Amy Packer ¹ Leena Habiballa ¹ Esteban Tato-Barcia ¹ Gerome Breen ¹ Helen J. Brooker ² Anne Corbett ² Ryan Arathimos ¹ Clive Ballard ² Adam Hampshire ³ Abbie Palmer ² Danai Dima ^1,4 Dag Aarsland ¹ Byron Creese ⁵ Margherita Malanchini ⁶ Timothy R. Powell ^1*

• ¹ King's College London, London, England, United Kingdom
• ² University of Exeter, Exeter, England, United Kingdom
• ³ Imperial College London, London, England, United Kingdom
• ⁴ City University of London, London, United Kingdom
• ⁵ Brunel University London, Uxbridge, London, United Kingdom
• ⁶ Queen Mary University of London, London, United Kingdom

Background: Telomere length (TL) has been linked to cognitive function, decline and dementia. This study aimed to explore whether both measured TL and genetic disposition for TL predict dimensions of cognitive performance in a longitudinal sample of older UK adults. Methods: We analysed data from PROTECT study participants aged ≥50 years without a dementia diagnosis, who had completed longitudinal cognitive testing. We calculated polygenic scores for telomere length (PGS-TL) for 7,877 participants and measured relative telomere length (RTL) in a subgroup of 846 participants using DNA extracted from saliva samples collected within six months either side of their baseline cognitive testing. Latent growth models were used to examine whether RTL and PGS-TL predict both baseline and longitudinal changes in cognitive performance (4 time-points, annually). Results: In the whole sample, we did not observe significant associations between either measure of telomere length and initial or longitudinal changes in cognitive performance. Stratifying by median age, in older adults (> ~62 years), longer baseline RTL showed a nominal association with poorer baseline verbal reasoning performance (n = 423, Mintercept = 47.58, B = -1.05, p = .011) and PGS-TL was associated with performance over time (n = 3,939; slope factor, Mslope = 3.23, B = -0.45, p = .001; slope 2 factor, Mslope 2 = 0.21, B = 0.13, p = .002). Conclusions: Our findings suggest either the absence of a significant relationship between telomere length (RTL and PGS-TL) and cognitive performance (baseline and change over time), or possibly a weak age-dependent and domain-specific relationship, in older adults of European ancestry. More research is needed in representative and ancestrally diverse samples over a longer assessment period. Alternative biological ageing indicators may still provide utility in the early detection of individuals at risk for cognitive decline (e.g., pace-of ageing epigenetic clocks).