Aβ Burden Research Articles

Surprising Role for Immune Cells in Mood and Memory: Impact of Regulatory T Cells

Chronic stress manifests as depressive- and anxiety-like behavior while recurrent stress elicits disproportionate psychiatric responses linked to stress-induced immunological priming. Based on this evidence, we explored causative mechanisms of how dietary polyphenolics influence Regulatory T Cells and explored their role in preventing mood disorder and Alzheimer’s disease (AD) type cognitive deterioration and neuropathology. Using a conditional Treg depletion transgenic mouse model (Foxp3 cKO), we investigated the cause-effect relationship of Treg expression in mood disorder and AD phenotype preclinically. Interestingly depression and anxiety-like behavior coincide with cognitive decline and AD-type Aβ burden in Foxp3 cKO/5xTg-AD mice by transient depletion of FoxP3. Our studies tentatively support strategies to attenuate Treg immune responses as a potential preventative strategy in attenuating AD-type phenotype.

Cystatin F (Cst7) drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer's disease.

Microglial endolysosomal (dys)function is strongly implicated in neurodegenerative disease. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimer's disease (AD) models and human AD brain, and that the emergence of this state is emphasised in females. Cst7 (encoding cystatin F) is among the most highly upregulated genes in these microglia. However, despite such striking and robust upregulation, the function of Cst7 in neurodegenerative disease is not understood. Here, we crossed Cst7-/- mice with the AppNL-G-F mouse to test the role of Cst7 in a model of amyloid-driven AD. Surprisingly, we found that Cst7 plays a sexually dimorphic role regulating microglia in this model. In females, Cst7-/-AppNL-G-F microglia had greater endolysosomal gene expression, lysosomal burden, and amyloid beta (Aβ) burden in vivo and were more phagocytic in vitro. However, in males, Cst7-/-AppNL-G-F microglia were less inflammatory and had a reduction in lysosomal burden but had no change in Aβ burden. Overall, our study reveals functional roles for one of the most commonly upregulated genes in microglia across disease models, and the sex-specific profiles of Cst7-/--altered microglial disease phenotypes. More broadly, the findings raise important implications for AD including crucial questions on sexual dimorphism in neurodegenerative disease and the interplay between endolysosomal and inflammatory pathways in AD pathology.

Nasal delivery of polymeric nanoDisc mobilizes a synergy of central and peripheral amyloid-β clearance to treat Alzheimer's disease.

The disequilibrium of amyloid β-peptide (Aβ) between the central and peripheral pools has been claimed as an initiating event in Alzheimer's disease (AD). In this study, we employ discoidal high-density lipoproteins (HDL-Disc) mimicking Aβ antibody for directional flux of Aβ from central to peripheral catabolism, with desirable safety and translation potential. Structurally, HDL-Disc assembly (polyDisc) is prepared with aid of chitosan derivative polymerization. After intranasal administration and response to slightly acidic nasal microenvironment, polyDisc depolymerizes into carrier-free HDL-Disc with chitosan derivatives that adhere to the mucosal layer to reversibly open tight junctions, helping HDL-Disc penetrate the olfactory pathway into brain. Thereafter, HDL-Disc captures Aβ into microglia for central clearance or ferries Aβ out of the brain for liver-mediated compensatory catabolism. For synergy therapy, intranasal administration of polyDisc can effectively reduce intracerebral Aβ burden by 97.3% and vascular Aβ burden by 73.5%, ameliorate neurologic damage, and rescue memory deficits in APPswe/PS1dE9 transgenic AD mice with improved safety, especially vascular safety. Collectively, this design provides a proof of concept for developing Aβ antibody mimics to mobilize a synergy of central and peripheral Aβ clearance for AD treatment.

Astrocyte-specific knockout of YKL-40/Chi3l1 reduces Aβ burden and restores memory functions in 5xFAD mice

Glial cell-mediated neuroinflammation and neuronal attrition are highly correlated with cognitive impairment in Alzheimer’s disease. YKL-40 is a secreted astrocytic glycoprotein that serves as a diagnostic biomarker of Alzheimer’s disease. High levels of YKL-40 are associated with either advanced Alzheimer’s disease or the normal aging process. However, the functional role of YKL-40 in Alzheimer’s disease development has not been firmly established. In a 5xFAD mouse model of Alzheimer’s disease, we observed increased YKL-40 expression in the cerebrospinal fluid of 7-month-old mice and was correlated with activated astrocytes. In primary astrocytes, Aβ1-42 upregulated YKL-40 in a dose-dependent manner and was correlated with PI3-K signaling pathway activation. Furthermore, primary neurons treated with YKL-40 and/or Aβ1-42 resulted in significant synaptic degeneration, reduced dendritic complexity, and impaired electrical parameters. More importantly, astrocyte-specific knockout of YKL-40 over a period of 7 days in symptomatic 5xFAD mice could effectively reduce amyloid plaque deposition in multiple brain regions. This was also associated with attenuated glial activation, reduced neuronal attrition, and restored memory function. These biological phenotypes could be explained by enhanced uptake of Aβ1-42 peptides, increased rate of Aβ1-42 degradation and acidification of lysosomal compartment in YKL-40 knockout astrocytes. Our results provide new insights into the role of YKL-40 in Alzheimer’s disease pathogenesis and demonstrate the potential of targeting this soluble biomarker to alleviate cognitive defects in symptomatic Alzheimer’s disease patients.

Protective effects of sleep duration and physical activity on cognitive performance are influenced by β‐amyloid and brain volume but not tau burden among cognitively unimpaired older adults

AbstractBackgroundSleep and physical activity have gained traction as modifiable risk factors for Alzheimer’s disease (AD). Sleep duration is linked to amyloid‐β (Aβ) clearance while physical activity is associated with brain volume maintenance. We investigate associations between sleep duration and physical activity and cognition by testing if sleep duration—cognition and physical activity—cognition are explained by Aβ deposition and brain volume, respectively. Additionally, we explore the mediating role of tau burden in these relationships.MethodThis cross‐sectional study obtained data from participants in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, a randomized clinical trial. Cognitively unimpaired participants underwent Aβ and tau PET and brain MRI prior to randomization. Cognitive performance was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Self‐reported nightly sleep duration and weekly physical activity were the primary predictors. Regional Aβ and tau pathologies and volumes were the proposed variables influencing sleep duration—cognition or physical activity—cognition relationships.ResultAβ PET data were obtained from 4322 participants (1208 with MRI, 59% female, 29% amyloid positive). Sleep duration was associated with an Aβ composite burden (β = ‐0.005,CI:(‐0.01,‐0.001)) and Aβ burden in the anterior cingulate (ACC) (β = ‐0.012,CI:(‐0.017,‐0.006)) and medial orbitofrontal cortices (MOC) (β = ‐0.009,CI:(‐0.014,‐0.005)) but not with brain structure. Composite (β = ‐1.54,CI:(‐1.93,‐1.15)), ACC (β = ‐1.22,CI:(‐1.54,‐0.90)) and MOC (β = ‐1.44,CI:(‐1.86,‐1.02)) Aβ burden were also associated with PACC. Sleep duration—PACC association was explained by Aβ burden in path analyses (Figure 1). Physical activity was not associated with Aβ but was associated with hippocampal (β = 10.57,CI: (1.06,20.08)), parahippocampal (β = 9.3,CI:(1.69,16.91)), entorhinal (β = 14.68,CI:(1.75,27.61), and fusiform gyral (β = 38.38,CI:(5.57, 71.18)) volumes, which were also positively associated with PACC (p<0.02 for hippocampus, entorhinal cortex, and fusiform gyrus). Physical activity—cognition relationship was explained by regional volumes (Figure 2). Tau was not related to sleep duration or physical activity, and it did not moderate relationships between cognition and sleep duration or physical activity.ConclusionSleep duration and physical activity are associated with cognition through independent paths of brain Aβ and brain volume, respectively, but not tau burden. Dementia risk reduction approaches that emphasize the adequate sleep duration and a physically active lifestyle may benefit those with risk for AD.

Sex and family history differences in Aβ and tau vulnerability in preclinical Alzheimer’s disease

AbstractBackgroundFemales and individuals with a family history (FH) of Alzheimer’s disease (AD) are considered at higher risk of sporadic AD. However, how sex and maternal/paternal heredity affects in vivo AD biomarkers is not well understood. Our objectives were to 1) assess if females or individuals with a first‐degree maternal FH of AD accumulate amyloid‐beta (Aβ) and/or tau faster than males or individuals with a first‐degree paternal FH of AD and 2) assess if both could influence the rate of Aβ driving tau in preclinical AD.MethodTwo hundred and thirty‐five older adults (age 68.3 ± 5.1 years, 69.8% female) from the PREVENT‐AD cohort, cognitively unimpaired at baseline, underwent [18F]‐NAV4694 and [18F]‐AV1451 positron emission tomography (PET) scans. Longitudinal PET scans were available for 106 individuals (4.3 ± 0.4 years follow‐up). We extracted and averaged the standard uptake value ratio (SUVr) in fronto‐parietal regions for Aβ and in temporal regions for tau. We performed t‐tests and ANOVA models to assess sex or maternal/paternal FH (FHsex) differences in Aβ and tau burden or annual change. We then performed linear regression models with an interaction term between Aβ and sex (or Aβ and FHsex) on tau burden and annual change, plus additional models to adjust for age and education.ResultSex and FHsex differences on Aβ and tau burden or annual rate of change did not reach significance although females tended to have higher tau SUVr at baseline (p = 0.053) (Figure 1 & 2). We found an interaction between Aβ and sex (𝛽 = ‐0.13, p = 0.008), and between Aβ and FHsex (𝛽 = 0.11, p = 0.03), on tau at baseline (Figure 3) suggesting that, for the same level of Aβ burden, females and individuals with paternal FH of AD had higher tau burden than males and individuals with maternal FH of AD. Results were similar when adjusted for age and education.ConclusionFemales and individuals with a paternal FH of AD might need less Aβ before developing AD‐related tau, but did not accumulate tau faster. Identifying individuals more vulnerable to AD pathology, by disentangling sex‐specific effects, would help to design personalized interventions for AD.

The relationship of neuroticism to amyloid and tau pathologies in cognitively normal older adults

AbstractBackgroundPrior work has shown that individuals with higher levels of neuroticism are at an increased risk of developing Alzheimer’s Disease (AD). Increasing evidence has indicated an association of increased neuroticism to increased amyloid‐beta (Aβ) and tau burdens, suggesting that this personality trait is a risk factor for increased pathological accumulations. However, the cross‐sectional nature of these studies do not offer the ability to infer causality. Here, we replicate and extend upon previous work, assessing the relationship of neuroticism to AD pathologies in 60 older adults across three time‐points.MethodThis study included 60 cognitively normal participants from the Dallas LifeSpan Brain Study, aged 50+, that completed three time‐points of cortical Aβ scanning and a baseline personality assessment. Linear regressions were used to model the relationship of neuroticism to cortical Aβ burden (n = 60) and cortical tau burden (n = 48). Utilizing linear mixed effects models, neuroticism was used to predict cortical Aβ accumulation over 7‐10 years.ResultWe found that the effects of neuroticism on AD pathologies differs by brain regions and facets of neuroticism. Most notably, increased neuroticism predicted increased global Aβ burden (p = .042) beyond the effects of baseline age, sex, education, and depressive symptoms. When we further investigated this relationship using the facets comprising the neuroticism score, only the anger‐hostility facet of neuroticism predicted increased global Aβ burden (p = .003). Regional investigations demonstrated a significant effect of neuroticism on Aβ burden in the anterior cingulate cortex (p = .028), lateral parietal cortex (p = .035), and the posterior cingulate cortex (p = .021) and a trending effect in the dorsolateral prefrontal cortex (DLPFC) (p = .054). Contrary to our hypotheses, we did not find a significant effect of neuroticism on global or regional Aβ accumulation. Tau analyses detected an effect of neuroticism on tau burden in the DLPFC (p = .03), a predetermined region of interest. Additionally, only the anger‐hostility facet of neuroticism significantly predicted global tau burden (p = .036).ConclusionThis work demonstrates that certain regions of the brain may be at an increased risk for AD pathologies in individuals with higher neuroticism. Specific facets of neuroticism, such as anger‐hostility, may also confer additional risk for these augmented accumulations.

Sex and family history differences in Aβ and tau vulnerability in preclinical Alzheimer’s disease

AbstractBackgroundFemales and individuals with a family history (FH) of Alzheimer’s disease (AD) are considered at higher risk of sporadic AD. However, how sex and maternal/paternal heredity affects in vivo AD biomarkers is not well understood. Our objectives were to 1) assess if females or individuals with a first‐degree maternal FH of AD accumulate amyloid‐beta (Aβ) and/or tau faster than males or individuals with a first‐degree paternal FH of AD and 2) assess if both could influence the rate of Aβ driving tau in preclinical AD.MethodTwo hundred and thirty‐five older adults (age 68.3 ± 5.1 years, 69.8% female) from the PREVENT‐AD cohort, cognitively unimpaired at baseline, underwent [18F]‐NAV4694 and [18F]‐AV1451 positron emission tomography (PET) scans. Longitudinal PET scans were available for 106 individuals (4.3 ± 0.4 years follow‐up). We extracted and averaged the standard uptake value ratio (SUVr) in fronto‐parietal regions for Aβ and in temporal regions for tau. We performed t‐tests and ANOVA models to assess sex or maternal/paternal FH (FHsex) differences in Aβ and tau burden or annual change. We then performed linear regression models with an interaction term between Aβ and sex (or Aβ and FHsex) on tau burden and annual change, plus additional models to adjust for age and education.ResultSex and FHsex differences on Aβ and tau burden or annual rate of change did not reach significance although females tended to have higher tau SUVr at baseline (p = 0.053) (Figure 1 & 2). We found an interaction between Aβ and sex (𝛽 = ‐0.13, p = 0.008), and between Aβ and FHsex (𝛽 = 0.11, p = 0.03), on tau at baseline (Figure 3) suggesting that, for the same level of Aβ burden, females and individuals with paternal FH of AD had higher tau burden than males and individuals with maternal FH of AD. Results were similar when adjusted for age and education.ConclusionFemales and individuals with a paternal FH of AD might need less Aβ before developing AD‐related tau, but did not accumulate tau faster. Identifying individuals more vulnerable to AD pathology, by disentangling sex‐specific effects, would help to design personalized interventions for AD.

Distinct effects of cholesterol profile components on amyloid and vascular burdens

AbstractBackgroundCholesterol plays important roles in β‐amyloid (Aβ) metabolism and atherosclerosis. However, the relationships of plasma cholesterol levels with Aβ and cerebral small vessel disease (CSVD) burdens are not fully understood in Asians. Herein, we investigated the relationships between plasma cholesterol profile components and Aβ and CSVD burdens in a large, non‐demented Korean cohort.MethodWe enrolled 1,175 non‐demented participants (456 with unimpaired cognition [CU] and 719 with mild cognitive impairment [MCI]) aged ≥ 45 years who underwent Aβ PET at the Samsung Medical Center in Korea. We performed linear regression analyses with each cholesterol (low‐density lipoprotein cholesterol [LDL‐c], high‐density lipoprotein cholesterol [HDL‐c], and triglyceride) level as a predictor and each image marker (Aβ uptake on PET, white matter hyperintensity [WMH] volume, and hippocampal volume) as an outcome after controlling for potential confounders.ResultIncreased LDL‐c levels (β = 0.014 to 0.115, p = 0.013) were associated with greater Aβ uptake, independent of the APOE e4 allele genotype and lipid‐lowering medication. Decreased HDL‐c levels (β = −0.133 to −0.006, p = 0.032) were predictive of higher WMH volumes. Increased LDL‐c levels were also associated with decreased hippocampal volume (direct effect β = −0.053, p = 0.040), which was partially mediated by Aβ uptake (indirect effect β = −0.018, p = 0.006).ConclusionOur findings highlight that increased LDL‐c and decreased HDL‐c levels are important risk factors for Aβ and CSVD burdens, respectively. Furthermore, considering that plasma cholesterol profile components are potentially modified by diet, exercise, and pharmacological agents, our results provide evidence that regulating LDL‐c and HDL‐c levels is a potential strategy to prevent dementia.

Developing Topics.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is found in over half of pathologically confirmed Alzheimer's disease (AD) dementia cases. However, the region-specific relationship between AD neuropathologic change (ADNC) and LATE-NC remains unclear. Here, we investigated the intraregional and interregional associations between ADNC and LATE-NC. We analyzed multi-regional postmortem neuropathology data from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). Quantitative ADNC burden was assessed with amyloid-β (Aβ) and tau immunohistochemistry in 8 brain regions. The Aβ burden was averaged across all regions, given strong inter-regional correlations. Semi-quantitative LATE-NC burden was assessed with TDP-43 immunohistochemistry in 7 brain regions, scored in 6 grades. Hippocampal sclerosis (HS) was defined as a severe neuronal loss in a mid-hippocampal coronal section, irrespective of ADNC or LATE-NC burden. We assessed the association between regional LATE-NC and global Aβ burden, adjusting for APOE ε4, age at death, and sex. Then, we tested the intra- and inter-regional associations between LATE-NC and tau, adjusting for Aβ, APOE ε4, age at death, and sex. We performed a post-hoc subgroup analysis in participants without HS. We analyzed the data from n = 1264 deceased ROSMAP participants (Table 1). Global Aβ was positively associated with LATE-NC in most regions (Fig.1A). Interestingly, even after accounting for Aβ and APOE ε4, tau and LATE-NC were positively associated within the entorhinal (t = 7.29, p = 5.4×10-13) and midfrontal cortex (t = 4.33, p = 1.6×10-5) but not within the hippocampus (Fig.1B, bold boxes). Tau and LATE-NC were positively correlated across most interregional pairs (Fig.1B) except for negative associations between hippocampal tau (CA1/subiculum) and frontal LATE-NC. There was no association between hippocampal tau and frontal LATE-NC in the HS(-) subgroup (n = 1143; inferior frontal, p = 0.67; midfrontal, p = 0.15), suggesting that extensive hippocampal neuronal loss in HS(+) cases could have artifactually driven the negative association between hippocampal tau and frontal LATE-NC. Aβ was positively associated with LATE-NC in most regions. Even after adjusting for Aβ and APOE ε4, tau was positively associated with LATE-NC across most regions, except for hippocampal tau and frontal LATE-NC. Further studies are required to determine the underlying mechanisms linking ADNC and LATE-NC.

CD147 associates cerebrovascular lesion with Aβ pathology in Alzheimer’s disease

AbstractBackgroundCerebrovascular abnormality is recognized as a major contributor to Alzheimer’s disease (AD). However, how cerebrovascular damage accelerates Aβ production/deposition remains poorly defined. CD147, a transmembrane molecule mainly expressed in cerebral small vessels, modulates γ secretase function and Aβ production in vitro. The present study was to study whether CD147 associated cerebrovascular damage with the Aβ pathology in autopsied human brains with AD, and whether CD147 in the CSF was related with CSF Aβ AD patients from China Aging and Neurodegenerative Initiative (CANDI) cohort.MethodAmounts of soluble CD147, membrane CD147 / Claudin‐5 / CD31 and insoluble Aβ43 /42 /40 from autopsied human brain tissue samples were assessed by ELISA, Luminex and MSD, respectively. In CANDI cohort, CSF Aβ40 and 42, CSF CD147, CSF Aβ43, and CSFAβ38 were measure with Simoa, Luminex, ELISA, and MSD, respectively. Linear regression models were used to evaluate the associations between CSF CD147 with cognitive decline (MMSE and cortical thickness), GFAP, NFL, Aβ burden (18F‐Flobetapir), and Aβ isoforms (Aβ43/42/40/38).ResultIn autopsied human AD brains, the lower soluble/membrane CD147 ratio was significantly associated with worse BBB integrity (lower Claudin‐5/CD31 ratio) and with higher levels of insoluble Aβ43 and Aβ42. In the CANDI cohort, lower CSF CD147 in AD patients was also significantly associated with higher level of Aβ burden. Interestingly, CSF CD147 show a stronger association with shorter Aβ isoforms (Aβ38 ≈ Aβ40 > Aβ42 > Aβ43). Decreasing CSF CD147 was significantly linked to worse cognitive function (MMSE and cortical thickness) and with higher levels of CSF GFAP and NFL. White matter hyperintensity was negatively significantly associated with CSF CD147.ConclusionCerebrovascular damage may impair the release of CD147 from vessels, thereby further exacerbate Aβ pathology via shifting the production of Aβ from longer to shorter isoforms. The findings suggest that soluble CD147 links cerebrovascular damage and Aβ pathology and cerebrovascular CD147 could be a potential therapeutic target for AD.

Clinical Variables Contributing to Identification of Mild Cognitive Impairment Individuals With Defined ATN Profile

AbstractBackgroundThe framework globally used to classify Alzheimer’s Disease stages for research purposes includes three core biomarkers: A) Aβ burden; T) tau pathology; and N) neuronal injury. A lack of consensus exists in linking cognitive and behavioral tests used in everyday clinical practice to biological stages of dementia as defined by the ATN classification. The aim of the current study is to identify the clinical variables that best classify individuals into biologically defined cognitive profiles.MethodA total of 751 subjects, from the Alzheimer’s Disease Neuroimaging Initiative cohort, were categorized into seven ATN groups: 112 cognitively unimpaired with ATN‐; 46 cognitively unimpaired with ATN or AT+; 65 cognitively unimpaired with T, N or TN+; 128 amnestic Mild Cognitive Impairment (aMCI) with ATN‐; 223 aMCI with ATN or AT+; 94 aMCI with T, N or TN+ and 83 dementia with ATN or AT+. The groups for which the features exhibited differences during data exploration were classified employing 28 cognitive, behavioral, and demographic features using a supervised machine learning algorithm, specifically, a random forest classifier in combination with a synthetic oversampling technique.ResultWe found that the selected features were not able to distinguish between all seven groups and in particular between the three cognitively unimpaired groups. Therefore, classification was only performed for the three ATN‐defined aMCI groups achieving 58% overall accuracy. The Logical Delayed Recall was the most relevant feature (explaining 17% of the variance), followed by the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale 13 (16%), Everyday Cognition Informant (8%), and Alzheimer’s Disease Assessment Scale 4 (8%). Marital status, Everyday Cognition Patient and sex were not relevant (0%).ConclusionCognitive and behavioral tests were not able to accurately distinguish cognitively unimpaired individuals with different biological profiles. Although accuracy could be improved, our first results showed that a test of delayed memory, one of general cognition, and one on activities of daily living are relevant variables for distinguishing between patients with aMCI and different biological profiles. During diagnosis, treatment monitoring, or in research contexts, these variables might be informative in differentiating the three ATN‐defined aMCI profiles, especially when biomarkers are not available.

Amyloid β‐dependent tau phosphorylation is triggered by reactive astrocytes in preclinical Alzheimer’s disease

AbstractBackgroundA significant percentage of Aβ‐positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, cognitive decline.Experimental literature suggest that reactive astrocytes are necessary to unleashing Aβ effects in pathological tau phosphorylation.Here we aimed to investigate whether astrocyte reactivity is key to determining the association of Aβ burden with early tau phosphorylation in preclinical Alzheimer’s disease (AD).MethodWe assessed 1,016 CU individuals from two research and one population‐based cohort (TRIAD, Pittsburgh and MYHAT) with Aβ (plasma or PET), plasma p‐tau and GFAP measures. Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aβ‐ individuals.Lowess method and linear regressions accounting for age and sex were used to model the trajectories of plasma p‐tau epitopes as a function of Aβ burden. Cohen’s d corrected for age and sex was used to estimate effect sizes between groups.ResultWe observed that plasma p‐tau181 levels increased as a function of Aβ only in CU Ast+ individuals from Pittsburgh (β = ‐0.35,t = 3.10,p = 0.003,Fig.1a,b), MYHAT (β = ‐0.20,t = 2.26,p = 0.026, Fig.1d,e) and TRIAD (β = 0.46,t = 2.92,p = 0.004;Fig.1g,h) cohorts. A significant interaction between Aβ burden and astrocyte reactivity status on plasma p‐tau181 levels was observed in the Pittsburgh (β = ‐0.29,t = 2.30,p = 0.022;Fig.1b), MYHAT (β = ‐0.19,t = 2.07,p = 0.038;Fig.1e) and TRIAD (β = 0.46,t = 2.92,p = 0.004;Fig.1h) cohorts.Cohen’s d analysis revealed that the presence of Aβ+ and Ast+ has a large magnitude of effect on tau phosphorylation (Cohen’s d:Pittsburgh = 0.67; MYHAT = 0.69;TRIAD = 0.98;Fig.1c,f,i), whereas Aβ+ in the absence of Ast+ presented a negligible effect size. Similar results were observed for plasma p‐tau231 and p‐tau217.Voxel‐wise analysis confirmed that Aβ levels in brain regions known to present early Aβ accumulation in AD associated with plasma p‐tau181 only in Ast+ individuals (Fig.2).Tau‐PET deposition occurred as a function of Aβ burden only in CU Ast+ (Fig.3a), affecting 100% and 62% of the extension of the Braak I and II regions, respectively (Fig.3b)ConclusionWe observed biomarker evidence across multiple cohorts that the presence of astrocyte reactivity, measured by plasma GFAP, plays a key role in the association of Aβ with early tau pathology in preclinical AD.Our results might have implications for the biological definition of preclinical AD and selecting individuals for early preventive clinical trials.

The effect of basal forebrain atrophy on the rate of cognitive decline in older adults without dementia

AbstractBackgroundIn early Alzheimer’s disease, degeneration of the cholinergic basal forebrain (BF) system correlates with amyloid‐β (Aβ) burden and contributes to cognitive decline, particularly in the domains of memory and attention processing. However, the nature of these interrelationships remains unclear. This study investigated the effects of Aβ and BF atrophy on cognitive decline of memory and attention in older individuals without dementia.MethodThe BF volumes were quantified from MRIs of 577 participants (73.3 ± 6.3 years old, 55.1% female) from the Australian Imaging, Biomarker and Lifestyle (AIBL) study, including 495 cognitive unimpaired (CU) individuals and 82 with mild cognitive impairment. Aβ‐PET assessment was completed at baseline, and Aβ+ was determined using Centiloid > 20. The cognitive decline in memory and attention was assessed using the relevant AIBL composite scores, over 6.0 ± 3.1 years (up to 13 years). BF z‐scores were calculated using the mean and standard deviation of BF volumes in the CU Aβ‐ group, and z‐scores < ‐1 was classified as BF atrophy (BF+). Participants were then grouped according to the Aβ status and presence of BF atrophy (Table 1). Linear mixed‐effects models assessed differences in rates of cognitive decline in memory and attention across different classification groups. Magnitudes of differences in slopes of decline were expressed using Cohen’s d. ResultIn Aβ‐ individuals, BF atrophy was associated with faster rates of cognitive decline in both memory and attention, with medium effect sizes (Table 2 and Figure 1). In re‐analyses restricted to Aβ+ subjects, BF atrophy remained related to memory decline (p = 0.035, d = 0.33) but not to decline in attention. Compared to Aβ‐ subjects without BF atrophy, both Aβ+ groups had faster decline in both domains, with large effect sizes (all d > 0.8).ConclusionThese findings indicate that the effects of Aβ and BF atrophy are additive in terms of their influence on the rate of decline in memory. However, BF atrophy influences the rate of decline in attention only in the absence of abnormal Aβ burden.

Astrocyte reactivity potentiates longitudinal tau tangle accumulation in cognitively unimpaired individuals

AbstractBackgroundAβ accumulation precedes tau pathology in cognitively unimpaired (CU) individuals, which is an event closely related to the development of cognitive symptoms. However, Aβ leads to tau pathology in some individuals, but not in others, suggesting the presence of other processes triggering the deleterious effects of Aβ in the early Alzheimer’s disease (AD) stages. It was already demonstrated that glial fibrillary acidic protein (GFAP)‐positive astrocytes can internalize tau and might contribute to its propagation. Here we investigated whether astrocyte reactivity is a key element to determining the longitudinal accumulation and spreading of tau pathology in CU individuals.MethodWe assessed 147 CU individuals from the TRIAD cohort with available baseline Aβ‐ and Tau‐PET, plasma p‐tau181 and GFAP. Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP levels of younger Aβ‐ individuals. Longitudinal analysis included 71 CU individuals with Tau‐PET (mean follow‐up:2.3 years).Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons. We measured the annual rate of progression in Tau uptake as the difference between follow‐up and baseline uptakes divided by the time between scans. To assess individuals’ percentage of abnormal regions, we used composite brain regions corresponding to Braak histopathological stages.ResultTau‐PET deposition occurred as a function of Aβ burden only in CU Ast+ and in regions expected to present the earliest tau deposition (Fig.1a). In the longitudinal analysis, we observed that the annual rate of tau‐PET accumulation was higher in the CU Ast+ group (Fig.2a) and predicted by baseline Aβ burden only in CU Ast+ (Fig.2b). Interestingly, while the baseline association was confined to the mesial temporal cortex, the longitudinal tau‐PET accumulation as a function of Aβ/Ast presented initial tau spread over the neocortex in Braak III‐IV regions (Fig.2c).ConclusionWe observed that Tau‐PET accumulation was highest in CU Ast+ individuals, with astrocyte reactivity being necessary for the spreading of tau over the neocortex. Our findings suggest that astrocyte reactivity is an important upstream event to unleash tau accumulation and spread in CU individuals, which might have implications for selecting individuals for early preventive clinical trials.

Plasma Alzheimer’s Disease Biomarkers and Brain Amyloid in a Multi‐Ethnic Aging Cohort

AbstractBackgroundDementia diagnoses are more common among Hispanic (HW) than non‐Hispanic white (NHW) older adults. Alzheimer’s disease (AD) is the most common neuropathological finding in patients with dementia. Plasma AD biomarkers have accelerated efforts towards increasing access to timely diagnosis, but existing data often come from cohorts lacking ethnic diversity. Clinical translation of plasma AD biomarkers requires continued evaluation in study cohorts that reflect the growing ethnic diversity of the population.MethodWe studied 379 older adults (age 71.9±7.8 years old, 60.2% female) from the 1Florida Alzheimer’s Disease Research Center who underwent blood draw and analysis for P‐tau181 (Quanterix). Of these, 240 completed Aβ‐PET (converted to Centiloids). Over half (57%) self‐identified as HW (32% Cuba, 18% South American, 7% other). Analyses included 1) comparing plasma biomarker concentrations between clinically normal (CN), amnestic MCI (amnMCI), amnestic dementia (amnDEM), and nonamnestic MCI/dementia (ANCOVA controlling for age), 2) evaluating P‐tau181 correlations with Aβ burden (Spearman’s rho), and 3) determining discriminability (AUC) of Aβ‐PET[+] from Aβ‐PET[‐]. Interactions between independent variables and ethnicity were evaluated to inform whether observed relationships differed between HW and non‐Hispanic white (NHW). Lastly, using a cutoff derived from the PET sub‐cohort, we investigated rates of P‐tau181‐defined “AD positivity” (plasmaAD[+]) between HW and NHW diagnosed with amnMCI. Additional data for plasma GFAP and NfL will also be presented.ResultsPlasma P‐tau181 was higher in amnMCI (p = .004, d = 0.53) and amnDEM (p<.001, d = 0.97) than CN. Higher P‐tau181 related to greater Aβ burden (ρ = .59 [.50‐.67], p<.001) and had good discriminability between Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86 [0.81‐0.91], Youden’s Index = 2.39 pg/mL). There were no significant interactions with ethnicity. Applying the P‐tau181 cutoff (2.39 pg/mL) to all amnMCI participants, HW diagnosed with amnMCI had lower odds of being plasmaAD[+] than NHW (36.5% vs. 58.5%; OR = 0.41 [0.21‐0.78], p = .006).ConclusionPlasma P‐tau181 may aid etiological diagnosis of cognitively impaired older adults from Hispanic and non‐Hispanic ethnic origins. Hispanic ethnicity alone does not significantly influence the interpretation of how plasma P‐tau181 relates to Aβ‐PET, but may be linked to greater likelihood of non‐AD causes of memory loss. Blood‐based biomarkers could help reduce barriers to clinical diagnosis and research participation that disproportionately impact underrepresented groups.

18F]‐D3FSP amyloid‐β PET imaging in elderly adults and Alzheimer’s disease

AbstractBackgroundN‐methylderivative of Amyvid (18F‐D3FSP) displayed very similar β‐amyloid (Aβ) targeting properties to the 18F‐florbetapir tracer, but it is not well established about the performance of 18F‐D3FSP Aβ positron emission tomography (PET) imaging in Alzheimer’s disease (AD).MethodIn this study, we recruited 142 Greater‐Bay‐Area Healthy Aging Brain Study (GHABS) participants from the community and completed Simoa plasma biomarkers, MRI imaging, 18F‐D3FSP Aβ PET imaging, and cognitive assessments. MRI images were segmented using FreeSurfer (v7.2.0) according to the Desikan–Killiany atlas. 18F‐D3FSP Aβ PET images were coregistered with their corresponding MRI scans, and intensity‐normalized to the mean uptakes in the whole cerebellum, cerebellar gray matter (cerebellar GM), brain stem (PONs), white matter, and big reference separately (Figure 1A). A cortical summary COMPOSITE 18F‐D3FSP standardized uptake value ratio (SUVR) in AD typical cortical regions was calculated. We used Gaussian Mixture Model to estimate 2 gaussian distributions of low and high Aβ for COMPOSITE SUVRs, and the threshold was defined as an SUVR corresponding to a 90% probability of belonging to the low‐Aβ distribution. COMPOSITE SUVRs were compared between Aβ‐ and Aβ+ groups. Finally, we investigated the association of COMPOSITE SUVR with plasma biomarkers, including age and sex as covariates.Result18F‐D3FSP Aβ PET imaging was capable of detecting fibrillary Aβ plaques in AD, and the Aβ+ group showed substantial Aβ deposition compared to the Aβ‐ group (Fig.1B). The dementia patients had more Aβ burden than the CU, SCD, and MCI individuals (Fig.1C), and the preclinical AD individuals (Aβ+/CU) showed significantly higher Aβ SUVRs than the Aβ‐/CI and Aβ‐/CU groups (Fig.1D). The comparisons of COMPOSITE SUVR between Aβ‐ and Aβ+ had a very high effect size, particularly in the brain stem reference region (Fig.2). Higher COMPOSITE SUVRs were related to lower plasma Aβ42/40 and higher plasma p‐Tau, GFAP, NfL concentrations, especially based on the composite big reference region (Fig.3).Conclusion[18F]D3FSP is an effective Aβ tracer to detect Aβ deposition in AD. Using the big reference may be optimal for calculating SUVR by considering the Aβ positive effect size and its correlation with Aβ, tau, neurodegeneration, and neuroinflammation measured in plasma.

Development and Comparison of a Novel Mid‐Region Directed p‐Tau 181 Assay with Tau Positron Emission Tomography in Alzheimer’s Disease

AbstractBackgroundSeveral blood‐based phosphorylated tau (p‐tau) assays that focus on the N‐terminus have been developed and established as non‐invasive biomarkers for detecting Alzheimer’s disease (AD) pathologies from their early stages. However, the p‐tau measured by these assays may not necessarily reflect the accumulation of tau lesions in the brain due to correlation with Aβ burden. Therefore, there remains a significant unmet need to develop blood‐based tau biomarkers that are interchangeable with tau deposits in the brain.MethodsWe have devised a novel Simoa assay that can detect N‐ and C‐terminally truncated fragment of p‐tau181 in plasma (QST assay), utilizing an antibody against the mid‐region of tau protein for capture, and an antibody AT270 for detection. The plasma p‐tau181 was measured with both the QST assay and a conventional p‐tau181 Simoa assay (Quanterix) in 164 subjects, including 40 cognitively normal (CN) individuals, 48 with AD continuum, 50 with progressive supranuclear palsy, and 26 with other frontotemporal lobar degeneration, who underwent Aβ (11C‐PiB) and tau (18F‐PM‐PBB3, Florzorotau) positron emission tomography (PET) scans. Subsequently, we conducted a head‐to‐head comparison of p‐tau181 assays in correlation with the imaging biomarker and cognitive dysfunction.ResultsQST p‐tau assay demonstrated inferior performance compared to the Quanterix assay in the qualification of Aβ PET (QST assay: AUC = 0.771, Quanterix assay: AUC = 0.867). Neither assay showed a significant correlation with Aβ PET accumulation in the AD group. Meanwhile, the QST assay exhibited excellent correlations with tau PET accumulation in regions indicative of AD including temporal cortex and neocortex (p<0.0005), whereas the Quanterix assay demonstrated non‐linear correlations with tracer binding. In trajectories from CN to AD continuum, the QST assay exhibited a linear association, as well as tau PET accumulation, while the Quanterix assay exhibited a sigmoidal curve association.ConclusionsWe have developed a new p‐tau181 assay directly correlated with tau PET accumulation. This quantitative system serves as a promising surrogate marker for tau lesions in the AD brain, which facilitate screening and monitoring of tau deposits in various settings, including developing disease‐modifying therapeutics.

Harmonization of amyloid and tau PET tracers in a multi‐center cohort from NIA Alzheimer’s disease research centers in the United States

AbstractBackgroundThe Standardized Centralized Alzheimer’s & related dementias Neuroimaging (SCAN) project harmonizes processing of prospectively acquired PET and MRI scans from Alzheimer’s disease research centers (ADRCs) across the USA. SCAN data will be integrated with other ADRC data streams within the National Alzheimer’s Coordinating Center (NACC), including the Uniform Data Set which includes rich longitudinal demographic, cognitive, and neuropathological data, resulting in a large, potentially representative cohort. The project has sought to accommodate site‐to‐site variation in image acquisition while permitting harmonization of imaging data, necessitating new analytic approaches for different PET tracers and PET scans without MRIs.MethodPET scans underwent preprocessing for quality control and smoothing to a uniform resolution. MRI‐free processing pipelines and positivity thresholds were developed for each beta‐amyloid (Aβ)‐PET tracer: [11C]PiB, [18F]florbetaben (FBB), [18F]florbetapir (FBP) and [18F]flutafuranol (NAV). A generic Aβ‐PET template was used for spatial normalization and cortical summary SUVRs were calculated in template space. Aβ‐positivity thresholds were determined by examining both MRI‐dependent thresholds transformed into MRI‐free units and a young control mean+2SD. Centiloid (CL) conversions were completed for each Aβ‐PET tracer. Tau‐PET tracers ([18F]flortaucipir (FTP) and [18F]MK‐6240) required tracer‐specific warping templates for best performance relative to gold‐standard MRI‐dependent processing. Demographic and clinical data were obtained from NACC.Result15 ADRCs have contributed data to SCAN as of January 2023. 477 participants had preprocessed, SCAN‐compliant (https://scan.naccdata.org/) Aβ‐PET scans and NACC data; 219 of these participants (46%) also had tau‐PET scans (Table 1). This cohort included 18% of individuals from underrepresented groups. Clinical diagnostic groups ranged from cognitively unimpaired to MCI and dementia (74% of whom had AD dementia). Using pooled Aβ‐PET data across 4 tracers in CLs, there were expected differences in Aβ burden by diagnosis group (Fig. 1) and positive associations with tau (Fig. 2).ConclusionSCAN has successfully harmonized PET data from more than a dozen US ADRCs yielding a large, clinically heterogeneous cohort of deeply phenotyped research participants. SCAN data will be compatible with ADNI data allowing for further pooling of data and greater statistical power to drive critical questions in AD and related dementias research.

Association between topographic distribution of dilated perivascular spaces and Alzheimer’s disease pathologies measured by 18F‐florbetaben and PI‐2620 PET

AbstractBackgroundDilated perivascular spaces (DPVS) has been hypothesized to be implicated in the development and/or progression Alzheimer’s disease (AD). However, evidence of a relationship between its topographic distribution and burden of AD pathologies has not been well‐established. We thus aimed to evaluate whether beta‐amyloid (Aβ) and tau burdens measured in positron emission tomography (PET) are associated with topographic distribution of DPVS.MethodFifty‐one patients with amnestic mild cognitive impairment or mild dementia due to possible AD were recruited. Aβ burden was measured as Centiloid (CL) scale from 18F‐florbetaben PET. Burden of tau on regions comprising Braak stage III‐IV of neurofibrillary pathology (Braak H, et al. 2006) was measured as standardized uptake value ratio (SUVR) from tau tracer PI‐2620 PET. DPVS were assessed in the basal ganglia (BG‐DPVS) and in the subcortical white matter (WM‐DPVS) in T1‐sequences of brain MRI. DPVS severities were rated by an established 4‐point semiquantitative score and were then classified as high degree (score>2) or low degree (score≤2) (Martinez‐Ramirez, et al. 2013). The patients were further categorized into 3 groups including patients with higher, equal, and lower score of BG‐DPVS compared to WM‐DPVS (BG>WM, BG = WM, and BG<WM, respectively) (Thanprasertsuk, et al. 2014). Multivariate analyses controlling for age, sex, and MoCA score were applied to ensure independent relationships of DPVS to Aβ‐CL and tau‐SUVR.ResultPatients with high degree of WM‐DPVS (n = 18), compared to ones with the low degree (n = 33), had higher burdens of both Aβ‐CL (median[IQR], 74.29[55.90‐102.02] versus 35.06[11.34‐57.57], p<0.001) and tau‐SUVR (1.46[1.24‐2.15] versus 1.16[1.07‐1.49], p = 0.001). Based on DPVS category, there were differences in both Aβ‐CL (p = 0.001) and tau‐SUVR (p = 0.009) among the BG>WM (n = 20), BG = WM (n = 13), and BG<WM (n = 18) groups, with apparently high disease‐specific pathologies of AD in the BG<WM group (Aβ‐CL = 74.29[46.60‐105.20], and tau‐SUVR = 1.50[1.24‐2.14]). There were no differences in Aβ‐CL and tau‐SUVR between patients with low and high degree of BG‐DPVS.ConclusionOur results suggest that WM‐DPVS is associated with the deposition of Aβ and tau in AD patients, while BG‐DPVS appears to have less substantial association.