Predicting cognitive resilience from midlife lifestyle and multi-modal MRI: A 30-year prospective cohort study

Abstract

Background There is significant heterogeneity in the clinical expression of structural brain abnormalities, including Alzheimer’s disease biomarkers. Some individuals preserve their memory despite the presence of risk factors or pathological brain changes, indicating resilience. We aimed to test whether resilient individuals could be distinguished from those who develop cognitive impairment, using sociodemographic variables and neuroimaging. Methods We included 550 older adults participating in the Whitehall II study with longitudinal data, cognitive test results, and multi-modal MRI. Hippocampal atrophy was defined as Scheltens Scores >0. Resilient individuals (n = 184) were defined by high cognitive performance despite hippocampal atrophy (HA). Non-resilient participants (n = 133) were defined by low cognitive performance (≥1.5 standard deviations (S.D.) below the group mean) in the presence of HA. Dynamic and static exposures were evaluated for their ability to predict later resilience status using multivariable logistic regression. In a brain-wide analysis we tested for group differences in the integrity of white matter (structural connectivity) and resting-state networks (functional connectivity). Findings Younger age (OR: 0.87, 95% CI: 0.83 to 0.92, p<0.001), higher premorbid FSIQ (OR: 1.06, 95% CI: 1.03 to 1.10, p<0.0001) and social class (OR 1 vs. 3: 4.99, 95% CI: 1.30 to 19.16, p = 0.02, OR 2 vs. 3: 8.43, 95% CI: 1.80 to 39.45, p = 0.007) were independently associated with resilience. Resilient individuals could be differentiated from non-resilient participants by higher fractional anisotropy (FA), and less association between anterior and posterior resting state networks. Higher FA had a significantly more positive effect on cognitive performance in participants with HA, compared to those without. Conclusions Resilient individuals could be distinguished from those who developed impairments on the basis of sociodemographic characteristics, brain structural and functional connectivity, but not midlife lifestyles. There was a synergistic deleterious effect of hippocampal atrophy and poor white matter integrity on cognitive performance. Exploiting and supporting neural correlates of resilience could offer a fresh approach to postpone or avoid the appearance of clinical symptoms.

Verbal intelligence is a more robust cross-sectional measure of cognitive reserve than level of education in healthy older adults

“…Unlike previous studies, due to the availability of two large neuroimaging datasets, we could demonstrate that independent effects of verbal intelligence on cognition were present in several brain-cognition models and were replicable. This validation of verbal intelligence as a CR proxy supports previous, narrower, associations between verbal intelligence and cognitive function in the presence of hippocampal atrophy [56], a neuropathological 'residual' measure of CR [55], a functional connectivity measure of CR based on task potency [9], and a possible neuromarker of CR, locus coeruleus signal intensity [107].…”

“…Other proxies were not assessed in this systematic review, although individual studies have reported positive evidence for CR effects in complete CR models. Verbal intelligence has been positively associated with cognition, controlling for global AD neuropathology or hippocampal atrophy in cognitively healthy [ 55 , 56 ] and cognitively impaired older adults [ 55 ]. Physical activity was positively associated with cognition in the presence of neuropathology [ 57 ] but not hippocampal atrophy [ 56 ].…”

Verbal Intelligence, Not Level of Education, Robustly Assesses Cognitive Reserve

“…While this proxy has been previously associated with cognitive function in older adults without controlling for brain structure (125,126), our results show that these associations are not independent of brain structure. This supports previous ndings of non-signi cant associations from the few complete CR models assessing this proxy adjusting for brain structure using GM volume and hippocampal atrophy (53,127). The disparity in the observed associations when brain structure is accounted for could be because the protective effects of exercise may be exerted via improved brain maintenance, i.e.…”

“…However, this moderation effect on tau deposition was not signi cant when the analysis was restricted to cognitively healthy older adults. Other studies have reported positive evidence for verbal intelligence as a CR proxy in cognitively healthy older adults, including a positive association with cognitive function controlling for hippocampal atrophy (53), and a moderation effect on the relationship between cognition and ber bundle length, an index of white matter microstructural integrity (54). In the latter study, the reported moderation effect may have been confounded by age, as age is negatively associated with both bre bundle length (55) and cognitive function (56,57), yet the analysis did not control for age.…”

“…Complete CR models assessing physical activity and social engagement have since been published. Con icting evidence has been reported for physical activity, which was positively associated with cognition in the presence of neuropathology (58) but not hippocampal atrophy (53). Positive evidence has also been reported for social engagement, which moderated the relationship between amyloid-beta deposition and cognitive decline (59).…”