Diagnosis of Alzheimer’s Disease: Understanding Tests and Scientific Advances

Alzheimer’s disease represents one of the major global challenges in public health. The increase in population longevity has significantly raised the number of cases, making the condition one of the leading causes of disability among older adults. 

 

According to the World Health Organization (WHO), the global scenario indicates that in 2021, approximately 57 million people were living with dementia worldwide, with more than 60% of these individuals residing in low- and middle-income countries. Alzheimer’s disease is a common form of dementia, with around 10 million new cases diagnosed annually [1]. 

 

Given this context, it is essential to understand how the early identification of Alzheimer’s disease can transform clinical management and support more effective therapeutic decisions. This content brings together updated information on diagnostic methods, including laboratory tests and supportive tools, and presents scientific advances that enhance accuracy in the detection and monitoring of the disease. Check it out below! 

What Is Alzheimer’s Disease and Why Is Early Diagnosis Essential? 

Alzheimer’s disease is defined as a progressive neurodegenerative disorder characterized by cognitive impairment—especially memory decline—associated with the typical neuropathological hallmarks: β-amyloid plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. 

 

Diagnosis may be established through clinical criteria (progressive cognitive decline, functional impairment) and increasingly through biological confirmation via biomarkers (amyloid PET, tau PET, or plasma/CSF assays) [2,3]. 

 

The main symptoms of Alzheimer’s disease include progressive impairment of episodic memory, particularly for recent events, followed by deficits in other cognitive functions such as language (difficulty retrieving words and naming objects), spatial orientation, attention, abstract reasoning and executive function. 

 

As the condition progresses, difficulties arise in performing daily tasks such as managing finances, preparing meals, personal hygiene and mobility, ultimately leading to loss of functional independence [2]. 

 

Early diagnosis allows initiation of symptomatic and disease-modifying interventions at early stages, when the potential impact on symptom progression and quality of life is greater. Anticipated identification supports care planning, access to approved therapies, inclusion in clinical trials, and psychosocial support for patients and families. 

 

In addition, early interventions may slow functional decline, optimize the management of comorbidities and facilitate cognitive rehabilitation strategies [4,5]. 

 

Alzheimer’s Disease Numbers in Brazil 

In Brazil, data indicate that between 2000 and 2019, more than 211,000 deaths were attributed to Alzheimer’s disease, with a predominance in women (64%). Most deaths occurred among individuals aged 80 years and older (73%), followed by those aged 70–79 years (23%) [6]. Between 2013 and 2022, 14,024 hospital admissions due to Alzheimer’s disease were recorded, with higher prevalence in the Southeast region, and the most affected age group was also 80 years or older [7]. 

 

Additionally, Brazil presented one of the highest age-adjusted prevalences of dementia in 2016, with approximately 1.7 million people affected, ranking among the top countries globally in number of cases [8]. 

 

These data highlight the significant impact of the disease on the quality of life of Brazilians, emphasizing the need for specific policies and investments in care and prevention for the country’s aging population. 

 

What Are the Main Tests for Diagnosing Alzheimer’s Disease? 

Diagnostic investigation for Alzheimer’s disease follows a stepwise approach beginning with structured cognitive tests capable of evaluating multiple domains and distinguishing the condition from other dementias, in addition to specific episodic memory tests recommended for early detection [3]. 

 

Imaging exams are indicated to rule out secondary causes and identify characteristic atrophy patterns. Laboratory tests involving biomarker analysis in CSF or plasma have gained increasing relevance for etiological confirmation [3]. Below are the main tests used for diagnosing Alzheimer’s disease. 

 

Cognitive and Neuropsychological Tests 

Cognitive and neuropsychological tests used for diagnosing Alzheimer’s disease—considering typical symptoms of progressive impairment in memory, language, spatial orientation, attention, abstract reasoning and executive function—include the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Addenbrooke’s Cognitive Examination–Revised (ACE-R), Mini-Cog and the Clock Drawing Test. 

 

These tools assess multiple cognitive domains and exhibit good accuracy in distinguishing Alzheimer’s disease from other causes of dementia [9–11]. 

 

For detailed assessment of episodic memory, tests such as the Free and Cued Selective Reminding Test (FCSRT), Rey Auditory Verbal Learning Test, California Verbal Learning Test and Logical Memory subtest of the Wechsler Memory Scale are recommended, as they evaluate both learning and retention, making them useful for identifying early impairment and differentiating Alzheimer’s disease from other conditions [9–11]. 

 

Verbal fluency tests, language assessment, attention measures, executive function tests and visuospatial tasks (such as the clock-drawing test) complement the neuropsychological battery, helping characterize the pattern of deficits and guide syndromic diagnosis. The selection of tests should consider clinical context, educational level and cultural background, with results compared to age- and education-adjusted normative data [9–11]. 

 

Imaging Exams 

The main imaging modalities used are magnetic resonance imaging (MRI) and positron emission tomography (PET scan), each with distinct and complementary roles [12]. 

 

MRI is recommended as the first exam after clinical evaluation, essential for excluding reversible causes of dementia and detecting characteristic atrophy patterns, particularly medial temporal lobe and hippocampal atrophy. 

 

While useful for identifying neurodegeneration and guiding differential diagnosis, MRI has limited sensitivity for detecting Alzheimer’s disease in early stages and does not distinguish specific dementia etiologies [12]. 

 

PET scans offer higher etiological specificity. FDG-PET evaluates brain metabolism, revealing the typical temporoparietal hypometabolism seen in Alzheimer’s disease, while frontal or temporal patterns suggest other dementias such as frontotemporal dementia or dementia with Lewy bodies. 

 

Amyloid PET detects β-amyloid deposits and is especially useful for confirming or excluding Alzheimer’s disease in atypical cases or early-onset presentations. 

 

Tau PET identifies tau aggregates with high accuracy for differentiating Alzheimer’s disease from other causes of dementia, especially in more advanced stages [12]. 

 

These imaging modalities contribute to differential diagnosis by revealing specific patterns of atrophy, hypometabolism or protein accumulation, enabling distinction between Alzheimer’s disease and vascular, frontotemporal, Lewy body and other neurodegenerative dementias. The choice of imaging depends on clinical context, availability and need for etiological confirmation [12]. 

 

Laboratory Tests 

Laboratory tests include both exclusion of secondary causes and analysis of specific blood biomarkers. Notable markers include the Aβ42/Aβ40 ratio—whose decline indicates amyloid plaque accumulation—and phosphorylated tau isoforms (p-tau181 and p-tau217), which are particularly sensitive for identifying tau pathology and distinguishing Alzheimer’s disease from other dementias. 

 

Markers such as neurofilament light chain (NfL), associated with neurodegeneration, and GFAP, related to astrocytic activation, complement biological assessment of the disease [13,14]. 

 

Combining these biomarkers increases diagnostic accuracy, supporting early identification even in primary care settings. General laboratory tests, including TSH, vitamin B12, and renal and hepatic function, remain essential to rule out treatable conditions but do not contribute to etiological definition of Alzheimer’s disease. 

 

The expanding availability of plasma biomarkers represents a significant advance by offering less invasive and more accessible methods for diagnostic support [13,14]. 

 

APOE Gene 

The apolipoprotein E (APOE) gene is the primary genetic risk factor for the late-onset, sporadic form of Alzheimer’s disease. There are three major alleles: E2, E3 and E4. 

 

• The E4 allele is associated with a significantly increased risk of Alzheimer’s; heterozygous individuals (E3/E4) have a 3- to 4-fold increased risk, while homozygotes (E4/E4) may have up to a 12-fold increased risk compared to the E3/E3 genotype. 

• The E2 allele is considered protective, reducing risk by approximately 40% in heterozygotes (E2/E3), and even more in E2/E2 homozygotes. 

• The E3 allele is the most common and is considered neutral regarding risk [15]. 

 

The influence of these alleles varies by ancestry, sex and age. E4-associated risk is more pronounced among individuals of European and Asian ancestry, lower among African descendants and Hispanics, and higher in women, especially between 60 and 70 years of age. 

 

The E2 allele, although protective, does not counteract the risk when paired with E4 (E2/E4 genotype), which behaves similarly to E4—with increased risk and similar neurodegeneration but slower progression [15]. 

 

APOE influences the onset and severity of β-amyloid and tau accumulation, modulating symptom onset and disease progression. APOE genotyping is not recommended for routine clinical diagnosis but is valuable for research, risk stratification and clinical trial design [15]. 

 

Blood Test for Alzheimer’s Disease: A Revolution in Early Diagnosis 

As mentioned earlier, blood tests for Alzheimer’s diagnosis are based on measuring plasma biomarkers that reflect cerebral amyloid and tau pathology. The main markers are the ratio between beta-amyloid peptides Aβ1-42 and Aβ1-40 (Aβ42/Aβ40) and phosphorylated tau isoforms (especially p-tau217 and p-tau181) [16]. 

 

The Aβ42/Aβ40 ratio decreases in individuals with cerebral amyloid plaque deposition and is useful for screening amyloid pathology. However, its standalone accuracy is lower than that of phosphorylated tau markers, as it may be influenced by peripheral factors and comorbidities. 

 

Aβ42/Aβ40 plasma accuracy for detecting amyloid-positive PET scans varies between 82% and 97% using mass spectrometry methods but is lower with conventional immunoassays [16]. 

 

Phosphorylated tau 217 (p-tau217) is the plasma marker with the highest diagnostic performance. Increases in p-tau217 occur early and track disease progression, with accuracy above 90% for differentiating Alzheimer’s disease from other dementias and for detecting amyloid-positive and tau-positive PET scans [17]. 

 

P-tau181 is also useful but performs less accurately than p-tau217 [17,18]. The p-tau217/Aβ42 ratio, or the percentage of p-tau217, shows accuracy equivalent to or even superior to CSF tests, with positive predictive values reaching 97–99% among cognitively impaired patients [19]. 

 

The major clinical advantage of these tests is the possibility of rapid, accessible, and non-invasive diagnosis, reducing the need for lumbar puncture or PET scans and enabling early screening and referral for treatment. 

 

The new plasma biomarkers (Aβ42/Aβ40, p-tau217, p-tau181) provide high diagnostic precision, particularly when combined, and represent a revolution in early and accessible detection of Alzheimer’s disease [16]. 

 

What Are the Main Differences Between the Tests? 

The tests have distinct purposes, and understanding these differences is essential to organizing the clinical investigation. Cognitive and neuropsychological tests represent the initial step and differ by directly assessing the patient’s cognitive performance. They identify patterns of impairment in memory, language, attention, and executive functions, helping raise clinical suspicion of Alzheimer’s disease, but they do not confirm its etiology. They are screening tools that help characterize the cognitive profile [3]. 

 

Imaging exams serve another purpose: differentiating Alzheimer’s from other structural causes and revealing anatomical or functional patterns consistent with the disease. MRI identifies atrophy in specific brain regions, while PET scans offer greater specificity by demonstrating metabolic changes or protein deposits. Thus, they differ from cognitive tests by providing anatomical or molecular evidence rather than behavioral data [3]. 

 

Laboratory tests, in turn, stand out for enabling biological assessment of the disease. Plasma and CSF biomarkers such as Aβ42/Aβ40 and phosphorylated tau directly reflect the presence of amyloid or tau pathology in the central nervous system, offering etiological confirmation. In contrast to imaging and cognitive tests, these biomarkers can detect very early changes and increasingly show high diagnostic performance [3]. 

 

Genotyping of the APOE gene serves a different function from the others. While the other examinations assist in diagnosing established disease, the genetic test assesses risk—not the presence—of Alzheimer’s. Therefore, it is not used in routine clinical diagnosis but rather in research and risk stratification [3]. 

 

Scientific Advances and New Developments in the Diagnosis of Alzheimer’s Disease 

Significant progress has been made in recent years regarding the understanding of Alzheimer’s pathophysiology and its diagnosis. These advances include the development of high-efficiency plasma tests and biomarkers, new PET techniques for detecting amyloid and tau proteins, and protocols that integrate artificial intelligence (AI) into the analysis of neuroimaging and cognitive performance. 

 

In terms of pathophysiology, a recent study led by Brazilian researchers and published in Nature Neuroscience analyzed neuroimaging data and biomarkers from more than 300 individuals. It showed that the progression of Alzheimer’s disease depends on inflammatory interactions between microglia and astrocytes. 

 

According to the study, astrogliosis occurred only when beta-amyloid deposition coincided with microglial activation—a condition that promoted increased tau phosphorylation and aggregation and was associated with worse cognitive performance. This finding helps explain why some individuals have amyloid accumulation without clinical symptoms [20]. 

 

The findings suggest that interventions targeting glial activation may complement anti-amyloid therapies, especially in the disease’s early phases. Integrating inflammatory biomarkers into risk stratification and therapeutic protocols allows for more comprehensive models of disease management [20]. 

 

AI integration in the diagnostic process has also advanced. Recently, a digital solution combining the QDRS questionnaire, completed by patients, with a passive AI marker that automatically analyzes electronic health record data was developed. 

 

This integration increased new diagnoses of Alzheimer’s disease and other dementias by 31%, and boosted the ordering of complementary exams by 41%, without adding time or steps to clinical care. The results were published in JAMA Network Open [21]. 

 

According to the study, the model provides a way to integrate AI in an automated manner, acting as an initial risk flag that can accelerate investigations and favor timely referrals—particularly in clinical contexts with limited capacity [21]. 

 

What Does the Future Hold for Diagnostic Testing in Alzheimer’s Disease? 

Without question, the future of Alzheimer’s diagnostics centers on the development of increasingly sensitive and precise plasma biomarkers, particularly those detecting beta-amyloid and phosphorylated tau. As previously mentioned, p-tau217 stands out for its diagnostic accuracy, performing comparably or even better than CSF biomarkers and amyloid PET, especially when combined with the Aβ42/Aβ40 ratio [17]. 

 

Recent Brazilian studies demonstrate that p-tau217 and the Aβ42/Aβ40 ratio show excellent diagnostic performance even in populations with lower educational levels, although they emphasize the need for local validation and adjustment for clinical and sociodemographic variables [22–24]. 

 

Alzheimer’s Disease and Its Relationship with the Gut Microbiome 

Growing evidence points to a complex and bidirectional interaction via the gut–brain–microbiota axis. Intestinal dysbiosis (altered composition and diversity of the microbiota) is associated with increased intestinal permeability and disruption of the blood–brain barrier. This allows translocation of endotoxins (such as lipopolysaccharides) and microbial metabolites into the central nervous system, intensifying neuroinflammation and microglial activation and promoting beta-amyloid aggregation and hyperphosphorylated tau—key features of Alzheimer’s pathology [25]. 

 

Clinical and preclinical studies show that Alzheimer’s patients present reduced microbial diversity, decreased Firmicutes and Bifidobacteria, and increased Bacteroidetes and Proteobacteria, as well as regional changes in genera such as Bacteroides and Phascolarctobacterium. These alterations begin as early as the mild cognitive impairment stage, suggesting an early role of the microbiota in disease pathophysiology [26]. 

 

Microbiota-derived metabolites such as short-chain fatty acids can modulate inflammatory and synaptic responses, while others—such as trimethylamine-N-oxide and bacterial amyloid peptides—promote neurodegeneration. Interventions that modulate the microbiota have shown neuroprotective effects in animal models, reducing neuroinflammation and preserving cognitive function, though clinical translation still requires controlled trials [27]. 

 

In summary, current scientific evidence demonstrates that intestinal dysbiosis can contribute to neuroinflammation, protein aggregation, and synaptic dysfunction in Alzheimer’s disease. Microbiota-modulating strategies represent a promising field for prevention and treatment.

 

For a deeper understanding of microbiota, its clinical implications, and its role in health maintenance, explore our dedicated article on the topic. 

 

Conclusion 

Scientific advances in Alzheimer’s diagnostics have strengthened our ability to identify the disease in its early stages, enabling more precise and timely interventions. Early recognition expands therapeutic possibilities, including access to treatments, specialized follow-up, and family planning. 

 

Early detection also allows clinicians to track disease progression more effectively and adjust care strategies according to the evolving stage. 

 

For individuals seeking evaluation, the first step is to consult a physician whenever persistent memory changes or other cognitive symptoms arise. Only a qualified specialist can determine which diagnostic methods are appropriate—from initial cognitive tests to imaging exams or plasma biomarkers when etiological confirmation is required. Conducting the investigation in specialized centers ensures structured assessment and clear guidance on next steps and available follow-up options. 

 

Which Tests Does SYNLAB Offer for Alzheimer’s Investigation? 

The inclusion of specific biomarkers such as plasma phosphorylated tau 217 and the CSF beta-amyloid/tau panel represents a major advancement in investigating Alzheimer’s disease. These tests help identify neurodegenerative changes years before full clinical manifestation, supporting early diagnosis and differentiation among dementia types. 

 

Distinguishing Alzheimer’s from other causes of cognitive impairment—such as frontotemporal dementia, vascular dementia, or Lewy body dementia—is essential for effective treatment decisions and proper clinical management. Incorporating these tests strengthens clinical practice with objective data aligned with international guidelines, providing patients with more precise and individualized care. 

 

SYNLAB offers innovative diagnostic solutions to support evaluation at different stages of clinical investigation: 

 

• Plasma Phosphorylated Tau 217 (p-tau217) 

Plasma p-tau217 has proven to be a highly effective biomarker in the differential diagnosis of dementias, especially Alzheimer’s disease. Its diagnostic performance is comparable to CSF biomarkers, reducing the need for invasive procedures such as lumbar puncture. 

 

• Plasma Phosphorylated Tau 181 (p-tau181) 

Plasma p-tau181 is an important biomarker in assessing neurodegenerative processes, especially in Alzheimer’s disease. Elevated levels reflect the specific tauopathy associated with Alzheimer’s, offering a less invasive alternative to CSF testing and supporting more precise differential diagnosis. 

 

• CSF Beta-Amyloid and Tau Panel 

CSF analysis of Beta-Amyloid 1-42, the Aβ1-42/Aβ1-40 ratio, and total tau protein is considered the gold standard for detecting biochemical changes characteristic of Alzheimer’s disease. This panel allows simultaneous identification of amyloid deposition and neuronal degeneration with high sensitivity and specificity. 

 

• ADGEN: Genetic Test for Alzheimer’s Disease Predisposition 

ADGEN analyzes four genes associated with Alzheimer’s disease—APP, PSEN1, PSEN2, and APOE — using next-generation sequencing (NGS). These variants are well-established in scientific literature and help estimate genetic risk, supporting early detection and clinical planning. 

 

Genetic analysis provides important complementary information, given that Alzheimer’s involves multiple factors, including hereditary components. 

 

The test is recommended for individuals with a family history of Alzheimer’s, those with mild or moderate cognitive changes, and individuals who wish to understand their genetic predisposition even without symptoms. By offering a detailed assessment of individual risk, ADGEN supports personalized monitoring and clinical decision-making. 

 

Get to Know SYNLAB – A Leader in Medical Diagnostic Services! 

Accurate and up-to-date testing is essential for precise diagnoses and better treatment guidance. SYNLAB is here to help. 

 

We offer diagnostic solutions with rigorous quality control to the companies, patients, and healthcare providers we serve. Present in Brazil for over 10 years, we operate in 36 countries across three continents and are leaders in diagnostic services in Europe. 

 

Contact the SYNLAB team to learn about our available tests. 

 

Frequently Asked Questions (FAQ) 

What is Alzheimer’s disease? 

It is a progressive neurodegenerative condition characterized by cognitive decline—particularly memory loss—associated with β-amyloid plaques and tau tangles in the brain. 

 

Why is early diagnosis important? 

Because it enables early interventions, slows functional decline, supports care planning, and increases access to therapies and clinical trials. 

 

What early signs should prompt medical evaluation? 

Progressive forgetting of recent events, difficulty naming objects, disorientation in familiar places, and loss of independence in daily activities. 

 

What are the main tests used in Alzheimer’s diagnosis? 

Cognitive tests, imaging exams (MRI, PET), and laboratory biomarkers in blood or CSF. 

 

Can a blood test help diagnose Alzheimer’s? 

Yes. Plasma biomarkers such as Aβ42/Aβ40, p-tau217, and p-tau181 support early detection and etiological confirmation using a less invasive method. 

 

What is the APOE gene and how is it related to Alzheimer’s? 

APOE is a gene associated with Alzheimer’s risk: the E4 allele increases susceptibility, while E2 is considered protective. However, APOE genotyping is not used as a routine diagnostic test. 

 

Does the gut microbiota play a role in Alzheimer’s? 

Evidence suggests that dysbiosis may contribute to neuroinflammation and protein aggregation, potentially influencing disease risk and progression. 

 

References: 

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