Data collection on PET and MRI data
We identified which contextual factors are associated with vascular and degenerative lesions as detected by structural MRI and amyloid-PET.
Structural MRI and amyloid PET data is used to verify which contextual factors are associated with vascular and degenerative lesions. Using the structural MRI and PET data, we will be able to detect (1) structural brain changes: volume of different brain regions and white and grey matter volume; (2) markers of cerebral small vessel disease such as white matter hyperintensities, asymptomatic lacunar infarcts, brain microbleeds, and enlarged perivascular spaces; (3) microstructural cerebral integrity: magnitude and direction of molecular diffusion in brain tissues; and (4) amyloid load.
Neuroimaging data was collected in a subsample of SNAC-K participants and the Rotterdam study.
Due to the COVID19 pandemic we replaced the 50 AD patients in the study by 50 healthy persons at high genetic risk based on their apolipoprotein E status. The genetic high-risk group comprises 19 patients who are homozogyous for the apolipoprotein E4 variant (APOE*4) and 31 patients who are heterozygous. These asymptomatic subjects will be labelled as ‘surrogate AD patients’ based on their genetic risk and will be compared to controls and those with MCI, as specified in the proposal.
Primary objective
The initial aim of this study was to collect data on MRI and PET for subjects with normal cognition, mild cognitive decline, and dementia. This objective was obtained by 1) a pilot study on PET and MRI data collection; 2) available measures on small vessel diseases, brain tissue volume, and Aβ amyloid deposition; and 3) a report based on the association between imaging markers, stroke, and cognitive dysfunctions.
Secondary objective
We aimed to investigate whether compensatory factors can modify the association between vascular risk factors and cognitive performance, considering the AD, stroke, and neuropathological changes in the brain which can be detected by MRI and PET. Task was completed in a previous reporting period and summarized in two reports on the modifying effect of compensatory factors on cognitive decline, taking into account the variability of vascular and neurodegenerative brain lesions, which can be detected by MRI and PET scans (Nordberg et al. 10.1038/nrneurol.2009.217 and Nordberg 10.1159/000197883)
We employed a quantitative strategy to assess amyloid status. To this end, we applied an established cut-off. Participants with a measured value above the cut-off were classified as amyloid positive. We selected participants Mild cognitive impairment (MCI) based on the presence of self-reported subjective memory complaints and the objective assessment of cognitive status using Mini Mental Status Examination (MMSE), an established screening tool of dementia.
The identification of the genetic high risk group is based on participants from the Rotterdam Study cohort that are included in the PET study. For these persons, a genome wide characterization is available. The metabolome was characterized using Nuclear Magnetic Resonance of the Nightingale Health platform.
Comparing of patients with MCI to normal controls
Comparing those with MCI and no cognitive impairment, no significant group-differences were observed for the matching variable age and sex but also the education levels, the frequency of hypertension, coronary heart disease, stroke, alcohol intake. Also, volumetric brain measures at MRI were very similar for those with impaired and normal cognition. We found amyloid status to be comparable between cognitively normal and impaired participants.
Comparing of participant as high and low genetic risk
Comparing those at high and low genetic risk, no significant group-differences were observed for the matching variable age and sex but also the education levels, the frequency of hypertension, coronary heart disease, stroke, alcohol intake. We find a borderline significant increase in the prevalence of white matter hyperintensity volume in those at high genetic risk. When comparing the genetic high and low genetic risk group, amyloid status was significantly different with more than 40% of the individuals as high risk showing a positive amyloid status compared to less than 4 % of the low-risk.
Analysis of metabolites
Based on the findings of WP2, we studied the association of the metabolites as measured in the Nightingales platform to amyloid PET positivity. At nominal significance, we find 51 metabolites associated to amyloid positivity. VLDLs showed the strongest association but also LDL, APOEB and various fatty acids were associated. No association reached FDR adjusted p-value of at least 0.05. We find the associations became weaker after further adjustment for APOE, but the association remained normally significant for many VLDL fractions.
Conclusion
Our analysis shows that in this population-based study, amyloid positivity is increased in the genetic high-risk groups. Amyloid accumulation is seen in precuneus, cingulate and lateral frontal cortices. Also white matter hyperintensities as a measure of small vessel disease is increased in the genetic high risk group. Further analyses on how amyloid positivity is associated vascular pathology in the brain is still ongoing. Our initial findings show that a large number of metabolites associated with amyloid positivity. The strongest evidence is seen for VLDL fractions, which are strongly associated to triglyceride and fatty acid metabolism.
Modifying effect of compensatory factors on the association of vascular risk factors with stroke and AD
Based on the two population-based cohort studies (SNAC-K and Rotterdam study) with data on brain reserve-related compensatory factors, vascular risk burden, cognitive assessment, and incident AD and stroke, analyses were performed to investigate whether 1) compensatory factors can modify the association between vascular risk factors and stroke, taking into account genetic susceptibility; 2) compensatory factors can modify the association between vascular risk factors and cognitive dysfunction, taking into account genetic susceptibility; and 3) there are common compensatory factors that can modify the association of vascular risk factors with the co-occurrence of stroke and cognitive dysfunction.
We first explored the association between vascular risk factor burden, brain MRI markers, and cognitive decline in SNAC-K population. We found that the effect of vascular risk facto burden on cognitive decline was mediated largely by mixed brain pathologies, such as vascular lesions and neurodegenerative changes.
We also found that diabetes is associated with a faster decline in perceptual speed and verbal abilities, while prediabetes is associated with lower memory performance in middle-age. However, the detrimental effects of hyperglycaemia seem to not affect memory over time.
We further made an in-depth analysis disentangling which risk factors are specific for either AD or stroke and which are common using SNAC-K. The common risk factors for both Stroke and AD are old age (70+), the APOE e4 allele, physical inactivity, heart disease, and subjectively feeling lonely. Intensive leisure time activity and a rich social network are protective factors only for AD, while hypertension and more cardiovascular burden are specific risk factors for stroke in an older population.
Modifying effect of compensatory factors on the association between stroke and cognitive dysfunction
Using data on brain reserve-related compensatory factors, vascular risk burden, incident stroke and stroke history, and follow-up cognitive assessments from two population-based cohort studies (SNAC-K and Rotterdam study), we found that diabetes and prediabetes accelerate cognitive decline and can predict microvascular lesions among dementia-free older adults. Diabetes is associated with ischemic stroke, which mediates 40% of the diabetes-dementia risk association. Active participation in leisure activities and having a rich social network may mitigate the risk of dementia in diabetes. In addition, we found that an active lifestyle doubled the positive effect of diet on cognitive function, and further lowered risk of MMSE decline by 30%. Higher education is associated with a lower risk of dementia after stroke or TIA, particularly in men, which might be explained by a higher cognitive reserve. High life course cognitive reserve may reduce the risk of dementia, especially in APOE ԑ4 carriers.
To verify the hypothesis that the lack of social support and loneliness predict cognitive decline and a higher risk of dementia, and that depressive symptoms accounts for this association, we included two cohorts of the Rotterdam Study and the SNAC-K study. The results show that in prospective analyses, loneliness was associated with a decline in the MMSE. Consistently, persons who were lonely at baseline had an increased risk of developing dementia. Neither perceived or structural social support was associated with cognitive decline or dementia. In conclusion, loneliness, the most subjective of the social health measures, predicted cognitive decline and incident dementia independent of depressive symptoms.
The associations of genetic, biological, and contextual factors with vascular and degenerative lesions detected by structural MRI and PET
We assessed the findings of the WP1-3. Using SNAC-K data, we found that a cognitive reserve indicator comprised of 4 observed factors over the life course—education, substantive work complexity, social network, and leisure activities—was associated with a reduced risk of dementia in a dose‐response manner. Additive interaction between the reserve indicator and APOE‐ε4 status was observed.
We examined the association between global brain perfusion and risk of transient ischemic attack (TIA) and ischemic stroke in the general population. We investigated whether associations were modified by retinal vessel calibers, small and large vessel disease, blood pressure, and heart rate. We found that lower global brain perfusion was associated with a higher risk of TIA, but not with the risk of ischemic stroke.
We investigated the if the role of AD implicated pathways in the predementia phase can provide new insight for preventive and clinical trials targeting disease specific pathways. Results suggests that the clinical spectrum of early AD pathology is explained by different biological pathways, in particular the endocytosis, clathrin/AP2 adaptor complex, and immune response pathways, that are independent of APOE‐ε4 status.
We also found that a cognitive reserve indicator encompassing education, early-life, mid-life, and late-life cognitive activities, and late-life social activities — was associated with a preserved cognitive function in a dose‐response manner.
Compensatory mechanisms that lower the risk of cognitive decline in people with vascular and neurodegenerative brain lesions
Within the population-based Rotterdam Study we have conducted an analysis in which we revisited the association of stroke of dementia to answer the question whether education, which strongly protects for AD and dementia, modifies the association between stroke and AD.
We found that only in men and women that received a low in education the risk of dementia is increased following stroke or TIA. The effect being stronger in men. Both in men and women the strength of association between on the hand stroke and TIA and on the other hand dementia decreases as the level of education increases.
Using the SNAC-K study, we explored the proportions of either AD or stroke cases that would be reduced by controlling the shared risk factors and promoting the shared protective factors. Approximately 26% of stroke/AD cases could be prevented if all individuals in a population had a high level of education, and 42% of stroke/AD cases could if all individuals in a population were free from any of the shared risk factors. In total, 58% of stroke/AD cases could be prevented by promoting a positive protective profile in individuals free from any of the shared risk factors.
We further explored if protective factors, i.e., leisure time activities, could compensate the harmful effect of brain changes on dementia risk. We found that the compensatory effect of active social life only existed among older adults without several vascular lesion changes, such as none or slight white matter hyperintensity changes with time.
We also found that high lifespan cognitive reserve indicator accumulated through education, early-life cognitive activities, midlife cognitive activities, late-life cognitive activities, and social activities in late life was associated with a reduction in risk of dementia in a dose-dependent manner.
