Effect of BDNF Val66Met on Memory Decline and Hippocampal Atrophy in Prodromal Alzheimer’s Disease: A Preliminary Study

Objective

Cross-sectional genetic association studies have reported equivocal results on the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met and risk of Alzheimer’s disease (AD). As AD is a neurodegenerative disease, genetic influences may become clearer from prospective study. We aimed to determine whether BDNF Val66Met polymorphism influences changes in memory performance, hippocampal volume, and Aβ accumulation in adults with amnestic mild cognitive impairment (aMCI) and high Aβ.

Methods

Thirty-four adults with aMCI were recruited from the Australian, Imaging, Biomarkers and Lifestyle (AIBL) Study. Participants underwent PiB-PET and structural MRI neuroimaging, neuropsychological assessments and BDNF genotyping at baseline, 18 month, and 36 month assessments.

Results

In individuals with aMCI and high Aβ, Met carriers showed significant and large decline in episodic memory (d = 0.90, p = .020) and hippocampal volume (d = 0.98, p = .035). BDNF Val66Met was unrelated to the rate of Aβ accumulation (d = −0.35, p = .401).

Conclusions

Although preliminary due to the small sample size, results of this study suggest that high Aβ levels and Met carriage may be useful prognostic markers of accelerated decline in episodic memory, and reductions in hippocampal volume in individuals in the prodromal or MCI stage of AD.     

Effects of the BDNF Val66Met Polymorphism and Met Allele Load on Declarative Memory Related Neural Networks

It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.     

BDNF Val66Met polymorphism moderates the link between child maltreatment and reappraisal ability

Child maltreatment is associated with increased risk for virtually all common mental disorders, but it is not yet clear why. One possible mechanism is emotion regulation ability. The present study investigated for the first time the influence of a BDNF Val66Met genotype × child maltreatment interaction on emotion regulation, and compared differential susceptibility and diathesis‐stress models. A sample of N = 254 healthy volunteers were genotyped for the BDNF Val66Met polymorphism and underwent an experimental assessment of reappraisal ability (i.e. the success of using reappraisal to downregulate negative affect). A self‐report instrument previously validated against a clinical interview was used to investigate child maltreatment. There was a significant BDNF Val66Met genotype × child maltreatment interaction (B = ?0.31, P < 0.015), with Met carriers showing both the lowest level of reappraisal ability in maltreated participants, and the highest level of reappraisal ability in non‐maltreated participants. By assessing alternative models, we found that the best fitting model was in line with strong differential susceptibility. As expected, reappraisal ability was negatively correlated with depressive symptoms. Therefore, the BDNF Val66Met polymorphism moderates the link between child maltreatment and emotion regulation ability. Future studies could investigate whether improving reappraisal in maltreated BDNF Met carriers results in reduced risk for mental disorders.     

Association of the Val66Met polymorphism of the brain-derived neurotrophic factor gene with schizophrenia in Russians

According to recent data, the brain-derived neurotrophic factor (BDNF) is involved in schizophrenia. An association of the Val66Met polymorphism of the BDNF gene has been reported, but the results of different studies are discrepant. The allele and genotype frequency distributions of BDNF were studied in 783 schizophrenics and 633 mentally healthy controls. Significant between-group differences were not detected. When the patients were stratified by sex and schizophrenia form, men with continuous (chronic) schizophrenia were found to have a significantly higher frequency of the Val/Val genotype as compared to men with the episodic form (P = 0.047). Clinical symptoms assessed by the PANSS in men with the Val/Val genotype were more severe than in men with the Met/Met genotype (P = 0.044). No difference in BDNF genotype frequency distribution was observed between female groups differing in disease form or the severity of clinical symptoms. It was concluded that the association of the Val66Met polymorphism with schizophrenia is affected by the sex of patients and clinical heterogeneity of the disease and that the Val/Val genotype is associated with more severe schizophrenia in males.     

Brain‐derived neurotrophic factor genotype is associated with brain gray and white matter tissue volumes recovery in abstinent alcohol‐dependent individuals

Neuroimaging studies have linked the methionine (Met) allele of the brain‐derived neurotrophic factor (BDNF) gene to abnormal regional brain volumes in several psychiatric and neurodegenerative diseases. However, no neuroimaging studies assessed the effects of this allele on brain morphology in alcohol use disorders and its demonstrated change during abstinence from alcohol. Here we assessed the effects of the BDNF Val66Met (rs6265) polymorphism on regional brain tissue volumes and their recovery during short‐term abstinence in treatment‐seeking alcohol‐dependent individuals. 3D T1 weighted magnetic resonance images from 62 individuals were acquired at 1.5 T at one week of abstinence from alcohol; 41 of the participants were rescanned at 5 weeks of abstinence. The images were segmented into gray matter (GM), white matter (WM) and cerebrospinal fluid and parcellated into regional volumes. The BDNF genotype was determined from blood samples using the TaqMan technique. Alcohol‐dependent Val (Valine)/Met heterozygotes and Val homozygotes had similar regional brain volumes at either time point. However, Val homozygotes had significant GM volume increases, while Val/Met heterozygotes increased predominantly in WM volumes over the scan interval. Longitudinal increases in GM but not WM volumes were related to improvements in neurocognitive measures during abstinence. The findings suggest that functionally significant brain tissue volume recovery during abstinence from alcohol is influenced by BDNF genotype.     

Effect of the brain-derived neurotrophic factor and the apolipoprotein E polymorphisms on disease progression in preclinical Alzheimer's disease

Genetic factors, such as apolipoprotein E (ApoE) polymorphisms, are thought to play an important role in the etiology of Alzheimer's disease (AD). Recent association studies have suggested that the Val66Met polymorphism in the brain-derived neurotrophic factor ( BDNF ) gene could play a role in the development of AD. To identify genotypic effects of the BDNF and the ApoE genes on disease progression in preclinical AD, we assessed morphological changes using serial magnetic resonance imaging during the preclinical period of AD in 35 individuals. When all subjects were analyzed as one group, progressive atrophy was noted in the limbic, paralimbic and neocortical areas. Individuals of the BDNF Val/Val genotype showed progressive atrophy in the left medial temporal areas, whereas the BDNF Met allele carriers showed additional changes in the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and the precuneus. An interaction between the BDNF genotype and progressive morphological changes was found in the PCC. The noncarriers for the ApoE ɛ4 allele showed progressive atrophy in the bilateral medial temporal areas. In addition to changes in the medial temporal areas, ɛ4 carriers showed progressive atrophy in the PCC, ACC and precuneus. An interaction between the ApoE genotype and progressive morphological change was noted in the right medial temporal area. The present preliminary study indicates that polymorphisms of the ApoE and the BDNF genes could affect disease progression in preclinical AD and implies that the Met-BDNF polymorphism could be an additional risk factor for rapid disease progression in preclinical AD.     

Interacting effect of BDNF Val66Met polymorphism and stressful life events on adolescent depression

There is a strong etiological link between brain‐derived neurotrophic factor and depression, but the neurocellular mechanisms and gene–environment interactions remain obscure. This study investigated whether one functional polymorphism in the brain‐derived neurotrophic factor gene (BDNF Val66Met) modulates the influence of stressful life events on adolescent depressive symptoms. A total of 780 pairs of ethnic Han Chinese adolescent twins, 11–17 years of age, were randomly assigned to one of two subgroups (twin1 and twin2). All subjects were genotyped as Val/Val, Val/Met or Met/Met, and assessed for depressive symptoms using the Children's Depression Inventory. The level of environmental stress was estimated by the frequency of stressful life events using the Life Events Checklist. The frequency of stressful life events was significantly correlated with depressive symptoms (twin1: β = 0.21, P = 0.01; twin2: β = 0.27, P < 0.01), but there was no significant main effect of the BDNF Val66Met genotype on depressive symptoms. In both subgroups, however, the interaction between the BDNF Val66Met genotype and stressful life event frequency was significant (twin1: β = 0.19, P = 0.01; twin2: β = 0.15, P = 0.04); individuals with one or two Val alleles demonstrated a greater susceptibility to both the detrimental effects of higher stress and the beneficial effects of lower stress compared to the Met/Met genotype. These findings support the ‘differential‐susceptibility’ hypothesis, whereby the BDNF Val allele modulates the influence of environmental stress on depression by enhancing the neuroplastic response to all life events.     

Association of Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism with Primary Dysmenorrhea

Primary dysmenorrhea (PDM), the most prevalent menstrual cycle-related problem in women of reproductive age, is associated with negative moods. Whether the menstrual pain and negative moods have a genetic basis remains unknown. Brain-derived neurotrophic factor (BDNF) plays a key role in the production of central sensitization and contributes to chronic pain conditions. BDNF has also been implicated in stress-related mood disorders. We screened and genotyped the BDNF Val66Met polymorphism (rs6265) in 99 Taiwanese (Asian) PDMs (20–30 years old) and 101 age-matched healthy female controls. We found that there was a significantly higher frequency of the Met allele of the BDNF Val66Met polymorphism in the PDM group. Furthermore, BDNF Met/Met homozygosity had a significantly stronger association with PDM compared with Val carrier status. Subsequent behavioral/hormonal assessments of sub-groups (PDMs = 78, controls = 81; eligible for longitudinal multimodal neuroimaging battery studies) revealed that the BDNF Met/Met homozygous PDMs exhibited a higher menstrual pain score (sensory dimension) and a more anxious mood than the Val carrier PDMs during the menstrual phase. Although preliminary, our study suggests that the BDNF Val66Met polymorphism is associated with PDM in Taiwanese (Asian) people, and BDNF Met/Met homozygosity may be associated with an increased risk of PDM. Our data also suggest the BDNF Val66Met polymorphism as a possible regulator of menstrual pain and pain-related emotions in PDM. Absence of thermal hypersensitivity may connote an ethnic attribution. The presentation of our findings calls for further genetic and neuroscientific investigations of PDM.     

Association of BDNF gene polymorphism with bipolar disorders in Han Chinese population

Recent data suggest that brain‐derived neurotrophic factor (BDNF) plays an essential role in neuronal plasticity and etiology of bipolar disorders (BPD). However, results from different studies have been inconsistent. In present study, 342 patients who met DSM‐IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for bipolar disorders type I (BPD‐I) or type II (BPD‐II) and 386 matched health controls were enrolled, and TaqMan® SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were applied to detect the functional polymorphism rs6265 (Val66Met) of BDNF gene. Treatment response to lithium and valproate was retrospectively determined. The association between Val66Met polymorphism and BPD, treatment response to mood stabilizers, was estimated. The genotype and allele distribution of Val66Met polymorphism between BPD patients and control subjects showed significant difference (genotype: χ² = 6.18, df = 2, P = 0.046; allele: χ² = 5.01, df = 1, P = 0.025) with Met allele as risk factor for disease susceptibility (OR = 0.79, 95%CI as 0.64–0.97). The post hoc analysis interestingly showed that Met allele had opposite effect on the treatment response for BPD‐I and BPD‐II separately. For BPD‐I patients, the response score in Val/Val group was significantly lower than that in Met allele carriers (t = ?2.27, df = 144, P = 0.025); for BPD‐II patients, the response score in Val/Val group was significantly higher than that in Met allele carriers (t = 2.33, df = 26, P = 0.028). Although these results should be interpreted with caution because of the limited sample for Val/Val genotype in BPD‐II patients (N = 5), these findings strengthen the hypothesis that BDNF pathway gets involved in the etiology and pharmacology of BPD and suggest the differences between BPD‐I and BPD‐II.     

Genetic variation on the BDNF gene is not associated with differences in white matter tracts in healthy humans measured by tract‐based spatial statistics

The brain‐derived neurotrophic factor (BDNF) is a member of the neurotrophin family and involved in nerve growth and survival. It has also become a major research focus in the investigation of both cognitive and affective processes in the human brain in the last years. Especially, a single nucleotide polymorphism on the BDNF gene called BDNF Val66Met gained a lot of attention, because of its effect on activity‐dependent BDNF secretion and its link to negative emotionality and impaired memory processes. A well‐replicated finding from genetic structural imaging showed that carriers of the less frequent 66Met allele show diminished gray matter volume in several areas of the temporal lobe. New imaging techniques like diffusion tensor imaging now allow investigating the influence of BDNF Val66Met on white matter integrity. We applied tract‐based spatial statistics in a brain image dataset including n = 99 healthy participants. No significant differences between the 66Met and homozygous 66Val carriers were observed when correcting for multiple comparisons. In summary, the BDNF Val66Met polymorphism seems not to play a substantial role with respect to the modulation of the white matter integrity in healthy subjects. Although not in the focus of this study, we also investigated the influence of Eysenck's Personality Questionnaire on the white matter tracts. No significant results could be observed.     

BDNF Val66Met Polymorphism Is Associated with Self-Reported Empathy

Empathy is an important driver of human social behaviors and presents genetic roots that have been studied in neuroimaging using the intermediate phenotype approach. Notably, the Val66Met polymorphism of the Brain-derived neurotrophic factor (BDNF) gene has been identified as a potential target in neuroimaging studies based on its influence on emotion perception and social cognition, but its impact on self-reported empathy has never been documented. Using a neurogenetic approach, we investigated the association between the BDNF Val66Met polymorphism and self-reported empathy (Davis’ Interpersonal Reactivity Index; IRI) in a sample of 110 young adults. Our results indicate that the BDNF genotype is significantly associated with the linear combination of the four facets of the IRI, one of the most widely used self-reported empathy questionnaire. Crucially, the effect of BDNF Val66Met goes beyond the variance explained by two polymorphisms of the oxytocin transporter gene previously associated with empathy and its neural underpinnings (OXTR rs53576 and rs2254298). These results represent the first evidence suggesting a link between the BDNF gene and self-reported empathy and warrant further studies of this polymorphism due to its potential clinical significance.     

Association between genes,stressful childhood events and processing bias in depression vulnerable individuals

The brain‐derived neurotrophic factor (BDNF) and catechol‐O‐methyltransferase (COMT) genes are relevant candidates for depression. Variation in these genes is associated with stress sensitivity and depressotypic cognitive biases. The interaction between genes and stressful events is considered as an important mechanism in the development of depression. This study examined the effects of the BDNF and COMT genes on biased processing and the interaction with childhood stress in vulnerable individuals. A total of 198 remitted depressed individuals performed an n‐back task with emotional facial stimuli (happy and sad). Childhood events were measured with a questionnaire. Genotype by childhood events interactions were analyzed for happy and sad expressions for BDNF (Val66Met; rs6265) and COMT (Val158Met; rs4680), individually and combined. BDNF and COMT both interacted significantly (P = 0.006 and P = 0.014, respectively) with childhood trauma on reaction time for happy faces. For both genes, Met‐carriers with childhood trauma showed less positive bias for happy faces than those without childhood trauma. Val‐carriers did not show a differential bias. Individuals with childhood trauma and 3 or 4 risk alleles (BDNF and COMT combined) showed less positive bias than those without childhood trauma (P = 0.011). The BDNF × COMT × childhood trauma interaction yielded a P = 0.055, but had limited power. A potential weakness is the measurement method of the childhood events, as negative bias might have affected participants' recall. Our findings endorse the association of BDNF and COMT with stress and depression and provide a possible intermediate, i.e. biased processing of positive information. Tailoring treatment to specific risk profiles based on genetic susceptibility and childhood stress could be promising.     

Modulating effect of Val66Met polymorphism of brain-derived neurotrophic factor gene on clinical and psychological characteristics of patients with schizophrenia

The brain-derived neurotrophic factor (BDNF) gene is an important candidate gene for schizophrenia. The association of BDNF with schizophrenia has been extensively analyzed using the polymorphism Val66Met. There is accumulating evidence that Val66Met is associated with clinical presentations of schizophrenia rather than with the disease itself. In this study, BDNF allele and genotype distributions were compared in patients (n = 1785) and healthy controls (n = 1092). There was no association between the Val66Met polymorphism and schizophrenia. The marker was not associated with the presence of the affective syndrome either. At the same time, the ValVal genotype was associated with higher anxiety levels in male patients as assessed with PANSS. Patients’ personality traits were characterized using the personality inventories EPI, MMPI, and STAI (n = 363), and their cognitive functions, attention (n = 282) and verbal fluency (n = 392), were evaluated. Patients with the ValVal genotype showed higher levels of anxiety (by MMPI) and better performance on neurocognitive tests. The genotype and trait anxiety (by STAI score) had an interaction effect on cognitive functions. In patients with higher anxiety, performance on cognitive tests did not depend on the genotype, while in patients with lower levels of anxiety, the ValVal genotype was associated with significantly better performance. This effect should be taken into account when studying associations of the Val66Met polymorphism with cognitive functions in patients with schizophrenia.     

Temporal and regional progression of Alzheimer’s disease‐like pathology in 3xTg‐AD mice

Accumulation of amyloid‐β (Aβ) and fibrillary tangles, as well as neuroinflammation and memory loss, are hallmarks of Alzheimer’s disease (AD). After almost 15 years from their generation, 3xTg‐AD mice are still one of the most used transgenic models of AD. Converging evidence indicates that the phenotype of 3xTg‐AD mice has shifted over the years and contradicting reports about onset of pathology or cognitive deficits are apparent in the literature. Here, we assessed Aβ and tau load, neuroinflammation, and cognitive changes in 2‐, 6‐, 12‐, and 20‐month‐old female 3xTg‐AD and nontransgenic (NonTg) mice. We found that ~80% of the mice analyzed had Aβ plaques in the caudal hippocampus at 6 months of age, while 100% of them had Aβ plaques in the hippocampus at 12 months of age. Cortical Aβ plaques were first detected at 12 months of age, including in the entorhinal cortex. Phosphorylated Tau at Ser202/Thr205 and Ser422 was apparent in the hippocampus of 100% of 6‐month‐old mice, while only 50% of mice showed tau phosphorylation at Thr212/Ser214 at this age. Neuroinflammation was first evident in 6‐month‐old mice and increased as a function of age. These neuropathological changes were clearly associated with progressive cognitive decline, which was first apparent at 6 months of age and became significantly worse as the mice aged. These data indicate a consistent and predictable progression of the AD‐like pathology in female 3xTg‐AD mice, and will facilitate the design of future studies using these mice.     

Demyelination in Mild Cognitive Impairment Suggests Progression Path to Alzheimer’s Disease

The preclinical Alzheimer''s disease (AD) - amnestic mild cognitive impairment (MCI) - is manifested by phenotypes classified into exclusively memory (single-domain) MCI (sMCI) and multiple-domain MCI (mMCI). We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR) in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata) and gray matter (GM: hippocampus; parahippocampal and lingual gyri). A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination.     

Changes in White Matter Integrity before Conversion from Mild Cognitive Impairment to Alzheimer’s Disease

Background

Mild cognitive impairment (MCI) may represent an early stage of dementia conferring a particularly high annual risk of 15–20% of conversion to Alzheimer’s disease (AD). Recent findings suggest that not only gray matter (GM) loss but also a decline in white matter (WM) integrity may be associated with imminent conversion from MCI to AD.

Objective

In this study we used Voxel-based morphometry (VBM) to examine if gray matter loss and/or an increase of the apparent diffusion coefficient (ADC) reflecting mean diffusivity (MD) are an early marker of conversion from MCI to AD in a high risk population.

Method

Retrospective neuropsychological and clinical data were collected for fifty-five subjects (MCI converters n = 13, MCI non-converters n = 14, healthy controls n = 28) at baseline and one follow-up visit. All participants underwent diffusion weighted imaging (DWI) and T1-weighted structural magnetic resonance imaging scans at baseline to analyse changes in GM density and WM integrity using VBM.

Results

At baseline MCI converters showed impaired performance in verbal memory and naming compared to MCI non-converters. Further, MCI converters showed decreased WM integrity in the frontal, parietal, occipital, as well as the temporal lobe prior to conversion to AD. Multiple regression analysis showed a positive correlation of gray matter atrophy with specific neuropsychological test results.

Conclusion

Our results suggest that additionally to morphological changes of GM a reduced integrity of WM indicates an imminent progression from MCI stage to AD. Therefore, we suggest that DWI is useful in the early diagnosis of AD.     

CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer's disease

Chemokine (C-C motif) receptor 2 (CCR2)-signaling can mediate accumulation of microglia at sites affected by neuroinflammation. CCR2 and its main ligand CCL2 (MCP-1) might also be involved in the altered metabolism of beta-amyloid (Aβ) underlying Alzheimer''s disease (AD). We therefore measured the levels of CCL2 and three other CCR2 ligands, i.e. CCL11 (eotaxin), CCL13 (MCP-4) and CCL26 (eotaxin-3), in the cerebrospinal fluid (CSF) and plasma of 30 controls and 119 patients with mild cognitive impairment (MCI) at baseline. During clinical follow-up 52 MCI patients were clinically stable for five years, 47 developed AD (i.e. cases with prodromal AD at baseline) and 20 developed other dementias. Only CSF CCL26 was statistically significantly elevated in patients with prodromal AD when compared to controls (p = 0.002). However, in patients with prodromal AD, the CCL2 levels in CSF at baseline correlated with a faster cognitive decline during follow-up (r _s = 0.42, p = 0.004). Furthermore, prodromal AD patients in the highest tertile of CSF CCL2 exhibited a significantly faster cognitive decline (p<0.001) and developed AD dementia within a shorter time period (p<0.003) compared to those in the lowest tertile. Finally, in the entire MCI cohort, CSF CCL2 could be combined with CSF Tau, P-tau and Aβ42 to predict both future conversion to AD and the rate of cognitive decline. If these results are corroborated in future studies, CCL2 in CSF could be a candidate biomarker for prediction of future disease progression rate in prodromal AD. Moreover, CCR2-related signaling pathways might be new therapeutic targets for therapies aiming at slowing down the disease progression rate of AD.     

The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease

There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer’s disease (AD), perhaps even before amyloid-β accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease.     

Changes in the detergent‐insoluble brain proteome linked to amyloid and tau in Alzheimer's Disease progression

Despite a key role of amyloid‐beta (Aβ) in Alzheimer's disease (AD), mechanisms that link Aβ plaques to tau neurofibrillary tangles and cognitive decline still remain poorly understood. The purpose of this study was to quantify proteins in the sarkosyl‐insoluble brain proteome correlated with Aβ and tau insolubility in the asymptomatic phase of AD (AsymAD) and through mild cognitive impairment (MCI) and symptomatic AD. Employing label‐free mass spectrometry‐based proteomics, we quantified 2711 sarkosyl‐insoluble proteins across the prefrontal cortex from 35 individual cases representing control, AsymAD, MCI and AD. Significant enrichment of Aβ and tau in AD was observed, which correlated with neuropathological measurements of plaque and tau tangle density, respectively. Pairwise correlation coefficients were also determined for all quantified proteins to Aβ and tau, across the 35 cases. Notably, six of the ten most correlated proteins to Aβ were U1 small nuclear ribonucleoproteins (U1 snRNPs). Three of these U1 snRNPs (U1A, SmD and U1‐70K) also correlated with tau consistent with their association with tangle pathology in AD. Thus, proteins that cross‐correlate with both Aβ and tau, including specific U1 snRNPs, may have potential mechanistic roles in linking Aβ plaques to tau tangle pathology during AD progression.