Brain structure and phenotypic profile of superagers compared with age-matched older adults: a longitudinal analysis from the Vallecas Project

Abstract

Background: Cognitive abilities, particularly memory, normally decline with age. However, some individuals, often designated as superagers, can reach late life with the memory function of individuals 30 years younger. We aimed to characterise the brain structure of superagers and identify demographic, lifestyle, and clinical factors associated with this phenotype.

Methods: We selected cognitively healthy participants from the Vallecas Project longitudinal cohort recruited between Oct 10, 2011, and Jan 14, 2014, aged 79·5 years or older, on the basis of their delayed verbal episodic memory score. Participants were assessed with the Free and Cued Selective Reminding Test and with three non-memory tests (the 15-item version of the Boston Naming Test, the Digit Symbol Substitution Test, and the Animal Fluency Test). Participants were classified as superagers if they scored at or above the mean values for a 50-56-year-old in the Free and Cued Selective Reminding Test and within one standard deviation of the mean or above for their age and education level in the three non-memory tests, or as typical older adults if they scored within one standard deviation of the mean for their age and education level in the Free and Cued Selective Reminding Test. Data acquired as per protocol from up to six yearly follow-ups were used for longitudinal analyses.

Findings: We included 64 superagers (mean age 81·9 years; 38 [59%] women and 26 [41%] men) and 55 typical older adults (82·4 years; 35 [64%] women and 20 [36%] men). The median number of follow-up visits was 5·0 (IQR 5·0-6·0) for superagers and 5·0 (4·5-6·0) for typical older adults. Superagers exhibited higher grey matter volume cross-sectionally in the medial temporal lobe, cholinergic forebrain, and motor thalamus. Longitudinally, superagers also showed slower total grey matter atrophy, particularly within the medial temporal lobe, than did typical older adults. A machine learning classification including 89 demographic, lifestyle, and clinical predictors showed that faster movement speed (despite no group differences in exercise frequency) and better mental health were the most differentiating factors for superagers. Similar concentrations of dementia blood biomarkers in superager and typical older adult groups suggest that group differences reflect inherent superager resistance to typical age-related memory loss.

Interpretation: Factors associated with dementia prevention are also relevant for resistance to age-related memory decline and brain atrophy, and the association between superageing and movement speed could provide potential novel insights into how to preserve memory function into the ninth decade.

Funding: Queen Sofia Foundation, CIEN Foundation, Spanish Ministry of Science and Innovation, Alzheimer's Association, European Research Council, MAPFRE Foundation, Carl Zeiss Foundation, and the EU Comission for Horizon 2020.

Translation: For the Spanish translation of the abstract see Supplementary Materials section.

Figure 1

Flow diagram of selection criteria FCSRT=Free and Cued Selective Reminding Test. *Both groups were examined using different and mutually exclusive reference values for the neuropsychological tests. Among the participants excluded from the superagers candidates, typical older adult candidates were found, and vice versa. Thus, the totals for exclusion do not equal 200.

Figure 2

Neuroanatomical differences between superagers (n=64) and age-matched typical older adults (n=55) Grey matter atrophy rates, individual trajectories and means (left) and means only (right). Shaded areas depict 95% confidence intervals. (A)Colourmaps of cross-sectional differences in grey matter volume. Figure insets show the thalamic nuclei where grey matter volume is greater in superagers than in typical older adults. Anatomical demarcations from the Automated Anatomical Labelling Atlas 3; family-wise error-corrected p<0·05; p values overlaid on sagittal and coronal sections. (B) Colourmaps of longitudinal differences in grey matter volume, showing slower grey matter volume loss in superagers than in typical older adults over time. Significant group by time interaction; family-wise error-corrected p<0·05; p values overlaid on sagittal and coronal sections. (C) Grey matter volume over time in two representative voxels (left hippocampus and right parahippocampal gyrus) showing the group mean and individual observations. (D) Section coordinates refer to standard MNI space and are given in mm. A=anterior. L=left. P=posterior. R=right. MNI=Montreal Neurological Institute.

Figure 3

Contributions of lifestyle and clinical variables to the classification of superagers Importance of the 89 variables included in the model. Variables with highest importance for superager classification are highlighted (red); negative importance values (marked with an asterisk) have no beneficial contribution to the superager classification of the predictive model. (A) Variables plotted by p value of importance. (B) Further details about all the variables included in this analysis are shown in appendix 2 (pp 21–45). BP=blood pressure. FAQ=Functional Activities Questionnaire. GDS=Geriatric Depression Score. NART=National Adult Reading Test (Spanish version). STAI=State-Trait Anxiety Inventory, where state reflects how an individual currently feels, and trait is how they generally feel. TAPS=finger tapping test.