Alzheimer's Disease Tau Research Articles

Tau PET: utility as a biomarker for chronic traumatic encephalopathy

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by tau deposition in the depths of the sulci associated with exposure to repetitive head impacts (RHI). It is a post‐mortem diagnosis. We previously reported a frontotemporal predominant tau 18F‐MK6240 PET pattern resembling the distribution of CTE in a retired Australian Rules Football player in the context of a moderate amyloid‐beta plaque burden.1 This study aimed to investigate the utility of 18F‐MK6240 PET as a potential biomarker for CTE in contact sports players with exposure to RHI (sRHI).MethodsRHI (n = 33) and age‐matched healthy controls (HC) (n = 32) completed amyloid (18F‐NAV4694) and tau (18F‐MK6240) PET scans. Amyloid PET was quantified in Centiloids. 18F‐MK240 standardized uptake value ratios (SUVRs) were generated for the dorsolateral prefrontal cortex and composite regions of interest (ROI) (frontal; mesial temporal; temporoparietal).ResultFor sRHI, the primary contact sport was Australian Rules Football (n = 17), boxing/kickboxing/martial arts (n = 11), rugby (n = 4) and soccer (n = 1), with 36.4% participating at a professional level. sRHI had a mean age of 54.2 (±9.2) (vs HC 53.0±9.5, p = 0.61), and 94% were male (vs HC 78%, p = 0.08). sRHI did not differ from HC in years of education (p = 0.46) but had more impaired MMSE (28.1±1.9 vs 29.3±0.8, p = 0.006, d = ‐0.80) and Clinical Dementia Rating scores (0.21±0.3 vs 0±0, p<0.001, d = 1.25). sRHI and HC did not differ in mean Centiloid values (2.9±8.4 vs 3.0±8.2). sRHI and HC did not differ in 18F‐MK6240 SUVR in the regions examined, and no differences were observed between professional and amateur sRHI.ConclusionContact sports players with exposure to repetitive head impacts did not differ from age‐matched healthy controls on 18F‐MK6240 SUVR in frontal, mesial temporal, and temporoparietal brain regions. Study limitations include the small sample size, heterogeneity in sports type and highest level of participation, and participants with relatively mild cognitive and functional impairments. Additionally, while 18F‐MK6240 has high affinity for 3R/4R tau in Alzheimer’s disease, its affinity in CTE, particularly important at early stages, remains unclear.

Tau and lipid coalescence drives early lipid dysregulation in Alzheimer’s disease

AbstractBackgroundIn Alzheimer’s disease (AD), intraneuronal tau protein accumulation into neurofibrillary tangles correlates with clinical signs and neurodegeneration1. Besides neurotoxic protein aggregation, dysregulation of lipid metabolism is emerging as a common disease mechanism2. The main regulators of lipid metabolism in the brain are astrocytes and astrocyte‐neuron communication is key to provide metabolic support to neuron3. While tau has been suggested to bind to lipids4, little is known about the potential tau‐lipid interactions in the brain, it’s role in neuron‐astrocyte crosstalk and how this relates to AD pathology.MethodsWe employ a multiscale approach harnessing human 2D and 3D multicellular models combined with advanced imaging techniques, spanning from single molecule insights to ultrastructural features and functional imaging. We aim to unravel the structural and functional complexity of emerging protein‐lipid landscapes in AD and to elucidate how their misregulation triggers early lipid dyshomeostasis.ResultsTau propagates in brain organoids in highly dynamic intracellular droplet‐like structures rich in lipids. Strikingly, the molecular identity of tau droplets is cell‐type specific; tau interact with lipids in neurons but not in astrocytes (fig.1‐2). The dynamics of neuronal tau‐lipid accumulations are driven by microtubule interactions and show liquid‐like behavior. Furthermore, highly dynamic tau‐lipid droplets transition to stillness overtime giving rise to a heterogenous spectrum of conformational ensembles of tau (fig.3).ConclusionTau‐lipid interactions in vivo are neuron‐specific. Lipid colocalization correlates with dramatic changes in the structural properties of tau. In neurons, tau and lipids coalesce in highly dynamic intracellular liquid‐like droplets that undergo time‐dependent transition to potential pathological states. Our results highlight intriguing functional implications of cell‐type specific tau‐lipid interactions impacting on neuron‐astrocyte communication and overall brain lipid metabolism. Targeting tau‐lipid interactions in neurons promise exciting new avenues in AD therapeutic strategies.1. Busche, et al. Synergy between amyloid‐β and tau in Alzheimer’s disease. Nat. Neurosci. (2020).2. Yin. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. FEBS J. (2022).3. Yang, et al. Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases. Cell Biosci. (2022).4. Sallaberry, et al. Tau and Membranes: Interactions That Promote Folding and Condensation. Front. Cell Dev. Biol. (2021).

Tau PET: utility as a biomarker for chronic traumatic encephalopathy

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by tau deposition in the depths of the sulci associated with exposure to repetitive head impacts (RHI). It is a post‐mortem diagnosis. We previously reported a frontotemporal predominant tau 18F‐MK6240 PET pattern resembling the distribution of CTE in a retired Australian Rules Football player in the context of a moderate amyloid‐beta plaque burden.1 This study aimed to investigate the utility of 18F‐MK6240 PET as a potential biomarker for CTE in contact sports players with exposure to RHI (sRHI).MethodsRHI (n = 33) and age‐matched healthy controls (HC) (n = 32) completed amyloid (18F‐NAV4694) and tau (18F‐MK6240) PET scans. Amyloid PET was quantified in Centiloids. 18F‐MK240 standardized uptake value ratios (SUVRs) were generated for the dorsolateral prefrontal cortex and composite regions of interest (ROI) (frontal; mesial temporal; temporoparietal).ResultFor sRHI, the primary contact sport was Australian Rules Football (n = 17), boxing/kickboxing/martial arts (n = 11), rugby (n = 4) and soccer (n = 1), with 36.4% participating at a professional level. sRHI had a mean age of 54.2 (±9.2) (vs HC 53.0±9.5, p = 0.61), and 94% were male (vs HC 78%, p = 0.08). sRHI did not differ from HC in years of education (p = 0.46) but had more impaired MMSE (28.1±1.9 vs 29.3±0.8, p = 0.006, d = ‐0.80) and Clinical Dementia Rating scores (0.21±0.3 vs 0±0, p<0.001, d = 1.25). sRHI and HC did not differ in mean Centiloid values (2.9±8.4 vs 3.0±8.2). sRHI and HC did not differ in 18F‐MK6240 SUVR in the regions examined, and no differences were observed between professional and amateur sRHI.ConclusionContact sports players with exposure to repetitive head impacts did not differ from age‐matched healthy controls on 18F‐MK6240 SUVR in frontal, mesial temporal, and temporoparietal brain regions. Study limitations include the small sample size, heterogeneity in sports type and highest level of participation, and participants with relatively mild cognitive and functional impairments. Additionally, while 18F‐MK6240 has high affinity for 3R/4R tau in Alzheimer’s disease, its affinity in CTE, particularly important at early stages, remains unclear.

Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities

AbstractBackgroundWhite matter injury had been mostly considered a result of chronic ischemia caused by cerebral small vessel disease. However, recent studies reported that white matter degeneration could also be an important pathophysiological feature in Alzheimer’s disease (AD). This study aimed to identify the relationship between AD biomarkers, particularly amyloid‐beta (Aβ) and tau deposition, with white matter hyperintensities (WMHs) representing cerebral white matter injury.MethodA total 456 older adults aging from 55 to 90 years including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV‐1451 PET for measuring tau deposition, and MRI scans with fluid‐attenuated inversion recovery image for measuring WMH volume. For PET scans, standard uptake value ratio (SUVR) was used for the analyses; combined regions of hemispheric white matter, inferior cerebellum and pons were used as the reference region when obtaining SUVRs. The relationships between Aβ or tau deposition and WMH volume were examined using multiple regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and baseline as well as change of WMH volume over 2 years were used as dependent variables.ResultBaseline Aβ deposition levels had significant positive association with longitudinal change of WMH volume over 2 years (β = 0.238, p = 0.009), but not with WMH volume at baseline. Baseline tau was not related with any of WMH volume at baseline and longitudinal change of WMH volume over 2 years. We also found significant interaction effect between baseline Aβ deposition level and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aβ deposition was associated with increase of WMH volume over 2 years in female (β = 0.427, p = 0.001), but not in male.ConclusionOur findings suggest that Aβ deposition, but not tau, accelerates cerebral white matter injury, particularly in female.

Relationships between KLOTHO and APOE4‐associated β‐amyloid and tau alterations across AD continuum

AbstractBackgroundApolipoprotein E ε4 allele (APOE4) is the leading genetic risk factor for Alzheimer’s disease (AD). APOE4 carriers (APOE4+) exhibit greater accumulation of the two AD neuropathological hallmarks, beta‐amyloid (β‐amyloid) and tau. KLOTHO KL‐VS heterozygosity (KL‐VSHET) attenuates APOE4‐related β‐amyloid and age‐related tau burden in cognitively normal individuals. It remains unclear whether this holds true for individuals with mild cognitive impairment (MCI) and AD. Here we investigate whether KL‐VSHET attenuates APOE4‐related cerebrospinal fluid (CSF) AD‐biomarker burden across the AD continuum.MethodMiddle‐aged and older adults (N = 396; MeanAge = 65) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center who were genotyped for KLOTHO and APOE and underwent CSF sampling were included in analyses. General linear models, covarying for sex, age, and AD family history, examined whether APOE4 yielded expected outcomes on β‐amyloid and tau burden. Follow‐up regression analyses, stratified by KL‐VS genotype [non‐carriers(KL‐VSNC,N = 293); KL‐VSHET (N = 103)], evaluated whether the APOE4 associations with β‐amyloid and tau differed between KL‐VSHET and KL‐VSNC. Analyses were stratified further by diagnosis [cognitively normal (N = 308) or MCI/AD (N = 88)] to investigate whether the relationships between APOE4 and β‐amyloid or tau differed among KL‐VSHET and KL‐VSNC in cognitively normal and MCI/AD participants.ResultResults for the entire sample, as well as stratified by KL‐VS status and diagnosis, are presented in Table 1. When the analysis was stratified by KL‐VS status, the APOE4+ effect on both β‐amyloid and tau burden was seen among KL‐VSNC but not KL‐VSHET. When further stratifying by diagnosis, the same pattern of attenuation among KL‐VSHET was observed for β‐amyloid burden in both cognitively normal individuals and MCI/AD whereas for tau burden, we only observed a non‐significant trend among cognitively normal persons (KL‐VSNC: p = 0.10; KL‐VSHET: p = 0.74).ConclusionKL‐VSHET attenuates both APOE4‐related CSF β‐amyloid and tau burden in cognitively normal individuals. This attenuation extends to CSF β‐amyloid but not tau accumulation in MCI/AD. These results add to the literature suggesting that KL‐VS heterozygosity is protective against APOE‐related biomolecular alterations that confer AD risk.

Pseudo‐longitudinal trajectories of cerebrovascular disease biomarkers in adults with Down syndrome across the lifespan

AbstractBackgroundAdults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, but it is unknown when cerebrovascular disease emerges across the lifespan.MethodAdults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n = 241; age = 25‐72, 44±10; 45% women; 77/11/12% Cognitively‐Stable/MCI‐DS/AD dementia) underwent harmonized MRI and received a cognitive diagnosis at a consensus conference. Cross‐sectional white matter hyperintensity volume (WMH; ischemic small vessel disease), enlarged perivascular space score (PVS; impaired toxin clearance), chronic infarcts (large vessel disease), and microbleeds (hemorrhagic small vessel disease/cerebral amyloid angiopathy) were fit against piece‐wise, left null regression models with age to estimate the age inflection point at which these cerebrovascular markers emerged. The residuals for each biomarker (i.e., more than expected for their age) were then regressed on diagnosis.ResultTotal WMH volume (0.01‐31.7, 4±4.6 cm3), enlarged PVS score (0‐26, 8±5), infarcts (15% have at least one), and microbleeds (12% have at least one) were present in this lifespan sample of adults with DS. There was a significant inflection point in the fourth decade of life for total WMH (37±6, p = 7E‐3), enlarged PVS (31±6, p = 3E‐6), and infarcts (31±9, p = 2E‐3), but not microbleeds (36±21, p = 0.7). Regionally, there were significant inflection points for frontal (36±6, p = 3E‐3), parietal (36±7, p = 0.02), and occipital (42±6, p = 0.02), but not temporal WMH (33±14, p = 0.3). AD dementia was associated with higher residuals in parietal (0.5±0.2, p = 0.02) and occipital WMH (0.6±0.3, p = 0.02).ConclusionIn adults with DS, there is cerebrovascular pathology on MRI that emerges around the same age as what has been reported for amyloid PET positivity and tau PET accumulation in this population. More posterior small vessel disease for a given age may arise with a diagnosis of AD, suggesting a cerebrovascular process in AD pathogenesis. Longitudinal assessment in relation to AD biomarkers, including amyloid and tau PET, will provide additional insight.

Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities

AbstractBackgroundWhite matter injury had been mostly considered a result of chronic ischemia caused by cerebral small vessel disease. However, recent studies reported that white matter degeneration could also be an important pathophysiological feature in Alzheimer’s disease (AD). This study aimed to identify the relationship between AD biomarkers, particularly amyloid‐beta (Aß) and tau deposition, with white matter hyperintensities (WMHs) representing cerebral white matter injury.MethodA total 456 older adults aging from 55 to 90 years including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aß deposition, [18F] AV‐1451 PET for measuring tau deposition, and MRI scans with fluid‐attenuated inversion recovery image for measuring WMH volume. For PET scans, standard uptake value ratio (SUVR) was used for the analyses; combined regions of hemispheric white matter, inferior cerebellum and pons were used as the reference region when obtaining SUVRs. The relationships between Aß or tau deposition and WMH volume were examined using multiple regression analysis. In this analysis, baseline Aß or tau were used as independent variables, and baseline as well as change of WMH volume over 2 years were used as dependent variables.ResultBaseline Aß deposition levels had significant positive association with longitudinal change of WMH volume over 2 years (ß = 0.238, p = 0.009), but not with WMH volume at baseline. Baseline tau was not related with any of WMH volume at baseline and longitudinal change of WMH volume over 2 years. We also found significant interaction effect between baseline Aß deposition level and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aß deposition was associated with increase of WMH volume over 2 years in female (ß = 0.427, p = 0.001), but not in male.ConclusionOur findings suggest that Aß deposition, but not tau, accelerates cerebral white matter injury, particularly in female.

Identification of genetic regions associated with Alzheimer ‘s disease blood‐based biomarkers in Mexican American families

AbstractBackgroundDementias are heterogeneous age‐associated neurodegenerative disorders generally included in the broad term, Alzheimer’s disease (AD) and related dementias (ADRD). ADRD affects individuals of all ethnicities, but Hispanic individuals show a 1.5‐fold higher risk when compared to non‐Hispanic whites. Many AD risk biomarkers have been proposed but not much is known about how genetic elements control their expression. We used 2000 genome sequenced Mexican Americans from extended pedigrees to identify genetic regions associated with AD blood‐based biomarkers.MethodA total of 70 Mexican American subjects were diagnosed as ADRD cases (h2 = 0.75, p = 2.6×10−5). We quantified plasma concentrations, using a QuanterixÒ elisa assay, of four AD candidate biomarkers AB40, AB42, TAU and NFL. We identified genomic regions associated with these biomarkers using a linear mixed model as implemented in SOLAR on a set of 28 million SNPs. Our genetic variance decomposition model is tailored for relatively rare diseases where extended pedigrees are available. Candidate SNPs identified were extensively annotated and their individual eQTL contribution to the expression of flanking genes defined.ResultThe heritability component of each AD biomarker was defined, and the most significant estimate observed for NFL (h2 = 0.33, p = 6.96×10−17). We tested the association between circulating tau and identified two genome‐wide significant associations for SNPs rs242557 (3.11×10−14) and rs242562 (1.34×10−13)(Figure 1). Both SNPs are common and located in the first and second introns of the gene MAPT, respectively, and are in a conserved region with chromatin accessibility for transcription factors, suggesting regulatory functions (Figure 2). We tested the association between both SNPs and flanking gene expression, identifying strong evidence of cis‐regulation with the expression of the antisense‐RNA (KANSL1_AS1) of the gene KANSL1.ConclusionThe identification of genetic variants associated with AD biomarkers is key to providing a reliable and cost‐effective genetic test for AD risk for the Hispanic population. The gene KANSL1 encodes a subunit of a histone acetylation enzyme and has been associated with Koolen‐de Vries Syndrome and cognitive impairment. The genetic associations are promising, but demand an independent validation to confirm their impact for the AD risk estimation.

Donanemab in Early Symptomatic Alzheimer’s Disease: Efficacy and Safety in TRAILBLAZER‐ALZ 2, a Phase 3 Randomized Clinical Trial

AbstractBackgroundIn TRAILBLAZER‐ALZ, donanemab cleared brain amyloid plaques and significantly slowed disease progression in early symptomatic Alzheimer’s disease (AD).MethodsTRAILBLAZER‐ALZ 2 (NCT04437511), a multicenter, randomized, double‐blind, placebo‐controlled trial, enrolled participants with early symptomatic AD and amyloid and tau pathology by positron‐emission tomography. The study randomized participants with low/medium‐tau (n = 1182) and high‐tau (n = 552) pathology (missing tau category, n = 2). Participants (randomized 1:1) received donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks (w) for 72w. Donanemab participants meeting amyloid clearance treatment completion criteria at 24w or 52w were switched to placebo in a blinded procedure.The primary outcomes were change in Integrated AD Rating Scale (iADRS) score from baseline at 76w in either the low/medium‐tau or combined (low/medium‐tau and high‐tau) populations. Statistical testing allocated most power (80% alpha spend) to low/medium‐tau population outcomes, with the remainder for combined population outcomes, which included clinical and biomarker assessments.ResultsIn the low/medium‐tau population, change in iADRS score at 76w was ‐6.02 with donanemab and ‐9.27 with placebo (difference, 3.25; 95% CI, 1.88 to 4.62; P<0.001), representing a 35.1% slowing of disease progression. Change in Clinical Dementia Rating Scale (CDR) – Sum of Boxes, the key secondary outcome, was 1.20 with donanemab and 1.88 with placebo (difference, ‐0.67; 95% CI ‐0.95 to ‐0.40; P<0.001), representing a 36.0% slowing. Participants receiving donanemab experienced a 38.6% lower risk of progressing to the next disease stage versus placebo over 76w (CDR‐Global score, Hazard Ratio = 0.61; P<0.001). Amyloid clearance at 24w, 52w and 76w was achieved in 34.2%, 71.3% and 80.1% of donanemab‐treated participants, respectively. Plasma P‐tau217 was significantly reduced by 39.3% from baseline with donanemab and increased by 8.4% with placebo at 76w (P<0.001). Significant, positive results across all clinical endpoints were also observed in the combined population. The incidence of serious adverse events was 17.4% (donanemab) and 15.8% (placebo), with three deaths among patients treated with donanemab who experienced serious ARIA. Adverse events with donanemab included amyloid‐related imaging abnormalities (ARIA)‐E (24.0%, 6.1% symptomatic); ARIA‐H (31.4%); and infusion‐related reactions (8.7%).ConclusionDonanemab treatment significantly slowed clinical progression at 76w and had a safety profile consistent with earlier studies.

Amyloid and tau pathology are associated with white matter properties in cognitively unimpaired older adults at risk of AD dementia

AbstractBackgroundWhite matter changes are hypothesized to be among the earliest changes occurring in the course of Alzheimer’s disease (AD). We investigated associations between AD pathology, namely amyloid and tau, and white matter microstructural changes in cognitively unimpaired individuals at risk of AD dementia. We expected higher levels of pathology to be related to lower free‐water‐corrected fractional anisotropy.MethodWe studied 223 cognitively normal older adults with PET and multi‐shell diffusion MRI from the PREVENT‐AD cohort. We first measured standardized uptake value ratios (SUVRs) in 40 brain regions for amyloid‐ß (Aß, i.e., lateral and medial prefrontal, parietal, lateral temporal, and cingulate cortical regions in both hemispheres) and 26 brain regions for tau (i.e., Braak stages I, III, and IV). We then used TractSeg, a deep learning framework, to segment 49 well‐established white matter bundles. We mapped free‐water‐corrected fractional anisotropy (FAT) in those bundles. Lastly, to explore the relationships between AD pathology and white matter microstructure across bundles, we applied two separate partial least squares analyses: one for Aß pathology and one for tau (Figure 1).ResultWe found one significant latent variable relating Aß pathology to FAT. Specifically, higher levels of Aß pathology were associated with the combination of higher levels of FAT within the rostral body of the uncinate fascicle and superior longitudinal fascicle (Figure 2A). We found two significant latent variables relating tau pathology to FAT for which higher levels of tau pathology were associated with elevated FAT within the uncinate fascicle, thalamo‐occipital bundle, optic radiation, inferior occipitofrontal fascicle, inferior longitudinal fascicle, middle longitudinal fascicle, etc. (Figure 2B).ConclusionIn cognitively unimpaired individuals at risk of AD, increased Aß and tau pathology were associated with higher levels of FAT in AD‐related bundles. These unexpected findings may suggest an inverted U‐shape pattern between AD pathology and FAT in the preclinical phase of AD for which FAT values would start by increasing before decreasing later in the course of the disease. This first increase might be a marker of early pathological processes such as neuroinflammation or swelling.

Herpes Simplex Virus Infection and in vivo Alzheimer’s Disease Pathologies

AbstractBackgroundInterest in the role of Herpes Simplex Virus (HSV) infection in the pathogenesis of Alzheimer’s disease (AD) has increased in recent years. However, previous studies yielded inconsistent findings and no studies have yet investigated the relationship between HSV infection and in vivo AD pathologies such as beta‐amyloid (Aβ) and tau deposition in brain. We examined whether the level of serum anti‐HSV immunoglobulin G (IgG) antibodies (HSV‐IgG), an index of past infection of HSV, is associated with in vivo Aβ and tau deposition in nondemented individuals. We also investigated the modulating effect of HSV‐IgG titer on the relationship between Aβ and tau deposition.MethodA total of 426 nondemented older individuals (55‐90 years old) were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. All participants underwent comprehensive clinical assessment, [11C]‐Pittsburgh Compound B positron emission tomography (PET), and blood sampling for measurement of serum HSV antibodies. A subset of participants (N = 129) underwent [18F] AV‐1451 PET. Individuals whose HSV‐IgG titer was lower than 25 percentile of the whole group was classified as the HSVlow group, while those with HSV‐IgG titer higher than 25 percentile were classified as the HSVhigh group.ResultThere was no significant difference in age, sex, clinical diagnosis (cognitive normal vs. mild cognitive impairment), and apolipoprotein E e4 positivity (APOE4) between the HSVlow (N = 106) and HSVhigh (N = 320) groups. In terms of AD biomarkers, neither global Aβ nor tau deposition was different between the HSVhigh and HSVlow groups, even after controlling the effect of age, sex, and APOE4. However, there was a significant HSV group x Aβ deposition interaction effect on tau deposition (p = 0.037), suggesting the level of HSV‐IgG modulates the relationship between Aβ and tau deposition. Subsequent subgroup analyses showed a significant positive association between Aβ and tau deposition only in the HSVhigh group (p < 0.001), but not in the HSVlow group.ConclusionOur finding suggests that past HSV infection may aggravate the influence of Aβ on tau deposition. In regard of AD prevention, the result also supports that more attention needed to be paid to controlling HSV infection.

Modulation of cannabinoid receptor‐2 alters brain clearance of human tau

AbstractBackgroundMultiple studies have demonstrated a strong neuroinflammatory response in the presence of Tau pathology, which is strongly associated with the clinical symptoms and cognitive decline found in Alzheimer’s disease (AD). The correlation between AD progression and tau pathologies, rather than Ab accumulation, suggests that targeting pathological tau may be a more effective therapeutic approach. Microglia have been implicated in tauopathies as they may contribute to tau phosphorylation and aggregation and the uptake and spread of seed‐competent tau to healthy neurons due to dysfunctional degradation. Cannabinoid type 2 receptors (CB2) are highly expressed in immune cells and upregulated in activated microglia under conditions of neurologic disease, such as AD. The pharmacological modulation of CB2 have demonstrated a reduction in inflammation and plaque deposition, suggesting a role of CB2 on the immune system to influence AD‐related pathologies and phenotypes. However, there are limited findings on the CB2 regulation of tau accumulation.MethodWe have generated organotypic brain slice cultures from CB2‐EGFP/f/f mice and transduced with rAAV‐P301L/S320F‐human tau, which previously has shown to accumulate total tau and develop insoluble tau species. Slices were treated with CB2‐selective compounds and evaluated for tau pathology and microglial phenotypes using real‐time imaging and biochemical analyses.ResultPrevious investigation in our lab of a synucleinopathy animal model revealed the capacity of CB2 signaling to alter the function of immune cells and reduce accumulation of phosphorylated human alpha‐synuclein. Furthermore, we have determined that treatment with a CB2 inverse agonist will increase phagocytosis of pHrodo E. coli bioparticles in microglia BV2 cultures stimulated by LPS. Our preliminary work in brain slices over‐expressing mutant human tau show a trend toward reduced ratio of phosphorylated tau (Ser202/Thr205) to total tau in the soluble protein fraction (p = 0.0549) in slices treated with CB2 inverse agonist SR144528 compared to vehicle. We are repeating the experiment and performing further evaluations in organotypic brain slice cultures from CB2‐KO mice.ConclusionThese studies will advance our understanding of the role of brain CB2 in pathologic tau removal and potentially highlight CB2 as a therapeutic target against tauopathies such as AD.

Does the Timing of Alzheimer’s Disease vary by Severity of Intellectual Disability in Down Syndrome?

AbstractBackgroundTrisomy 21 causes Down syndrome (DS) and is a recognized cause of Alzheimer’s disease (AD). The triplication of the amyloid precursor protein gene leads to an overexpression of amyloid‐beta (Aβ), which accumulates into extracellular plaques, followed by intracellular neurofibrillary tau tangles (Lott & Head, 2019). However, variability in the age of AD onset in DS spans 25+ years (Iulita et al., 2022). As the DS field moves to AD clinical trials, it is important to identify factors related to this variability, such as premorbid severity of intellectual disability (ID). We compared the age‐trajectory of the AD biomarkers Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type (full, mosaic, translocation) and APOE statusMethodAnalyses involved 361 adults with DS (M = 45.22 years, SD = 9.92) from the Alzheimer’s Biomarkers Consortium‐Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was recorded. PET was acquired using [11C] PiB for Aβ, and [18F] AV‐1451 for tau in 162 participants. Aβ was quantified using the centiloid method and tau was quantified as SUVR (reference: cerebellar cortex) in a composite region determined as the volume‐weighted average of select FreeSurfer 5.3, T1 MR‐based components.ResultsGeneral linear models controlling for site, age, trisomy type and APOE status indicated no significant effect of premorbid ID level by age on the cognitive outcomes (Figure 1a‐e). There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET (Figure 2a‐b). There was not a significant difference in age of those with mild cognitive impairment‐DS (MCI‐DS) or dementia by premorbid ID level (Figure 3).ConclusionThis study adds to the characterization of the time course of AD pathology and clinical symptomology in DS. Findings provide robust evidence of a similar time course in AD trajectory across severity of ID, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials. Premorbid IQ may have little effect on AD biomarkers in DS in contrast to findings in neurotypical populations.

Clinical effects of Lewy body pathology in clinically unimpaired and cognitively impaired individuals – A prospective longitudinal study

AbstractBackgroundAggregates of misfolded α‐synuclein are the underlying pathology of Lewy body (LB) disease. Little is known about the early effects of LB pathology in preclinical (i.e., pre‐symptomatic) individuals. Further, there is poor knowledge about the independent clinical effects of Lewy body (LB) pathology in patients with cognitive decline, especially when coexisting with Alzheimer’s disease (AD) pathology.MethodHere, we examined the effects of LB pathology using a cerebrospinal fluid α‐synuclein seeding aggregation assay in 1,182 cognitively and neurologically unimpaired participants as well as 882 participants with mild cognitive impairment or dementia from the BioFINDER‐1 and BioFINDER‐2 studies.ResultIn clinically unimpaired individuals, we found that 8% were LB‐positive, 26% Aβ‐positive (12% of those were also LB‐positive), and 16% tau‐positive. LB pathology had independent and significant negative effects on cross‐sectional and longitudinal global cognition and memory. These were similar in magnitude to the effects of tau pathology and more pronounced than those of Aβ pathology. Participants with both LB and AD (Aβ and tau) pathology exhibited faster cognitive decline than those with just LB or AD pathology. LB, but not AD, pathology was associated with reduced sense of smell.In cognitively impaired individuals, we found that 23% of participants had LB pathology, of whom only 32% fulfilled clinical criteria of Parkinson’s disease or dementia with Lewy bodies, and 54% exhibited AD pathology (amyloid‐β+ and tau+). Within the LB‐positive group, 48% also had AD‐pathology. In the AD‐positive group, 17% of patients with mild cognitive impairment and 24% of those with dementia were also LB‐positive. LB pathology was associated with worse attention/executive, visuospatial, and motor function independently of AD pathology. Moreover, LB pathology was also independently associated with a faster longitudinal decline in all examined cognitive functions.ConclusionThis study highlights the cognitive effects of LB pathology, independent from AD pathology, in clinically unimpaired individuals, which will be important to consider for prognosis and design of both preclinical AD and LB disease trials.Further, analyzing LB status, in addition to amyloid‐β and tau, in cognitively impaired individuals provides a better precision medicine approach identifying patient subgroups with different clinical trajectories.

Level of blood Tau and p‐Tau : a non‐invasive approach for the diagnosis of Alzheimer’s Disease(AD)

AbstractBackgroundProminent expression of Tau and phosphorylated Tau in cerebrospinal fluid (CSF) is one of the well‐known hallmarks of the Alzheimer’s disease (AD). High levels of p‐Tau can easily differentiate AD from other neurodegenerative disease. However, the serum levels of these proteins in AD patients are not well explored. This study provides an alternative non‐invasive approach to diagnose the disease by evaluating the level of Tau and p‐Tau181 in serum samples.MethodBlood samples were collected from 39 AD patients, 37 MCI patients and 37 elderly individuals as controls. Quantification of tau and pTau in serum samples was done with the help of a label free real time Surface Plasmon Resonance technology, and further validated by Western Blot. Statistical analysis, including Receiver Operating Characteristic (ROC), was done for further affirmation.ResultThe concentrations of serum Tau and p‐Tau181 were significantly higher (p<0.00001) in AD (Tau; 47.49±9.00ng/µL, p‐Tau181; 0.161±0.04 ng/µL) compared to MCI (Tau; 39.26±7.78 ng/µL, p‐Tau181; 0.135±0.02 ng/µL) and were further compared to elderly controls (Tau; 34.92±6.58 ng/µL, p‐Tau181; 0.122±0.01 ng/ µL). A significant (p<0.0001) downhill correlation was found between Tau as well as p‐Tau181 levels with HMSE and MoCA score.ConclusionThis study for the first time reports the concentration of Tau and p‐Tau181 in serum of AD and MCI patients. The cut‐off values of Tau and p‐Tau181 of AD and MCI patients with sensitivity and specificity reveal that serum level of these proteins can be used as a predictive marker for AD and MCI.

Developing Topics.

E2814 is a human IgG1 antibody that binds to microtubule binding region of tau (MTBR-tau), a critical domain for the seeding and spreading of tau pathology in Alzheimer's Disease (AD). It is being developed for the treatment of AD by stopping tau propagation and slowing the associated cognitive decline. E2814 has been evaluated in healthy and Dominantly Inherited Alzheimer's Disease (DIAD) participants for safety, pharmacokinetics (PK), and cerebrospinal fluid (CSF) target engagement. Seventy-two healthy participants were enrolled in single and multiple ascending dose cohorts of Study 001 (NCT04231513) and received randomized, double-blind, placebo-controlled treatment of E2814. Intravenous infusion of single and multiple doses (once every 4 weeks for three times) were administered. In Study 103 (NCT04971733), 7 DIAD participants with confirmed mutations and mild to moderate cognitive impairment were enrolled and received open-label treatment of E2814. Four sequential doses were evaluated as intravenous infusion every 4 weeks. Serum and CSF PK, and CSF target engagement (by analyzing both bound and unbound MTBR-tau299 and MTBR-tau354 [containing the epitopes of E2814]) were measured in both healthy and DIAD participants, as well as safety assessments. CSF MTBR-tau243 recapitulating AD tau pathology was also measured in DIAD participants using methods previously described (Horie et al., J Prev Alz Dis 2022). E2814 was safe and well-tolerated over a wide dose range. No infusion-related reactions or other clinically significant safety signals were observed with single or repeated dose administration for up to 15 months. E2814 showed a dose-related increase in serum and CSF exposure with CSF-to-serum ratio of ∼0.2%, comparable between healthy and DIAD participants. CSF target engagement was demonstrated by concentration-related and sustained MTBR-tau299 and MTBR-tau354 binding in healthy and DIAD participants. More importantly, E2814 elicited a rapid and robust reduction on MTBR-tau243, a neurofibrillary tangle-specific biomarker, in DIAD participants. E2814 demonstrated promising safety, PK and CSF target engagement profile in DIAD participants, and showed evidence of downstream effects on tangle-specific biomarker MTBR-tau243. Data supports further evaluation in the ongoing Ph2/3 DIAN-TU Tau NexGen Platform Study in DIAD (NCT05269394) and future exploration in sporadic AD.

The Interplay of Tau and Amyloid Beta Pathologies in Alzheimer's Disease

Alzheimer’s is a progressive neurodegenerative disease that is associated with cognitive decline and dementia. It is characterized by the buildup of beta-amyloid (Aβ) plaques and neurofibrillary tau tangles in the brain. The Aβ plaques are formed through insoluble Aβ fragments clumping together in between neurons and blocking synaptic function. On the other hand, neurofibrillary tau tangles are formed through the misfolding of tau monomers which then accumulate within neurons. Although original research focused on the two components separately, recent research has attempted to view the interplay between Aβ and tau to figure out the impact and discover potential treatments for Alzheimer’s. A lot about Alzheimer’s is still unknown and we are still figuring out how exactly the plaques and tangles are created. Alzheimer’s currently does not have a cure, but there are FDA-approved treatments that can differ depending on the stage of Alzheimer’s. These medications are synthesized to either slow disease progression or alleviate the symptoms temporarily. The objectives of this paper are to investigate the relationship between the beta-amyloid plaques and the tau tangles, explore their combined impact, and consider the implications of their interactions that will potentially help us treat Alzheimer’s in the future.

Association of Tooth Loss with Alzheimer's Disease Tau Pathologies Assessed by Positron Emission Tomography.

Deterioration of the oral environment is one of the risk factors for dementia. A previous study of an Alzheimer's disease (AD) model mouse suggests that tooth loss induces denervation of the mesencephalic trigeminal nucleus and neuroinflammation, possibly leading to accelerated tau dissemination from the nearby locus coeruleus (LC). To elucidate the relevance of oral conditions and amyloid-β (Aβ) and tau pathologies in human participants. We examined the number of remaining teeth and the biofilm-gingival interface index in 24 AD-spectrum patients and 19 age-matched healthy controls (HCs). They also underwent positron emission tomography (PET) imaging of Aβ and tau with specific radiotracers, 11C-PiB and 18F-PM-PBB3, respectively. All AD-spectrum patients were Aβ-positive, and all HCs were Aβ-negative. We analyzed the correlation between the oral parameters and radiotracer retention. No differences were found in oral conditions between the AD and HC groups. 11C-PiB retentions did not correlate with the oral indices in either group. In AD-spectrum patients, brain-wide, voxel-based image analysis highlighted several regions, including the LC and associated brainstem substructures, as areas where 18F-PM-PBB3 retentions negatively correlated with the remaining teeth and revealed the correlation of tau deposits in the LC (r = -0.479, p = 0.018) primarily with the hippocampal and neighboring areas. The tau deposition in none of the brain regions was associated with the periodontal status. Our findings with previous preclinical evidence imply that tooth loss may enhance AD tau pathogenesis, promoting tau spreading from LC to the hippocampal formation.

C-Src regulates δ-secretase activation and truncated Tau production by phosphorylating the E3 ligase Traf6

The accumulation of abnormal Tau protein is a common feature of various neurodegenerative diseases. Truncated Tau, resulting from cleavage by asparaginyl endopeptidase (AEP, δ-secretase), promotes its own phosphorylation and aggregation. Our study focused on understanding the regulatory mechanisms of AEP activation and its interaction with other proteins. We discovered that c-Src plays a critical role in mediating the activation and polyubiquitination of AEP in response to epidermal growth factor (EGF) stimulation. Additionally, we investigated the involvement of tumor necrosis factor receptor-associated factor 6 (Traf6), an E3 ligase, in the regulation of AEP levels and its interaction with c-Src. Knockdown of Traf6 effectively inhibited c-Src-induced AEP activation. To gain further insights into the molecular mechanisms, we employed mass spectrometry (MS) to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src. By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. Pharmacological inhibition of c-Src reduced the phosphorylation of Traf6 and inhibited AEP activation in neurons derived from human induced pluripotent stem cells (hiPSCs). Conditional knockout of Traf6 in neurons prevented c-Src-induced AEP activation and subsequent Tau truncation in vivo. Moreover, phosphorylation of Traf6 is highly correlated with AEP activation, Tau368 and pathological Tau (AT8) in Alzheimer's disease (AD) brain. Overall, our study elucidates the role of c-Src in regulating AEP-cleaved Tau through phosphorylating Traf6. Targeting the c-Src/Traf6 pathway may hold potential for the treatment of AD and other tauopathies.

Tau seed amplification assay reveals relationship between seeding and pathological forms of tau in Alzheimer’s disease brain

Tau seed amplification assays (SAAs) directly measure the seeding activity of tau and would therefore be ideal biomarkers for clinical trials targeting seeding-competent tau in Alzheimer’s disease (AD). However, the precise relationship between tau seeding measured by SAA and the levels of pathological forms of tau in the AD brain remains unknown. We developed a new tau SAA based on full-length 0N3R tau with sensitivity in the low fg/ml range and used it to characterize 103 brain samples from three independent cohorts. Tau seeding clearly discriminated between AD and control brain samples. Interestingly, seeding was absent in Progressive Supranuclear Palsy (PSP) putamen, suggesting that our tau SAA did not amplify 4R tau aggregates from PSP brain. The specificity of our tau SAA for AD brain was further supported by analysis of matched hippocampus and cerebellum samples. While seeding was detected in hippocampus from Braak stages I-II, no seeding was present in AD cerebellum that is devoid of tau inclusions. Analysis of 40 middle frontal gyrus samples encompassing all Braak stages showed that tau SAA seeding activity gradually increased with Braak stage. This relationship between seeding activity and the presence of tau inclusions in AD brain was further supported by robust correlations between tau SAA results and the levels of phosphorylated tau212/214, phosphorylated tau181, aggregated tau, and sarkosyl-insoluble tau. Strikingly, we detected tau seeding in the middle frontal gyrus already at Braak stage II-III, suggesting that tau SAA can detect tau pathology earlier than conventional immunohistochemical staining. In conclusion, our data suggest a quantitative relationship between tau seeding activity and pathological forms of tau in the human brain and provides an important basis for further development of tau SAA for accessible human samples.