Table 1.

Advantages and limitations of biomarkers for Alzheimer’s disease.

Biomarker	Advantages	Limitations
Genetic	Insights into an individual’s genetic predisposition Insights into pathogenesis Early detection and risk assessment Development of personalized treatment strategies Clinical trial recruitment	Incomplete penetrance and gene expression Complex interactions with other factors Limited predictive accuracy Cost and accessibility Lack of treatment options Rarely used for routine clinical diagnosis of AD
Brain imaging CT	Provide detailed structural information Preferable to MRI for non-collaborative patients Relatively low cost Greater accessibility in developing countries	Not sensitive to early changes Limited quantitative measurements Lack of functional information Radiation exposure Inferior soft tissue detail Not considered as a standard biomarker for early diagnosis of AD
Brain imaging MRI	Insight into the microstructural, functional and molecular alterations occurring in the brain (DTI, MRS, fMRI) No radiation exposure Early diagnosis Quantification of brain atrophy Longitudinal monitoring of disease progression Distinguishing AD from other neurodegenerative disorders	Cost and availability Time consuming Patient cooperation Complexity of interpretation: expertise is required for the analysis of images Limited molecular information in comparison to PET scans Limited specificity and overlap with ageing Potentially missing early disease-related alterations Contrast side effects
Brain imaging PET scan	Early detection allowing for timely intervention and treatment planning Objective measurement of the extent and distribution of beta-amyloid and tau pathology in the brain Differentiation of AD from other forms of dementia Tracking disease progression Clinical trial recruitment	Cost and availability Exposition to ionizing radiation Time consuming Possibility of false positive and false negative results Ethical considerations in asymptomatic individuals Complexity of interpretation: expertise is required for the analysis of images Contrast side effects
Cerebrospinal fluid	Proximity to the brain—contains brain proteins High concentration of biomarkers Capacity to test numerous potential biomarkers Standardized methodology High accuracy in the diagnostic procedures Potential detection of AD in its early stages, even before significant clinical symptoms Longitudinal monitoring of disease progression Can be used as outcome measures to assess the efficacy of potential therapies	Invasive procedure Requires hospitalization Need for specialized expertise and equipment for collection and analysis Relatively high cost Risk of complications (infection, headache) A less acceptable procedure among the general population A risk of inducing harm, fear and anxiety in the patient Complex interpretation, as biomarker levels may vary due to age, gender and underlying health conditions
Blood	Minimally invasive and simple sampling Cost- and time-efficient Widespread use Reproducible and simple to measure Easy to implement in large populations Ability to test a large number of biomarkers The possibility of repeated sampling and measurements Initial diagnostic examination in a complex diagnostic procedure	Relatively low concentration of the potential biomarkers due to the presence of the blood–brain barrier Significant dilution of analytes caused by the volume ratio between the blood and the CSF Unreliability of findings—blood is a complex fluid—non-specific biomarkers may be expressed from sources other than the CNS Possible influence on the concentration levels of biomarkers due to liver or plasma proteolytic degradation, plasma protein or blood cell adhesion and kidney excretion The sensitivity and specificity of blood biomarkers for AD are still considerably low
Saliva	Easily accessible and non-invasive collection technique Repeatable collection—opportunity to monitor biomarker fluctuations Cost-effective and minimally stressful Without risk of infection Suitable for a wide range of individuals Convenient and reproducible sample collection Accessibility without regard to location or time limitations	Lack of standardisation in collection procedures (stimulated versus unstimulated samples), pre-processing and storage of samples Lack of validated studies Lack of results replicated in broader, multicentre and longitudinal investigations Difficulties in collecting saliva due to poor compliance of elderly patients, particularly with AD Limited sensitivity and specificity Saliva is a pooled sample from different salivary glands—potential influence on the sample composition Influence of ageing, oral health, circadian variations, environmental factors, psychogenic disorders, medication use, local and systemic pathology and treatment
Tears	Close association between eye and the brain Easily accessible and non-invasive collection technique Repeatable collection—opportunity to monitor biomarker fluctuations Cost-effective and minimally stressful Without risk of infection Suitable for a wide range of individuals Convenient and reproducible sample collection Accessibility without regard to location or time limitations	Lack of standardisation in collection procedures, pre-processing and storage of samples Lack of validated studies Lack of results that have been replicated in broader, multicentre and longitudinal investigations. Small volume sample size Tear production and drainage can influence the concentration of biomarkers The influence of circadian rhythms and environmental factors

AD: Alzheimer’s disease; MRI: magnetic resonance imaging; DTI: diffusion tensor imaging; MRS: MR spectroscopy; fMRI: functional MRI; CNS central nervous system.