Amyloid and lipids in the pathology of Alzheimer disease

In the last decade, we have witnessed an avalanche of information about the morphological and biochemical changes that occur in Alzheimer disease (AD). This knowledge has provided new strategies for treatment and identified possible approaches for prevention. Because AD pathology is relentlessly progressive, occurring over years or decades, successful treatment will depend on early intervention and therefore recognition of risk factors that lead to the development of this dementia. In the present review, we advance some of the alterations of lipid and membrane metabolism, alone or in association with β-amyloid peptide (AP), as pivotal components of AD pathophysiology. At present, the 40 and 42 amino acid long Aβ, resulting from the intracellular proteolytic processing of the β-amyloid precursor protein (AβPP), have deservedly taken center stage in investigations throughout the world. Fibrillar Aβ42 and Aβ40 are preferentially deposited in neuritic plaques1 and in vascular walls2, respectively. In a very limited number of families, genetic mutations invariably lead to AD dementia. The discovery of over 40 different mutations in the genescoding for AβPP and presenilins 1 and 2 provides clear evidence of multiple etiologies for familial AD3,4. However, in sporadic AD, which represents over 95% of the patients with this dementia, the underlying genetic, physiological and environmental factors leading to Aβ deposition remain elusive.