Proof-of-concept recall-by-genotype study of extremely low and high Alzheimer’s polygenic risk reveals autobiographical deficits and cingulate cortex correlates

Tom Lancaster, Byron Creese, Valentina Escott-Price, Ian Driver, Georgina E. Menzies, Zunera Khan, Anne Corbett, Clive Ballard, Julie Williams, Kevin Murphy, Hannah L. Chandler

Research output: Contribution to journalArticlepeer-review

1 Citation (SciVal)

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.
Original languageEnglish
Article number213
Number of pages10
JournalAlzheimer's Research and Therapy
Volume15
Early online date12 Dec 2023
DOIs
Publication statusPublished - 12 Dec 2023

Bibliographical note

Availability of data and materials:
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.

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