Abstract
Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ1–42, tau, and phospho-tau181p (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample.
Highlights
Age is the strongest risk factor for sporadic Alzheimer disease (AD) [1,2], the most common cause of dementia
The point estimates for successive 5-year intervals are derived from independent linear mixed effect modeling without a baseline age term, and show the mean change experienced by participants in each 5-year age group, in each diagnostic category
We present three lines of evidence indicating that AD proceeds more aggressively among younger elderly than among older elderly individuals, leading to a blurring of the distinction between AD and healthy controls (HCs) among the oldest old
Summary
Age is the strongest risk factor for sporadic Alzheimer disease (AD) [1,2], the most common cause of dementia. That the burden of AD lesions in individuals with AD decreases with age [17], while cognitive and structural changes might be more salient in younger rather than older individuals with AD [18]. This may reduce the ability to detect AD among the oldest old, potentially contributing to the controversy over whether AD incidence rates go up, down, or remain stable after age 85 [16]. We explored the implication of the observed age-related differences in atrophic and clinical rates of decline for clinical trial design, and for disease biomarker trajectories
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