Hypothesis review: Alzheimer's overture guidelines.

Area of Science:

• Neuroscience
• Pathology
• Gerontology

Background:

• Current Alzheimer's disease (AD) classification assumes beta-amyloid drives sporadic AD (sAD) pathogenesis.
• Neuropathological diagnosis relies on concurrent senile plaques (SPs) and neurofibrillary tangles (NFTs).
• NFTs precede SPs by decades and are more prevalent in aging brains than SPs.

Purpose of the Study:

• To introduce a new concept and definition for brain aging and sporadic Alzheimer's disease (sAD).
• To propose an alternative model for sAD pathogenesis and progression.

Main Methods:

• Review and re-evaluation of existing neuropathological and genetic data on sAD.
• Conceptual framework development based on the temporal and spatial relationship of pathological hallmarks.
• Integration of genetic risk factors and molecular changes into a multifactorial model.

Main Results:

• sAD is proposed as a multifactorial, progressive neurodegenerative process.
• Early and predominant feature is 3R+4Rtau NFTs, followed by beta-amyloid and SPs.
• NFTs and SPs exhibit distinct regional distributions.
• Pathology is preceded or paralleled by molecular changes in cell membranes, metabolism, neuroinflammation, and vasculature.
• Disease progression involves neuron loss, brain atrophy, and varied clinical manifestations from pre-clinical AD to dementia.

Conclusions:

• The AD overture model challenges the primacy of beta-amyloid in sAD.
• It emphasizes the early role of NFTs and multifactorial influences in brain aging and AD.
• This framework necessitates a re-evaluation of diagnostic criteria and therapeutic strategies for sAD.