Petersen, Ronald C.

AbstractBackgroundKnowledge of the temporal evolution among plasma Alzheimer’s biomarkers and PET will inform disease pathophysiology and appropriate implementation of plasma biomarkers (Therneau, NeuroImage 2021; Betthauser, Brain 2022). This study investigates the relative timing of progression of plasma p‐tau181, p‐tau217, GFAP, and amyloid PET on individual and population levels.MethodWe included 957 participants from the Mayo Clinic Study of Aging with clinical diagnoses of cognitively unimpaired (n = 732), MCI (n = 205), and Alzheimer’s clinical syndrome dementia (n = 20). An accelerated failure time (AFT) model was fit with amyloid (PiB) PET, plasma p‐tau217 (Meso Scale Discovery, Lilly), plasma p‐tau181, and GFAP (Simoa, Quanterix HD‐X) as quad‐variate endpoints, and sex, APOE genotype status, and education as covariates. The model output included a per subject adjustment or time‐shift for each biomarker indicating how much earlier or later it was estimated to progress relative to the average participant, the correlation (R) between adjustments for each pair of biomarkers, and the impact of covariates on each biomarker’s timing. Secondly, we estimated progression at a given age for selected cutpoints.ResultTemporal trajectories for each biomarker are shown in Figure 1. Individual‐level adjustments between plasma p‐tau217 and amyloid PET were highly correlated, R = 0.69(0.64‐0.74); how early or late an individual progressed on plasma p‐tau217 explained 48% of the variation in relative timing of amyloid PET progression. Associations of plasma p‐tau181 and GFAP with amyloid PET individual adjustments were moderate and low, respectively (Figure 2). Using the chosen cutpoints, the estimated order of biomarker progression was GFAP, amyloid PET, plasma p‐tau181, and plasma p‐tau217 (Figure 3).ConclusionOn the individual level, the strong association of the relative timing of progression of plasma p‐tau217 and amyloid PET supports that these processes are mechanistically related. The relatively lower associations of the timing of p‐tau181 and GFAP with amyloid PET likely reflect a lower biological association and greater measurement noise for p‐tau181. The individual adjustments, the primary output of this model, are independent of cutpoints. On the population level, relative timing of biomarker change is highly dependent on the cutpoints applied. This true for any analysis that employs cutpoints, regardless of the approach.

AbstractBackgroundPredictive models of tau‐PET accumulation have largely relied on the functional connectome to estimate its spatial patterns in Alzheimer’s disease (AD). Patterns of global functional organization represent a promising avenue as they encapsulate many biological properties relevant to neurodevelopment, cognition and degeneration. We compared approaches based on local connectivity (from task‐free fMRI) and global organization (from FDG‐PET) to predict regional tau‐PET across AD phenotypes.MethodWe included 430 cognitively unimpaired (CU) individuals (214 A+T‐, 216 A+T+) and 62 amnestic mild cognitive impairment (aMCI), 64 amnestic AD, 21 dysexecutive AD (dAD), 41 logopenic progressive aphasia (LPA) and 49 posterior cortical atrophy (PCA) patients (all A+T+) from the Alzheimer’s Disease Research Center, Mayo Clinic Study of Aging, and Neurodegenerative Research Groups (referred to as “Mayo cohort”). The connectivity approach consisted of assessing the relationship between a region’s tau level and its functional connectivity to the region of highest tau (epicenter). The global organization approach consisted of 1) performing a principal component analysis on 3000 FDG‐PET images that did not overlap with the Mayo cohort, 2) projecting FDG‐PET images of the Mayo cohort onto the low‐dimensional space generated in Step 1 and extracting corresponding weighted values across the first 100 components, 3) using these weighted values as predictors of regional tau‐PET in a linear model and determining optimal parameters based on predicted R 2 values, and 4) using the parameters from the model built in Step 3 to predict tau‐PET in the ADNI cohort (n = 86) (Fig.2).ResultThe connectivity‐based approach yielded adjusted R 2 values ranging from 0.19‐0.45 across diagnostic groups (Fig.1). The global organization approach yielded averaged adjusted R 2 and predicted R 2 values of 0.71 and 0.63, respectively, in the Mayo cohort. Out‐of‐sample median R 2 in the ADNI cohort was 0.41 (range 0.10‐0.60) (Fig.3).ConclusionAn unbiased approach based on the global functional organization of the brain and using an imaging modality widely used in clinical settings outperformed a connectome‐based one to predict regional tau‐PET across the AD phenotypic spectrum. Patterns of tau accumulation may better relate to the large‐scale physiology of the brain underlying specific mental functions rather than local connectivity factors.

AbstractBackgroundWhite matter (WM) plays an important role in cognitive function and undergoes substantial changes due to aging and increase in AD and AD related dementia (AD/ADRD) pathologies. While recent work proposed measurement of global WM changes from diffusion MRI as biomarkers for Cerebrovascular disease (CVD) such as PSMD and free water, there needs to be a better understanding of WM changes due to AD/ADRD pathologies. The goal of our recent work was to understand white matter changes with CVD and AD – common pathologies in AD/ADRD ‐ utilizing data from Mayo Clinic Study of Aging and Mayo ADRC.MethodUsing diffusion MRI (dMRI) in 718 participants from Mayo Clinic Study of Aging (mean age = 71.1 years, 56% male), we investigated relationships between commonly used dMRI measures and vascular risk as well as global amyloid PET. In a subset of 233 participants who were amyloid‐PET positive and also competed Tau‐PET (flortaucipir) from Mayo Clinic Study of Aging and Mayo ADRC, we investigated associations between regional flortaucipir SUVRs in Braak stages and regional WM changes.ResultsWe found greater frontal lobe WM damage with increasing vascular risk across all dMRI measures. We previously validated the strong relationship between the genu of the corpus callosum (anterior interhemispheric connections) dMRI measurements made on antemortem scans and cerebrovascular pathology observed on postmortem tissue (Nguyen et. al. Acta Neuropathologica 2022) supporting the utility of genu of the corpus callosum dMRI measures as a potential CVD biomarker. Also, we found greater posterior WM damage with increasing amyloid burden. Among the 233 amyloid positive participants, we found spatially dependent WM degeneration associated with regional flortaucipir SUVRs in Braak stages with greater extent of posterior WM damage. Further, dMRI measurements of the WM damage provided complementary information about disease staging and progression of AD in addition to flortaucipir SUVR measurements.ConclusionsAnterior WM measurements may be more specific to CVD and posterior WM changes are seen with increasing AD pathological burden. Our results suggest that WM changes observed with CVD and typical AD may be different and have clinical utility for differential diagnosis and disease staging.

AbstractBackgroundInter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, and maintenance of the blood‐brain‐barrier (BBB) properties. The breakdown of BBB in Alzheimer’s disease (AD) is well‐established, but precise underlying molecular changes remain unclear. Additionally, whether GVU molecular alterations observed in AD brains are also detected in blood from living patients is unknown. Further, these GVU molecular perturbations require further investigation in different model systems to identify both human brain‐specific and cross‐species conserved alterations. In this study, we investigated prioritized GVU molecules altered in AD brains for their conservation in blood and cross‐species model systems.MethodsWe performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in AD and control brains. We analyzed this data to detect cell‐specific GVU molecular perturbations and their interactions. We investigated molecular interactions between vascular and astrocyte clusters, the major cell types of the GVU of the BBB. To determine whether GVU transcriptional alterations detected in the brain are preserved in the blood, existing blood expression, genetic, and neuroimaging data from two longitudinal antemortem cohorts were analyzed. Using model systems, including mouse, drosophila, and zebrafish, we evaluated the cross‐species conservation of the top GVU alterations detected in AD brains.ResultsBrain snRNAseq revealed transcriptional profiles of 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as pericytes, endothelia and perivascular fibroblasts. We identified differentially expressed genes and their enriched pathways within these clusters and observed the highest levels of transcriptional changes within pericytes. Vascular targets that interact with astrocytic ligands have biological functions in cell signaling, angiogenesis, amyloid ß metabolism, and cytoskeletal architecture. We discovered that genetic variants influencing blood expression levels of some of the prioritized GVU genes were associated with neuroimaging burden of cerebrovascular disease in living human cohorts. Our ongoing studies in model systems revealed conservation of some of the top prioritized molecular perturbations across species.ConclusionOur findings prioritized by multiscale, cross‐tissue human data revealed GVU perturbations within interacting pericyte and astrocyte molecules, which are conserved across multiple cross‐species models. These results nominate new molecular targets and mechanistic insights for BBB disruptions in AD.

AbstractBackgroundIncreasing evidence suggests that transactive response DNA‐binding protein 43 (TDP‐43) pathology in Alzheimer’s Disease (AD), or AD‐TDP, can be diffuse or limbic‐predominant. Understanding whether diffuse AD‐TDP has genetic, clinical, and pathological features that differ from limbic AD‐TDP could have clinical and research implications. We aimed to better characterize the clinicopathologic features of diffuse AD‐TDP and differentiate it from limbic‐predominant AD‐TDP pathology.MethodThree hundred sixty‐three participants were prospectively recruited and followed in the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group and died between May 1999 and August 2021. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. At postmortem evaluation, they showed Alzheimer’s disease neuropathologic changes and TDP‐43‐immunoreactive inclusions. The distribution of TDP‐43 pathology was assessed using the Josephs 6‐stage scheme. Participants with TDP‐43 stages 1‐3 were classified as Limbic, while those with stages 4‐6 were classified as Diffuse. Neuropathologically defined frontotemporal lobar degeneration cases were excluded. Multivariable logistic regression was used to identify clinicopathological features that predicted diffuse TDP‐43 pathology at postmortem. We hypothesized that the Diffuse group would show impairment in cognitive domains beyond episodic memory and more hippocampal sclerosis.ResultsThe cohort was 61% female and old at onset (median:76 years [IQR:70‐82]) and death (median:88 years [IQR:82‐92]). Fifty‐four percent (n = 197) were classified as Limbic and 46% (n = 166) as Diffuse. A “clinical” multivariate logistic regression fit to 85 participants with all clinical variables of interest showed that later age at onset (OR:1.09, 95%CI:1.01‐1.19;P = 0.03), longer disease duration (OR:1.17, 95%CI:1.02‐1.36;P = 0.03) and higher Neuropsychiatric Inventory scores (OR:1.14, 95%CI:1.01‐1.28;P = 0.03) all independently increased the odds of being Diffuse, while higher Trails Making Test‐B (OR:0.99, 95%CI:0.98‐0.99;P = 0.02) and Block Design Test scores (OR:0.91, 95%CI:0.85‐0.99;P = 0.023) independently decreased the odds of being Diffuse. A “pathology” multivariate logistic regression fit to 233 cases with all neuropathological data revealed that widespread amyloid‐β pathology corresponding to Thal phases 3‐5 all significantly decreased the odds of diffuse pathology by 80‐90%, while hippocampal sclerosis increased it sixfold (OR:6.18, 95% CI:2.93‐13.03;P<0.001).ConclusionsDiffuse AD‐TDP shows clinicopathological features that differ from Limbic AD‐TDP, which could have public health implications relating to treatment and research on AD and dementia.

AbstractBackgroundTwo major risk factors of Alzheimer’s disease (AD) are advanced age and the APOE‐ε4 risk allele. However, despite having these risk factors, some individuals escape from developing AD or have slower cognitive decline. In this study we hypothesized that “resilient” individuals, defined as those who remain cognitively normal despite being >80 years‐old and carrying at least one copy of the APOE‐ε4 allele, have concerted changes in their blood transcriptomes that are associated with resilience to AD.MethodWe generated blood RNA‐sequence data from 105 APOE‐ε4 carriers from the Mayo Clinic Study of Aging (MCSA) who remained cognitively normal after age 80 (resilient), or who developed mild cognitive impairment (MCI) or AD (non‐resilient). Weighted gene co‐expression network analysis (WGCNA) was performed to evaluate the association of the blood co‐expression network with primary phenotypes of resilience and memory scores. To validate our findings, we constructed a consensus co‐expression network using both MCSA and a replication cohort of blood microarray data from 91 Alzheimer’s Disease Neuroimaging Initiative (ADNI) study participants who had a similar demographic profile. We annotated the consensus modules for their enrichment of cell types, biological processes, genes within previously published genome‐wide significant (GWS) AD‐associated loci, and genes that reside in consensus modules built from seven brain regions across three different autopsy cohorts. To identify genetic variants regulating blood consensus module co‐expression, we performed module quantitative trait locus (modQTL) analysis.ResultWe found co‐expression modules significantly (q<0.05) correlated with the memory phenotype, logical memory delayed recall, across both MCSA and ADNI cohorts. Some of these modules were enriched with blood cell types and biological processes, including telomere maintenance, mitochondrial functions, and immune response. We found 1 module significantly (q<0.05) enriched with genes near GWS AD‐associated loci and 4 modules with genes in brain consensus modules. Lastly, we found 8 modQTLs significantly (Bonferroni‐p<0.05) associated with the co‐expression of 5 different modules.ConclusionWe identified blood co‐expression modules, biological pathways and specific genetic variants associated with cognitive resilience in the presence of AD risk factors. This study provides novel insights into the potential role of peripheral blood in the development of and resilience to AD.

Abstract Background Early diagnosis of Alzheimer’s disease (AD) is crucial for ensuring patients have timely access to essential care. Given the symptoms of early AD are often subtle, it is important that both primary care physicians (PCPs) and neurologists are able to diagnose their patients. Several sources of evidence have indicated that most PCPs and neurologists lack knowledge, competence, and confidence regarding recognition of early forms of AD. To address the clinical practice gaps, a series of CME‐certified programs covering the symptoms, assessment, and diagnosis of early forms of AD were developed. Method The data presented here are based on outcomes from four online CME‐certified multimedia programs housed on a single destination page. Each CME‐certified program utilized expert physicians to educate learners on recognizing early forms of AD. Each CME program asked a series of pre‐post questions designed to assess immediate changes in knowledge, competence, or confidence. The questions were grouped into clinically relevant themes. The educational effect for all of the programs was determined by using a paired‐samples t‐test to identify significant differences between pre‐ and post‐assessment responses for each question. Data across all four programs were collected from February 2022 through December 2022. All four programs were promoted to an audience of US‐ and ex‐US physicians. Result Participation across the four programs ranged from 543 to 2,510 PCPs and 256 to 1,025 neurologists. PCPs and neurologists demonstrated significant (P<0.05) pre‐vs post education improvements on the following themes: biomarkers in AD, clinical trial outcomes, cognitive assessment scales, diagnosis of AD, diagnosis of mild cognitive impairment (MCI), and symptoms differentiating AD from MCI. Participation in the education also significantly (P<0.001) improved confidence in the identification of early forms of AD among PCPs and neurologists. No substantial differences in knowledge, competence, or confidence were seen for either clinician group based on geographic location of the learner. Conclusion The results indicated that clinicians who participated in CME‐certified curriculum‐based education in multiple formats were better prepared to recognize early forms of AD. Future education should continue to discuss the use of clinical strategies to recognize early forms of AD.

Abstract Background Easily accessible and self‐administered cognitive assessments that can aide early identification of individuals at risk for Alzheimer’s disease (AD) dementia are critical for timely intervention. Mayo Test Drive (MTD) is a remote, self‐administered, multi‐device compatible, web‐based cognitive assessment (Stricker et al., 2022). We investigated continuous associations between MTD and amyloid and tau PET biomarkers and compared the strength of association to PET biomarkers and in‐person cognitive measures. Method 556 adults from the Mayo Clinic Study of Aging participated (mean age = 70.6; mean education = 16.0 years; 50.7% female; 97.5% white). Participants were predominantly cognitively unimpaired (95.3%; 4.7% had a consensus diagnosis of mild cognitive impairment). Participants completed (1) brain amyloid and tau PET scans, (2) in‐person neuropsychological assessment including Mayo Preclinical Alzheimer’s disease Cognitive Composite (Mayo‐PACC) and Global‐z, and (3) remote MTD comprised of the Stricker Learning Span (SLS) and the Symbols test, which are combined into an MTD composite. Multiple regressions adjusted for age, sex, and education queried associations between imaging biomarkers [amyloid meta‐region of interest (ROI), tau meta‐ROI, and tau entorhinal cortex (EC)‐ROI)] and composite and subtest scores from remote and in‐person measures. Davidson‐Mackinnon J‐test compared R‐squared values of models with remote versus in‐person composites. Result Lower performances on MTD composite and Mayo‐PACC were associated with higher amyloid meta‐ROI (p’s<.05; Table 1). MTD composite was also negatively associated with tau meta‐ROI and EC‐ROI (p’s<.05). For memory measures, SLS sum of trials was negatively associated with tau meta‐ROI (p = .01) and EC‐ROI (p<.001) with no associations between AVLT sum of trials and PET (p’s = .06; Table 2). Among processing speed/executive function measures, worse Trails B performance was associated with higher amyloid meta‐ROI (p<.001). Symbols and Digit Symbol Coding were not associated with PET (p’s = .29). A multivariable model with MTD explained significantly less variance (p = .04) for amyloid meta‐ROI (adjusted R‐squared = 0.165) than a multivariable model with Mayo‐PACC (adjusted R‐squared = 0.176); remote and in‐person composite measures were comparable for other associations (p’s>.05). Conclusion MTD is associated with continuous measures of amyloid and tau PET biomarkers of AD, demonstrating criterion validity for MTD. Several associations were comparable to relationships between gold‐standard in‐person neuropsychological tests and imaging biomarkers.

Abstract Background Brief self‐administered cognitive assessments deployed remotely and combined with plasma biomarkers of Alzheimer’s disease (AD) are well suited to assess clinical symptoms and underlying biology in large‐scale decentralized studies. We investigated whether associations of self‐administered cognitive measures and plasma biomarkers were comparable to associations of in‐person cognitive measures and plasma biomarkers. Method Participants included 327 adults from the Mayo Clinic Study of Aging (mean age = 70.8; 48% female; mean education = 16.0 years; 96.9% white). Most (94.5%) were cognitively unimpaired; 5.5% had consensus diagnosis of mild cognitive impairment. Participants completed Mayo Test Drive (MTD; Stricker et al., 2022), a remote, self‐administered, multi‐device compatible web‐based cognitive assessment comprised of the Stricker Learning Span (SLS) and Symbols test that are combined into a MTD composite. Participants also completed in‐person neuropsychological assessment (global‐z; Mayo Preclinical Alzheimer’s disease Cognitive Composite [Mayo‐PACC]) and fasting venipuncture. Plasma was assayed via HD‐X simoa platform for amyloid‐beta (Aß)‐42 and Aß‐40 to create an Aß42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) using the N4PE Quanterix kit as well as phosphorylated‐tau protein 181 (p‐tau181). P‐tau181, GFAP, and NfL were log10‐transformed. Multiple regression analyses adjusting for age, sex, and education examined associations between plasma biomarkers and composite and subtest scores from remote and in‐person measures. Davidson‐Mackinnon J‐test compared R‐squared values of models with remote versus in‐person composites. Result Lower performances on MTD, global‐z, and Mayo‐PACC (Table 1) were associated with higher GFAP (p’s = .02), NfL (p’s = .003), and p‐tau181 (p’s = .04). For memory, worse SLS and AVLT sum of trials were associated with higher GFAP (p’s = .01) and NfL (p’s = .03). For processing speed/executive function, worse Symbols and Trails B were associated with higher p‐tau181 (p’s = .02). Worse Trails B and Digit Symbol Coding were associated with higher NfL (p’s = .02), and worse Digit Symbol Coding was associated with lower Aß42/40 (p = 0.03; Table 2). A multivariable model with MTD explained significantly more variance (p = .04) for NfL (adjusted R‐squared = 0.461) than a multivariable model with Mayo‐PACC (adjusted R‐squared = 0.447); remote and in‐person composite measures were comparable for other associations (p’s>.05). Conclusion Remote and in‐person composite measures showed comparable associations with AD‐related plasma biomarkers, supporting MTD’s criterion validity.

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aß), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aß40, Aß42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aß40/42. Lower Aß40/42 indicates increased Aß pathology. Plasma Aß40, Aß42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aß and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p<0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p<0.001) and NfL (p<0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p<0.001). After accounting for age, plasma Aß40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.