Laboratory plays critical role in revolutionising Alzheimer’s careLaboratory plays critical role in revolutionising Alzheimer’s care

Alzheimer’s disease (AD) is diagnosed neuropathologically by the presence of amyloid beta (Aβ) plaques and tau neurofibrillary tangles. Aβ plaques accumulate 10 to 30 years before the onset of dementia and contribute to the spread of tau pathology across the brain. Although the exact mechanism linking Aβ and tau spread is unclear, it likely involves increased tau phosphorylation. Tau pathology spreads in a stereotypic order, potentially along four distinct trajectories, each associated with different clinical outcomes.

Current diagnostic methods for Alzheimer’s disease

Current diagnostic methods for AD include imaging and cerebrospinal fluid (CSF) biomarkers. Aβ PET scans and CSF Aβ levels are used to detect Aβ plaques, and tau PET scans, particularly with the flortaucipir tracer, to detect tau tangles. In terms of CSF biomarkers, Aβ42 and phosphorylated tau (p-tau) levels are crucial for diagnosing AD, with p-tau217 showing strong correlations with tau tangles and Aβ plaques.

Markers of neurodegeneration, such as hippocampal volume from MRI scans and CSF markers like total tau (t-tau) and neurofilament light (NfL), provide insights into the disease’s progression. NfL, in particular, reflects ongoing neurodegeneration and correlates with disease severity. While these biomarkers help guide diagnosis and prognosis, their use remains primarily in specialised settings, and blood-based biomarkers for AD are emerging as potential game-changers for more accessible and cost-effective diagnosis in both clinical practice and research.

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The emergence of blood-based biomarkers

Blood-based biomarkers (BBMs) are emerging as valuable tools for diagnosing and monitoring AD and related disorders. Plasma Aβ42/Aβ40 ratios correlate with brain Aβ plaques, though assay performance varies significantly. Mass spectrometry-based assays demonstrate superior accuracy compared to immunoassays, which perform less reliably. Incorporating APOE genotype into prediction models enhances accuracy by around 10 per cent.

High-sensitivity plasma assays for p-tau isoforms, such as p-tau181, p-tau217, and p-tau231, reliably detect AD pathology. Among these, p-tau217 shows the strongest correlation between plasma and CSF levels and better diagnostic performance. Plasma p-tau231 appears sensitive to early Aβ plaque accumulation, while p-tau181 and p-tau217 are linked to both Aβ plaques and tau tangles, with p-tau217 showing stronger associations.

NfL reflects active neurodegeneration across neurodegenerative diseases, including AD, though its effect size is smaller in plasma than in CSF. Glial fibrillary acidic protein (GFAP) levels, indicative of reactive astrocytes, increase with early Aβ pathology and can predict cognitive decline and conversion to AD dementia. GFAP is also elevated in other neurodegenerative disorders, emphasising its broad utility.

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Blood-based biomarkers in early Alzheimer’s detection

BBMs are proving effective in detecting AD-related pathology even in cognitively unimpaired individuals and those with subjective cognitive decline. High-performing plasma assays for p-tau181, p-tau217, p-tau231, Aβ42/Aβ40, and GFAP can identify early AD brain changes, with p-tau231 and Aβ42/Aβ40 particularly suited for detecting the earliest stages of amyloid pathology.

Combining plasma p-tau and Aβ42/Aβ40 enhances diagnostic accuracy in these early stages, where Aβ42/Aβ40 assays may play a more prominent role than in later disease progression. While there is currently limited clinical demand for diagnosing AD in cognitively normal individuals, this may change with the potential approval of anti-amyloid therapies (e.g., lecanemab, donanemab) in the coming years. BBMs could also be valuable for individuals with subjective cognitive decline whose cognitive test results are normal but who exhibit gradual cognitive deterioration, similar to their use in patients with mild cognitive impairment.

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Challenges and future directions in Alzheimer’s diagnosis

Most patients with cognitive symptoms are managed in primary care, where accurate AD diagnosis is challenging due to the lack of accessible, cost-effective diagnostic tools. Currently, 50 to 70 per cent of patients with cognitive impairment go unrecognised or misdiagnosed, especially in early stages like subjective cognitive decline (SCD) or mild cognitive impairment (MCI). This leads to insufficient diagnostic clarity, suboptimal treatment strategies, and unnecessary investigations.

AD BBMs hold promise for improving diagnostic and prognostic capabilities in primary care, as CSF and PET imaging are impractical in this setting. Ongoing prospective studies aim to validate the use of AD BBMs by assessing their impact on diagnosis, treatment, and prediction of AD dementia in non-demented individuals. Regulatory approval and widespread adoption of BBMs in primary care depend on such studies. Once validated, educational resources will be essential to guide primary care physicians in the appropriate use, interpretation, and application of BBM results, developed collaboratively with dementia experts and patient representatives.

The future of Alzheimer’s care and diagnosis

The landscape of AD management is undergoing a transformative shift. AD is increasingly being treated as a chronic condition, with advancements in early diagnosis, disease-modifying treatments, risk reduction strategies, and improved care coordination. Diagnostic tools have evolved significantly, starting with CSF tests and PET imaging, and now include reliable plasma biomarkers like p-tau217 and Aβ42/Aβ40 ratios, which correlate well with established AD pathology markers.. =

Dr. Laila Osama Abdel Wareth, MBBCh, FRCPc, FCAP, is the Chief Executive Officer of the National Reference Laboratory, UAE.