👤 Martin Dichgans

In Alzheimer's disease, carriage of the ApoE4 risk allele is linked to faster tau accumulation at lower amyloid-PET levels, thereby accelerating disease progression. However, it remains unclear whether this ApoE4-facilitated transition from amyloidosis to tauopathy is mechanistically promoted by increased secretion of phosphorylated (p)tau, a key intermediate that drives the amyloid-to-tauopathy transition, or alternatively by increased ptau-driven tau aggregation. Therefore, we investigated where along the amyloid-to-tau axis ApoE4 accelerates tau aggregation and assessed i) whether ApoE4 increases ptau secretion or ii) whether ApoE4 increases ptau-associated tau aggregation. To this end, we analysed two large-scale APOE-genotyped cohorts covering the full Alzheimer's disease spectrum (ADNI: n=201) as well as a preclinical cohort (A4-LEARN: n=200), integrating baseline amyloid-PET, plasma ptau217 and CSF ptau181 with longitudinal tau-PET. Using linear regression, we tested whether ApoE4-carriage moderates i) amyloid-PET-associated plasma ptau217 increases or ii) ptau217-associated tau spreading from local epicentres across patient-tailored tau spreading stages. All analyses were independently validated across both cohorts, including an additional replication in an ADNI subset (n=115) with available CSF ptau181 measures as an alternative marker of ptau secretion. Finally, we used logistic regression to determine ApoE4 allele count-stratified plasma ptau217 thresholds marking early pathological tau-PET increases. We found that ApoE4 did not facilitate amyloid-PET-associated ptau increases, suggesting that amyloid-related ptau secretion is not altered by ApoE4-carriage. Contrastingly, we found that plasma ptau217 elevations were linked to faster tau-PET spread from local epicentres across connected brain regions in an ApoE4-allele dose-dependent manner, independent of amyloid (ADNI/A4-LEARN: mean β=0.44/0.56, p<0.001/<0.001). Lastly, we found that a higher ApoE4 allele count was linked to lower ptau217 thresholds marking transition to tauopathy, i.e. early abnormal tau-PET increases, consistently across both samples (ADNI: 0/1/2 ApoE4 alleles=0.62/0.34/0.15pg/ml, representing ∼45% and ∼76% reductions from non-carriers; Fujirebio ptau217 assay; A4/LEARN: 0/1/2 ApoE4 alleles=0.31/0.23/0.18pg/ml, representing ∼26% and ∼42% reductions; Eli Lilly ptau217 assay). These findings suggest that ApoE4, i.e. the key genetic risk factor for sporadic Alzheimer's disease, facilitates amyloid-dependent tau aggregation in an allele dose-dependent manner by enhancing the ptau-driven spread of fibrillar tau, leading to an earlier transition from amyloidosis to tauopathy at lower ptau217 levels. This has implications for plasma ptau-based screening approaches and therapeutic timing of anti-amyloid drugs in ApoE4 carriers: Specifically, ApoE4 carriers may require genotype-adjusted ptau thresholds to detect Alzheimer's disease pathophysiology, as well as anti-amyloid treatment at lower ptau levels to prevent the transition to tauopathy, which ultimately drives neurodegeneration and cognitive decline. Show less

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology. Show less

The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. British Heart Foundation. Show less

Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial. Show less

We identified a marker in LINGO1 showing genome-wide significant association (P = 1.2 x 10(-9), odds ratio = 1.55) with essential tremor. LINGO1 has potent, negative regulatory influences on neuronal survival and is also important in regulating both central-nervous-system axon regeneration and oligodendrocyte maturation. Increased axon integrity observed in Lingo1 mouse [corrected] knockout models highlights the potential role of LINGO1 in the pathophysiology of ET [corrected] Show less