Rissman, Robert A.

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

Abstract Background pTau217 is a well validated plasma biomarker for Alzheimer's disease (AD), sensitive to the accumulation of amyloid pathology in the preclinical stages of disease. We leveraged whole blood RNA sequencing and plasma pTau217 measures of amyloid burden to identify blood transcriptomic gene‐network changes that relate to plasma pTau217 levels in cognitively normal older adults. We then quantified the abundance of cell populations from the transcriptomic data to identify blood cell abundance alterations that correlate with plasma ptau217 levels. Method Whole blood RNA sequencing and plasma pTau217 data were obtained from 1739 participants in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study. RNAseq data were aligned, sorted, counted, batch normalized, and iteratively adjusted for covariates. 20,718 genes were available for analysis following quality control. Plasma samples ( n = 1597) were analyzed for pTau217 using the Eli Lilly and Company Diagnostics Laboratory immunoassay. Samples from 724 participants (63% females, mean age 71, 61% amyloid+) with RNA sequencing and biomarker data were used for analysis. Cell fractions were quantified using CIBERSORTx (LM22 used as reference) and WGCNA was used to calculate gene co‐expression modules. Linear regression related gene module expression or cell fraction to mean pTau217 levels covarying for age, sex, education, APOE ε2 and ε4 status. Correction for multiple comparisons used the false discovery rate. Gene enrichment was performed using Gene Ontology. Result Five gene modules were associated with plasma pTau217. For the turquoise module (β=‐0.81, p.fdr=0.005), higher expression was associated with higher p ‐tau217 while higher expression in the blue (β=‐0.70, p.fdr=0.01), lightcyan (β=‐0.68, p.fdr=0.01), grey60 (β=‐0.64, p.fdr=0.02), and brown (β=‐0.55, p.fdr=0.04) modules were associated with lower p ‐tau217. These modules were enriched for phagocytosis, ribonucleoprotein complex biogenesis, immunoglobulin mediated immune response, nucleosome assembly, and cytoplasmic translation pathway genes. In cell fraction analysis, higher predicted abundance of neutrophils related to ptau217 levels (β=0.33, p.fdr=0.03). Conclusion Our results demonstrate an association between immune response and epigenetic pathway genes with plasma pTau217 levels in preclinical AD. Future work will seek to clarify whether these signatures also relate to brain amyloid PET to evaluate blood transcription networks as complementary biomarkers to improve preclinical prediction.

Abstract Limbic predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is highly prevalent in late life and a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC). LATE‐NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE‐NC is associated with a more rapid course. With the emergence of anti‐amyloid therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co‐pathology with LATE‐NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE‐NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). Highlights Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE‐NC) is a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease‐modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE‐NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

AbstractBackgroundAnti‐amyloid immunotherapies modestly slow disease progression in early symptomatic AD; addition of other therapeutic modalities may be necessary to achieve larger treatment effects. Therapies that directly target tau can potentially produce substantial clinical benefit because the accumulation of insoluble tau protein is strongly correlated with the progression of AD. Which tau therapies are likely to be efficacious, whether or not to combine them with anti‐amyloid therapies, and which individuals are most likely to benefit are important unresolved questions that would require multiple parallel design trials to answer. Platform (umbrella) trials test multiple therapies in the same trial, allowing for substantial savings in time, cost and participant burden.MethodATP is a new NIH‐funded Phase 2 clinical trial platform that will be conducted as part of the AD Clinical Trials Consortium (ACTC) in partnership with industry and philanthropic groups. The goal is to investigate the effects of tau therapies on the biological hallmarks of AD including insoluble and soluble tau species, amyloid and other biomarkers of neurodegeneration. ATP will initially evaluate two tau therapies alone or in combination with an anti‐amyloid therapy. 900 participants with late preclinical or early prodromal AD (CDR 0 or 0.5) will be randomized to six arms for two years of blinded treatment, followed by an optional open label extension (Figure 1). At least 20 percent of participants will be from underrepresented groups. The primary endpoint is 18F MK6240 tau PET, with key secondary endpoints including plasma P‐tau and MTBR243‐tau, amyloid PET and clinical assessments (CDR‐SB, PACC5). Inclusion criteria are based on plasma P‐tau217, clinical status and regional 18F MK6240 uptake.ResultTwo tau therapies and an anti‐amyloid therapy have been chosen for inclusion in ATP and startup is underway. The final design, choice of therapies and design as well as plans for inclusion of additional tau therapies after the trial begins and other details will be presented.ConclusionThe ATP is a six arm factorial design platform trial that is planned to begin in late 2024 or early 2025 that will support efficient development of tau and combination therapies for early, sporadic AD.

Abstract The observation that aging is regulated by microRNAs (miRNA) and at the same time represents the greatest risk factor for Alzheimer's disease (AD), prompted us to examine the circulating miRNA network in AD beyond aging. We here show that plasma miRNAs in aging are downregulated and predicted to be preferentially targeted to the extracellular vesicle (EV) content. In AD, miRNAs are further downregulated, display altered proportions of motifs relevant to their loading into EVs and secretion propensity, and are forecast to be found exclusively in EVs. The circulating miRNA network in AD, therefore, reflects pathological exacerbation of the aging process whereby physiological suppression of AD pathology by miRNAs becomes insufficient. image

Abstract The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post‐mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. Highlights Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance

Abstract Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p < 0.0001). These data demonstrate differences in hippocampal p-tau burden and regional distribution in CTE compared to PART that might be helpful in differential diagnosis and reveal insights into disease pathogenesis.

AbstractIntroductionRepresentation of Mexican Americans in Alzheimer's disease (AD) clinical research has been extremely poor.MethodsData were examined from the ongoing community‐based, multi‐ethnic Health & Aging Brain among Latino Elders (HABLE) study. Participants underwent functional exams, clinical labs, neuropsychological testing, and 3T magnetic resonance imaging of the brain. Fasting proteomic markers were examined for predicting mild cognitive impairment (MCI) and AD using support vector machine models.ResultsData were examined from n = 1649 participants (Mexican American n = 866; non‐Hispanic White n = 783). Proteomic profiles were highly accurate in detecting MCI (area under the curve [AUC] = 0.91) and dementia (AUC = 0.95). The proteomic profiles varied significantly between ethnic groups and disease state. Negative predictive value was excellent for ruling out MCI and dementia across ethnic groups.DiscussionA blood‐based screening tool can serve as a method for increasing access to state‐of‐the‐art AD clinical research by bridging between community‐based and clinic‐based settings.

Stroke is a leading cause of the adult disability epidemic in the United States, with a major contribution from poststroke cognitive impairment and dementia (PSCID), the rates of which are disproportionally high among the health disparity populations. Despite the PSCID’s overwhelming impact on public health, a knowledge gap exists with regard to the complex interaction between the acute stroke event and highly prevalent preexisting brain pathology related to cerebrovascular and Alzheimer disease or related dementia. Understanding the factors that modulate PSCID risk in relation to index stroke event is critically important for developing personalized prognostication of PSCID, targeted interventions to prevent it, and for informing future clinical trial design. The DISCOVERY study (Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery), a collaborative network of thirty clinical performance clinical sites with access to acute stroke populations and the expertise and capacity for systematic assessment of PSCID will address this critical challenge. DISCOVERY is a prospective, multicenter, observational, nested-cohort study of 8000 nondemented ischemic and hemorrhagic stroke patients enrolled at the time of index stroke and followed for a minimum of 2 years, with serial cognitive evaluations and assessments of functional outcome, with subsets undergoing research magnetic resonance imaging and positron emission tomography and comprehensive genetic/genomic and fluid biomarker testing. The overall scientific objective of this study is to elucidate mechanisms of brain resilience and susceptibility to PSCID in diverse US populations based on complex interplay between life-course exposure to multiple vascular risk factors, preexisting burden of microvascular and neurodegenerative pathology, the effect of strategic acute stroke lesions, and the mediating effect of genomic and epigenomic variation.

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.