Mental stimulation and multimodal trials to prevent cognitive impairment and Alzheimer ́s disease

Theoretical models of dynamic biomarkers underlying the development of Alzheimer´s Disease (AD) acknowledge that there is inter-individual variability in the cognitive performance associated with any level of AD pathology. Mentally stimulating activities such as schooling, occupation, and leisure activities, may contribute to this variability, but it is yet unclear how this can be best assessed, and how such effects can vary across AD severity and among individuals at-risk for cognitive impairment. The association between mental stimulation and cognitive performance also suggests that it is important to account for mental stimulation levels in randomized clinical trials (RCTs) comparing rates of cognitive change between interventions (i.e., drugs, lifestyle interventions) and controls. The aim of this thesis was to investigate a) how pre-existing levels of occupational complexity affect the cognitive outcomes of a multimodal lifestyle-based RCT among older adults at increased risk for dementia based on a validated risk score b) if occupational complexity is associated to cognitive performance among individuals at-risk for dementia, including individuals in the early stages of symptomatic AD (prodromal AD) and c) if occupational complexity is associated with resilience to AD pathology, measured with validated biomarkers and neuroimaging among individuals at-risk for cognitive impairment and with prodromal AD.

The four studies in this thesis were based on data from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), the Karolinska University Hospital electronic database and biobank for clinical research (GEDOC) and The Multimodal Prevention Trial for Alzheimer´s Disease (MIND-ADmini).

Study I. This study used data from the FINGER study (N=1026) to investigate if preexisting levels of occupational complexity were associated with cognitive function at baseline, and if occupational complexity was associated with the rate of change in cognition during the 2-year intervention period. For all measures of occupational complexity, higher levels of complexity were associated with better cognitive outcomes at baseline. Occupational complexity was not associated with the rate of cognitive change during the intervention, except for the executive function outcome, for which higher levels of complexity with data predicted increased improvement ((ß[SE]: .028[.014], p=.044).

Study II. This study used data from the FINGER neuroimaging cohort, to investigate if the association between occupational complexity and cognition was moderated by measures of brain integrity, both in terms of magnetic resonance imaging (MRI, N=126) and Pittsburgh-B Compound – Positron Emission Tomography (PiB-PET, N=41). The results showed that higher levels of occupational complexity were associated with better cognitive performance for some outcomes after adjusting for Alzheimer’s Disease Signature (ADS) and medial temporal atrophy (MTA). However, for most types of neuropathology and cognitive outcomes, moderation effects indicated that higher occupational complexity levels were associated with better cognitive performance only in people with higher brain integrity, suggesting lack of occupational complexity-related resilience mechanisms.

Study III. This study investigated the association between mental stimulation (occupational complexity and education) and validated AD biomarkers, Aβ1–42, p-tau and t-tau measured in cerebrospinal fluid (CSF). Using data from the GEDOC database, 174 individuals with prodromal AD were included, and analyses were adjusted for cognitive function. The results indicated that both higher occupational complexity and education were associated with higher levels of p-tau and t-tau. For education the association with tau pathology was age dependent. No association was found with Aβ1– 42. This suggests that higher education and occupational complexity may provide resilience against tau-related pathology in prodromal AD.

Study IV. This study used data from FINGER, GEDOC, and MIND-ADmini, thus including a total of 1410 individuals, 1207 at-risk for dementia and 203 with Prodromal AD. The aim was to to compare the two most common rating systems for occupational complexity, the Occupation Information Network (O*NET) and the Dictionary of Occupational Titles (DOT) and assess if there was an association between occupational complexity and episodic memory performance among individuals at-risk for dementia. The study found that higher occupational complexity was only associated with memory performance in the FINGER cohort but not the two prodromal AD cohorts. The correlation between the two rating systems was moderate to strong, and highly significant (Spearman’s rho = 0.5-0.6, p <.001).

Conclusions. Higher levels of Occupational complexity are associated with better cognitive performance among older individuals at-risk for dementia (and with no substantial cognitive impairment), but does not affect the intervention effect in the FINGER multidomain lifestyle-based RCT, apart from the effect on executive function. Occupational complexity does not seem to provide strong resilience against neuropathology among individuals at-risk for cognitive impairment. Among individuals with prodromal AD, higher levels of occupational complexity do seem to provide resilience to tau-related pathology measured with CSF markers but is not associated with better episodic memory performance. Measuring occupational complexity with the DOT or O*NET system seems to yield similar results, as the two systems scores are correlated.

List of scientific papers

I. Rydström A., Darin-Mattsson A., Kåreholt I., Ngandu T., Lehtisalo J., Solomon A., Antikainen R., Bäckman L., Hänninen T., Laatikainen T., Levälahti E., Lindström J., Paajanen T., Havulinna S., Peltonen M., Sindi S., Soininen H., Neely AS., Strandberg T., Tuomilehto J., Kivipelto M., Mangialasche F. Occupational complexity and cognition in the FINGER multidomain intervention trial. Alzheimer's Dement. 2022; 18: 2438– 2447.
https://doi.org/10.1002/alz.12561

II. Rydström A., Stephen R., Kåreholt I., Darin Mattsson A., Ngandu T., Lehtisalo J., Bäckman L., Kemppainen N., Rinne J., Sindi S., Soininen H., Vanninen R., Solomon A., Mangialasche F. The role of brain integrity in the association between occupational complexity and cognitive performance in subjects with increased risk of dementia. Gerontology. 2023 Apr 18.
https://doi.org/10.1159/000530688

III. Rydström A., Kåreholt I., Verrijp M., Rosenberg, A., Darin-Mattsson A, Andel R., Bäckman L., Hagman G., Sindi S., Kivipelto M., Mangialasche F. Education and occupational complexity are associated to the burden of neuropathology in prodromal Alzheimer´s disease. [Manuscript]

IV. Rydström A., Kåreholt I., Bäckman L., Hagman G., Andersen P., Lehtisalo J., Darin-Mattsson A., Ngandu T., Rosenberg, A., Sindi S., Thunborg, C., Duval C., Pantel J., Hartmann T., Kivipelto M., Mangialasche F. Occupational complexity and memory performance in people at risk of dementia: comparison of two ratings systems of occupational complexity. [Manuscript]