di
Anna Giulia Cattaneo, DBSM, Via J-H Dunant, 3, 21000 Varese, Italy.

Molecular biology has provided, since its earlier days, valuable tools for featuring otherwise obscure syndromes, Alzheimer disease (AD) between others. While at least three genetic markers are known to be associated with the rare early-onset autosomal-dominant AD, namely APP, PSEN1, and PSEN2, only the linkage with the chromosome 19q13, and the APOE gene polymorphism seems to be associated with increased susceptibility for late-onset AD (LOAD). The presence of a variant of APOE, encoding for the Apolipoprotein E epsilon 4 type (APOEe4) has been found strongly associated with LOAD even in heterozygous individuals, and nevertheless it is not sufficient to explain the phenotypic variance of this syndrome. Two main research objectives have been developed to improve the early predictivity and potential usefulness in applying preventive measures, as evident from a search on this topic at the NCBI database limited to the past two years.

One objective is aimed to find additional markers, associated to the AD at its very early stage and easy to be detected. APOE centrally affects the lipid metabolism in the brain and influences, among others, the activity of cholinesterase and bytyrylcholinesterase, and possibly the production of beta amiloid and is involved in lipid metabolism and transport. In recent years, the association of APOEe4 with a number of easily measurable markers, possibly linked with the LOAD, has been tested. Hypertension and innate proinflammatory cytokine profile developing in middle aged is associated with higher risk to develop the AD later in life. CSF markers have been considered, mainly the tau and the hyperphoshporylated tau proteins, the isoprostane, the beta amiloid and mainly the ratio Abeta42/Abeta40, and Beta amiloid secretase activity (BACE1). The predictivity of these markers remains unclear, being mostly associated with the aging process itself, even in non demented patients. Their significance must be validated by longitudinal studies.

The studies on early brain function and morphology changes seem to be much more interesting. APOEe4 genotype has been found to be associated with the severity of EEG changes in patients affected by LOAD. Their non-demented, younger relatives carrying APOEe4 genotype showed increased excitability and dysfunction of deep brain and alpha rhythm-generating structures. Early hippocampal loss, accelerated over 12 months, has been observed at the MRI as a very early sign of cognitive impairment; this finding, however, does seem to be AD exclusive, being observed even in mild cognitive impairment not evolving into a true Alzheimer's disease. A very interesting study (PNAS, 2009, 106: 7209-7214) on a large (98) number of individuals has been conducted by examining the results of the fMRI. The investigators were able to demonstrate the presence of hippocampal hyperactivation in APOEe4 carriers either at rest or during a memory encoding task. This result can represent a very early sign of brain dysfunction, decades before the onset of any symptom of AD, and in the complete absence of functional or morphological changes in the brain and in the resting cerebral blood flow.

The genetic polymorphism is the subject of the second line of researches, aimed to find a possible explanation of the phenotypic variance of LOAD. Several population studies (listed below) have been reported, and more than 10,000 individuals, from families presenting the LOAD, or non related, aged but cognitively healthy controls, have been investigated. However, the results are still contrasting, mainly because of the methods used and the density of genetic considered. More uniform criteria and worldwide coordination of efforts could be of help to improve the impact of these kind of research on clinical fields and to speed up the grown of knowledge.

Epidemiologic studies on genetic polymorphism published in 2008-2009 and deposited at the Pub Med database:
" Ir J Med Sci. 2008, 177: 29-33. Irish population, Polymorphisms (-491A/T and -427T/C) at the promoter region of the APOE gene not associated with LOAD.
" Eur J Hum Genet. 2008, 16: 202-208. Swedish families: 1289 microsatellite markers (distance: 2.85 cM) not associated with LOAD.
" Neurogenetics. 2008, 9: 51-60. Caribbean Hispanic families: 376 microsatellite markers (distance: 9.3 cM) Multiple loci involved (as a previous study of the Swedish group, with only 365 markers).
" Am J Med Genet B Neuropsychiatr Genet. 2008, 147B(6): 778-783. Sibling pairs form Sweden, Norway, UK, USA 10 microsatellite markers on chromosome 19. Only the APOEe4 is linked to LOAD.
" Arch Neurol. 2008; 65:1518-1526. Genome wide scan using approximately 6000 single-nucleotide polymorphic markers (distance of 0.65 cM). Multiple markers associated with LOAD and sporadic AD.
" J Nutr Health Aging. 2009, 13: 214-219. Spanish population: Polymorphism: APOE rs429358 (SNP112)/rs7412 (SNP158). Association is stronger in homozygous.
" Am J Hum Genet. 2008, 83: 623-632. USA residents of European descents. rs4420638 probably reflects APOE-epsilon4. Sporadic AD associated with rs11159647, on chromosome 14q31.
" Eur J Hum Genet. 2009, 17: 938-945. Italian population: Significant associations: positive: APOEe4 rs449647 A/A and rs405509 G/G genotypes. Negative: APOEe4 rs449647 A/T and rs405509 T/T genotypes.
" Brain Res. 2008, 1187:52-7. Northern Han-Chinese population: G allele of CETP (cholesteryl ester transfer protein) gene, D442G may have a potential protective effect against the development of sporadic AD, especially in APOE epsilon4 carriers.