Survival Differences Between Individuals With Typical and Atypical Phenotypes of Alzheimer Disease

Survival estimates for individuals with Alzheimer disease (AD) are informative to understand the disease trajectory, but precise estimates for atypical AD variants are scarce. Atypical AD variants are characterized by nonamnestic phenotypes, an early onset, and lower prevalence of APOEε4 carriership, which affect the AD trajectory. We aimed to provide survival estimates for posterior cortical atrophy (PCA), logopenic variant primary progressive aphasia (lvPPA), and behavioral AD (bvAD) and to evaluate the effect of these atypical AD diagnoses beyond known mortality determinants.

From the Amsterdam Dementia Cohort, we retrospectively selected patients with biomarker-confirmed sporadic AD presenting at the memory clinic in the mild cognitive impairment or dementia stage. Patients were classified into atypical AD phenotypes (PCA, lvPPA, bvAD; multidisciplinary consensus and retrospective case finding) and a typical AD reference group (excluding unclassifiable atypical presentations or unconfirmed future AD dementia). Survival estimates from the first visit to death/censoring (Central Public Administration) were determined (Kaplan-Meier analysis) and compared (log-rank tests) across diagnostic groups. To assess associations of atypical AD with mortality, Cox proportional hazard models were constructed including age, sex, education, MMSE score, and APOEε4 carriership (model 1), followed by adding the atypical AD group (model 2) or atypical AD variants (model 3). A likelihood ratio test was performed to compare the fit of model 1 and model 2.

A total of 2,081 patients (aged 65 ± 8 years, 52% female) were classified as typical AD (n = 1,801) or atypical AD (n = 280; PCA [n = 112], lvPPA [n = 86], and bvAD [n = 82]). 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 durations across the atypical AD variants were consistently, albeit nonsignificantly, 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). Including atypical AD improved the model fit (model 2; χ² = 8.88, p = 0.003) and was associated with 31% increased mortality risk compared with typical AD (hazard ratio [HR] = 1.31 [1.10-1.56], p = 0.002). In model 3, contributions of the variants were as follows: 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.

Survival in atypical AD (PCA, lvPPA, bvAD) was shorter compared with typical AD. These atypical variants are associated with increased mortality beyond age, sex, education, APOEε4 carriership, and disease severity. Future studies are required to address generalizability of these findings and to identify factors that explain the observed survival differences.