Antecedents of intact cognition and dementia at age 90 years: a prospective study

The factors leading to the development of clinical dementia remain puzzling. Of seven major factors commonly associated with Alzheimer’s disease (AD): diabetes, midlife hypertension, smoking, depression, low educational attainment, cognitive inactivity, and physical inactivity (Barnes and Yaffe 2011), none have been consistently identified by prospective studies to play a causal role in AD. One reason for debate is the lack of multi-decade studies. Shorter, decade-long prospective studies (Bennett et al 2005, Albert et al 1995, Kawas et al 2000) can produce unreliable solutions, which may confuse association with cause. For example, are depression and diminished physical and intellectual activity causes of dementia or are they premonitory symptoms? A second reason for debate is the absence of autopsy examination. Most of these seven risk factors for AD, compellingly documented in the review by Barnes and Yaffe, have a known causal effect on small vessel disease. To claim causal attribution of these risk factors to AD arises from the fact that clinical dementia correlates only modestly with autopsy evidence of either AD or small vessel pathology alone (MRC CFAS 2001, Schneider et al 2007, Riley et al 2002). Rather, dementia is much more likely to occur when small vessel disease and amyloid plaques and tau tangles occur together making an either/or diagnosis uncertain. This suggests that the alleged predictors of AD may actually be predicting dementia partially due to small vessel disease (de la Torre, 2013). In addition, longitudinal studies like the Nun Study (Snowdon 1997) and the Rush Memory and Aging Project (Bennett et al 2005) have provided dramatic case studies reflecting discrepancies between Braak Staging of AD neuropathology and severity of dementia. Our study uses 70 years of prospectively collected longitudinal data to examine the environmental predictors of sustained intact cognition and of dementia by age 90. The value of our study lies in the fact that due to high education (76% attended graduate school) and social class, our sample is unusually long-lived and had less than the expected number of risk factors for early vascular disease. (U.S. Census data reveals that the 30% survival at 90 of the original 268 men in our Study was roughly 10 times the expected proportion for white men born in 1920. (National Vital Statistics Reports 2007). When the Study members were contrasted to an Inner City comparison group (Vaillant 2002), both vascular risk factors and mortality (10 years difference) differed significantly. The Inner City men manifested diabetes, a BMI > 29, and heavy smoking (40+ pack-years) three times more frequently than our Study sample and a diastolic blood pressure at age 50 >89 mm hg twice as often. The present report is of the 196 College men (out of an original cohort of 268) who survived until age 70—when the first Study members developed dementia—and who have been followed prospectively every two years from adolescence until death or age 90 (Vaillant 2002, Vaillant 2012). First, the Study provides a means of addressing many of the cart/horse temporality directionality questions related to the environmental contributions to dementia. Second, because of the cohort’s relatively low prevalence of vascular risk factors, it is possible to question whether these are not risk factors for vascular dementia rather than AD. Third, the long follow-up permits examination of childhood risk factors for dementia. Admittedly, due to its small numbers and selected cohort, our study will only be hypothesis generating.