Rates of decline in Alzheimer disease decrease with age

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, Aβ(1-42), tau, and phospho-tau(181p) (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.

Figure 1. Mixed effects model fit for annual atrophy rates, allowing for linear change with age.

Data points plotted, with 95% confidence intervals, are independent estimates of the atrophy rates for successive 5-year intervals for a mixed effects model fit without an age-dependent term. Slopes and p-values of the linear fits of atrophy rates with age for each cohort are shown in Table 2. Note that atrophy rate is shown by a signed value; thus a reduction in atrophy rate with age is evidenced by a positive slope in the linear fit. Legend: red  = AD; blue  =  MCI; green  = HC.

Figure 2. Mixed effects model fit for annual rates of clinical decline, allowing for linear change with age.

Data points plotted, with 95% confidence intervals, are independent estimates of rates of change for successive 5-year intervals for a mixed effects model fit without an age-dependent term. Slopes and p-values of the linear fits for each diagnostic group are shown in Table 3. Legend: red  = AD; blue  =  MCI; green  = HC.

Figure 3. Linear fit to baseline CSF and cognitive measures, along with independent estimates of baseline measures (with 95% confidence intervals) at successive 5-year intervals.

Legend: red  =  AD; blue  =  MCI; green  =  HC.

Figure 4. Linear fit to baseline structural MRI measures, along with independent estimates of baseline measures (with 95% confidence intervals) at successive 5-year intervals.

Figure 5. Data points show percentage, for successive 3-year age groups, of participants who progressed to dementia within 36-months from baseline.

Linear fit to data has slope  = −0.94 [%/year] (standard error  = 0.11, p = 0.00016). Ratios give the number of those who developed dementia to the total number of MCI participants, for each 3-year age window.

Figure 6. Estimated sample sizes with respect to age, per arm, to detect a 25% reduction in rate of change in MCI participants relative to age-matched change in HCs, at the p<0.05 level with 80% power assuming a 24 month trial with scans every six months.

Sample sizes are estimated using a linear mixed effects model with fixed intercepts (no relative change at baseline) and random slopes and linear dependence on age applied to all data available up through 36 months. Dashed lines show the 95% confidence intervals.

Figure 7. Estimated sample sizes, with respect to age, per arm, to detect a 25% reduction in rate of change in AD subjects relative to age-matched change in HCs.

Other details are as described in the caption to Figure 6.