Men and women have different risk profiles for both MCI and progression to dementia. Intervention programmes should focus principally on risk of stroke in men and depressive symptomatology and use of anticholinergic medication in women.

BackgroundAmyloid 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 findingsWe 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. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers—total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42—in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

The relative rarity of primary progressive (PP) and transitional progressive (TP) multiple sclerosis has meant that little documentation of cognitive function in such patients is currently available. The aim of this study was to investigate the cognitive skills of patients with PP and TP multiple sclerosis relative to matched healthy controls, and to examine the relationship of this impairment to MRI parameters. Sixty-three patients (43 PP, 20 TP) were individually matched with healthy controls, who undertook the same cognitive tasks as the patient group. The neuropsychological assessment comprised Rao's brief repeatable battery, a reasoning test, and a measure of depression. Patients also underwent T1- and T2-weighted brain MRI. These patients were taken from a larger cohort (158 PP, 33 TP) in whom it had been demonstrated that the re were no significant differences between the mean scores of the PP and TP groups on any of the cognitive variables. The 63 patients were therefore taken as one group for comparison with the healthy controls. These patients performed significantly worse than the controls in tests of verbal memory, attention, verbal fluency and spatial reasoning. An impairment index was constructed and applied to the patient data. This correlated modestly with T2-lesion load (r = 0.45, P = 0.01), T1-hypointensity load (r = 0.45, P = 0.01) and cerebral volume (r = -0.35, P = 0.01). Thus, PP and TP multiple sclerosis patients demonstrate significant cognitive dysfunction when compared with matched healthy controls. The relationship between this impairment and MRI parameters is moderate, suggesting that cognitive dysfunction in PP and TP multiple sclerosis has a complex and multifactorial aetiology, which is not adequately explained by pathology as demonstrated on conventional MRI.

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Reduced semantic fluency performances have been reported in the preclinical phase of Alzheimer's disease (AD). To investigate the cognitive processes underlying this early deficit, this study analyzed the verbal production of pre-demented subjects for the animals category with the qualitative parameters related to clustering (i.e. the ability to generate words belonging to semantic subcategories of animals) and switching (i.e. the ability to shift from one subcategory to another) proposed by Troyer.This qualitative analysis was applied to the PAQUID cohort, a 17-year longitudinal population-based study. The performances on the animal verbal fluency task of 51 incident cases of possible and probable AD were analyzed at the onset of dementia, 2 years and 5 years before dementia onset. Each case was matched for age, sex and education to two control subjects leading to a sample of 153 subjects. The mean cluster size and the raw number of switches were compared in the two samples. The results revealed a significantly lower switching index in the future AD subjects than in the elderly controls including 5 years before dementia incidence. A significant decline in this parameter was evidenced all along the prodromal phase until the clinical diagnosis of dementia. In contrast, the mean cluster size could not discriminate the two groups. Therefore the results support the hypothesis that impaired shifting abilities -rather than semantic memory storage degradation-could explain the early decline in semantic fluency performance occurring in the predementia phase of AD.

A high plasma EPA concentration may decrease the risk of dementia, whereas high ratios of n-6 to n-3 fatty acids and of AA to DHA may increase the risk of dementia, especially in depressed older persons. The role of EPA in dementia warrants further research.

The SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

Several recent studies have provided substantial support for the proposal that a decrease in inhibitory processing may play an important role in cognitive changes occurring in the early stages of Dementia of the Alzheimer Type (DAT). The question addressed by the present study was whether these deficits are the result of the failure of a general inhibitory mechanism, or whether DAT is associated with selective decreases in a subset of inhibitory processes. For this, a computerized battery of tasks assessing several inhibitory mechanisms was administered to 28 mild DAT patients and 28 matched elderly adults. The results showed that DAT patients failed to produce Negative Priming effects and were severely impaired in the Stroop task. However, no evidence was found for an impairment on the Go-No go task and only limited impairment on the Stop Signal task, suggesting that in the early stages of the disease, not all inhibitory mechanisms are uniformly impaired.