Early-onset Alzheimer's Disease Patients Research Articles

Relationship between dementia severity and behavioural and psychological symptoms in early-onset Alzheimer's disease.

The features of behavioural and psychological symptoms of dementia (BPSD) are influenced by dementia stage. In early-onset Alzheimer's disease (EOAD), the association between BPSD and dementia stage remains unclear because of the difficulty of recruiting subjects with a wide range of disease severity. We used a combination of community-based and hospital-based approaches to investigate the relationship between dementia severity and BPSD in EOAD patients. Sixty-three consecutive EOAD outpatients and 29 EOAD patients from a community-based survey were divided into three dementia severity groups according to the Clinical Dementia Rating scale (CDR): mild (CDR 0.5-1, n = 55), moderate (CDR 2, n = 17), and severe (CDR 3, n = 20). BPSD were rated using the Neuropsychiatric Inventory. Scores of the Neuropsychiatric Inventory subscales agitation, euphoria, apathy, disinhibition, irritability, and aberrant motor behaviour increased significantly with increased dementia severity. Hallucinations were greater in the moderate group than in the mild group. For delusions, depression, and anxiety, no significant differences were observed among the three severity groups. The pattern of apathy, agitation, disinhibition, irritability, and aberrant motor behaviour worsening with severity progression in EOAD is similar to the pattern in late-onset Alzheimer's disease. In contrast, hallucinations, depression, and anxiety showed different patterns in EOAD.

Early- versus late-onset Alzheimer's disease: 3-year outcomes of cholinesterase inhibitor treatment in routine clinical practice

Background: Alzheimer’s disease (AD) is an insidiously progressive neurodegenerative disorder that is characterized by multiple cognitive impairments and gradual loss of independence in carrying out activities of daily living (ADL). Currently, the predominant therapy for mild-to-moderate AD is cholinesterase inhibitors (ChEIs), which have been shown to have positive effects on symptoms compared with placebo in randomized clinical trials. There is an increased interest in dominantly inherited and early-onset AD, and in new treatments aimed at blocking the course of the disease. Therapies that are expected to modify disease progression should be assessed thoroughly over many years, and advances in understanding of the expected long-term outcomes for individuals with different ages at the onset of AD require well-designed observational studies. This study aimed to identify potential differences in clinical characteristics, longitudinal outcomes, and endpoints in patients with early- vs late-onset AD in routine clinical practice. Methods: The Swedish Alzheimer Treatment Study (SATS) is a prospective, open, nonrandomized multicenter study for the assessment of ChEI treatment in a routine clinical setting. In total, 1,258 outpatients with a clinical diagnosis of probable or possible AD were included. Of these, 1,021 participants were defined as having mild-to-moderate AD (Mini-Mental State Examination (MMSE) score, 10–26) and were enrolled in the present study. The age at AD onset was estimated by a clinician who specialized in dementia disorders. The age at onset was younger than 65 years in 143 individuals (14%) and 65 years or older in 874 (4 missing data). Patients were assessed using cognitive tests (MMSE and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog)) and functional capacity scales (Instrumental Activities of Daily Living scale (IADL) and Physical Self-Maintenance Scale (PSMS)) at baseline, after 2 months (MMSE only), and every 6 months for 3 years. Eventual dates of nursing home placement and death were recorded. Results: The presence of apolipoprotein E (APOE) e4-alleles was more frequent among the early-onset AD patients (2 e4-alleles, 29%; 1 e4-allele, 46%; 0 e4-alleles, 25%) vs late-onset patients (2 e4-alleles, 13%; 1 e4-allele, 54%; 0 e4-alleles, 33%; P < 0.001). At the start of ChEI therapy, the mean age was 62.7 years (95% confidence interval (CI), 61.8–63.6) for the early-onset patients compared with 77.3 years (95% CI, 77.0–77.6) for the late-onset patients (P < 0.001). The duration of illness was longer in the early-onset group than in the late-onset group (4.1 years (95% CI, 3.6–4.7) vs 2.9 years (95% CI, 2.8–3.0); P < 0.001). The early-onset group had more years of education compared with the late-onset group (10.1 years (95% CI, 9.6–10.5) vs 9.3 years (95% CI, 9.2–9.5); P = 0.004). In the entire cohort, 64% were females and the cognitive ability at baseline was assessed as a mean MMSE score of 21.4 points (95% CI, 21.2–21.6) and ADAS-cog score of 20.8 points (95% CI, 20.2–21.3); these values did not differ significantly between groups. Individuals with early-onset AD exhibited less functional impairment compared with those with late-onset AD (IADL score, 13.9 points (95% CI, 13.0–14.8) vs 16.3 points (95% CI, 15.9–16.7); P < 0.001 and PSMS score, 6.7 points (95% CI, 6.5–6.9) vs 7.6 points (95% CI, 7.5–7.8); P < 0.001)) and took fewer concomitant medications (1.8 (95% CI, 1.5–2.0) vs 3.1 (95% CI, 3.0–3.3); P < 0.001). During the study, the mean annual deterioration in ADAS-cog score from baseline for the early- and late-onset groups was 5.0 points (95% CI, 3.7–6.4) vs 2.9 points (95% CI, 2.4–3.5; P = 0.003). The corresponding declines/year for the entire cohort were 1.3 points (95% CI, 0.9–1.8) for MMSE score, 2.7 points (95% CI, 2.4–2.9) for IADL score, and 1.2 points (95% CI, 1.1–1.4) for PSMS score; these did not differ significantly between groups. Twenty-three percent of all patients were admitted to nursing homes during the study, and 38% completed the 3-year SATS; these values did not differ significantly between groups. After 3 years, 6% of the early- and 15% of the late-onset individuals had died (P = 0.002). The ChEI dose received during the study did not differ between groups. Conclusion: This AD study performed in a routine clinical setting shows that more sensitive cognitive measures such as ADAS-cog are required to detect the potential faster decline among early-onset AD patients. Despite better functional performance and fewer concomitant medications at the start of ChEI treatment, early-onset patients had a similar rate of deterioration in ADL and need for institutionalization to the late-onset group. This emphasizes the clinical importance of functional assessments even among younger patients. The possibility of younger individuals living longer after a diagnosis of AD raises questions about the need to provide 24-hour care adapted specifically for this group. (Less)

Cognitive profiles and neuropsychiatric symptoms in Korean early-onset Alzheimer's disease patients: a CREDOS study.

Early-onset Alzheimer's disease (EOAD, onset age < 65 years) may differ from late-onset Alzheimer's disease (LOAD) in terms of cognitive profiles and neuropsychiatric symptoms. There have been few studies for Korean EOAD patients using well-structured databases. Previous studies focusing on cognitive profiles between the two groups had a variety of demographic data and comparability. The purpose of this study was to identify the unique profiles of cognitive functions and neuropsychiatric symptoms in Korean EOAD patients that differentiate from LOAD. Through propensity score matching, a total of 435 patients with EOAD and a total of 435 patients with LOAD were included in this nationwide, multicenter, hospital-based study. Each patient underwent comprehensive neurological examination, interview for caregiver, neuropsychological tests, and brain magnetic resonance imaging. Neuropsychological test results showed worse performances on frontal/executive functions, visuospatial function, and visual memory in EOAD patients as compared to LOAD patients. In terms of neuropsychiatric symptoms, apathy was more common in EOAD patients, while delusions were more prevalent in LOAD patients. The differences in neuropsychiatric symptoms between the two groups were most pronounced in patients with the APOE ε4 allele, suggesting that neuropsychiatric symptoms in AD may be influenced by the APOE genotype. Our results suggested that EOAD may be an important phenotype, fronto-parietal dysfunction, in the spectrum of AD, and this finding can provide for early diagnosis of EOAD patients.

Effect of the CALHM1 G330D and R154H human variants on the control of cytosolic Ca2+ and Aβ levels.

CALHM1 is a plasma membrane voltage-gated Ca2+-permeable ion channel that controls amyloid-β (Aβ) metabolism and is potentially involved in the onset of Alzheimer's disease (AD). Recently, Rubio-Moscardo et al. (PLoS One (2013) 8: e74203) reported the identification of two CALHM1 variants, G330D and R154H, in early-onset AD (EOAD) patients. The authors provided evidence that these two human variants were rare and resulted in a complete loss of CALHM1 function. Recent publicly available large-scale exome sequencing data confirmed that R154H is a rare CALHM1 variant (minor allele frequency (MAF) = 0.015%), but that G330D is not (MAF = 3.5% in an African American cohort). Here, we show that both CALHM1 variants exhibited gating and permeation properties indistinguishable from wild-type CALHM1 when expressed in Xenopus oocytes. While there was also no effect of the G330D mutation on Ca2+ uptake by CALHM1 in transfected mammalian cells, the R154H mutation was associated with defects in the control by CALHM1 of both Ca2+ uptake and Aβ levels in this cell system. Together, our data show that the frequent CALHM1 G330D variant has no obvious functional consequences and is therefore unlikely to contribute to EOAD. Our data also demonstrate that the rare R154H variant interferes with CALHM1 control of cytosolic Ca2+ and Aβ accumulation. While these results strengthen the notion that CALHM1 influences Aβ metabolism, further investigation will be required to determine whether CALHM1 R154H, or other natural variants in CALHM1, is/are associated with EOAD.

Clinical and Neuroimaging Characterization of Chinese Dementia Patients with PSEN1 and PSEN2 Mutations

Background: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two common forms of primary neurodegenerative dementia. Mutations in 3 genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset AD. Methods: We performed gene sequencing in PSEN1, PSEN2, and APP in 61 AD and 35 FTD Chinese patients. Amyloid load using ¹¹C-labeled Pittsburgh compound B (¹¹C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using ¹⁸F-fludeoxyglucose PET were evaluated in patients carrying mutations. Results: We identified 1 known pathogenic PSEN1 (p.His163Arg, c.488A>G) mutation and 3 novel PSEN2 mutations in 6 patients. The novel mutation PSEN2 (p.His169Asn, c.505C>A) was identified in 1 patient with familial late-onset AD and in 1 sporadic FTD patient. The PSEN2 (p.Val214Leu, c.640G>T; p.Lys82Arg, c.245A>G) mutations were identified in 2 early-onset AD patients and 1 early-onset AD patient, respectively. Three patients with PSEN2 mutations were observed to have PIB retention on the cortex and striatum. One patient with the FTD phenotype was not observed to have PIB retention. Conclusion: PSEN2 mutations are common in the Chinese Han population with a history of AD and FTD. Pathogenic mutations or risk variants in the PSEN2 gene can influence both FTD and AD phenotypic traits and show variations in neuroimaging characterization. © 2014 S. Karger AG, Basel

Widespread disruption of functional brain organization in early-onset Alzheimer's disease.

Early-onset Alzheimer’s disease (AD) patients present a different clinical profile than late-onset AD patients. This can be partially explained by cortical atrophy, although brain organization might provide more insight. The aim of this study was to examine functional connectivity in early-onset and late-onset AD patients. Resting-state fMRI scans of 20 early-onset (<65 years old), 28 late-onset (≥65 years old) AD patients and 15 “young” (<65 years old) and 31 “old” (≥65 years old) age-matched controls were available. Resting-state network-masks were used to create subject-specific maps. Group differences were examined using a non-parametric permutation test, accounting for gray-matter. Performance on five cognitive domains were used in a correlation analysis with functional connectivity in AD patients. Functional connectivity was not different in any of the RSNs when comparing the two control groups (young vs. old controls), which implies that there is no general effect of aging on functional connectivity. Functional connectivity in early-onset AD was lower in all networks compared to age-matched controls, where late-onset AD showed lower functional connectivity in the default-mode network. Functional connectivity was lower in early-onset compared to late-onset AD in auditory-, sensory-motor, dorsal-visual systems and the default mode network. Across patients, an association of functional connectivity of the default mode network was found with visuoconstruction. Functional connectivity of the right dorsal visual system was associated with attention across patients. In late-onset AD patients alone, higher functional connectivity of the sensory-motor system was associated with poorer memory performance. Functional brain organization was more widely disrupted in early-onset AD when compared to late-onset AD. This could possibly explain different clinical profiles, although more research into the relationship of functional connectivity and cognitive performance is needed.

Early‐onset Alzheimer's disease: a global cross‐sectional analysis

Little is known about factors associated with early-onset Alzheimer's disease (EOAD), which occurs before 65 years of age. The identification of factors of EOAD might provide insights into Alzheimer's disease (AD) pathogenesis. Data from over 3000 subjects with AD from C-Path Online Data Repository were used to compare demographics, comorbidities and prescribed medications between EOAD and late-onset Alzheimer's disease (LOAD). The generalized estimating equations binomial model was used to identify factors associated with EOAD, allowing for within-trials correlation (multiple patients from one single trial). Despite the similar proportions in White, Asian and Black between EOAD and LOAD, a significantly higher proportion of EOAD population was from other races: Native American Indian, Alaskan and Hawaiian and other minorities (including Hispanics) (P < 0.0001); and were more likely to have anxiety or depression (P < 0.0001). A high proportion of the LOAD population reported a history of AD from any relative (70% vs. 58%); atrial fibrillation, hypertension, heart disease, stroke, hypercholesterolaemia and hypothyroidism were over-represented in LOAD (P < 0.01). LOAD patients used more risperidone and donepezil (P < 0.01). The multivariable model results showed that, compared with LOAD, EOAD patients were more frequently from other races and were more likely to have anxiety or depression, with less hypertension, stroke and atrial fibrillation. Early-onset Alzheimer's disease is found more frequently in Native American Indians, Alaskans, Hawaiians and other minorities, including Hispanics; patients with EOAD have more anxiety or depression. EOAD occurs independently of hypertension, stroke and atrial fibrillation.

Cognitive decline in patients with Alzheimer's disease and its related factors in a memory clinic setting, Shanghai, China.

ObjectivesProgressive cognitive decline is a characteristic hallmark of AD. It is important to identify prognostic markers to improve patient care and long-term planning. We aimed to identify the characteristics of disease progression in AD patients, focusing on cognitive decline and its related factors.MethodsClinically diagnosed AD patients in a memory clinic were followed. The mini–mental state examination (MMSE) and a battery of other neuropsychological tests were performed to assess the rate of cognitive decline and to analyze the related factors.ResultsA total of 165 AD patients were analyzed for cognitive changes. The MMSE scores declined at a rate of 1.52 points per year. Most neuropsychological test scores deteriorated significantly over time. Younger and early-onset AD patients deteriorated more rapidly than older and late-onset patients in global cognition and executive function. Men declined faster in memory but slower in attention than women. Higher education was associated with more rapid deterioration in visuo-spatial ability. Family history, hypertension and cerebral vascular disease were also associated with disease progression.ConclusionAttention, executive and visuo-spatial functions deteriorate at faster rates than other cognitive functions in AD patients. Age and age at onset were the main factors that associated with deterioration.

Altered proteolysis in fibroblasts of Alzheimer patients with predictive implications for subjects at risk of disease.

There is great interest in developing reliable biomarkers to support antemortem diagnosis of late-onset Alzheimer's disease (AD). Early prediction and diagnosis of AD might be improved by the detection of a proteolytic dysfunction in extracts from cultured AD fibroblasts, producing altered isoelectrophoretic forms of the enzyme transketolase (TK-alkaline bands). The TK profile and apolipoprotein E (APOE) genotype were examined in fibroblasts from 36 clinically diagnosed probable late-onset sporadic AD patients and 38 of their asymptomatic relatives, 29 elderly healthy individuals, 12 neurological non-AD patients, and 5 early-onset AD patients. TK alterations occurred in (i) several probable AD patients regardless of age-of-onset and severity of disease; (ii) all early-onset AD patients and APOE ε4/4 carriers; and (iii) nearly half of asymptomatic AD relatives. Normal subjects and non-AD patients were all negative. Notably, culture conditions promoting TK alterations were also effective in increasing active BACE1 levels. Overall, the TK assay might represent a low-cost laboratory tool useful for supporting AD differential diagnosis and identifying asymptomatic subjects who are at greater risk of AD and who should enter a follow-up study. Moreover, the cultured fibroblasts were confirmed as a useful in vitro model for further studies on the pathogenetic process of AD.

Differences in Anxiety Among Patients With Early- Versus Late-Onset Alzheimer’s Disease

The authors sought to evaluate the incidence and correlates of anxiety in early-onset Alzheimer's disease (EOAD) versus the more typical late-onset AD (LOAD). A group of 23 EOAD and 22 LOAD patients were compared by the Neuropsychiatric Inventory Anxiety subscale. Demographic and disease-related relationships with anxiety were evaluated, as well as types of anxiety symptoms that were endorsed. EOAD patients had significantly more anxiety symptoms than LOAD patients. Among those with EOAD, anxiety was associated with male gender, higher Mini-Mental State Exam score, and separation from caregivers. Among LOAD patients, anxiety was associated with psychotic and activating psychiatric symptoms. These results have implications for the management and alleviation of anxiety in AD.

Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer’s Disease Patients Alter Calcium Homeostasis

Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer’s disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca2+-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca2+ permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca2+ influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca2+ influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.

Genetic Association between Neurotrophin-3 Polymorphisms and Alzheimer's Disease in Japanese Patients

Background: Some polymorphisms of the neurotrophin family have previously been investigated as candidate genes for Alzheimer's disease (AD). In the present study, we examined whether neurotrophin-3 (NTF-3) polymorphisms are genetic risk factors in patients with AD. Methods: From a sample of 507 subjects, we recruited 248 age-matched subjects divided into 2 groups: AD patients (n = 143) and normal controls (NCs) (n = 105). We identified 3 representative NTF-3 single nucleotide polymorphisms (SNPs): rs6332, rs6489630, and rs4930767. Next, we statistically compared the allele frequencies of each SNP between the AD and NC groups in the early-onset (<65 years) cases under a more limited age-matched condition. Results: We found a significant association between rs6332 and the total group of AD patients (p = 0.013) and significant associations between both rs6332 (p = 0.033) and rs6489630 (p = 0.035) and early-onset AD patients. Conclusion: These results suggest that NTF-3 SNPs may not only be associated with AD itself, but also with early-onset AD in Japanese patients, assuming that the NTF-3 gene may have age-related effects on neurodegenerative diseases.

The diagnostic utility of EEG in early-onset dementia: a systematic review of the literature with narrative analysis

Early-onset dementia (EOD) is characterized by functionally impairing deterioration in memory, language, personality or visuospatial skills emerging under the age of 65. Cerebral functioning can be assessed by visual electroencephalography (EEG) interpretation. The aim of this systematic review is to evaluate the diagnostic utility of visual EEG in EOD focusing on Alzheimer's disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Medline, Embase, Scopus, Web of Knowledge, and Google Scholar were systematically searched for studies where EEGs were included in the diagnostic evaluation of patients with dementia under the age of 65. Each paper was quality assessed and the results grouped according to dementia cause with a narrative summary. 4,157 papers were screened, 12 studies met the eligibility criteria with a total of 965 patients. An abnormal EEG was common to all causes of EOD. EEG abnormalities are more severe in early-onset AD patients. EEG severity grade is independent of disease duration. Slow wave activity is common to all dementias, but is most prominent in DLB. Frontal intermittent rhythmic delta activity could be considered as supportive for the diagnosis of DLB as can a Grand Total EEG score of over 9.5. EEG is usually normal in FTD. Focal changes can be seen in advanced VAD. Studies employed small patient groups, varying diagnostic criteria, and only a minority of patient diagnoses was pathologically confirmed. EEG may be useful as an adjunct in the diagnosis of DLB and AD. Further prospective well-powered studies are required to investigate diagnostic utility more robustly.

Widespread disruption of functional brain organization in early-onset Alzheimer's disease patients

Widespread disruption of functional brain organization in early-onset Alzheimer's disease patients

Swedish mutant APP suppresses osteoblast differentiation and causes osteoporotic deficit, which are ameliorated by N-acetyl-L-cysteine

Reduced bone mineral density and hip fracture are frequently observed in patients with Alzheimer's disease (AD). However, mechanisms underlying their association remain poorly understood. Amyloid precursor protein (APP) is a transmembrane protein that is ubiquitously expressed in bone marrow stromal cells (BMSCs), osteoblasts (OBs), macrophages (BMMs), and osteoclasts (OCs). Mutations in the APP gene identified in early-onset AD patients are believed to cause AD. But little is known about APP's role in bone remodeling. Here, we present evidence for Swedish mutant APP (APPswe) in suppression of OB differentiation and function in culture and in mouse. APP expression in BMSCs increases during aging. Ubiquitous expression of APPswe in young adult Tg2576 transgenic mice (under the control of a prion promoter) recaptured skeletal "aging-like" deficits, including decreased OB genesis and bone formation, increased adipogenesis and bone marrow fat, and enhanced OC genesis and bone resorption. Remarkably, selective expression of APPswe in mature OB-lineage cells in TgAPPswe-Ocn mice (under the control of osteocalcin [Ocn] promoter-driven Cre) also decreased OB genesis and increased OC formation, resulting in a trabecular bone loss. These results thus suggest a cell-autonomous role for APPswe in suppressing OB formation and function, but a nonautonomous effect on OC genesis. Notably, increased adipogenesis and elevated bone marrow fat were detected in young adult Tg2576 mice, but not in TgAPPswe-Ocn mice, implying that APPswe in BMSCs and/or multicell types in bone marrow promotes bone marrow adipogenesis. Intriguingly, the skeletal aging-like deficits in young adult Tg2576 mice were prevented by treatment with N-acetyl-L-cysteine (NAC), an antioxidant, suggesting that reactive oxygen species (ROS) may underlie APPswe-induced osteoporotic deficits. Taken together, these results demonstrate a role for APPswe in suppressing OB differentiation and bone formation, implicate APPswe as a detrimental factor for AD-associated osteoporotic deficit, and reveal a potential clinical value of NAC in the treatment of osteoporotic deficits. © 2013 American Society for Bone and Mineral Research.

White matter microstructural damage in Alzheimer's disease at different ages of onset

White matter (WM) microstructural damage and its relationship with cortical abnormalities were explored in early-onset Alzheimer's disease (EOAD) compared with late-onset AD (LOAD) patients. Structural and diffusion tensor magnetic resonance images were obtained from 22 EOAD patients, 35 LOAD patients, and 40 healthy controls. Patterns of WM microstructural damage and cortical atrophy, as well as their relationships, were assessed using tract-based spatial statistics, tractography and voxel-based morphometry. Compared with LOAD, EOAD patients had a more severe and distributed pattern of WM microstructural damage, in particular in the posterior fibers of cingulum and corpus callosum. In both groups with Alzheimer's disease, but especially in LOAD patients, correlations between cingulum and corpus callosum fractional anisotropy and parietal, temporal, and frontal cortical volumes were found. In conclusion, WM microstructural damage is more severe in EOAD compared with LOAD patients. Such damage follows different patterns of topographical distribution in the 2 patient groups.

Different patterns of gray matter atrophy in early- and late-onset Alzheimer’s disease

We assessed patterns of gray matter atrophy according to-age-at-onset in a large sample of 215 Alzheimer’s disease (AD) patients and 129 control subjects with voxel-based morphometry using 3-Tesla 3D T1-weighted magnetic resonance imaging. Local gray matter amounts were compared between late- and early-onset AD patients and older and younger control subjects, taking into account the effect of apolipoprotein E. Additionally, combined effects of age and diagnosis on volumes of hippocampus and precuneus were assessed. Compared with age-matched control subjects, late-onset AD patients exhibited atrophy of the hippocampus, right temporal lobe, and cerebellum, whereas early-onset AD patients showed gray matter atrophy in hippocampus, temporal lobes, precuneus, cingulate gyrus, and inferior frontal cortex. Direct comparisons between late- and early-onset AD patients revealed more pronounced atrophy of precuneus in early-onset AD patients and more severe atrophy in medial temporal lobe in late-onset AD patients. Age and diagnosis independently affected the hippocampus; moreover, the interaction between age and diagnosis showed that precuneus atrophy was most prominent in early-onset AD patients. Our results suggest that patterns of atrophy might vary in the spectrum of AD.

Ecological Evaluation of Executive Functions in Mild Cognitive Impairment and Alzheimer Disease

Executive deficits characterize the initial phases of Alzheimer disease (AD) and mild cognitive impairment (MCI), and are clinically correlated to neuropsychiatric symptoms and functional loss. The aim of this study was to determine the accuracy of the Behavioral Assessment of the Dysexecutive Syndrome test (BADS) for comparing the performance between patients with amnestic MCI (aMCI) and mild AD and for detecting early signs of alterations in executive functions. BADS was performed on 60 healthy controls, 20 patients with aMCI, and 40 mild probable AD patients (20 early-onset AD patients and 20 late-onset AD patients). Significant differences in battery performance were found among groups on the BADS subtests Rule Shift Cards, Program of Action, Zoo Map, 6 Modified Elements, and 3 total scores. Early changes in executive functions were detected in both AD (irrespective of age of onset) and aMCI patients. The BADS proved useful for differentiating between these patient groups. Our results confirmed the presence of early alterations in executive functions among aMCI and mild AD patients.

Definite Behavioral Variant of Frontotemporal Dementia with C9ORF72 Expansions Despite Positive Alzheimer's Disease Cerebrospinal Fluid Biomarkers

Hexanucleotide expansion repeats in the C9ORF72 gene are a major cause of familial and, to a lesser extent, sporadic frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and FTLD-ALS. To examine whether C9ORF72 expansions could be involved in early-onset Alzheimer's disease (EOAD), we genotyped the hexanucleotide repeat region in a large cohort of 114 EOAD patients who all had positive AD cerebrospinal fluid (CSF) biomarkers. We found hexanucleotide expansion repeats of the C9ORF72 gene in 3 out of 114 patients (2.6%). We raise several hypotheses to explain our results and discuss the current status of AD CSF biomarkers in the dementia diagnostic algorithm.

PSEN1 Mutation Carriers Present Lower Cerebrospinal Fluid Amyoid-β42 Levels than Sporadic Early-Onset Alzheimer's Disease Patients but no Differences in Neuronal Injury Biomarkers

Most cases of early-onset Alzheimer's disease (EOAD) are sporadic. A minority of EOAD are caused by specific genetic defects in PSEN1, PSEN2, or AβPP genes. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarker comparisons between sporadic and monogenic EOAD are practically inexistent. CSF and MRI data from 14 amnestic-onset sporadic EOAD (sEOAD) subjects were compared with data from 8 symptomatic PSEN1 mutation carriers (PSEN1) and 14 age-matched cognitively-preserved controls. CSF concentrations of amyloid-β (Aβ)(42), total tau (t-tau), and phosphorylated tau (p-tau) were determined. Cortical thickness (CTh) and grey matter loss were compared between groups and correlated with CSF biomarkers. PSEN1 had significantly lower CSF Aβ(42) levels compared to sEOAD (mean 244.8 pg/ml versus 381.4 pg/ml; p = 0.006), but no differences in t-tau or p-tau. Both sEOAD and PSEN1 showed widespread CTh loss in AD target areas when compared with controls. No differences were found in the direct comparison between sEOAD and PSEN1 CTh after adjusting for age and Mini-Mental Status Examination scores. Neither was a correlation found between Aβ(42) levels and CTh. CTh in the left superior parietal and caudal middle frontal areas was negatively correlated with t-tau values. In conclusion, PSEN1 had lower Aβ(42) CSF levels compared with sEOAD, suggesting a greater cerebral deposition of Aβ(42). These differences in Aβ(42) deposition were not significantly reflected in the brain structure, and CTh was only correlated with total tau. The lack of significant differences in relation to t-tau and p-tau levels and to the severity of CTh or grey matter loss suggests a similar level of neuronal injury despite higher Aβ(42) load in PSEN1.