Biological and environmental predictors of heterogeneity in neurocognitive ageing

Maintaining a youthful brain structure and function throughout life may be the single most important determinant of successful cognitive aging. In this study, we addressed heterogeneity in brain aging by making image-based brain age predictions and relating the brain age prediction gap (BAPG) to cognitive change in aging. Structural, functional, and diffusion MRI scans from 351 participants were used to train and evaluate 5 single-modal and 4 multimodal prediction models, based on 7 regression methods. The models were compared on mean absolute error and whether they were related to physical fitness and cognitive ability, measured both currently and longitudinally, as well as study attrition and years of education. Multimodal prediction models performed at a similar level as single-modal models, and the choice of regression method did not significantly affect the results. Correlation with the BAPG was found for current physical fitness, current cognitive ability, and study attrition. Correlations were also found for retrospective physical fitness, measured 10 years prior to imaging, and slope for cognitive ability during a period of 15 years. The results suggest that maintaining a high physical fitness throughout life contributes to brain maintenance and preserved cognitive ability.

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“…All included subjects were part of the Betula prospective cohort study on memory, health, and aging ( Nilsson et al. 1997 ; Nyberg et al. 2020 ).…”

Section: Methodsmentioning

confidence: 99%

“…For more detailed information on subject inclusion in the Betula study, see ( Nilsson et al. 1997 ; Nyberg et al. 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Multimodal Image Analysis of Apparent Brain Age Identifies Physical Fitness as Predictor of Brain Maintenance

et al. 2021

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“…Dementia diagnoses were based on multiple sources of clinical information, comprising written and computerized medical records, supplemented by outcomes from the Betula study health and cognitive assessments (for detailed description see [33]). The Diagnostic and Statistical Manual of Mental Disorders 4 th edition (DSM-IV) was used for dementia classification [43].…”

Section: Clinical Characterization and Dementia Diagnosis Assessmentsmentioning

confidence: 99%

Short leukocyte telomeres predict 25-year Alzheimer’s disease incidence in non-APOE ε4-carriers

Hackenhaar

Josefsson

Adolfsson

et al. 2021

Preprint

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Background: Leukocyte telomere length (LTL) has been shown to predict Alzheimer's disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E ( APOE ) ε4 allele carriage, the strongest genetic AD predictor. Methods: We analysed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess the cause-specific risk of AD between rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards. Results: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1-24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL- APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non- APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404–7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947–2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD. Conclusions: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non- APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.

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“…Seven hundred and fifty-six participants with longitudinal MRI were included from the European Lifebrain project (1672 scans, baseline age 19–89 [mean = 59.8, SD = 16.4], mean follow-up interval 2.3 years, range 0.3–4.9, SD = 1.2) ( https://www.lifebrain.uio.no/ ) ( Fjell et al, 2019 ), including major European brain studies: Berlin Study of Aging-II (BASE-II) ( Bertram et al, 2014 ; Gerstorf et al, 2016 ), the BETULA project ( Nyberg et al, 2020 ), the Cambridge Centre for Ageing and Neuroscience study (Cam-CAN) ( Shafto et al, 2014 ), and University of Barcelona brain studies ( Abellaneda-Pérez et al, 2019 ; Rajaram et al, 2016 ; Vidal-Piñeiro et al, 2014 ). The study was approved by the Regional Committee for Medical and Health Research Ethics South, Norway (2017/653).…”

Section: Methodsmentioning

confidence: 99%

The genetic organization of longitudinal subcortical volumetric change is stable throughout the lifespan

Fjell

Grydeland

Wang

et al. 2021

eLife

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Development and aging of the cerebral cortex show similar topographic organization and are governed by the same genes. It is unclear whether the same is true for subcortical regions, which follow fundamentally different ontogenetic and phylogenetic principles. We tested the hypothesis that genetically governed neurodevelopmental processes can be traced throughout life by assessing to which degree brain regions that develop together continue to change together through life. Analyzing over 6000 longitudinal MRIs of the brain, we used graph theory to identify five clusters of coordinated development, indexed as patterns of correlated volumetric change in brain structures. The clusters tended to follow placement along the cranial axis in embryonic brain development, suggesting continuity from prenatal stages, and correlated with cognition. Across independent longitudinal datasets, we demonstrated that developmental clusters were conserved through life. Twin-based genetic correlations revealed distinct sets of genes governing change in each cluster. Single nucleotide polymorphisms-based analyses of 38127 cross-sectional MRIs showed a similar pattern of genetic volume-volume correlations. In conclusion, coordination of subcortical change adheres to fundamental principles of lifespan continuity and genetic organization.

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Biological and environmental predictors of heterogeneity in neurocognitive ageing

Cited by 90 publications

References 248 publications

Multimodal Image Analysis of Apparent Brain Age Identifies Physical Fitness as Predictor of Brain Maintenance

Multimodal Image Analysis of Apparent Brain Age Identifies Physical Fitness as Predictor of Brain Maintenance

Short leukocyte telomeres predict 25-year Alzheimer’s disease incidence in non-APOE ε4-carriers

The genetic organization of longitudinal subcortical volumetric change is stable throughout the lifespan

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