategy that significantly improved the efficiency and power of the study. Thus, we further demonstrate that the recall-by-genotype of AD-PRS from wider samples is a promising approach for the detection, assessment, and intervention in specific individuals with increased AD genetic risk.
Genome-wide association studies demonstrate that Alzheimer’s disease (AD) has a highly polygenic architecture, where thousands of independent genetic variants explain risk with high classification accuracy. This AD polygenic risk score (AD-PRS) has been previously linked to preclinical cognitive and neuroimaging features observed in asymptomatic individuals. However, shared variance between AD-PRS and neurocognitive features are small, suggesting limited preclinical utility.
Methods:
Here, we recruited sixteen clinically asymptomatic individuals (mean age 67; range 58–76) with either extremely low / high AD-PRS (defined as at least 2 standard deviations from the wider sample mean (N = 4504; N EFFECTIVE = 90)) with comparable age sex and education level. We assessed group differences in autobiographical memory and T1-weighted structural neuroimaging features.
Results:
We observed marked reductions in autobiographical recollection (Cohen’s d = − 1.66; P FDR = 0.014) and midline structure (cingulate) thickness (Cohen’s d = − 1.55, P FDR = 0.05), with no difference in hippocampal volume (P > 0.3). We further confirm the negative association between AD-PRS and cingulate thickness in a larger study with a comparable age (N = 31,966, β = − 0.002, P = 0.011), supporting the validity of our approach.
Conclusions:
These observations conform with multiple streams of prior evidence suggesting alterations in cingulate structures may occur in individuals with higher AD genetic risk. We were able to use a genetically informed research design strategy that significantly improved the efficiency and power of the study. Thus, we further demonstrate that the recall-by-genotype of AD-PRS from wider samples is a promising approach for the detection, assessment, and intervention in specific individuals with increased AD genetic risk.
| Original language | English |
|---|---|
| Article number | 213 |
| Number of pages | 10 |
| Journal | Alzheimer's Research and Therapy |
| Volume | 15 |
| Issue number | 1 |
| Early online date | 12 Dec 2023 |
| DOIs | |
| Publication status | Published - 12 Dec 2023 |
Data Availability Statement
The wider genetic data that support the findings of this study are available from the PROTECT cohort, but restrictions apply to the availability of these data, which were used under licence for the current study, and so are not publicly available. The behaviour / MRI datasets generated and/or analysed during the current study are not publicly available as participants did not consent to public data sharing, but code supporting all inferences are available from the corresponding author on reasonable request.Funding
TL acknowledges funding via Ser Cymru II fellowship [PNU-80762-CU-14]. HC & ID funded by Wellcome Strategic Award [104943/Z/14/Z]. HC, ID, and KM are funded by a Wellcome Senior Fellowship [WT200804 and WT224267]. BC is funded in part through the MRC Proximity to Discovery: Industry Engagement Fund (External Collaboration, Innovation and Entrepreneurism: Translational Medicine in Exeter 2 (EXCITEME2) ref. MC_PC_17189). VE-P acknowledges funding received from a Medical Research Council grant (MR/L010305/1). This work is supported by the UK Dementia Research Institute which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council (UKDRI-3003), Alzheimer’s Society and Alzheimer’s Research UK.
| Funders | Funder number |
|---|---|
| NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust | |
| King's College London | |
| The Wellcome Trust | WT224267, 104943/Z/14/Z, WT200804 |
| Medical Research Council | MC_PC_17189, MR/L010305/1, UKDRI-3003 |
| National Institute for Health and Care Research | |
| Alzheimer's Society | |
| Alzheimer's Research UK | |
| UK Dementia Research Institute | |
| NIHR Leicester Biomedical Research Centre |
Keywords
- Alzheimer’s disease
- Neuroimaging
- Polygenic risk score
- Recall-by-genotype
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
- Cognitive Neuroscience