Biomarkers.

The association between obesity and Alzheimer's disease (AD) is complex. Recent studies indicated the relationships between obesity and AD may differ by sex, and women may benefit from being overweight in terms of AD risk. We investigated whether sex modifies the associations of obesity with tau positron emission tomography (PET), amyloid PET, and cognition in preclinical AD. We included 387 cognitively-unimpaired amyloid-positive participants (221 women, 166 men, 87.6% non-Hispanic White) with available 18F-flortaucipir PET, 18F-florbetapir PET, and completed the Preclinical Alzheimer Cognitive Composite (PACC) tests from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. Participants were categorized based on body mass index (BMI: kg/m2): normal-weight (BMI: 18.5-25), overweight (BMI: 25-30), and obese (BMI≥30). Significant sex by BMI category interactions on PACC and its components: Mini-Mental State Examination (MMSE) and Reminding Test-Free+Total Recall (FCSRT96) revealed that overweight and obese women outperformed normal-weight women on FCSRT96, while obese men showed poorer MMSE performance than normal-weight men. These interactions were independent of APOE4. There were no significant interactions of sex by BMI category on tau and amyloid PET. However, sex-stratified analyses observed obesity was associated with less regional tau and mean cortical amyloid in women, not in men. This study found that in preclinical AD, overweight and obesity were associated with better verbal memory in women, whereas obesity was associated with worse global cognition among men. Future studies focusing on the mechanism for this relationship may inform sex-specific interventions for AD prevention.

Early Detection and Treatment of Age-Related Cognitive Decline

Early and late change on the preclinical Alzheimer's cognitive composite in clinically normal older individuals with elevated amyloid β

To determine whether a digital clock-drawing test, DCTclock, improves upon standard cognitive assessments for discriminating diagnostic groups and for detecting biomarker evidence of amyloid and tau pathology in clinically normal older adults (CN). Participants from the Harvard Aging Brain Study and the PET laboratory at Massachusetts General Hospital were recruited to undergo the DCTclock, standard neuropsychological assessments including the Preclinical Alzheimer Cognitive Composite (PACC), and amyloid/tau PET imaging. Receiver operating curve analyses were used to assess diagnostic and biomarker discriminability. Logistic regression and partial correlations were used to assess DCTclock performance in relation to PACC and PET biomarkers. A total of 300 participants were studied. Among the 264 CN participants, 143 had amyloid and tau PET imaging (Clinical Dementia Rating [CDR] 0, Mini-Mental State Examination [MMSE] 28.9 ± 1.2). An additional 36 participants with a diagnosis of mild cognitive impairment or early Alzheimer dementia (CDR 0.5, MMSE 25.2 ± 3.9) were added to assess diagnostic discriminability. DCTclock showed excellent discrimination between diagnostic groups (area under the receiver operating characteristic curve 0.86). Among CN participants with biomarkers, the DCTclock summary score and spatial reasoning subscores were associated with greater amyloid and tau burden and showed better discrimination (Cohen d = 0.76) between Aβ± groups than the PACC (d = 0.30). DCTclock discriminates between diagnostic groups and improves upon traditional cognitive tests for detecting biomarkers of amyloid and tau pathology in CN older adults. The validation of such digitized measures has the potential of providing an efficient tool for detecting early cognitive changes along the AD trajectory. This study provides Class II evidence that DCTclock results were associated with amyloid and tau burden in CN older adults.

Incremental value of plasma biomarkers in predicting clinical decline among cognitively unimpaired older adults: Results from the A4 trial

Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease. To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+). This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022. Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined. The 447 A4 participants (A+ group, 392; and normal β-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867 = -2.597; P = .03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin. This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

Investigating the Factor Structure of the Preclinical Alzheimer Cognitive Composite and Cognitive Function Index across Racial/Ethnic, Sex, and Aβ Status Groups in the A4 Study.

BackgroundSecondary prevention clinical trials for Alzheimer’s disease (AD) target amyloid accumulation in asymptomatic, amyloid-positive individuals, but it is unclear to what extent other pathophysiological processes, such as small vessel cerebrovascular disease, account for participant performance on the primary cognitive outcomes in those trials. White matter hyperintensities are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) that reflect small vessel cerebrovascular disease. They are associated with cognitive functioning in older adults and with clinical presentation and course of AD, particularly when distributed in posterior brain regions. The purpose of this study was to examine to what degree regional WMH volume is associated with performance on the primary cognitive outcome measure in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, a secondary prevention trial.MethodsData from 1791 participants (59.5% women, mean age (SD) 71.6 (4.74)) in the A4 study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) companion study at the screening visit were used to quantify WMH volumes on T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Cognition was assessed with the preclinical Alzheimer cognitive composite (PACC). We tested the association of total and regional WMH volumes with PACC performance, adjusting for age, education, and amyloid positivity status, with general linear models. We also considered interactions between WMH and amyloid positivity status.ResultsIncreased frontal and parietal lobe WMH volume was associated with poorer performance on the PACC. While amyloid positivity was also associated with lower cognitive test scores, WMH volumes did not interact with amyloid positivity status.ConclusionThese results highlight the potential of small vessel cerebrovascular disease to drive AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered when evaluating outcome in trials, both as potential effect modifiers and as a possible target for intervention or prevention.

Variability in cognitive decline in preclinical Alzheimer's disease (AD) presents a significant challenge in evaluating treatment effects in clinical trials. This study developed models to forecast cognitive progression and assessed their potential to improve the precision of treatment effect estimates in future trials. Data were from the Phase III Anti-Amyloid Treatment trial of Solanezumab in amyloid-positive asymptomatic preclinical AD. Due to no significant cognitive decline differences between groups, the Solanezumab arm (n=549) was used for training, and the placebo arm (n=559) for validation. Cognitive decline was assessed as 24-week changes in Preclinical Alzheimer's Cognitive Composite (PACC) score over 216 weeks. A predictive model for PACC decline was developed using demographics, APOE ε4 status, and baseline clinical assessments (PACC composite score, its components, and CDR-SB), employing Stochastic Gradient Boosting. The added value of amyloid PET Centiloid (CL), plasma pTau217 (electrochemiluminescence assay), MRI morphometrics, and tau PET measures (375-participant substudy) were evaluated. Model performance was optimized via cross-validation and validated in the placebo group. The impact of baseline PACC decline predictions as an Alzheimer's Prognostic Covariate (APC) on treatment effect assessments was evaluated in trial simulations. A model with demographics, CL, and clinical assessments explained 16% of PACC decline at week 216 (R²=0.16), improving over CL or clinical assessments alone (p<0.05). Adding MRI increased R² to 0.23 (p<0.05); replacing CL with plasma pTau217 or tau PET raised it to 0.25 and 0.42, respectively. Without tau PET in the model, key baseline predictors were pTau217, CL, PACC, MMSE, inferior temporal area, and entorhinal volume. When tau PET was included, it became the strongest predictor, with fusiform, inferior temporal, and supramarginal regions being the most predictive. Simulations showed baseline prediction of PACC decline as APC can reduce treatment effect variance by 20.3%, increase power from 80% to 88%, or reduce sample size by 21.5%. Incorporating tau PET further reduces variance by 37%, increases power to 94%, and decreases sample size by 35%. Baseline tau PET was the strongest predictor of PACC decline. Using baseline-predicted PACC decline as APC can enhance treatment effect estimates and trial efficiency in preclinical AD.

BackgroundPlasma glial fibrillary acidic protein (GFAP) is associated with amyloid‐β (Aβ) and tau, but their causal relationships remain unclear. We used Mendelian randomization (MR; using genetic causal anchors to avoid reverse causation) to clarify the causal relationship between plasma/brain GFAP, Aβ, and tau.MethodsStudy participants are from two independent datasets: the Harvard Aging Brain Study (HABS) and the Religious Orders Study/the Rush Memory and Aging Project (ROSMAP) (Table 1). From HABS, we used baseline plasma GFAP (MSD platform) and Aβ (PiB PET cortical composite with partial volume correction [PVC]) and longitudinal inferior temporal (IT) tau (FTP PET SUVR with PVC) data. From ROSMAP, we used post‐mortem frontal cortex GFAP expression (RNA‐Seq) and midfrontal Aβ and tau burden (immunohistochemistry). We used linear regressions to assess the relationship between APOE ε4, GFAP, and Aβ. For MR, we performed instrumental variable (IV) analyses using APOE ε4 as the instrument. In HABS, we used linear mixed effect models to assess baseline GFAP ‐ longitudinal IT tau association. In ROSMAP, we assessed the cross‐sectional GFAP ‐ tau association (linear regression). All variables were standardized, and all models were adjusted for age and sex.ResultIn HABS, APOE ε4 carriers had higher baseline plasma GFAP (n=324, β=0.32, p=0.0025), but this association attenuated after adjusting for Aβ (p=0.42). MR suggested the causal effect of Aβ on plasma GFAP (2SLS β=0.40, p=0.0018). Baseline plasma GFAP predicted longitudinal increase in IT tau (n=187, β=0.051, p=1.9×10‐4); this association attenuated after adjusting baseline Aβ and its time‐interaction (p=0.16). We observed consistent results in ROSMAP: APOE ε4 carriers had higher frontal GFAP expression (n=609, β=0.26, p=0.0051), but this association attenuated after adjusting for Aβ (p=0.11). MR supported the causal effect of Aβ on brain GFAP (2SLS β=0.39, p=0.0085). The frontal GFAP– tau association (β=0.10, p=0.012) weakened after controlling for Aβ (p=0.50).ConclusionOur study leveraging APOE ε4 as a genetic causal anchor supports that Aβ is at the causal upstream of increased brain GFAP gene expression and elevated plasma GFAP (Figure 1A). By contrast, the neocortical tau – GFAP association is likely confounded by Aβ (Figure 1B‐C).

Cerebral microhemorrhages (CMHs) are detectable by magnetic resonance imaging (MRI). CMHs in deep brain regions are linked to hypertensive vasculopathy, while those in lobar regions with amyloid beta (Aβ) deposition in blood vessels. This study aims to determine the association between anti-thrombotic treatment and CMH prevalence among cognitively asymptomatic adults, and to assess the role of Aβ markers, apolipoprotein E (APOE) ε4 carrier status, and cardiovascular risk factors in CMH development. Using baseline data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies, we examined CMH presence via 3T MRI, along with medication use, APOE ε4 carrier status, medical history, and blood pressure. Our analysis showed a significantly higher prevalence of CMHs in the A4 cohort (17.3%) compared to the LEARN cohort (2.6%). Factors such as male sex, age, Aβ markers, and APOE ε4 status were significantly associated with higher CMH prevalence in the A4 cohort. However, anti-thrombotic treatment did not show association with overall CMHs. Male sex, age>75, amyloid beta (Aβ) burden, and apolipoprotein E (APOE) ε4 homozygosity are significantly associated with higher prevalence of CMHs (cerebral microhemorrhages) in a cohort of cognitively asymptomatic individuals. Male sex, age>75, Aβ burden, and APOE ε4 homozygosity are significantly associated with higher prevalence of lobar CMHs in a cohort of cognitively asymptomatic individuals. Anti-platelet or anti-coagulant usage were not associated with an increased prevalence of CMHs in either brain location or overall, in a cohort of cognitively asymptomatic individuals. History of a lipid disorder is associated with a higher prevalence of lobar CMHs in a cohort of cognitively asymptomatic individuals.

BackgroundWhile physical activity (PA) may promote resilience to cognitive decline and AD dementia, the mechanisms underlying this effect are poorly understood. Our group previously demonstrated lower levels of functional connectivity (rs‐fcMRI) in the default, salience, and control networks were associated with greater prospective cognitive decline, both alone and synergistically with β‐amyloid (Buckley and Schultz et al., 2017). In this context, we assessed whether higher PA may be associated with greater connectivity, and whether PA effects on connectivity may mediate the relationship of PA to prospective cognitive decline.MethodA waist mounted pedometer was used to record PA (steps/day during one week) in 167 cognitively unimpaired adults aged 63‐90 (mean 74.0; SD 6.1) participating in the Harvard Aging Brain Study. Participants underwent baseline rs‐fcMRI and β‐amyloid imaging with Pittsburgh Compound B PET. We analyzed rs‐fcMRI in the 3 networks previously associated with cognitive decline (default, salience, and control) as well as in 4 motor or sensory networks in which connectivity strength is not associated with cognitive change. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite (PACC). We used linear regression to examine associations between PA and connectivity in these networks, controlling for age, sex, and APOE e4 status. We conducted exploratory analyses using linear mixed effects models to examine if associations between PA and connectivity strength may partially explain PA associations with cognitive decline in the context of elevated β‐amyloid.ResultHigher baseline PA was significantly associated with increased connectivity in the default, salience, and control networks (all p&lt;0.017) after adjusting for covariates and controlling for multiple comparisons. PA was not associated with connectivity in any of the other networks examined. Greater connectivity in these networks was a weak partial mediator of PA's association with longitudinal PACC decline in participants with elevated β‐amyloid (figure 1).ConclusionGreater PA is associated with increased connectivity in three networks (default, salience, and control) in which greater connectivity is associated with less cognitive decline. One potential mechanism by which PA may promote resilience to cognitive decline is through increased functional connectivity in a core set of AD‐relevant cognitive networks.

The chief difference between a primary prevention trial (PPT) and secondary prevention trial (SPT) in Alzheimer's disease (AD) is related to the targeted participant group. As currently conceptualized, a PPT recruits asymptomatic individuals from the general population while an SPT recruits only asymptomatic (or preclinical) individuals who are biomarker-positive for AD1. Recent examples of the latter include the AD kindred trial in Antioquia, Colombia, which recruits only subjects who are E280A mutation carriers with a familial history of early onset disease, and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial, which targets adults age 70 years and older with high brain amyloid levels as determined by a PET scan. The latter is the subject of the Donohue et al. manuscript2, which seeks to identify a primary endpoint for that SPT.

Plasma p-tau217 predicting brain-wide tau accumulation in preclinical AD

Recent proposals suggest that sleep may be a factor associated with accumulation of two core pathological features of Alzheimer's disease (AD): tau and β-amyloid (Aβ). Here we combined PET measures of Aβ and tau, electroencephalogram sleep recordings, and retrospective sleep evaluations to investigate the potential utility of sleep measures in predicting in vivo AD pathology in male and female older adults. Regression analyses revealed that the severity of impaired slow oscillation-sleep spindle coupling predicted greater medial temporal lobe tau burden. Aβ burden was not associated with coupling impairment but instead predicted the diminished amplitude of <1 Hz slow-wave-activity, results that were statistically dissociable from each other. Additionally, comparisons of AD pathology and retrospective, self-reported changes in sleep duration demonstrated that changes in sleep across the lifespan can predict late-life Aβ and tau burden. Thus, quantitative and qualitative features of human sleep represent potential noninvasive, cost-effective, and scalable biomarkers (current and future forecasting) of AD pathology, and carry both therapeutic and public health implications.SIGNIFICANCE STATEMENT Several studies have linked sleep disruption to the progression of Alzheimer's disease (AD). Tau and β-amyloid (Aβ), the primary pathological features of AD, are associated with both objective and subjective changes in sleep. However, it remains unknown whether late life tau and Aβ burden are associated with distinct impairments in sleep physiology or changes in sleep across the lifespan. Using polysomnography, retrospective questionnaires, and tau- and Aβ-specific PET, the present study reveals human sleep signatures that dissociably predict levels of brain tau and Aβ in older adults. These results suggest that a night of polysomnography may aid in evaluating tau and Aβ burden, and that treating sleep deficiencies within decade-specific time windows may serve in delaying AD progression.