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. 2025 May 27;104(10):e213603.
doi: 10.1212/WNL.0000000000213603. Epub 2025 Apr 28.

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

Ilse Bader  1   2 , Colin Groot  1   2 , Wiesje M Van Der Flier  1   2   3 , Yolande A L Pijnenburg  1   2 , Rik Ossenkoppele  1   2   4
Affiliations

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

Ilse Bader et al. Neurology. .

Abstract

Background and objectives: 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.

Methods: 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.

Results: 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: HRPCA = 1.35 (1.05-1.73), p = 0.019; HRlvPPA = 1.27 (0.94-1.69), p = 0.114; HRbvAD = 1.31 (0.94-1.83), p = 0.105.

Discussion: 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.

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Conflict of interest statement

I. Bader reports no disclosures relevant to the manuscript. C. Groot is supported by a Dementia Fellowship grant from ZonMW (10510022110010). Research programs of W.M. Van Der Flier have been funded by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health ∼ Holland, Topsector Life Sciences & Health, Stichting Dioraphte, Gieskes-Strijbis Fonds, Stichting Equilibrio, Edwin Bouw Fonds, Pasman Stichting, Stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics. W.M. Van Der Flier holds the Pasman chair. W.M. Van Der Flier is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health ∼ Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). W.M. Van Der Flier is project leader of TAP-dementia, funded by ZonMw (#10510032120003) and supported by Avid Radiopharmaceuticals, Amprion and Gieskes-Strijbis Fonds. W.M. Van Der Flier has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. W.M. Van Der Flier is a consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai. W.M. Van Der Flier participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. W.M. Van Der Flier is a member of the steering committee of EVOKE/EVOKE+ (NovoNordisk). All funding is paid to her institution. W.M. Van Der Flier is a member of the steering committee of Project Alzheimer's Value Europe and Think Brain Health. W.M. Van Der Flier was associate editor of Alzheimer, Research & Therapy in 2020/2021. W.M. Van Der Flier is associate editor at Brain. Y.A.L. Pijnenburg has received funding from the Dutch Brain Foundation, ZonMW, NWO and the Mooiste Contact Fonds (both paid to her institution). Projects of R. Ossenkoppele received support of the European Research Council, ZonMw, NWO, National Institute of Health, Alzheimer Association, Alzheimer Nederland, Stichting Dioraphte, Cure Alzheimer's fund, Health Holland, European Research Area (in Personalised Medicine), Alzheimerfonden, Hjarnfonden, Avid Radiopharmaceuticals, Janssen Research & Development, Roche, Quanterix and Optina Diagnostics. R. Ossenkoppele was speaker at symposia organized by GE Healthcare. R. Ossenkoppele is an advisory board/steering committee member for Asceneuron, Biogen and Bristol Myers Squibb. All the aforementioned has been paid to the institutions. R. Ossenkoppele is part of the editorial board of Alzheimer's Research & Therapy and the European Journal of Nuclear Medicine and Molecular Imaging. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Flow Diagram of the Study Sample
AD = Alzheimer disease; bvAD = behavioral variant AD; CBS = corticobasal syndrome; lvPPA = logopenic variant primary progressive aphasia; MCI = mild cognitive impairment; PCA = posterior cortical atrophy; SCD = subjective cognitive decline.
Figure 2
Figure 2. Kaplan-Meier Curves for Typical AD and Atypical AD
Kaplan-Meier curves show the survival curves for all atypical AD variants combined (A) and for the separate atypical AD variants (B). Vertical lines indicate the median survival durations as reported in the legend. Of note, <50% of the bvAD had deceased (i.e., 48%). AD = Alzheimer disease; bvAD = behavioral variant AD; lvPPA = logopenic variant primary progressive aphasia; PCA = posterior cortical atrophy.
Figure 3
Figure 3. Cox Proportional Hazard Models to Evaluate the Influence of Atypical AD Variants (PCA, lvPPA, and bvAD) on Mortality
Cox proportional hazard models (n = 1931, number of events = 1,195) were constructed to evaluate the impact of an atypical AD diagnosis on mortality while also exploring the associations for age, sex, education, MMSE score, and APOEε4 genotype. AD = Alzheimer disease; bvAD = behavioral variant AD; HR = hazard ratio; lvPPA = logopenic variant primary progressive aphasia; MMSE = Mini-Mental State Examination; PCA = posterior cortical atrophy.
See this image and copyright information in PMC

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