Early-onset Alzheimer's Disease Group Research Articles

Socioemotional Dysfunction From Temporal Lobe Involvement in Frontotemporal Dementia: A Preliminary Report.

Socioemotional changes, rather than cognitive impairments, are the feature that defines behavioral variant frontotemporal dementia (bvFTD). Investigators have attributed the socioemotional changes in bvFTD and other dementias to frontal lobe dysfunction; however, recent work implies a further contribution from right anterior temporal disease. The authors evaluated relationships between regional brain atrophy and socioemotional changes in both bvFTD and early-onset Alzheimer's disease (EOAD). This study explored the neuroanatomical correlations of performance on the Socioemotional Dysfunction Scale (SDS), an instrument previously shown to document socioemotional changes in bvFTD, among 13 patients with bvFTD not preselected for anterior temporal involvement and 16 age-matched patients with early-onset Alzheimer's disease (EOAD). SDS scores were correlated with volumes of regions of interest assessed with tensor-based morphometric analysis of MRI images. As expected, the bvFTD group had significantly higher SDS scores overall and smaller frontal regions compared with the EOAD group, which in turn had smaller volumes in temporoparietal regions. SDS scores significantly correlated with lateral anterior temporal lobe (ATL) atrophy, and a regression analysis that controlled for diagnosis indicated that SDS scores predicted lateral ATL volume. Within the bvFTD group, higher SDS scores were associated with smaller lateral and right ATL regions, as well as a smaller orbitofrontal cortex. Within the EOAD group, higher SDS scores were associated with a smaller right parietal cortex. This study confirms that, in addition to orbitofrontal disease, there is a prominent right and lateral ATL origin of socioemotional changes in bvFTD and further suggests that right parietal involvement contributes to socioemotional changes in EOAD.

White matter hyperintensities are higher among early-onset Alzheimer's disease participants than their cognitively normal and early-onset nonAD peers: Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study. We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study.

One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

Characterizing Early-Onset Alzheimer Disease Using Multiprobe PET/MRI: An AT(N) Framework-Based Study.

Early-onset Alzheimer disease (EOAD) is rare, highly heterogeneous, and associated with poor prognosis. This AT(N) Framework-based study aimed to compare multiprobe PET/MRI findings between EOAD and late-onset Alzheimer disease (LOAD) patients and explore potential imaging biomarkers for characterizing EOAD. Patients with AD who underwent PET/MRI in our PET center were retrospectively reviewed and grouped according to the age at disease onset: EOAD, younger than 60 years; and LOAD, 60 years or older. Clinical characteristics were recorded. All study patients had positive β-amyloid PET imaging; some patients also underwent 18 F-FDG and 18 F-florzolotau PET. Imaging of the EOAD and LOAD groups was compared using region-of-interest and voxel-based analysis. Correlation of onset age and regional SUV ratios were also evaluated. One hundred thirty-three patients were analyzed (75 EOAD and 58 LOAD patients). Sex ( P = 0.515) and education ( P = 0.412) did not significantly differ between groups. Mini-Mental State Examination score was significantly lower in the EOAD group (14.32 ± 6.74 vs 18.67 ± 7.20, P = 0.004). β-Amyloid deposition did not significantly differ between groups. Glucose metabolism in the frontal, parietal, precuneus, temporal, occipital lobe, and supramarginal and angular gyri was significantly lower in the EOAD group (n = 49) than in the LOAD group (n = 44). In voxel-based morphometry analysis, right posterior cingulate/precuneus atrophy was more obvious in the EOAD ( P < 0.001), although no voxel survived family-wise error correction. Tau deposition in the precuneus, parietal lobe, and angular, supramarginal, and right middle frontal gyri was significantly higher in the EOAD group (n = 18) than in the LOAD group (n = 13). Multiprobe PET/MRI showed that tau burden and neuronal damage are more severe in EOAD than in LOAD. Multiprobe PET/MRI may be useful to assess the pathologic characteristics of EOAD.

Regional Comparison of Imaging Biomarkers in the Striatum between Early- and Late-onset Alzheimer's Disease.

Striatal changes in the pathogenesis of Alzheimer's disease (AD) is not fully understood yet. We compared structural and functional image differences in the striatum between patients with early onset AD (EOAD) and late onset AD (LOAD) to investigate whether EOAD harbors autosomal dominant AD like imaging findings. The clinical, neuropsychological and neuroimaging biomarkers of 77 probable AD patients and 107 elderly subjects with normal cognition (NC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI)-2 dataset were analyzed. Enrolled each subject completed a 3-Tesla MRI, baseline 18F-FDG-PET, and baseline 18F-AV-45 (Florbetapir) amyloid PET studies. AD patients were divided into two groups based on the onset age of clinical symptoms (EOAD <65 yrs; LOAD ≥65 yrs). A standardized uptake value ratio of the striatum and subcortical structures was obtained from both amyloid and FDG-PET scans. Structural MR imaging analysis was conducted using a parametric boundary description protocol, SPHARM-PDM. Of the 77 AD patients, 18 were EOAD and 59 were LOAD. Except for age of symptom onset, there were no statistically significant differences between the groups in demographics and detailed neuropsychological test results. 18F-AV-45 amyloid PET showed marked β-amyloid accumulation in the bilateral caudate nucleus and left pallidum in the EOAD group. Intriguingly, the caudate nucleus and putamen showed maintained glucose metabolism in the EOAD group compared to the LOAD group. Our image findings in the striatum of EOAD patients suggest that sporadic EOAD may share some pathophysiological changes noted in autosomal dominant AD.

Hyperconnectivity matters in early-onset Alzheimer's disease: a resting-state EEG connectivity study

ObjectivesThe aim of this study was to differentiate individuals with early-onset Alzheimer's disease (EOAD) and identify differences of functional connectivity in resting-state EEG between individuals with EOAD and late-onset AD (LOAD) in comparison with both healthy young and elderly individuals. MethodsForty EOAD and 56 LOAD patients were included along with 51 demographically matched young, and 54 elderly healthy individuals as controls to the EOAD and LOAD groups. Four minutes of resting-state EEG were recorded during the eyes-closed condition. The absolute value of imaginary coherence (ICoh) was measured for connectivity. The maximum values of ICoh were measured at delta (0.5-3.5 Hz), theta (4-7.5Hz), alpha (8-13 Hz), alpha-1 (8-10 Hz), alpha-2 (10.5-13 Hz), beta (13-30 Hz), beta-1 (13-20 Hz), and beta-2 (20.5-30 Hz) frequency bands. ResultsIndividuals with EOAD showed higher coherence values in all frequency bands than LOAD patients. Compared to young healthy controls (YHC), EOAD had increased ICoh values in theta and beta-2 bands, whereas LOAD had lower ICoh values in the alpha-1 band than elderly healthy controls (EHC). Lastly, patients with EOAD demonstrated negative moderate correlations between language domains and beta-1 ICoh values. ConclusionTo the authors’ knowledge, this is the first study evaluating coherence alterations among early-and late-onset AD patients and the diagnostic value of coherence measures. It was suggested that EOAD patients had more severe pathological changes compared with LOAD.

Neuropsychiatric symptoms in early onset Alzheimer's disease and frontotemporal dementia

AbstractBackgroundHaving in mind a significant percentage of atypical presentations at disease onset (behavioral symptoms, depression, psychotic symptoms or non‐cognitive cognitive deficits), understanding clinical heterogeneity of early onset Alzheimer's disease (EOAD) and frontotemporal dementia (EOFTD) can improve early diagnosis and differentiation between these clinical entities.Our objective was to investigate the heterogeneity of neuropsychiatric symptoms (NPS) in EOAD and EOFTD spectrum.MethodTwo hundred and seven consecutive patients with EOAD and EOFTD spectrum, diagnosed according to the current clinical criteria, were recruited from the Neurology Clinic, Clinical Centre of Serbia. Sociodemographic and clinical characteristics were evaluated using a pre‐designed semi‐structured questionnaire while neuropsychiatric symptoms (NPS) were evaluated using Neuropsychiatric Inventory (NPI).ResultEOAD and EOFTD patients did not differ in age, age at disease onset, duration of the disease, gender and education. In comparison to EOAD, patients in the EOFTD spectrum expressed agitation, euphoria, apathy, disinhibition, irritability, aberrant motor behavior and dietary changes more frequently. EOFTD behavioral variant patients expressed apathy, aberrant motor behavior and disinhibition more often than patients with PPA, while in PPA anxiety was represented. In EOAD group total NPI score correlated with clinical dementia rating scale score. In the advanced stages of dementia, EOAD patients expressed agitation and irritability more frequently than at disease onset, while in advanced EOFTD agitation and aberrant motor behavior were more frequent than in the earlier stages of the disease. Amnestic and non‐amnestic presentation of EOAD did not differ in frequency on NPSConclusionNPS are a hallmark of behavioral variant of EOFTD and later stages of EOAD.

Presynaptic dopaminergic function in early-onset Alzheimer's disease: an FP-CIT image study

We aimed to investigate whether amyloid-β (Aβ) positive early-onset Alzheimer's disease (EOAD) patients have presynaptic dopaminergic deficits on in vivo 18F-FP-CIT PET imaging. We enrolled 34 EOAD patients and 9 cognitively normal controls (NC), all of whom underwent 18F-florbetaben and 18F-FP-CIT PET at Samsung Medical Center. We assessed motor symptoms using Unified Parkinson's Disease Rating Scale (UPDRS) and divided the EOAD patients into 2 groups using a UPDRS cutoff of 10. We compared regional florbetaben and FP-CIT uptake across the NC and the 2 EOAD groups with lower and higher UPDRS and investigated the associations between regional florbetaben or FP-CIT uptake and UPDRS in EOAD patients. Among the 30 EOAD patients who were Aβ positive on florbetaben PET, the higher UPDRS (>10) group (n = 9) had a longer disease duration (7.2 ± 3.3 vs. 4.1 ± 1.8, p = 0.002), and had a tendency to have lower Mini-Mental State Examination (9.6 ± 7.9 vs. 15.0 ± 6.0, p = 0.052) than the lower UPDRS (≤10) group (n = 21). Across the NC and the 2 EOAD groups, there were no significant differences in FP-CIT uptake in caudate (p = 0.122) and putamen (p = 0.685) or florbetaben uptake in midbrain (p = 0.890). Finally, regression analyses showed that UPDRS was not associated with FP-CIT uptake in caudate (p = 0.913) or putamen (p = 0.407), or with florbetaben PET uptake in caudate (p = 0.553), putamen (p = 0.617), midbrain (p = 0.843), or global cortex (p = 0.658). This study showed that parkinsonian signs in EOAD patients may be related with mechanisms other than presynaptic dopaminergic deficit. Our finding is clinically important because it suggests that L-dopa treatment in EOAD with parkinsonian signs may not improve motor symptoms.

Three-year changes of cortical 18F-FDG in amnestic vs. non-amnestic sporadic early-onset Alzheimer's disease.

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. Eighty-two participants meeting criteria for early-onset (< 65years) 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 ± 1.23years. All of the participants underwent a work-up at baseline and every year during the follow-up period, which includes clinical examination, neuropsychological testing, genotyping, cerebrospinal fluid biomarker assays, and structural MRI and 18F-FDG PET. Vertex-wise partial volume-corrected glucose metabolic maps across the entire cortical surface were generated and longitudinally assessed together with the neuropsychological scores using linear mixed-effects modeling as a function of amnestic and non-amnestic sporadic forms of early-onset Alzheimer's disease. Similar evolution patterns of glucose metabolic decline between amnestic and non-amnestic forms were observed in widespread neocortical cortices. However, only non-amnestic forms appeared to have a greater reduction of glucose metabolism in lateral orbitofrontal and bilateral medial temporal cortices associated with more severe declines of neuropsychological performance compared with amnestic forms. Furthermore, results suggest that glucose metabolic decline in amnestic forms would progress along an anterior-to-posterior axis, whereas glucose metabolic decline in non-amnestic forms would progress along a posterior-to-anterior axis. We found differences in spatial distribution and temporal trajectory of glucose metabolic decline between amnestic and non-amnestic early-onset Alzheimer's disease groups, suggesting that one might want to consider treating the two forms of the disease as two separate entities.

Voxel-Based Acetylcholinesterase PET Study in Early and Late Onset Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset. The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age. 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value <0.05 on cluster-level and cluster extent over 30 voxels. Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart. Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.

Identification of rare RTN3 variants in Alzheimer's disease in Han Chinese.

Reticulon 3 (RTN3) is a neuronally-expressed reticulon family protein that was previously shown to negatively regulate BACE1, a protease that is required for the generation of β-amyloid peptides (Aβ) from amyloid precursor protein. Despite biochemical and morphological evidence that supports a role of RTN3 in the formation of neuritic amyloid plaques, no systematic analyses of RTN3 mutations in patients with Alzheimer's disease (AD) have yet been reported. RTN3 were targeted sequenced in 154 sporadic early-onset and 285 late-onset AD patients. Luciferase reporter assay and kymographs were performed to analysis the expression of RNT3 and BACE1-RFP particle mobility on cells transfected with wild-type or variants RTN3 constructs. We identified heterozygous variants such as c.-8G>T, c.17C>A, c.42C>T, and c.116C>T from patients in the early-onset AD group and c.-8G>T, c.17C>A, from patients in the late-onset AD group. Such variants of RTN3 were not observed in control individuals. Further biochemical studies show that the RTN3 c.-8G>T variant in the 5'-untranslated region appears to cause reduced expression of RTN3. The RTN3 c.116 C>T variant causes a change of codon T39 to M39 (T39M). Overexpression of RTN3 T39M in cultured neurons led to impaired axonal transport of BACE1. The variants found in this study are likely genetic modifiers for RTN3-mediated formation of neuritic plaques in AD.

Medial-Vowel Writing Difficulty in Korean Syllabic Writing: A Characteristic Sign of Alzheimer's Disease.

Background and PurposeKorean-speaking patients with a brain injury may show agraphia that differs from that of English-speaking patients due to the unique features of Hangul syllabic writing. Each grapheme in Hangul must be arranged from left to right and/or top to bottom within a square space to form a syllable, which requires greater visuospatial abilities than when writing the letters constituting an alphabetic writing system. Among the Hangul grapheme positions within a syllable, the position of a vowel is important because it determines the writing direction and the whole configuration in Korean syllabic writing. Due to the visuospatial characteristics of the Hangul vowel, individuals with early-onset Alzheimer's disease (EOAD) may experiences differences between the difficulties of writing Hangul vowels and consonants due to prominent visuospatial dysfunctions caused by parietal lesions.MethodsEighteen patients with EOAD and 18 age-and-education-matched healthy adults participated in this study. The participants were requested to listen to and write 30 monosyllabic characters that consisted of an initial consonant, medial vowel, and final consonant with a one-to-one phoneme-to-grapheme correspondence. We measured the writing time for each grapheme, the pause time between writing the initial consonant and the medial vowel (P1), and the pause time between writing the medial vowel and the final consonant (P2).ResultsAll grapheme writing and pause times were significantly longer in the EOAD group than in the controls. P1 was also significantly longer than P2 in the EOAD group.ConclusionsPatients with EOAD might require a higher judgment ability and longer processing time for determining the visuospatial grapheme position before writing medial vowels. This finding suggests that a longer pause time before writing medial vowels is an early marker of visuospatial dysfunction in patients with EOAD.

Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer’s disease

Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease.

Alzheimer's disease: The influence of age on clinical heterogeneity through the human brain connectome

IntroductionOne major factor that influences the heterogeneity of Alzheimer's disease (AD) is age: younger AD patients more frequently exhibit atypical forms of AD. We propose that this age-related heterogeneity can be understood better by considering age-related differences in atrophy in the context of large-scale brain networks subserving cognitive functions that contribute to memory. MethodsWe examined data from 75 patients with mild AD dementia from Alzheimer's Disease Neuroimaging Initiative. These individuals were chosen because they have cerebrospinal fluid amyloid and p-tau levels in the range suggesting the presence of AD neuropathology, and because they were either younger than age 65 years early-onset AD (EOAD) or age 80 years or older late-onset AD (LOAD). ResultsIn the EOAD group, the most prominent atrophy was present in the posterior cingulate cortex, whereas in the LOAD group, atrophy was most prominent in the medial temporal lobe. Structural covariance analysis showed that the magnitude of atrophy in these epicenters is strongly correlated with a distributed atrophy pattern similar to distinct intrinsic connectivity networks in the healthy brain. An examination of memory performance in EOAD dementia versus LOAD dementia demonstrated relatively more prominent impairment in encoding in the EOAD group than in the LOAD group, with similar performance in memory storage in LOAD and EOAD but greater impairment in semantic memory in LOAD than in EOAD. DiscussionThe observations provide novel insights about age as a major factor contributing to the heterogeneity in the topography of AD-related cortical atrophy.

A Comparison of the Behavioral and Psychological Symptoms of Dementia (BPSD) in Early-Onset and Late-Onset Alzheimer's Disease - A Study from South East Asia (Kashmir, India).

BackgroundA gradual increase in the longevity due to advancement of treatment modalities and a subsequent surge in elderly population in India have led to a growing curiosity in the geriatric age group with Alzheimer’s disease (AD). Behavioral and psychological symptoms of dementia (BPSD) represent epiphenomena of AD. However, no comprehensive study has been carried out in South East Asia (Kashmir, India), to assess the behavioral and psychological symptoms in subtypes of AD.ObjectivesThe purpose of this study was to assess BPSD in early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD).Material and MethodsThe study was conducted in the Memory clinic of the postgraduate department of psychiatry, Government Medical College, Kashmir, India from January 2012 to March 2014. The diagnosis of AD patients was done according to NINCDS-ADRDA criteria. A total of 80 patients of AD were screened (40 with age of onset less than 65, and 40 with age of onset greater than 64). Neuropsychiatric inventory (NPI) was the instrument used for evaluating symptoms of BPSD. The data was analyzed using paired t-test.ResultsThe mean age of presentation of EOAD and LOAD was 63.10 years and 84.28 years, respectively, and the difference between the two was found to be statistically significant. The LOAD group had significantly higher symptom severity for delusions, agitation, anxiety, disinhibition, and nighttime behavioral disturbances (NBD) than the EOAD group (p ≤.0001).ConclusionThe behavioral and psychological symptoms are significantly severe in late onset subtype compared to the early onset subtype of Alzheimer’s disease in the Kashmiri (Indian) population.

SNCA Gene Polymorphism may Contribute to an Increased Risk of Alzheimer's Disease.

The purpose of this study is to elucidate the association between α-synuclein (SNCA) polymorphisms and the risk of Alzheimer's disease (AD). The PCR-RFLP was applied to detect SNCA gene rs6532190, rs3775430, and rs10516846 polymorphisms in 98 AD patients and 105 healthy elderly. The GG frequency of rs10516846 was evidently increased in AD group than control group (P < 0.05). There was a significant difference in SNCA level between the AD and control groups (P < 0.01). In the AD group, the SNCA level in cerebrospinal fluid of GG (rs10516846) carriers was increased as compared with AA carriers (P < 0.05). The GG (rs10516846) frequency of the early-onset AD group is significantly higher than that of the late-onset AD group (P < 0.05). The frequency of rs3775430 GG was lower in the early-onset group than that in the late-onset group (0% vs. 16.7%). The SNCA level in cerebrospinal fluid of GG (rs10516846) carriers in the early-onset AD group is higher than that of AA carriers (P < 0.05). SNCA gene polymorphism may be associated with an increased risk of AD and GG genotype of rs10516846 and elevated SNCA level in CSF may increase the risk of early-onset AD.

Cerebrospinal fluid biomarkers for Alzheimer's disease: the role of apolipoprotein E genotype, age, and sex.

IntroductionCerebrospinal fluid (CSF) biomarkers improve the diagnostic accuracy for Alzheimer’s disease (AD), even at the predementia stage of the disease. The ε4-allele of apolipoprotein E (ApoE ε4), female sex, and older age are well-known risk factors for AD. It is unclear how these risk factors affect the CSF biomarkers in patients with AD.AimThe objective of this study was to investigate the associations of ApoE ε4, sex, and age with CSF biomarker levels in a unicenter sample of patients with AD that includes a high proportion of patients with early-onset AD (EOAD).MethodsThe CSF levels of amyloid-β 1-42 (Aβ1-42) and total-tau of 117 subjects with mild to moderate AD (55 late-onset AD and 62 EOAD) were assessed. All subjects underwent ApoE genotyping, clinical evaluation, comprehensive neuropsychological assessments, and neuroimaging. Associations between CSF biomarker levels, ApoE ε4 allele frequency, age, and sex were evaluated.ResultsIn the whole patient sample and in the late-onset AD subgroup ε4 homozygous subjects had significantly lower CSF Aβ1-42 levels compared with ε4 heterozygous subjects and ε4 noncarriers. This association was not detected in the EOAD group. Age group, sex, and severity of cognitive decline did not have a significant impact on CSF Aβ1-42 levels. No significant associations were found between ApoE ε4 allele frequency and CSF total-tau levels.ConclusionApoE ε4 allele is associated with a reduction of CSF Aβ1-42 levels. This result is consistent with the findings of several previous studies. In the subgroup of patients with EOAD this association was not replicated. Larger studies are necessary to further investigate associations between ApoE ε4 allele frequency and CSF biomarker levels in patients with EOAD.

Early-onset and late-onset Alzheimer's disease are associated with distinct patterns of memory impairment

The goal of this study was to investigate the specific patterns of memory breakdown in patients suffering from early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). Twenty EOAD patients, twenty LOAD patients, twenty matched younger controls, and twenty matched older controls participated in this study. All participants underwent a detailed neuropsychological assessment, an MRI scan, an FDG-PET scan, and AD patients had biomarkers as supporting evidence of both amyloïdopathy and neuronal injury. Results of the neuropsychological assessment showed that both EOAD and LOAD groups were impaired in the domains of memory, executive functions, language, praxis, and visuoconstructional abilities, when compared to their respective control groups. EOAD and LOAD groups, however, showed distinct patterns of memory impairment. Even though both groups were similarly affected on measures of episodic, short term and working memory, in contrast semantic memory was significantly more impaired in LOAD than in EOAD patients. The EOAD group was not more affected than the LOAD group in any memory domain. EOAD patients, however, showed significantly poorer performance in other cognitive domains including executive functions and visuoconstructional abilities. A more detailed analysis of the pattern of semantic memory performance among patient groups revealed that the LOAD was more profoundly impaired, in tasks of both spontaneous recall and semantic recognition. Voxel-Based Morphometry (VBM) analyses showed that impaired semantic performance in patients was associated with reduced gray matter volume in the anterior temporal lobe (ATL) region, while PET-FDG analyses revealed that poorer semantic performance was associated with greater hypometabolism in the left temporoparietal region, both areas reflecting key regions of the semantic network. Results of this study indicate that EOAD and LOAD patients present with distinct patterns of memory impairment, and that a genuine semantic impairment may represent one of the clinical hallmarks of LOAD.

Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants

Early-onset Alzheimer's disease (EOAD) accounts for 1%–2% of all Alzheimer's disease (AD) subjects, with large variation in the reported genetic contribution of known dementia genes. In this pilot study, we genetically characterized a German EOAD cohort (23 subjects) by whole-exome sequencing, capturing variants in all recognized AD and frontotemporal dementia genes. After variant filtering, we identified 7 events of altogether 6 different rare variants in 6 subjects, including 4 novel variants. Four of the 6 variants, observed in 5 different index subjects (5/23 = 22%), were considered to be possibly pathogenic. These included 2 presenilin 2 (PSEN2) variants (p.N141I—previously denoted as a Volga German variant, observed in 2 index subjects; and p.L238P), 1 amyloid precursor protein (p.I716M), and 1 presenilin 1 (ΔE9). Using a control exome data set of 96 ethnically matched neurodegenerative disease controls (Parkinson's disease), we identified only 1 variant (PSEN2 p.T18M) (1%), demonstrating a significantly higher mutational burden in the EOAD group (p > 0.0001). Our findings demonstrate a substantial frequency of variants in dementia genes in EOAD, including several seemingly “sporadic” subjects. This indicates that heritability in EOAD might be higher than assumed. The finding of 3 subjects carrying potential pathogenic PSEN2 variants suggests that, in specific populations PSEN2 variants might be as frequent as (or more frequent than) presenilin 1, for example, in German populations which are influenced by Volga German heritage. Variants in AD genes were also associated with rare phenotypes such as frontal AD or primary progressive aphasia, demonstrating the need to screen AD genes in frontotemporal dementia-like phenotypes.

Early-onset versus late-onset Alzheimer’s disease in tunisia

Previous reports stated globally that approximately 10% of Alzheimer's disease cases present before 65 years old. Whether early and late onset Alzheimer's were “one entity or two” still questionable. Our aim was to determine prevalence of Early Onset Alzheimer's Disease (EOAD) and to compare its demographic and genetic characteristics to Late-Onset Alzheimer's Disease (LOAD) in Tunisia. In an observational study, we retrospectively reviewed the database of 1065 AD patients followed at the memory clinic of Razi Hospital-Tunisia between July 2002 and August 2014 (12 years). Two groups (EOAD and LOAD) were defined upon patients symptoms arousal before or after the age of 65. Demographic, clinical and pedigree data of patients were compared. 209 EOAD (19.6%) and 775 LOAD (72.7%) were identified. Mean age at onset was 57.3 years for group 1 and 75.1 years in group 2. Sex ratio was respectively 0.97 and 0.7. Mean MMSE at diagnosis was higher in EOAD group (14/30 Vs 12/30 for LOAD) but also was the mean time for diagnosis (4.1 year Vs 3.4 year for LOAD). A positive familial history of dementia was found in 41.3% of EOAD versus 44.7% for LOAD. Familial AD was found in 36.8% of EOAD Vs in 40.3% LOAD with a majority of non mendelian heredity for both groups (72.8% Vs 73.4%). However AD inheritence was higher in group1 (=21.4% Vs 13.7%) while AR one in group 2 (5.6% Vs 12.7%). Prevalence of EOAD in Tunisia seems to be higher than expected. We did not found significant differences between the two groups despite in the sex-ratio. Further investigations should focus on symptomatic and gentic differences.