Browsing by Subject "Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS)"

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    Heterogeneous clinical phenotypes of sporadic Early‐onset Alzheimer’s disease: A data‐driven approach
    (Wiley, 2025-01-03) Putcha, Deepti; Katsumi, Yuta; Touroutoglou, Alexandra; Dage, Jeffrey L.; Eloyan, Ani; Nudelman, Kelly N.; Carrillo, Maria C.; Rabinovici, Gil D.; Apostolova, Liana G.; Dickerson, Bradford C.; Hammers, Dustin B.; LEADS Consortium; Neurology, School of Medicine
    Background: Early‐onset Alzheimer’s disease (EOAD) manifests prior to the age of 65. Clinical presentation of EOAD is distinct from that of late‐onset Alzheimer’s disease, and is characterized as having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS) described their sample as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the range of EOAD presentation, we applied a neuropsychological data‐driven method to phenotypic subtyping within the LEADS cohort. Method: Data from 169 amyloid‐positive EOAD participants with composite data in all cognitive domains (Episodic Memory, Executive Functioning, Speed/Attention, Language, and Visuospatial) were analyzed. Our approach consisted of comparing the relative levels of baseline impairment in each cognitive domain. Education‐corrected normative comparisons were made using a sample of 98 aged‐matched cognitively normal participants. A cut‐off of 1 SD below all other composite domain scores was applied to indicate a phenotype of “predominant” impairment in a given cognitive domain. Individuals were otherwise considered to have a phenotype best characterized by multidomain impairment. Result: We identified 6 phenotypic subtypes of EOAD (Table 1): Dysexecutive‐predominant (22% of sample), Amnestic‐predominant (11%), Language‐predominant (11%), Visuospatial‐predominant (15%), Mixed Amnestic/Dysexecutive‐predominant (11%), and Multidomain (30%). These subtypes did not differ on age, age‐at‐symptom‐onset, sex, or overall clinical severity (p>0.05). Groups differed on global cognitive functioning (MMSE) such that the Amnestic‐predominant group performed better than other domain‐predominant subtypes of EOAD (p>0.05). In contrast to the heterogeneity observed from our 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% were visuospatial‐predominant, and 5% were language‐predominant. Conclusion: Applying a neuropsychological data‐driven method of phenotyping EOAD individuals uncovered a more detailed understanding of the diversity of presenting heterogeneity in this atypical AD group compared to clinical judgment alone. These results suggest that clinicians and patients may over‐prioritize memory dysfunction during subjective reporting at the expense of non‐memory symptoms, which has important implications for diagnostic accuracy and treatment considerations. We plan to investigate the patterns of cortical atrophy and network dysfunction subserving this heterogeneity.
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    Longitudinal cognitive trajectories in sporadic early‐onset Alzheimer’s Disease: Findings from LEADS
    (Wiley, 2025-01-03) Hammers, Dustin B.; Eloyan, Ani; Thangarajah, Maryanne; Taurone, Alexander; Wong, Bonnie; Dage, Jeffrey L.; Nudelman, Kelly N.; Carrillo, Maria C.; Rabinovici, Gil D.; Dickerson, Bradford C.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of Medicine
    Background: Early Onset Alzheimer’s Disease (EOAD) is a rare condition that manifests prior to the age of 65, and affects approximately 5% of patients with Alzheimer’s disease. The Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS) is the largest prospectively‐evaluated cohort of participants with sporadic EOAD in the United States, initiated to better understand the features of this condition. The current analyses sought to examine longitudinal cognitive trajectories of patients with EOAD over time. Method: Data from 100 participants with amyloid‐positive EOAD, 30 participants with amyloid‐negative cognitive impairment (EOnonAD), and 65 cognitively normal age‐matched participants were compared. All had at least three study visits. Cognitive trajectories across a comprehensive cognitive battery across 24‐56 months were examined using mixed‐effects modeling, including the years of onset x diagnostic group interaction controlling for years since onset, education, sex, and the random effect of each participant. Result: Across all measures, clinical groups generally displayed declines over time, with performances for the EOAD group tending to approach the lower limit of performance ranges (Figure 1). Relatedly, significantly greater slopes of decline were seen over time for the EOAD group than the CN group across all cognitive domains evaluated (ps<.001; Table 1). When comparing between clinical groups, greater declines were also evident for the EOAD group relative to the EOnonAD group for a screener of global cognition, and for specific measures of attention, verbal fluency, processing speed, language, and delayed story recall (ps .001 to .049; Table 2). No differences in trajectory were observed between clinical groups for unstructured verbal memory, visual memory, or visuospatial skills (ps>.05; Tables 1 and 2). Conclusion: In addition to worse cognition at baseline, sporadic EOAD participants displayed pronounced declines in cognition over 24‐56 months across all domains evaluated. Relative to the EOnonAD group, cognitive trajectories appear to be worse predominantly for executive and attentional processes, with variability across episodic memory tasks. This suggests that EOAD pathology is not solely directed at memory functioning. Future research will focus on comparing cognitive trajectories of EOAD and late‐onset AD, in an effort to understand similarities and differences in the types and rates of cognitive trajectories.