Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer's disease: a neuropsychological data-driven approach

Abstract

Background: The clinical presentations of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort.

Methods: Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of "predominant" impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes.

Results: We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia.

Conclusion: A neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations.

Keywords: Alzheimer’s disease; Clinical; Cognition; Early-onset; Neuropsychology; Phenotypes; Variants.

Fig. 1

Schematic of phenotypic classifications based on neuropsychological data. The top row delineates the cognitive composite z-scores (Executive Function, Episodic Memory, Language, and Visuospatial). SD = standard deviation

Fig. 2

Phenotypic variants of EOAD. A comparison of EOAD phenotypic variants derived from (A) a neuropsychological data-driven approach and (B) a clinical judgment based approach. Percent of the total sample is graphed by phenotypic classification in both approaches. PCA = Posterior Cortical Atrophy. PPA = Primary Progressive Aphasia

Fig. 3

Schematic depiction of EOAD diagnostic classifications by method. The left side of the figure lists the four diagnostic variants of EOAD based on clinical judgment and the right side lists the six data-drive phenotypic variants of EOAD. The colors within this schematic are linked to the diagnoses made by clinical judgment, and can be used to visually link what proportion of each diagnosis made by clinical judgment comprises each of the six neuropsychological data-driven phenotypic variants. PCA = Posterior Cortical Atrophy. PPA = Primary Progressive Aphasia

Fig. 4

Neuropsychological profile of 6 distinct EOAD phenotypic variants. Normalized data (z-scores) are shown in each cognitive domain for each distinct EOAD phenotypic variant (DYS = Dysexecutive Predominant, AMN = Amnestic Predominant, LANG = Language Predominant, VSP = Visuospatial Predominant, MIXED = Mixed Amnestic/Dysexecutive, and MULTI = Multidomain). For visualization purposes, data were excluded from six extreme outlier datapoints defined as greater than 3 standard deviations from the mean (5 individuals labeled as Language Predominant and 1 labeled as Visuospatial Predominant). Full reporting of means and standard deviations inclusive of these individuals is included in the Supplementary Materials

Fig. 5

Spatial topography of cortical atrophy in 6 distinct neuropsychological data-driven EOAD phenotypic variants based on neuropsychological test profiles. Colored vertices on the cortical surface maps indicate areas where EOAD participants, on average, showed greater atrophy than cognitively normal control participants at a vertex-wise threshold of W < -0.75

Fig. 6

Spatial topography of cortical atrophy in 4 EOAD phenotypes based on clinical judgment. Colored vertices on the cortical surface maps indicate areas where EOAD participants, on average, showed greater atrophy than cognitively normal control participants at a vertex-wise threshold of W < 0.75