Abstract
Background
Variability exists in trajectories of Alzheimer’s disease (AD). We aimed to identify
genetic modulators of clinical progression in AD.
Methods
We conducted the first genome-wide survival study on AD using a two-stage approach.
The discovery and replication stage separately included 1,158 and 211,817 non-demented
individuals from Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the UK Biobank
(UKB) (325 and 1,103 progressed in average follow-up of 4.33 and 8.63 years). Cox
proportional hazards models were applied with time to AD dementia as the phenotype
of clinical progression. A series of bioinformatic analyses and functional experiments
were performed to validate the novel findings.
Results
We found that APOE and PARL (presenilin-associated rhomboid-like), a novel locus tagged by rs6795172 (Hazard
ratio =1.66, P=1.45×10-9), were significantly associated with AD clinical progression, and were successfully
replicated. The novel locus was linked to accelerated cognitive changes, higher tau
levels, and faster atrophy of AD-specific brain structures which were also verified
in UKB neuroimaging follow-up. Gene analysis and Summary-data-based Mendelian Randomization
indicated PARL as the most functionally-relevant gene in the locus. Expression quantitative trait
locus analyses and dual-luciferase reporter assays confirmed that PARL expression could be regulated by rs6795172. Three different AD mouse models consistently
showed decreased PARL expression accompanied by elevated tau levels, and in vitro experiments revealed
that knockdown/overexpression of PARL inversely changed tau levels.
Conclusions
Collectively, genetic, bioinformatic, and functional evidence suggests that PARL modulates clinical progression and neurodegeneration in AD. Targeting PARL may potentially
modify Alzheimer’s progression and have implications for disease-modifying therapies.
Keywords
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Article info
Publication history
Accepted:
February 22,
2023
Received in revised form:
January 5,
2023
Received:
September 2,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
