Mari Blomberg

Cerebrospinal fluid Aβ42 is increased early in sporadic Alzheimer's disease and declines with disease progression

All mutations known to cause familial Alzheimers disease (AD) act by increasing the levels of soluble β‐amyloid peptide (Aβ), especially the longer form, Aβ42. However, in vivo elevation of soluble Aβ in sporadic AD has so far not been shown. In the present study, we used enzyme‐linked immunosorbent assays specific for Aβ42 and Aβ40 to investigate cerebrospinal fluid from sporadic AD at different stages of disease severity, to clarify the roles of Aβ42 and Aβ40 during disease progression. We also evaluated three other groups—one group of patients with mild cognitive impairment who were at risk of developing dementia, a cognitively intact, nondemented reference group diagnosed with depression, and a perfectly healthy control group. We found that Aβ42 is strongly elevated in early and mid stages of AD, and thereafter it declines with disease progression. On the contrary, Aβ40 levels were decreased in early and mid stages of AD. The group of cognitively impaired patients and the depression reference group had significantly higher levels of Aβ42 than the healthy control group, implying that Aβ42 is increased not only in AD, but in other central nervous system conditions as well. Our data also point out the importance of having thoroughly examined control material. The initial increase and subsequent decrease of Aβ42 adds a new biochemical tool to follow the progression of AD and might be important in the monitoring of therapeutics. Ann Neurol 1999;45:504–511

Levels of α- and β-secretase cleaved amyloid precursor protein in the cerebrospinal fluid of Alzheimer's disease patients

Alternative cleavage of the amyloid precursor protein (APP) results in generation and secretion of both soluble APP (sAPP) and β-amyloid (Aβ). Aβ is the main component of the amyloid depositions in the brains of Alzheimers disease (AD) patients. Using Western blotting, we compared the levels of α-secretase cleaved sAPP, β-secretase cleaved sAPP and total sAPP, in cerebrospinal fluid (CSF) from 13 sporadic AD patients and 13 healthy controls. Our findings show significant amounts of β-secretase cleaved sAPP in CSF. There was no statistically significant difference in the levels of β-secretase cleaved sAPP between AD patients and controls. The levels of α-secretase cleaved sAPP and total sAPP were, however, found to be significantly lower in the AD patients than in the controls.

Interaction between estrogen receptor 1 and the ε4 allele of apolipoprotein E increases the risk of familial Alzheimer's disease in women

Estrogens may be implicated in the development of Alzheimers disease (AD). Most of their effects are mediated via receptors whose function and expression may be modified by DNA polymorphisms. Here the estrogen receptor 1 gene (ESR1) polymorphisms XbaI and PvuII were analyzed in 214 AD patients and 290 controls. In logistic regression analysis, a significantly increased risk of familial AD due to interaction between the ESR1 xx genotype and the apolipoprotein E epsilon4 allele was observed in women in a Swedish clinic-based sample, taking subjects who had neither the xx genotype nor epsilon4 as reference (OR 11.3, 95% CI 2.9-43.8). The risk of AD was more pronounced in early-onset (OR 22.0, 95% CI 3. 7-132.7) than in late-onset (OR 6.0, 95% CI 1.2-29.7) female patients. For women carrying the pp genotype together with epsilon4 the risk of AD was similarly elevated. Likewise in a Swedish community-based set of women, an increased risk of familial AD was observed in subjects who had either the ESR1 xx or pp genotype together with epsilon4. Furthermore, the Pp genotype frequency was found to be significantly increased in Finnish women with sporadic AD. We, thus, conclude that the ESR1 gene may have a role in the development of AD in females.

Increasing cerebrospinal fluid tau levels in a subgroup of Alzheimer patients with apolipoprotein E allele ϵ4 during 14 months follow-up

The concentration of tau protein is elevated in the cerebrospinal fluid (CSF) in Alzheimers disease (AD), suggesting that CSF tau may be a useful biochemical diagnostic marker for this disorder. We investigated CSF tau concentrations on two occasions in AD (n = 18), mild cognitive impairment (MCI, n = 9) and other dementing disease (OD, n = 9) by ELISA (Innotest hTau Antigen, Innogenetics, Belgium). Tau levels were statistically significant higher in the AD group than in MCI and OD groups on both occasions. Twelve of the AD patients showed increasing values of tau at follow-up and six demonstrated diminished values. All AD patients with increasing tau were carriers of one or two epsilon 4 alleles of the apolipoprotein E (APOE, gene. Of those AD cases with decreasing tau levels only three individuals had the epsilon 4 allele, a difference that was statistically significant (P < 0.05). These findings suggest that there may be apolipoprotein E (apoE) isoform-specific differences of tau regulation in AD.

White matter lesions in Alzheimer patients are influenced by apolipoprotein E genotype

To analyse the influence of apolipoprotein E (APOE) genotype on the extent of white matter lesions (WMLs) in Alzheimer’s disease (AD), we examined 60 AD patients with magnetic resonance imaging. The WMLs were rated visually in different brain regions. The patients with the APOE genotype σ4/4 had more extensive WMLs in the deep white matter than patients with genotypes σ3/3 and σ3/4. There was a correlation with age for WMLs in the deep white matter in patients with the APOE σ3/3 genotype. In patients carrying at least one σ4 allele, the WMLs showed no age correlation. The results could imply that in APOE allele σ4 carriers, the WMLs represent a pathological process related to the aetiology of the disease.

Investigations of a CA repeat in the oestrogen receptor beta gene in patients with Alzheimer's disease.

Several studies have shown that oestrogen treatment after menopause decreases the risk for Alzheimers disease (AD). It is also known that oestrogen stimulates the outgrowth of nerve cells and that apolipoprotein E (Apo E) synthesis and amyloid precursor protein (APP) metabolism are regulated by oestrogen. Recently a new oestrogen receptor was identified, oestrogen receptor β (ERβ), located at chromosome 14q22-24. Several genes close to this chromosomal region have been implicated in AD, but the results are conflicting. Our hypothesis was that variations in the ERβ gene could be the underlying cause to the positive findings in these genes and we have therefore investigated a CA repeat1 in intron 5 of the ERβ gene. Three hundred and thirty-six AD cases and 110 healthy age-matched controls were included in this study. Fourteen different alleles were found with frequencies between 0.1 and 37%. There was no significant difference between AD cases and controls when all alleles were compared. However, allele 5 was seen in 13.6% of the controls but only in 8.0% of AD cases (P=0.014; odds ratio (OR)=0.55). No AD patient homozygous for this allele was seen but three controls were homozygous. In conclusion, our findings suggest the ERβ allele 5 to be a protective factor. However, this has to be confirmed in a larger population.

Cerebrospinal fluid apolipoprotein E (apoE) levels in Alzheimer's disease patients are increased at follow up and show a correlation with levels of tau protein.

Apolipoprotein E (apoE) levels were compared in cerebrospinal fluid (CSF) taken on two occasions, with an average 15 months follow up, from groups of patients with Alzheimers disease (AD: n = 18), mild cognitive impairment (MCI; n = 9) and other dementia disorders (ODD; n = 9). In these groups, CSF apoE levels were between 2-3-fold higher than values for a group of 27 healthy age-matched controls. CSF apoE levels in the AD group were significantly increased at follow up, compared to levels obtained on the first sampling occasion. For the same cases it had been shown previously that CSF tau protein levels were increased at follow up [Blomberg, M., Jensen, M., Basun, H., Lannfelt, L. and Wahlund, L-O., Neurosci. Lett., 214 (1996) 163-166]. The AD, but not MCI, ODD or control groups, also showed statistically significant correlations between CSF apoE and tau protein levels at both the first (r = 0.585, P < 0.01) and follow up (r = 0.695, P > 0.001 ) samplings. It is concluded that CSF measures of both apoE and tau may reflect an intimate relationship between these two proteins in AD and could prove useful in monitoring the progression of this condition.

CSF markers related to pathogenetic mechanisms in Alzheimer's disease

Summary. Serum amyloid P component (SAP) and complement C1q are found highly co-localized with extracellular fibrillar amyloidβ (Aβ) deposits in Alzheimers disease (AD) brain. Conflicting data were reported earlier about the cerebrospinal fluid (CSF) levels of SAP and C1q in AD compared to controls. The objective of the present study was to compare the levels of Aβ1–42, tau, C1q and SAP in CSF of a well characterized group of AD patients and controls, and to assess the association with dementia severity.Significantly decreased CSF levels of Aβ1–42 were observed in the AD group (480 ± 104 ng/L) as compared to controls (1,040 ± 213 ng/L), whereas tau levels were significantly higher in patients with AD (618 ± 292 ng/L) than in controls (277 ± 136 ng/L). Combining the results of Aβ1–42 and tau measurements resulted in a clear separation between the AD group and the controls. No significant differences in CSF levels of SAP and C1q were observed between the well characterized AD patients and non demented control group. Furthermore, we could not demonstrate a correlation between SAP and C1q CSF levels and the severity of the disease, expressed in Mini-Mental State Examination (MMSE) scores. Therefore, in our opinion these factors can be excluded from the list of potentially interesting biomarkers for AD diagnosis and progression.

Tau Immunoreactivity Detected in Human Plasma, But No Obvious Increase in Dementia

Tau proteins are central to the neuropathology of Alzheimer’s disease and tau levels in cerebrospinal fluid are elevated in affected individuals. In this study, we investigated the presence of tau in plasma from subjects with Alzheimer’s disease (n = 16), frontotemporal dementia (n = 10), vascular dementia (n = 16) and from healthy controls (n = 15). By using an ELISA with monoclonal tau antibodies, tau immunoreactivity was detected in approximately 20% of the subjects. However, no difference between the disease and control groups was seen. After gel filtration of tau immunopositive plasma, the peak reactivity was found in the 160-kD fraction, indicating the source to be tau-like molecules of high-molecular-weight or polymers of low-molecular-weight tau isoforms. We conclude that measurements of tau in plasma cannot be utilized diagnostically for Alzheimer’s disease or for the other dementias investigated.

EEG slowing and cerebrospinal fluid tau levels in patients with cognitive decline.

WE explored the relationship between cerebrospinal fluid (CSF) tau levels as indirect markers of tau-related pathology in Alzheimers disease (AD) and EEG slowing, a typical neurophysiological finding in the disease. A positive correlation between CSF tau levels and ratio of alpha/delta global field power was found in 14 AD patients (r = 0.65, p = 0.01). This relationship was better approximated by polynomial fit of 2nd degree (p = 0.002). A subgroup of AD patients (n = 7) with higher tau levels and shorter duration of illness showed a strong relationship between CSF tau levels and alpha/theta (r = 0.83, p = 0.02), and alpha/delta (r = 0.87, p = 0.01) ratios of the global field power. There were no significant correlations between EEG slowing and CSF tau levels in 12 patients with mild cognitive dysfunction or in 14 healthy control subjects. That a strong inverse linear correlation exists in AD patients with higher levels of tau and shorter duration of illness may imply that with longer illness duration CSF tau levels decrease due to neuronal death.