Braak Stage Research Articles

Tau seeds from Alzheimer's disease brains trigger tau spread in macaques while oligomeric-Aβ mediates pathology maturation.

The "prion-like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid-β (Aβ) have never been experimentally studied in primates phylogenetically close to humans. We injected 17 macaques in the entorhinal cortex with nanograms of seeding-competent tau aggregates purified from AD brains or control extracts from aged-matched healthy brains, with or without intracerebroventricular co-injections of oligomeric-Aβ. Pathological tau injection increased cerebrospinal fluid (CSF) p-tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD-related molecular networks were impacted by tau seeds injections regardless of Aβ injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total-tau concentration, and pre- and postsynaptic degeneration only in Aβ co-injected macaques. Oligomeric-Aβ mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading. This study supports the "prion-like" properties of misfolded tau extracted from AD brains. This study empirically validates the Braak staging in an anthropomorphic brain. This study highlights the role of oligomeric Aβ in driving the maturation and toxicity of tau pathology. This work establishes a novel animal model of early sporadic AD that is closer to the human pathology.

High percentage of blood-based T-cell receptor gamma V9-JP recombinations associated with amyotrophic lateral sclerosis: extensive retention of the JP KKIK amino acid motif

Exome and RNAseq files prepared from blood samples can be mined for adaptive immune receptor recombinations and thus for the complementarity determining region-3 (CDR3) amino acid (AA) sequences, important for antigen binding. In this report, the T-cell receptor gamma (TRG) recombinations were mined from amyotrophic lateral sclerosis (ALS) blood sample exome and RNAseq files, mainly inspired by: (i) a high level of gamma-delta T-cells in Parkinson’s disease and (ii) TRG CDR3 AA features associated with a higher Braak stage in Alzheimer’s disease. Results indicated a high percentage of V9-JP recombinations from ALS blood sample genomics files, in comparison to TRG recombinations obtained from a large number of blood and other tissue samples not representing ALS. This result is discussed in the context of potential phospholipid sponging by adaptive immune receptors and potential impacts on membrane rigidity and amyloid development.

Study of molecular patterns associated with ferroptosis in Parkinson's disease and its immune signature.

Parkinson's disease is the second most common neurodegenerative disease in the world. We downloaded data on Parkinson's disease and Ferroptosis-related genes from the GEO and FerrDb databases. We used WCGAN and Random Forest algorithm to screen out five Parkinson's disease ferroptosis-related hub genes. Two genes were identified for the first time as possibly playing a role in Braak staging progression. Unsupervised clustering analysis based on hub genes yielded ferroptosis isoforms, and immune infiltration analysis indicated that these isoforms are associated with immune cells and may represent different immune patterns. FRHGs scores were obtained to quantify the level of ferroptosis modifications in each individual. In addition, differences in interleukin expression were found between the two ferroptosis subtypes. The biological functions involved in the hub gene are analyzed. The ceRNA regulatory network of hub genes was mapped. The disease classification diagnosis model and risk prediction model were also constructed by applying hub genes based on logistic regression. Multiple external datasets validated the hub gene and classification diagnostic model with some accuracy. This study explored hub genes associated with ferroptosis in Parkinson's disease and their molecular patterns and immune signatures to provide new ideas for finding new targets for intervention and predictive biomarkers.

Spatiotemporal Correlation between Amyloid and Tau Accumulations Underlies Cognitive Changes in Aging.

It is poorly known how Aβ and tau accumulations associate at the spatiotemporal level in the in vivo human brain to impact cognitive changes in older adults prior to AD symptoms onset. In this study, we used a graph theory-based spatiotemporal analysis to characterize the cortical patterns of Aβ and tau deposits and their relationship with cognitive changes in the Harvard Aging Brain Study (HABS) cohort. We found that the temporal accumulations of interlinked Aβ and tau pathology display distinctive spatiotemporal correlations associated with early cognitive decline. Notably, we observed that baseline Aβ deposits-Thal amyloid phase Ⅱ-related to future increase of tau deposits, Braak stages Ⅰ-Ⅳ, both displaying linkage to the decline in multi-domain cognitive scores. We also found unimodal tau-to-tau and cognitive impairment associations in broad areas of Braak stages Ⅰ-Ⅳ. The unimodal Aβ-to-Aβ progressions were not associated with cognitive changes. Our results revealed a multifaceted correlation of the spatiotemporal Aβ and tau associations with cognitive decline over time, in which tau-to-tau and tau-Aβ interactions, and not Aβ independently, might be critical contributors to clinical trajectories toward AD in older adults.

Characterization of cerebellar amyloid-β deposits in Alzheimer disease.

Cerebellar amyloid-β (Aβ) plaques are a component of the diagnostic criteria used in Thal staging and ABC scoring for Alzheimer disease (AD) neuropathologic change. However, Aβ deposits in this anatomic compartment are unique and under-characterized; and their relationship with other pathological findings are largely undefined. In 73 cases of pure or mixed AD with an A3 score in the ABC criteria, parenchymal (plaques) and vascular (cerebral amyloid angiopathy [CAA]) cerebellar Aβ-42 deposits were characterized with respect to localization, morphology, density, and intensity. Over 85% of cases demonstrated cerebellar Aβ-42 parenchymal staining that correlated with a Braak stage V-VI/B3 score (p < 0.01). Among the 63 with cerebellar Aβ-42 deposits, a diffuse morphology was observed in 75% of cases, compact without a central dense core in 32%, and compact with a central dense core in 16% (all corresponding to plaques evident on hematoxylin and eosinstaining). Cases with Purkinje cell (PC) loss showed higher proportions of PC layer Aβ-42 staining than cases without PC loss (88% vs 44%, p = 0.02), suggesting a link between Aβ-42 deposition and PC damage. Among all 73 cases, CAA was observed in the parenchymal vessels of 19% of cases and in leptomeningeal vessels in 44% of cases.

Florbetapir PET-assessed demyelination is associated with faster tau accumulation in an APOE ε4-dependent manner.

The main objectives were to test whether (1) a decrease in myelin is associated with enhanced rate of fibrillar tau accumulation and cognitive decline in Alzheimer's disease, and (2) whether apolipoprotein E (APOE) ε4 genotype is associated with worse myelin decrease and thus tau accumulation. To address our objectives, we repurposed florbetapir-PET as a marker of myelin in the white matter (WM) based on previous validation studies showing that beta-amyloid (Aβ) PET tracers bind to WM myelin. We assessed 43 Aβ-biomarker negative (Aβ-) cognitively normal participants and 108 Aβ+ participants within the AD spectrum with florbetapir-PET at baseline and longitudinal flortaucipir-PET as a measure of fibrillar tau (tau-PET) over ~ 2 years. In linear regression analyses, we tested florbetapir-PET in the whole WM and major fiber tracts as predictors of tau-PET accumulation in a priori defined regions of interest (ROIs) and fiber-tract projection areas. In mediation analyses we tested whether tau-PET accumulation mediates the effect of florbetapir-PET in the whole WM on cognition. Finally, we assessed the role of myelin alteration on the association between APOE and tau-PET accumulation. Lower florbetapir-PET in the whole WM or at a given fiber tract was predictive of faster tau-PET accumulation in Braak stages or the connected grey matter areas in Aβ+ participants. Faster tau-PET accumulation in higher cortical brain areas mediated the association between a decrease in florbetapir-PET in the WM and a faster rate of decline in global cognition and episodic memory. APOE ε4 genotype was associated with a worse decrease in the whole WM florbetapir-PET and thus enhanced tau-PET accumulation. Myelin alterations are associated in an APOE ε4 dependent manner with faster tau progression and cognitive decline, and may therefore play a role in the etiology of AD.

Uncovering elevated tau TPP motif phosphorylation in the brain of Alzheimer's disease patients.

A wide array of post-translational modifications of the tau protein occurs in Alzheimer's disease (AD) and they are critical to pathogenesis and biomarker development. Several promising tau markers, pT181, pT217, and pT231, rely on increased phosphorylation within a common molecular motif threonine-proline-proline (TPP). We validated new and existing antibodies against pT217, pT231, pT175, and pT181, then combined immunohistochemistry (IHC) and immunoassays (ELISA) to broadly examine the phosphorylation of the tau TPP motif in AD brains. The tau burden, as examined by IHC and ELISA, correlates to Braak stages across all TPP sites. Moreover, we observed regional variability across four TPP motif phosphorylation sites in multiple brains of sporadic AD patients. We conclude that there is an elevation of TPP tau phosphorylation in AD brains as disease advances. The regional variability of pTPP tau suggests that examining different phosphorylation sites is essential for a comprehensive assessment of tau pathology.

In vivo Braak staing using 18F‐MK‐6240 PET in Alzheimer’s disease

AbstractBackgroundThis study aimed to identify the distribution of [18F]MK‐6240 PET retention and classified according to Braak staging in Alzheimer’s disease (AD). We also evaluated the relationship between [18F]MK‐6240 PET retention and cognitive functions and neurodegeneration.MethodWe enrolled 194 participants including 70 CU (cognitively unimpaired elderly participants older than 60 years old), 56 MCI, 60 probable AD, and 8 patients who had dementia other than AD (subcortical vascular dementia (n = 3), semantic variant primary progressive aphasia (n = 2), frontotemporal dementia (n = 2), corticobasal syndrome (n = 1)). All participants underwent 3T MRI, [18F]MK‐6240, and [18F]Flutemetamol (FLUTE) PET scans, APOE genotyping, and detailed neuropsychological tests. Braak staging was defined as the stages where regional SUVR of ROIs composing each Braak stage &gt; = 1.3. We assessed the Braak staging in the subjects. Correlation analyses between global retention of MK‐6240 PET and neuropsychological test results or neurodegeneration were performed using linear regression.ResultThe proportion of amyloid positivity was 11.4% in CU, 45.5% in MCI, and 83.3% in probable AD. Among probable AD (n = 60), 12 patients were classified to other dementia after amyloid PET and tau PET confirmation. Main Braak stage was Braak 0 in CU, Braak III/IV in amyloid (+) MCI, Braak V/VI in AD dementia. In CU an patents with AD spectrum, global retention of MK‐6240 PET was significantly correlated with MMSE, CDR SOB, language, visuospatial function, memory and frontal/executive functions. In addition, global retention of MK‐6240 PET was correlated with the MRI markers for neurodegeneration, that is, mean cortical thickness and hippocampal volumes.Conclusion [ 18F]MK‐6240 PET successfully identified the Braak staging and associated with amyloid pathology and clinical phenotype in patients with AD. MK‐6240 PET also correlated with cognitive functions and neurodegeneration. MK6240 is a promising tau PET tracer with the potential to be sensitive surrogate markers of AD.

Tracing the spatial extent of cortical tau over time in Alzheimer’s disease

AbstractBackgroundNeuropathological studies defined the paradigm that tau—the pathological hallmark of Alzheimer’s disease (AD)—spreads homogenously across individuals from the medial temporal lobe to the neocortex. This staging system is referred to as Braak stages. However, neuroimaging studies have since highlighted significant inter‐regional and inter‐individual differences in tau spreading patterns. We investigated the spatial extent of cortical tau over time in the amnestic AD spectrum.MethodWe included 195 amyloid‐positive ADNI participants that had at least two tau‐PET scans (90 cognitively unimpaired [CU], 66 with mild cognitive impairment [MCI], 39 with AD dementia; average follow‐up 2.6 years). We derived regional thresholds of tau positivity for 64 cortical regions and the amygdalae using Gaussian mixture modeling and applied them to all tau scans. The same approach was used to obtain thresholds for composite regions corresponding to the Braak stages. For each region, we calculated the rate of change in the amount (i.e., standardized uptake value ratio [SUVR] change) of tau pathology and the annual change in the positivity status (i.e., spatial extent change). These rates were compared between diagnostic groups using linear mixed models.ResultAcross diagnostic groups, change in tau positivity followed Braak staging; over 90% of participants positive at follow‐up either progressed or were already positive on a previous Braak stage at baseline (Fig‐1AI) and greater SUVR change was observed in temporal regions (Fig‐1B). However, across the brain, there was heterogeneity between individual patterns of tau positivity progression (Fig‐1AII). This heterogeneity was most striking in MCI patients, where many regions progressed from low to high levels of tau (Fig‐1C). Regional SUVR change did not differ between participants with AD or with MCI (Fig‐2A), but participants with MCI showed the fastest change in regional positivity compared to participants with AD and CU participants. (Fig‐2B)ConclusionWhile tau propagation follows Braak staging, inter‐individual differences can be found by considering a fine‐grained approach of regional progression to positivity. Furthermore, participants with MCI have the highest number of regions becoming abnormal annually. Our research pushes the importance of considering the entire brain when studying change in tau pathology, particularly before AD diagnosis.

Low circulating choline levels correlate with Alzheimer’s disease pathology severity and cognitive impairment

AbstractBackgroundModifiable environmental risk factors may help reduce Alzheimer’s disease (AD) incidence. Choline plays key roles in healthy body and brain function (Blusztajn, 1998) and supplementation above the adequate daily intake (ADI) reduces AD pathology (Velazquez et al., 2019). Choline deficiency increases AD risk and pathology (Dave et al., 2023; Yuan et al., 2022). Notably, recent reports estimate that ∼90% of Americans do not reach the ADI for dietary choline (Zeisel, 2017), making it imperative to better understand the link between choline and AD risk.MethodWe obtained serum samples from severe AD (AD‐Sev; Braak stage VI), moderate AD (AD‐Mod; Braak stage IV), and healthy control (CON; &lt; Braak stage III) subjects (n = 12/group; balanced for sex) from the Banner Sun Health Research Institute’s Brain and Body Donation Program. Cognitive test scores (Mini‐Mental State Examination (MMSE)), plaque burden, and Braak stage was characterized by Banner Sun Health. We assessed free choline, acetylcholine (ACh), and TNFα levels. Gas‐chromatography‐mass spectrometry was used to profile aqueous metabolites and short‐chain fatty acids.ResultThere were no significant group differences for post‐mortem interval (M = 3.79). We found disease associated differences, where AD‐Sev and AD‐Mod patients had lower levels of free choline and ACh, and higher levels of pro‐inflammatory cytokine TNFα, than CON. AD‐Mod showed a significant difference in all these measurements compared to AD‐Sev. Free choline and ACh were positively correlated to MMSE scores, whereas free choline and ACh levels were negatively correlated with total plaque and Braak Stage. Free choline and ACh were negatively correlated with TNFα. Metabolomics analysis revealed significant differences (p &lt; 0.05) in the metabolisms of beta‐alanine, linoleic acid, and of taurine and hypotaurine.ConclusionCollectively, as free choline and ACh levels decreased, AD pathology increased. Free choline was also associated with MMSE score. Increased TNFα was observed in cases with lower choline, illustrating increased inflammation. Together, this data expands on our recent (Dave et al., 2023) and others (Yuan et al., 2022) publications, highlighting links between low choline and AD risk.

In‐vivo Braak Stage Distribution of Screened and Randomized Participants from Auτonomy, a Phase 2 Anti‐p‐tau Monoclonal Antibody Trial in Early Symptomatic Alzheimer’s Disease

AbstractBackgroundTau PET is the gold standard for in‐vivo quantification of tau neurofibrillary tangles (NFT) which, along with amyloid plaques and neurodegeneration, constitute the pathological hallmarks of Alzheimer’s Disease (AD). The ongoing Autonomy trial (NCT04619420) enrolls participants presenting with mild cognitive impairment (MCI) or mild AD dementia who are tau PET positive. The Janssen plasma p217+tau assay is being used as a pre‐screen for eligibility to proceed to tau PET to reduce participant burden and improve screening efficiency. Using preliminary screening data available to date, we report on the in‐vivo PET‐based Braak stage distribution and compare the outcomes to published, histology‐based Braak staging.MethodNFT levels were quantified using 18F‐MK‐6240 SUVR in Braak Regions Of Interest (ROI)[1] using cerebellar gray as the reference region. In‐vivo Braak staging (Braakiv) was implemented following the approach by Biel et al.[2], with 18F‐flortaucipir to 18F‐MK‐6240 SUVR threshold conversion from Gogola et al.[3]. Participants with atypical[2] stages were reassigned to the Braak stage corresponding to the highest Braak ROI with average SUVR &gt; 1.4. The screening results reported herein are from the first 355 participants with available biomarker screening data.ResultOf 355 screened participants, 90% were assigned to typical Braakiv stages. Of the 10% atypical stages, 94% were lacking elevated uptake in Braak 2 ROI. When using the coerced stage assignment, the average Braakiv stage was 3.7 across all screened participants and 3.6 in randomized participants (Figure 1). For the 221 randomized participants, 59% were Braakiv stage 4 or less, and 40% were Braakiv stage 3 or less.ConclusionIn early Alzheimer’s disease participants who were screened with tau PET in the ongoing Autonomy trial, the average Braakiv stage was consistent with the average histology‐based Braak stage in MCI patients of 3.57 [4]. These results further support the use of tau PET‐based in‐vivo staging[5] as a proxy for histology‐based Braak staging. [1] Schöll et al. Neuron 2016. [2] Biel, D., et al. Alz Res Therapy 2021. [3] Gogola A. et al. J Nucl Med. 2022. [4] Markesbery WR. J Alzheimers Dis. 2010. [5] Therriault, J. et al. Nat Aging 2022

In‐vivo Braak Stage Distribution of Screened and Randomized Participants from Auτonomy, a Phase 2 Anti‐p‐tau Monoclonal Antibody Trial in Early Symptomatic Alzheimer’s Disease

AbstractBackgroundTau PET is the gold standard for in‐vivo quantification of tau neurofibrillary tangles (NFT) which, along with amyloid plaques and neurodegeneration, constitute the pathological hallmarks of Alzheimer’s Disease (AD). The ongoing Auτonomy trial (NCT04619420) enrolls participants presenting with mild cognitive impairment (MCI) or mild AD dementia who are tau PET positive. The Janssen plasma p217+tau assay is being used as a pre‐screen for eligibility to proceed to tau PET to reduce participant burden and improve screening efficiency. Using preliminary screening data available to date, we report on the in‐vivo PET‐based Braak stage distribution and compare the outcomes to published, histology‐based Braak staging.MethodNFT levels were quantified using 18F‐MK‐6240 SUVR in Braak Regions Of Interest (ROI)[1] using cerebellar gray as the reference region. In‐vivo Braak staging (Braakiv) was implemented following the approach by Biel et al.[2], with 18F‐flortaucipir to 18F‐MK‐6240 SUVR threshold conversion from Gogola et al.[3]. Participants with atypical[2] stages were reassigned to the Braak stage corresponding to the highest Braak ROI with average SUVR &gt; 1.4. The screening results reported herein are from the first 355 participants with available biomarker screening data.ResultOf 355 screened participants, 90% were assigned to typical Braakiv stages. Of the 10% atypical stages, 94% were lacking elevated uptake in Braak 2 ROI. When using the coerced stage assignment, the average Braakiv stage was 3.7 across all screened participants and 3.6 in randomized participants (Figure 1). For the 221 randomized participants, 59% were Braakiv stage 4 or less, and 40% were Braakiv stage 3 or less.ConclusionIn early Alzheimer’s disease participants who were screened with tau PET in the ongoing Auτonomy trial, the average Braakiv stage was consistent with the average histology‐based Braak stage in MCI patients of 3.57 [4]. These results further support the use of tau PET‐based in‐vivo staging[5] as a proxy for histology‐based Braak staging.[1] Schöll et al. Neuron 2016.[2] Biel, D., et al. Alz Res Therapy 2021.[3] Gogola A. et al. J Nucl Med. 2022. [4] Markesbery WR. J Alzheimers Dis. 2010.[5] Therriault, J. et al. Nat Aging 2022

Effects of cholesterol depletion, pro‐inflammatory cytokines and the apolipoprotein E isoforms on ABCA7 protein levels in human neural cell lines and brain tissue

AbstractBackgroundStrong evidence from diverse sources points to adenosine triphosphate‐binding cassette transporter subfamily A member 7 (ABCA7) as a major risk factor in Alzheimer’s disease (AD). However, the mode of its involvement with the disease and many aspects of its function are understood incompletely.MethodHuman microglia cells C20 and HMC3 and neuronal cells SK‐N‐SH were either depleted in cholesterol using methyl‐β‐cyclodextrin and/or rosuvastatin or treated with pro‐inflammatory cytokines IL‐1β, IL‐6 or TNFα, and ABCA7 protein levels in these cells were then assessed using a validated monoclonal antibody. ABCA7 levels were also assessed using the antibody in the parietal cortex from 170 donors, who were genotyped for the APOE isoforms.ResultLarge (∼75%) reductions in intracellular cholesterol and saturating amounts of pro‐inflammatory cytokines IL‐1β and TNFα reduced ABCA7 protein by, respectively, 36.8±9.1% (mean±standard deviation, two‐tailed t test p = 0.0002, n = 4), 53.0±22.6% (p = 0.002, n = 4) and 59.2±8.0% (p = 0.0006, n = 4) in C20 cells and by similar percentages in HMC3 cells. Similarly severe cholesterol depletion had no effect on ABCA7 and IL‐1β and TNFα moderately increased ABCA7 amounts in SK‐N‐SH cells. IL‐6 had no effect on ABCA7 expression in any cell line. IL‐1β and TNFα significantly cross‐induced each other’s secretion in C20 cells. We have previously shown that ABCA7 protein levels drop suddenly during AD pathogenesis between Braak and Braak stages I and II in the human brain. Among the individuals without AD pathology or with Braak stage I pathology, ABCA7 levels were lower in APOE4 carriers without reaching statistical significance (0.74, 0.35‐2.51 vs 1.5, 0.30‐3.16 ABCA7/GAPDH ratios; median, 25%‐75% interval; Mann‐Whitney p = 0.44, n = 68 vs 14); among the individuals with Braak stages II‐V, ABCA7 was also lower in APOE4 carriers (0.21, 0.07‐1.07 vs 0.55, 0.11‐1.35; Mann‐Whitney p = 0.18, n = 53 vs 35). The comparison groups were matched for age, sex and PMI.ConclusionThe effect of cholesterol depletion on ABCA7 expression is tissue specific. ABCA7 functions are homeostatic and not compatible with inflammation in microglia. If APOE4 has an effect on ABCA7 levels, it is smaller than the reduction in ABCA7 between Braak stages I and II. These findings improve our understanding of ABCA7 pathophysiology.

Tracing the spatial extent of cortical tau over time in Alzheimer’s disease

AbstractBackgroundNeuropathological studies defined the paradigm that tau—the pathological hallmark of Alzheimer’s disease (AD)—spreads homogenously across individuals from the medial temporal lobe to the neocortex. This staging system is referred to as Braak stages. However, neuroimaging studies have since highlighted significant inter‐regional and inter‐individual differences in tau spreading patterns. We investigated the spatial extent of cortical tau over time in the amnestic AD spectrum.MethodWe included 195 amyloid‐positive ADNI participants that had at least two tau‐PET scans (90 cognitively unimpaired [CU], 66 with mild cognitive impairment [MCI], 39 with AD dementia; average follow‐up 2.6 years). We derived regional thresholds of tau positivity for 64 cortical regions and the amygdalae using Gaussian mixture modeling and applied them to all tau scans. The same approach was used to obtain thresholds for composite regions corresponding to the Braak stages. For each region, we calculated the rate of change in the amount (i.e., standardized uptake value ratio [SUVR] change) of tau pathology and the annual change in the positivity status (i.e., spatial extent change). These rates were compared between diagnostic groups using linear mixed models.ResultAcross diagnostic groups, change in tau positivity followed Braak staging; over 90% of participants positive at follow‐up either progressed or were already positive on a previous Braak stage at baseline (Fig‐1AI) and greater SUVR change was observed in temporal regions (Fig‐1B). However, across the brain, there was heterogeneity between individual patterns of tau positivity progression (Fig‐1AII). This heterogeneity was most striking in MCI patients, where many regions progressed from low to high levels of tau (Fig‐1C). Regional SUVR change did not differ between participants with AD or with MCI (Fig‐2A), but participants with MCI showed the fastest change in regional positivity compared to participants with AD and CU participants. (Fig‐2B)ConclusionWhile tau propagation follows Braak staging, inter‐individual differences can be found by considering a fine‐grained approach of regional progression to positivity. Furthermore, participants with MCI have the highest number of regions becoming abnormal annually. Our research pushes the importance of considering the entire brain when studying change in tau pathology, particularly before AD diagnosis.

Association of tau burden with sleep disordered breathing in adults with Down syndrome

AbstractBackgroundAdults with Down syndrome (DS) overproduce the amyloid precursor protein and nearly all evidence clinical symptoms of Alzheimer’s Disease (AD) dementia in later life. Sleep disordered breathing, and specifically, obstructive sleep apnea (OSA), is common in adults with DS. OSA has been associated with risk of AD in adults without DS, and sleep disturbances may have a bidirectional relationship with AD pathology. We hypothesized that greater tau burden is associated with subsequent sleep disordered breathing in a time‐lagged design.MethodsEighty young adults with DS (37±8 yrs, 49% women, 94% cognitively‐stable/6% MCI‐DS) from the ABC‐DS study underwent tau PET ([18F]‐AV1451, Braak stage SUVRs) and were assessed 4±0.7 years after PET using WatchPAT home sleep testing. Sleep variables included oxygen desaturation index (ODI) and apnea‐hypopnea index (AHI). General linear models assessed tau burden on later sleep impairments. Models were run in the whole group and the cognitively‐stable group alone, with and without age adjustment. Analyses were run using overall sleep measures and those in REM and non‐REM (NREM) sleep separately.ResultsIn unadjusted models, greater tau in early, middle, and late Braak stages were associated with a higher ODI, while greater tau in middle Braak stages was associated with a higher AHI. In the cognitively‐stable group alone, greater tau in early and middle, but not late, Braak stages were associated with a higher ODI, while greater tau in middle Braak stages was associated with a higher AHI. Adjusting for age, greater tau in late Braak stages was associated with ODI in the whole group and the cognitively‐stable group alone. Associations for overall sleep measures were driven by NREM measures (Table 1).ConclusionIn adults with DS with a high prevalence of OSA, tau burden was associated with subsequent intermittent nocturnal hypoxemia as measured by the ODI during NREM sleep. These findings align with those in adults without DS, linking AD pathology, disturbed sleep, witnessed apneas, and nocturnal hypoxemia. Both longitudinal and randomized studies are required to clarify cause‐effect relationships, including the presence of mediating and/or moderating variables such as reduction in sleep depth or continuity.

Association of FDG‐PET with co‐pathologies in autopsy‐proven AD

AbstractBackgroundThe presence of multiple pathologies is the rule and not the exception in Alzheimer’s disease (AD). The goal of this study was to assess whether 18F fluorodeoxyglucose (FDG) PET can provide information about the presence of non‐AD pathologies in autopsy‐proven AD patients.MethodOur cohort included 55 patients with antemortem FDG‐PET and autopsy‐proven intermediate/high ADNC from the UCSF Neurodegenerative Diseases Brain Bank. All patients underwent FDG‐PET. Standardized uptake value ratio (SUVR) images were computed using the pons as reference region. W‐maps (adjusted Z‐score maps) were created, comparing each patient to a group of 187 controls (age range: 20‐96, 40% males). Voxel‐wise correlations were computed to verify the unique contribution of each neuropathology to cerebral hypometabolism, while controlling for age, sex, time between FDG‐PET scan and death, scanner type, Thal and Braak staging, and the presence of all other co‐pathologies. Associations between SUVR values in specific region of interests (ROIs) were also assessed. The ROIs included were the following: Landau AD ROI for AD pathology, Cingulate Island Sign (CIS) for Lewy body disease, Inferior/Medial Temporal Lobe (IMT) and IMT/Frontal Supraorbital (IMT/FSO) ratios for limbic‐predominant age‐related TDP43 encephalopathy neuropathologic change (LATE‐NC).ResultMean age was 63.8 ± 10.5, mean time between FDG and death was 6.2 ± 2.8, and mean MMSE was 21.1 ± 7.1 at the time of PET (Table 1). Group averaged W‐map showed the typical temporo‐parietal AD pattern; hypometabolism in these regions was associated with higher Thal phase and Braak stage (Figure 1). Lewy body disease (LBD), argyrophilic grain disease (AGD), aging‐related tau astrogliopathy (ARTAG), cerebral amyloid angiopathy (CAA) and vascular brain injury (VBI) were associated with hypometabolism in small discrete regional clusters (Figure 2). The Landau AD ROI was associated with both Thal (rs = ‐0.325, p = .015) and Braak stages (rs = ‐0.447, p&lt;.001). The CIS sign was not associated with the presence of LBD (t(53) = 1.01, p = 0.319). Both the IMT (t(53) = ‐2.25, p = .028) and IMT/FSO (t(53) = ‐3.40, p = .001) ratios were associated with the presence of LATE‐NC.ConclusionCo‐pathologies make a relatively small contribution to hypometabolism in patients with intermediate‐high ADNC. Novel biomarkers are needed for precise detection of co‐pathologies.

Deciphering the molecular signature of selective neuronal vulnerability in the wake‐promoting lateral hypothalamic area in Alzheimer’s disease: A digital multiplexed gene expression study across Braak stages

AbstractBackgroundSleep/wake disturbance is a common and debilitating symptom of Alzheimer’s disease (AD) that precedes cognitive loss. The lateral hypothalamic area (LHA) is critical in orchestrating the sleep/wake cycle through the neuropeptide orexin and melanin‐concentrating hormone. We previously demonstrated that LHA neurons accumulate AD‐tau from Braak stage (BB) 0 and losses ∼72% of neurons by BB6. Little is known about the molecular changes underlying LHA vulnerability during AD progression. We investigated RNA expression changes in LHA across Braak stages to close this gap.MethodWe dissected LHA from 30um‐thick sections of the brain from healthy control (HC) and subjects at progressive AD stages and extracted RNA using conventional techniques. We ran RNA transcriptomic assay using customized and neuropathology nCounter® (Nanostring) panels. The Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when log2 fold‐change was &gt; = |1| and the p‐value was &lt;0.05.ResultWe found an upregulation of HCRTR1, LDHC, NKX6, and SLC11A1 from early stages (BB2‐3), whereas HCRTR2 RNA levels remained stable. Circadian gene PER2 was downregulated from the intermediate stages (BB4). Gene Ontology analyses detected dysregulation of neuropeptide‐ligand interaction pathways from early AD. Linoleic acid metabolism, fat digestion and absorption, and immune pathways became dysregulated at intermediate stages, while glycolysis and gluconeogenesis pathways were in late stages (BB5‐6). Of note, it is critical to consider that the massive LHA neuronal loss during AD progression may confound the interpretation of changes in late stages because of the few remaining neurons.ConclusionnCounter® is suitable for identifying transcriptome changes in LHA, even at early AD stages. Molecular profiling of LHA across the Braak stage revealed that the earliest changes are associated with an imbalance in neurotransmitter receptors, while the decline in metabolism and increased inflammation marked the intermediate stage. The late‐stage AD is characterized by hypoglycemia and energy deficit. Notably, discrepancies in receptor behavior can inform more effective symptomatic treatment for sleep dysfunction in AD.

Amyloid/Tau/Neurodegeneration (ATN) image‐based biomarker trajectories of Alzheimer’s disease through 5‐year longitudinal follow‐up

AbstractBackgroundTo investigate the progression of Alzheimer’s disease (AD) in image‐based Amyloid/Tau/Neurodegeneration (ATN) biomarkers through 5‐year longitudinal follow‐up.MethodAmong the participants who completed 18F‐florbetaben (FBB) for amyloid and 18F‐flortaucipir (FTP) for tau positron emission tomography (PET), and brain magnetic resonance (MR) imaging for neurodegeneration at a first visit, we enrolled the 145 participants who the studies at least twice [67 amyloid negative cognitive unimpaired (A‐CU), 10 amyloid positive cognitive unimpaired (A+CU), 68 amyloid positive cognitive impaired (A+CI)]. 70 participants completed the scans twice (25.2±3.1, months), and 75 participants completed the scans three times (57.9±7.4, months). We estimated the temporal trajectories of ATN biomarkers using a restricted cubic spline model and modified Euler method between baseline and annual change rates. The standardized uptake value ratio of FBB/FTP PET and hippocampal volume were used for representing each ATN biomarker, respectively.ResultThe FBB curve of the global cortex and AD‐specific regions reaches a plateau with a sigmoid appearance. FTP curves in the regions for Braak stages I‐II and III‐IV show similar sigmoid appearance while the global cortical and stage V‐VI tau curves show an exponential increase continuously. The hippocampal volume curve shows a linear decrease until the time point when the tau accumulation begins in the Braak stage I‐II, then decreases to a reversed sigmoid appearance.ConclusionLike the already known saturation of amyloid burden, it was also shown that the tau burden of the region for Braak stages I‐II and III‐IV saturated, but not in Braak stages V‐VI. Hippocampal atrophy seems to accelerate when tau begins to accumulate in early Braak stage regions. In future work, it is necessary to enroll patients at an advanced stage and collaborate with an international cohort.

Identification of Necessary Plasma Biomarkers for Prediction of Alzheimer’s Disease Neuropathologic Change

AbstractBackgroundPlasma biomarkers for Alzheimer’s disease (AD) such as phosphorylated tau protein 181 (p‐tau 181), neurofilament light chain (NfL), amyloid‐β 42/40 ratio (Aβ42/40), and glial fibrillary acidic protein (GFAP) have shown high performance in the discrimination of those with clinical mild cognitive impairment (MCI) or dementia from cognitively unimpaired individuals, but few population‐based autopsy studies have evaluated the neuropathological correlates of plasma biomarkers.MethodWe utilized a population‐based prospective study of 350 participants with autopsy and antemortem plasma biomarker data. Plasma biomarkers Aβ42/40 ratio, p‐tau181, GFAP, and NfL were measured using Quanterix Simoa assays. We predicted AD neuropathological change (ADNC), Braak staging, and neuritic plaque score using these plasma biomarkers and investigated the added utility of cognitive and demographic information. We utilized a variable selection procedure in cross‐validated (CV) logistic regression models by minimizing the Bayesian Information Criterion to identify the best set of predictors for a given outcome among plasma biomarkers, demographic variables, and neuropsychological tests included in the Mayo Clinic Preclinical Alzheimer Cognitive Composite (Mayo‐PACC).ResultADNC was best predicted with plasma GFAP, NfL, p‐tau181 biomarkers along with APOE ε4 carrier status and Mayo‐PACC cognitive score (CV AUC = 0.821). Braak staging was best predicted using plasma GFAP, p‐tau181, and cognitive scores (CV AUC = 0.788). Neuritic plaque score was best predicted using plasma Aβ42/40 ratio, p‐tau181, GFAP, and NfL biomarkers (CV AUC = 0.778). Inclusion of plasma biomarkers demonstrated significantly better prediction of Braak staging (p&lt;0.01) and neuritic plaque score (p&lt;0.01), but not ADNC (p = 0.13), when compared to models that included only cognitive and demographic information. Univariate models consistently underperformed in comparison to multivariate models.ConclusionPlasma biomarkers can provide valuable predictive information about the presence of AD pathology, which can facilitate earlier recognition and diagnosis of AD. Incorporation of demographic and cognitive variables along with plasma variables in multivariable models will improve prediction accuracy of AD pathology, specifically Braak staging and ADNC.

Association of FDG‐PET with co‐pathologies in autopsy‐proven AD

AbstractBackgroundThe presence of multiple pathologies is the rule and not the exception in Alzheimer’s disease (AD). The goal of this study was to assess whether 18F fluorodeoxyglucose (FDG) PET can provide information about the presence of non‐AD pathologies in autopsy‐proven AD patients.MethodOur cohort included 55 patients with antemortem FDG‐PET and autopsy‐proven intermediate/high ADNC from the UCSF Neurodegenerative Diseases Brain Bank. All patients underwent FDG‐PET. Standardized uptake value ratio (SUVR) images were computed using the pons as reference region. W‐maps (adjusted Z‐score maps) were created, comparing each patient to a group of 187 controls (age range: 20‐96, 40% males). Voxel‐wise correlations were computed to verify the unique contribution of each neuropathology to cerebral hypometabolism, while controlling for age, sex, time between FDG‐PET scan and death, scanner type, Thal and Braak staging, and the presence of all other co‐pathologies. Associations between SUVR values in specific region of interests (ROIs) were also assessed. The ROIs included were the following: Landau AD ROI for AD pathology, Cingulate Island Sign (CIS) for Lewy body disease, Inferior/Medial Temporal Lobe (IMT) and IMT/Frontal Supraorbital (IMT/FSO) ratios for limbic‐predominant age‐related TDP43 encephalopathy neuropathologic change (LATE‐NC).ResultMean age was 63.8 ± 10.5, mean time between FDG and death was 6.2 ± 2.8, and mean MMSE was 21.1 ± 7.1 at the time of PET (Table 1). Group averaged W‐map showed the typical temporo‐parietal AD pattern; hypometabolism in these regions was associated with higher Thal phase and Braak stage (Figure 1). Lewy body disease (LBD), argyrophilic grain disease (AGD), aging‐related tau astrogliopathy (ARTAG), cerebral amyloid angiopathy (CAA) and vascular brain injury (VBI) were associated with hypometabolism in small discrete regional clusters (Figure 2). The Landau AD ROI was associated with both Thal (rs = ‐0.325, p = .015) and Braak stages (rs = ‐0.447, p&lt;.001). The CIS sign was not associated with the presence of LBD (t(53) = 1.01, p = 0.319). Both the IMT (t(53) = ‐2.25, p = .028) and IMT/FSO (t(53) = ‐3.40, p = .001) ratios were associated with the presence of LATE‐NC.ConclusionCo‐pathologies make a relatively small contribution to hypometabolism in patients with intermediate‐high ADNC. Novel biomarkers are needed for precise detection of co‐pathologies.