Alzheimer’s Disease Nears an Inflection Point in Diagnosis and Care

Alzheimer’s disease (AD) has reached a milestone that would have been difficult to imagine just a decade ago.

Blood-based diagnostic tests have entered clinical use. Amyloid-targeting therapies are slowing disease progression in early-stage patients. And experts are debating whether AD should be defined biologically, before symptoms ever appear, and whether it might soon be thought of as a chronic, manageable condition.

Yet for all this momentum, two Cleveland Clinic Lou Ruvo Center for Brain Health neurologists with extensive AD experience believe that the field has not fully reached a new era. Instead, it stands on the threshold of one.

“There’s been more action over the past five years than there had been for a long time,” says Charles Bernick, MD, MPH, Senior Director, Cognitive Disorders, and a veteran AD researcher. “We’re probably very close to changing how we think about things. The paradigm shift may occur relatively soon.”

What clinicians and patients are seeing now is the culmination of decades of work, says Dylan Wint, MD, Medical Director of Cleveland Clinic Nevada, home to the Lou Ruvo Center for Brain Health’s Las Vegas location.

“The things they’ve been hearing about over the past five to 10 years in studies and the research lab are now actually able to touch them in the clinic,” says Dr. Wint, shown with a patient in the photo above. “There's a sense out there of hope, and a real shift. We’re on the verge of a breakthrough in our understanding of, and ability to manage, this disease.”

True transformation, however, hinges on what happens next.

Both physicians caution that major challenges must be overcome if AD is to be screened for and prevented, and for progression in diagnosed patients to be halted rather than delayed.

Changing diagnostic capabilities

One of the most significant changes underway involves how AD is defined, and how and when it can be diagnosed.

Until relatively recently, a presumptive AD diagnosis was based solely on clinical evaluation — history-taking, cognitive testing and the elimination of other potential causes of altered cognition. Confirmation of AD was only possible postmortem with the identification of characteristic amyloid-beta plaques and tau neurofibrillary tangles in autopsied brain tissue.

Within the past two decades, the development of cerebrospinal fluid (CSF) biomarkers that indirectly measure amyloid plaque burden and the advent of brain imaging using positron emission tomography (PET) to visualize pathologic amyloid deposits made antemortem AD diagnosis feasible in specialized clinical settings.

In the past five years, several blood-based biomarker (BBM) tests have become commercially available to estimate AD-associated amyloid pathology in patients exhibiting cognitive impairment. They are less invasive and expensive than PET and CSF testing and can be administered in primary care offices. However, the variable accuracy of individual BBM assays means that they cannot yet be used as a substitute for PET or CSF; less accurate BBMs are intended to be used as triaging tests, with positive results requiring confirmatory testing with PET and CSF.

This evolution in diagnostic capabilities is reshaping how clinicians — and patients — think about the disease. AD is beginning to look more like other chronic medical conditions, with detectable pathology, quantifiable risk and, increasingly, treatment options tied to appearance of the earliest symptoms.

“From the clinical standpoint, we now have the availability of imaging tests, blood tests and disease-modifying medications like we have for so many other conditions,” Dr. Wint says. “It’s demystifying [AD] somewhat for both the average neurologist and the primary care doctor.”

A biology-based definition of AD

The development of BBMs was a powerful catalyst for an Alzheimer's Association workgroup of researchers and clinicians to recommend in 2024 that AD be redefined.

Instead of basing diagnosis on the appearance of symptoms of cognitive decline, they reframed AD as a biological process that begins with assay-detectable neuropathologic changes, well before symptoms arise. The workgroup proposed that abnormalities on amyloid PET, CSF biomarker tests or sufficiently accurate BBMs — alone or in combination — are sufficient to establish that a person has AD, regardless of whether symptoms are present.

Biological-based diagnosis is standard in many other areas of medicine, such as oncology, the workgroup noted — a point with which Drs. Bernick and Wint concur. “We don't say that someone who has a cancerous polyp in their colon doesn't have colon cancer because they don't yet have symptoms,” Dr. Wint says.

But a biology-based definition of AD has some important caveats and introduces new complexities.

First, an amyloid-positive BBM finding in an asymptomatic patient isn’t necessarily prognostic of outcome.

“I think it is true that if you have the biology of the disease, you have the disease,” Dr. Bernick says. “But the implications are different for different age groups. If you’re 60 and have amyloid plaque, you have a high risk over your [remaining] lifetime of becoming symptomatic. If you’re 80 and have plaque, you may never progress to symptomatology in your lifetime.”

As with other chronic diseases, factors such as genetics, lifestyle and socioeconomic stressors also influence an individual AD patient’s journey.

“You wouldn’t believe the number of people I’ve had to talk down” about a positive BBM test result being determinative of imminent dementia, Dr. Wint says.

Analogies to prostate-specific antigen testing for prostate cancer highlight this tension: Early detection can enable intervention, but ambiguities about what a positive finding means can have unintended consequences.

Second, an amyloid-centric diagnostic definition of AD doesn’t acknowledge other contributing biological factors such as tauopathy, neuroinflammation and neurodegeneration and the spectrum of related dementias that can result.

“We may be making a mistake by trying to redefine Alzheimer’s disease by these amyloidopathies/tauopathies while retaining the Alzheimer's disease name,” Dr. Wint says.

The situation is comparable to Pick’s disease, he says, which once was synonymous with frontotemporal dementia itself but is now recognized as one example of a group of related degenerative processes that each can cause frontotemporal dementia.

“We may need to come up with a formulation that’s similar,” Dr. Wint says — a grouping of related dementias defined by their relative amounts of amyloidopathy, tauopathy, neuroinflammation and neurodegeneration, with AD as a specific subset.

The impact of amyloid-targeting drugs

The ability to biologically diagnose AD prior to symptom onset would be a hollow achievement without therapeutic options.

Today, the availability of disease-modifying drugs creates a clear rationale for earlier and more precise AD diagnosis. The arrival of the amyloid-targeting monoclonal antibody therapies aducanumab (now off market), lecanemab and donanemab represents an important step forward, but one that requires careful framing and patient communication.

At present, lecanemab and donanemab are approved only for patients with AD who already show early signs of cognitive and functional impairment, as a means of delaying — but not preventing — progression. They are used initially for up to 18 months to reduce plaque burden.

Lecanemab is also approved for follow-on maintenance dosing, either by intravenous infusion or at-home subcutaneous injections, to prolong the benefit of therapy and continue slowing disease progression.

Of those Lou Ruvo Center for Brain Health AD patients eligible for maintenance lecanemab therapy, most have opted to stay with monthly in-clinic infusion rather than weekly self-injection at home. “My experience has been that, because the infusions have turned out to be much less burdensome than people imagined, they have not had much problem with continuing that,” Dr. Wint says.

MRI-detectable brain edema and microhemorrhages known as amyloid‐related imaging abnormalities (ARIAs) are a recognized side effect of anti-amyloid therapy. But because the ARIA risk falls to placebo-like levels after six months, MRI monitoring generally is not needed by the time maintenance therapy begins. “We would only monitor if someone has ARIA symptoms,” Dr. Bernick says.

Results from the open-label extension of the CLARITY AD clinical trial published in late 2025 showed that maintenance lecanemab dosing continued to produce treatment efficacy for as long as three years in terms of suppressed amyloid plaque levels and significantly slowed cognitive decline.

The ongoing CLARITY AD trial — in which Cleveland Clinic has participated — will determine if lecanemab’s benefits last beyond 36 months in patients with early AD. It’s unknown whether either lecanemab or donanemab can prevent or slow progression in asymptomatic biomarker plaque-positive patients. The active AHEAD 3-45 and TRAILBLAZER-ALZ 3 trials intend to answer that question within several years.

“If they read out as positive, then that’s a paradigm change,” Dr. Bernick says. “Then people will be identified before they become symptomatic and they'll be treated with whatever agents we have and that's going to change everything.”

Meanwhile, for patients with early AD, “the longer you can keep them from progressing to moderate and severe stages, that's a real win,” Dr. Bernick says. “It’s a relentlessly progressive disease, but you can change the slope of the trajectory.”

Challenges to be addressed

Even as AD research and treatment advance, practical challenges loom large.

The ability to detect preclinical plaque accumulation and the proposal for biomarker positivity to constitute an AD diagnosis could result in millions more people being classified as having the disease. That raises concerns about overdiagnosis and anxiety and has downstream implications for medical costs, insurance coverage and access to care.

Should BBM testing be widely offered, particularly without the current availability of preventive treatment for those who test positive? Are neurologists and primary care physicians prepared to counsel and manage a potential flood of newly diagnosed AD patients?

“It's a good thing we have these tests,” Dr. Bernick says. “But until we have preventive treatments, I don't think we should” use them as screening tools in asymptomatic people.

Amyloid-targeting therapies are expensive, costing tens of thousands of dollars annually. They also require infrastructure — infusion centers, MRI monitoring and specialized personnel — that may not be readily available outside large urban medical centers.

“These treatments are labor-intensive,” Dr. Bernick says. “We can do it here because we have the personnel, but how do you apply it if you're in a small practice?”

If clinical trials confirm the drugs’ ability to suppress plaque formation long-term in early AD patients and to slow or stop progression in asymptomatic patients, the demand will escalate, compounding the affordability and access issues.

“We need to come up with solutions,” Dr. Wint says. “We purchased a portable MRI scanner and we're going to research whether it can be used to monitor people in rural locations for ARIAs, among other things.”

Differences in access extend beyond geography. Biological differences in amyloid burden across populations may affect eligibility for treatment, potentially exacerbating existing differences in care access.

“The Black population, for example, has lower levels of amyloid at the same level of severity of Alzheimer’s disease,” Dr. Wint says. “So if you're using amyloid plaque burden as the key to entry for anti-amyloid medicines, you're going to disproportionately exclude African Americans. And if there’s a large population for whom amyloid burden doesn’t seem to be a significant driver, our amyloid-centric approach to Alzheimer’s disease will impede development of effective treatments for a significant segment of the population.”

What the near future might look like

For now, AD remains a progressive illness with limited though meaningful tools to slow its clinical course. But a more hopeful future is coming into focus.

In the next decade or so, Drs. Bernick and Wint foresee a confluence of developments that will improve treatment, edge AD closer to a manageable chronic condition and perhaps lay the groundwork for preventive strategies. They include:

• A fuller understanding of the disease process that incorporates the interplay between proteinopathies, neuroinflammation, neurodegeneration, genetics, lifestyle, socioeconomics and other factors
• Combination or sequential therapies that target multiple AD components, not just amyloid
• Additional BBMs that can characterize tau burden, neuroinflammation and neurodegeneration
• Refined clinical trials that leverage biomarkers to ensure participants have actionable therapeutic targets and to determine if the intended intervention is affecting the target
• Better predictors of an individual’s risk of developing AD and improved means of reducing that risk

“I think we’ll have a more multidimensional diagnostic, research and therapeutic picture” of AD, Dr. Wint says.

Inevitably, there will be more questions than answers.

“It's the nature of science to want to make a discovery and to make a change,” Dr. Wint says. “But I think uncovering new questions is at least as valuable. There are very few final answers.”