If you’re wondering where Alzheimer’s research might be headed after the latest large-scale failure of a clinical trial based on the “amyloid hypothesis,” check this out.

Plaques. Tangles. Clumps. These are all pathological signs of neurodegenerative diseases that scientists can see under the microscope. But they don’t explain most of the broader trends of cognitive resilience or decline in aging individuals. What’s missing?

A recent proteomics analysis in Nature Communications from Emory researchers identifies key proteins connected with cognitive trajectory – meaning the rate at which someone starts to decline and develop mild cognitive impairment or dementia.

This paper fits in with the multi-year push for “unbiased” Alzheimer’s/aging research at Emory. The lead and senior authors are Aliza and Thomas Wingo, with proteomics from biochemist Nick Seyfried and company.

The proteins the Emory team spotlights are not the usual suspects that scientists have been grinding on for years in the Alzheimer’s field, such as beta-amyloid and tau. They’re proteins connected with cellular energy factories (mitochondria) or with synapses, the connections between brain cells.

“Our most notable finding is that proteins involving mitochondrial activities or synaptic functions had increased abundance among individuals with cognitive stability regardless of the burden of β-amyloid plaques or neurofibrillary tangles,” the authors write. “Taken together, our findings and others highlight that mitochondrial activities would be a fruitful research target for early prevention of cognitive decline and enhancement of cognitive stability.”

Remember that this is an association: we can’t really say that mitochondrial proteins are the drivers of cognitive stability or simply an indicator of it. The brain tissue samples came from part of the prefrontal cortex, so other parts of the brain may look different, too. The 143 participants in the study came from the Arizona Study of Aging and Neurodegenerative Disorders and the Baltimore Longitudinal Study of Aging.

Some of the key resilience-associated proteins will be familiar to neuroscientists, such as synaptic scaffold protein PSD-95 and memory consolidation protein HOMER1. Others whose abundance is associated with pathology, such as myelination proteins NEFM and MBP, may suggest therapeutic targets.