Late-onset Alzheimer's Disease Group Research Articles

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.

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.

Utility of the Neurobehavioral Cognitive Status Examination (COGNISTAT) in differentiating between depressive states in late-life depression and late-onset Alzheimer's disease: a preliminary study.

BackgroundIt is often difficult to differentiate between the depressive states seen in late-life depression and late-onset Alzheimer’ disease (AD) in the clinical setting.MethodsThirty-four outpatients were recruited, all fulfilling the criteria of aged 65 years or above, scores of 14 or more on the Hamilton depression rating scale (HAM-D), and 26 or less on the Mini-Mental State Examination (MMSE). At the initial visit, they were administered the Neurobehavioral Cognitive Status Examination (COGNISTAT). At 1 month, a diagnosis of either senile depression (n = 24) or Alzheimer’ disease (n = 10) was made.ResultsThe COGNISTAT revealed that the late-life depression group showed significantly higher scores in orientation and comprehension subtests compared with the AD group. At the study endpoint (6 months after treatment), MMSE detected significant improvements in the late-life depression group (n = 15), but no changes in the late-onset AD group (n = 7). Scores for memory, similarities, and judgment on the second COGNISTAT were significantly improved in the depressed group, whereas calculation scores deteriorated significantly in the AD group.ConclusionThe COGNISTAT could prove useful in differentiating late-life depression from late-onset AD, despite similar scores on MMSE.

Formulaic language in Alzheimer's disease

Background: Studies of productive language in Alzheimer's disease (AD) have focused on formal testing of syntax and semantics but have directed less attention to naturalistic discourse and formulaic language. Clinical observations suggest that individuals with AD retain the ability to produce formulaic language long after other cognitive abilities have deteriorated. Aims: This study quantifies production of formulaic expressions in the spontaneous speech of individuals with AD. Persons with early and late onset forms of the disease were compared. Methods & Procedures: Conversational language samples of individuals with early (n = 5) and late onset (n = 6) AD and healthy controls (n = 5) were analysed to determine whether formulaic language, as measured by the number of words in formulaic expressions, differs between groups. Outcomes & Results: Results indicate that individuals with AD, regardless of age of onset, used significantly more formulaic expressions than healthy controls. The early and late onset AD groups did not differ on formulaic language measures. Conclusions: These findings contribute to a dual process model of cerebral function, which proposes differing processing principles for formulaic and novel expressions. In this model, subcortical areas, which remain intact into late in the progression of Alzheimer's disease, play an important role in the production of formulaic language. Applications to clinical practice include identifying preserved formulaic language and providing informed counselling to patient and family.

Comparison of entorhinal cortex atrophy between early‐onset and late‐onset Alzheimer's disease using the VSRAD, a specific and sensitive voxel‐based morphometry

The most characteristic symptom of Alzheimer's disease (AD) is episodic memory impairment, which is closely associated with atrophy of the entorhinal cortex. Meanwhile, atypical symptoms are more frequent in early-onset AD than in late-onset AD, suggesting that the former subtype has less atrophy in the entorhinal cortex. Therefore, we investigated whether the degree of atrophy in the entorhinal cortex is different between the two subtypes of AD using the voxel-based specific regional analysis system for AD (VSRAD) targeting this region. The subjects consisted of 198 patients with AD. They were divided into two groups, that is, the early-onset AD group with the onset under age 65 years (n = 18) and the late-onset AD group with the onset at age 65 years or over (n = 180). The degree of atrophy in the entorhinal cortex was quantified by application of the VSRAD to magnetic resonance imaging data, and a Z-score >2 was defined as significant atrophy according to previous studies. The early-onset group had significantly lower Z-scores than the late-onset group (mean ± SD: 1.83 ± 0.92 vs 2.90 ± 1.40, p < 0.01). The analysis of covariance with possible confounding factors as covariates also showed that Z-scores were significantly lower in the early-onset group than in the late-onset group (p < 0.01). The proportion of patients with atrophy was significantly lower in the early-onset group than in the late-onset group (44% vs 71%, p < 0.05). The present study using the VSRAD suggests that early-onset AD shows less atrophy in the entorhinal cortex than late-onset AD.

Cognitive Differences between Early- and Late-Onset Alzheimer's Disease

Although neuropathologic studies showed that early-onset Alzheimer's disease (EAD) and "senile dementia" were indistinguishable, clinical studies suggested that EAD and late-onset Alzheimer's disease (LAD) were cognitively distinct. We sought to investigate whether EAD and LAD are cognitively different by comparing patients at the extremes of the ages of onset in order to maximize features that might separate them. We compared 44 men with EAD (age of onset less than 65 years) with 44 men with LAD (age of onset 84 years or older) on an intake cognitive screening examination on initial presentation. The EAD and LAD groups did not differ on dementia or most cognitive variables. Compared with EAD, the LAD group had worse verbal fluency and motor-executive functions. These differences disappeared when age differences were taken into account. We conclude that Alzheimer's disease is a clinically heterogeneous disorder whose manifestations can vary with age of onset. These differences indicate age-related vulnerabilities in this disease.

Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers

Beeri et al. describe an interesting postmortem study of Alzheimer disease (AD) patients and controls.1 We have also investigated coronary atherosclerosis, cardiovascular disease, and cardiac valve pathology in AD subjects and controls.2 The number of autopsies examined in our study was similar to that reported by Beeri et al. We analyzed general systemic autopsy data from 84 neuropathologically confirmed AD patients and from 60 non-AD control patients using a grade of membership model. All cases of AD were Braak stage IV, V, or VI. Consistent with reports from our center3 and others, the late onset AD groups had elevated APOE e4 frequency. However, the late onset AD groups also had frequent mitral and aortic valve dilation, evidence of ventricular pathology, or both. In contrast to the report by Beeri et al., we observed only modest systemic and coronary atherosclerosis in the …

Alpha 1-antichymotrypsin level in cerebrospinal fluid is closely associated with late onset Alzheimer's disease.

The levels of alpha 1-antichymotrypsin (ACT) in cerebrospinal fluid (CSF) from 66 sporadic Alzheimer's disease (AD) patients and 54 normal controls were measured by enzyme immunoassay and compared. There was no correlation (r = 0.259, n = 54) between the ACT level and normal aging. The levels of ACT were significantly higher in the total AD group (p < 0.01) than in the normal control group. Dividing AD patients into early onset AD (n = 27) and late onset AD groups (n = 39), the mean level of CSF ACT in the late onset AD group was significantly higher than that in the normal control group (p < 0.001) and that in the early onset AD group (p < 0.01). Thus, the level of ACT in CSF is closely associated with late onset AD.

AMYLOID β PROTEIN AND α 1-ANTICHYMOTRYPSIN IN CEREBROSPINAL FLUID AS POSSIBLE BIOCHEMICAL MARKERES FOR ALZHEIMER'S DISEASE

The levels of amyloid β protein (Aβ) and α1-antichymotrypsin (ACT) in cerebrospinal fluid (CSF) were evaluated as diagnostic markers of Alzheimer's disease (AD). The total of 95 subjects included 38 patients with AD, 14 with early-onset AD and 24 with late-onset AD, 25 normal control subjects, and 32 patients with other neurological diseases. The ACT levels were also examined in CSF from 66 patients with AD, 27 with early-onset AD and 39 with late-onset AD, and 54 normal control subjects. The level of Ag in the CSF of early-onset AD patients (n=14, 4.14 ± 1.37 pmol/ml) was significantly higher than in the age-matched controls (n=12, 2.27 ± 1.44 pmol/ml) (p<0.01). The level of CSF ACT in the late-onset AD group (n = 22, 5. 92±4.88μg/ml) was higher than in the normal control group (n=24, 2.27±1.40μg/ml) (p <0. 01). In the study of ACT in the larger group of subjects, the ACT level in the CSF of late-onset AD group (n=38, 7.02±5.18, μg/ml) was significantly higher than in the normal control group (n=53, 2.81±1.39μg/ml) (p<0.001). Thus, it is concluded that Aβ levels in the CSF are elevated in early-onset AD patients, and that the CSF ACT levels are elevated in late-onset AD patients. Clinical evaluation referring to both markers should be useful for the clinical diagnosis of AD.

AN ANALYSIS OF LYMPHOCYTE3H-N-METHYL-SCOPOLAMINE BINDING IN NEUROLOGICAL PATIENTS

Muscarinic cholinergic receptors were analysed in lymphocyte membranes from 35 patients with early (n = 20) and late onset (n = 15) Alzheimer's disease (AD), 86 patients with other neurological disorders and 60 normal controls by the specific binding of 3H-N-methyl-scopolamine (3H-NMS). The number of binding sites of 3H-NMS (Bmax) was significantly decreased both in early and late onset AD groups as compared with age-matched controls, by 54% and 40%, respectively, whereas the apparent binding affinity (Kd) was the same in all disease and control groups. In addition, the average Bmax in early AD was significantly lower than in late AD. The density of the binding of 3H-NMS was also significantly lower in a subgroup of old subjects with Down's syndrome (DS), whereas no changes were found in younger individuals with DS or in patients with Parkinson's disease, whether they were demented or not, multi-infarct dementia, myasthenia gravis or epilepsy. In the AD group, the difference in binding sites was unrelated either to the severity of dementia or disease duration. Treatment of the patients with cholinergic agents did not alter the binding values in any of the examined group. We conclude that the alteration of lymphocyte muscarinic receptors is highly associated with AD, but whether this reflects the central cholinergic deficit in these patients is uncertain.