Cholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer’s disease (AD) and results are contradictory.

We performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.

Two of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p = 0.016; rs4900442: p = 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p = 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p = 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p = 0.001) and cholesterol (p < 0.001).

Our results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.

The natural course of cognitive performance, electrophysiological alterations and brain atrophy in ageing and Alzheimer's disease (AD) has been investigated in numerous studies, but only few attempts have been made to examine the relationship between clinical, electroencephalographic (EEG) and morphological changes with quantitative methods prospectively over longer periods of time.

Fifty-five patients with clinically diagnosed AD and 66 healthy elderly controls were examined biannually using a cognitive test (CAMCOG), EEG band power and volumetric estimates of brain atrophy.

On average cognitive performance deteriorated by 28 points on the CAMCOG in the AD group, the alpha/theta ratio decreased by 0.2, and the proportion of intracranial cerebrospinal fluid volume increased by 3.5% during a 2-year period. Similar changes were observed after a second 2-year interval. A multiple regression model demonstrated a significant influence of age on cognition and atrophy and a significant influence of the estimated duration of symptoms on cognition, alpha/theta ratio and brain atrophy at the initial examination. Cognitive performance at the first examination exerted significant effects on the performance and also on brain atrophy at re-examination after 2 or 4 years, whereas the EEG and neuroimaging findings at the previous examination were exclusively related to the corresponding findings at the follow-up examinations. In the control group no significant cognitive, EEG and morphological changes were observed after 2 and 4 years.

After 2 consecutive follow-up periods, we were able to verify significant deteriorations of cognition accompanied by neurophysiological and neuroradiological changes in AD, but not in normal ageing. In clinically diagnosed AD, cognitive performance at the follow-up examination could not be predicted by the previous alpha/theta ratio or by the previous degree of global brain atrophy, whereas the cognitive test score determined not only performance, but also structural findings at follow-up. Performance on cognitive tests appears to be a more sensitive indicator of the degenerative process than EEG band-power and morphological changes in manifest AD. Neuroimaging, neurophysiology and genetic risk markers may be more important for the early differential diagnosis than for the prediction of the course of illness.

We examined the differences in volume of the ventricular and extracerebral cerebrospinal fluid spaces in normal ageing and in probable Alzheimer's disease (AD) and we tried to investigate the effects of the severity of illness on the morphometric differentiation of AD and ageing, the principal components underlying brain atrophy in both conditions, and the correlations of these measurements with clinical findings.

Forty patients with probable AD were matched with 40 non-demented elderly controls. Both groups underwent standardised clinical tests and unenhanced cranial computed tomography for post hoc volumetric analysis.

The lateral and third ventricles and the anterior and lateral fissures were significantly larger in AD than in normal ageing. The volumes of the lateral ventricle and lateral fissure permitted a highly efficient differentiation between normal ageing and AD even at the mild stage of dementia, and this differentiation was improved further in the more severe stages of illness. We identified one principal component underlying brain atrophy in normal ageing and two components in AD: a ‘grey matter’ component accounting for sulcal and third ventricular enlargement, and a ‘white matter’ component for lateral ventricular enlargement. In AD, most of the volumetric measurements were significantly correlated with cognitive impairment, but in the group of non-demented elderly controls they were correlated with age.

Volumetric indices of brain atrophy permit a highly efficient differentiation between normal ageing and AD even in the mild stages of illness and this demonstrates that substantial structural brain changes have developed in the preclinical phase of illness. We suggest that there is an uncoupling between lateral ventricular enlargement and cortical brain atrophy in AD.