Biomarkers for Alzheimer’s disease

SUSHRUT -A Magazine of Pharmaceutical Sciences

Volume 1, Issue 1, August 2024, Pages 11-13

Biomarkers for Alzheimer’s disease

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August 2024 ➧ A MAGAZINE OF PHARMACEUTICAL SCIENCES ➧ ¹ Department of Pharmaceutical Sciences, Jharkhand Rai University, Ranchi, Jharkhand, 834010, India, ➧ ² Department of Pharmacy, Ranchi Collage of Pharmacy, Jharkhand 834003, India ➧ Volume 1

The search for meaningful biomarkers is one of the hottest areas of Alzheimer research. These biomarkers should be specific, suitable for routine use in clinical practice, and indicate specific stages of the disease. The emergence of novel biomarkers, such specific microRNA populations, downstream molecules associated with Amyloid-β (Aβ) and tau toxicity, and ultrasensitive detection of seeding-competent Aβ and tau populations are currently being explored for use as early, low-invasive, sensitive, and specific diagnostic probes. Currently under development, seeding aggregation assays are extremely sensitive techniques that exploit the functional properties of Aβ oligomers to seed the polymerization of monomeric Aβ. Recent advances in such innovative techniques may result in a blood-based diagnostic test for Alzheimer disease. Forthcoming research will reveal whether the coveted diagnostic test for Alzheimer disease is a real possibility.. Read More

: Alzheimer Research, Biomarkers, Amyloid-β

Introduction

Alzheimer's disease (AD) is a leading cause of dementia, beginning with mild memory issues that progress to severe cognitive impairment and functional decline. By the time AD is clinically diagnosed, significant neuronal loss and neuropathological changes are evident. Early intervention with neuroprotective drugs can potentially halt further damage, making early diagnosis crucial.

Identifying individuals with mild symptoms before full-blown dementia is essential. Current diagnostic approaches include imaging techniques and cerebrospinal fluid (CSF) biomarkers to classify AD. Given the projected increase in AD cases and associated costs from 2030 to 2050, research is focusing on early detection of the transition from normal aging and mild cognitive impairment (MCI) to dementia.

The concept of MCI has evolved, recognizing subtypes such as amnesic and nonamnesic, the latter involving executive function deficits like attention and problem-solving. Early AD diagnosis often involves analyzing the medial temporal lobe memory system, with memory impairments correlating with medial temporal lobe atrophy and hypoactivation [1].

Novel approaches such as mitochondrial electrophysiology and electrodermal activity analysis have the potential to identify early alterations in brain function prior to the manifestation of neuropathology or severe symptoms. Prodromal AD, Typical AD, Atypical AD, Mixed AD, and Preclinical States of AD are among the diagnostic classification categories that the National Institute on Aging and Alzheimer's Association has proposed. While typical AD is characterized by progressive memory deficits and cognitive problems, prodromal AD is characterized by early signs including episodic memory loss. Less prevalent phenotypes are associated with atypical AD, while concomitant illnesses are present in mixed AD. Alzheimer's pathology reflects early brain alterations, and presymptomatic AD and asymptomatic at-risk are the two categories of preclinical states [2].

Biomarkers and Risk Factors in Alzheimer’s Disease

Visuospatial deficits and significant parietooccipital atrophy on MRI can indicate neurodegeneration leading to conditions such as posterior cortical atrophy or optical dysfunction in Alzheimer's Disease (AD). Symptoms commonly include logopenia, aphasia, and various forms of cognitive impairment. Additionally, presenile dementia and hemiparkinsonism can share features with AD, though their coexistence is rare.

Biomarkers are crucial for diagnosing AD, particularly when Mild Cognitive Impairment (MCI) is present. The accuracy of predicting AD in MCI patients improves when both Amyloid-β (Aβ) and neuronal injury biomarkers are positive. While Aβ alone provides an intermediate probability, the absence of Aβ measurement with a single neurologic damage biomarker suggests a lower likelihood of developing AD.

Age plays a significant role in AD progression, with pathological lesions density increasing with age. Early-onset familial AD, occurring before age 60, is inherited in an autosomal dominant manner and is linked to mutations in the amyloid precursor protein (APP) gene on chromosome 21. These mutations lead to Aβ plaque formation and are detectable in cerebrospinal fluid (CSF) and plasma using imaging techniques like Positron Emission Tomography (PET).

Key biomarkers include Aβ and phosphorylated tau proteins, which increase the likelihood of AD development. These biomarkers can be detected through various in vivo and in vitro methods, including Scanning Tunneling Microscopy and Optical Imaging. MRI and PET also reveal patterns of atrophy and hypometabolism in brain regions affected by AD.

Genetic factors, such as the presence of the Apolipoprotein E (ApoE) gene, especially its fourth form, increase AD risk, with age between 65 and 75 being particularly susceptible. Other biomarkers of interest include CSF α-synuclein and mitochondrial dysfunction, which affects ATP production and neuronal health. Metal ions, such as zinc, copper, and iron, contribute to oxidative stress and Aβ toxicity, influencing AD development [3].

Figure 1: An overview of biomarkers and techniques for early diagnosis of Alzheimer's disease (Copyright by Springer Link) [4].

Recent studies also focus on novel biomarkers like YKL-40, elevated D-serine levels, and specific microRNAs (miR-31, miR-93, miR-143, and miR-146a) found in AD patients. Blood pressure changes are observed years before AD onset, though its exact role in disease progression remains unclear [3].

Overall, early and accurate diagnosis using a combination of biomarkers and imaging techniques is essential for managing AD and preventing its severe consequences.

Conclusion

Definitive diagnosis of Alzheimer’s Disease (AD) requires post-mortem examination, as neuroimaging faces challenges due to clinical and pathological variability. While all AD patients experience a Mild Cognitive Impairment (MCI) phase, not all MCI patients develop AD, and progression rates vary. Biomarkers in cerebrospinal fluid and plasma, along with amyloid imaging, offer insights into AD neuropathology when structural MRI falls short. Genetic mutations contribute to less than 2% of cases, with age being a major risk factor. Early diagnosis using a combination of biomarkers and imaging is crucial for effective management and intervention.

References and Bibliography

1. Pais M, Martinez L, Ribeiro O, Loureiro J, Fernandez R, Valiengo L, et al. Early diagnosis and treatment of Alzheimer’s disease: new definitions and challenges. Braz J Psychiatry. 2020 Jan 24; S1516-44462020005001205. doi: http:/10.1590/1516-4446-2019-0735
2. Andersen E, Casteigne B, Chapman WD, et.al. Diagnostic biomarkers in Alzheimer’s disease. Biomarkers in Neuropsychiatry. 2021, Volume 5,100041, ISSN 2666-1446, https://doi.org/10.1016/j.bionps.2021.100041.
3. Guzman-Martinez L, Maccioni RB, Farías GA, Fuentes P, Navarrete LP. Biomarkers for Alzheimer's Disease. Curr Alzheimer Res. 2019;16(6):518-528. doi: 10.2174/1567205016666190517121140.
4. Rani, S., Dhar, S.B., Khajuria, A. et al. Advanced Overview of Biomarkers and Techniques for Early Diagnosis of Alzheimer’s Disease. Cell Mol Neurobiol 2023; 43: 2491–2523. https://doi.org/10.1007/s10571-023-01330-y