No abstract

Depression is a frequent condition in Alzheimer's disease (AD). The prevalence of depressive symptoms depends on the severity of dementia and the instruments used. Our aim was to assess the prevalence of depression dependent on the severity of dementia by four different scales: The 15-point Geriatric Depression Scale (GDS), the Montgomery and Asperg Depression Scale (MADRS), the Cornell Scale for Depression in Dementia (CSDD) and the Nurses Observation Scale for Geriatric Patients (NOSGER). The study population consisted of 316 patients with Alzheimer's disease from a psychiatric out-patients memory-clinic, which was divided into two groups: mild AD (Mini-Mental Status Examination (MMSE) > or = 18) and moderate to severe AD (MMSE <18). Additionally, internal consistency and correlation of these scales were calculated. Prevalence of depression ranged between 27.5 and 53.4% in mild AD and between 36.3 and 68.4% in moderate to severe AD. Internal consistency was good in all scales (Cronbach's alpha .63-.85). For MADRS and CSDD it was independent of the stage of AD, while in GDS and NOSGER internal consistency decreased with severity of dementia. Correlation between the scales was better in mild AD than moderate to severe AD; the best results were obtained for the correlation between CSDD and MADRS in both groups. We conclude that in our study population CSDD and MADRS were the most consistent tools for detecting depression in AD independently of the severity of dementia.

Clinical differential diagnosis of early-onset dementia (EOD) includes familial Alzheimer disease (FAD) and hereditary prion disease. In both disease entities, postmortem brain histopathological examination is essential for unambiguous diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, whereas mutations in the prion protein (PrP) gene are associated with prion disease. To investigate the proportion of EOD attributable to known genes, we prospectively (i.e., antemortem) screened these four genes for mutations by sequencing genomic PCR products from patients with EOD before age 60 years. Family history for dementia was positive (PFH) in 16 patients, negative (NFH) in 17 patients, and unknown (UFH) in 3 patients. In 12 patients, we found five novel mutations (in PS1, F105L; in PS2, T122P and M239I; and in PrP, Q160X and T188K) and five previously reported mutations (in APP, in three patients who were most likely unrelated, V717I; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all considered to be disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found two mutations (APP V717I) in two of the three UFH patients, and only one mutation (PrP T188K) in 1 of the 17 patients with NFH. We conclude that because of the lack of specific antemortem diagnostic markers for FAD and hereditary prion disease, all four genes should be included in a molecular diagnostic program in patients with EOD who had PFH.

CST3 is a susceptibility gene for late-onset AD, especially in patients aged 75 years and older. To our knowledge, CST3 B is the first autosomal recessive risk allele in late-onset AD.

alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.