👤 Günter Höglinger

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

Progressive supranuclear palsy (PSP) is mainly a sporadic disease. It has a multifactorial etiology and an interaction between environmental and genetic factors causes disease. While elucidation of environmental risks for PSP is still in its infancy, much has been learned about the genetic etiological component of PSP during the past few years. This article reviews genes that convey risk for PSP. All genes have been identified in association studies. Only those genes with the standard threshold for genome-wide significance of P < 5E-8 are covered. These genes include MAPT, KANSL1, PLEKHM1, STX6, MOBP, EIF2AK3, SLC01 A2, DUSP10, APOE, RUNX2, TRIM11, NFASC/CNTN2 and LRRK2. The physiologic function of these genes is described and their potential role in the etiology of PSP is discussed. Show less

The 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP). To investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP. Utilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP. We found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub-haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up-regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down-regulating KANSL1. Single-nucleus RNA-seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up-regulates LRRC37A/LRRC37A2 in neuronal cells. The copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Show less

This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated ("bagged") decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95%CI, 86.3%-86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10 Show less

Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society. Show less