Life course, genetic, and neuropathological associations with brain age in the 1946 British Birth Cohort: a population-based study.

BACKGROUND

A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age.

METHODS

Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy.

FINDINGS

Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 [95% CI 1·5 to 3·0]) and 69 years (β=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD.

INTERPRETATION

Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility.

FUNDING

Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests This research was funded by a Wolfson Clinical Research Fellowship awarded to AZW, and a Selfridges Group Foundation award (UB170045), with leveraged funding from Alzheimer's Research UK (ARUK-PG2014-1946, ARUK-PG2017-1946), Medical Research Council Dementia Platforms UK (CSUB19166), the Wolfson Foundation (PR/ylr/18575) and the Alzheimer's Association (SG-666374-UK BIRTH COHORT). AZW has served as a medical monitor for Neuroscience Trials Australia receiving no personal compensation, and has an Alzhiemer's Research UK travel grant. CAL is now a full-time employee of Roche Products and a shareholder in Hoffmann La Roche. HZ has served on scientific advisory boards and as a consultant for AbbVie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, reMYND, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg, which is a part of the GU Ventures Incubator Program (outside the submitted work). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018- 02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (USA [201809- 2016862]), the Alzheimer's Disease Strategic Fund and the Alzheimer's Association (ADSF-21–831376-C, ADSF-21–831381-C, and ADSF-21–831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (FO2019–0228), the EU's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie (grant agreement number 860197 [MIRIADE]), the EU Joint Program for Neurodegenerative Disorders (JPND2021–00694), and the UK Dementia Research Institute at UCL. HZ is the Chair of the Alzheimer's Associaiton Global Biomarker Standardization Consotrium. FB is on the steering committee or is an iDMC member for Biogen, Merck, Roche, EISAI, and Prothena, and is a consultant for Roche, Biogen, Merck, IXICO, Jansen, and Combinostics. FB has research agreements with Merck, Biogen, GE Healthcare, and Roche, is a co-founder and shareholder of Queen Square Analytics, and a board member of the journals Neurology, Radiology, MSJ, and Neuroradiology. He was Editor In Chief of Clinical Neuroradiology – the ESNR textbook (Springer), and has had projects funced by the UK MS Society, Dutch Foundation MS Research, NOW (Picture project) and IMI-EU (Amypad project). NCF's research group has received payment for consultancy or for conducting studies from Biogen, Eli Lilly Research Laboratories, Ionis, and Roche. NCF receives no personal compensation for the aforementioned activities. NCF has served on a Data Safety Monitoring Board for Biogen. JHC is a scientific consultant for Claritas HealthTech and Queen Square Analytics, and a shareholder in Claritas HealthTech. JMS has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), has consulted for Roche Pharmaceuticals, Biogen, Merck, and Eli Lilly, has given educational lectures sponsored by GE Healthcare, Eli Lilly, and Biogen, and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. The genetic analyses were funded by the Brain Research Trust (UCC14191). Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly, kindly provided the (18)F-florbetapir tracer free of cost, but had no role in the design, conduct, analysis, or reporting of Insight 46 study findings. AK was supported by a Wolfson Clinical Research Fellowship and a Weston Brain Institute and Selfridges Group Foundation award (UB170045) that also funded the serum NFL analyses. The HD-1 Analyser at UCL was funded by a Multi-User Equipment grant from the Wellcome Trust. TDP was supported by a Wellcome Trust Clinical Research Fellowship (200109/Z/15/Z) and is supported by a National Institute for Health and Care Research clinical lectureship. The NSHD, MR, and AW are funded by the MRC (MC_UU_00019/1, MC_UU_00019/3), with MR acknowledging additional support from the US Alzheimer's Society. VE-P would like to thank the Joint Programming for Neurodegeneration (JPND—MRC: MR/T04604X/1) and the Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics (MRC: MR/L010305/1). FB, NCF, and JMS are supported by the National Institute for Health Research Queen Square Dementia Biomedical Research Unit and the Leonard Wolfson Experimental Neurology Centre. GL was supported by the UK Dementia Research Institute at Cardiff, UK. JMS is supported by UCL Hospitals Biomedical Research Centre, Engineering and Physical Sciences Research Council (EP/J020990/1), British Heart Foundation (PG/17/90/33415), and the EU's Horizon 2020 research and innovation programme (666992). JHC acknowledges funding from UK Research and Innovation and the MRC (MR/R024790/2). All other authors declare no competing interests.