Neuroanatomical spread of amyloid β and tau in Alzheimer's disease: implications for primary prevention.

With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer's disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer's disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P < 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer's disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation

Time to Amyloid Positivity and Preclinical Changes in Brain Metabolism, Atrophy, and Cognition: Evidence for Emerging Amyloid Pathology in Alzheimer's Disease

Background: Aβ pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Aβ information is usually measured cross-sectionally and dichotomized to classify subjects as Aβ-positive or Aβ-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Aβ pathology. In this study, we use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition.Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we estimated the points at which rates of fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to the time to Aβ-positivity. Points of initial acceleration in rates of decline were estimated using mixed-effects models with penalized regression splines.Results: Acceleration of rates of FDG PET were observed to occur 20+ years before the conventional threshold for Aβ-positivity. Subtle signs of cognitive dysfunction were observed 10+ years before Aβ-positivity.Conclusions: Aβ may have subtle associations with other hallmarks of Alzheimer's disease before Aβ biomarkers reach conventional thresholds for Aβ-positivity. Therefore, we propose that emerging Aβ pathology occurs many years before cognitively healthy elders reach the current threshold for Aβ positivity (preclinical AD). To allow prevention in the earliest disease stages, AD clinical trials may be designed to also include subjects with Aβ biomarkers in the sub-threshold range

Association between Apolipoprotein e ϵ2 vs ϵ4, Age, and β-Amyloid in Adults without Cognitive Impairment

Importance: Although the most common recent approach in Alzheimer disease drug discovery is to directly target the β-amyloid (Aβ) pathway, the high prevalence of apolipoprotein E ϵ4 (APOE ϵ4) in Alzheimer disease and the ease of identifying ϵ4 carriers make the APOE genotype and its corresponding protein (apoE) an appealing therapeutic target to slow Aβ accumulation. Objective: To determine whether the ϵ2 allele is protective against Aβ accumulation in the presence of the ϵ4 allele and evaluate how age and the APOE genotype are associated with emerging Aβ accumulation and cognitive dysfunction. Design, Setting, and Participants: This cross-sectional study used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4 Study) collected from April 2014 to December 2017 and analyzed from November 2019 to July 2020. Of the 6943 participants who were a part of the multicenter clinical trial screening visit, 4432 were adults without cognitive impairment aged 65 to 85 years who completed a fluorine 18-labeled (18F)-florbetapir positron emission tomography scan, had APOE genotype information, and had a Clinical Dementia Rating of 0. Participants who were taking a prescription Alzheimer medication or had a current serious or unstable illness that could interfere with the study were excluded. Main Outcomes and Measures: Aβ pathology, measured by 18F-florbetapir positron emission tomography and cognition, measured by the Preclinical Alzheimer Cognitive Composite. Results: A total of 4432 participants were included (mean [SD] age, 71.3 [4.7] years; 2634 women [59.4%]), with a mean (SD) of 16.6 (2.8) years of education and 1512 (34.1%) with a positive Aβ level. APOE ϵ2 was associated with a reduction in both the overall (standardized uptake value ratio [SUVR], ϵ24, 1.11 [95% CI, 1.08-1.14]; ϵ34, 1.18 [95% CI, 1.17-1.19]) and the age-dependent level of Aβ in the presence of ϵ4, with Aβ levels in the APOE ϵ24 group (n = 115; ϵ24, 0.005 SUVR increase per year of age) increasing at less than half the rate with respect to increasing age compared with the APOE ϵ34 group (n = 1295; 0.012 SUVR increase per year of age; P =.04). The association between Aβ and decreasing Preclinical Alzheimer Cognitive Composite scores did not differ by APOE genotype, and the reduced performance on the Preclinical Alzheimer Cognitive Composite in APOE ϵ4 carriers compared with noncarriers was completely mediated by Aβ (unadjusted difference in composite scores between ϵ4 carriers and noncarriers = -0.084, P =.005; after adjusting for 18F-florbetapir = -0.006, P =.85; after adjusting for 18F-florbetapir and cardiovascular scores = -0.009, P =.78). Conclusions and Relevance: These findings suggest that the protective outcome of carrying an ϵ2 allele in the presence of an ϵ4 allele against Aβ accumulation is important for potential treatments that attempt to biochemically mimic the function of the ϵ2 allele in order to facilitate Aβ clearance in ϵ4 carriers. Such a treatment strategy is appealing, as ϵ4 carriers make up approximately two-thirds of patients with Alzheimer disease dementia. This strategy could represent an early treatment option, as many ϵ4 carriers begin to accumulate Aβ in early middle age.

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

Background and Objectives: There is considerable heterogeneity in the association between increasing β-amyloid (Aβ) pathology and early cognitive dysfunction in preclinical Alzheimer 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 examined an array of genetic variants that may influence the relationships among Aβ, brain structure, and cognitive performance in 2 large cohorts. Methods: In 2,953 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) study, interactions between genetic variants and 18F-Florbetapir PET standardized uptake value ratio (SUVR) to predict the Preclinical Alzheimer Cognitive Composite (PACC) were assessed. Genetic variants identified in the A4 study were evaluated in the Alzheimer 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. Results: In the A4 study, 4 genetic variants significantly moderated the association between Aβ load and cognition. Minor alleles of 3 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; and 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 the A4 and ADNI. In the 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 the 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. Discussion: 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 the A4 and accelerated cognitive decline and brain atrophy in the ADNI may help to identify those at the highest risk of accelerated progression of AD