Alzheimer's disease: perspectives for the new millennium.

Abstract

This Perspectives series on Alzheimer’s disease is dedicated to the late Professor Henry M. Wisniewski, whose ceaseless devotion to the field over the last four decades has paved the way for many more decades of discovery and hope in the battle against this dreadful disease. Age-related impairments in cognition and memory have been known since ancient times, but the clinical-pathological features of the syndrome, now termed “Alzheimer’s disease” (AD), were not documented in the medical literature until the first decade of this century. It is now established that AD, a complex and genetically heterogeneous disorder, is the most common type of dementia occurring in mid-to-late life, affecting 7–10% of individuals over 65 years of age and perhaps 40% of persons over 80 years of age. The prevalence of this disease, which now affects more than 4 million individuals in the US, is increasing because of very significant shifts in life expectancy and demographic parameters; it is estimated that in 2050, about 25% of the population will be over 65 years of age. In 1907, Alois Alzheimer reported the case of a middle-aged woman who developed memory deficits and progressive loss of cognitive abilities accompanied by morbid jealousy. Autopsy disclosed the now-recognized classic pathology of AD — the presence of numerous neurofibrillary tangles (NFTs) and senile plaques (SPs) in the neocortex and hippocampus. The majority of patients with the “sporadic AD” disease exhibit clinical signs during the seventh decade, whereas individuals with inherited AD (see below) often become demented in mid-life. Affected individuals show abnormalities of memory, problem solving, language, calculation, visuospatial perceptions, judgment, and behavior; some cases show psychotic symptoms, such as hallucinations and delusions. Activities of daily living become increasingly impaired; in late stages of the disease, patients are often mute, incontinent, and bedridden and usually die of intercurrent medical illnesses. AD selectively affects neurons in certain brain regions and neural systems, including nerve cells in the cortex, hippocampus, amygdala, anterior thalamus, basal forebrain, and several brainstem monoaminergic nuclei. Many affected nerve cells exhibit intracellular accumulations of NFTs, poorly soluble filaments comprised principally of phosphorylated tau, a microtubule-associated protein. Because phosphorylated tau binds microtubules poorly and alters their stability, modifications of tau could have effects on intracellular transport, cellular geometry, and neuronal viability. SPs, abundant in the amygdala, hippocampus, and neocortex in cases of AD, are comprised of dystrophic neurites (abnormal nerve extensions) in proximity to deposits of highly fibrillogenic 42 amino acid Aβ peptides (Aβ42) that aggregate into β-pleated sheets. Deposition of Aβ in the neural parenchyma occurs early and selectively in AD. Aβ peptides are derived from β-amyloid precursor proteins (APPs) and generated by the concerted actions of as-yet unidentified proteolytic activities, termed “β-secretase” and “γ-secretase.” These Aβ deposits likely act to recruit additional proteins, including α1-antichymotrypsin, components of the complement cascade, and apolipoproteins, and these complexes may attract astrocytes and microglial cells that are often conspicuous around plaques. Over the past 5 years, we have witnessed an explosion of information pertaining to the accuracy of clinical-pathological diagnoses, genetic risk factors, mechanisms of disease, and potential therapeutic strategies. The contributors to this Perspectives series on AD highlight the extraordinary advances in these arenas and offer perspectives for future investigations in the field.