Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening.

Purpose: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD).

Methods: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients.

Phenotype and imaging features associated with APP duplications.

Background: APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers.

Methods: Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls.

Longitudinal Analysis of Brain-Predicted Age in Amnestic and Non-amnestic Sporadic Early-Onset Alzheimer's Disease.

Predicted age difference (PAD) is a score computed by subtracting chronological age from "brain" age, which is estimated using neuroimaging data. The goal of this study was to evaluate the PAD as a marker of phenotypic heterogeneity and severity among early-onset Alzheimer's disease (EOAD) patients. We first used 3D T1-weighted (3D-T1) magnetic resonance images (MRI) of 3,227 healthy subjects aged between 18 and 85 years to train, optimize, and evaluate the brain age model.

A multimodal, longitudinal study of cognitive heterogeneity in early-onset Alzheimer's disease.

Background And Purpose: Alzheimer's disease (AD) is a heterogeneous pathology. Young patients with AD are particularly likely to have an atypical presentation. The objectives of the present cluster analysis were to determine whether patients with early-onset AD (EOAD) had several distinct cognitive profiles and to compare the resulting clusters with regard to clinical, neuroimaging, and laboratory characteristics.

Three-year changes of cortical F-FDG in amnestic vs. non-amnestic sporadic early-onset Alzheimer's disease.

Purpose: To examine and compare longitudinal changes of cortical glucose metabolism in amnestic and non-amnestic sporadic forms of early-onset Alzheimer's disease and assess potential associations with neuropsychological performance over a 3-year period time.

Methods: Eighty-two participants meeting criteria for early-onset (< 65 years) sporadic form of probable Alzheimer's disease and presenting with a variety of clinical phenotypes (47 amnestic and 35 non-amnestic forms) were included at baseline and followed up for 1.44 ± 1.

Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer's Disease Before 51 Years.

Background: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants.

Objective: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD.

The relationship between CSF biomarkers and cerebral metabolism in early-onset Alzheimer's disease.

Purpose: One can reasonably suppose that cerebrospinal spinal fluid (CSF) biomarkers can identify distinct subgroups of Alzheimer's disease (AD) patients. In order to better understand differences in CSF biomarker patterns, we used FDG PET to assess cerebral metabolism in CSF-based subgroups of AD patients.

Methods: Eighty-five patients fulfilling the criteria for probable early-onset AD (EOAD) underwent lumbar puncture, brain F-FDG PET and MRI.

Low Prevalence and Clinical Effect of Vascular Risk Factors in Early-Onset Alzheimer's Disease.

Background: Determinants of early-onset Alzheimer's disease (EOAD) are not well known. In late-onset AD, vascular risk factors (VRFs) are associated with earlier clinical manifestation.

Objective: The objective of this study was to assess the putative association between VRFs and EOAD.

F-FDG PET hypometabolism patterns reflect clinical heterogeneity in sporadic forms of early-onset Alzheimer's disease.

Until now, hypometabolic patterns and their correlations with neuropsychological performance have not been assessed as a function of the various presentations of sporadic early-onset Alzheimer's disease (EOAD). Here, we processed and analyzed the patients' metabolic maps at the vertex and voxel levels by using a nonparametric, permutation method that also regressed out the effects of cortical thickness and gray matter volume, respectively. The hypometabolism patterns in several areas of the brain were significantly correlated with the clinical manifestations.

APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.

Background: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.

Methods And Findings: We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170.

Seizures in dominantly inherited Alzheimer disease.

Objective: To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations.

Methods: A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded.

ABCA7 rare variants and Alzheimer disease risk.

Objective: To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting.

Methods: We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls.

Results: After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons.

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years.

Memory loss during lenalidomide treatment: a report on two cases.

Background: There are many reports of cognitive dysfunction in patients receiving chemotherapy or targeted therapies. Many antineoplastic agents may be involved in the condition also known as "chemo brain" or "chemo fog".

Case Presentation: Two male patients (aged 41 and 70) with multiple myeloma developed severe, rapidly progressing cognitive impairment (mostly involving episodic memory) and loss of independence in activities of daily living during lenalidomide-based treatment.

TREM2 R47H variant as a risk factor for early-onset Alzheimer's disease.

The rs75932628-T variant of the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has recently been identified as a rare risk factor for late-onset Alzheimer's disease (AD). In this study we examined the association between TREM2 exon 2 variants and early-onset AD in a sample of Caucasian subjects of French origin including 726 patients with age of onset ≤65 years and 783 controls. Only the rs75932628-T variant (predicted to cause an R47H substitution) conferred a significant risk for early-onset AD (OR, 4.

Reasons that prevent the inclusion of Alzheimer's disease patients in clinical trials.

Aim: To assess reasons that prevent Alzheimer's disease (AD) patients from being included in clinical trials.

Methods: In 2009, we reviewed the Lille Memory Clinic's case database to identify patients suitable for inclusion in four AD clinical trials. An initial selection was made on the basis of four criteria: (i) a diagnosis of AD (with or without white matter lesions [WML]), (ii) age, (iii) mini mental state examination (MMSE) score and (iv) symptomatic treatment of AD (cholinesterase inhibitors/memantine).

The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers.

We describe 56 novel autosomal dominant early-onset Alzheimer disease (ADEOAD) families with PSEN1, PSEN2, and AβPP mutations or duplications, raising the total of families with mutations on known genes to 111 (74 PSEN1, 8 PSEN2, 16 AβPP, and 13 AβPP duplications) in the French series. In 33 additional families (23% of the series), the genetic determinism remained uncharacterized after this screening. Cerebrospinal fluid (CSF) biomarker levels were obtained for patients of 58 families (42 with known mutations and 16 without genetic characterization).

Contribution of single photon emission computed tomography to the differential diagnosis of dementia in a memory clinic.

To evaluate the contribution of single photon emission computed tomography (SPECT) to the differential diagnosis of dementia, we studied 48 consecutive patients (median age: 63) with a degenerative or vascular dementia, a 99mTc-HMPAO SPECT imaging, and a diagnostic confirmation (autopsy or genetic mutation). The SPECT scans were visually rated by two nuclear medicine physicians (first blinded to the clinical data, then with the data). Comparisons between clinical diagnoses and/or SPECT imaging and neuropathology were performed.

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease.

Studying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases.