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Objective: Polygenic variation accounts for a substantial portion of the risk of Alzheimer's disease (AD), but its effect on the rate of fibrillar‐tau accumulation as a key driver of dementia symptoms is unclear. Methods: We combined the to‐date largest number of genetic risk variants of AD (n = 85 lead single‐nucleotide polymorphisms [SNPs]) from recent genome‐wide association studies (GWAS) to generate a polygenic score (PGS). We assessed longitudinal tau‐positron emission tomography (PET), amyloid‐PET, and cognition in 231 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using the PGS, together with global amyloid‐PET, we predicted the rate of tau‐PET increases in Braak‐stage regions‐of‐interest and cognitive decline. We also assessed PGS‐risk enrichment effects on the required sample size in clinical trials targeting tau pathology. Results: We found that a higher PGS was associated with higher rates of tau‐PET accumulation, in particular at elevated amyloid‐PET levels. The tau‐PET increases mediated the association between PGS and faster cognitive decline. Risk enrichment through high PGS afforded sample size savings by 34%. Interpretation: Our results demonstrate that the PGS predicts faster tau progression and thus cognitive decline, showing utility to enhance statistical power in clinical trials. ANN NEUROL 2023;93:819–829 [ABSTRACT FROM AUTHOR]

Background: Progression of fibrillar tau is a key driver of neurodegeneration and cognitive decline in Alzheimer's disease (AD), however which factors predict the rate of tau accumulation at the patient‐level is unclear. Here we propose to employ a polygenic score (PGS) for the prediction of tau accumulation and cognitive changes in AD, which could be useful for selection of individuals with faster tau progression in clinical trials. Methods: We included 231 ADNI participants with longitudinal measurements of tau‐PET, amyloid‐PET, cognitive data and genotype data. We computed a PGS based on 85 independent lead SNPs from two recent large GWAS (DOI:10.1101/2020.10.01.20200659; DOI:10.1038/s41588‐021‐00921‐z), excluding all APOE variants. Using linear mixed effect models, we computed the individual rates of change in each of the biomarkers. In linear regression models we tested whether PGS can predict the rate of tau‐PET changes in Braak‐stage ROIs (Figure 1A) and cognitive changes. In order to assess whether amyloid mediates the effect of PGS on tau accumulation we performed sensitivity analyses in subgroups categorized by amyloid status as well as tested the interaction between the PGS and global amyloid‐PET. We further estimated sample size required for detection of hypothetical treatment effect on the rate tau accumulation using power analysis. Results: Higher PGS was associated with higher accumulation rates of tau‐PET in cortical regions (Braak 3+4:β=0.306, pFDR<0.001; Braak 5+6:β=0.262, pFDR<0.001; Figure 1B). A higher PGS was further associated with faster decline in episodic memory (β=‐0.223, pFDR<0.001; Figure 1C) and global cognition (β=0.280, pFDR<0.001; Figure 1C). The observed effects of PGS on cognitive changes were mediated by higher tau‐PET accumulation (Figure 2). We found a synergistic effect between PGS and elevated amyloid‐PET levels on the rate of tau‐PET accumulation such that the PGS effects on tau‐PET accumulation were stronger particularly at elevated amyloid levels (Figure 3). Selection of individuals with highest PGS yielded a 32‐33% saving in required sample size to detect a treatment effect on tau accumulation. Conclusion: Higher polygenic score is associated with faster tau accumulation and may be a useful tool for risk stratification in disease‐modifying treatments on tau. [ABSTRACT FROM AUTHOR]

Objective: Ischemic stroke etiology remains undetermined in 30% of cases. We explored the genetic architecture of stroke classified as undetermined to test if mechanisms and risk factors underlying large‐artery atherosclerotic (LAAS), cardioembolic (CES), and small‐vessel stroke (SVS) contribute to its pathogenesis. Methods: We analyzed genome‐wide data from 16,851 ischemic stroke cases and 32,473 controls. Using polygenic risk scores for LAAS, CES, and SVS, we assessed the genetic overlap with stroke of undetermined source and used pairwise genomewide association study (GWAS‐PW) to search for shared loci. We then applied Mendelian randomization (MR) to identify potentially causal risk factors of stroke of undetermined source. Results: Genetic risk for LAS, CES, and SVS was associated with stroke of undetermined source pointing to overlap in their genetic architecture. Pairwise analyses revealed 19 shared loci with LAAS, 2 with CES, and 5 with SVS that have been implicated in atherosclerosis‐related phenotypes. Genetic liability to both carotid atherosclerosis and atrial fibrillation was associated with stroke of undetermined source, but the association with atrial fibrillation was attenuated after excluding cases with incomplete diagnostic workup. MR analyses showed effects of genetically determinants of blood pressure, diabetes, waist‐to‐hip ratio, inflammatory pathways (IL‐6 signaling, MCP‐1/CCL2 levels), and factor XI levels on stroke of undetermined source. Interpretation: Stroke of undetermined source shares genetic and vascular risk factors with other stroke subtypes, especially LAAS, thus highlighting the diagnostic limitations of current subtyping approaches. The potentially causal associations with carotid atherosclerosis and atherosclerotic risk factors might have implications for prevention strategies targeting these mechanisms. ANN NEUROL 2022;91:640–651 [ABSTRACT FROM AUTHOR]

Background: Pure Alzheimer's disease (AD), characterized by combined amyloid and tau pathology, is not the most prevalent form of the disease as non‐AD pathologies (e.g., alpha‐synuclein and TDP‐43) are commonly observed postmortem. The role of AD and non‐AD pathologies is unclear in relation to disease heterogeneity. Therefore, we investigated whether antemortem MRI‐based atrophy subtypes of AD differ in postmortem neuropathological features and comorbid non‐AD pathologies. Methods: We selected individuals from the ADNI with antemortem MRI evaluating brain atrophy within 2 years before death; antemortem diagnosis of AD dementia/mild cognitive impairment; and a postmortem‐confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena using a recent conceptual framework: typicality (spanning limbic predominant AD to hippocampal sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathological evaluation included AD hallmarks (amyloid‐beta, tau), non‐AD pathologies (alpha‐synuclein, TDP‐43) and concomitant pathological burden. Partial correlations assessed the associations between antemortem atrophy subtype dimensions and postmortem neuropathological outcomes. Results: In 31 individuals (mean age = 80y, 26% females), antemortem typicality was significantly associated with neuropathological features: amyloid‐beta (rho = ‐0.39 overall), tau (rho = ‐0.38 regionally), neuritic plaque density (rho = ‐0.4 overall), alpha‐synuclein (rho = ‐0.39 regionally), TDP‐43 (rho = ‐0.49 overall), and concomitance pathological burden (rho = ‐0.59 regionally). This suggests that limbic predominant AD was associated with higher burden of these pathologies compared to hippocampal sparing AD. Antemortem severity was significantly associated with concomitant pathological burden (rho = ‐0.43 regionally), such that typical AD showed higher burden than minimal atrophy AD. Conclusions: Based on our direct antemortem‐to‐postmortem validation, we hypothesize that: (a) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non‐AD pathologies; (b) limbic predominant AD and typical AD subtypes may share similar biological pathways, making them more vulnerable to the investigated AD and non‐AD pathologies compared to hippocampal sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing prevailing knowledge of biological heterogeneity in AD. [ABSTRACT FROM AUTHOR]