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Abstract 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.

AbstractBackgroundWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use at the midway point of data collection of the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS). We compared amyloid‐positive early‐onset Alzheimer’s disease (EOAD) participants and amyloid‐negative early‐onset non‐Alzheimer’s disease [EOnonAD]) participants across NPS domains and psychotropic medication categories.Method282 participants enrolled in LEADS were compared across diagnostic groups – amyloid‐positive EOAD (n = 212) and amyloid‐negative EOnonAD (n = 70). All participants were between ages 40 and 64 at baseline. NPS were measured with the Neuropsychiatric Inventory – Questionnaire (NPI‐Q) and Geriatric Depression Scale – Short Form (GDS‐SF). Medications were categorized into psychotropic category (e.g., antidepressants, antipsychotics, benzodiazepines). Groups were compared on NPI‐Q using binary logistic regression adjusting for sex and disease severity, on GDS‐SF using linear regression adjusting for sex and disease severity, and on psychotropic medication use using Chi square or Fisher’s exact test.ResultDemographic data are presented in Table 1. Average total NPI‐Q score was higher in EOnonAD than EOAD (p = .002, ŋp 2 = .03). Regardless of diagnostic group, informants endorsed Affective behaviors most frequently (76.2%). EOAD informants endorsed fewer Distress‐Tension behaviors (p = .02, OR = .498) and Impulse Control behaviors (p = .01, OR = .438). EOAD informants also endorsed apathy (p < .001, OR = .316), irritability (p = .02, OR = .498), and disinhibition (p = .04, OR = .476) at lower frequency than EOnonAD. GDS‐SF showed that the EOnonAD participants self‐reported more symptoms of depression than the EOAD group (p = .002, ŋp 2 = .03). (Table 2A). A minority of participants, regardless of diagnostic group, reported psychotropic medication use (35%). There was higher use in EOnonAD (38%) than EOAD (24%) (p = .03, Cohen W = .14) (Table 2B).ConclusionNPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants, despite EOnonAD being less severely impaired. LEADS continues to collect data. Future studies will examine etiologies that may be larger drivers of NPS than AD neuropathology, mediators (e.g., race, ethnicity) in the association between NPS and diagnostic group classication, compare NPS in EOAD vs. LOAD, and examine longitudinal changes in neuropsychiatric profiles.

Abstract INTRODUCTION We aimed to describe baseline amyloid‐beta (Aβ) and tau‐positron emission tomograrphy (PET) from Longitudinal Early‐onset Alzheimer's Disease Study (LEADS), a prospective multi‐site observational study of sporadic early‐onset Alzheimer's disease (EOAD). METHODS We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)‐PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ−) based on the combination of visual read by expert reader and image quantification. RESULTS 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid‐PET; 231 (95.1%) of them were tau‐PET positive (A+T+). Tau‐PET signal was elevated across cortical regions with a parietal‐predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau‐PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS 72% of patients with clinical EOAD were positive on both amyloid‐ and tau‐PET. Amyloid‐positive patients with EOAD had high tau‐PET signal across cortical regions. In EOAD, tau‐PET mediated the relationship between amyloid‐PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau‐PET.

AbstractINTRODUCTIONThe Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early‐onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD.METHODSWe transcribed RAVLT recordings from 303 subjects in the Longitudinal Early‐Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J‐curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables.RESULTSCompared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter‐syndromic differences were noted with raw score, primacy, recency, J‐curve, and stopping time.DISCUSSIONRAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores.Highlights RAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing‐based scores add value over traditional count‐based scores

Abstract INTRODUCTION We compared white matter hyperintensities (WMHs) in early‐onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early‐onset amyloid‐negative cognitively impaired (EOnonAD) groups in the Longitudinal Early‐Onset Alzheimer's Disease Study. METHODS We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t ‐tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. RESULTS EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. DISCUSSION EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. Highlights This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early‐onset amyloid‐negative cognitively impaired (EOnonAD) groups across all brain regions.

AbstractIntroductionOne goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early‐onset Alzheimer's disease (EOAD).MethodsCerebrospinal fluid (CSF) concentrations of Aβ1‐40, Aβ1‐42, total tau (tTau), pTau181, VILIP‐1, SNAP‐25, neurogranin (Ng), neurofilament light chain (NfL), and YKL‐40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated.ResultsBiomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP‐25, and Ng in EOAD differed significantly from cognitively normal and early‐onset non‐AD dementia; NfL, YKL‐40, and VILIP‐1 did not. Across groups, all biomarkers except SNAP‐25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP‐25 were correlated with at least one cognitive measure.DiscussionThis study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

AbstractIntroductionWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early‐onset Alzheimer's disease (EOAD; onset 40‐64 years) at the midway point of data collection for the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS).MethodsBaseline NPS (Neuropsychiatric Inventory – Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups – amyloid‐positive EOAD (n = 212) and amyloid negative early‐onset non‐Alzheimer's disease (EOnonAD; n = 70).ResultsAffective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD.DiscussionOverall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late‐onset AD.

AbstractObjectiveThe Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early‐onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data‐collection mid‐point.MethodsData from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid‐positive EOAD [n = 212], and amyloid‐negative early‐onset non‐Alzheimer's disease [EOnonAD; n = 70]).ResultsCognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures.ConclusionsWe present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant.HIGHLIGHTS Findings represent the most comprehensive baseline characterization of sporadic early‐onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.

AbstractOBJECTIVEInvestigation of learning slopes in early‐onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early‐onset dementia with and without β‐amyloid positivityMETHODData from 310 participants in the Longitudinal Early‐Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determinedRESULTSWorse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric—the learning ratio (LR)—outperformed other learning slope calculations across analysesCONCLUSIONSLearning slopes appear to be sensitive to early‐onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses.Highlights Learning is impaired in amyloid‐positive EOAD, beyond cognitive severity scores alone. Amyloid‐positive EOAD participants perform worse on learning slopes than amyloid‐negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.