Perrin, Richard J.

AbstractBackgroundThe balance between production, clearance, and toxicity of Ab peptides is central to AD pathobiology. Though highly variable in terms of age of symptom onset (AAO), hundreds of pathogenic variants in Presenilin‐1 (PSEN1) cause autosomal dominant forms of AD (ADAD). PSEN1 forms the catalytic core of the γ‐secretase complex and thereby directly mediates the production of longer, aggregation‐prone Aβ peptides relative to shorter, non‐aggregating peptides. We hypothesized that the broad AAO and biomarker heterogeneity seen across ADAD would be predictable based on mutation‐specific differences in γ‐secretase function, as measured by a ratio of production of shorter vs. longer Aβ species.MethodsAβ‐37, 38, 40, 42, and 43 production was quantified from 162 unique PSEN1 variants expressed in HEK293 cells engineered to lack endogenous wild‐type PSEN1/2 (Figure 1). Prediction of AAO was carried out in 107 PSEN1 variants (characterized by Liu et al, 2022) and then replicated with a set 55 unique PSEN1 variants represented in the Dominantly Inherited Alzheimer Network (DIAN; n = 190 corresponding variant carriers with detailed cognitive and biomarker data; Figure 2).ResultsMutation‐level variations in Aβ production, including a novel composite representing γ‐secretase function (lower score = less g‐processivity), from the cellular model were highly predictive of actual AAO across the 162 mutants examined (Non‐DIAN variants [N = 107]: r = 0.71, p <2.2e‐16; DIAN variants [N = 55]: r = 0.61, p = 6.10e‐07). Our cell‐based γ‐secretase function composite was strongly associated with cerebral PiB‐PET β‐amyloid burden (B[SE] = ‐0.03[0.01], p = 4.06e‐07), MRI gray matter volume (B[SE] = 44.22[6.4], p = 5.15e‐01), cerebrospinal fluid Aβ42/40 (B[SE] = 6.3e‐04[1.5e‐04], p = 4.46e‐05) and phosphorylated tau‐217 (B[SE] = ‐0.01[0.002], p = 1.98e‐05), Clinical Dementia Rating®‐ Sum of Boxes (B[SE] = ‐0.07[0.02], p = 4.86e‐05), and Mini‐Mental State Exam (B[SE] = 0.11[.03], p = 2.17e‐04).ConclusionsBiochemical variations in γ‐secretase function across PSEN1 pathogenic variants broadly predicted the cross‐sectional clinical, cognitive, and biomarker course of ADAD, including AAO. These findings elucidate the critical link between γ‐secretase function, Aβ production, and severity of AD. The novel approach designed here also represents a tool to account for heterogeneity in ADAD clinical trials and to assess the pathogenicity of PSEN1 variants of unknown significance or with limited family history.

AbstractBackgroundTriplication of the APP allele in Down syndrome (DS) leads to excess amyloid production and Alzheimer’s disease (AD) related cognitive decline. Key biomarkers (amyloid, tau, neurodegeneration) can identify pathological processes that occur before clinical symptoms and more precisely stage adults with DS along the AD continuum. Previous research has used changes in cortical thickness (CT) as an indicator of neurodegeneration in autosomal‐dominant AD1, but not DS‐related AD. It is unclear when and where cortical thinning occurs along the AD continuum in DS and if these differences are associated with increasing AD pathology.MethodCross‐sectional analysis compared DS participants from the Alzheimer Biomarkers Consortium‐Down Syndrome (106 amyloid‐/cognitively unimpaired, nonclinical, 20% reserved for receiver‐operating characteristic, ROC, analyses; 45 amyloid+/cognitively unimpaired, preclinical; 27 amyloid+/cognitively impaired, clinical) who had amyloid positron emission tomography and magnetic resonance imaging (MRI). Amyloid positivity was defined using standardized uptake value ratio (partial volume corrected) cortical mean values (1.42/1.19 for PIB/AV452) and impairment was based on consensus diagnosis. CT differences between nonclinical and clinical groups were calculated in FreeSurfer v5.3 for multiple thresholds (p<.05/.01/.005/.001/.0005/.0001) using a cluster‐wise false discovery rate of .001, corrected across hemispheres, after controlling for age and sex. CT values were extracted for each threshold and used in ROC analyses (nonclinical reserved participants compared against preclinical and preclinical compared against clinical) to identify key cortical regions that best discriminated amyloid positivity and between unimpaired and impaired.ResultSignificant decreases in parietal and inferior temporal CT were observed between nonclinical and clinical (Figures 1 and 2). ROC analyses identified regions in the left (threshold .05) and right (threshold .005) hemispheres that best differentiated nonclinical from preclinical. Observed area under the curves (AUCs) of .772 and .830 exceeded those previously reported for autosomal‐dominant AD (.547/.540)1. Analyses differentiating preclinical from clinical observed AUCs of .786 for left (threshold .0005) and .770 for right (threshold .0005) hemispheres.ConclusionCT differences primarily within posterior cortical regions differentiated adults with DS by amyloid status and cognitive impairment. CT differences were more diffuse for amyloid positivity but more focal for impairment.1. Dincer (2020). NeuroImage: Clinical, 28, 102491.2. Su (2019). Alzheimer’s Dement, 11, 180‐190.

AbstractBackgroundAdults with Down Syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia as they age. This is attributed to triplication of the amyloid precursor protein gene. Recent work demonstrated that amyloid is elevated in DS and accumulates in a similar topography to autosomal dominant AD (ADAD). Tau accumulation is the second hallmark of AD and may be measured using tau positron emission tomography (PET) imaging. The pattern of tau accumulation remains unknown in DS.MethodIn a cross‐sectional analysis we evaluated amyloid and tau positron emission tomography (PET) in 124 participants with DS (109 cognitively stable, 8 symptomatic, 7 no consensus), 29 ADAD mutation carriers (26 asymptomatic, 3 symptomatic), and 201 cognitively normal non‐mutation carriers (CN). Regional cortical standard uptake value ratios (SUVR) for tau imaging were obtained and compared by cognitive status. Similarly, regional cortical amyloid SUVR were obtained and converted to centiloids. We then compared the magnitude of tau burden as well as spatial spread of tau across groups relative to amyloid burden.ResultCompared to CN, tau PET binding was elevated in participants with (µDS = 2.12 ± 0.22 SUVR, µADAD = 2.52 ± 0.37 SUVR) and without (µDS = 1.24 ± 0.15 SUVR, µADAD = 1.16 ± 0.19 SUVR) cognitive changes. For both groups, tau increased with increasing amyloid (centiloids). In some regions, DS had greater tau burden for a given amyloid level (centiloids) (Figure 1). There was increased spatial distribution of tau throughout the brain for participants with DS compared to CN. In contrast, tau burden was more focal in participants with ADAD with tau primarily elevated in posterior regions (Figure 2).ConclusionWhile tau burden was higher with symptomatic disease for both groups, significant differences existed in the overall amount and spatial spread. Tau spread was greatest in participants with DS and more diffuse compared to ADAD. These results indicate a substantial tau burden is present in DS, and suggest not only anti‐amyloid but also tau‐reducing agents should be considered for treating cognitive decline in adults with DS.

AbstractBackgroundDisease‐modifying therapies for Alzheimer’s Disease (AD) are likely most beneficial when initiated in the pre‐symptomatic phase. To track success of such interventions fluid biomarkers became instrumental, with neurofilament light chain (NfL) showing particular promise. We previously reported that serum NfL increases in pre‐symptomatic phases of familial (autosomal‐dominantly inherited) AD (fAD) and that within‐person rate‐of‐change in NfL is an earlier predictor of fAD symptom onset compared to cross‐sectional levels. The aim of the study at hand was to extend these initial findings in a larger cohort.MethodParticipants enrolled in the Dominantly Inherited Alzheimer Network (DIAN) with matched cross‐sectional and longitudinal cerebrospinal fluid (CSF; n = 962) as well as plasma (n = 1294) samples were used. NfL measurements have been performed on the SIMOA platform using commercially available assay‐kits. To investigate the influence of physiological factors independent from AD, we first analyzed whether age and body mass index (BMI) could account for observed variation in inter‐individual CSF and plasma NfL levels considering non‐carrier family‐members (NC) as a healthy control group. Next, utilizing estimated years to symptom onset (EYO) and previously published methods (Preische et al., 2019), we determined the point in disease course when baseline and longitudinal CSF and plasma NfL concentrations started to increase in mutation carriers (MC) relative to NC, after adjusting for age and BMI.ResultOur results reveal a tight correlation of CSF and blood NfL values within MC as well as NC (figure 1A‐B). However, within NC, after correction for age and BMI, some unexplained variability remained (figure 1C). Further, a decrease of the NfL plasma/CSF ratio over age was found after correcting for BMI (figure 1D). The discrimination of MC from NC was equally good for plasma compared to CSF, being possible on the group level as early as around ‐15 to almost ‐20 EYO depending on the modelling (figure 2).ConclusionOur results support plasma equivalently to CSF NfL as a clinically useful biomarker to longitudinally track neurodegeneration in fAD. The systemic factors influencing physiological NfL values in blood should be investigated in future studies to further improve interpretation of this biomarker.

AbstractCarriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (μ) and standard deviation (σ) of standardized image intensities of T1‐weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR‐μ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1‐σ and FLAIR‐σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR‐μ decreased and T1‐σ and FLAIR‐σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity‐based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients.

Abstract Approximately 5% of Alzheimer’s disease cases have an early age at onset (&lt;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 &lt; 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 &lt; 0.001), Trail Making Test Part B (P &lt; 0.001) and digit span (P &lt; 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 &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.

AbstractINTRODUCTIONStudies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD).METHODSThree hundred twenty‐five mutation carriers (55% female) and one hundred eighty‐six non‐carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross‐sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography (11C‐PiB PET) and structural magnetic resonance imaging (MRI).RESULTSFemale carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences.DISCUSSIONOur findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD.

AbstractThe Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co‐pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI‐4 aims to address by enrolling a diverse cohort.

Abstract Brain metabolism perturbation can contribute to traits and diseases. We conducted the first large-scale CSF and brain genome-wide association studies, which identified 219 independent associations (59.8% novel) for 144 CSF metabolites and 36 independent associations (55.6% novel) for 34 brain metabolites. Most of the novel signals (97.7% and 70.0% in CSF and brain) were tissue specific. We also integrated MWAS-FUSION approaches with Mendelian Randomization and colocalization to identify causal metabolites for 27 brain and human wellness phenotypes and identified eight metabolites to be causal for eight traits (11 relationships). Low mannose level was causal to bipolar disorder and as dietary supplement it may provide therapeutic benefits. Low galactosylglycerol level was found causal to Parkinson’s Disease (PD). Our study expanded the knowledge of MQTL in central nervous system, provided insights into human wellness, and successfully demonstrates the utility of combined statistical approaches to inform interventions.