Biomarkers.

Area of Science:

• Neuroscience
• Biochemistry
• Medical Imaging

Background:

• The relationship between amyloid (Aβ) and tau pathology in Alzheimer's disease (AD) remains unclear, complicating therapeutic interventions targeting the Aβ-tau pathway.
• Preclinical evidence suggests Aβ enhances neuronal excitability and tau spreads based on neural activity.
• Recent findings indicate Aβ-related connectivity increases promote tau spread, but whether this reflects hyperexcitability is unknown.

Purpose of the Study:

• To investigate if Aβ accumulation leads to neuronal hyperactivity in Alzheimer's disease.
• To determine if this Aβ-induced hyperactivity drives tau accumulation.
• To explore potential therapeutic targets for the Aβ-tau axis in AD.

Main Methods:

• Utilized resting-state fMRI with a novel excitatory/inhibitory (E/I) ratio algorithm to assess neuronal activity in 586 subjects across the AD spectrum.
• Employed FDG-PET to measure glucose metabolism, a marker of neuronal activity, in 638 AD spectrum patients, with a subset also undergoing tau-PET.
• Analyzed post-mortem brain tissue from AD patients and controls for c-Fos expression, a marker of ante-mortem neuronal activity.

Main Results:

• Found a higher E/I ratio in amyloid-positive individuals, indicating Aβ-associated hyperexcitability.
• Observed a positive correlation between regional amyloid-PET and FDG-PET, suggesting increased neuronal activity in Aβ-rich areas.
• Demonstrated that Aβ-PET prediction of future tau accumulation is improved by including FDG-PET, with hypermetabolism mediating Aβ's effect on tau.

Conclusions:

• Aβ accumulation induces a shift towards neuronal hyper-excitability in the brain.
• This neuronal hyperactivity manifests as increased glucose metabolism, which in turn promotes Aβ-related tau accumulation.
• Aβ-induced neuronal hyper-excitability presents a potential therapeutic target for mitigating the Aβ-tau axis in Alzheimer's disease.