The moment dementia begins is not the diagnosis

For people diagnosed with mild cognitive impairment (MCI), the future is uncertain. Some remain cognitively stable for years. Others progress to Alzheimer’s disease and related dementias. What determines who converts and who does not remains one of the most puzzling questions in neurodegenerative research.

Rather than treating Alzheimer’s disease as a single endpoint, Rahul Srinivasan and Michelle Hook — both associate professors with the Texas A&M University Naresh K. Vashisht College of Medicine at Texas A&M Health — are focusing on the key biological moment that precedes it: the transition from MCI to dementia. Their collaborative project, supported by a seedling grant from the Texas A&M Health Dementia and Alzheimer’s Research Initiative (DARI), asks whether this transition can be understood mechanistically and if intervening during that transition could change long-term outcomes.

“What we’re really trying to do,” Srinivasan said, “is mitigate the conversion of people with mild cognitive impairment to Alzheimer’s disease and related dementias.”

A societal cliff hidden in plain sight

MCI is often misunderstood as an early form of dementia, but the reality is more complex. Roughly 20% of people over the age of 60 worldwide have MCI, and many continue to maintain a relatively good quality of life.

The challenge lies in what happens next.

Between 40% to 50% of people with MCI eventually progress to Alzheimer’s disease or related dementias, a transition Srinivasan described as a steep decline from relative independence to “quite a difficult time,” not only for the individual but also their caregivers. It’s a significant issue, transforming a large, independent segment of the aging population into one requiring intensive medical and social support.

This communal toll adds urgency to research exploring this transition. Hook stressed a “very strong societal need to try and mitigate the conversion” from MCI to dementia — not after the fact, but before quality of life collapses.

Studying conversion, not just disease

Most Alzheimer’s research has centered on one area of the brain — the hippocampus — and advanced disease stages. But this focus may be too narrow.

“One part of the brain starts to degenerate, and then the second part of the brain starts to degenerate,” Hook said. “And it’s that second part of the brain that is essentially critical.”

Emerging studies indicate that multiple brain regions beyond those classically associated with Alzheimer’s are affected during disease progression. This realization prompted Srinivasan and Hook to think differently about how and where conversion occurs, in addition to what biological systems might govern vulnerability during this transition.

One region of particular interest is the ventral tegmental area (VTA), which plays roles in both cognition and reward. Evidence suggests that connectivity between the VTA and regions such as the medial prefrontal cortex and amygdala is altered during neurodegenerative progression. The team believes these circuit-level changes may explain why some people develop dementia while others do not.

Why cytisine became the probe

Cytisine, a drug that helps people stop smoking, has emerged as the project’s most unexpected element.

Studies have shown the risk for Parkinson’s disease is significantly reduced in people who smoke or consume tobacco — a pattern that perplexed the team.

“Of the thousands of chemicals in cigarette smoke, nicotine was the first candidate we wanted to look at,” Srinivasan said.

That curiosity ultimately led the team to cytisine, a smoking-cessation drug that interacts with the same biological systems without the harmful effects of tobacco.

Several practical features make cytisine particularly useful for research. Its pharmacology is well understood, it can be taken orally, and it has been used safely for decades as a smoking-cessation therapy in parts of Europe. In the United States, it is currently being evaluated in Phase 2 clinical trials for the same purpose.

But in this project, cytisine is not primarily being pursued as a treatment. Instead, researchers are using it as a scientific probe — an experimental tool that allows them to test how nicotine-related signaling pathways might influence brain health.

By activating these pathways in a controlled way, the team hopes to better understand a key mystery in cognitive aging: Why some people with mild cognitive impairment progress to dementia while others remain stable for years.

A collaborative, integrative approach

“This is not something that can be done by a single person,” Srinivasan noted. The integration of his expertise in disease progression and pharmacology and Hook’s background in behavior allows the same question to be examined from complementary angles, linking circuit-level biology with drug-based intervention.

That integration is also where the DARI seedling grant plays a critical role. Rather than funding a single experiment, the initiative supports projects that connect ideas across stages, systems and disciplines. For Srinivasan and Hook, it provides the space to generate the data needed to frame larger questions about dementia risk and progression.

“To really challenge an idea like this, you need data,” Srinivasan said. “This kind of funding helps us generate the data needed to leverage the project forward.”

Rethinking when intervention matters

The team is careful not to frame their work as a cure. Instead, the goal is to redefine when intervention might be most effective. By targeting the biological processes that govern conversion rather than late-stage pathology, the research aims to shift how dementia prevention is conceptualized.

At a societal level, even modest delays in conversion could have profound effects: preserving independence, reducing caregiver burden, and easing strain on health care systems. By focusing on the transition point where quality of life begins to plummet, the work aligns mechanistic neuroscience with real-world impact.

In doing so, the project reframes Alzheimer’s disease not as an abrupt diagnosis, but as a process with an identifiable and potentially actionable moment of change.

By Pooja Chettiar, Texas A&M Health