Miller, Bruce L.

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.

ObjectiveMicrotubule‐associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task‐free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers.MethodsWe compared cross‐sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed‐based analyses to examine connectivity within networks associated with the 4 most common MAPT‐associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole‐brain connectivity analyses. We applied K‐means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole‐brain connectivity profiles.ResultsSymptomatic and presymptomatic carriers had connectivity disruptions within MAPT‐syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole‐brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline.InterpretationNetwork connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632–646

ImportancePhysical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown.ObjectiveTo examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD.Design, Setting, and ParticipantsThis cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms.ExposuresBaseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity.Main Outcomes and MeasuresAnnual plasma NfL concentrations were measured with single-molecule array technology.ResultsOf 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, −22.7 to −4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, −52.2 to −8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, −43.4 to −7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training).Conclusions and RelevanceIn this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.

AbstractBackgroundFrontotemporal dementia spectrum disorders (FTD) display complex neuropathological substrates and poor clinicopathological correlations, which hinders therapy development. Plasma P‐tau217 is an emerging tool to screen for Alzheimer’s disease (AD) pathology and may have diagnostic value in FTD.MethodPlasma P‐tau217 was measured cross‐sectionally by electrochemiluminescence in FTD patients referred to ALLFTD from ARTFL (n = 628, 45.7% female, median age 66 ± 12 years). P‐tau217 differences by baseline phenotype, disease severity and genotype were determined with non‐parametric tests and general linear models. Associations between P‐tau217 and measures of disease severity and neuropsychological performance were determined with linear regressions corrected for age, sex, phenotype and APOE.ResultThe sample included 33% behavioral variant FTD, 23.6% primary progressive aphasia (PPA), 28.5% atypical parkinsonism, 1.6% amnestic dementia (AmDem), 2.8% FTD/motoneuron disease, 3% mild cognitive/behavioral impairment and 7.5% healthy controls. Only 1.6% carried FTD‐causing mutations. P‐tau217 was not related to age (r = 0.034, 95%CI ‐0.03 – 0.12, p = 0.4). Compared to controls (0.18 ± 0.07 pg/mL), P‐tau217 was elevated only in AmDem (0.58 ± 0.9 pg/mL, p = 0.001) and logopenic PPA (lvPPA, 0.71 ± 0.62 pg/mL p < 0.001). P‐tau217 ≥ 0.42 pg/mL effectively discriminated AmDem and lvPPA from all other phenotypes (AUC 0.87, 95%CI 0.77 – 0.96, p = 0.001, 77% sensitivity, 92% specificity). AmDem (60%) and lvPPA (91.7%) had the highest prevalence of high (≥ 0.42 pg/mL) P‐tau217, and the highest prevalence of APOE4 (AmDem 40%, lvPPA 63.6%). APOE4 carriers (0.23 ± 0.22 pg/mL) had higher P‐tau217, than non‐carriers (0.19 ± 0.09 pg/mL), regardless of phenotype (APOE effect p = .002, APOE x phenotype, p = 0.44). P‐tau217 was associated with worse clinical severity, mood, memory and executive function, but not with worse motor symptoms or social cognition.ConclusionWhen FTD is suspected, high plasma P‐tau217 is strongly associated with amnestic dementia and logopenic PPA phenotypes. Pending completion of ongoing neuropathological, CSF and molecular neuroimaging analyses, the data support the use of plasma P‐tau217 to identify atypical AD as a cause or AD as a co‐pathology contributing to FTD clinical presentation.

AbstractBackgroundClinical trials for tauopathies require novel biomarkers for disease detection and monitoring. One previous study found functional connectivity (FC) alterations in presymptomatic (preSx) MAPT mutation carriers (Whitwell et al., 2011), yet studies have not examined FC networks along the MAPT disease continuum. We hypothesized that both symptomatic (Sx) and preSx MAPT mutation carriers would show FC alterations compared to healthy controls (HC).MethodLeveraging task‐free fMRI data from the UCSF Memory and Aging Center and the ARTFL/LEFFTDS Consortia (Boeve et al., 2019), we compared 14 Sx and 33 preSx to 80 HC to characterize their FC profiles. Using a seed‐based approach, we studied FC within networks associated with different MAPT clinical syndromes (i.e., salience network [SN] for behavioral variant frontotemporal dementia, default mode network [DMN] for Alzheimer’s‐like amnestic syndrome, corticobasal syndrome [CBS] and progressive supranuclear palsy [PSP] networks). Complementing the seed‐based approach, we next calculated whole‐brain intra‐/inter‐network FC matrices for 14 networks (Brown et al., 2019), and applied K‐means clustering to assess whether preSx displayed heterogeneous connectivity profiles. ComBat was applied to harmonize multi‐site imaging data (Fortin et al., 2017, 2018). Thresholding was set at a joint height and extent threshold of p<0.05 (uncorrected) with age, sex, education and handedness as nuisance covariates.ResultCompared to HC, Sx featured disrupted FC within key hubs of all four networks, and regions of cerebellar and pontine hyperconnectivity within CBS and PSP networks. As seen in Sx vs. HC, preSx had similar anatomical patterns of SN/CBS network hypoconnectivity and CBS/PSP network hyperconnectivity vs. HC. In contrast to Sx, who had DMN disruption, preSx showed DMN hyperconnectivity vs. HC.Whole‐brain analyses revealed that Sx had disrupted intra‐/inter‐network FC in networks involving the insula/anterior temporal lobe. Clustering analysis identified two preSx subgroups. Compared to HC, preSx1 principally had disrupted FC across networks including those disrupted in Sx, whereas preSx2 mainly demonstrated hyperconnectivity.ConclusionSx and preSx both demonstrated robust FC alterations. Future studies will investigate whether the preSx subgroup whose whole‐brain FC was similar to Sx in that it showed principally FC disruption may be at greater risk for imminent symptom conversion and/or neurodegeneration.

AbstractBackgroundProgranulin (GRN) mutations cause autosomal dominant frontotemporal lobar degeneration. Clinical trials for GRN‐targeted therapies are underway, yet reliable biomarkers to predict onset and track disease progression remain elusive. Task‐free functional MRI (tf‐fMRI) connectivity may be more sensitive than structural measures for detecting presymptomatic changes (Dopper, 2014; Premi, 2016). Presymptomatic GRN feature tf‐fMRI hyperconnectivity that is more pronounced in older carriers presumably closer to symptom onset, suggesting hyperconnectivity may be a harbinger of disease (Lee, 2019). To aid the interpretation of hyperconnectivity, we explored relationships of structural and tf‐fMRI measures with candidate fluid biomarkers for GRN: CSF complement proteins C3b and C1q, which drive neurodegeneration in GRN ‐/‐ mice (Lui, 2016) and plasma neurofilament light chain (NfL), a marker of axonal injury.MethodWe studied 20 symptomatic GRN (Sx), 39 presymptomatic GRN (preSx), and 67 healthy‐controls (HC). Cross‐sectional CSF C3b, C1q, and plasma NfL concentrations were compared between groups. Correlations controlling for age assessed relationships between fluid biomarkers and symptom severity (CDR®+NACC‐FTLD box score). Voxelwise multiple regression models examined interactions between fluid biomarkers and gene status on grey matter probability maps (GM) and voxelwise tf‐fMRI whole‐brain weighted degree (WBD) maps.ResultComplement concentrations were similar between Sx, preSx, and HC. Across all GRN, C3b concentrations increased with symptom severity (r=0.34, p=0.04). In Sx, but not preSx, higher C3b was associated with increased WBD in medial‐frontal regions, left insula, and thalamus compared to HC. Sx had higher NfL concentrations compared to preSx and HC. Across all GRN and in Sx, higher NfL was associated with greater symptom severity (r=0.60, p<0.001; r=0.72, p<0.001). In Sx, higher NfL was associated with lower GM in precuneus and bilateral frontoinsular cortices, but not WBD, compared to HC. In preSx, higher NfL was associated with increased WBD in thalamus and right temporal regions, but not GM, compared to HC.ConclusionC3b and NfL concentrations correlated with symptom severity. C3b concentrations were associated with tf‐fMRI connectivity alterations in Sx while NfL concentrations were associated with connectivity alterations in preSx. Longitudinal studies are needed to determine temporal relationships between altered connectivity, atrophy, complement, NfL rise, and symptom onset.