Johnson, Erik C. B.

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.

Importance Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P &amp;lt; .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P &amp;lt; .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration ClinicalTrials.gov Identifier: NCT04623242

Abstract The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN, MAPT) compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. ‘Hub’ proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

AbstractBackgroundThe pathophysiological mechanisms driving frontotemporal lobar degeneration (FTLD) disease progression and corresponding biomarkers that capture these changes are not fully understood. We leveraged high‐throughput proteomics to identify networks of co‐expressed CSF proteins and candidate biomarkers for prediction of disease progression in adults with autosomal dominant FTLD mutations.Method113 adults carrying autosomal dominant FTLD mutations (C9orf72/GRN/MAPT) and 38 noncarrier controls from the ALLFTD consortium completed baseline lumbar puncture and longitudinal neuropsychological testing. CSF was assayed for SOMAmer proteomics on SOMAscan® v3.0 (4,140 proteins). Network analysis identified weighted protein co‐expression modules, which were annotated via gene ontology and cell‐type enrichment analysis. Disease age estimates that capture proximity to symptom onset were derived from a Bayesian disease progression model incorporating genotype‐specific clinical (cognition, CDR®+NACC FTLD) and biomarker (brain volume, plasma NfL) information. At baseline, local‐weighted regression examined module z‐scores (based on mean/SD of module levels [first principal component] in noncarriers) in relation to disease age. Longitudinal linear mixed‐effects models examined global cognitive trajectories in relation to baseline module z‐scores, as well as individual proteins within prognostic modules.ResultNetwork analysis identified 32 CSF protein co‐expression modules (37 to 223 proteins/module). 16 modules showed mutation‐related deviations from noncarriers. Deviations in ion transport, neurodevelopmental, metabolic, and transcriptional modules occurred several decades before estimated symptom onset (disease age: ‐30 to ‐20 years) and persisted across disease age. Deviations in neuroinflammatory and ubiquitination/autophagy modules occurred ∼10 years before estimated symptom onset. Sharp deviations in RNA binding, protein phosphorylation, neurogenesis, synaptic function, and lysosomal modules occurred near symptom onset (disease age: ‐1 to 4 years). Baseline synaptic and neurogenesis modules were the strongest prognosticators of cognitive decline (module x time: bs>.10, ps<.05). Within these modules, individual proteins with stronger intramodular connectivity exhibited stronger associations with cognitive decline (e.g., synaptic/transmembrane module: r = .40, p = 2.85e‐6; e.g., EPHA5, LRRTM2).ConclusionLarge‐scale analysis of the CSF proteome reveals a biologically‐diverse landscape of protein networks associated with presymptomatic and symptomatic stages of autosomal dominant FTLD. Synaptic and neuron‐enriched protein networks exhibited prodromal deviations that forecasted incipient cognitive decline. ‘Hub’ proteins derived from these affected networks warrant further validation as candidate biomarkers for early FTLD disease progression.

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.

Abstract Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.