Our epidemiological findings suggest a U-shaped association, rather than a linear relation, between LVEF and markers of abnormal brain aging. Participants in both the lowest and highest LVEF quintiles had cross-sectional evidence of abnormal cognitive changes as compared to the middle referent group. The observation that lower LVEF is associated with abnormal brain changes extends prior literature examining patients with severe cardiomyopathies, which reported reduced LVEF was associated with memory,4,21
and sequencing impairments.22
In the absence of clinical heart failure and prevalent CVD, our findings suggest that lower levels of LVEF are also related to abnormal brain aging. It is noteworthy that the lowest quintile of LVEF (which had significant associations with visuospatial memory and object recognition) included a majority of participants with clinically normal values (i.e., 55–62%). The observation that even low normal values of systolic function can be associated with cross-sectional markers of abnormal brain aging is consistent with our recent work reporting low normal values of cardiac index are associated with smaller brain volumes.18
The mechanism underlying associations between lower resting LVEF and abnormal brain aging is unknown. Despite auto-regulatory mechanisms, cerebral blood flow values are low in heart transplant candidates but return to normal following heart transplantation.23
Disruption of cerebral perfusion may contribute to clinical or subclinical brain injury by propagating or exacerbating cerebrovascular disease, including alterations in microvessel structure, expression of vascular cell receptors, microvessel permeability changes, and vascular remodeling.24,25
Chronic cerebral hypoperfusion in animals leads to the development8,9
of white matter changes. Another pathological mechanism could be AD, as rats develop AD-related neuropathology, including diffuse beta-amyloid peptide and amyloid precursor protein expression in the hippocampus, entorhinal cortex, and neocortex, following acute cessation of blood flow.26
Chronic cerebral hypoperfusion places the brain at risk for amyloid deposition, resulting in neuronal death in transgenic AD mice.27
More research is needed to understand the mechanism accounting for the associations reported here.
An unexpected observation from the current study was that participants with the highest (top quintile) LVEF values also had poorer cognitive performances in verbal and visuospatial memory, executive functioning, and visuoperceptual abilities as compared to the referent. These findings persisted despite adjusting for multiple covariates, excluding participants with prevalent CVD, and post-hoc consideration of additional possible confounders (e.g., enhanced inflammatory process, greater BMI, lower cardiac index, or LV hypertrophy). The mechanism underlying this observation is unknown. Whereas healthy LVEF values may be good for brain health, very high LVEF values may correspond to subtle cognitive impairment. Alternatively, our observation may reflect an epiphenomenon or another pathological process that was not analytically considered in our models, such as anemia or thyroid disease.28
The observed U-shaped association between LVEF and cognitive aging requires further study, including the clinical significance of cognitive impairment, such as early functional loss.29
Our study has several strengths, including the large community-based cohort free of clinical dementia and stroke, comprehensive ascertainment of possible confounders, innovative cardiac imaging, rigorous quality control procedures, and core reading laboratory for processing measurements, blinded to the participants’ cognitive status. However, there are methodological limitations. The cohort is predominantly white, of European descent, and middle-aged to elderly, so the generalizability to other races, ethnicities, and age groups is unknown. The ambulatory nature of the cohort, exclusion of participants with clinical stroke or dementia, and inclusion of individuals willing to undergo MRI yielded a healthier sample, reducing the likelihood of detecting relations that may be present in individuals with more comorbities. The smaller dataset available for analyses relating LVEF to hippocampal volume may have been insufficiently powered. Analyses were cross-sectional and observational; hence, we are unable to establish a causal connection between cardiac function and brain measures. The potential for false positive findings given the multiple statistical tests is also a concern. By accounting for multiple potential confounders, we may have ‘over-adjusted’ our models, as LVEF may predispose to cognitive impairment through intermediate mechanisms, such as hypertension or diabetes. Finally, the cardiac MRI data were acquired on average 2.5 years prior to the brain MRI and neuropsychological data.