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

Lorenzini, Luigi; Collij, Lyduine E.; Tesi, Niccoló; Vilor‐Tejedor, Natàlia; Ingala, Silvia; Blennow, Kaj; Foley, Christopher; Frisoni, Giovanni B.; Haller, Sven; Holstege, Henne; van der van der Lee, Sven; Martinez‐Lage, Pablo; Marioni, Riccardo E.; McCartney, Daniel L.; O’ Brien, John; Oliveira, Tiago Gil; Payoux, Pierre; Reinders, Marcel; Ritchie, Craig; Scheltens, Philip; Schwarz, Adam J.; Sudre, Carole H.; Waldman, Adam D.; Wolz, Robin; Chatelat, Gael; Ewers, Michael; Wink, Alle Meije; Mutsaerts, Henk J. M. M.; Gispert, Juan Domingo; Visser, Pieter Jelle; Tijms, Betty M.; Altmann, Andre; Barkhof, Frederik

doi:10.1002/alz.14096

Alzheimer's & Dementia

2024

DOI: 10.1002/alz.14096

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

Luigi Lorenzini,

Lyduine E. Collij,

Niccoló Tesi

et al.

Abstract: INTRODUCTIONUnraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine.METHODSWe computed pathway‐specific genetic risk scores (GRSs) in non‐demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity.RESULTSCSF amyloidbeta and … Show more

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2024

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Cited by 2 publications

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Non‐APOE variants predominately expressed in smooth muscle cells contribute to the influence of Alzheimer's disease genetic risk on white matter hyperintensities

Chandler,

Wheeler,

Escott‐Price

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONWhite matter hyperintensity volumes (WMHVs) are disproportionally prevalent in individuals with Alzheimer's disease (AD), potentially reflecting neurovascular injury. We quantify the association between AD polygenic risk score (AD‐PRS) and WMHV, exploring single‐nucleotide polymorphisms (SNPs) that are proximal to genes overexpressed in cerebrovascular cell species.METHODSIn a UK‐Biobank sub‐sample (mean age = 64, range = 45–81 years), we associate WMHV with (1) AD‐PRS estimated via SNPs across the genome (minus apolipoprotein E [APOE] locus) and (2) AD‐PRS estimated with SNPs proximal to specific genes that are overexpressed in cerebrovascular cell species.RESULTSWe observed a positive association between non‐APOE‐AD‐PRS and WMHVs. We further demonstrate an association between WMHVs and AD‐PRS constructed with SNPs that are proximal to genes over‐represented in smooth muscles cells (SMCs; β = 0.135, PFWE < 0.01) and internally replicated (PDISCOVERY+REPLICATION < 0.01).DISCUSSIONCommon AD genetic risk could explain physiological processes underlying vascular pathology in AD. SMC function may offer a treatment target to prevent WMHV‐related AD pathophysiology prior to the onset of symptoms.Highlights Alzheimer's disease (AD) risk factors such as apolipoprotein E (APOE) ε4, link to increased white matter hyperintensity volume (WMHV). WMHVs indicate vascular risk and neurovascular injury in AD. The broader genetic link between AD risk and WMHV is not fully understood. We quantify AD polygenic risk score (PRS) associations with WMHV, excluding APOE. AD‐PRS in smooth muscle cells (SMCs) shows a significant association with increased WMHV.

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Non‐APOE variants predominately expressed in smooth muscle cells contribute to the influence of Alzheimer's disease genetic risk on white matter hyperintensities

Chandler,

Wheeler,

Escott‐Price

et al. 2024

Alzheimer's & Dementia

View full text Add to dashboard Cite

show abstract

Towards cascading genetic risk in Alzheimer’s disease

Altmann,

Aksman,

Oxtoby

et al. 2024

Brain

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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, where each of the biomarkers can be either positive (+) or negative (-). Over the past decades genome wide association studies have implicated about 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 employed 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 significant effect (HR=2.88; 95% CI: 1.70-4.89; P<0.001), while 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 APOE-e4 burden contribution was reduced (HR=1.62 95% CI: 1.05-2.51; P=0.031), while 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 transition between ATN stages, a better understanding of the molecular processes leading to Alzheimer’s disease as well as opening therapeutic windows for targeted interventions.

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

Cited by 2 publications

References 66 publications

Non‐APOE variants predominately expressed in smooth muscle cells contribute to the influence of Alzheimer's disease genetic risk on white matter hyperintensities

Non‐APOE variants predominately expressed in smooth muscle cells contribute to the influence of Alzheimer's disease genetic risk on white matter hyperintensities

Towards cascading genetic risk in Alzheimer’s disease

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