EOAD Patients Research Articles

C-07 Global Precedence: Examining Contributing Effects of Age and Cognitive Functioning

Abstract Objective Global precedence (GP) is an individual’s ability to readily identify global (gestalt) features when both global and local (internal) details are presented. Prior research shows that both age and neurodegenerative diseases, such as Alzheimer’s, affect GP. The goal of the current study is to examine differences in GP between individuals with early-onset Alzheimer’s disease (EOAD; before age 65) and healthy controls (HC). Method Fourteen EOAD patients and 6 HC’s recruited from Behavioral Neurology at an academic medical center were included in the current analysis. EOAD participants were diagnosed by clinical history, routine labs, neuroimaging, and neurological examination. Exclusion criteria included unstable medical conditions and history of severe head injury, psychotic disorder, or psychoactive substance use. All participants completed a Mini Mental Status Examination (MMSE) to assess overall cognitive functioning and a 4-item Navon's paradigm task (consisting of a larger letter whose shape is composed of smaller repeats of a different letter) to assess for GP. Results Linear regression analysis was performed, with the total score on Navon task as the dependent variable and age, MMSE score, and study group as predictor variables. Analysis yielded significant findings, suggesting a difference in GP performance between the two groups. However, coefficients suggested that while age did not contribute to the between-group difference, MMSE scores significantly accounted for our findings. In fact, when effects of MMSE scores were controlled, the between-group difference was no longer significant. Conclusion Findings suggest that individuals with EOAD perform worse on tasks of GP, which may be secondary to overall cognitive decline.

Novel GRN mutations in Koreans with Alzheimer’s disease

Backgrounds Alzheimer’s disease (AD) and fronto-temporal dementia (FTD) are the two most common neurodegenerative diseases leading to early onset dementia ( T) and c.IVS8+23_+26delTGGG, which occurred independently in two EOAD patients (frequenct of 2/89, 2.2%). Using a combination of clinical and association studies, in silico prediction, and 3-D modeling software, we suggest that both mutations are probably pathogenic and involved in FTD. Conclusion: Our data suggest that it would be important to re-examine EOAD patients who had been diagnosed when the FTD spectrum was not well described and the causative FTD genes had not yet been identifed. In addition, we propose initially analyzing genes associated with the frst form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia.

Differences in cortical perfusion detected by arterial spin labeling in nonamnestic and amnestic subtypes of early-onset Alzheimer's disease

ObjectivesEarly-onset Alzheimer's disease (EOAD) begins before the age of 65 and is characterized by a faster clinical course and the frequency of nonamnestic symptoms compared to late onset Alzheimer disease (LOAD). However, the pathophysiological process of EOAD remains unclear. We expected that ASL may show widespread cortical hypoperfusion in EOAD compared to LOAD and in nonamnestic EOAD compared to amnestic EOAD. MethodsIn this study, 26 EOAD patients (16 amnestic and 10 nonamnestic patients), 29 LOAD patients and 12 healthy controls underwent pseudo-continuous ASL and 3D FFE T1 sequences. Statistical comparisons between EOAD, LOAD and control groups were made after surface-based analysis of CBF maps in regressing out the cortical thickness. ResultsASL showed a more severe hypoperfusion in nonamnestic EOAD patients compared to amnestic EOAD ones, with mean CBF values (± std) of 26.9 (± 3.8) and 46.6 (± 24.1) mL/100 g/min respectively (P = 0.014), located in the bilateral temporo-parietal neocortex, the precuneus, the posterior cingulate cortices (PCC) and frontal lobes. Comparison between EOAD and LOAD patients showed a trend to hypoperfusion in the left parietal lobe, PCC and precuneus in EOAD (P < 0.001 uncorrected). ConclusionsDifferent patterns of hypoperfusion between nonamnestic and amnestic EOAD subtypes were identified, with a more severe and extensive hypoperfusion in nonamnestic patients. A trend towards more severe hypoperfusion was detected in EOAD compared to LOAD. Further studies are needed to validate ASL as a potential tool for the distinction of EOAD subtypes and the prediction of the time course of the disease.

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.

Differences in hippocampal subfield volume are seen in phenotypic variants of early onset Alzheimer's disease.

The most common presentation of early onset Alzheimer's disease (EOAD – defined as symptom onset <65 years) is with progressive episodic memory impairment – amnestic or typical Alzheimer's disease (tAD). However, EOAD is notable for its phenotypic heterogeneity, with posterior cortical atrophy (PCA) – characterised by prominent higher-order visual processing deficits and relative sparing of episodic memory – the second most common canonical phenotype. The hippocampus, which comprises a number of interconnected anatomically and functionally distinct subfields, is centrally involved in Alzheimer's disease and is a crucial mediator of episodic memory. The extent to which volumes of individual hippocampal subfields differ between different phenotypes in EOAD is unclear. The aim of this analysis was to investigate the hypothesis that patients with a PCA phenotype will exhibit differences in specific hippocampal subfield volumes compared to tAD. We studied 63 participants with volumetric T1-weighted MRI performed on the same 3T scanner: 39 EOAD patients [27 with tAD and 12 with PCA] and 24 age-matched controls. Volumetric estimates of the following hippocampal subfields for each participant were obtained using Freesurfer version 6.0: CA1, CA2/3, CA4, presubiculum, subiculum, hippocampal tail, parasubiculum, the molecular and granule cell layers of the dentate gryus (GCMLDG), the molecular layer, and the hippocampal amygdala transition area (HATA). Linear regression analyses comparing mean hippocampal subfield volumes between groups, adjusting for age, sex and head size, were performed. Using a Bonferonni-corrected p-value of p < 0.0025, compared to controls, tAD was associated with atrophy in all hippocampal regions, except the parasubiculum. In PCA patients compared to controls, the strongest evidence for volume loss was in the left presubiclum, right subiculum, right GCMLDG, right molecular layer and the right HATA. Compared to PCA, patients with tAD had strong evidence for smaller volumes in left CA1 and left hippocampal tail. In conclusion, these data provide evidence that hippocampal subfield volumes differ in different phenotypes of EOAD.

TAU AND AMYLOID CAUSE DISRUPTION IN WHITE MATTER CONNECTIVITY DIFFERENTLY FOR EARLY- AND LATE-ONSET ALZHEIMER'S DISEASE

Early-onset (EOAD) and late-onset Alzheimer's disease (LOAD) are known to have heterogeneous pathogenesis. The detection of the extracellular amyloid plaques and intraneuronal neurofibrillary tangles, important component of AD brain, is available owing to development of tracers for positron emission tomography (PET). The white matter (WM) connectivity can be acquired by diffusion-weighted magnetic resonance imaging (MRI) and is recently commonly used for classification of AD. In this study, we recruited 33 young controls (YC), 32 old controls (OC), 50 EOAD patients, and 38 LOAD patients with T1- and diffusion-weighted MRI, amyloid PET and tau PET. The PET images were acquired by using [18F]THK5351 and [18F]Flutemetamol as tracers of tau and amyloid pathology and global standardized uptake value ratios (SUVRs) were calculated for them. We constructed FA-weighted WM networks from MR images and computed w-scores of EOAD and LOAD using YC and OC networks respectively with covariates. We performed permutation-based cluster-based statistics for correlation analysis between disruption of WM connectivity and global SUVRs and for group comparison of disruption of WM connectivity between ADs. In the global association study, EOAD patients showed significantly decreased WM connectivity with increased tau SUVRs and LOAD patients showed same trends with amyloid SUVRs at the threshold of -0.5. In the former analysis, the hub regions are the right gyrus rectus, the left superior parietal lobule, and the left precuneus. In the later analysis, the hub region is the left middle occipital gyrus. For the group comparison study, EOAD patients showed significantly greater WM connectivity than LOAD patients at the threshold of 10, and the hub region is the left inferior parietal lobule. A. WM connectivity of EOAD in association with Global Tau

The Progressive Acalculia Presentation of Parietal Variant Alzheimer's Disease.

Many patients with early-onset Alzheimer's disease (EOAD; age of onset <65 years) have non-amnestic presentations involving language (logopenic primary progressive aphasia, lvPPA), visuospatial abilities (posterior cortical atrophy, PCA), and even asymmetric symptoms consistent with corticobasal syndrome (CBS). An inferior parietal lobule variant of EOAD commonly presents with progressive difficulty with calculations. We reviewed 276 EOAD patients for presentations with predominant acalculia. These patients were diagnosed with clinically probable Alzheimer's disease (AD) verified by positron emission tomography (PET) or cerebrospinal fluid amyloid-β or tau biomarkers. We identified 18 (9M/9F) (6.5%) EOAD patients with progressive acalculia that did not meet most criteria for lvPPA, visual PCA, or CBS. Their ages of onset and presentation were 56.6 (5.0) and 59.4 (6.5), respectively. Their acalculia was consistent with a primary acalculia ("anarithmetia") not explained by language or visuospatial impairments. Many also had anomia (14/18), ideomotor apraxia (13/18), and the complete Gerstmann's syndrome (7/18). Visual analysis of their diverse magnetic resonance imaging disclosed biparietal atrophy, disproportionately worse on the left. Primary acalculia may be the most common manifestation of an inferior parietal presentation of EOAD affecting the left intraparietal sulcus. This parietal variant also commonly involves progressive anomia, ideomotor apraxia, and other elements of Gerstmann's syndrome. The early recognition of patients with this variant, which is distinguishable from lvPPA, visual PCA, or CBS, would be facilitated by its recognition as a unique subtype of EOAD.

Early-Onset Alzheimer’s Disease and Metabolic Dysfunction, a Comparative Review

Alzheimer’s disease is quickly becoming one of the most known diseases in the country due to its devastating effects and lack of treatment options. Within this lethal disease, there is a smaller group, those individuals that are diagnosed with early-onset Alzheimer’s disease. It is understood that these individuals see faster effects of the disease and die considerably sooner, but it is not understood why. This review compares the early-onset (EOAD) and late-onset (LOAD) types to try and determine some of the most blaring differences between the two. The genetic basis linking EOAD and LOAD has been the apolipoprotein E gene (APOE) to indicate metabolic alteration with the e4 allele specifically. The topographical atrophy disparities between EOAD and LOAD supported the more noticeable cognitive differences between the two Alzheimer’s disease categories. The faster and wider spread atrophy of EOAD patients correlates with the difficulty they experience with attention, language, visuo-spatial, and executive functions. Finally, brain metabolism differs between both AD subtypes as well, where EOAD indicates the wide spread damage and metabolic breakdown across more diverse regions of the brain.

Neuropsychiatric Profile in Early Versus Late Onset Alzheimer's Disease.

The aim of this study was to investigate the frequency and severity of neuropsychiatric symptoms (NPS) in patients with early onset Alzheimer's disease (EAOD) and late onset AD (LOAD). Patients were selected from a specialized memory outpatient clinic. The Mini-Mental State Examination, the Neuropsychiatric Inventory (NPI), and the Global Deterioration Scale results were analyzed. By comparing EOAD (n = 35) and LOAD (n = 35) patients, no significant differences were found in clinical or demographic variables, matched for sex, education, and disease severity. There were no differences between groups in total NPI frequency or severity scores. The most common NPS were irritability, apathy, anxiety, and depression. We found an association of NPI scores with disease severity and duration, which was more specific in patients with LOAD and was also associated with the presence of delusions and hallucinations. Despite subtle differences, NPS is considered important in the assessment of patients with AD, regardless of the age of onset.

Visual Ratings of Medial Temporal Lobe Atrophy Correlate with CSF Tau Indices in Clinical Variants of Early-Onset Alzheimer Disease

Background/Aims: Prior studies of late-onset Alzheimer disease (AD) have reported that cerebrospinal fluid (CSF) tau levels correlate with hippocampal/medial temporal lobe atrophy. These findings suggest that CSF tau indices in AD may reflect tau-related neurodegeneration in the medial temporal lobe. However, it remains uncertain whether elevated CSF tau levels in the clinically heterogeneous subtypes of early-onset AD (EOAD; amnestic, posterior cortical atrophy [PCA], and logopenic progressive aphasia [LPA]) are attributable to similar underlying mechanisms. Methods: We identified 41 EOAD patients (18 amnestic, 14 with LPA, and 9 with PCA) with CSF and brain MRI data. Semiquantitative ratings were used to assess medial temporal lobe atrophy and PCA, which were compared to CSF biomarker indices. Results: Lower CSF tau levels were seen in PCA relative to amnestic EOAD and LPA, but similar ratings for medial temporal lobe atrophy and PCA were seen across the groups. After adjustments for demographics and cognitive performance, both total (p = 0.004) and hyperphosphorylated (p = 0.026) tau levels correlated with medial temporal lobe atrophy across this EOAD cohort. Conclusions: These results replicate prior findings in late-onset AD and support the hypothesis that CSF tau levels primarily reflect tau-related neurodegenerative changes in the hippocampus/medial temporal lobe across the clinical subtypes of EOAD.

DISTINGUISHING NON-AMNESTIC FROM AMNESTIC VARIANTS OF EARLY-ONSET ALZHEIMER’S DISEASE ON NEUROPSYCHOLOGICAL TESTS

Patients with early-onset Alzheimer's disease (AD) include those with typical amnestic AD and those with atypical, non-amnestic presentations, including language, visuospatial, or executive disturbances, who have more focal neocortical localization early in the disease. There are no neuropsychological profiles to distinguish these non-amnestic variants as a group from typical amnestic presentations. We compared neuropsychological measures of 41 patients meeting AA-NIA criteria for AD and having an age of onset of <65 years of age. Based on the initial extensive physician clinical evaluation, these 41 patients were divided into amnestic (n=22 including 14 male/8 female; mean years for age-58.4, disease duration-3.2, education-16.1 years) vs. non-amnestic (n=19 including 8 male/11 female; mean years for age-59.7, disease duration-4.0, education-16.2). The two patient groups were of comparable severity on functional measures and had fluorodeoxyglucose positron emission tomography (FDG-PET) or cerebrospinal fluid biomarker confirmation of their disease. We then analyzed neuropsychological differences between these two groups. Six measures emerged as having either sensitivities of ≥0.8 or specificities of ≥0.9 for typical amnestic vs. non-amnestic AD (See Table 1). The amnestic EOAD patients were worse on the California Verbal Learning Test (CVLT) delayed recall scores, including “Savings Score” (free long-delayed recall/last registration trial) especially because of better memory registration and had many more false positives on CVLT recognition memory testing. In comparison, the non-amnestic AD patients were worse on Forward Digit Span, Trailmaking B time, Boston Naming Test (uncued), CVLT memory registration, and the Southern California Figure-Ground Test. 17 of the 19 non-amnestic EOAD patients were abnormal on all 6 tests, and the Trailmaking B added the highest specificity at 0.92. These results reveal significantly different neuropsychological profiles for the non-amnestic variants of AD, as a group, from typical AD. The findings suggest neuropsychological measure for differentiation of these variants that including measures of early impairment in mental control and executive abilities, uncued naming, memory registration, and mid-level visuospatial processing.

PATTERNS OF CORTICAL NEUROANATOMICAL ABNORMALITITES IN TYPICAL AND ATYPICAL SPORADIC FORMS OF EARLY-ONSET ALZHEIMER’S DISEASE

In addition to cortical thickness used as a biomarker of cortical atrophy, recent studies pointed out neuroanatomical abnormalities of the cerebral cortex in AD by morphology analysis of cortical sulci width and depth. As far as we know, no previous study based on high-resolution extensive structural surface features (cortical thickness, fractal dimension, smoothed absolute mean curvature and sulcal depth) assessed on the whole brain whether distinct finer microstructural alterations were presented according to typical or atypical presentation of sporadic EOAD. We included 54 subjects meeting criteria for probable AD dementia with early-onset (< 60 years) and sporadic form, that were classified as typical (amnestic presentation) or atypical (non-amnestic presentation, i.e. language, visuospatial and executive dysfunction) by consensus. 12 healthy controls age and sex matched with both typical and atypical EOAD groups were also included. Clinical characteristics are reported in Table 1. T1 images were processed with CAT toolbox that allowed measurement of cortical thickness and reconstructions of the central surface (Dahnke et al. 2012). Then 3D vertexwise surface features were computed. We assessed smoothed surface features maps of subjects across the entire common cortical surfaces using a non-parametric statistical analysis, keeping significant clusters at P < 0.05 family-wise error corrected. Both typical and atypical EOAD presented wide cortical atrophy compared to controls but more marked in atypical (Figure 1). Table 2 depicted also higher affection in atypical than typical concerning complementary surface features: FD was reduced with a predominance of the left hemisphere (Figure 2), mean curvature was increased in gyri (“peaked” appearance) and decreased in sulci (sulcal widening) (Figure 3) and sulcal depth was locally reduced (Figure 4) compared to controls. Results were consistent with previous studies in EOAD patients showing wider and shallower sulcal shape in temporal lobe. Moreover, it had been reported that left hemisphere was more severely affected than right in AD. Surface features complementary to cortical thickness seemed to be more localized in EOAD and suggested more extensive and significant patterns of microstructural alterations in atypical than typical EOAD. These differences should be taken into account in further longitudinal studies or therapeutic interventions. Cortical atrophy patterns in typical EOAD as compared to healthy subjects (A), in atypical EOAD as compared to healthy subjects (B), and in atypical as compared to typical EOAD (C) mapped on common cortical surfaces; Color distinguish significance strength of clusters revealed by statistical analysis: color scale is defined from red (less significant) to yellow (more significant) (All visible clusters have corrected p-value < 0.05). Reduced fractal dimension patterns in typical EOAD as compared to healthy subjects (A), and in atypical EOAD as compared to healthy subjects (B) mapped on common cortical surfaces; Color distinguish significance strength of clusters revealed by statistical analysis: color scale is defined from red (less significant) to yellow (more significant) (All visible clusters have corrected p-value < 0.05). Reduced smoothed absolute mean curvature patterns in typical EOAD as compared to healthy subjects (A), and in atypical EOAD as compared to healthy subjects (B) mapped on common cortical surfaces; Increased smoothed absolute mean curvature patterns in typical EOAD as compared to healthy subjects (C), and in atypical EOAD as compared to healthy subjects (D) mapped on common cortical surfaces; Color distinguish significance strength of clusters revealed by statistical analysis: color scale is defined from red (less significant) to yellow (more significant) (All visible clusters have corrected p-value < 0.05). Reduced sulcal depth patterns in typical EOAD as compared to healthy subjects (A), and in atypical EOAD as compared to healthy subjects (B) mapped on common cortical surfaces; Color distinguish significance strength of clusters revealed by statistical analysis: color scale is defined from red (less significant) to yellow (more significant) (All visible clusters have corrected p-value < 0.05).

A POSSIBLE PATHOGENIC PSEN2 MUTATION, H169N IN A KOREAN EOAD PATIENT

Alzheimer’s disease is the most prevalent type of senile dementia, occurs mostly in the elderlies. Early onset form of disease is highly associated with genetics, since 3 genes can play role in disease onset: APP, PSEN1, and PSEN2. PSEN2 is a quite rare causative factor, but several emerging studies are available on it. 100 EOAD patients for complex genetic profiling with a gene panel of 50 genes, established as several causative and risk factor genes, and mutations were validated by standard sequencing and SSCP studies. We found a known PSEN2 mutation, H169N in an EOAD patient. Family studies and in silico modeling will be performed on it. PSEN2 H169N was found in a Chinese family, and phenotype was diverse, since AD and FTD symptoms were also appeared in the carriers. However, segregation in the disease was not established yet. This study might confirm that PSEN2 H169N could be associated with AD/dementia phenotype.

NOVEL, PSEN1 T119I MUTATION IN AN EARLY-ONSET ALZHEIMER'S DISEASE PATIENT

Alzheimer’s disease is the most common form of senile dementia, occurs mostly in the elder ages. Early onset form of disease could be associated with genetics, where 3 genes were established to play role in disease onset: APP, PSEN1, and PSEN2. PSEN1 is the most common causative gene for EOAD. Next generation sequencing approaches have been performed with a gene panel of 50 neurodegenerative disease-associated genes, published last year. 100 EOAD patients were screened, and the mutations were verified by standard sequencing and SSCP studies. A novel mutation T119I was found in one of the EOAD patient. This mutation was not reported any of the known EOAD mutation databases, neither in the HapMap or ExAC database. In silico modeling will be performed on its pathogenic nature. More studies are needed on PSEN1 T119I, however, since it is located on the conservative TM-I, it might be possible that this variant could result significant changes in PSEN1. A similar mutation PSEN1 T116I was already reported, which was established as pathogenic mutation. This could be evidence that PSEN1 T119I could be a pathogenic mutation.

Memory Impairment at Initial Clinical Presentation in Posterior Cortical Atrophy.

Posterior cortical atrophy (PCA) is characterized by core visuospatial and visuoperceptual deficits, and predominant atrophy in the parieto-occipital cortex. The most common underlying pathology is Alzheimer's disease (AD). Existing diagnostic criteria suggest that episodic memory is relatively preserved. The aim of this study was to examine memory performance at initial clinical presentation in PCA, compared to early-onset AD patients (EOAD). 15 PCA patients and 32 EOAD patients, and 34 healthy controls were entered into the study. Patients were tested on the Addenbrooke's Cognitive Examination (ACE-R), consisting of subscales in memory and visuospatial skills. PCA and EOAD patients were significantly impaired compared to controls on the ACE total score (p < 0.001), visuospatial skills (p < 0.001), and memory (p < 0.001). Consistent with the salient diagnostic deficits, PCA patients were significantly more impaired on visuospatial skills compared to EOAD patients (p < 0.001). However, there was no significant difference between patient groups in memory. Further analysis of learning, recall, and recognition components of the memory subscale showed that EOAD and PCA patients were significantly impaired compared to controls on all three components (p < 0.001), however, there was no significant difference between EOAD and PCA patients. The results of this study show that memory is impaired in the majority of PCA patients at clinical presentation. The findings suggest that memory impairment must be considered in assessment and management of PCA. Further study into memory in PCA is warranted, since the ACE-R is a brief screening tool and is likely to underestimate the presence of memory impairment.

Comparison between Early-Onset and Late-Onset Alzheimer's Disease Patients with Amnestic Presentation: CSF and 18F-FDG PET Study

Background/Aims: To investigate the differences in brain glucose consumption between patients with early onset of Alzheimer's disease (EOAD, aged ≤65 years) and patients with late onset of Alzheimer's disease (LOAD, aged >65 years). Methods: Differences in brain glucose consumption between the groups have been evaluated by means of Statistical Parametric Mapping version 8, with the use of age, sex, Mini-Mental State Examination and cerebrospinal fluid values of Aβ_1-42, phosphorylated Tau and total Tau as covariates in the comparison between EOAD and LOAD. Results: As compared to LOAD, EOAD patients showed a significant decrease in glucose consumption in a wide portion of the left parietal lobe (BA7, BA31 and BA40). No significant differences were obtained when subtracting the EOAD from the LOAD group. Conclusions: The results of our study show that patients with EOAD show a different metabolic pattern as compared to those with LOAD that mainly involves the left parietal lobe.

Memory impairment at initial clinical presentation in posterior cortical atrophy

Posterior cortical atrophy (PCA) is characterized by core visuospatial and visuoperceptual deficits, and predominant atrophy in the parieto-occipital cortex. The most common underlying pathology is Alzheimer's disease (AD). Existing diagnostic criteria suggest that episodic memory is relatively preserved. The aim of this study was to examine memory performance at initial clinical presentation in PCA, compared to early-onset AD patients (EOAD). 15 PCA patients and 32 EOAD patients, and 34 healthy controls were entered into the study. Patients were tested on the Addenbrooke's Cognitive Examination (ACE-R), consisting of subscales in memory and visuospatial skills. PCA and EOAD patients were significantly impaired compared to controls on the ACE total score (p < 0.001), visuospatial skills (p < 0.001), and memory (p < 0.001). Consistent with the salient diagnostic deficits, PCA patients were significantly more impaired on visuospatial skills compared to EOAD patients (p < 0.001). However, there was no significant difference between patient groups in memory. Further analysis of learning, recall, and recognition components of the memory subscale showed that EOAD and PCA patients were significantly impaired compared to controls on all three components (p < 0.001), however, there was no significant difference between EOAD and PCA patients. The results of this study show that memory is impaired in the majority of PCA patients at clinical presentation. The findings suggest that memory impairment must be considered in assessment and management of PCA. Further study into memory in PCA is warranted, since the ACE-R is a brief screening tool and is likely to underestimate the presence of memory impairment.

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. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

Differentiated clinical presentation of early and late-onset Alzheimer's disease: is 65 years of age providing a reliable threshold?

Early-onset and late-onset Alzheimer's disease (EOAD and LOAD) are two forms of the disease with the same characteristic neuropathological hallmarks. However, higher burdens of neuritic plaques and neurofibrillary tangles in frontal and parietal lobes have been found in EOAD than in LOAD patients. Thus, the EOAD subjects may have a differentiated clinical presentation compared to the LOAD ones. Some authors have found less hippocampal memory presentations and more focal cortical abnormalities (such as visuoconstructive or executive dysfunction) in EOAD than LOAD patients. The aim of the present study was to determine which initial clinical profiles differ between EOAD and LOAD; and to analyze whether another age cut-off could discriminate better between EOAD and LOAD clinical presentations than the conventional limit of 65. All patients fulfilling NINCDS-ADRDA criteria for probable Alzheimer's disease who referred to our Hospital between October 2007 and December 2012 were included in the study. The conventional age limit of 65 was established to distinguish between EOAD and LOAD. Baseline neuropsychological scores, adjusted for age and education, were compared between both groups. A total of 181 patients (38 EOAD, 143 LOAD) entered in the analysis. Sex distribution and time of evolution of symptoms did not differ between groups. The EOAD patients performed worse than LOAD in attentional, imitation praxis and verbal learning tests. In addition, the age cut-off of 70 was found to differentiate between early- and late-onset groups better than the standard cut-off of 65 years old. Our results support a differentiated neuropsychological impairment pattern in EOAD compared to LOAD.

Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European early-onset dementia consortium study

Meta-analysis of existing genome-wide association studies on Alzheimer's disease (AD) showed subgenome-wide association of an intronic variant in the sequestosome 1 (SQSTM1) gene with AD. We performed targeted resequencing of SQSTM1 in Flanders-Belgian AD patients selected to be enriched for a genetic background (n = 435) and geographically matched nonaffected individuals (n = 872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European early-onset dementia cohorts (926 early-onset Alzheimer’s disease [EOAD] patients and 1476 nonaffected individuals). Of the 61 detected exonic variants in SQSTM1, the majority were rare (n = 57). Rare variant (minor allele frequency <0.01) burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts. Common variants p.D292= and p.R312= showed nominal association with AD (odds ratiop.D292= = 1.11 [95% confidence interval = 1–1.22], p = 0.04), only when including the Flanders-Belgian cohort in the meta-analysis. We cannot exclude a role of SQSTM1 genetic variability in late-onset AD, but our data indicate that SQSTM1 does not play a major role in the etiology of EOAD.