Timely Identification of Alzheimer's Disease: Bridging the Diagnostic Gap and the Role of Biomarkers

Alzheimer's disease (AD) remains the most common neurodegenerative disorder globally and accounts for nearly 60-80% of dementia cases, representing a major and growing public health challenge⁽¹⁾. However, its early diagnosis still remains a challenge, delaying timely intervention and potential benefits from the therapies. Early identification of AD is thus recognized as critical, particularly with the advent of disease-modifying therapies and improved diagnostic tools.

Understanding the Silent Progression of Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by a prolonged asymptomatic phase followed by the gradual onset of clinical symptoms, most notably short-term memory impairment, which progresses to broader cognitive decline over time⁽²⁾. The formation of amyloid-beta (Aβ) plaques, tau-mediated neurofibrillary tangles, and finally neurodegeneration constitute the underlying disease process, which starts years to decades before symptoms appear^(7,14).

Importantly, Aβ deposition reaches significant levels before clinical symptoms appear, highlighting a crucial window for early detection and intervention^(7,14).

Challenges in Early Diagnosis of Alzheimer’s Disease

Despite advances in understanding AD pathology, early diagnosis remains challenging. Several barriers contribute to delaying the diagnosis, including:

• Limited clinician time

• Difficulty in accurately identifying Alzheimer’s disease pathology

• Misinterpreting the early symptoms as normal ageing⁽²⁾

As a result, substantial diagnostic gaps persist:

• Diagnosis is delayed by approximately 2-3 years after symptom onset^(3,4)

• Up to 1 in 6 clinically diagnosed patients lack AD pathology at autopsy⁽⁵⁾

• Nearly 75% of dementia cases remain undiagnosed⁽⁶⁾

These barriers collectively delay intervention and reduce the potential window of benefit from emerging therapies.

Differential Diagnosis of Alzheimer’s disease (AD) and the Spectrum of Dementia

Accurate diagnosis of AD requires differentiation from other causes of cognitive impairment. Potential reversible or alternative causes include depression, delirium, normal pressure hydrocephalus, cerebrovascular disease, vitamin B12 deficiency, infections, malignancy, substance abuse, and medication side effects^(8,10,11). Alzheimer's exists within a broader dementia spectrum, with other types including vascular dementia, Lewy body dementia, frontotemporal dementia, and hippocampal sclerosis⁽⁹⁾. Notably, mixed dementia is increasingly recognized, with over 50% of patients showing evidence of multiple pathologies⁽⁹⁾.

Clinicians may like to remain vigilant for early indicators across neurocognitive domains, including memory loss, disorientation, language difficulties, impaired judgment, behavioural changes, and social withdrawal⁽¹²⁾. Early recognition of these features can facilitate prompt evaluation and diagnosis.

Role of Biomarkers in Alzheimer’s Disease (AD)

The incorporation of biomarkers has transformed the diagnostic landscape of Alzheimer's Dementia (AD). Both amyloid and tau biomarkers are now widely recognized and recommended in contemporary diagnostic guidelines⁽⁷⁾.

Available biomarker testing tools include:

• Positron emission tomography (PET)-based imaging

• Cerebrospinal fluid (CSF) biomarkers

• Emerging plasma-based biomarkers⁽⁷⁾

Biomarkers play a crucial role in early detection and screening, diagnostic confirmation, disease staging, and guiding therapeutic decision-making^(1,7). Modern diagnostic criteria increasingly emphasize the need for biomarker evidence to confirm AD pathology, marking a shift toward biologically defined disease classification⁽¹³⁾.

Importance of Timely Diagnosis

• Enables early therapeutic interventions

• Facilitates care, planning, and decision-making

• Allows patients and caregivers to anticipate disease progression⁽¹⁾

All elderly patients presenting with cognitive, behavioural, or functional changes, either self-reported or noted by caregivers, should undergo evaluation for possible dementia risk⁽¹⁵⁾.

Early diagnosis not only improves clinical outcomes but also empowers patients and their families to adapt proactively to the evolving disease trajectory.

Key Takeaways

• Alzheimer’s disease continues to pose significant diagnostic challenges, particularly in its early stages. Delayed, missed, or incorrect diagnoses remain common, largely due to subtle symptom onset and limitations in clinical recognition.
• The integration of biomarkers into clinical practice represents a paradigm shift, enabling more accurate and timely diagnosis. As therapeutic options expand, early detection will become increasingly central to improving patient outcomes.
• Bridging the diagnostic gap in AD requires heightened awareness, systematic evaluation of cognitive symptoms, and broader adoption of biomarker-driven approaches in routine clinical practice.

Abbreviations

AD-Alzheimer’s Disease; Aβ- Amyloid-Beta; PET- Positron Emission Tomography; CSF-Cerebro-Spinal Fluid;

References

1. Hampel H, et al. Nat Aging. 2022;2(8):692-703.

2. Porsteinsson AP, et al. J Prev Alzheimers Dis. 2021;8(3):371-386.

3. Balasa M, et al. Neurology. 2011;76(20):1720-1725.

4. Sabbagh MN, et al. Neurol Ther. 2017;6(Suppl 1):83-95.

5. Beach TG, et al. J Neuropathol Exp Neurol. 2012;71(4):266-273.

6. Dubois B, et al. Alzheimers Res Ther. 2023;15(1):175.

7. Iaccarino L, et al. J Prev Alzheimers Dis. 2023;10(3):426-442.

8. National Collaborating Centre for Mental Health. Dementia: A NICE-SCIE Guideline. 2007.

9. 2023 Alzheimer’s disease facts and figures. Alzheimers Dement. 2023;19(4):1598-1695.

10. Bello VME, Schultz RR. Dement Neuropsychol. 2011;5(1):44-47.

11. Piccini C, et al. J Neurol Sci. 1998;153:172-181.

12. NIH National Institute on Aging (NIA). 2022.

13. Abdelnour C, et al. Alzheimers Res Ther. 2022;14(1):112.

14. Jack CR Jr, et al. Lancet Neurol. 2013;12(2):207-216.

15. Atri A. Med Clin North Am. 2019;103(2):263-293.

CMAT-22273 | 6th April 2026

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