The Future of Alzheimer's Disease Diagnosis

Two anti-amyloid drugs are now available to patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s Disease, slowing disease progression.^1,2 

These treatments are most effective in the earliest symptomatic stages of the disease.^1,2 However, effective diagnosis can often take a year or more.^3,4 Recent advances with diagnostic tools; including biomarker-based tests, digital cognitive assessments and retinal imaging; could help clinicians diagnose Alzheimer’s Disease earlier and more accurately. 

Digital cognitive tests to assess cognitive decline

Digital cognitive assessments show promise to detect subtle cognitive changes, including those associated with early Alzheimer’s disease, and may offer advantages in terms of speed, accessibility, and independent administration. 

These tools can help clinicians determine whether a patient would benefit from a more comprehensive cognitive assessment and potential biomarker testing.^5–7 However, digital cognitive tests are so new that standardized clinical guidelines for their use are still being developed.⁸

Multiple digital cognitive tools are cleared by the FDA which includes: ⁹

• Automated Neuropsychological Assessment Metrics (ANAM: a computerized cognitive battery that measures multiple components of cognitive function including memory, attention, concentration, problem-solving, and decision-making. The assessment typically requires 20 to 25 minutes.¹⁰
• Cambridge Neuropsychological Test Automated Battery (CANTAB Mobile®): a touchscreen-based, self-administered cognitive test that assesses visuospatial episodic memory, mood (depression), and functional status (everyday tasks). The assessment takes under 10 minutes and provides an age-adjusted report with outputs for memory and mood.¹¹
• Cognigram: A 10 to 15-minute computerized test, that can be administered at home or in the clinic, evaluates domains such as attention, learning, memory, psychomotor function and working memory. It is designed to detect subtle cognitive changes.¹²
• Cognision: A 60-minute test that uses electroencephalography and measurement of auditory evoked potential to assess cognitive impairment.¹³ 
• Cognivue Clarity: A self-administered 10-minute test that evaluates memory, visuospatial ability, executive function, processing speed, and discrimination. The test uses a joystick for user input. Additionally, its Amyloid Risk Measure (CARM) algorithm provides a predictive metric for amyloid positivity.¹⁴
• Cognetivity CognICA: A five-minute, self-administered computerized test often taken on a tablet that requires patients to complete categorization tasks, such as determining whether an image represents an animal. The test assesses processing speed and accuracy as proxies for cognitive function.¹⁵

Confirming and staging Alzheimer’s pathology

Mild cognitive impairment (MCI) may be caused by a number of underlying conditions unrelated to Alzheimer’s disease, including hormonal or vitamin deficiencies, certain medications, sleep disorders, and depression.¹⁶ Some of these causes are potentially reversible with appropriate treatment.^16,17

Once causes unrelated to Alzheimer’s disease have been ruled out, biomarker testing can be used to detect Alzheimer’s disease pathology and determine disease stage. Patients diagnosed with MCI due to AD or early AD dementia may be eligible for anti-amyloid disease-modifying therapies, which have been shown to slow disease progression to a modest degree^1,2 For a more detailed overview of biomarker testing, refer to our previous article. 

Blood-based biomarkers

According to recommendations from the Global CEO Initiative on Alzheimer’s disease, blood tests intended for triaging use in primary care settings should demonstrate ≥90% specificity and ≥85% sensitivity for detecting amyloid pathology. In specialty care, the recommended specificity may be slightly lower, ≥75–85%, depending on the availability of follow-up confirmatory testing, such as CSF analysis or amyloid PET imaging.¹⁸ When the results are indeterminate, additional testing with CSF analysis or PET imaging may be needed to confirm the presence of amyloid pathology. When used as a standalone confirmatory tool, BBM tests should perform comparably to CSF assays, with both sensitivity and specificity near 90%.¹⁹

Several blood tests are available in the U.S. as laboratory-developed tests (LDTs), which are offered through individual laboratories but are not FDA-cleared. Unlike LDTs, the first FDA-cleared plasma-based in vitro diagnostic (IVD) test for Alzheimer’s disease was authorized on May 16th, 2025: the Lumipulse® G pTau 217/β-Amyloid 1-42 Plasma Ratio. This test is intended to aid in the detection of amyloid pathology in adults over 50 with symptoms of cognitive decline.²⁰

Cerebrospinal fluid biomarkers

Cerebrospinal fluid is collected through a lumbar puncture and analyzed for Alzheimer’s disease biomarkers. Confirmation of amyloid pathology in CSF is achieved by measuring the ratios of pTau 181/ β-Amyloid 1-42, β-Amyloid 1-42/40, or tTau/β-amyloid 1-42.²¹Because of their reliability, Cerebrospinal fluid biomarkers are often used as confirmatory tests before initiating anti-amyloid therapy.²²

Imaging biomarkers

PET imaging is commonly used to confirm amyloid pathology by utilizing a radioactive tracer to bind beta-amyloid (β-Amyloid) plaques in the brain. There are currently three FDA-approved fluorine-18 radiotracers to detect β-Amyloid: 18F-florbetapir, 18F-flutemetamol, 18F-florbetaben.²³ Tau PET imaging, using the FDA-approved tracer 18F-flortaucipir, is not used for diagnostic confirmation but may aid in staging the disease by assessing the regional distribution of neurofibrillary tangles.^23,24

New tests on the horizon

Several digital cognitive and biomarker-based tests are currently in development. While some are already available for clinical use, they have not yet received FDA clearance:

• Digital tests that help screen for cognitive impairment
  • Tools that assess vocal biomarkers, analyzing changes in speech patterns and tempo, that may indicate MCI.²⁵
  • Remote AI-driven cognitive testing batteries.^5,26
  • Wearables and passive monitoring systems, including in-home sensors that collect information and detect potential changes in gait, heart rate, physical activity, and sleep patterns to identify early signs of cognitive decline.²⁷
  • Eye-tracking assessments that measure gaze points and eye movements to provide insights into cognitive function, visual attention, memory, and processing speed.²⁸
• Blood biomarker tests 
  • Several companies and laboratories offer blood tests that measure biomarkers, such as pTau-217, pTau217/npTau-217, β-Amyloid 1-42/1-40, NfL, and GFAP.¹⁹
  • Blood-based biomarker research continues to accelerate. A growing number of exploratory biomarkers are under investigation for their potential to capture disease heterogeneity, and aid in staging or monitoring progression These include SNAP-25, sTREM2, p-tau231, p-tau205, MTBR-tau, NPTX2, GFAP, and composite scores based on multiple biomarkers.^29–34
    • SNAP-25: A marker of synaptic degeneration associated with cognitive decline.³⁰ 
    • sTREM2: The soluble, cleaved form of the microglial membrane receptor TREM2, detectable in CSF and blood. Elevated sTREM2 reflects microglial activation and neuroinflammation, and higher levels are associated with increased risk of MCI and Alzheimer’s disease. However, while it might indicate cognitive decline, sTREM might not be reliable to distinguish between disease stages.³¹ 
    • p-tau231: A phosphorylated tau isoform that increases in the earliest stages of AD and is enriched in pre-tangles.³²
    • p-tau205: A phosphorylated tau isoform that correlates with brain atrophy and hypometabolism, reflects later tau pathology, and is closely associated with tau PET signal.³²
    • MTBR-tau: A tau protein fragment reflecting insoluble tau aggregates, closely associated with tau tangle pathology and elevated during the symptomatic, later stages of the disease.³³
    • NPTX2: A protein involved in synaptic transmission and neuronal excitability.²⁹ Low levels are associated with tau load and cortical atrophy, but not amyloid burden.²⁹ 
    • GFAP: A marker of astroglia activation, associated with early amyloid deposition and disease progression.³⁴
• Cerebrospinal fluid tests
  • YWHAG/NPTX2 ratio, SNAP-25 and VAMP-2 are being investigated as biomarkers predictive of cognitive decline and synaptic injury/dysfunction.²⁹
  • YWHAG: A member of the YWHA family of proteins that regulate tau phosphorylation and accumulation.²⁹
  • NPTX2: A protein involved in synaptic transmission and neuronal excitability.²⁹ Low levels are associated with tau load and cortical atrophy but not amyloid burden.²⁹
  • YWHAG/NPTX2 ratio: A biomarker of synaptic dysfunction and cognitive impairment in Alzheimer’s. It increases with aging, predicts AD onset and progression, and may help stratify patients by risk of future cognitive decline.
  • SNAP-25: A presynaptic protein and marker of synaptic degeneration associated with cognitive decline and cortical atrophy.³⁰
  • VAMP –2: A synaptic vesicle protein linked to synaptic degeneration; its levels change across the AD continuum and are associated with cognitive impairment and tau pathology.³⁵
• Retinal and brain imaging tests in development
  • Multimodal neuroimaging data analyzed by machine learning algorithms to discriminate between healthy controls, MCI, and Alzheimer’s, with promising but still research-stage diagnostic performance.³⁶
  • Proton magnetic resonance spectroscopy (MRS) measures changes in metabolites, including N-acetyl aspartate and myo-inositol, as well as their ratio, to predict amyloid-β pathology.³⁷
  • Retinal imaging and optical coherence tomography are being investigated as non-invasive tools to detect early structural and vascular changes in the retina that may be associated with Alzheimer’s disease.^38,39

The future of Alzheimer’s diagnosis

The rollout of new imaging, CSF/blood-based tests, digital tools, and retinal/eye-tracking biomarkers has the potential to significantly improve diagnosis and patient care over the next decade. These innovations could enable remote assessment of cognitive impairment, assist in the identification and confirmation of biomarkers, and monitor disease progression more effectively.