An atypical phenotype is a risk factor for higher mortality in Alzheimer’s disease
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Survival estimates for individuals with Alzheimer’s disease (AD) are informative to understand the full disease trajectory, but precise estimates for atypical AD variants are scarce. Atypical AD variants are characterized by non-amnestic phenotypes, an early-onset and lower prevalence of APOE ε 4 -carriership, which are all possible modulators of clinical trajectories. We aimed to provide survival estimates for posterior cortical atrophy (PCA; “visual-AD”), logopenic variant primary progressive aphasia (lvPPA; “language-AD”) and behavioral-AD (bvAD), and to evaluate the effect of phenotypical atypicality beyond known mortality-determinants.
Methods
This observational study included 2081 amyloid-positive patients (age 65±8 years) from the Amsterdam Dementia Cohort classified as typical AD (n=1801) or atypical AD (n=280; PCA [n=112], lvPPA [n=86], and bvAD [n=82]). Survival estimates from first-visit (∼time-of-diagnosis) to death/censoring (Central Public Administration) were determined (Kaplan-Meier analysis) and compared (Log-Rank tests) across diagnostic groups. To assess effects of atypical AD on mortality, cox proportional-hazard models were performed including age, sex, education, MMSE-score and APOE ε 4 -carriership (model-1), followed by adding the atypical AD group (model-2) or atypical AD variants individually (model-3), while using typical AD as reference. A likelihood ratio test was performed between model-1 and 2 to assess whether atypical AD improved the model-fit.
Results
The estimated median survival time for atypical AD of 6.3 years (95%CI: [5.8-6.9]) was shorter than for typical AD (7.2[7.0-7.5], p=0.02). Median survival times across the atypical AD variants were consistently shorter (PCA: 6.3[5.5-7.3], p=0.055); lvPPA: 6.6[5.7-7.7], p=0.110; bvAD: 6.3[5.0-9.1], p=0.121, 48% deceased). In cox proportional-hazards model-1, male sex (HR=1.46[1.30-1.64], p<0.001), age (HR=1.02[1.01-1.03], p<0.001), and MMSE (HR=0.94[0.93-0.96], p<0.001) were associated with increased mortality risk. APOE ε 4 heterozygosity was associated with reduced mortality risk compared to non-carriers (HR=0.85[0.74-0.97], p=0.015). In model-2, atypical AD improved the model fit (model 2; χ²=8.88, p=0.003) and was associated with 31% increased mortality risk compared to typical AD (HR=1.31[1.10-1.56], p=0.002). In model-3, contributions of the variants were: HR PCA =1.35[1.05-1.73], p=0.019; HR lvPPA =1.27[0.94-1.69], p=0.114; HR bvAD =1.31[0.94-1.83], p=0.105].
Conclusions
Survival in atypical AD was shorter compared to typical AD. Atypicality appears an important risk factor for mortality beyond age, sex, education, APOE ε 4 -carriership and disease severity.
Trial registration information
NA.
