Diagnosis and Assessment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative condition, characterized by the accumulation of extra-neuron beta-amyloid protein (plaques) and intra-neuron tau protein (tangles) in the brain.¹The stages of AD are classified by degree of cognitive impairment, ranging from no AD symptoms in the preclinical form to severe symptoms in later stages (Figure 1).^1,2

Recognizing the Symptoms of Alzheimer's Disease

One of the earliest and most common symptoms of AD is memory loss, specifically “recent” memory impairment with relative sparing of long-term memory (Table 1).^2,4 Patients with AD may eventually develop difficulties with problem-solving, judgment, organization and executive function, as well as subsequently impaired multitasking and abstract thinking.² With disease progression, there arises the inability to complete tasks and reduced insight, potentially impacting the capability to safely perform activities like driving.⁴

In later stages, language disorders and trouble with visuospatial skills emerge.² Moderate-to-late stages of AD may also include neuropsychiatric symptoms such as apathy, lack of inhibition, psychosis, agitation, social withdrawal, and wandering, and these are associated with a more rapid decline if present early.^2,4 In end-stage AD, difficulties with verbal communication and movement can result in patients being bed-bound and incontinent, with total dependence on caregivers.^1,2

Making the Diagnosis of Alzheimer's Disease

Since AD generally worsens over time, early diagnosis benefits both patients and their caregivers.² It allows them to address modifiable risk factors that may delay cognitive decline, start treatment or enroll in clinical trials before severe stages have set in, and potentially preserve daily functioning for longer.¹Early diagnosis of AD also gives patients and caregivers additional time to learn how to manage behavioral symptoms, discuss future planning and personal/financial issues, address safety concerns, and establish a support network.¹

The diagnosis of AD starts by obtaining an accurate history, especially from family members and caregivers.² A complete physical exam, including neurologic examination, helps rule out other potential causes of dementia.² Recent studies suggest that anosmia may be an early marker of AD, but more research is needed and this is not a widely used diagnostic finding.⁶

Detailed cognitive, neurologic, and psychological evaluation can provide a great deal of information about preservation or loss of independent function, as well as presence/types of neuropsychiatric symptoms.⁴ Mental status exams, especially those evaluating concentration, attention, memory, language, praxis, and visuospatial and executive functioning, can help document the presence and stage of dementia.^2,4 Furthermore, formal neuropsychological testing and cognitive assessments can not only establish a dementia baseline, but also help distinguish among other forms of dementia (pseudodementia, Lewy body dementia, vascular dementia, and frontotemporal lobar degeneration) as well as assess competencies for performing potentially dangerous tasks.⁴ Neuropsychological testing is also the most reliable method for detecting MCI.²Click here to view and download a cognitive assessment toolkit provided by the Alzheimer’s Association^®.

While not yet recommended for routine diagnostic use, several serologic, plasma, and advanced imaging biomarkers are being researched to help support an AD diagnosis.^4,⁷Molecular biomarkers identify specific protein deposits in the brain, like amyloid plaques found in amyloid plaques or tau proteins found in neurofibrillary tangles.⁴Topographic (neurodegenerative) biomarkers help locate regional pathologic brain changes associated with AD (Table 2).³ Neuroimaging, including magnetic resonance imaging (MRI) and functional brain imaging (eg, amyloid/tau PET and single-photon emission computed tomography [SPECT]) may also help rule out other potential causes of dementia (Figure 2).^2,4 More recently, focus has shifted to pTau217, i.e. tau phosphorylated at amino acid 217, as this biomarker has consistently shown high performance in differentiating AD from other neurodegenerative disorders and in detecting AD pathology in patients with MCI.⁸ A biomarker utilizing the plasma pTau217/Aβ1-42 ratio was cleared by the FDA on May 16, 2025, for aiding in the diagnosis of amyloid plaques in symptomatic patients aged 55 years or older.⁹

Recent data from longitudinal studies have compared time-related changes in fluid biomarkers with disease progression.¹¹

The Significance of Comorbidities¹² for Alzheimer's Disease

The most common comorbidities associated with AD are type 2 diabetes, cardiovascular disease, depression, and inflammatory bowel disease. A key factor in these common chronic diseases is the presence of inflammation. Research is ongoing as to whether inflammation is a cause or effect of AD; it is likely that it has a bidirectional influence on this neurodegenerative disorder.

Regardless, the presence of these comorbidities in AD patients may have significant implications for the treatment and prognosis of AD. Similarly, certain lifestyle factors, like diet and exercise, may also have an impact on cognitive function.¹²

References

Alzheimer’s Association®. 2025 Alzheimer’s Disease Facts and Figures. https://www.alz.org/getmedia/ef8f48f9-ad36-48ea-87f9-b74034635c1e/alzheimers-facts-and-figures.pdf
Kumar A, Sidhu J, Lui F, Tsao JW. Alzheimer disease. StatPearls. Last Update: February 12, 2024. https://www.ncbi.nlm.nih.gov/books/NBK499922/
Porsteinsson AP, Isaacson RS, Knox S, Sabbagh MN, Rubino I. Diagnosis of early Alzheimer’s disease: Clinical practice in 2021. J Prev Alzheimers Dis. 2021;8:371-386.
Wolk DA, Dickerson BC. Clinical features and diagnosis of Alzheimer disease. UpToDate. Last update: September 30, 2024. https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-alzheimer-disease
National Institute on Aging (NIA). What are the Signs of Alzheimer’s Disease. Reviewed October 18, 2022. https:www.nia.nih.gov/health/what-are-signs-alzheimers-disease
Tian Q, Bilgel M, Moghekar AR, Ferrucci L, Resnick SM. Olfaction, Cognitive impairment, and PET biomarkers in community-dwelling older adults. J Alzheimers Dis. 2022;86:1275-1285.
Alzheimer’s Association®. Global biomarker standardization consortium (GBSC). https://www.alz.org/research/for_researchers/partnerships/gbsc
Tahami Monfared AA, Phan NTN, Pearson I, et al. A systematic review of clinical practice guidelines for Alzheimer’s disease and strategies for future advancements. Neurol Ther. 2023;12:1257-1284.
Hu S, Yu H, Gao J. The pTau217/Aβ_1-42 plasma ratio: The first FDA-cleared blood biomarker test for diagnosis of Alzheimer’s disease. Drug Discov Ther. 2025;19:208-209.
Murray ME, Kouri N, Lin WL, Jack CR Jr, Dickson DW, Vemuri P. Clinicopathologic assessment and imaging of tauopathies in neurodegenerative diseases. Alzheimers Res Ther. 2014;6:1.
Lista S, Santos-Lozano A, Emanuele E, et al. Monitoring synaptic pathology in Alzheimer’s disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives. Mol Psychiatry. 2024;29:847-857.
Santiago JA, Potashkin JA. The Impact of Disease Comorbidities in Alzheimer’s Disease. Front Aging Neurosci. 2021;13:631770.