Cardiovascular Risk Factors and Cognition in the Oldest Old: What Doesn't Kill You Makes You (Cognitively) Stronger?

Abstract

Evidence implicating cardiovascular risk factors (CVRFs) in cognitive compromise comes primarily from studies of elderly who are in their 70s. CVRFs in the cognitively healthy oldest-old (85+) have rarely been studied. We present results from several clinical and neuropathological studies suggesting that some relationships consistently observed in the young-old are weakened or even reversed with increasing age. The clinical studies assessed cognitive function and CVRFs (lipid panel, C-reactive protein, plasma homocysteine, and ejection fraction and left atrial diameter from echocardiogram) in 150+ (numbers vary slightly depending on the CVRF) very old cognitively healthy participants. Partial correlations controlling for age, sex, and education were used to examine the relationship between four cognitive domains (memory, executive functions, attention, and language) and individual CVRFs. The neuropathological studies assessed the relationships between diabetes and hypertension medication use with the hallmark lesions of Alzheimer's disease, neuritic plaques and neurofibrillary tangles. ANCOVA controlling for age at death, dementia severity, and sex compared extent of NPs and NFTs in several brain regions, in groups with and without medications, separately for oldest-old and young-old. Contrary to the expected in young elderly, all CVRFs assessed were associated with better cognitive performance, particularly with executive functions. Diabetes medications (concomitant insulin with hypoglycemic medications) and hypertension medications (of any kind) were associated with less AD neuropathology, but these associations were consistently weaker in the oldest-old. The consistent pattern for elevated systemic CVRFs with better cognitive function and the weaker relationships of CVRF medication use with AD neuropathology in the oldest-old is striking and consistent with recent reports from other groups. While limited by the cross-sectional nature of the analyses, one potential explanation for these findings is that cognitive functions are less vulnerable to the neurobiological effects of CVRFs in persons who for genetic/epigenetic/environmental reasons survive to extreme old age. An alternative explanation is antagonistic pleiotropy, i.e. those who survive to extreme age undergo continuous and complex physiological adaptations that contribute to longevity and healthy cognition. In either case, clinical or mechanistic extrapolation of relationships of CVRFs with cognitive compromise in young-old to the oldest-old might be erroneous.