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AD Early Diagnosis
Emerging Tools for Early Alzheimer’s Detection and Treatment

Released: October 30, 2025

David S. Geldmacher
David S. Geldmacher, MD, FANA, FACP
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Key Takeaways
  • Alzheimer’s disease presents an increasing burden on the healthcare system, with rising prevalence among older adults and limited access to specialists, necessitating greater frontline clinical engagement and preparedness.
  • Early and accurate diagnosis is now more feasible than ever, thanks to advances in biomarkers, imaging, and careful clinical assessment, including detection at the prodromal stage of mild cognitive impairment.
  • Symptomatic treatments, like acetylcholinesterase inhibitors and memantine, offer meaningful functional preservation, but remain underused despite consistent evidence supporting their benefit.
  • New monoclonal antibody–based therapies targeting amyloid have ushered in a transformative era, offering a measurable slowing of disease progression but also raising important considerations about safety, cost, and appropriate patient selection.

Introduction
A persistently increasing prevalence of Alzheimer’s disease (AD) has been predicted for decades, and the illness is now recognized as a major public health issue, with annual direct healthcare costs of more than $350 million per year in the United States. The burden of the illness on medical practice is substantial. Approximately one in 10 people older than 65 years of age has AD or related forms of dementia (ADRD), and people in this age range account for more than one quarter of all primary care visits in the United States. AD prevalence approximately doubles every 5 years after age 65 years, eventually affecting more than 33% of people older than 90 years of age. Care of patients with AD is notably complex, spanning management of cognitive and neuropsychiatric symptoms, progressive disability, and complicated family caregiving situations. As a result, more than 2 in every 5 patients affected by dementia die in nursing homes. Not surprisingly, many primary care providers feel ill-equipped to manage patients through the course of AD. Already protracted waiting times for neurologists and other specialists are expected to continue to lengthen well into the 2030s. Fortunately, there are promising developments in the field that should help to facilitate earlier, more accurate diagnosis and slow progression of the illness.

Disease Overview
AD was first reported in 1906 but became widely recognized as a cause of dementia among older adults only in the 1980s. Pathologically, the disease is defined by the accumulation of neuritic amyloid plaques and neurofibrillary tangles in the cerebral cortex. Plaques are composed of dense extraneuronal accumulations of insoluble β-amyloid peptide accompanied by activated microglial cells and neuronal fragments (neurites). β-amyloid is a normally produced brain peptide that accumulates abnormally, resulting in plaques that are the first pathologic finding to emerge in AD. Tangles arise intracellularly and consist of hyperphosphorylated tau peptide; tangle formation represents a failure of the neuronal cytoskeleton, leading to disruption of intracellular transport, loss of function, and neuronal death. Tangles are typically located in the cerebral cortex of the temporal lobe and adjacent cortical association areas. This localization contributes to the losses in memory, language, visuospatial function, and behavioral regulation characteristic of dementia with AD pathology.

Presentation
Clinically, AD is characterized by an insidious onset and progressive course of cognitive decline, especially in episodic memory, most often followed by losses in language skills, executive function, and visuospatial ability. Many older adults complain of “short-term memory loss,” but this term has little meaning in clinical settings because it describes different phenomena for different people, including forgetting a familiar name or the reason for entering a room. Memory loss raising concern for AD involves forgetfulness of recent activities (not just conversations) or repetitiveness within a conversation. Increasing difficulty finding common nouns and verbs can be another red flag for AD. Patients are often unaware of these issues and may deny their relevance when raised by family members. Historically, a loss of daily function attributable to the cognitive failures—that is, “dementia” (or major neurocognitive impairment in the DSM-5)—was required for the diagnosis of AD, but a prodromal state of cognitive decline without functional loss, mild cognitive impairment (MCI), is now recognized as part of the AD spectrum and represents an important stage for potential intervention.

Diagnosis
Many nonneurodegenerative factors can contribute to cognitive symptoms among older adults, and these should be considered. Laboratory blood panels can assess metabolic factors, thyroid function tests, and vitamin levels, especially vitamin B12. Brain imaging, typically with MRI, is standard of care and should consider cerebral cortical atrophy, cerebrovascular change (including white matter hyperintensities), and other potential structural abnormalities. Careful clinical assessment should include potential adverse cognitive effects of medications (both prescribed and over the counter), mood issues (including both depressive and anxious symptoms), pain, and disrupted sleep. These represent treatable conditions that exacerbate cognitive losses even when AD is present. The FDA has now approved blood-based biomarker tests for AD, but their use and interpretation require nuance. In general, commercially available, high-sensitivity tests are most useful for ruling out AD pathology rather than establishing it. The current gold-standard tests to establish an AD pathologic diagnosis are combined FDA-approved amyloid/tau assays with high specificity in cerebrospinal fluid or 18F-FDG PET scans with ligands that bind to plaques in the cerebral cortex. However, caution is warranted when interpreting amyloid biomarker results because more than 40% of cognitively unimpaired people older than 80 years of age may have detectable cortical amyloid.

Symptomatic Treatment
Pharmacologic treatment for AD symptoms has a well-established evidence basis but is often undervalued. The centrally acting acetylcholinesterase inhibitors (AChEIs: donepezil, galantamine, and rivastigmine) have consistently demonstrated effectiveness in delaying cognitive and functional decline among treated patients with mild and moderate dementia due to AD. They are available in a variety of oral and transdermal forms. Although marked improvement in memory and other cognitive symptoms is not typical for these agents, delayed decline—that is, relative preservation of cognition and function for 9-12 months—can be expected. Over the longer term, benefits may be present for several years (relative to the untreated course), and reduced risk for and prolonged time to nursing home placement are frequently reported outcomes. Most patients tolerate the AChEI agents with few adverse effects, and changes in drug or formulation to reduce adverse effects usually can be identified. The AChEI agents have not been approved by the FDA for use in patients with MCI, but many neurologists will initiate treatment during the MCI phase when AD pathology is suspected or confirmed.

Memantine, a partial NMDA receptor antagonist, has demonstrated efficacy in delaying decline for people with moderate and severe stages of AD dementia, with greater reported efficacy when administered in combination with chronic AChEI use than in monotherapy. It is a generally well-tolerated oral drug but has not been approved by the FDA for use in MCI or mild dementia.

Neuropsychiatric symptoms ranging from apathy to psychosis are major problems in AD. Agitation is a frequent complaint, especially as dementia progresses. Placebo-controlled trials suggest that serotonin-selective reuptake inhibitors, notably escitalopram and sertraline, may provide benefit for nonpsychotic agitation. Brexpiprazole received FDA approval for the treatment of agitation associated with AD, but like all other antipsychotic agents, it carries a boxed warning for serious adverse effects when used in older adults with dementia.

Amyloid Targeting Treatment
Recent years have seen a tremendous advance in AD therapeutics, with monoclonal antibody agents that target the amyloid peptide. Two are commercially available in 2025, lecanemab and donanemab, and others are in development. These are indicated for patients with MCI or mild dementia associated with AD pathology. Although they differ somewhat in epitope targets, both agents reduced progression of cognitive and functional losses compared with placebo over an 18-month course of treatment. PET scans showed rapid and substantial reduction of cortical amyloid compared with placebo. Like prior amyloid-targeting monoclonal antibodies, lecanemab and donanemab are each associated with significant rates of amyloid-related imaging abnormalities (ARIA), including edema (effusions) and hemorrhages. The frequency of ARIA is associated with APOE4 gene dose, with homozygotes having higher rates than heterozygotes and noncarriers having the lowest risk. Establishing APOE4 status is, therefore, an important step in counseling patients on potential risks of therapy. Regular, scheduled MRI scanning to screen for ARIA is part of the monitoring for these, with minor variations between agents. The labeling for donanemab indicates once-monthly IV dosing and allows discontinuation if follow-up amyloid testing is negative after 12 months. Lecanemab’s dose regimen is by IV infusion every 2 weeks for 18 months, followed by weekly subcutaneous maintenance dosing over the long term. The FDA is expected to announce a decision on initiating lecanemab with subcutaneous dosing in 2026.

Conclusion
AD is a complex disorder with major impact on patients, families, healthcare services, and public health. It has seen revolutionary change in diagnostic and treatment approaches in the last 3 years, and continued rapid progress is expected through the end of the decade and beyond. This progress will likely involve new therapeutic targets, new classes of drugs, and enhanced risk reduction—or even preventive—approaches.

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