Autosomal Dominant Early-onset Alzheimer Research Articles

APP antisense oligonucleotides reduce Aβ aggregation and rescue endolysosomal dysfunction in Alzheimer's disease.

APP gene dosage is strongly associated with Alzheimer's disease (AD) pathogenesis. Genomic duplication of the APP locus leads to autosomal dominant early-onset AD. Individuals with Down syndrome (trisomy of chromosome 21) harbor 3 copies of the APP gene and invariably develop progressive AD with highly characteristic neuropathological features. Restoring expression of APP to the equivalent of that of two gene copies, or lower, is a rational therapeutic strategy, as it would restore physiological levels of neuronal APP protein without the potentially deleterious consequences of inadvertently inducing loss of APP function. Here we find that antisense oligonucleotides (ASOs) targeting APP are an effective approach to reduce APP protein levels and rescue endolysosome and autophagy dysfunction in APP duplication human induced pluripotent stem cell (hiPSC)-derived cortical neurons. Importantly, using ultrasensitive single-aggregate imaging techniques, we show that APP targeting ASOs significantly reduce both intracellular and extracellular Aβ-containing aggregates. Our results highlight the potential of APP ASOs as a therapeutic approach for forms of AD caused by duplication of the APP gene, including monogenic AD and AD related to Down syndrome.

Generation and characterization of an iPS cell line (PUMCi006-A) from skin fibroblasts of a patient with an M239T mutation in PSEN2 gene

Presenilin-2 (PSEN2) mutation is one of the pathogenic factors of autosomal dominant early-onset Alzheimer's disease (EOAD). We generated a human induced pluripotent stem cell (iPSC) line from fibroblasts of an EOAD patient carrying PSEN2 mutation (c.716 T > C) utilizing Sendai reprogramming kit. The resulting iPSC line carried patient-specific point mutation, exhibited typical iPSC morphology, retained a normal karyotype, expressed pluripotency markers, and could form embryoid bodies. Established iPSC line serve as valuable resource for EOAD disease pathogenesis modelling and drug screening.

Familial Early-Onset Alzheimer's Caused by Novel Genetic Variant and APP Duplication: A Cross-Sectional Study.

The clinical characteristics of symptomatic and asymptomatic carriers of early- onset autosomal dominant Alzheimer's (EOADAD) due to a yet-undescribed chromosomal rearrangement may add to the available body of knowledge about Alzheimer's disease and may enlighten novel and modifier genes. We report the clinical and genetic characteristics of asymptomatic and symptomatic individuals carrying a novel APP duplication rearrangement. Individuals belonging to a seven-generation pedigree with familial cognitive decline or intracerebral hemorrhages were recruited. Participants underwent medical, neurological, and neuropsychological evaluations. The genetic analysis included chromosomal microarray, Karyotype, fluorescence in situ hybridization, and whole genome sequencing. Of 68 individuals, six females presented with dementia, and four males presented with intracerebral hemorrhage. Of these, nine were found to carry Chromosome 21 copy number gain (chr21:27,224,097-27,871,284, GRCh37/hg19) including the APP locus (APP-dup). In seven, Chromosome 5 copy number gain (Chr5: 24,786,234-29,446,070, GRCh37/hg19) (Chr5-CNG) cosegregated with the APP-dup. Both duplications co-localized to chromosome 18q21.1 and segregated in 25 pre-symptomatic carriers. Compared to non-carriers, asymptomatic carriers manifested cognitive decline in their mid-thirties. A third of the affected individuals carried a diagnosis of a dis-immune condition. APP extra dosage, even in isolation and when located outside chromosome 21, is pathogenic. The clinical presentation of APP duplication varies and may be gender specific, i.e., ICH in males and cognitive-behavioral deterioration in females. The association with immune disorders is presently unclear but may prove relevant. The implication of Chr5-CNG co-segregation and the surrounding chromosome 18 genetic sequence needs further clarification.

White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer’s disease that emerge prior to dementia

BackgroundTo promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer’s disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer’s disease, in relation to age and symptom severity.MethodsThis is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer’s Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers.ResultsThe mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance.ConclusionsThe volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer’s disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer’s disease that is closely related to the progression of clinical symptoms.

The novel I213S mutation in PSEN1 gene is located in a hotspot codon associated with familial early-onset Alzheimer's disease

Mutations in presenilin 1 gene (PSEN1) are the most common causes of autosomal dominant early-onset Alzheimer's disease (EOAD). We report a novel PSEN1 mutation (I213S) that was discovered in an Italian patient with a family history of early-onset dementia, who developed a slowly progressive cognitive decline since the age of 40 years. Clinical investigations, including neuropsychological assessment, brain MRI and 18-fluorodeoxyglucose PET, as well as cerebrospinal fluid biomarkers, supported the diagnosis of EOAD. Genetic studies identified a novel missense mutation at codon 213 (I213S). Three other mutations at the same codon have been described in association with EOAD. Previous in silico, in vitro and in vivo studies indicated that these mutations affect the functional properties of γ-secretase and are most likely pathogenic. In silico algorithms suggested that even the I213S mutation has similar deleterious effects on PSEN1 structure and function. Overall, these data strongly support a role of hotspot site for the codon 213 of PSEN1, and provide evidence that the genetic variants located on this site cause EOAD.

TRIM25 nonsense mutation (p.C168*) as the probable cause of early-onset autosomal dominant Alzheimer's disease.

Patients with early-onset dementia (EOD) often have a high genetic burden, and EOD kindreds with an autosomal dominant pattern of inheritance (ADPI) are particularly powerful for gene identification studies. We present the clinical phenotype and a whole-exome sequencing (WES) study of a Spanish EOD family with ADPI, including five affected and two unaffected siblings. The proband case was negative for mutations in a Next Generation Sequencing panel of genes associated with neurodegenerative dementias. Candidate pathogenic mutations were prioritized according to frequency in population databases, impact/pathogenicity scores, and segregation (including a disease-free second branch of the family). Final candidate genes were also examined in a set of Spanish-origin FTD cases (n=583) and controls (n=493), plus in a Belgian WES dataset of AD (n=236) and FTD (n=269) cases. Affected siblings had an average disease onset of 60.2 years (range 56-63 years). Two had a behavioral rather than an amnestic phenotype, developing some psychotic features and significant parkinsonism after treatment with risperidone. However, CSF biomarkers in one patient were indicative of an AD pathology. WES was conducted in four affected and one unaffected siblings (all of them APOEε 4,4). Variant prioritization pointed to 16 candidate variants, including three loss of function variants, two in-frame deletions, and 11 missense. Additional genetic analysis of another unaffected sibling, a fifth affected sibling with incipient disease, plus four unaffected relatives from the second branch narrowed the list to two candidate genes: TRIM25 (p.C186*, CADD score 36) and EEA1 (p.V693A, CADD 18.2). TRIM25 is a cytoplasmic protein that functions as an ubiquitin E3 ligase and is involved in the innate immune response, while EEA1 is an endosomal trafficking protein. Potentially pathogenic (CADD>20) rare variants were found in the studied populations in EEA1 (0,7-3,8%; Spanish-Belgian) and TRIM25 (0-0,7%). All except one were missense variants of uncertain significance. Importantly, in TRIM25 which is highly intolerable for loss of function mutations, we identified one additional nonsense mutation in TRIM25 in a frontal-type dementia case. We conclude that in this EOD family, the nonsense mutation in TRIM25 is the most likely causal mutation.

Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication.

Background and ObjectiveTo report a triplication of the amyloid-β precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD).MethodsFour copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription–digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers.ResultsBeginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls.DiscussionIncreased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.

The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation.

Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid β (Aβ). Here, we describe the Uppsala APP mutation (Δ690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) Aβ42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing β-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aβ, AβUpp1-42Δ19-24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.

A Novel Probable Pathogenic PSEN2 Mutation p.Phe369Ser Associated With Early-Onset Alzheimer's Disease in a Chinese Han Family: A Case Report

The pathogenesis of Alzheimer's disease is complex, and early-onset Alzheimer's disease (EOAD) is mostly influenced by genetic factors. Presenilin-1, presenilin-2 (PSEN2), and amyloid precursor protein are currently known as the three main causative genes for autosomal dominant EOAD, with the PSEN2 mutation being the rarest. In this study, we reported a 56-year-old Chinese Han proband who presented with prominent progressive amnesia, aphasia, executive function impairment, and depression 5 years ago. The 3-year follow-up showed that the patient experienced progressive brain atrophy displayed on magnetic resonance imaging (MRI) and dramatic cognitive decline assessed by neuropsychological evaluation. This patient was clinically diagnosed as EOAD based on established criteria. A heterozygous variant (NM_000447.2: c.1106T>C) of PSEN2 was identified for the first time in this patient and her two daughters. This mutation causing a novel missense mutation (p.Phe369Ser) in transmembrane domain 7 encoded by exon 11 had not been reported previously in 1000Genomes, ExAC, or ClinVar databases. This mutation was predicted by four in silico prediction programs, which all strongly suggested that it was damaging. Our results suggest that this novel PSEN2 Phe369Ser mutation may alter PSEN2 protein function and associate with EOAD.

Nutritional Assessment in Patients with Early-Onset Autosomal Dominant Alzheimer's Disease Due to PSEN1- E280A Genetic Variant: A Cross-Sectional Study.

Weight loss and malnutrition are frequent findings in late-onset and sporadic presentations of Alzheimer's Disease (AD). However, less is known about nutritional status in Early-Onset Autosomal Dominant AD (EO-ADAD). To analyze the association between nutritional status and other clinical and sociodemographic characteristics in individuals with a genetic form of EO-ADAD. Cross-sectional study with 75 non-institutionalized participants from a cohort of Autosomal Dominant AD (13 with mild cognitive impairment and 61 with dementia, ages from 38 to 67 years) underwent a structured clinical assessment with emphasis on nutritional status. Primary outcome was nutritional status and it was measured using the Mini Nutritional Assessment (MNA). Patients were categorized according to MNA total score, as undernourished (MNA ≤23.5) and well-nourished (MNA ≥ 24). Sociodemographic and clinical variables identified as potential predictors or confounders of nutritional status were also collected. Undernourishment by MNA was present in 57.3% of the sample. Forty-two percent of participants had abnormal BMI values considered lower than 18.5 or higher than 24.9 kg/m2. Total BMI values were similar in well and undernourished patients (median 24.2 IQR 3.59 and median 23.9 IQR 4.42, respectively, p=0.476). When comparing well and undernourished groups, we found statistically significant differences for variables: severity of dementia (p=0.034), frailty (p=0.001), multimorbidity (p=0.035) and, polymedication (p=0.045). Neither adjusted logistic regression nor the Poisson regression showed that any clinical or sociodemographic variables explained undernourishment. Undernourishment was a frequent finding in our sample of EO-ADAD, especially in later stages of the disease. Patients with polymedication, multimorbidity, frailty and severe dementia show differences in their nutritional status with a tendency to be more frequently undernourished. Further studies with larger sample sizes are needed to establish this association.

Autosomal dominant early onset Alzheimer's disease in the Mexican state of Jalisco: High frequency of the mutation PSEN1 c.1292C>A and phenotypic profile of patients.

Mutations in three genes (APP, PSEN1, and PSEN2) are the main cause of the autosomal dominant early-onset Alzheimer's disease (AD-EOAD). In PSEN1, the A431E (c.1292C>A, rs63750083) mutation is suspected to have exerted a founder effect in the State of Jalisco, Mexico. In Guadalajara, Jalisco, Mexico, this mutation was found in 46 index cases evaluated for AD-EOAD. In our genealogical analysis, 301 affected relatives of the mutation carriers were identified, 195 of whom were already deceased at the time of interview. Moreover, 560 descendants had a 50% risk of carrying the mutation, and 348 were potentially at risk. A systematic phenotyping was performed in 39 patients. The mean onset age was 42.5 ± 3.9 years, and no significant difference in onset age was observed between the male and female patients. Furthermore, a substantial clinical heterogeneity and high frequencies of spastic paraparesis, language disorders, and neuropsychiatric symptoms were observed. To our knowledge, the investigated families represent the second biggest population carrying a PSEN1 mutation in Latin America, offering a unique opportunity to study the genetic basis of Alzheimer's disease. Addressing AD-EOAD warrants an integral approach involving a deep understanding of its clinical behavior, as well as counseling protocols and prevention studies.

A family‐based genetic study identifies mutations in TLR9 impairing receptor activation: A role for innate immunity in AD pathogenesis

AbstractBackgroundFamily‐based genetic studies in early‐onset Alzheimer disease (EOAD), prompting early gene discoveries, remain powerful for the identification of novel genes in AD. Causal mutations in APP, PSEN1 and PSEN2 explained <10% of EOAD patients, while several EOAD families remained genetically unexplained. We identified a multigenerational Flanders‐Belgian family with autosomal dominant EOAD. DNA, biomaterials and clinical data from two consecutive informative generations were available: 5 AD patients (onset 64.2±13.2 years, range 52‐85) of which 2 with a definite neuropathological diagnosis and 9 unaffected/at‐risk individuals.MethodWhole exome sequencing of 4 patients. Selection of shared rare non‐synonymous variants, validation of co‐segregation with disease and variants frequency assessment using massive parallel‐targeted sequencings (MPS). We used genotyping of STR markers to define haplotypes. Coding regions of candidate genes were sequenced using MPS in a Belgian cohort of 320 EOAD (onset 57.8±5.9y, range 33‐65) and 1166 late‐onset (LO)AD (onset 77.1±6.5y, range 66‐96) patients and a control cohort of 934 persons (inclusion 70.45±9.2y, range 52‐100). Variants pathogenicity was predicted using CADD scores cutoff>20. Evaluation of functional effects by NF‐κB luciferase assay.ResultThree rare variants co‐segregated with AD in the family: CCR3 p.F249Hfs*23 (rs561062190), ZNF589 p.T355M (rs376706270) and TLR9 p.E317D (novel) and are located within a co‐segregating haplotype block of 15.3 cM at ch3p21. Only the TLR9 variant was absent in controls. TLR9 is a DNA‐sensing receptor expressed in immune cells, recognizes unmethylated CpG oligonucleodides and is responsible for innate immune cells activation and mounting acquired responses. The NF‐κB luciferase assay showed that p.E317D, located within the ligand sensor pocket of TLR9, caused a 50% reduction in receptor activation. TLR9 resequencing identified additional rare variants carriers: 7 in EOAD (7/320, 2.19%) and 19 in LOAD (19/1166, 1.63%) patients and 8 in controls (8/934, 0.86%), while TLR9 p.E317D was absent. Of the rare variants, 16 were in patient‐only, 3 in patients and controls and 5 in controls‐only. The NF‐κB luciferase assay indicated reduced TLR9 activation for the novel variants specific to EOAD patients and with a CADD score >20.ConclusionWe discovered TLR9 as candidate gene in AD with a mechanism of loss of receptor activation.

A novel mutation in PSEN1 (p.Arg41Ser) in an Argentinian woman with early onset Parkinsonism

IntroductionMutations in presenilin-1 (PSEN1) account for the majority of cases of familial autosomal dominant early-onset Alzheimer's disease (AD) as well as in sporadic forms. Atypical presentations are reported including extrapyramidal signs. In the last years, a pleiotropic effect of some PSEN1 variants has been reported in Parkinson's disease (PD). Objectiveto report a new PSEN1 mutation characterized by early-onset Parkinsonism (EOPD) without dementia or classical AD biomarkers phenotype. Patient and methodsAn Argentinian 46 years old woman was diagnosed with EOPD at 35 years old with no family history of neurodegenerative disorders. Her medical history included iron deficiency and anemia since childhood.A brain MRI showed moderate frontal atrophy. 18FDG-PET and PiB-PET as well as CSF biomarkers were inconclusive for AD. Two neuropsychological examinations were compatible with a mild non amnestic cognitive impairment. Whole blood DNA was extracted and whole exome sequencing and analysis was performed. Results and conclusionA heterozygous novel missense PSEN1 mutation (position 14:73637540, A > T, pArg41Ser) was identified as a likely causative mutation in this patient. To the best of our knowledge, this case is the first PSEN1 mutation with a l-dopa responsive Parkinsonism lacking distinctive classical AD biomarkers. This case opens a new window to explore the pathophysiological link among PSEN1 and EOPDs and contributes to increase the phenotypes of PSEN1 variants.

Loss of presenilin 2 age-dependently alters susceptibility to acute seizures and kindling acquisition

Patients with Alzheimer's disease (AD) experience seizures at higher rates than the general population of that age, suggesting an underexplored role of hyperexcitability in AD. Genetic variants in presenilin (PSEN) 1 and 2 genes lead to autosomal dominant early-onset AD (ADAD); patients with PSEN gene variants also report seizures. Pharmacological control of seizures in AD may be disease-modifying. Preclinical efficacy of FDA-approved antiseizure drugs (ASDs) is well defined in young adult rodents; however, the efficacy of ASDs in aged rodents with chronic seizures is less clear. The mechanism by which ADAD genes lead to AD remains unclear, and even less studied is the pathogenesis of epilepsy in AD. PSEN variants generally all result in a biochemical loss of function (De Strooper, 2007). We herein determined whether well-established models of acute and chronic seizure could be used to explore the relationship between AD genes and seizures through investigating whether loss of normal PSEN2 function age-dependently influenced susceptibility to seizures and/or corneal kindling acquisition. PSEN2 knockout (KO) and age-matched wild-type (WT) mice were screened from 2- to 10-months-old to establish age-dependent focal seizure threshold. Additionally, PSEN2 KO and WT mice aged 2- and 8-months-old underwent corneal kindling such that mice were aged 3- and 9-months old at the beginning of ASD efficacy testing. We then defined the dose-dependent efficacy of mechanistically distinct ASDs on kindled seizures of young versus aged mice to better understand the applicability of corneal kindling to real-world use for geriatric patients. PSEN2 KO mice demonstrated early-life reductions in seizure threshold. However, kindling acquisition was delayed in 2-month-old PSEN2 KO versus WT mice. Young male WT mice took 24.3 ± 1.3 (S.E.M.) stimulations to achieve kindling criterion, whereas age-matched PSEN2 KO male mice took 41.2 ± 1.1 stimulations (p < .0001). The rate of kindling acquisition of 8-month-old mice was no longer different from WT. This study demonstrates that loss of normal PSEN2 function is associated with age-dependent changes in the in vivo susceptibility to acute seizures and kindling. Loss of normal PSEN2 function may be an underexplored molecular contributor to seizures. The use of validated models of chronic seizures in aged rodents may uncover age-related changes in susceptibility to epileptogenesis and/or ASD efficacy in mice with AD-associated genotypes, which may benefit the management of seizures in AD.

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 Aβ42/Aβ40 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.

Copy Number Variants in miR-138 as a Potential Risk Factor for Early-Onset Alzheimer's Disease.

Early-onset Alzheimer's disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100%. With the exception of rare mutations in APP, PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative for autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1. This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD.

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease.

Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) mutations are responsible for autosomal dominant early-onset Alzheimer’s disease (AD-EOAD). To analyze the phenotypes and genotypes of EOAD patients, we performed comprehensive clinical assessments as well as mutation screening of PSEN1, PSEN2, and exons 16 and 17 of APP by Sanger sequencing in the three Chinese EOAD families. We identified two novel mutations of PSEN1 (Y256N and H214R) in samples from these families, and a de novo mutation of PSEN1 (G206V) in a patient with very early-onset sporadic Alzheimer’s disease. A combination of bioinformatics tools based on evolutionary, structural and computational methods predicted that the mutations were all deleterious. These findings suggest that PSEN1 Y256N, H214R, and G206V need to be considered as potential causative mutations in EOAD patients. Further functional studies are needed to evaluate the roles of these mutations in the pathogenesis of AD.

Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer's disease

IntroductionLittle is known about effects of physical activity (PA) in genetically driven early-onset autosomal dominant Alzheimer's disease (AD). MethodsA total of 372 individuals participating at the Dominantly Inherited Alzheimer Network study were examined to evaluate the cross-sectional relationship of PA with cognitive performance, functional status, cognitive decline, and AD biomarkers in cerebrospinal fluid. Mutation carriers were categorized as high or low exercisers according to WHO recommendations. ResultsMutation carriers with high PA showed significantly better cognitive and functional performance and significantly less AD-like pathology in cerebrospinal fluid than individuals with low PA. Mutation carriers with high PA scored 3.4 points better on Mini Mental State Examination at expected symptom onset and fulfilled the diagnosis of very mild dementia 15.1 years later compared with low exercisers. DiscussionThese results support a beneficial effect of PA on cognition and AD pathology even in individuals with genetically driven autosomal dominant AD.

A pathogenic &lt;em&gt;PSEN2&lt;/em&gt; p.His169Asn mutation associated with early-onset Alzheimer&amp;rsquo;s disease

BackgroundAutosomal dominant early-onset Alzheimer’s disease (EOAD) is genetically heterogeneous and has been associated with mutations in 3 different genes, coding for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). Most frequent cases are associated with mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare.MethodsPatient who presented progressive memory decline in her 50s was enrolled in this study. A broad battery of neuropsychological tests and neuroimaging was applied to make the diagnosis. Genetic tests were performed in the patient to evaluate possible mutations using next-generation sequencing (NGS). The pathogenic nature of missense mutation and its 3D protein structure prediction were performed by in silico prediction programs.ResultsA pathogenic mutation in the PSEN2 gene in a Korean patient associated with EOAD was identified. Targeted Next-generation sequencing and Sanger sequencing revealed a heterozygous C to A transition at position 505 (c.505C>A), resulting in a probably missense mutation at codon 169 (p.His169Asn) in PSEN2. PolyPhen-2 and SIFT software analyses predicted this mutation to be a probable damaging variant. This hypothesis was supported by the results of 3D in silico modelling analyses that predicted the p.His169Asn may result in major helix torsion due to histidine to asparagine substitution. Mutation may cause additional stresses with hydrophobic residues on the surface that interact inside the transmembrane domain III, which is a conserved domain in PSEN2 His169.ConclusionThese findings revealed that the p.His169Asn might be an important residue in PSEN2, which may alter the functions of PSEN2, suggesting its potential involvement with AD phenotype. Future functional studies are needed to evaluate the role of PSEN2 p.His169Asn mutation in AD disease progression.