Background Non-Alcoholic Fatty Liver Disease (NAFLD), now referred to as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is a widespread and complex health issue characterized by the accumulation of lipids in liver cells, not linked to alcohol consumption or other known liver problems. Despite its strong association with insulin resistance and obesity, a notable proportion of lean individuals develop NAFLD, suggesting the involvement of additional factors. Mitochondrial dysfunction has emerged as a potential contributor, given its role in lipid homeostasis and the generation of reactive oxidative species (ROS). Methods In this study, we took advantage of the mtDNA mutator mouse model, characterized by oxidative phosphorylation deficiency due to accelerated accumulation of mitochondrial DNA (mtDNA) mutations, to investigate how mitochondrial dysfunction affects liver homeostasis triggering fat accumulation. Results We found that mitochondrial dysfunction induces liver steatosis and inflammation in this mouse model at a young age, independent of obesity. Using quantitative mass spectrometry, we reveal that mitochondrial dysfunction alters the levels of multiple proteins involved in lipid metabolism, cholesterol homeostasis, and inflammation. In vitro data show a shift in cellular metabolism toward the glycolytic pathway and confirm the upregulation of inflammatory genes. These changes are associated with oxidative stress and occur independently of mtDNA molecule release into the cytoplasm. Conclusion Our findings demonstrate that liver steatosis might develop as result of mitochondrial dysfunction without obesity and insulin resistance, underscoring the importance of mitochondrial dysfunction in NAFLD development in lean individuals and providing valuable insights into the molecular mechanisms underlying this complex metabolic disorder. This mouse model offers a unique platform for further investigations aimed at unraveling the intricacies of NAFLD pathogenesis and potential therapeutic targets beyond conventional risk factors. ### Competing Interest Statement D.A.S is a consultant to, board member of, and owns equity in MetroBiotech (an EdenRoc company) and Life Bioscences, both working on longevity-based medicines. For list of all DAS activities see: . The other authors declare no conflict of interest in relation to this work. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. National Institutes of HealthNational Institutes of Health, https://ror.org/01cwqze88, R21OD037651, R00AG055683

Hereditary spastic paraplegia type 5 (SPG5) is an autosomal recessive neurological disorder caused by mutations in the CYP7B1 gene, which encodes cholesterol 7α-hydroxylase, an essential enzyme in cholesterol metabolism. These mutations lead to elevated levels of 25- and 27-hydroxycholesterol, oxysterols known to be neurotoxic and blood-brain-barrier permeable. Their accumulation contributes significantly to SPG5 pathogenesis, resulting in spastic gait disturbance and severely impaired quality of life. Using a Cyp7b1-/- mouse model that mirrors the metabolic phenotype of SPG5, we developed a gene therapy approach to correct oxysterol imbalance. We designed an AAV8-TTR-hCYP7B1 vector to deliver the CYP7B1 gene specifically to the liver. Following intravenous administration, oxysterol levels in blood and liver were rapidly normalized, even at low doses (1E10), with no observed toxicity at the highest tested dose (1E11). Despite these promising peripheral results, oxysterol levels in the brain, particularly 27-hydroxycholesterol, remained only partially corrected six weeks post-treatment. Our findings suggest that while liver-targeted gene therapy is effective at restoring peripheral cholesterol metabolism, a successful therapeutic strategy for SPG5 must also address central nervous system involvement. We conclude that successful treatment of SPG5 would require a novel gene therapeutic approach that also targets the CNS.

Introduction: Brain calcifications are frequent findings on imaging. In a small proportion of cases, these calcifications are associated with pathogenic gene variants, hence termed primary familial brain calcification (PFBC). The clinical penetrance is incomplete and phenotypic variability is substantial. This paper aims to characterize a Swedish PFBC cohort including 25 patients: 20 from seven families and five sporadic cases. Methods: Longitudinal clinical assessment and CT imaging were conducted, abnormalities were assessed using the total calcification score (TCS). Genetic analyses, including a panel of six known PFBC genes, were performed in all index and sporadic cases. Additionally, three patients carrying a novel pathogenic copy number variant in SLC20A2 had their cerebrospinal fluid phosphate (CSF-Pi) levels measured. Results: Among the 25 patients, the majority (76%) displayed varying symptoms during the initial assessment including motor (60%), psychiatric (40%), and/or cognitive abnormalities (24%). Clinical progression was observed in most patients (78.6%), but there was no significant difference in calcification between the first and second scans, with mean scores of 27.3 and 32.8, respectively. In three families and two sporadic cases, pathogenic genetic variants were identified, including a novel finding, in the SLC20A2 gene. In the three tested patients, the CSF-Pi levels were normal. Conclusions: This report demonstrates the variable expressivity seen in PFBC and includes a novel pathogenic variant in the SLC20A2 gene. In four families and three sporadic cases, no pathogenic variants were found, suggesting that new PFBC genes remain to be discovered.

The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24S-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced CYP46A1 levels are observed in Alzheimer's disease (AD). In this study, we report that CYP46A1 overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched CYP46A1 overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. CYP46A1 overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD and found that 24OH negatively correlates with neurodegeneration markers only in women. We suggest that CYP46A1 activation is a valuable pharmacological target for enhancing estrogen signaling in women at risk of developing neurodegenerative diseases.

The oxysterol 27-hydroxycholesterol (27OHC) is produced by the enzyme sterol 27-hydroxylase (Cyp27A1) and is mainly catabolized to 7α-Hydroxy-3-oxo-4-cholestenoic acid (7-HOCA) by the enzyme cytochrome P-450 oxysterol 7α-hydroxylase (Cyp7B1). 27OHC is mostly produced in the liver and can reach the brain by crossing the blood-brain barrier. A large body of evidence shows that CYP27A1 overexpression and high levels of 27OHC have a detrimental effect on the brain, causing cognitive and synaptic dysfunction together with a decrease in glucose uptake in mice. In this work, we analyzed two mouse models with high levels of 27OHC: Cyp7B1 knock-out mice and CYP27A1 overexpressing mice. Despite the accumulation of 27OHC in both models, Cyp7B1 knock-out mice maintained intact learning and memory capacities, neuronal morphology, and brain glucose uptake over time. Neurons treated with the Cyp7B1 metabolite 7-HOCA did not show changes in synaptic genes and 27OHC-treated Cyp7B1 knock-out neurons could not counteract 27OHC detrimental effects. This suggests that 7-HOCA and Cyp7B1 deletion in neurons do not mediate the neuroprotective effects observed in Cyp7B1 knock-out animals. RNA-seq of neuronal nuclei sorted from Cyp7B1 knock-out brains revealed upregulation of genes likely to confer neuroprotection to these animals. Differently from Cyp7B1 knock-out mice, transcriptomic data from CYP27A1 overexpressing neurons showed significant downregulation of genes associated with synaptic function and several metabolic processes. Our results suggest that the differences observed in the two models may be mediated by the higher levels of Cyp7B1 substrates such as 25-hydroxycholesterol and 3β-Adiol in the knock-out mice and that CYP27A1 overexpressing mice may be a more suitable model for studying 27-OHC-specific signaling. We believe that future studies on Cyp7B1 and Cyp27A1 will contribute to a better understanding of the pathogenic mechanisms of neurodegenerative diseases like Alzheimer’s disease and may lead to potential new therapeutic approaches.

Background: Midlife hypercholesterolemia is a risk factor for dementia, possibly via vascular-related pathways. Another proposed factor linking elevated systemic cholesterol levels and neurodegenerative diseases is the oxidized cholesterol metabolite 27-hydroxycholesterol (27-OH) that is able to pass the blood-brain barrier. High levels of 27-OH harm neuronal integrity and function, yet the effect of high 27-OH levels on oligodendrocyte function remains unexplored. Since abnormal myelin structure results in the disconnection of neural networks that is an early phenomenon in neurodegenerative diseases, this study aimed to determine whether 27-OH affects myelination in the brain. Methods: Effects of 27-OH treatment were investigated both in isolated and co-cultured oligodendrocytes. Transgenic female mice with increased systemic 27-OH levels (Cyp27Tg) underwent behavioural testing and their brains were immunohistochemically stained and lysed for immunoblotting. CSF samples from a memory clinic cohort were analysed for associations between 27-OH and myelin proteins. Results: Whereas human oligodendroglioma cells were resistant to high levels of 27-OH (10 µM), cell death was induced in primary rat oligodendrocytes already at low concentrations (0.5 µM). Long-term effects from treatment with 1 µM 27-OH stimulated differentiation of oligodendrocytes in murine 3D co-cultures. Female Cyp27Tg mice demonstrated learning deficits in the Morris Water Maze compared to non-transgenic littermates. Levels of myelin basic protein were increased in the corpus callosum of Cyp27Tg mice but adenomatous polyposis coli clone 1 (CC1) and platelet-derived growth factor receptor α (PDGFR1α) were unaltered, while levels of myelin oligodendrocyte glycoprotein were decreased in myelin enriched fractions. Levels of 27-OH in the CSF of memory clinic patients were associated with increased levels of the oligodendrogenesis regulating enzyme 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNPase; β = 0.38, p = 0.022). Conclusions: The hypercholesterolemia associated 27-OH alters the rate of differentiation from progenitor cells into mature oligodendrocytes and influences oligodendrocyte viability suggesting that 27-OH reduces the oligodendrocytic ability for appropriate remodelling in the ageing brain by reducing the pool of progenitor cells.

Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography - mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.

Niemann-Pick Type C disease (NPC) is a rare, incurable, autosomal-recessive, lysosomal storage disorder with protean and progressive neurovisceral manifestations characterized by accumulation of intracellular unesterified cholesterol. The investigational use of 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) in the treatment of NPC has shown promising results in improving life expectancy and reducing neurological damage in this patient population. This case report describes two children with the neurological form of NPC: a 5-year-old male patient in advanced stage of the disease and an 11-year-old female patient in moderately advanced stage. Despite treatment with the enzyme inhibitor, miglustat, both patients continued to exhibit severe neurodegeneration. High intrathecal (900mg) and low intravenous (350-500mg/kg) doses of HP-β-CD (Trappsol®Cyclo™) were administrated twice monthly to the patients in addition to miglustat therapy. The patients were monitored clinically as well as by imaging, laboratory, and biomarker (e.g., total tau protein [T-tau]; phosphorylated tau [P-tau]; neurofilament light [NFL], oxysterols) studies over a period of 16 to 22 months. The combination therapy of miglustat and HP-β-CD resulted in disease stabilization in both patients. The combination therapy demonstrated a good safety profile, and no adverse effects on hearing were observed. Additionally, CSF biomarkers appeared useful in monitoring neuronal damage. Large, randomized studies are needed to confirm these findings.

Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early stage atherosclerosis development when adult. To explore this apparent paradox, we analyzed plasma lipoproteins from the same 10 bears in winter (hibernation) and summer using size exclusion chromatography, ultracentrifugation, and electrophoresis. LDL binding to arterial proteoglycans (PGs) and plasma cholesterol efflux capacity (CEC) were also evaluated. The data collected and analyzed from bears were also compared with those from healthy humans. In bears, the cholesterol ester, unesterified cholesterol, TG, and phospholipid contents of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans but did not change seasonally in bears. Bear LDL was larger, richer in TGs, showed prebeta electrophoretic mobility, and had 5-10 times lower binding to arterial PGs than human LDL. Finally, plasma CEC was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL for arterial PGs and an elevated CEC of bear plasma.

ABSTRACTCholesterol turnover and CYP46A1 regulation are reported to be crucial for memory functions. An increasing body of evidence shows that CYP46A1 activation is able to reduce Alzheimer’s Disease (AD) pathological processes. In this study we report for the first time that CYP46A1 overexpression and increase of 24S-hydroxycholesterol (24OH) induces sex-specific changes in synaptic functions in aged mice, being beneficial in females while detrimental in males. The positive effects on cognition in aged CYP46A1 overexpressing female mice were accompanied by morphological changes in dendritic spines and enhancement of estrogen receptor signaling in hippocampus. In aged males, CYP46A1 overexpression leads to anxiety-like behavior and worsening of spatial memory, followed by decreased dendritic spine density and higher 5α-dihydrotestosterone (DHT) levels in hippocampus. Further, analysis of cerebrospinal fluid (CSF) from AD, mild cognitive impairment and healthy patients revealed that 24OH was negatively associated to markers of neurodegeneration in women but not in men. Based on our results, CYP46A1 activation may represent a pharmacological target that could specifically enhance brain estrogen receptor signaling in women at risk of developing AD. Finally, this study highlights the importance of taking into account the sex-dimension in both preclinical and clinical studies of neurodegenerative diseases like AD.

Background and Aims: Plasma cholesterol (TC) and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than in healthy humans. Yet, bears display no signs of atherosclerosis. To explore this apparent paradox, lipoprotein structure and function of brown bears were analyzed and compared with those of healthy humans.

Excessive enterocyte lipid accumulation, with the suggested term lipid malabsorption syndrome (LMS), is frequently observed in Atlantic salmon (Salmo salar L), in small fish in fresh water as well as in large fish in seawater. The symptoms indicate insufficient supply of components involved in lipid assimilation. The questions addressed in the present work were whether dietary supply of components involved in phospholipid and sterol metabolism might prevent LMS. Atlantic salmon (35 fish, 330 g per 600 L tank) were fed a low fish meal diet (LF) as such or supplemented with taurocholate at two levels (3.5 and 6.9 g/kg), cholesterol (2.0 g/kg), taurine (0.8 g/kg), phosphatidylcholine (15.1 g/kg), choline (3.7 g/kg), cysteine (0.8 g/kg) or methionine (1.0 g/kg). A high fish meal diet (HF) was also included. The overall growth rate of the fish was high (TGC > 4.2) with no significant effects of diet. Fish fed the LF diet showed increased relative weight of the pyloric and mid intestine and excessive lipid accumulation in the enterocytes, characteristics which were nearly absent in fish fed the HF diet and the LF diet supplemented with choline and phosphatidylcholine. The phosphatidylcholine supplemented diet showed significantly higher lipid digestibility than the LF diet. None of the other supplements eliminated the signs of excessive enterocyte lipid accumulation. Phosphatidylcholine down-regulated pcyt1a, involved in the phosphatidylcholine synthesis, and both choline and phosphatidylcholine induced apoaIV, important in lipoprotein assembly, and markedly suppressed the lipid droplet marker plin2. Methionine supplementation did not stimulate endogenous synthesis of choline. Cholesterol supplementation suppressed sterol uptake and de novo cholesterol synthesis, and induced sterol efflux from the intestinal mucosa. Taurocholate and taurine induced their respective metabolic pathways. All feed supplements, in particular cholesterol and cysteine, down-regulated genes related to antiviral, chemokine, antigen presentation, immunoglobulinfunctions, as well as of extracellular proteases. The results of this study confirm the results from our previous study showing that choline or phosphatidylcholine is a necessary ingredient in low fish meal diets.

The liver X receptors Lxrα/NR1H3 and Lxrβ/NR1H2 are ligand-dependent nuclear receptors critical for midbrain dopaminergic (mDA) neuron development. We found previously that 24(S),25-epoxycholesterol (24,25-EC), the most potent and abundant Lxr ligand in the developing mouse midbrain, promotes mDA neurogenesis in vitro. In this study, we demonstrate that 24,25-EC promotes mDA neurogenesis in an Lxr-dependent manner in the developing mouse midbrain in vivo and also prevents toxicity induced by the Lxr inhibitor geranylgeranyl pyrophosphate. Furthermore, using MS, we show that overexpression of human cholesterol 24S-hydroxylase (CYP46A1) increases the levels of both 24(S)-hydroxycholesterol (24-HC) and 24,25-EC in the developing midbrain, resulting in a specific increase in mDA neurogenesis in vitro and in vivo, but has no effect on oculomotor or red nucleus neurogenesis. 24-HC, unlike 24,25-EC, did not affect in vitro neurogenesis, indicating that the neurogenic effect of 24,25-EC on mDA neurons is specific. Combined, our results indicate that increased levels of 24,25-EC in vivo, by intracerebroventricular delivery in WT mice or by overexpression of its biosynthetic enzyme CYP46A1, specifically promote mDA neurogenesis. We propose that increasing the levels of 24,25-EC in vivo may be a useful strategy to combat the loss of mDA neurons in Parkinson's disease.

While the presence and abundance of the major oxysterols and cholestenoic acids in the circulation is well established, minor cholesterol metabolites may also have biological importance and be of value to investigate. In this study by observing the metabolism of deuterium-labelled cholesterol in the pdgfbret/ret mouse, a mouse model with increased vascular permeability in brain, and by studying the sterol content of plasma from the CYP46A1 transgenic mouse overexpressing the human cholesterol 24S-hydroxylase enzyme we have been able to identify a number of minor cholesterol metabolites found in the circulation, make approximate-quantitative measurements and postulate pathways for their formation. These "proof of principle" data may have relevance when using mouse models to mimic human disease and in respect of the increasing possibility of treating human neurodegenerative diseases with pharmaceuticals designed to enhance the activity of CYP46A1 or by adeno-associated virus delivery of CYP46A1.

Abstract Hereditary spastic paraplegia type 5 is a neurodegenerative disease caused by loss of function mutations in the CYP7B1 gene encoding the oxysterol 7-α-hydroxylase involved in bile acid synthesis in the liver. Lack of CYP7B1 leads to an accumulation of its oxysterol substrates, in particular 25-hydroxycholesterol and 27-hydroxycholesterol that are able to cross the blood brain barrier and have neurotoxic properties. A potential therapeutic strategy for SPG5 is the replacement of CYP7B1 by administration of mRNA. Here we studied the intravenous application of formulated mouse and human CYP7B1 mRNA in mice lacking the endogenous Cyp7b1 gene. A single dose injection of either mouse or human CYP7B1 mRNA led to a pronounced degradation of oxysterols in liver and serum within 2 days of treatment. Pharmacokinetics indicate a single injection of human CYP7B1 mRNA to be effective in reducing oxysterols for at least 5 days. Repetitive applications of mRNA were safe for at least 17 days and resulted in a significant reduction of neurotoxic oxysterols not only in liver and serum but also to some extent in brain. Our study highlights the potential to use mRNA as a novel therapy to treat patients with SPG5 disease.

In contrast to cholesterol itself the side-chain oxidized metabolites 24S-hydroxycholesterol (24OH) and 27-hydroxycholesterol (27OH) are able to pass the blood-brain barrier and the blood-CSF barrier. Most 27OH in circulation is formed extracerebrally and according to catheterization experiments about 5 mg of it is taken up by the brain per 24 h. 24OH is almost exclusively produced in the brain and about 6 mg fluxes from the brain into the circulation per 24 h. In addition to these major fluxes a very minor fraction of these two oxysterols flux from the circulation into CSF. Isotope experiments have shown that almost all 27OH in CSF originates from the circulation and evidence has been presented that this is the case also with a substantial part of 24OH. The levels of both 24011 and 27OH in CSF are thus affected by the integrity of the blood-CSF barrier with higher levels when the barrier is defect. Both levels of 24OH and 27OH in CSF are increased in connection with neurodegeneration and in general the increase in 24OH levels is higher than the increase in 27OH levels. A number of observations in different type of patients including measurements of other biochemical markers support that the increase in levels of 24OH due to neurodegeneration is due to a release of this oxysterol or its precursor cholesterol from dying neuronal cells. In contrast the increase in levels of 27OH is likely to be a consequence of reduced metabolism due to loss of the neuronal enzyme CYP7B1. We discuss the driving forces behind the fluxes of oxysterols in the brain, the limitations in the flux across the barriers and the diagnostic potential for side-chain oxidized oxysterols in CSF.

Hereditary spastic paraplegia type 5 is a neurodegenerative disease caused by loss-of-function mutations in the CYP7B1 gene encoding the oxysterol 7-alpha-hydroxylase involved in bile acid synthesis in the liver. Lack of CYP7B1 leads to an accumulation of its oxysterol substrates, in particular 25-hydroxycholesterol and 27-hydroxycholesterol that are able to cross the bloodbrain barrier and have neurotoxic properties. A potential therapeutic strategy for SPG5 is the replacement of CYP7B1 by administration of mRNA. Here, we studied the intravenous application of formulated mouse and human CYP7B1 mRNA in mice lacking the endogenous Cyp7b1 gene. A single-dose injection of either mouse or human CYP7B1 mRNA led to a pronounced degradation of oxysterols in liver and serum within 2 days of treatment. Pharmacokinetics indicate a single injection of human CYP7B1 mRNA to be effective in reducing oxysterols for at least 5 days. Repetitive applications of mRNA were safe for at least 17 days and resulted in a significant reduction of neurotoxic oxysterols not only in liver and serum but also to some extent in the brain. Our study highlights the potential to use mRNA as a novel therapy to treat patients with SPG5 disease.

24S-hydroxycholesterol (24OHC) and Tau are produced in neuronal cells and neurodegeneration leads to increased flux of both of them into cerebrospinal fluid (CSF). In the present study, CSF levels of 24OHC and 27S-hydroxycholesterol (27OHC) along with those of Tau, P-Thr181-Tau and Aβ42 were measured in patients with early Parkinson's disease (PD), Corticobasal syndrome (CBS), Corticobasal Degeneration (CBD), and controls. Using mouse models with increased or no formation of Tau protein and increased production of 24OHC, we have also tested the hypothesis that there is a direct association between neuronal turnover of 24OHC and Tau. The levels of 24OHC are increased, at a group level, in patients with PD or CBS. We found significant correlations between levels of 24OHC and Tau or P-Thr181-Tau in CSF from patients with PD, CBS or CBD. There were no similar correlations between 24OHC and Aβ42 in CSF from these patients. The neuronal levels of 24OHC were not altered in Tau knockout or Tau overexpressing mice. Vice versa, Tau species levels were not changed in Cyp46 overexpressing mice with increased neuronal levels of 24OHC. We conclude that the strongly correlative fluxes of 24OHC and Tau from neuronal cells to CSF are likely to be secondary to neurodegeneration and not due to direct interaction between the two factors. We suggest that this high correlation reflects a rapid neurodegeneration of specific neuronal subtypes with simultaneous release of 24OHC and Tau into the CSF.