What are the Causes of Late-Life Cognitive Decline?
Abstract & Commentary
By Richard S. Isaacson, MD
Associate Professor of Neurology (Education), Weill Cornell Medical College
Dr. Isaacson reports that he is a scientific advisor/consultant for Novartis and Accera.
Synopsis: Contrary to popular belief, a longitudinal study has found that much of late-life cognitive decline was not secondary to the three most common neurodegenerative disease pathologies.
Source: Boyle PA, et al. Much of late life cognitive decline is not due to common
neurodegenerative pathologies. Ann Neurol 2013; online at wileyonlinelibrary.com.
DOI: 10.1002/ana.23964.
With the first wave of the baby boomer generation nearing their 70s, and considering that age is the number one risk factor for cognitive decline, determining the causal relationships behind progression of dementia is essential. Managing pre-symptomatic cognitive decline from a standpoint of both risk reduction and prevention of dementia is crucial, and targeted therapies may be defined by the most common disease pathologies.
The three most common causes of dementia in older age include dementia due to Alzheimer’s disease (AD), vascular dementia (VD), and Lewy body dementia (LBD). These three diseases also account for the majority of cases of mild cognitive impairment (MCI). AD is the most common neurodegenerative dementia and affects millions of individuals, with many millions more affected as caregivers and family. Because the pathology of AD precedes symptom onset sometimes by decades, there is significant interest in developing preventive intervention strategies that target earlier stages of disease. Although vascular risk factor modification may be associated with reduced rates of VD, disease modification in LBD is less clear. The pathologic indices of AD, VD, and LBD accumulate in the brains of older persons with and without dementia, but the extent to which they account for late-life cognitive decline remains unknown. Earlier identification of at-risk individuals could lead to faster diagnoses, better stratification of patients, and ultimately to more effective preventive treatments.
In the current study, the authors tested the hypothesis that these pathologic indices account for the majority of late-life cognitive decline. Using participants from two large and highly regarded longitudinal clinical-pathologic studies, with > 95% follow-up participation rates for survivors and autopsy rates > 80% (the Rush Memory and Aging Project; Religious Orders Study), postmortem neuropathologic examinations provided quantitative measures of three measures of AD (global AD pathology, tangles, and amyloid), two measures of VD (macroscopic infarcts and microinfarcts), and one measure of neocortical Lewy body pathology, in 856 participants. Detailed annual cognitive function data were available for up to 18 years, and included a mean of 7.5 annual evaluations (including 17 cognitive tests), with participants in both studies undergoing uniform, structured, annual clinical evaluations (including detailed annual cognitive testing and neurologic examinations). The authors also used random coefficient models to examine the linear relation of pathologic indices with global cognitive decline. Since cognitive decline may accelerate in the few years prior to death, analysis was further conducted via random change point models to first determine when the rate of cognitive decline increased prior to death (indicating the onset of terminal decline) and characterize rates of cognitive decline before and after its onset. They then examined the relation of the pathologic indices with the onset of terminal decline and rates of change before and after its onset.
Results showed that while the pathologic indices of the three most common causes of dementia are important determinants of cognitive decline in their older aged cohort, contrary to the hypothesis, they only explained a total of 41% of the variation in cognitive decline (even when multiple pathologic indices of AD, VD, and LBD were examined simultaneously). The authors concluded that the majority of the variation in cognitive decline remained unexplained. This suggests that a large proportion of late-life cognitive decline is driven by factors other than the pathologic indices of AD, VD, and LBD, which are the primary focus of scientific efforts to prevent cognitive impairment and dementia. Further, in random change point models, the common pathologic indices accounted for less than one-third of the variation in the onset of terminal decline, and rates of preterminal and terminal decline.
New research focused on the neurobiological basis of pathologically unexplained cognitive decline is imperative. Strategies are urgently needed to effectively combat the ever-growing public health crisis posed by cognitive decline in older age. This study had several limitations (e.g., measures of disease processes, especially particularly cerbrovascular disease, were incomplete; additional pathologic indices were not quanified) and several additional factors that also likely contributed to the high rate of unexplained causes (e.g., indices may lack specificity, measures of cerebrovascular disease were incomplete, inability to examine the contribution of small vessel disease, not accounting for hippocampal sclerosis or other recently described pathologies). However, even considering these limitations, investigation of an alternative explanation is warranted. Along these lines, one recent study published in Science Translational Medicine discovered that deficiency of the histone-binding protein RbAp48 was related to age-related memory loss (ARML), with its expression deteriorating with age.1ARML, an area of active research, may be one of the more common syndromes apart from AD, VD, and LBD associated with cognitive decline. ARML is just one example of a condition with unclear neuropathologic indices, and implications for diagnosis, treatment, and prevention of cognitive decline.
Reference
1.Pavlopoulos E, et al. Molecular mechanism for age-related memory loss: The histone-binding protein RbAp48. Sci Transl Med 2013;5:200ra115.
