Alzheimer’s May Be a Whole-Body Disease, Not Just a Brain Disorder

New research using fruit flies reveals that Alzheimer’s disease affects far more than just the brain, with disease proteins causing distinct patterns of damage throughout the body. Scientists have created the first complete cell-by-cell map showing how two key Alzheimer’s proteins—Aβ42 and Tau—impact different tissues in dramatically different ways, offering new insights into why patients experience such varied symptoms.

The study, published in the journal Neuron, used advanced genetic techniques to examine over 600,000 individual cells across 219 distinct cell types in flies engineered to develop Alzheimer’s-like conditions. This comprehensive atlas of disease effects may help scientists identify new biomarkers for early diagnosis and develop treatments targeting specific body systems affected in Alzheimer’s patients.

What makes this research particularly significant is its whole-body approach to a disease typically viewed as brain-centric. Could this broader perspective lead to breakthroughs in how we understand and treat Alzheimer’s disease?

Different Proteins, Different Body Systems

The researchers discovered remarkable differences in how each Alzheimer’s protein impacts the body. When they expressed Aβ42 (which forms amyloid plaques in human brains) in fruit fly neurons, the damage remained mostly limited to the nervous system, with sensory neurons being particularly vulnerable.

“Aβ42 expression primarily affected the nervous system. Sensory neurons involved in vision, audition and olfaction were particularly vulnerable. A decline in the sense of smell can be an early symptom of Alzheimer’s disease, and in this study we identified specific olfactory neurons affected by Aβ42 in fruit flies,” said co-first author Ye-Jin Park, a graduate student co-mentored by Dr. Li and Dr. Hugo Bellen.

The findings align with what many Alzheimer’s patients experience, as loss of smell is often one of the earliest detectable symptoms of the disease. Importantly, the research pinpointed exactly which smell-detecting neurons were most affected.

Tau Accelerates Aging Throughout the Body

In contrast, when researchers expressed Tau protein (which forms neurofibrillary tangles in human Alzheimer’s) in fly neurons, they observed widespread changes throughout the body’s peripheral tissues—particularly in metabolism, digestion, and reproductive systems.

“Tau expression in neurons led to significant changes, mostly in peripheral tissues, for instance altered fat metabolism and digestion and reduced fecundity. These alterations mimic age-associated changes, suggesting that Tau expression accelerates aging,” said co-first author Dr. Tzu-Chiao Lu, a postdoctoral associate in the Li lab. “We found that neuronal connectivity and other factors that mediate brain-body communication were disrupted in Tau flies.”

These Tau-induced changes outside the brain closely resembled patterns typically seen in aging, suggesting that Tau protein may actually accelerate the aging process throughout the body.

Common Features Across Species

To determine whether their findings might be relevant to human disease, the researchers compared their fruit fly data with mouse and human Alzheimer’s datasets. They discovered a striking pattern: a conserved “LDH-high” cell cluster—neurons with high levels of lactate dehydrogenase—was present in Alzheimer’s samples across all three species.

This conserved signature suggests that similar cellular stress responses occur in human Alzheimer’s patients as in the fruit fly model, strengthening the case that the fly findings may translate to human disease.

The research also identified fat metabolism abnormalities in both fly and mouse models of tauopathy (Tau protein accumulation). These consistent patterns across different animals suggest these changes likely occur in human Alzheimer’s patients as well.

A Comprehensive Body Map of Alzheimer’s Effects

The study represents the first comprehensive cell atlas for Alzheimer’s disease across an entire organism, dubbed the “Alzheimer’s Disease Fly Cell Atlas.” The team used single-nucleus RNA sequencing to profile gene expression in individual cells throughout the entire body of flies expressing either Aβ42 or Tau proteins.

The findings paint a picture of Alzheimer’s as a systemic disorder, where brain pathology triggers cascading effects throughout the body:

• Sensory systems (vision, hearing, smell) are particularly vulnerable to Aβ42 toxicity
• Endoplasmic reticulum stress response is activated in neurons exposed to Aβ42
• Fat metabolism becomes dysregulated in flies and mice expressing Tau protein
• Gut tissue shows signs of premature aging when exposed to Tau protein
• Brain-body communication pathways become disrupted, particularly by Tau

Implications for Human Disease

This holistic view of Alzheimer’s disease could significantly impact how we understand, diagnose, and treat the condition. By revealing how different tissues respond to Alzheimer’s proteins, researchers may be able to identify new biomarkers in blood or other easily accessible tissues.

“These and other findings described in the Alzheimer’s Disease Fly Cell Atlas improve our understanding of how Alzheimer’s disease-associated proteins, Aβ42 and Tau, affect an organism as a whole,” said Bellen, co-corresponding author of the work. Bellen is a Distinguished Service Professor of Molecular and Human Genetics at Baylor and chair in neurogenetics in the Duncan NRI.

The study’s implications extend beyond fruit flies. If similar systemic effects occur in humans with Alzheimer’s, doctors may need to monitor and address multiple body systems affected by the disease, not just the brain.

The research team has made their comprehensive atlas publicly available to promote further investigation into brain-body connections in neurodegeneration. This resource provides a foundation for exploring how Alzheimer’s affects the entire body and may accelerate the discovery of new therapeutic approaches that target these systemic effects.