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Research into AD has revealed that cognitive manifestation tends to differ depending on age of onset, such that younger patients often present with worse cognitive abilities than their older counterparts until the age of 75 - with a reversal of the relationship after 75-years-old (Barnes et al., 2018). As recent work has identified a unique cognitive profile for Early-Onset Alzheimer's Disease (EOAD) relative Late-Onset Alzheimer's Disease (Hammers et al., 2025), it is unknown if the nature of the association between age and cognitive severity at presentation also differs across conditions. Cross-sectional baseline cognitive data were analyzed from 401 EOAD participants enrolled in the Longitudinal Early-Onset AD Study (Apostolova et al., 2019) and 314 LOAD participants from the Alzheimer's Disease Neuroimaging Initiative. A series of linear spline regression models were conducted with age at enrollment as the predictor and the specific domain composite score as the outcome variable, after accounting for sex and APOE ε4 status. For each model, a knot was selected at age 65, with linear regression applied to a total of two segments surrounding that single knot. As seen in Table 1, cognitive impairments (z-scores <-1.5) were common across domains for EOAD and LOAD. Significant differences existed in the slopes of Processing Speed/Attention (p=.002), Executive Functioning (p<.001), and Episodic Immediate Memory (p=.007) performance between age-segments in the model (Figure 1). For example, performance on the domain composites for Processing Speed/Attention and Executive Functioning increased significantly for EOAD participants as the age of enrollment increased (βs=0.19-0.27, ps<.001), whereas the performance for LOAD participants on these domains also increased - but to a lesser extent - as age increased. No age-relationship was observed for Episodic Delayed Memory, Language, or Visuospatial performances (ps=.06-.34). Results suggest a unique relationship between EOAD and LOAD populations for the age at enrollment and cognitive severity for executive and processing/learning domains. This supports previous findings that EOAD manifests clinically in a distinct fashion than LOAD in these domains. In the age of disease-modifying treatments, results highlight the importance of assessing for cognitive declines in individuals starting much earlier than age 65.

Background Research into AD has revealed that cognitive manifestation tends to differ depending on age of onset, such that younger patients often present with worse cognitive abilities than their older counterparts until the age of 75 – with a reversal of the relationship after 75‐years‐old (Barnes et al., 2018). As recent work has identified a unique cognitive profile for Early‐Onset Alzheimer’s Disease (EOAD) relative Late‐Onset Alzheimer’s Disease (Hammers et al., 2025), it is unknown if the nature of the association between age and cognitive severity at presentation also differs across conditions. Method Cross‐sectional baseline cognitive data were analyzed from 401 EOAD participants enrolled in the Longitudinal Early‐Onset AD Study (Apostolova et al., 2019) and 314 LOAD participants from the Alzheimer’s Disease Neuroimaging Initiative. A series of linear spline regression models were conducted with age at enrollment as the predictor and the specific domain composite score as the outcome variable, after accounting for sex and APOE ε4 status. For each model, a knot was selected at age 65, with linear regression applied to a total of two segments surrounding that single knot. Result As seen in Table 1, cognitive impairments (z‐scores <‐1.5) were common across domains for EOAD and LOAD. Significant differences existed in the slopes of Processing Speed/Attention (p=.002), Executive Functioning (p<.001), and Episodic Immediate Memory (p=.007) performance between age‐segments in the model (Figure 1). For example, performance on the domain composites for Processing Speed/Attention and Executive Functioning increased significantly for EOAD participants as the age of enrollment increased (βs=0.19‐0.27, ps<.001), whereas the performance for LOAD participants on these domains also increased – but to a lesser extent – as age increased. No age‐relationship was observed for Episodic Delayed Memory, Language, or Visuospatial performances (ps=.06‐.34). Conclusion Results suggest a unique relationship between EOAD and LOAD populations for the age at enrollment and cognitive severity for executive and processing/learning domains. This supports previous findings that EOAD manifests clinically in a distinct fashion than LOAD in these domains. In the age of disease‐modifying treatments, results highlight the importance of assessing for cognitive declines in individuals starting much earlier than age 65.

INTRODUCTION Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller‐scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. METHODS Z‐score cognitive‐domain composites for 311 amyloid‐positive sporadic EOAD and 314 amyloid‐positive LOAD participants were calculated from baseline data from age‐appropriate control cohorts. Z‐score composites were compared between AD groups for each domain. RESULTS After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. DISCUSSION Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non‐amnestic impairments in younger patients to ensure proper identification and intervention using disease‐modifying treatments. Highlights Both early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same‐aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv‐PPA), and frontal‐variant AD.

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. 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. 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). 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.

Background Widespread cognitive impairments have previously been documented in Early‐Onset Alzheimer’s Disease (EOAD) relative to cognitively normal (CN) same‐aged peers or those with cognitive impairment without amyloid pathology (Early‐Onset non‐Alzheimer’s Disease; EOnonAD; Hammers et al., 2023). Prior preliminary work has similarly observed worse cognitive performance being associated with earlier ages in EOAD participants enrolled in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS; Apostolova et al., 2019). It is unclear, however, if these age effects are seen across early‐onset conditions, and whether cognitive discrepancies among diagnostic groups are uniform across the age spectrum. The objective of the current study is to more‐extensively examine the impact of age‐at‐baseline on cognition within LEADS, with emphasis placed on the influence of diagnostic group on these associations. Method Expanded cross‐sectional baseline cognitive data from 573 participants (CN, n = 97; EOAD, n = 364; EOnonAD, n = 112) enrolled in the LEADS study (aged 40‐64) were analyzed. Multiple linear regression analyses were conducted to investigate associations between age‐at‐baseline and cognition for each diagnostic group – and their interaction among diagnoses – controlling for gender, education, APOE ε4 status, and disease severity. Result See Table 1 for demographic characteristics of our sample. Linear regression showed a significant interaction effect for the cognitive domain of Executive Functioning (p = .002). Specifically, while the EOAD group displayed a positive relationship between age‐at‐baseline and Executive Functioning performance (β = 0.08, p = .02; Figure 1), the CN group displayed a negative relationship (β = ‐0.04, p = .008) and the EOnonAD group displayed no relationship (β = ‐0.01, p = .50). A similar main‐effect for age was observed for the EOAD group when examining Visuospatial Skills (β = 0.12, p = .04), however no other age effects were evident across other diagnostic groups or cognitive domains (Episodic Memory, Language, or Speed/Attention; Table 2). Conclusion Building off preliminary work, our results suggest that executive functioning may be disproportionately impacted earlier in the disease course in participants with EOAD relative to other diagnostic groups. This finding appears to be unique to executive functioning, as it was absent in other cognitive domains and remained after accounting for disease severity. This highlights the need for further investigation into executive dysfunction early in the course of EOAD.

Background Early‐onset Alzheimer’s disease (EOAD) occurs before age 65 and has more diverse disease presentations than late‐onset AD. To improve our understanding of phenotypic heterogeneity among EOAD individuals, we analyzed cognitive scores using data‐driven statistical analysis. Method Baseline cognitive data from 286 sporadic EOAD individuals from the Longitudinal EOAD study (LEADS) were transformed to z‐scores using data from 95 cognitively normal (CN) individuals. Cognitive composites were generated for domains of memory, language, speed/attention, visuospatial, and executive function. Residuals from linear regression models on Z‐scores adjusted for age, sex, and education were obtained. Cluster analysis using the Ward method on the cognitive domain residuals was performed and scree plot using the pseudo T‐squared determined the optimal number of clusters for the EOAD sample. We also compared gray matter density (GMD) of each EOAD cluster to CN participants using voxel‐wise multiple linear regressions. Results Three clusters of cognitive performance were identified from the EOAD sample. Disease duration was not significantly different across clusters. Using a z‐score of ‐1.5 SD as the impairment threshold, all clusters were impaired across most domains (Table 1). Cluster‐3 was more impaired than cluster‐2 in all domains (Table 2; all p<.0001), and in all domains except episodic memory compared to cluster‐1 (all p<.01). Cluster‐1 (n = 71; 85.9% amnestic) was most impaired in executive function, visuospatial, and speed/attention. Cluster‐2 (n = 133; 88.7% amnestic) was most impaired in episodic memory. Cluster‐3 (n = 82; 69.5% amnestic) was most impaired in executive function, visuospatial, and speed/attention (Table 1). 3D‐comparisons showed all EOAD clusters had reduced GMD compared to CN. Cluster‐1 and cluster‐3 both showed widespread atrophy, with cluster‐3 being more severe. Cluster‐2 showed the most atrophy in the temporal and parietal lobes (Figure 1). Conclusion We identified heterogeneity in cognitive patterns among sporadic EOAD individuals. Cluster‐3 appeared to reflect widespread impairment, and cluster‐2 represented an amnestic‐only presentation. Despite comparable disease duration, some EOAD patients progress faster, while some are more resilient. 3D‐comparisons showed neurodegenerative changes affecting brain regions responsible for respective impaired cognitive functions in each cluster (e.g., cluster‐2 is primarily amnestic‐impaired and has temporoparietal atrophy). Future work should explore amyloid‐PET and tau‐PET burden.

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.

Widespread cognitive impairments have previously been documented in Early-Onset Alzheimer's Disease (EOAD) relative to cognitively normal (CN) same-aged peers or those with cognitive impairment without amyloid pathology (Early-Onset non-Alzheimer's Disease; EOnonAD; Hammers et al., 2023). Prior preliminary work has similarly observed worse cognitive performance being associated with earlier ages in EOAD participants enrolled in the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS; Apostolova et al., 2019). It is unclear, however, if these age effects are seen across early-onset conditions, and whether cognitive discrepancies among diagnostic groups are uniform across the age spectrum. The objective of the current study is to more-extensively examine the impact of age-at-baseline on cognition within LEADS, with emphasis placed on the influence of diagnostic group on these associations. Expanded cross-sectional baseline cognitive data from 573 participants (CN, n = 97; EOAD, n = 364; EOnonAD, n = 112) enrolled in the LEADS study (aged 40-64) were analyzed. Multiple linear regression analyses were conducted to investigate associations between age-at-baseline and cognition for each diagnostic group - and their interaction among diagnoses - controlling for gender, education, APOE ε4 status, and disease severity. See Table 1 for demographic characteristics of our sample. Linear regression showed a significant interaction effect for the cognitive domain of Executive Functioning (p = .002). Specifically, while the EOAD group displayed a positive relationship between age-at-baseline and Executive Functioning performance (β = 0.08, p = .02; Figure 1), the CN group displayed a negative relationship (β = -0.04, p = .008) and the EOnonAD group displayed no relationship (β = -0.01, p = .50). A similar main-effect for age was observed for the EOAD group when examining Visuospatial Skills (β = 0.12, p = .04), however no other age effects were evident across other diagnostic groups or cognitive domains (Episodic Memory, Language, or Speed/Attention; Table 2). Building off preliminary work, our results suggest that executive functioning may be disproportionately impacted earlier in the disease course in participants with EOAD relative to other diagnostic groups. This finding appears to be unique to executive functioning, as it was absent in other cognitive domains and remained after accounting for disease severity. This highlights the need for further investigation into executive dysfunction early in the course of EOAD.

INTRODUCTION Early‐onset and late‐onset Alzheimer's disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head‐to‐head comparison of cortical atrophy in EOAD and LOAD, using two large and well‐characterized cohorts (LEADS and ADNI). METHODS We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early‐stage AD), along with cognitively unimpaired participants. RESULTS After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD. DISCUSSION Our findings point to the clinical utility of MRI‐based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment. Highlights Early‐onset Alzheimer's disease (EOAD) and late‐onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia.

INTRODUCTION Recent work has identified unique cognitive profiles for early‐onset Alzheimer's disease (EOAD) relative to late‐onset Alzheimer's disease (LOAD), however, examination has been limited in determining whether the association between age and cognitive severity at presentation also differs across conditions. METHODS A series of linear spline regression models was conducted across baseline cognitive data from 325 EOAD and 314 LOAD participants, after accounting for education, sex, and apolipoprotein ε4 status. RESULTS Significant differences existed in the relationship between baseline age and cognitive performance between EOAD and LOAD samples for Processing Speed/Attention, Executive Functioning, and Episodic Immediate Memory. Younger participants from both EOAD and LOAD groups performed disproportionately worse on non‐amnestic cognitive domains, with this occurring to a greater extent in EOAD than LOAD. DISCUSSION In the age of disease‐modifying treatments, results highlight the importance of assessing for cognitive declines in individuals starting much earlier than age 65. Highlights Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants each displayed cognitive impairments relative to same‐aged peers across most domains. Both groups displayed positive relationships between impairment among non‐amnestic cognitive domains and baseline age. This relationship displayed a significantly greater effect in EOAD than LOAD, with domains of Processing Speed/Attention and Executive Functioning skills being the most pronounced. Of those participants developing AD, age displayed a disproportionate impact on their symptom onset.