Hassenstab, Jason

Abstract The grey matter of the brain develops and declines in coordinated patterns during the lifespan. Such covariation patterns of grey matter structure can be quantified as grey matter networks, which can be measured with magnetic resonance imaging. In Alzheimer’s disease, the global organization of grey matter networks becomes more random, which is captured by a decline in the small-world coefficient. Such decline in the small-world value has been robustly associated with cognitive decline across clinical stages of Alzheimer’s disease. The biological mechanisms causing this decline in small-world values remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and small-world coefficient in mutation carriers (N = 219) and non-carriers (N = 136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Amyloid beta, Tau, synaptic (Synaptosome associated protein-25, Neurogranin) and neuronal calcium-sensor protein (Visinin-like protein-1) preceded loss of small-world coefficient by several years, while increased levels in CSF markers for inflammation (Chitinase-3-like protein 1) and axonal injury (Neurofilament light) co-occurred with decreasing small-world values. This suggests that axonal loss and inflammation play a role in structural grey matter network changes.

AbstractINTRODUCTIONWe investigated longitudinal associations between self‐reported exercise and Alzheimer's disease (AD)‐related biomarkers in individuals with autosomal dominant AD (ADAD) mutations.METHODSParticipants were 308 ADAD mutation carriers aged 39.7 ± 10.8 years from the Dominantly Inherited Alzheimer's Network. Weekly exercise volume was measured via questionnaire and associations with brain volume (magnetic resonance imaging), cerebrospinal fluid biomarkers, and brain amyloid beta (Aβ) measured by positron emission tomography were investigated.RESULTSGreater volume of weekly exercise at baseline was associated with slower accumulation of brain Aβ at preclinical disease stages β = –0.16 [–0.23 to –0.08], and a slower decline in multiple brain regions including hippocampal volume β = 0.06 [0.03 to 0.08].DISCUSSIONExercise is associated with more favorable profiles of AD‐related biomarkers in individuals with ADAD mutations. Exercise may have therapeutic potential for delaying the onset of AD; however, randomized controlled trials are vital to determine a causal relationship before a clinical recommendation of exercise is implemented.Highlights Greater self‐reported weekly exercise predicts slower declines in brain volume in autosomal dominant Alzheimer's disease (ADAD). Greater self‐reported weekly exercise predicts slower accumulation of brain amyloid beta in ADAD. Associations varied depending on closeness to estimated symptom onset.

Abstract This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer’s disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating® (CDR®). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR®. Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.

Abstract Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer’s disease (AD). Computational simulations and animal experiments have hinted at the theory of activity-dependent degeneration as the cause of this hub vulnerability. However, two critical issues remain unresolved. First, past research has not clearly distinguished between two scenarios: hub regions facing a higher risk of connectivity disruption (targeted attack) and all regions having an equal risk (random attack). Second, human studies offering support for activity-dependent explanations remain scarce. We refined the hub disruption index to demonstrate a hub disruption pattern in functional connectivity in autosomal dominant AD that aligned with targeted attacks. This hub disruption is detectable even in preclinical stages, 12 years before the expected symptom onset and is amplified alongside symptomatic progression. Moreover, hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in amyloid-beta positron emission tomography cortical markers, consistent with the activity-dependent degeneration explanation. Taken together, our findings deepen the understanding of brain network organization in neurodegenerative diseases and could be instrumental in refining diagnostic and targeted therapeutic strategies for AD in the future.

Abstract Approximately 5% of Alzheimer’s disease patients develop symptoms before age 65 (early-onset Alzheimer’s disease), with either sporadic (sporadic early-onset Alzheimer’s disease) or dominantly inherited (dominantly inherited Alzheimer’s disease) presentations. Both sporadic early-onset Alzheimer’s disease and dominantly inherited Alzheimer’s disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer’s disease and dominantly inherited Alzheimer’s disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer’s disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer’s Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer’s disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50–70 cerebellar grey reference and FDG30–60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer’s disease, sporadic early-onset Alzheimer’s disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen’s d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer’s V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer’s disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer’s disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer’s disease versus sporadic early-onset Alzheimer’s disease. Sporadic early-onset Alzheimer’s disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer’s disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer’s disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer’s disease.

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 < .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 < .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

ImportanceFrontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD.ObjectiveTo evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations.Design, Setting, and ParticipantsIn this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)–based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes.ExposureParticipants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests.Main Outcomes and MeasuresInternal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy.ResultsIn the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, −2.49 [95% CI, −0.19 to −0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = −0.49 [95% CI, −0.72 to −0.25]; P < .001) but not a composite of traditional neuropsychological measures (β = −0.14 [95% CI, −0.42 to 0.14]; P = .32).Conclusions and RelevanceThe findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

AbstractINTRODUCTIONIncreasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double‐blind phase 3 DIAN‐TU‐001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab.METHODSWe used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker.RESULTSLC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid‐no‐change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid‐reduction class exhibited reductions in the annual decline rates compared to the amyloid‐growth class across multiple biomarker, clinical, and cognitive outcomes.DISCUSSIONLC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials.Highlights We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid‐reduction class exhibited remarkably better outcomes compared to the amyloid‐growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects.

Abstract Approximately 5% of Alzheimer’s disease cases have an early age at onset (<65 years), with 5–10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer’s disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer’s disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer’s disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer’s disease enrolled at the University of California San Francisco Alzheimer’s Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer’s disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P < 0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer’s disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer’s disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.

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 < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .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 < .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.