Rethinking Alzheimer's: Why the Origins of the Disease Might Not Be in the Brain

César Cunha

Researcher’s Chronicle | For decades, the scientific community has viewed Alzheimer’s disease through a relatively narrow lens: as a condition that begins and ends in the brain. When we think of Alzheimer’s, we inevitably think of neurons, amyloid plaques, and memory loss. We think of the central nervous system as the exclusive stage upon which the disease unfolds.

But what if science has been looking in the wrong place?

That is precisely the question guiding the work of César Cunha, a PhD researcher specializing in human genomics at the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, and Associate Research Fellow at the Broad Institute of MIT and Harvard in Boston. César’s scientific journey did not begin in neuroscience. With a background in biochemistry and environmental biotechnology, it was his fascination with complex biological systems that gradually led him to explore the genetic mechanisms shaping human disease. Today, through two innovative preprint studies, he is contributing to a profound shift in how we understand Alzheimer’s disease.

A Whole-Body Problem, Not Just a Brain Disease

Using advanced genomic tools and machine learning models, César and his colleagues mapped the genetic determinants of Alzheimer’s disease across dozens of human tissues, multiple brain regions, and diverse cell types.

Maersk Tower - Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen

The results were unexpected.

The genetic risk associated with Alzheimer’s does not appear to be predominantly enriched in the brain. Instead, the strongest signals emerge from peripheral tissues and systems, particularly the immune system and metabolic pathways.

The analogy César uses helps clarify this perspective: obesity manifests as excess body fat, yet its genetic roots lie in how the brain regulates hunger and energy balance. Similarly, although Alzheimer’s devastating pathology ultimately manifests in the brain, its genetic origins may lie in how the peripheral immune system ages and responds over time. The research even identified a possible “critical window of susceptibility” between ages 55 and 60, during which peripheral immune activation may set the stage for future cognitive decline.

Obesity, Diabetes, and an Inverted Assumption

The research went further, exploring the link between cardiometabolic conditions and Alzheimer’s risk. The findings revealed a pattern influenced by biological sex:

• In women, a higher body mass index appears to be the more significant risk factor.

• In men, type 2 diabetes carries greater weight in genetic predisposition.

Perhaps the most surprising finding, however, was this: genetic variants associated with higher Alzheimer’s risk correlate with a chronic predisposition to lower blood pressure and lower blood glucose levels, challenging long-standing medical assumptions.

These discoveries do not merely refine biological models; they question existing preventive and clinical strategies.

A New Hope for Treatment 

Distinguishing where a disease ends from where it begins is crucial to stopping it.

If Alzheimer’s is, as these findings suggest, a systemic disease with peripheral roots, then an exclusive focus on the brain may be limiting our therapeutic strategies. By shifting scientific attention beyond the central nervous system, entirely new possibilities for early intervention emerge, potentially decades before clinical symptoms appear.

This paradigm shift does not diminish the importance of neurodegeneration. Rather, it reframes it as a consequence, not necessarily the origin.

Broad Institute of MIT and Harvard, Boston

Alzheimer’s in Society: Making the Invisible, Visible

Beyond its biomedical implications, César Cunha’s work, Associate Member of SPOT Nordic, also highlights a persistent social challenge: the widespread misunderstanding of Alzheimer’s disease.

Too often, early signs are dismissed as a “normal part of aging.” This misconception reduces the urgency of early intervention and perpetuates stigma. Alzheimer’s is not simply occasional forgetfulness; it is a progressive systemic failure with devastating consequences for patients, families, and public health systems. After diagnosis, many individuals gradually become socially invisible. The burden of care falls silently upon families and caregivers, often without adequate support. The disease is treated as a private tragedy, when in reality it represents a structural challenge in an increasingly aging society.

Genomic breakthroughs are crucial scientific milestones. But they cannot succeed in isolation. Before comprehensive prevention and treatment strategies can be effectively implemented, a fundamental shift in public awareness is required. Society must recognize the true complexity and holistic impact of Alzheimer’s, on patients, loved ones, and healthcare systems alike. Only by making the invisible visible can we build the foundation of empathy necessary to support tomorrow’s clinical solutions.

Referências:

Cunha, C., [Authors], Claussnitzer, M., Loos, R., Kilpeläinen, T. (2026). Genomic partitioning of Alzheimer’s disease in humans reveals non-CNS etiology. medRxiv.

Cunha, C., [Authors], Kilpeläinen, T., Loos, R. (2026). Genomics link obesity and type 2 diabetes to Alzheimer’s disease to unveil novel biological insights. medRxiv.v.