Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non‐demented individuals

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(9), P. 6146 - 6160

Published: July 29, 2024

Abstract INTRODUCTION Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, a key step toward precision medicine. METHODS We computed pathway‐specific scores (GRSs) in non‐demented individuals investigated AD variants predict cerebrospinal fluid (CSF) imaging biomarkers reflecting pathology, cardiovascular, white matter integrity, brain connectivity. RESULTS CSF amyloidbeta phosphorylated tau were most GRSs. Inflammatory pathways associated with cerebrovascular disease, whereas quantitative measures of lesion microstructure integrity predicted by clearance migration pathways. Functional connectivity alterations involved signal transduction synaptic communication. DISCUSSION This study reveals distinct profiles association pathophysiological aspects predementia stages AD, unraveling the substrates heterogeneity AD‐associated endophenotypes promoting forward understanding development personalized therapies. Highlights Polygenic for encompasses six that can be quantified scores, differentially relate biomarkers. are mostly burden. White health membrane functional communication

Language: Английский

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Polygenic risk discriminates Lewy body dementia from Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Lewy body dementia (LBD) shares genetic risk factors with Alzheimer's disease (AD), including apolipoprotein E (APOE), but is distinguishable at the genome-wide level. Polygenic scores (PRS) may therefore improve diagnostic classification. We assessed classification using AD-PRS excluding APOE (AD-PRSno APOE), score (APOE-RS), and plasma phosphorylated tau 181 (p-tau181), in 83 participants LBD, 27 positron emission tomography amyloid beta (Aβ)positive mild cognitive impairment or AD (MCI+/AD), 57 controls. Together AD-PRSno APOE-RS performed similarly to p-tau181 discriminating MCI+/AD from controls (area under curve 76% vs. 79%) LBD (71% 72%). In Aβ positivity was significantly associated APOE-RS, not APOE, p-tau181. Combining improved discrimination of (81%) (75%), detection (82%). deposition while also beyond APOE. explains phenotypic variance captured by investigated (AD) polygenic (PRS), (p-tau181) classify (LBD). achieved similar accuracy without contributed LBD. Amyloid AD-PRS, accuracy.

Language: Английский

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Disentangling genetic risks for development and progression of Alzheimer’s disease

Brain, Journal Year: 2024, Volume and Issue: 147(8), P. 2604 - 2606

Published: July 17, 2024

This scientific commentary refers to ‘Towards cascading genetic risk in Alzheimer’s disease’ by Altmann et al. (https://doi.org/10.1093/brain/awae176).

Language: Английский

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