Shared and unique effects of ApoEε4 and pathogenic gene mutation on cognition and imaging in preclinical familial Alzheimer's disease.

BACKGROUND: Neuropsychology and imaging changes have been reported in the preclinical stage of familial Alzheimer's disease (FAD). This study investigated the effects of APOEε4 and known pathogenic gene mutation on different cognitive domains and circuit imaging markers in preclinical FAD. METHODS: One hundred thirty-nine asymptomatic subjects in FAD families, including 26 APOEε4 carriers, 17 APP and 20 PS1 mutation carriers, and 76 control subjects, went through a series of neuropsychological tests and MRI scanning. Test scores and imaging measures including volumes, diffusion indices, and functional connectivity (FC) of frontostriatal and hippocampus to posterior cingulate cortex pathways were compared between groups and analyzed for correlation. RESULTS: Compared with controls, the APOEε4 group showed increased hippocampal volume and decreased FC of fronto-caudate pathway. The APP group showed increased recall scores in auditory verbal learning test, decreased fiber number, and increased radial diffusivity and FC of frontostriatal pathway. All three genetic groups showed decreased fractional anisotropy of hippocampus to posterior cingulate cortex pathway. These neuropsychological and imaging measures were able to discriminate genetic groups from controls, with areas under the curve from 0.733 to 0.837. Circuit imaging measures are differentially associated with scores in various cognitive scales in control and genetic groups. CONCLUSIONS: There are neuropsychological and imaging changes in the preclinical stage of FAD, some of which are shared by APOEε4 and known pathogenic gene mutation, while some are unique to different genetic groups. These findings are helpful for the early identification of Alzheimer's disease and for developing generalized and individualized prevention and intervention strategies.

Neural Networks in Autosomal Dominant Alzheimer's Disease: Insights From Functional Magnetic Resonance Imaging Studies.

Alzheimer's disease (AD) is the most common form of dementia, with no cure to stop its progression. Early detection, diagnosis, and intervention have become the hot spots in AD research. The long asymptomatic and slightly symptomatic phases of autosomal dominant AD (ADAD) allow studies to explore early biomarkers and the underlying pathophysiological changes. Functional magnetic resonance imaging (fMRI) provides a method to detect abnormal patterns of brain activity and functional connectivity in vivo, which correlates with cognitive decline earlier than structural changes and more strongly than amyloid deposition. Here, we will provide a brief overview of the network-level findings in ADAD in fMRI studies. In general, abnormalities in brain activity were mainly found in the hippocampus, the medial temporal lobe (MTL), the posterior cortex, the cingulate cortices, and the frontal regions in ADAD. Moreover, ADAD and sporadic AD (SAD) have similar fMRI changes, but not with aging.

Fluid Biomarkers in Clinical Trials for Alzheimer's Disease: Current and Future Application.

Alzheimer's disease (AD) research is entering a unique moment in which enormous information about the molecular basis of this disease is being translated into therapeutics. However, almost all drug candidates have failed in clinical trials over the past 30 years. These many trial failures have highlighted a need for the incorporation of biomarkers in clinical trials to help improve the trial design. Fluid biomarkers measured in cerebrospinal fluid and circulating blood, which can reflect the pathophysiological process in the brain, are becoming increasingly important in AD clinical trials. In this review, we first succinctly outline a panel of fluid biomarkers for neuropathological changes in AD. Then, we provide a comprehensive overview of current and future application of fluid biomarkers in clinical trials for AD. We also summarize the many challenges that have been encountered in efforts to integrate fluid biomarkers in clinical trials, and the barriers that have begun to be overcome. Ongoing research efforts in the field of fluid biomarkers will be critical to make significant progress in ultimately unveiling disease-modifying therapies in AD.

Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study.

Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer's disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer's disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer's disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10-19, 2.49 × 10-23, 1.35 × 10-67, and 4.81 × 10-9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P < 5.0 × 10-8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer's disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer's disease, suggesting that our models can predict Alzheimer's disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer's disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer's disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.

Blood neuro-exosomal synaptic proteins predict Alzheimer's disease at the asymptomatic stage.

INTRODUCTION: Exosomes are an emerging candidate for biomarkers of Alzheimer's disease (AD). This study investigated whether exosomal synaptic proteins can predict AD at the asymptomatic stage. METHODS: We conducted a two-stage-sectional study (discovery stage: AD, 28; amnestic mild cognitive impairment [aMCI], 25; controls, 29; validation stage: AD, 73; aMCI, 71; controls, 72), a study including preclinical AD (160) and controls (160), and a confirmation study in familial AD (mutation carriers: 59; non-mutation carriers: 62). RESULTS: The concentrations of growth associated protein 43 (GAP43), neurogranin, synaptosome associated protein 25 (SNAP25), and synaptotagmin 1 were lower in AD than in controls (P < .001). Exosomal biomarker levels were correlated with those in cerebrospinal fluid (R2  = 0.54-0.70). The combination of exosomal biomarkers detected AD 5 to 7 years before cognitive impairment (area under the curve = 0.87-0.89). DISCUSSION: This study revealed that exosomal GAP43, neurogranin, SNAP25, and synaptotagmin 1 act as effective biomarkers for prediction of AD 5 to 7 years before cognitive impairment.

PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease.

INTRODUCTION: The PSENs/APP mutation distribution in Chinese patients with familial Alzheimer's disease (FAD) remains unclear. We aimed to analyze the genetic features of Chinese FAD pedigrees with and without PSENs/APP mutations. METHODS: In total, 1330 patients with Alzheimer's disease (AD) or mild cognitive impairment in 404 pedigrees were enrolled from the Chinese Familial Alzheimer's Disease Network. PSENs/APP mutations and APOE frequencies were determined. RESULTS: In total, 13.12% of pedigrees carried PSENs/APP missense mutations, 3.71% carried PSENs/APP synonymous/untranslated region variants, and 83.17% did not carry PSENs/APP mutations. Eleven missense mutations were first identified. In patients without PSENs/APP mutations, 44.31% carried one APOEε4 allele, and 14.85% two APOEε4 alleles. DISCUSSION: The new PSENs/APP mutations indicate heterogeneity in AD pathogenesis between Chinese and other ethnic groups. The low mutation rate suggests the involvement of other genes/factors in Chinese FAD. APOEε4 might be a major gene for some FAD without PSENs/APP mutations.

Identification of a novel PSEN1 Gly111Val missense mutation in a Chinese pedigree with early-onset Alzheimer's disease.

Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) genes account for the majority of autosomal dominant Alzheimer's disease (AD), with PSEN1 being the most common. We screened these genes for mutations in a Chinese proband from an autosomal dominant early-onset AD pedigree. Early-onset AD is defined as the age at onset of AD < 65 years. A heterozygous variant (c.332G > T) of PSEN1, which results in a missense mutation (p.Gly111Val), was identified. Three prediction programs suggested this mutation was disease causing. When PSEN1 Gly111Val was overexpressed in HEK293/APPswe cells, the ratio of Aß42/Aß40 was significantly increased compared with that of wild-type PSEN1. Our results suggest that this novel PSEN1 Gly111Val mutation may play a pathogenic role in AD.

Concordance between the assessment of Aß42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid.

INTRODUCTION: Neuronal-derived exosomal Aß42, T-tau, and P-T181-tau have been demonstrated to be biomarkers of Alzheimer's disease (AD). However, no study has assessed the association of Aß42, T-tau, and P-T181-tau between exosomes and CSF. METHODS: This was a multicenter study with two-stage design. The subjects included 28 AD patients, 25 aMCI patients, and 29 controls in the discovery stage; the results of which were confirmed in the validation stage (73 AD, 71 aMCI, and 72 controls). RESULTS: The exosomal concentrations of Aß42, T-tau, and P-T181-tau in AD group were higher than those in aMCI and control groups (all P < .001). The level of each exosomal biomarker was highly correlated with that in CSF. DISCUSSION: This study verified the agreement between CSF and blood exosomal biomarkers and confirmed that exosomal Aß42, T-tau, and P-T181-tau have the same capacity as those in CSF for the diagnosis of AD and aMCI.

A Novel PSEN1 M139L Mutation Found in a Chinese Pedigree with Early-Onset Alzheimer's Disease Increases Aß42/Aß40 ratio.

BACKGROUND: Presenilin1 (PSEN1) is the most common gene related to familial Alzheimer's disease (AD). Only several mutation types from Chinese have been reported, with less biological function research conducted. OBJECTIVES: We explore the pathological function of PSEN1 M139L, a mutation located at α-helix of PSEN1 transmembrane 2, using predictive programs and in vitro study and compare its effects on Aß production to those of an artificial PSEN1 S141G located at non α-helix mutation face. METHODS: APP, PSEN1, and PSEN2 genes were screened for mutations using Sanger sequencing in the DNA samples of the proband and additional available family members. Disease-mutation cosegregation analysis and three software programs were performed to predict the mutation's pathogenicity. In vitro, we investigated the impact of these mutations on Aß production in HEK293-APPswe cells using lentiviral vectors harboring PSEN1 WT, PSEN1 M139L, the positive control (PSEN1 M139V) and the non α-helical mutation (PSEN1 S141G). In addition, we co-transfected PSEN1 and tau into cells to determine the mutations' impact on tau phosphorylation. RESULTS: PSEN1 M139L mutation was discovered in the index patient and four affected siblings. Cosegregation analysis and silicon prediction suggested the mutation was probably disease causing. In vitro studies demonstrated that both PSEN1 M139L and PSEN1 S141G caused elevated ratios of Aß42/Aß40, but changes of tau phosphorylation were not detected. CONCLUSION: The novel PSEN1 M139L mutation found in familial AD increases the Aß42/Aß40 ratio significantly. Mutations at non α-helical mutation face of PSEN1 TM2 can affect Aß production and the region may play a key role in PSEN1 function.