Preclinical Alzheimer Cognitive Composite Research Articles

Subjective cognitive decline across ethnoracial groups in the A4 study.

The associations between subjective cognitive decline (SCD),cognition,and amyloid were explored across diverse participants in the A4 study. Five thousand one hundred and fifty-one non-Hispanic White, 262 non-Hispanic Black, 179 Hispanic-White, and 225 Asian participants completed the Preclinical Alzheimer Cognitive Composite (PACC),self- and study partner-reported Cognitive Function Index (CFI). A subsample underwent amyloid positron emission tomography (18 F-florbetapir) (N=4384). We examined self-reported CFI, PACC, amyloid, and study partner-reported CFI by ethnoracial group. The associations between PACC-CFI and amyloid-CFI were moderated by race. The relationships were weaker or non-significant in non-Hispanic Black and Hispanic White groups. Depression and anxiety scores were stronger predictors of CFI in these groups. Despite group differences in the types of study partners, self- and study partner-CFI were congruent across groups. SCD may not uniformly relate to cognition or AD biomarkers in different ethnoracial groups. Nonetheless, self- and study partner-SCD were congruent despite differences in study partner type. Highlights Association between SCD and objective cognition was moderated by ethnoracial group. Association between SCD and amyloid was moderated by ethnoracial group. Depression and anxiety were stronger predictors of SCD in Black and Hispanic groups. Study-partner and self-reported SCD are congruent across groups. Study-partner report was consistent despite difference in study partner types.

Impact of asthma on the brain: evidence from diffusion MRI, CSF biomarkers and cognitive decline.

Chronic systemic inflammation increases the risk of neurodegeneration, but the mechanisms remain unclear. Part of the challenge in reaching a nuanced understanding is the presence of multiple risk factors that interact to potentiate adverse consequences. To address modifiable risk factors and mitigate downstream effects, it is necessary, although difficult, to tease apart the contribution of an individual risk factor by accounting for concurrent factors such as advanced age, cardiovascular risk, and genetic predisposition. Using a case-control design, we investigated the influence of asthma, a highly prevalent chronic inflammatory disease of the airways, on brain health in participants recruited to the Wisconsin Alzheimer's Disease Research Center (31 asthma patients, 186 non-asthma controls, aged 45-90 years, 62.2% female, 92.2% cognitively unimpaired), a sample enriched for parental history of Alzheimer's disease. Asthma status was determined using detailed prescription information. We employed multi-shell diffusion weighted imaging scans and the three-compartment neurite orientation dispersion and density imaging model to assess white and gray matter microstructure. We used cerebrospinal fluid biomarkers to examine evidence of Alzheimer's disease pathology, glial activation, neuroinflammation and neurodegeneration. We evaluated cognitive changes over time using a preclinical Alzheimer cognitive composite. Using permutation analysis of linear models, we examined the moderating influence of asthma on relationships between diffusion imaging metrics, CSF biomarkers, and cognitive decline, controlling for age, sex, and cognitive status. We ran additional models controlling for cardiovascular risk and genetic risk of Alzheimer's disease, defined as a carrier of at least one apolipoprotein E (APOE) ε4 allele. Relative to controls, greater Alzheimer's disease pathology (lower amyloid-β42/amyloid-β40, higher phosphorylated-tau-181) and synaptic degeneration (neurogranin) biomarker concentrations were associated with more adverse white matter metrics (e.g. lower neurite density, higher mean diffusivity) in patients with asthma. Higher concentrations of the pleiotropic cytokine IL-6 and the glial marker S100B were associated with more salubrious white matter metrics in asthma, but not in controls. The adverse effects of age on white matter integrity were accelerated in asthma. Finally, we found evidence that in asthma, relative to controls, deterioration in white and gray matter microstructure was associated with accelerated cognitive decline. Taken together, our findings suggest that asthma accelerates white and gray matter microstructural changes associated with aging and increasing neuropathology, that in turn, are associated with more rapid cognitive decline. Effective asthma control, on the other hand, may be protective and slow progression of cognitive symptoms.

Harmonizing the preclinical Alzheimer cognitive composite for multicohort studies.

Studies are increasingly examining research questions across multiple cohorts using data from the preclinical Alzheimer cognitive composite (PACC). Our objective was to use modern psychometric approaches to develop a harmonized PACC. We used longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and Australian Imaging, Biomarker and Lifestyle Study of Ageing (AIBL) cohorts (n = 2,712). We further demonstrated our method with the Anti-Amyloid Treatment of Asymptomatic Alzheimer's Disease (A4) Study prerandomized data (n = 4,492). For the harmonization method, we used confirmatory factor analysis (CFA) on the final visit of the longitudinal cohorts to determine parameters to generate latent PACC (lPACC) scores. Overlapping tests across studies were set as "anchors" that tied cohorts together, while parameters from unique tests were freely estimated. We performed validation analyses to assess the performance of lPACC versus the common standardized PACC (zPACC). Baseline (BL) scores for the zPACC were centered on zero, by definition. The harmonized lPACC did not define a common mean of zero and demonstrated differences in baseline ability levels across the cohorts. Baseline lPACC slightly outperformed zPACC in the prediction of progression to dementia. Longitudinal change in the lPACC was more constrained and less variable relative to the zPACC. In combined-cohort analyses, longitudinal lPACC slightly outperformed longitudinal zPACC in its association with baseline β-amyloid status. This study proposes procedures for harmonizing the PACC that make fewer strong assumptions than the zPACC, facilitating robust multicohort analyses. This implementation of item response theory lends itself to adapting across future cohorts with similar composites. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Genetic Moderation of the Association of β-Amyloid With Cognition and MRI in Alzheimer Disease.

There is considerable heterogeneity in the association between increasing amyloid β (Aβ) pathology and early cognitive dysfunction in preclinical Alzheimer's disease (AD). At this stage, some individuals show no signs of cognitive dysfunction, while others show clear signs of decline. The factors explaining this heterogeneity are particularly important for understanding progression in AD but remain largely unknown. In this study, we examine an array of genetic variants that may influence the relationships among Aβ, brain structure, and cognitive performance in two large cohorts. In 2953 cognitively-unimpaired participants from the A4 study, interactions between genetic variants and 18F-Florbetapir PET standardized uptake value ratio (SUVR) to predict the Preclinical Alzheimer's Cognitive Composite (PACC) were assessed. Genetic variants identified in the A4 study were evaluated in the Alzheimer's Disease Neuroimaging Initiative (ADNI, N=527) for their association with longitudinal cognition and brain atrophy in both cognitively unimpaired participants and those with mild cognitive impairment. In A4, four genetic variants significantly moderated the association between Aβ load and cognition. Minor alleles of three variants were associated with additional decreases in PACC scores with increasing Aβ SUVR (rs78021285, β =-2.29, SE=0.40, pFDR=0.02, nearest gene ARPP21; rs71567499, β =-2.16, SE=0.38, pFDR=0.02, nearest gene PPARD; rs10974405, β =-1.68, SE=0.29, pFDR=0.02, nearest gene GLIS3). The minor allele of rs7825645 was associated with less decrease in PACC scores with increasing Aβ SUVR (β =0.71, SE=0.13, pFDR=0.04, nearest gene FGF20). The genetic variant rs76366637, in linkage disequilibrium with rs78021285, was available in both A4 and ADNI. In A4, rs76366637 was strongly associated with reduced PACC scores with increasing Aβ SUVR (β =-1.01, SE=0.21, t=-4.90, p<0.001). In ADNI, rs76366637 was associated with accelerated cognitive decline (χ2=15.3, p=0.004) and atrophy over time (χ2=26.8, p<0.001), with increasing Aβ SUVR. Patterns of increased cognitive dysfunction and accelerated atrophy due to specific genetic variation may explain some of the heterogeneity in cognition in preclinical and prodromal AD. The genetic variant near ARPP21 associated with lower cognitive scores in A4 and accelerated cognitive decline as well as brain atrophy in ADNI may help to identify those at the highest risk of accelerated progression of Alzheimer's disease.

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.

Disparities in Alzheimer's disease (AD) are well-documented among different racial/ethnic groups and between sex/genders. Neuropsychological assessment provides important information about cognitive changes and can offer valuable insights into disparities. However, neuropsychological measures must be comparable across racial/ethnic and sex/gender groups to accurately interpret disparities. To evaluate measurement invariance (equivalence) of the Preclinical Alzheimer Cognitive Composite (PACC) and the Cognitive Function Index across racial/ethnic, sex/gender, and β-amyloid (Aβ) status groups. Cross-sectional analysis of screening data from the Anti-Amyloid in Asymptomatic AD (A4) Study. The study enrolled participants aged 65-85 from sites across the United States, Canada, Australia, and Japan. Participants completed the PACC and the Cognitive Function Index. Participants classified as cognitively normal also underwent a Positron Emission Tomography (PET) scan to determine Aβ status. Participants self-identified as non-Hispanic White (n=5241), non-Hispanic Black (n=267), Asian (n=228), or Hispanic White (n=225) as well as male (n=2885) or female (n=3076). Among those who underwent a PET scan, 3115 were classified as Aβ- and 1309 were classified as Aβ+. We found support for a one-factor model for both the PACC and Cognitive Function Index across the full sample and in samples stratified by race/ethnicity, sex/gender, and Aβ status. The one-factor model of the PACC and Cognitive Function Index demonstrated scalar measurement invariance across racial/ethnic, sex/gender, and Aβ status groups. Our findings suggest that performance on the PACC and Cognitive Function Index can be compared across the racial/ethnic, sex/gender, and Aβ status groups examined in this study.

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

Background and objectivesSleep and physical activity have gained traction as modifiable risk factors for Alzheimer’s disease. Sleep duration is linked to amyloid-β clearance while physical activity is associated with brain volume maintenance. We investigate how sleep duration and physical activity are associated with cognition by testing if the associations between sleep duration or physical activity to cognition are explained by amyloid-β burden and brain volume, respectively. Additionally, we explore the mediating role of tau deposition in sleep duration—cognition and physical activity—cognition relationships. MethodsThis cross-sectional study obtained data from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, a randomized clinical trial. In trial screening, cognitively unimpaired participants (age 65–85 years) underwent amyloid PET and brain MRI; APOE genotype and lifestyle questionnaire data were obtained. 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 relationships between sleep duration or physical activity and cognition. ResultsAβ data were obtained from 4322 participants (1208 with MRI, 59% female, 29% amyloid positive). Sleep duration was associated with a Aβ composite score (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)). Composite (β = −1.54, 95% 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 deposition was associated with PACC. Sleep duration—PACC association was explained by Aβ burden in path analyses. Physical activity 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 positively associated with PACC (p < 0.02 for hippocampus, entorhinal cortex and fusiform gyrus). Physical activity—cognition relationship was explained by regional volumes. PET tau imaging was available for 443 participants. No direct sleep duration—tau burden, physical activity by tau burden, or mediation by regional tau was observed in sleep duration—cognition or physical activity—cognition relationships. DiscussionSleep duration and physical activity are associated with cognition through independent paths of brain Aβ and brain volume, respectively. These findings implicate neural and pathological mechanisms for the relationships between sleep duration and physical activity on cognition. Dementia risk reduction approaches that emphasize the adequate sleep duration and a physically active lifestyle may benefit those with risk for Alzheimer’s disease.

Lower synaptic density and higher neurofibrillary tau are associated with worse cognitive performance

AbstractBackgroundSynaptic loss is a major feature of symptomatic Alzheimer’s disease (AD). PET radioligands for synaptic vesicle glycoprotein 2A (SV2A) provide an index for synaptic density in the brain. While development of these tracers is a major advance for the field of AD, little is yet known about regional synapse loss in AD or the extent to which synapse loss accounts for cognitive dysfunction in vivo. Here we tested whether regional synaptic density measured with [11C]UCB‐J is associated with cognition. Secondarily, we examined the association between tau, measured using [18F]MK‐6420 PET, and cognitive dysfunction.MethodParticipants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study (Table 1). Cognitive functioning was measured using the Preclinical Alzheimer Cognitive Composite (PACC)(Donohue et al, 2014). Neurofibrillary tau in the entorhinal cortex (ERC) was detected using [18F]MK‐6420 SUVR. A global measure of synaptic density was calculated using volume‐averaged DVRs in the medial temporal lobe (hippocampus, entorhinal cortex, parahippocampus, and perirhinal cortex), superior and inferior parietal cortices, and the frontal lobe. Pearson’s correlations assessed the following relationships: PACC : ERC tau, PACC : global synaptic density, and PACC : regional synaptic density.ResultERC tau and PACC score showed a significant inverse relationship: r = ‐0.51, P = 0.004. While global synaptic density and PACC score were not significantly related, when individual regions were tested, hippocampal synaptic density showed a significant positive relationship with the PACC score (P = 0.05) (Figure 1A).ConclusionERC tau PET SUVR was robustly associated with poorer cognitive performance. While synapse loss has been observed among multiple regions in AD, our preliminary results suggest that synapse loss in the hippocampus is most closely associated with cognitive dysfunction. This preliminary work suggests that ERC tau is more strongly associated with Alzheimer’s‐related cognitive decline than global or hippocampal synaptic density in participants who are mostly cognitively unimpaired. Future work will include group comparisons between participants with and without significant amyloid and tau pathology, as well as exploratory analyses into which regions are most significantly affected by Alzheimer’s‐associated synaptic loss.

Multiparity and brain‐age interact with amyloid aggregation to determine cognitive performance in cognitively unimpaired middle‐aged women

AbstractBackgroundHow pregnancy influences women's brain aging later in life remains controversial. Whereas multiparity has been associated with decelerated brain aging, it has been also identified as a risk factor for Alzheimer’s disease (AD). However, the impact of of childbirths on cognitive performance in women at higher risk of developing AD is underresearched. We investigated whether the association between multiparity, brain‐age and amyloid (Aβ) aggregation contributes to cognitive performance in cognitively unimpaired (CU) middle‐aged women.MethodWe included 223 CU parous women from the ALFA+ study (age 49‐74) who underwent cognitive assessment and had valid T1w MRI, and [18F]‐flutemetamol Aβ PET. As controls, 152 men were included. Parity was categorized as 1/≥2 children. The difference between chronological and biological brain age (brain‐age delta) was estimatied by predicting the latter using a pretrained machine learning algorithm on cerebral morphological measurements. Aβ‐positivity was defined as Aβ PET ≥ 30 Centiloids. The Preclinical Alzheimer Cognitive Composite (PACC) was computed. PACC was the dependent variable in linear models using the parity, brain‐age, and Aβ status as predictors. Age, education, age at first birth, and Body Mass Index (BMI) were used as covariates. Interaction term with the parity*brain‐age*Aβ status was modeled.Result25.7% of women had one child (n=7 [12.3%] Aβ‐positive), and 74.3% had two or more children (n=25 [15.1%] Aβ‐positive). There were no significant differences in PACC (p=0.701) or Aβ status (p=0.071). Multiparity women showed a significant decelerated brain‐aging (p=0.017) than women with one childbirth. A parity*brain‐age*Aβ status interaction (p=0.021) revealed that among women with one childbirth, an accelerated brain‐aging was associated with a worse PACC performance in those that are Aβ‐positive (p=0.008), while this association was not found in Aβ‐negative (p=0.702) (Figure 1). The same interaction was not found among men (p=0.234).ConclusionOur results suggest that the interaction between parity, brain‐age, and Aβ aggregation contributes to cognitive performance in women later in life. Multiparity might exert a neuroprotective effect in cognitive performance in women at higher risk of developing AD. This finding represents an important contribution to the knowledge of female‐specific AD risk factors and women’s brain aging.

Association of Cognition with Alcohol Consumption in Cognitively Unimpaired Older Adults: Results from the A4 study

AbstractBackgroundExcessive alcohol intake and no alcohol intake are associated with an increased risk of dementia relative to low to moderate alcohol consumption. We aimed to investigate the cross‐sectional association between different levels of alcohol consumption and cognition in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4 Study). We examined whether this association would differ between sexes or based on individuals’ β‐amyloid (Aβ) status (Aβ+ vs Aβ‐; Aβ+: PET Composite SUVR &gt; 1.15, Aβ‐: Others).MethodA total of 4387 cognitively unimpaired older adults who had both objective and subjective cognitive assessments and amyloid Positron Emission Tomography (PET) imaging. Participants were classified into 4 categories based on their average daily alcohol use: none, one, two, and three or more drinks/day. Multivariable linear regression was used to test the main effects as well as interactions with sex and Aβ levels.ResultParticipants were on average 71.28 (SD = 4.67) years old and 59% female. In the whole population, individuals who reported no alcohol consumption had lower scores on the Preclinical Alzheimer Cognitive Composite (PACC) compared to those who reported consuming one (β[SE] = 0.19[0.08], p = 0.017) or two (β[SE] = 0.22[0.11], p = 0.05) drinks/day (Table 1, Figure 1). In sex‐stratified analysis, the association between alcohol consumption and cognition was more prominent in females. Female participants who consumed two drinks/day had better performance on PACC (β[SE] = 0.32[0.16], p = 0.043) and Cognitive Function Index (CFI; β[SE] = ‐0.27[0.12], p = 0.026) compared to those who reported no alcohol consumption (Figure 2). In an Aβ status‐stratified sample, the association between alcohol consumption and cognition was present only in the Aβ‐ subgroup. Among Aβ‐ individuals, those who consumed one drink/day had better performance on PACC (β[SE] = 0.28[0.09], p = 0.003) and CFI (β[SE] = ‐0.18[0.07], p = 0.009) compared to those who reported no alcohol consumption (Figure 3). The interaction between Aβ status and alcohol consumption on cognition was not significant.ConclusionLow or moderate consumption of alcohol is associated with better cognitive performance in cognitively unimpaired individuals. The association is more prominent in Aβ‐ individuals, which might indicate that the pathophysiologic mechanism underlying the effect of alcohol on cognition is independent of AD‐pathology. The interaction with Aβ status requires further investigation with larger samples consuming 3 or more drinks/day.

Evaluation of ethnoracial differences in self‐ and study partner‐reported subjective cognitive decline in the A4 Study screen data

AbstractBackgroundSubjective cognitive decline (SCD) may represent an early clinical manifestation of Alzheimer’s disease (AD) pathology. There is evidence of an association between amyloid deposition and SCD. Given disparities in risk of AD and cognitive impairment across ethnoracial groups, there is need to evaluate SCD, cognition, and markers of AD across diverse samples, as well as study partners as reporters of SCD.MethodParticipants included 267 non‐Hispanic Black, 5241 non‐Hispanic White, 225 Hispanic White, and 228 Asian individuals who presented for screening for the Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) study (N = 5961). Participants completed the Preclinical Alzheimer Cognitive Composite (PACC) and self‐ and study partner‐report of SCD (Cognitive Function Instrument/CFI). A subsample of participants underwent amyloid PET (N = 4416). In a series of within‐group linear regressions, we evaluated the relationships between 1) self‐reported SCD and cognitive performance 2) study partner‐ and self‐reported SCD, and 3) participant amyloid status and SCD.ResultAsian participants self‐reported the highest SCD and non‐Hispanic White participants reported the lowest. Controlling for age, education, and gender, PACC performance was significantly associated with self‐reported SCD in non‐Hispanic White (R2 = 0.039, b = ‐0.141, p &lt; .0001), non‐Hispanic Black (R2 = 0.055, b = ‐0.158, p &lt; .01), and Asian samples (R2 = 0.093, b = ‐0.318, p &lt; .0001), with better PACC performance associated with lower CFI. PACC was not significantly associated with CFI in the Hispanic sample (R2 = .003, b = ‐0.097, p = .0636). Self‐ and study partner report of SCD were significantly correlated in all groups. Amyloid burden was associated with greater self‐reported SCD in non‐Hispanic White (R2 = 0.018, b = 0.452, p &lt; .001) and Asian samples (R2 = 0.046, b = 1.58, p &lt; .01), but not in the non‐Hispanic Black (R2 = 0.020, b = ‐.501, p = .277) and Hispanic participants (R2 = 0.016, b = 0.638, p = .169).ConclusionSCD appears similarly related to cognitive performance across most groups, and there is alignment between self‐ and study‐partner report of SCD across groups. There is evidence of variability in the association between AD biomarkers and SCD across racial groups, albeit in a smaller subsample with PET imaging. Future work should evaluate sociocultural factors that may contribute to differences in the value of SCD in individuals at risk for symptomatic AD.

Longitudinal tau burden partially mediates synergistic influence of vascular risk and amyloid‐beta on cognitive decline in clinically normal older adults

AbstractBackgroundVascular risk is increasingly recognized as an important contributor to late‐life cognitive impairment. Elevated vascular risk and amyloid‐beta (Aβ) burden have been synergistically associated with greater cognitive decline, however the underlying mechanisms remain unclear. We examined the combined effects of baseline vascular risk and Aβ on longitudinal tau burden. We further investigated the extent to which tau accumulation mediates the synergistic effects of increased vascular risk and Aβ on prospective cognitive decline.MethodWe included data from 175 older adults (cognitively unimpaired at baseline) from the Harvard Aging Brain Study (HABS) (Table 1). Baseline Aβ burden was measured with Pittsburgh Compound‐B (PiB) PET. Baseline vascular risk was quantified using the office‐based Framingham Heart Study general cardiovascular disease risk score (FHS‐CVD). Tau burden was measured longitudinally with Flortaucipir‐PET in inferior temporal cortex (ITC), an early site of neocortical tau accumulation and a region of interest based on prior work. Cognition was assessed longitudinally using Preclinical Alzheimer Cognitive Composite (PACC). Using linear mixed effects models, we examined the interactive effects of FHS‐CVD and Aβ on longitudinal ITC tau accumulation, adjusting for age, sex and APOE ε4 status. Next, we examined the FHS‐CVD*Aβ interaction using floodlight/Johnson‐Neyman analysis to determine the level of Aβ at which effects on ITC tau accumulation became significant. Using moderated mediation analysis, we further examined whether tau accumulation mediated the FHS‐CVD*Aβ interactive effects on PACC decline.ResultIndividual ITC‐tau trajectories are shown in Figure 1. We found an interaction between higher baseline FHS‐CVD and elevated Aβ with greater longitudinal ITC‐tau accumulation (Figure 2; Table 2). Floodlight analysis showed the FHS‐CVD*Aβ interaction became significant (p&lt;0.05) at PiB‐DVR&gt;1.22, lower than the conventional threshold for amyloid‐positivity (PiB‐DVR&gt;1.32). Moderated mediation models revealed ITC‐tau accumulation partially mediated (30%) the effect of FHS‐CVD on PACC decline at high (PiB‐DVR=1.85: β=‐0.48, p&lt;0.001) but not low (PiB‐DVR=1.17: β=‐0.16, p=0.09) levels of baseline Aβ (Figure 3).ConclusionVascular risk may interact with Aβ to promote cognitive decline partially through accelerating tau accumulation, even at subthreshold levels of Aβ. Further studies are needed to elucidate other mechanisms that mediate the remaining effects of this clinically important interaction.

Longitudinal tau burden partially mediates synergistic influence of vascular risk and amyloid‐beta on cognitive decline in clinically normal older adults

AbstractBackgroundVascular risk is increasingly recognized as an important contributor to late‐life cognitive impairment. Elevated vascular risk and amyloid‐beta (Aβ) burden have been synergistically associated with greater cognitive decline, however the underlying mechanisms remain unclear. We examined the combined effects of baseline vascular risk and Aβ on longitudinal tau burden. We further investigated the extent to which tau accumulation mediates the synergistic effects of increased vascular risk and Aβ on prospective cognitive decline.MethodWe included data from 175 older adults (cognitively unimpaired at baseline) from the Harvard Aging Brain Study (HABS) (Table 1). Baseline Aβ burden was measured with Pittsburgh Compound‐B (PiB) PET. Baseline vascular risk was quantified using the office‐based Framingham Heart Study general cardiovascular disease risk score (FHS‐CVD). Tau burden was measured longitudinally with Flortaucipir‐PET in inferior temporal cortex (ITC), an early site of neocortical tau accumulation and a region of interest based on prior work. Cognition was assessed longitudinally using Preclinical Alzheimer Cognitive Composite (PACC). Using linear mixed effects models, we examined the interactive effects of FHS‐CVD and Aβ on longitudinal ITC tau accumulation, adjusting for age, sex and APOE ε4 status. Next, we examined the FHS‐CVD*Aβ interaction using floodlight/Johnson‐Neyman analysis to determine the level of Aβ at which effects on ITC tau accumulation became significant. Using moderated mediation analysis, we further examined whether tau accumulation mediated the FHS‐CVD*Aβ interactive effects on PACC decline.ResultIndividual ITC‐tau trajectories are shown in Figure 1. We found an interaction between higher baseline FHS‐CVD and elevated Aβ with greater longitudinal ITC‐tau accumulation (Figure 2; Table 2). Floodlight analysis showed the FHS‐CVD*Aβ interaction became significant (p&lt;0.05) at PiB‐DVR&gt;1.22, lower than the conventional threshold for amyloid‐positivity (PiB‐DVR&gt;1.32). Moderated mediation models revealed ITC‐tau accumulation partially mediated (30%) the effect of FHS‐CVD on PACC decline at high (PiB‐DVR=1.85: β=‐0.48, p&lt;0.001) but not low (PiB‐DVR=1.17: β=‐0.16, p=0.09) levels of baseline Aβ (Figure 3).ConclusionVascular risk may interact with Aβ to promote cognitive decline partially through accelerating tau accumulation, even at subthreshold levels of Aβ. Further studies are needed to elucidate other mechanisms that mediate the remaining effects of this clinically important interaction.

Rates of cortical thinning in Alzheimer’s disease signature regions: pathological influences and cognitive consequences in members of the 1946 British birth cohort

AbstractBackgroundConsistent patterns of reduced cortical thickness (so‐called signature regions) have been identified in early Alzheimer’s disease (AD), including in the pre‐dementia stages, but studies investigating the pathological underpinnings and cognitive consequences of longitudinal changes in these regions have been limited.Method337 cognitively normal participants (mean [SD] age 70.5 [0.6] years) underwent 18F‐florbetapir amyloid‐ß PET, volumetric MRI, and cognitive assessment as part of Insight 46, a sub‐study of the 1946 British birth cohort (Table 1 for characteristics). Baseline and follow‐up T1‐weighted MRI (mean [SD] interval 2.4 [0.2] years) were processed using Freesurfer’s longitudinal stream (v.7.1.0) and cortical thickness was derived in two AD signatures (Table 2 footnote for details). Linear regression was used to test whether rates of change in AD signature cortical thickness were influenced by baseline amyloid‐ß deposition (positive/negative status or continuous SUVR) or white matter hyperintensity volume (WMHV; a marker of presumed cerebrovascular disease), and whether they were related to longitudinal cognitive change as measured using the Preclinical Alzheimer Cognitive Composite (PACC). Covariates included sex, age at baseline scan, childhood cognition, educational attainment, and socioeconomic position. Interaction terms were added to test whether associations with longitudinal cognitive change differed by baseline amyloid‐ß status.ResultHigher baseline WMHV was associated with faster rates of cortical thinning in AD signature regions, but baseline amyloid‐ß status and SUVR were not (Table 2; Figure 1). There were differential effects of rates of change in AD signature cortical thickness by baseline amyloid‐ß status, whereby greater rates of AD signature cortical thinning predicted faster rates of PACC decline in amyloid‐ß positive participants only (Table 3; Figure 2).ConclusionCortical thinning in AD signature regions may arise via non‐amyloid‐ß pathways in cognitively normal elderly. However, the presence of amyloid‐ß may make individuals more susceptible to the effects of faster rates of cortical thinning in these regions (or vice versa) since these factors interact to influence rates of cognitive decline. These findings provide insight into processes that might underlie progression to dementia in later life and have implications for the utility of AD signature cortical thickness as a biomarker in the preclinical phase of AD.

Cerebrovascular injury markers explain the effect of systemic vascular risk on cognitive decline in older adults with lower amyloid burden

AbstractBackgroundSystemic vascular risk is a well‐established contributor to late‐life cognitive decline, yet the mechanism is not completely understood. We investigated whether neuroimaging‐based measures of vascular injury (white matter hyperintensity (WMH) volume, Peak width of Skeletonized Mean Diffusivity (PSMD), and relative cerebral blood flow (rCBF)) could explain the effect of systemic vascular risk on cognitive decline using longitudinal data from the Harvard Aging Brain Study.MethodWe used the Framingham Heart Study cardiovascular disease risk score (FHS‐CVD) as an index of systemic vascular risk. We extracted WMH from structural MRI (https://hypermapp3r.readthedocs.io/) and PSMD from diffusion MRI (http://www.psmdmarker.com). We performed kinetic modeling on dynamically‐acquired PiB‐PET data to extract 1) amyloid burden as the distribution volume ratio (PiB‐DVR) and 2) relative tracer delivery (PiB‐R1 via MRTM reference‐tissue analysis as a proxy of rCBF). Global cognition was assessed using Preclinical Alzheimer Cognitive Composite (PACC).We considered two linear mixed effect models to examine whether cerebrovascular injury markers could explain the FHS‐CVD effect on PACC change over time: 1) FHS‐CVD on PACC change controlling for age, sex, years of education, and PiB‐DVR; 2) the previous model including WMH, PSMD, and PIB‐R1. Analyses were stratified by high (PiB+) and low (PiB‐) baseline amyloid burden.ResultFigure 1 illustrates the relationships between demographics and neuroimaging measures at baseline. Table 1 shows the demographics and study information. We observed a significant effect of FHS‐CVD on PACC change (PiB‐: t=‐3.9, p&lt;0.001 (Table 2); PiB+: t=‐2.6, p=0.008). When the cerebrovascular injury markers were included in the model, the effect of FHS‐CVD was reduced in the PiB‐ group while PSMD and PiB‐R1 explained PACC change (Table 3; Figure 2). The second model fit was significantly better than the first model (L.ratio= 25.9, p&lt;0.001). The effects remained significant after controlling for gray matter volume. In contrast, cerebrovascular injury measures did not explain the effect of FHS‐CVD on PACC change in the PIB+ group.ConclusionThese results demonstrate that cerebrovascular injury largely explains the effect of systemic vascular risk on cognitive decline in older adults with lower amyloid burden suggesting mechanisms by which a higher systemic vascular risk impacts brain function.

Defining the ATN framework using longitudinal biomarker trajectories reveals an emerging amyloid accumulation group

AbstractBackgroundThe ATN framework is defined by cross‐sectional biomarkers of β‐amyloid (Aβ), tau and neurodegeneration. Given that prevention trials, e.g., AHEAD 3‐45, are focused on individuals who have lower Aβ than established thresholds, we investigated whether defining the ATN framework using longitudinal biomarker trajectories might better identify an at‐risk sample within this boundary. Here, we applied a data‐driven method to re‐define the ATN with longitudinal biomarker data from the Harvard Aging Brain Study (HABS) and we then replicated this longitudinal framework in ADNI.Method157 HABS participants were clinically‐normal at baseline and underwent at least two Pittsburgh Compound‐B [PiB]‐PET, Flortaucipir‐PET, and T1‐weighted MRI scans. To define longitudinal ATN, we applied latent class mixture models (LCMM) to each biomarker (global Aβ DVR, entorhinal tau SUVr, ICV‐adjusted hippocampal volume) separately, adjusting for age, and including random intercept and slopes. Akaike information criteria (AIC) determined the best‐fitting models out of two‐group or three‐group solutions with linear or spline‐link functions. We compared longitudinal ATN profiles on demographics and an optimized estimate of cognitive change (derived from longitudinal Preclinical Alzheimer Cognitive Composite (PACC) data).ResultAβ trajectories (Fig.1a) were best categorized by one stable (A→) and two accumulating subgroups, a predominantly amyloid‐negative at baseline subgroup (A‐↑) and an entirely amyloid positive at baseline subgroup (A+↑). Tau (Fig.1b) and neurodegeneration (Fig.1c) were optimally defined by stable (T→/N→) vs accumulating/atrophying (T↑/N↑) groups, respectively. These groups were replicated in ADNI (Fig.2). The entire A‐↑ subgroup were stable on T and N (A‐↑/T→/N→) and were predominantly A‐/T‐/N‐ at baseline (86%; Table 1). By contrast, 38% of A+↑ individuals changed on T, or T&amp;N. A‐↑/T→/N→ demographically most closely resembled the longitudinally‐stable ATN group (A→/T→/N→), but were older, more likely to carry e4+ and exhibited higher baseline Aβ (Table 2). Although demonstrating Aβ accumulation, A‐↑/T→/N→ did not exhibit greater cognitive decline versus the stable group (A→/T→/N→; Fig. 3).ConclusionOur findings suggest that a longitudinal biomarker run‐in of Aβ‐PET may be useful for the identification of early‐risk groups for prevention trials. Future work will establish whether other features (e.g. genetics, neuroinflammatory markers, functional imaging) can help to distinguish this cohort.

Vascular endothelial-cadherin as a marker of endothelial injury in preclinical Alzheimer disease.

Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD. Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n=700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Aβ42/Aβ40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) (n=534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD. CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T±N±; n=558) or those with amyloid and tau pathologies (A+T+N±; n=259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid-PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Aβ42/Aβ40, p-tau181, and global amyloid burden with cognitive outcomes in preclinical AD. Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages.

Association of Emerging β-Amyloid and Tau Pathology With Early Cognitive Changes in Clinically Normal Older Adults.

Alzheimer disease (AD) clinical trials are moving earlier in the disease process according to emerging signs of β-amyloid (Aβ) and tau pathology. If early treatment is the right time for intervention, it is critical to find the right test to optimize cognitive outcome measures for clinical trials. We sought to identify cognitive measures associated with the earliest detectable signs of emerging Aβ and tau pathology. One hundred twelve clinically normal adults with longitudinal Pittsburgh compound B (PiB)-PET, 18F-flortaucipir (FTP)-PET, and cognitive data for ≥7 years were included from the Harvard Aging Brain Study (HABS). Analyses assessed those initially classified as PiB- (less than Centiloid [CL] 20) and then expanded to include PiB+ individuals up to CL40, the approximate threshold beyond which neocortical tau proliferation begins. Separate linear mixed-effects models assessed the effects of emerging global Aβ (PiB slope) and tau (baseline FTP level and FTP slope) in the entorhinal and inferior temporal (IT) cortices on multiple cognitive tasks and the Preclinical Alzheimer's Cognitive Composite (PACC) over time. Steeper PiB slopes were associated with declining processing speed (Digit Symbol Substitution Test [DSST], Trail Making Test Part A) in those <CL20 and expanded to include learning/memory retrieval (FCSRT-FR], Selective Reminding Test Total Recall [SRT-tr], Logical Memory Immediate Recall) in the <CL40 group. FTP had limited effects under CL20, with only rising right IT FTP slope related to declining FCSRT-FR and SRT-tr learning/memory retrieval. When we expanded to include those initially <CL40, rising FTP level or slope was related to declines across all tasks, and PiB slope effects on memory retrieval but not DSST score were reduced. A composite measure of processing speed and memory retrieval tasks provided the strongest prediction of decline under CL40, while PACC score remained optimal at high levels of Aβ (>CL40). Early, Aβ-mediated cognitive slowing was detected for processing speed measures, while early memory retrieval declines were associated with emerging Aβ and tau pathology. Composites of these measures may help determine whether anti-Aβ or anti-tau therapies administered at the first signs of pathology might preserve cognitive function. This study provides Class I evidence that in clinically normal older adults, emerging PET-detected AD pathology is associated with declining processing speeds and memory retrieval.

Utility of Polygenic Risk Scoring to Predict Cognitive Impairment as Measured by Preclinical Alzheimer Cognitive Composite Score.

The utility of Polygenic Risk Scores (PRS) is gaining increasing attention for generating an individual genetic risk profile to predict subsequent likelihood of future onset of Alzheimer's disease (AD), especially those carry two copies of the APOE E3 allele, currently considered at neutral risk in all populations studied. To access the performance of PRS in predicting individuals whilst pre-symptomatic or with mild cognitive impairment who are at greatest risk of progression of cognitive impairment due to Alzheimer's Disease from the Alzheimer's Disease Neuroimaging Initiative (ADNI) as measured by the Preclinical Alzheimer Cognitive Composite (PACC) score profile. Design: A longitudinal analysis of data from the ADNI study conducted across over 50 sites in the US and Canada. Multi-centre genetics study. 594 subjects either APOE E3 homozygotes or APOE E3/E4 heterozygotes who upon entry to the study were diagnosed as cognitively normal or with mild cognitive impairment. Use of genotyping and/or whole genome sequencing data to calculate polygenic risk scores and assess its ability to predict subsequent cognitive decline as measured by PACC over 5 years. Results: Assessing both cognitively normal and mild cognitive impaired subjects using a PRS threshold of greater than 0.6, the high genetic risk participant group declined more than the low risk group over 5 years as measured by PACC score (PACC score reduced by time). Our findings have shown that polygenic risk score provides a promising tool to identify those with higher risk to decline over 5 years regardless of their APOE alleles according to modified PACC profile, especially its ability to identify APOE3/E3 cognitively normal individuals who are at most risk for early cognitive decline. This genotype accounts for approximately 60% of the general population and 35% of the AD population but currently would not be considered at higher risk without access to expensive or invasive biomarker testing.

Sensitivity of the Preclinical Alzheimer's Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer's Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial.

Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials. To evaluate the association between amyloid (Aβ) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer's Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS). Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis. The EARLY study was conducted at 143 centers across 14 countries. 3,569 cognitively unimpaired older adults (Clinical Dementia Rating of 0; aged 60-85 years) screened for inclusion in the EARLY study with Aβ status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aβ levels (Aβ-, n=2,824) and those with pathological Aβ levels (Aβ+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aβ1-42. Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aβ groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aβ status. Of 3,569 participants, 2,116 were women (59%); 3,006 were Caucasian (84%); mean (SD) age was 68.98 (5.28) years. Aβ+ participants performed worse versus Aβ- participants on all cognitive composites though the magnitude of the Aβ effect was generally small. The Aβ+/- effect size for the PACC (Cohen's d=-0.15) was significantly greater than the RBANS (d=-0.097) while the PACC5 effect size (d=-0.139) was numerically larger than the RBANS. When examining subscores from the composites, memory tests (i.e., Free and Cued Selective Reminding Test, Figure Recall) and speed of processing (i.e., Digit-Symbol/Coding on the PACC/RBANS) exhibited the largest Aβ+/- effect sizes. Cross-sectional relationships between Aβ and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aβ+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aβ status cross-sectionally cannot be generalized to sensitivity to change over time.

Impact of sex and APOE ε4 on the association of cognition and hippocampal volume in clinically normal, amyloid positive adults.

IntroductionCognitive decline follows pathological changes including neurodegeneration on the Alzheimer's disease continuum. However, it is unclear which cognitive domains first become affected by neurodegeneration in amyloid‐positive individuals and if sex or apolipoprotein (APOE) ε4 status differences affect this relationship.MethodsData from 1233 cognitively unimpaired, amyloid‐positive individuals 65 to 85 years of age were studied to assess the effect of hippocampal volume (HV) on cognition and to evaluate differences due to sex and APOE ε4 status.ResultsLower HV was linked with worse performance on measures of memory (free recall, total recall, logical memory delayed recall, Mini‐Mental State Examination [MMSE]), executive functioning (digit symbol substitution, DSS), and the Preclinical Alzheimer's Cognitive Composite (PACC). Among both women and APOE ε4+ individuals, all cognitive measures, except MMSE, were associated with HV. DSS and PACC had the largest effect sizes in differentiating early and intermediate stage neurodegeneration.DiscussionDespite all cognitive measures being associated with HV, cognitive tests show differences in detecting early or late signs of neurodegeneration. Differences exist in association between cognition and neurodegeneration based on sex and APOE ε4 status