Abstract
Age is the most robust risk factor for Alzheimer’s dementia, however there is little data on the relation of age to Alzheimer’s disease (AD) and other common neuropathologies that contribute to Alzheimer’s dementia. We use data from two community-based, clinical-pathologic cohorts to examine the association of age with AD and other common pathologies. Participants were 1420 autopsied individuals from the Religious Orders Study or Rush Memory and Aging Project who underwent annual clinical evaluations for diagnosis of Alzheimer’s dementia, mild cognitive impairment (MCI), and level of cognition. The neuropathologic traits of interest were pathologic AD according to modified NIA-Reagan criteria, three quantitative measures of AD pathology (global AD pathology score, β-amyloid load and PHFtau tangle density), macro- and micro-scopic infarcts, neocortical Lewy bodies, TDP-43 and hippocampal sclerosis. Semiparametric generalized additive models examined the nonlinear relationship between age and the clinical and pathological outcomes. The probability of Alzheimer’s dementia at death increased with age such that for every additional year of age, the log odds of Alzheimer’s dementia was 0.067 higher, corresponding to an odds ratio of 1.070 (p < 0.001). Results were similar for cognitive impairment and level of cognition. By contrast, a nonlinear relationship of age with multiple indices of AD pathology was observed (all ps < 0.05), such that pathologic AD reached a peak around 95 years of age and leveled off afterwards; the quantitative measures of AD pathology were significantly lower at ages above 95. The association of age with other neuropathologies was quite distinct from that of AD in that most increased with advancing age. AD pathology appears to peak around 95 years of age while other common pathologies continue to increase with age.
Highlights
Increasing age is the most robust risk factor for Alzheimer’s dementia
Because Alzheimer’s dementia, cognitive impairment, and Alzheimer’s disease (AD) diagnosis each represent a dichotomization on an underlying continuum [15], we examined the association of age with continuous measures of cognition and AD pathology
Our data is consistent with prior studies showing a steady rise of non-AD pathologies with advancing age [5, 14, 26] and with others that found that pathologies other than AD become increasingly more important drivers of dementia and cognitive impairment in the oldest-old [17, 20]. These findings suggest that interventions that target non-AD neuropathologies, hippocampal sclerosis, TDP-43 pathology, and vascular disease may be of greatest utility in the oldest-old, the most rapidly growing segment of the population in the USA and other developed countries
Summary
Increasing age is the most robust risk factor for Alzheimer’s dementia. Population-based studies show that the age-specific incidence and prevalence of Alzheimer’s dementia increase markedly after age 65 [9, 19, 21]. Most studies suggest that the incidence and prevalence of Alzheimer’s dementia continues to increase across the entire age spectrum, including in the oldest-old [6, 7]. While several studies suggest that the relation of AD to dementia is weaker in the oldest-old [11, 29], limited data is available on the association of age with AD and other common neuropathologies in very old persons [5, 26]. We extend our prior work by examining both linear and Farfel et al Acta Neuropathologica Communications (2019) 7:104 non-linear associations of age with Alzheimer’s dementia, cognition, multiple indices of AD and other common neuropathologies in more than 1400 persons aged 66 to 108 at death
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