Beth E. Snitz

INTRODUCTION: We report the development and validation of a novel computational tool to cross-convert plasma pTau217 results from different assays to facilitate recruitment for therapeutic trials and observational studies. METHODS: Participants underwent Aβ PET imaging and plasma pTau217 measurement on up to three assay platforms across three cohorts. We then developed conversion equations using Deming regression – collectively named Biomarker Convert – and evaluated robustness using independent research cohorts. Finally, we modeled the potential impact of pTau217 screening on trial enrollment. RESULTS: While absolute plasma pTau217 concentrations differed, the assays had similar predictive characteristics for Aβ positivity (LC-MS/MS [C ₂ N], AUC=0.952; Janssen Simoa, AUC=0.946; Lumipulse, AUC=0.929). Biomarker Convert enabled transformation of plasma pTau217 data across assays independent of Aβ PET and clinical status. Plasma pTau217 reduced Aβ PET scans in the model screening paradigm by >60%. DISCUSSION: Biomarker Convert equations enable harmonization of plasma pTau217 values from immunoassay and mass spectrometry platforms, supporting direct data comparison.

Plasma phosphorylated tau 217 (p-tau217) levels have been shown to parallel neurofibrillary tangle and cognitive decline over time. Although recent clinical trials have demonstrated exploratory drug effects on plasma p-tau217, little is known about plasma p-tau217 effect size and performance as an endpoint in Alzheimer disease (AD) clinical trials. Therefore, the objective of this study was to assess the longitudinal performance and potential utility of plasma p-tau217 as a primary endpoint in early-stage AD clinical trials. This retrospective study included participants from 4 cohorts: ADNI (a multisite observational study), BICWALZS (a South Korean memory clinic-based cohort), MYHAT-NI (a Southwestern Pennsylvania population-based cohort), and WRAP (older adults at risk for AD). Eligible participants had plasma p-tau217 measurements at least at 2 timepoints, along with baseline Aβ PET imaging and clinical assessments. Linear mixed-effects models were used to assess associations between plasma p-tau217 trajectories and clinical or biomarker outcomes. Effect size was defined as the mean annual rate of change in p-tau217 divided by its standard deviation. We calculated the sample size required for a hypothetical clinical trial designed to detect a 25% drug effect with 80% power at a 0.05 test level. A total of 716 individuals were included in the analysis: 413 cognitively unimpaired (CU) participants (58.6% female; mean age = 70.6 years, SD = 7.9) and 303 cognitively impaired (CI) participants (54.7% female; mean age = 73.2 years, SD = 7.4). In Aβ-positive individuals, the annual rate of change in plasma p-tau217 was similar between CU (0.07 pg/mL/y, SD = 0.11) and CI (0.08 pg/mL/y, SD = 0.13) groups. Effect size was 0.64 and 0.62 in CU and CI Aβ-positive individuals, respectively. The minimum sample size required per study group to detect a 25% drug effect was 610 for the CU Aβ-positive and 664 for the CI Aβ-positive group. Notably, selecting individuals with intermediate Aβ levels (Centiloid 20-40) yielded higher effect sizes (CU: 0.85; CI: 0.72), which reduced the required sample sizes per study group to 342 for CU and 492 for CI. Our findings support that changes in plasma p-tau217 represent a robust endpoint for clinical trials targeting CU or CI individuals with Aβ pathology.

Background: Extracranial carotid artery calcification (ECAC) is a known risk factor for the development of cardiovascular diseases (CVD) and has been associated with an increased risk of dementia and Alzheimer's disease. However, the relationship between ECAC and amyloid-β (Aβ) deposition in older adults has not been fully understood. Objective: This study aims to determine the relationship between ECAC and Aβ deposition in very old adults. Methods: 90 participants (87.2 ± 2.7 years old, 96% whites, 63% males) without dementia from an observational study were included in the cross-sectional analysis. Aβ deposition in the brain was assessed using the ¹¹ C-labeled Pittsburgh compound-B positron emission tomography (PiB-PET) scans performed in 2009 and 2011. Carotid artery plaque and ECAC status were measured via high-resolution carotid ultrasonography in 2011. Results: Among the participants, 82 (91%) had carotid plaques, and 46 (51%) were globally Aβ positive by PiB-PET. ECAC was less frequently observed in the Aβ positive group compared to the Aβ negative group (90% versus 81%, p = 0.3). The odds of Aβ positivity in those with ECAC were 62% lower than in those without ECAC. However, the association was not statistically significant (OR = 0.38, 95% CI: [0.08, 1.76 ], p = 0.2). Conclusions: In the population whose average age is older than 85 without dementia, there is no statistically significant association between ECAC and Aβ deposition after adjusting for confounding factors. The relationship between ECAC and dementia in older adults warrants further analysis in a larger and more racially and ethnically diverse population.

Background: Alzheimer's disease (AD) is driven by amyloid-β (Aβ) plaque accumulation, but the mechanisms behind this process remain unclear. Omega-3 fatty acids, particularly docosahexaenoic acid (DHA), may offer protective effects, though their relationship with Aβ accumulation is not fully understood. Objective: This study investigated whether serum DHA and eicosapentaenoic acid (EPA) levels, measured 6–9 years before imaging, were inversely associated with cerebral Aβ deposition in cognitively normal older adults in Japan, a population known for high omega-3 intake. We focused on individuals identified as Aβ-positive based on positron emission tomography (PET) scans, as they are at higher risk for AD progression, to assess DHA's potential in mitigating early amyloid pathology. Methods: An analytical sample of 97 older adults (75–89 years) from the Suita Study was analyzed. Serum DHA and EPA levels were assessed between 2008 and 2012, and amyloid PET was performed between 2016 and 2019. Multiple regression analyses were conducted, adjusting for age, sex, APOE4 status, and cardiometabolic disease. Results: Among 97 participants (49% males, 8.2% APOE4 carriers), 37.1% (n = 36) had cardiometabolic disease, and 29.8% (n = 29) were Aβ positive. In Aβ-positive individuals, higher serum DHA levels were significantly associated with lower Aβ deposition independent of age, sex and APOE4 status (standardized β = -0.423, p = 0.030). This became non-significant after additionally adjusting for cardiometabolic disease (β = -0.382, p = 0.059). No significant association was found between EPA and Aβ deposition. Conclusions: Higher long-term DHA levels may help reduce Aβ accumulation in those at risk for AD, supporting its potential role in early prevention.

Background: The relationship between subtle cognitive decline and Alzheimer's disease (AD) pathology as measured by biomarkers in settings outside of specialty memory clinics is not well characterized. Objective: To investigate how subtle longitudinal cognitive decline relates to neuroimaging biomarkers in individuals drawn from a population-based study in an economically depressed, small-town area in southwestern Pennsylvania, USA. Methods: A subset of participants without dementia (N = 115, age 76.53 years ± 6.25) from the Monongahela Youghiogheny Healthy Aging Team (MYHAT) study completed neuroimaging including magnetic resonance imaging (MRI) measures of AD-signature region cortical thickness and white matter hyperintensities (WMH), Pittsburgh compound B (PiB)-positron emission tomography (PET) for amyloid-β (Aβ) deposition, and [ ¹⁸ F]AV-1451-PET for tau deposition. Neuropsychological evaluations were completed at multiple timepoints up to 11 years prior to neuroimaging. Aβ positivity was determined using a regional approach. We used linear mixed models to examine neuroimaging biomarker associations with retrospective cognitive slopes in five domains and a global cognitive composite. Results: Among Aβ(+) participants (38%), there were associations between (i) tau Braak III/IV and language decline (p < 0.05), (ii) cortical thickness and both memory decline (p < 0.001) and global cognitive decline (p < 0.01), and (iii) WMH and decline in executive function (p < 0.05) and global cognition (p < 0.05). Among Aβ(-) participants, there was an association between tau Braak III/IV and decline on tests of attention/psychomotor speed (p < 0.05). Conclusions: These findings confirm an Aβ-dependent early AD biomarker pathway, and suggest a possible Aβ-independent, non-AD process underlying subtle cognitive decline in a population-based sample of older adults without dementia.

While the highest prevalence of dementia occurs in individuals older than 80 years, most imaging studies focused on younger populations. The rates of β-amyloid (Aβ) accumulation and the effect of Alzheimer disease (AD) pathology on progression to dementia in this age group remain unexplored. In this study, we examined the relationship between changes in Aβ deposition over time and incident dementia in nondemented individuals followed during a period of 11 years. We examined 94 participants (age 85.9 + 2.8 years) who had up to 5 measurements of Pittsburgh compound-B (PiB)-PET and clinical evaluations from 2009 to 2020. All 94 participants had 2 PiB-PET scans, 76 participants had 3 PiB-PET scans, 18 participants had 4 PiB-PET scans, and 10 participants had 5 PiB-PET scans. The rates of Aβ deposition were compared with 120 nondemented individuals younger than 80 years (69.3 ± 5.4 years) from the Australian Imaging, Biomarker, and Lifestyle (AIBL) study who had 3 or more annual PiB-PET assessments. By 2020, 49% of the participants developed dementia and 63% were deceased. There was a gradual increase in Aβ deposition in all participants whether they were considered Aβ positive or negative at baseline. In a Cox model controlled for age, sex, education level, APOE-4 allele, baseline Mini-Mental State Examination, and mortality, short-term change in Aβ deposition was not significantly associated with incident dementia (HR 2.19 (0.41-11.73). However, baseline Aβ burden, cortical thickness, and white matter lesions volume were the predictors of incident dementia. Aβ accumulation was faster (p = 0.01) in the older cohort (5.6%/year) when compared with AIBL (4.1%/year). In addition, baseline Aβ deposition was a predictor of short-term change (mean time 1.88 years). There was an accelerated Aβ accumulation in cognitively normal individuals older than 80 years. Baseline Aβ deposition was a determinant of incident dementia and short-term change in Aβ deposition suggesting that an active Aβ pathologic process was present when these participants were cognitively normal. Consequently, age may not be a limiting factor for the use of the emergent anti-Aβ therapies.

Background: Cardiovascular (CV) disease is associated with dementia and Alzheimer’s disease (AD), but its relationship with AD pathology remains elusive. We examined whether mid‐life arterial stiffness, endothelial function, and blood pressure are associated with late‐life beta‐amyloid (Aß) and tau burden.Method: Participants in the Heart Strategies Concentrating on Risk (SCORE) study completed cardiovascular phenotyping between 2003‐2005 (midlife; 45‐59 years) and up to three brain PET sessions between 2018‐2022 (late‐life; >65 years). Mid‐life assessments included augmentation index (AI75; N = 134) as a measure of arterial stiffness, Framingham reactive hyperemia index (fRHI; N = 130) as a measure of endothelial function, and systolic‐blood pressure (SBP; N = 141); late‐life measures were global [¹¹C]Pittsburgh Compound‐B (PiB) standardized uptake value ratio (SUVR) and regional (medial temporal, entorhinal, inferior temporal, amygdala) [¹⁸F]flortaucipir (FTP) SUVR as indices of Aß and tau deposition, respectively. In individual linear regression models, we tested associations of mid‐life AI75, RHI, and SBP with late‐life PiB and FTP SUVRs. We used mixed effects models to examine these relationships longitudinally. All models were adjusted for time between CV and PET measurements, baseline age, sex, racialization, apolipoprotein‐E4, BMI, and history of hypertension, high cholesterol, smoking, and diabetes.Result: In multivariable models, higher mid‐life SBP was associated with lower late‐life FTP SUVR in the medial temporal lobe (β = ‐0.20, p = 0.04) and inferior temporal gyrus (β = ‐0.23, p = 0.01; Table 1); higher mid‐life SBP was also negatively associated with FTP SUVR trajectories in these regions (medial temporal lobe: β = ‐0.0004, p = 0.02; inferior temporal gyrus: β = ‐0.001, p = 0.01; Table 2). We did not detect significant relationships of mid‐life AI75 or RHI with late‐life FTP SUVRs (p≥0.05) or between any mid‐life cardiovascular measures and late‐life PiB SUVR (p≥0.08).Conclusion: In this dementia‐free, community‐based cohort, higher mid‐life SBP was associated with lower late‐life regional tau deposition and accumulation. Though counterintuitive, our findings are consistent with results of cross‐sectional studies, which suggest that CV risk factors may be followed by an initial brain arteriole response that is protective against tau accumulation through early years of late‐adulthood^1,2. Future studies should interrogate the potential mechanisms and age‐modifying effects that may underlie the relationship between mid‐life CV risk factors and late‐life tau deposition.

Background: Functional MRI (fMRI) studies have associated impaired memory networks with increase in AD pathology. Recently, cross‐sectional analyses found b‐amyloid (Aβ) deposition associated with different patterns of hippocampal connectivity in a memory task based on sex and white matter hyperintensity volume (WMHV). However, cross‐sectional studies don’t provide insight into the driving mechanisms of network change. In this longitudinal study, we identify risk factors based on sex that are associated with memory network connectivity changes.Method: Our study included 54 cognitively normal older adults (N = 34 female, mean age 74.6 years) with MRI scans on average 2.43 (SD 0.82) years apart. T1w, T2‐FLAIR MRI, and PiB PET were collected to quantify cortical volume, WMHV and Aβ deposition, respectively. Task fMRI was collected while participants performed face‐name associative memory tasks. Left and right hippocampus seeds were used to estimate functional connectivity between hippocampus and voxels in the brain. Second‐level analyses were performed to determine regions of interest (ROI) with significant differences in sex by time interaction (p<0.001). The mean beta values were extracted from the significant ROIs for post‐hoc analysis where we performed multivariate linear regression analyses to find correlations with connectivity change (follow‐up minus baseline).Result: Three ROIs presented significant sex by time interactions: left‐right hippocampus, hippocampus‐anterior cingulate cortex (ACC), and hippocampus‐medial frontal gyrus. The change in left‐right hippocampus connectivity increased for women and decreased for men (Fig.1). For the other ROIs, connectivity increased for men and decreased for women (Fig.2). Left‐right hippocampal connectivity change had a significant sex‐WMHV interaction effect (p<0.01), where only women had a positive association between connectivity change and baseline WMHV. Hippocampus‐ACC connectivity change had a significant sex‐Aβ interaction (p<0.01), with greater baseline Aβ associated with increased connectivity change for men and decreased for women.Conclusion: We observed sex‐differences in risk architecture for altered hippocampal connectivity. In the presence of vascular pathology and Aβ, women appear to experience local hippocampal connectivity and decrease hippocampal‐frontal connectivity. Meanwhile, men experienced hippocampal‐frontal connectivity with increased Aβ burden. Characterizing these sex differences in memory network alterations can help guide the development of sex‐specific prevention and treatment strategies.

Background: Black/African American (AA) older adults are twice as likely as Non‐Hispanic White (NHW) older adults to be diagnosed with Alzheimer’s Disease (AD) and related dementias. Inflammation and brain beta‐amyloid (Ab) may play a differential role in AD pathophysiology in AA and NHW older adults. We hypothesized that there would be racialized group differences in inflammation, amyloid deposition, and everyday discrimination.Method: One hundred and ninety‐eight participants (Table 1) were recruited in Pittsburgh, PA and the surrounding areas as a part of the Human Connectome Project. Blood‐based biomarkers of inflammatory markers interleukin 6 (IL6) and tumor necrosis factor alpha (TNFa) were examined. Brain Ab was quantified using Pittsburgh Compound‐B (PiB) Positron Emission Tomography (PET) imaging standardized uptake value ratio (SUVr). Experiences of discrimination were measured on a subset of 66 participants (mean age = 62.62±9.37 years, 46.97% AA) using the Everyday Discrimination Scale (EDS). Analysis of covariance, controlling for age, were conducted to examine the racialized group differences for TNFa, IL6, Ab SUVr. Independent samples t‐tests were conducted to compare EDS by racialized group.Result: Participants. AA participants were on average 6.58 years younger than NHW participants and more likely to have a clinical diagnosis of impaired without complaints, mild cognitive impairment (MCI), or AD (all p’s<.05) (Table 1). Additionally, in the subset of participants with EDS data, AA participants experienced higher total discrimination than NHW participants (p<.05).Inflammation. NHW participants had higher TNFa inflammation levels than AA participants (p = .029). No differences by racialized group were observed for IL6.PiB‐PET. The frequency of amyloid positivity was higher in NHW than AA participants (p = <.001). Global Ab SUVr was higher in NHW than AA participants (p<.05).Conclusion: The results from this study provide evidence of higher peripheral blood inflammation and PiB PET binding in NHW than AA participants, but higher likelihood of clinical diagnoses and more experiences of discrimination in the AA than in NHW participants. Future investigation of these racialized differences as they relate to age and other determinants of health are needed.

Background: The SARS‐CoV‐2 coronavirus has been associated with structural brain changes, consistent with its neurological manifestations. Recent studies showed a specific predilection for brainstem glial activation and hypometabolism, possibly indicating involvement of the locus coeruleus. The locus coeruleus (LC) modulates many cognitive functions and behaviors and its norepinephrine projections regulate both immune responses and vascular reactivity. We aimed to examine differences in LC integrity between COVID‐19 survivors and controls.Method: Participants are enrolled across 3 US and 1 UK sites using harmonized cognitive and 7T MR‐imaging protocols. Here, we analyzed data from 18 participants enrolled at Houston Methodist (12 COVID‐19 survivors, 6 controls; Figure 1). COVID‐19 survivors were required to have had a positive antigen test and an illness syndrome consistent with COVID‐19. Healthy controls were required to have no significant pre‐existing medical, neurologic, or psychiatric illness and no illness requiring hospitalization in the last 2 years. LC imaging was performed using a dedicated 7T MT‐TFL sequence (0.4×0.4×0.5mm). A site‐specific normalized template was constructed using ANTs/FSL. The entire average LC integrity as well as voxel‐wise integrity values were compared between COVID‐19 survivors and controls using a robust linear regression (age‐controlled and threshold free cluster enhancement corrected). LC integrity was correlated with age, sex, ethnicity and cognition using Spearman’s rank correlation.Result: Average LC integrity was not correlated with age, sex, or Hispanic ethnicity (p>0.3). COVID‐19 survivors did not differ from Controls when examining the entire LC (p = 0.54). Voxel‐wise analyses revealed a small cluster (19 voxels) in the middle portion of the left LC where COVID‐19 survivors exhibited lower LC integrity than controls (p = 0.005; Figure 2). Integrity of this cluster was not related to age or Hispanic ethnicity (p = 0.9). LC integrity did not correlate with cognitive performance within the COVID‐19 survivors (Trail Making Test B: p = 0.43; Craft Story delayed recall p = 0.47; MoCA p = 0.84).Conclusion: Consistent with previous animal and human studies, our initial findings provide evidence for neuroinvasive potential of SARS‐CoV‐2 localized in the middle LC. In the future, we aim to expand our sample and link these observations to the neurocognitive sequelae of COVID‐19.