This study demonstrates that the presence of the apoE4 allele can exacerbate neuropsychological deficits associated with CVD risk as indexed by FSRP. It appears that SBP is driving this effect since it was the only risk factor whose impact on neuropsychological performance was significantly modified by the presence of the apoE4 allele. This suggests that the presence of the apoE4 allele in combination with high SBP may produce synergistic effects with respect to functional ability. This interaction may significantly exacerbate the progression and acceleration of cognitive decline in those with high SBP, although more research is needed in this area.
Although we confirmed previous Framingham Heart Study findings that Q4-FSRP was significantly associated with MRI measures, the lack of significant FSRP and apoE interactions on brain structures may be because the specific imaging techniques used were not optimal for detecting the neural changes resulting from apoE4/CVD risk factor interaction. It could be that the neural changes associated with the alterations in neuropsychological performance are associated with changes in the neural integrity of the white matter. This could be addressed in a future study examining white matter with Diffusion Tensor Imaging. In contrast to our expectations, the effect of DM was only significantly modified by the presence of apoE4 for the white matter hyperintensities MRI variable (tables and ). It is possible that other factors associated with the development of AD such as family history or lifestyle might be more important moderators of DM’s effect on the brain and neuropsychological function.
Consistent with our previous studies, we found that, overall, Q4-FSRP was associated with poorer performance on Visual Reproductions-D.R. and Trail Making Test-B; but was not associated with the other NP measures. One possible contributing factor may be that that increased stroke risk factors are more likely to lead to attenuated executive functions (associated with lower frontal lobe volume and reflected in performance on Trail Making Test-B) as well as reduced ability in the domain of non-verbal organization, as reflected in poor performance on the complex visual designs. This relationship is highlighted further by the our findings that the interactions between Q4-FSRP and apoE4 status were significant for our memory measures, e.g., Logical Memory-D.R., Paired Associates-D.R., Visual Reproductions-D.R., and executive function e.g., Trail Making Test-B. In each of these interactions, the negative relationship between stroke risk and neuropsychological performance was significant only for individuals in possession of the E4 allele. These findings suggest that the presenece of apoE4 leads to synergistic effects, greatly increasing the negative consequences of some stroke risk factors.
Many previous investigations have demonstrated that CVD risk factors can lead to subtle morphometric changes, especially to frontal subcortical structures. We believe that examining the interaction of the relationship between various CVD and genetic risk factors for dementia suggests that a strict dichotomy between microvascular disease and AD is inappropriate. The findings of this investigation, combined with the work of previous studies, suggest that the factors underlying the clinical presentations of vascular cognitive impairment and AD are interrelated, complex and dynamic. Effective treatment strategies for treating or preventing either disease should therefore address both the factors traditionally associated with vascular cognitive impairment (e.g., blood pressure, cholesterol, glucose levels and atherosclerosis) as well as those traditionally associated with Alzheimer’s disease (i.e. apoE4).
The strengths of our study are the large community-based sample, the availability of multiple CVD and neuroanatomical measures and the use of a comprehensive, standardized battery of neuropsychological tests in all participants.
Our study also has several limitations. We do not have repeated measures of brain MRI and neuropsychological testing, and hence cannot determine if the neuroanatomical and physiological alterations preceded or followed the onset of neuropsychological decline. Additionally, our participants are of predominantly European decent, which restricts the generalizability of our results to other ethnicities/races.
While the issues discussed above reflect limitations of our investigation, we view this research as one in a series of steps towards a more comprehensive understanding of the factors that increase risk for cognitive decline amongst geriatric populations. We hope that understanding the factors that increase the risk for cognitive decline will facilitate improved treatments and encourage preventative health behaviors, allowing geriatric populations to extend functional independence.