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Objective Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) differ in many respects. Here, we address the issue of possible differences in fibrillar amyloid pathology as measured by positron emission tomography (PET), which remains unresolved due to the lack of large‐scale comparative studies. Methods Three hundred ninety‐nine cognitively impaired participants younger than 65 years of age from the multicenter Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and 450 cognitively impaired participants older than 65 years from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent clinical assessment, brain magnetic resonance imaging (MRI), and amyloid PET and were included in this study. We compared amyloid PET outcomes (positivity rate based on visual read and quantified tracer uptake expressed as Centiloids [CLs]) between the 2 cohorts and studied their association with age, sex, APOE genotype, and cognition. Results The amyloid positivity rate was higher in LEADS (78%, 95% confidence interval [CI] = 74–82) than in ADNI (71%, 95% CI = 67–75, p = 0.02). Lower Mini‐Mental State Examination (MMSE) and APOE4 genotype increased the odds of amyloid positivity in both cohorts. Visually positive scans had higher CLs in LEADS (EOAD, mean = 95.3 ± 26.1) than in ADNI (LOAD, mean = 80.9 ± 36.8, p < 0.0001), predominantly in parietal cortex/precuneus, superior temporal, and frontal cortices. In amyloid‐positive patients, (1) CLs were higher in female patients in both cohorts; (2) APOE4 carriership was associated with lower CLs in EOAD, which was not observed in LOAD; and (3) correlations between CLs and MMSE scores were significantly stronger in EOAD than in LOAD. Interpretation Differences in the burden of amyloid pathology may contribute to differences in clinical and anatomic patterns in sporadic EOAD and LOAD, and have implications for optimizing therapeutic strategies in each group. ANN NEUROL 2025;98:236–248

Abstract 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.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%–8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early‐onset dementia. METHODS Data from 307 cognitively normal (CN) volunteer participants and those with amyloid‐positive EOAD or amyloid‐negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed‐effects modeling. RESULTS The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD. DISCUSSION EOAD declined 2–4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease‐modifying medications. Highlights Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD.

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 Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early‐onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS We analyzed MRI scans to define the sporadic EOAD‐signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early‐onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS The EOAD‐signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD‐signature atrophy was associated with the severity of cognitive impairment. DISCUSSION The EOAD‐signature atrophy is a reliable and clinically valid biomarker of AD‐related neurodegeneration that could be used in clinical trials for EOAD. Highlights We developed an early‐onset Alzheimer's disease (EOAD)–signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD‐signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P &amp;lt; .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P &amp;lt; .001]; ADNI: t = 9.1 [P &amp;lt; .001]; HABS: t = 5.4 [P &amp;lt; .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P &amp;lt; .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

AbstractINTRODUCTIONWe used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early‐onset Alzheimer's disease (EOAD).METHODSWe included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non‐Alzheimer's disease (EOnonAD) participants from the Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel‐wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden.RESULTSEOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non‐carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non‐carriers also had greater gray matter atrophy than female ε4 carriers.DISCUSSIONThe effects of sex and APOE ε4 must be considered when studying these populations.HIGHLIGHTS Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early‐onset Alzheimer's disease (EOAD), early‐onset non‐AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

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.