Towards cascading genetic risk in Alzheimer’s disease

Brain · 2024 · 11 citations

• Oncology
• Internal medicine
• Medicine

Alzheimer's disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer's disease. Here, we investigate whether genetic risk for Alzheimer's disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimer's disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer's disease, in addition to opening therapeutic windows for targeted interventions.

Donanemab in Early Symptomatic Alzheimer Disease

JAMA · 2023 · 2382 citations

• Medicine
• Internal medicine
• Pediatrics

Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration: ClinicalTrials.gov Identifier: NCT04437511.

Anatomically interpretable deep learning of brain age captures domain-specific cognitive impairment

Proceedings of the National Academy of Sciences · 2023 · 116 citations

• Psychology
• Audiology
• Neuroscience

= 359). In individuals with MCI (54% of whom were diagnosed with dementia within 10.9 y from MRI acquisition), BA is significantly better than CA in capturing dementia symptom severity, functional disability, and executive function. Profiles of sex dimorphism and lateralization in brain aging also map onto patterns of neuroanatomic change that reflect cognitive decline. Significant associations between BA and neurocognitive measures suggest that the proposed framework can map, systematically, the relationship between aging-related neuroanatomy changes in CN individuals and in participants with MCI or AD. Early identification of such neuroanatomy changes can help to screen individuals according to their AD risk.

Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Nature Medicine · 2022 · 131 citations

• Medicine
• Oncology
• Internal medicine

Staging tau pathology with tau PET in Alzheimer’s disease: a longitudinal study

Translational Psychiatry · 2021 · 65 citations

• Oncology
• Psychology
• Internal medicine

F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer's disease could be illustrated with biomarker measurement under NIA-AA framework. Clinical-neuroimaging-neuropathological studies in other cohorts are needed to validate these findings.

Perivascular spaces in the brain: anatomy, physiology and pathology

Nature Reviews Neurology · 2020 · 848 citations

• Medicine
• Pathology
• Neuroscience

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

Nature Communications · 2020 · 338 citations

• Neuroscience
• Medicine
• Biology

In Alzheimer's diseases (AD), tau pathology is strongly associated with cognitive decline. Preclinical evidence suggests that tau spreads across connected neurons in an activity-dependent manner. Supporting this, cross-sectional AD studies show that tau deposition patterns resemble functional brain networks. However, whether higher functional connectivity is associated with higher rates of tau accumulation is unclear. Here, we combine resting-state fMRI with longitudinal tau-PET in two independent samples including 53 (ADNI) and 41 (BioFINDER) amyloid-biomarker defined AD subjects and 28 (ADNI) vs. 16 (BioFINDER) amyloid-negative healthy controls. In both samples, AD subjects show faster tau accumulation than controls. Second, in AD, higher fMRI-assessed connectivity between 400 regions of interest (ROIs) is associated with correlated tau-PET accumulation in corresponding ROIs. Third, we show that a model including baseline connectivity and tau-PET is associated with future tau-PET accumulation. Together, connectivity is associated with tau spread in AD, supporting the view of transneuronal tau propagation.

Sibling Spillovers

The Economic Journal · 2020 · 36 citations

• Sociology
• Developmental psychology
• Psychology

Abstract It is notoriously difficult to identify peer effects within the family. Using administrative data on children from both Florida and Denmark, the paper examines the effects of having a disabled younger sibling. To address the identification challenge, the paper compares the differential effects for first- and second-born children in three-plus-child families, taking advantage of the fact that birth order influences the amount of time that a child spends in early childhood with their younger siblings, disabled or not. The paper finds evidence that, relative to the first born, the second child in a family is differentially affected when the third child is disabled.

Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease

Nature Communications · 2020 · 532 citations

• Neuroscience
• Biology
• Psychology

Tau is a hallmark pathology of Alzheimer's disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (Aβ). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-PET in 312 individuals along Alzheimer's disease continuum. Up to 70% of the variance in the overall spatial pattern of tau can be explained by our model. Surprisingly, the ESM predicts the spatial patterns of tau irrespective of whether brain Aβ is present, but regions with greater Aβ burden show greater tau than predicted by connectivity patterns, suggesting a role of Aβ in accelerating tau spread. Altogether, our results provide evidence in humans that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain Aβ.