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Researchers are proposing that Alzheimer's disease may be better understood as a body-wide breakdown in how cells clear waste and regulate energy, not only as a disease of the brain.

“Alzheimer's may not originate solely in the brain but be a body-wide failure of cellular clearance and energy production that surfaces in the brain first,” said Professor Payam Barnaghi, Chair in Machine Intelligence Applied to Medicine in the Department of Brain Sciences and corresponding author of the paper. 

Researchers want to extend a model organised around the brain, and within it around two proteins, amyloid and tau. In a published in Communications Medicine on 3 September 2026, the authors argue that this framing may be too narrow to explain the full picture. 

It is a hypothesis, not a proven mechanism. The paper says the exact causal mechanisms of Alzheimer's remain unclear, and the authors call for long-term, multi-organ studies to test it. 

Alzheimer's is a progressive brain disease in which two proteins build up abnormally: beta-amyloid clumps between brain cells and tau tangles form inside them. Together with the loss of brain cells and their connections, this gradually erodes memory, thinking and daily life. 

A scattered set of risk factors 

“Alzheimer's research is organised around the brain, and within the brain, around amyloid and tau,” explained Professor Barnaghi. 

The Comment notes that neurodegenerative diseases develop through complex interactions among physiological, genetic, metabolic, hormonal and pathological changes over time, and says current approaches struggle to capture them. 

“The conditions accumulating in people's medical records before diagnosis are overwhelmingly bodily – cardiovascular, metabolic, inflammatory, endocrine,” said Professor Barnaghi. 

The paper draws on the team's earlier study of UK Biobank hospital records. For Alzheimer's, that study found depressive episodes, osteoporosis and type 1 diabetes appearing up to 20 years before diagnosis. It covered in-patient records only and shows an association, not a cause. 

Professor Barnaghi also pointed to another clue: warning signs of brain degeneration can be picked up in blood tests, and the same signs turn up across several neurodegenerative diseases, not just Alzheimer's. 

The authors suggest that the common thread may be lysosomal and mitochondrial dysfunction, the “machinery” cells use to clear waste and generate energy. As Professor Barnaghi notes, neurons carry the cumulative cost of that failure because they are long-lived. The paper says the impact on them is disproportionately greater because they live longer than most other cells in the body. 

Targeting systemic dysfunctions 

The paper addresses several problems that a brain-only model struggles to explain. Cardiovascular disease, diabetes and genetic factors such as APOE-ε4 (a gene variant linked to higher Alzheimer's risk) are among the best-studied risk factors, but the authors say they are often examined separately or only in relation to a limited set of variables. 

Midlife management of comorbidity becomes potentially disease-modifying, which is also an equity argument, since comorbidity burden falls more heavily on deprived populations, and prevention through routine care reaches people who may never access disease-modifying therapies. Professor Payam Barnaghi Chair in Machine Intelligence Applied to Medicine Department of Brain Sciences | 51³Ô¹ÏÍø

There's also a puzzling disconnect: anti-amyloid drugs (medications that target and remove amyloid plaque, a build-up of sticky protein clumps in the brain) can clear substantial amounts of plaque, yet the paper notes that they slow clinical decline only modestly.

The authors read this as a sign that amyloid is one part of a broader, multifactorial process, and suggest that effective treatments may also need to address the whole-body dysfunction. This is their interpretation, and the evidence on these drugs is debated among researchers. 

Beyond science 

According to the paper, another implication concerns when and through what route prevention might work. The authors say that treating accumulated comorbidity as a modifiable contributor reframes the management of metabolic, cardiovascular and inflammatory conditions in midlife as a potential route to delaying or preventing neurodegeneration. 

“Midlife management of comorbidity becomes potentially disease-modifying, which is also an equity argument, since comorbidity burden falls more heavily on deprived populations, and prevention through routine care reaches people who may never access disease-modifying therapies,” Professor Barnaghi noted. 

The equity point is Professor Barnaghi's own view and is not tested in the Comment. It rests on earlier evidence: a study of 1.75 million people registered with Scottish general practices in 2007 found that multiple long-term conditions began 10 to 15 years earlier in the most deprived areas than in the most affluent. 

* Professor Payam Barnaghi, Antigone Fogel, Ramin Nilforooshan, Valeria Ricotti and Thomas Voit hold equity in Vesalic Ltd, a company developing diagnostic biomarkers for neurodegenerative diseases. The other authors declare no competing interests. 

More:  

• Barnaghi, P., Fogel, A., Walsh, C. et al. Applying a systemic approach that extends beyond the brain to Alzheimer’s disease pathogenesis. Commun Med 6, 475 (2026). https://doi.org/10.1038/s43856-026-01831-z