Article Title : Lack of Evidence for Interactions Between APOE and Klotho Genotypes on Cognitive, Dementia and Brain Imaging Metrics in UK Biobank.

Importance: Recent research has suggested that genetic variation in the Klotho (KL) locus 29 may modify the association between apolipoprotein e ( APOE ) e4 genotype and cognitive 30 impairment. 31 Objective: Large-scale testing for associations and interactions between KL and APOE 32 genotypes vs. risk of dementia (n=1,570 cases), cognitive abilities (n=174,513) and brain 33 structure (n = 13,158) in older (60+ years) participants. 34 Design, setting and participants: Cross-sectional and prospective data (UK Biobank). 35 Main outcomes and measures: KL status was indexed with heterozygosity of the rs9536314 36 polymorphism (vs. not), in unrelated people with vs. without APOE e4 genotype, using 37 regression and interaction tests. We assessed non-demented cognitive scores (processing 38 speed; reasoning; memory; executive function), multiple structural brain imaging, and clinical 39 dementia outcomes. All tests were corrected for age, sex, assessment centre, eight principal 40 components for population stratification, genotypic array, smoking history, deprivation, and 41 self-reported medication history. 42 Results: APOE e4 presence (vs. not) was associated with increased risk of dementia, worse 43 cognitive abilities and brain structure differences. KL heterozygosity was associated with 44 less frontal lobe grey matter. There were no significant APOE/KL interactions for cognitive, 45 dementia or brain imaging measures (all P>0.05). 46 Conclusions and relevance: We found no evidence of APOE/KL interactions on cognitive, 47 dementia or brain imaging outcomes. This could be due to some degree of cognitive test 48 imprecision, generally preserved participant health potentially due to relatively young age, 49 type-1 error in prior studies, or indicative of a significant age-dependent KL effect only in the 50 context of marked AD pathology. 51