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. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). RESULTS: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. CONCLUSION: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.

The relationship between social deprivation and a frailty index of cumulative deficits in French middle-aged caregivers.

BACKGROUND: The Institut Pasteur de Lille, in the north of France, has implemented a large, multidisciplinary health check, which aims to identify frailty in middle-aged caregivers. We aimed to construct an adapted frailty index of cumulative deficit (FI-CD) and study the associated factors, in particular socioeconomic factors. METHODS: The cross-sectional study included caregivers aged 45 to 65. A 34-item FI-CD including deficits adapted to a middle-aged population (related to cognition and autonomy, dietetics, physical activity, comorbidities, functional signs, lab values and paraclinical examinations) was constructed in accordance with standard procedures. It was calculated as a ratio of deficits present out of the total number of possible deficits, giving a continuous score between 0 and 1. Scores > 0.25 and >  0.4 were classified as frailty and severe frailty, respectively. Univariate and multivariate associations were studied using linear regressions. RESULTS: One hundred and seventeen caregivers were included; among them, 111 were analyzed due to missing values. The mean FI-CD was 0.22 ± 0.08. Forty (36%) individuals were classified as frailty and three (2.7%) as severe frailty. In multivariate analysis, FI-CD was significantly associated with age (beta [95% confidence interval] = 0.005 [0.002; 0.009] per 1-year increase, p = 0.005) and social deprivation (beta = 0.054 [0.007; 0.102], p = 0.025). A significant interaction was observed between and age and social deprivation (p = 0.036). The adjusted relationship between FI-CD and age was beta = 0.010 [0.002; 0.019], p = 0.017 in precarious caregivers, and beta = 0.003 [- 0.001; 0.007], p = 0.19 in non-precarious caregivers. CONCLUSIONS: The study suggested that the 34-item FI-CD could have clinical utility in the management of middle-aged caregivers. Social deprivation appeared as an important factor associated with frailty, highlighting the importance of early care and social support for precarious caregivers.

Characteristics and progression of patients with frontotemporal dementia in a regional memory clinic network.

BACKGROUND: Due to heterogeneous clinical presentation, difficult differential diagnosis with Alzheimer's disease (AD) and psychiatric disorders, and evolving clinical criteria, the epidemiology and natural history of frontotemporal lobar degeneration (FTD) remain elusive. In order to better characterize FTD patients, we relied on the database of a regional memory clinic network with standardized diagnostic procedures and chose AD patients as a comparator. METHODS: Patients that were first referred to our network between January 2010 and December 2016 and whose last clinical diagnosis was degenerative or vascular dementia were included. Comparisons were conducted between FTD and AD as well as between the different FTD syndromes, divided into language variants (lvFTD), behavioral variant (bvFTD), and FTD with primarily motor symptoms (mFTD). Cognitive progression was estimated with the yearly decline in Mini Mental State Examination (MMSE). RESULTS: Among the patients that were referred to our network in the 6-year time span, 690 were ultimately diagnosed with FTD and 18,831 with AD. Patients with FTD syndromes represented 2.6% of all-cause dementias. The age-standardized incidence was 2.90 per 100,000 person-year and incidence peaked between 75 and 79 years. Compared to AD, patients with FTD syndromes had a longer referral delay and delay to diagnosis. Patients with FTD syndromes had a higher MMSE score than AD at first referral while their progression was similar. mFTD patients had the shortest survival while survival in bvFTD, lvFTD, and AD did not significantly differ. FTD patients, especially those with the behavioral variant, received more antidepressants, anxiolytics, and antipsychotics than AD patients. CONCLUSIONS: FTD syndromes differ with AD in characteristics at baseline, progression rate, and treatment. Despite a broad use of the new diagnostic criteria in an organized memory clinic network, FTD syndromes are longer to diagnose and account for a low proportion of dementia cases, suggesting persistent underdiagnosis. Congruent with recent publications, the late peak of incidence warns against considering FTD as being exclusively a young-onset dementia.

Does amnesia specifically predict Alzheimer's pathology? A neuropathological study.

Amnesia is a key component of Alzheimer's disease (AD) and the most important feature of its clinical diagnosis but its specificity has recently been challenged. This study investigated the ability of amnesia to predict AD in a clinicopathological dementia series. Ninety-one patients to which free and cued verbal memory assessment was administered during early cognitive decline, were followed until autopsy. Patients' histological diagnoses were classified as pure AD, mixed AD, and non-AD pathologies. Data-driven automated classification procedures explored the correspondence between memory performance and pathological diagnoses. Classifications revealed 3 clusters of performance reflecting different levels of amnesia. Little correspondence between these clusters and the presence of AD pathology was retrieved. A third of patients with pure/mixed AD pathology were non-amnesic at presentation and ≈45% of patients without AD pathology were amnesic. Data-driven prediction of AD pathology based on memory also had a poor accuracy. Free and cued memory assessments are fair tools to diagnose an amnesic syndrome but lack accuracy to predict AD pathology.

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). Next, data on patients fulfilling these criteria were reviewed against all the inclusion/exclusion criteria for four clinical trials performed in 2009 at the Memory Clinic. Reasons for non-inclusion were analyzed. RESULTS: Two hundred and five patients were selected according to the four initial criteria. Reasons for subsequently not including some of patients in clinical trials were abnormalities on MRI (56.9%, 88.9% of which were WML), unauthorized medication (37.3%), the lack of a study partner/informant (37.1%), the presence of a non-authorized disease (24.4%), contraindication to MRI (9%), a change in diagnosis over time (3.9%), visual/auditory impairments (2.9%), alcohol abuse (2%) and an insufficient educational level (1%). CONCLUSION: A high proportion of AD patients presented with vascular abnormalities on MRI. This was not unexpected, since the patients were selected from the database and, as shown in epidemiologic studies, cerebrovascular diseases are frequently associated with AD. The presence of a study partner is essential for enabling a patient to participate in clinical trials because of the need to record reliably primary and secondary outcomes.