Hypothesis review: Alzheimer's overture guidelines

National Institute on Aging–Alzheimer's Association definition and classification of sporadic Alzheimer's disease (sAD) is based on the assumption that β‐amyloid drives the pathogenesis of sAD, and therefore, β‐amyloid pathology is the sine‐qua‐non condition for the diagnosis of sAD. The neuropathological diagnosis is based on the concurrence of senile plaques (SPs) and neurofibrillary tangles (NFTs) designated as Alzheimer's disease neuropathological changes. However, NFTs develop in the brain decades before the appearance of SPs, and their distribution does not parallel the distribution of SPs. Moreover, NFTs are found in about 85% of individuals at age 65 and around 97% at age 80. SPs occur in 30% at age 65 and 50%–60% at age 80. More than 70 genetic risk factors have been identified in sAD; the encoded proteins modulate cell membranes, synapses, lipid metabolism, and neuroinflammation. Alzheimer's disease (AD) overture provides a new concept and definition of brain aging and sAD for further discussion. AD overture proposes that sAD is: (i) a multifactorial and progressive neurodegenerative biological process, (ii) characterized by the early appearance of 3R + 4Rtau NFTs, (iii) later deposition of β‐amyloid and SPs, (iv) with particular non‐overlapped regional distribution of NFTs and SPs, (v) preceded by or occurring in parallel with molecular changes affecting cell membranes, cytoskeleton, synapses, lipid and protein metabolism, energy metabolism, neuroinflammation, cell cycle, astrocytes, microglia, and blood vessels; (vi) accompanied by progressive neuron loss and brain atrophy, (vii) prevalent in human brain aging, and (viii) manifested as pre‐clinical AD, and progressing not universally to mild cognitive impairment due to AD, and mild, moderate, and severe AD dementia.