Alzheimer Disease Workup

Updated: Jul 07, 2023
  • Author: Shaheen E Lakhan, MD, PhD, MS, MEd, FAAN; Chief Editor: Jasvinder Chawla, MD, MBA  more...
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Approach Considerations

Alzheimer disease (AD) is a clinical diagnosis. However, ancillary imaging studies (eg, computed tomography [CT]; magnetic resonance imaging [MRI]; single-photon emission CT [SPECT]; or positron emission tomography [PET]) and laboratory tests may be used. These tests help exclude other possible causes for dementia (eg, cerebrovascular disease, cobalamin [vitamin B12] deficiency, syphilis, thyroid disease).

Diagnostic criteria established by the National Institute on Aging (NIA) and the Alzheimer’s Association are intended principally to facilitate research. However, the NIA-AA also proposed “core clinical criteria” for diagnosis of mild cognitive impairment (MCI) by health care providers without access to cerebrospinal fluid (CSF) testing or advanced imaging. [71] The NIA-AA criteria for diagnosis of dementia due to AD are clinical, with biomarkers in an assisting, nonessential role. [72]


Blood Studies

Laboratory tests can be performed to rule out other conditions that may cause cognitive impairment. Current recommendations from the American Academy of Neurology (AAN) include measurement of the cobalamin (vitamin B12) level and a thyroid function screening test. Additional investigations are left up to the physician, to be tailored to the particular needs of each patient. Initial test results that require further investigation include the following:

  • Abnormalities in complete blood cell count and cobalamin (vitamin B12) levels require further workup to rule out hematologic disease

  • Abnormalities found in screening of liver enzyme levels require further workup to rule out hepatic disease

  • Abnormalities in thyroid-stimulating hormone (TSH) levels require further workup to rule out thyroid disease

  • Abnormalities in rapid plasma reagent (RPR) require further workup to rule out syphilis

  • Abnormalities in HIV serology and/or PCR require further workup to rule out HIV/AIDS

  • Abnormalities in paraneoplastic antibodies require further workup to rule out autoimmune encephalitis

  • Abnormalities in CSF proteins tau, P-tau, and 14-3-3 require further workup to rule out Creutzfeldt-Jakob disease

There is a possible link between vitamin D deficiency and cognitive impairment. [77, 78] However, vitamin D deficiency has not been identified as a reversible cause of dementia.


Brain MRI or CT Scanning

American Academy of Neurology (AAN) recommendations indicate that structural neuroimaging with either a noncontrast computed tomography (CT) scan or magnetic resonance image (MRI) is appropriate in the initial evaluation of patients with dementia, in order to detect lesions that may result in cognitive impairment (eg, stroke, small vessel disease, tumor).

Imaging studies are particularly important for ruling out potentially treatable causes of progressive cognitive decline, such as chronic subdural hematoma or normal-pressure hydrocephalus. [1] In patients with AD, brain MRIs or CT scans can show diffuse cortical and/or cerebral atrophy, but these findings are not diagnostic of AD.

In clinical research studies, atrophy of the hippocampi (structures important in mediating memory processes) on coronal MRI is considered a valid biomarker of AD neuropathology. Nonetheless, measurement of hippocampal volume is not used in routine clinical care in the diagnosis of AD.

A study by Chen et al suggests that resting state functional MRI can help classify patients with AD, patients with amnestic mild cognitive impairment (MCI), and cognitively healthy patients. [79] Default mode network (DMN) imaging appears to distinguish AD, MCI, and controls well, and it may complement positron emission tomography (PET) scanning or prove to be more sensitive. [80]

A study by McMillan et al suggests that MRI may provide a reasonably accurate, noninvasive surrogate for cerebrospinal fluid (CSF) biomarkers, reducing the need for lumbar puncture in discriminating AD from frontotemporal lobar degeneration (FTLD). [81, 82] The investigators derived a structural brain pattern from MRI that predicts the ratio of total tau to β-amyloid in CSF, to discriminate AD from FTLD. In this way, they were able to differentiate between the 2 dementia types 75% of the time. [81, 82]

Other investigators have suggested that MRI plus biomarkers may be key to finding early AD. [83, 84] In a cross-sectional, longitudinal cohort study of 207 older adults with normal cognition, investigators found a correlation between decay in the DMN, as observed on resting-state functional connectivity MRI (rs-fcMRI), and levels of 2 CSF biomarkers of early AD. This suggests that rs-fcMRI may be an effective noninvasive means of detecting early asymptomatic AD. [83, 84]

In the study, Ances and colleagues reported that decreases in DMN integrity had an independent association with reductions in CSF amyloid beta 42 and increases in CSF phosphorylated tau181. [83, 84] Moreover, the posterior cingulate cortex and the medial temporal lobe, 2 regions that are frequently impacted by AD, were found to have the most prominent decreases in functional connectivity.

For more information, see the Medscape Reference article Imaging of Alzheimer Disease.


SPECT or PET scanning

Brain scanning with SPECT or PET (see the image below) is not recommended for the routine workup of patients with typical presentations of AD. These modalities may be useful in atypical cases or when a form of frontotemporal dementia is a more likely diagnosis. [85]

Image courtesy of NIH. Image courtesy of NIH.

The Amyloid Imaging Taskforce (AIT), an assembly of experts from the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging (SNMMI), developed guidelines for the use of amyloid β (Aβ) positron emission tomography (PET) imaging to clarify diagnoses of AD or frontotemporal dementia. The guidelines outline 3 scenarios in which determining amyloid positivity or negativity would increase the level of diagnostic certainty and alter patient management.

According to the guidelines, amyloid imaging is appropriate in patients with persistent or progressive unexplained mild cognitive impairment, in those satisfying core clinical criteria for possible AD because of unclear clinical presentation, and in patients with progressive dementia and atypically early age of onset. The committee recommends against imaging in asymptomatic individuals and patients with a clear AD diagnosis with typical age of onset. Scanning cannot be used to stage dementia or determine its severity, and it should not be used in lieu of genotyping for suspected autosomal mutation carriers. [86]

Florbetapir F 18 (AMYViD) was approved by the FDA in April 2012 as a diagnostic imaging agent. It is indicated for PET brain imaging of beta-amyloid neuritic plagues in adults being evaluated for Alzheimer disease or other cognitive decline. [87, 88, 89]

Approval for florbetapir F 18 was based on 3 clinical studies that examined images from healthy adult patients as well as patients with a range of cognitive disorders, including some terminally ill patients who had agreed to participate in a postmortem brain donation program. Measurements from postmortem cortical amyloid burden correlated with median florbetapir F 18 scores. [90]

In a study by Clark et al, the presence and density of beta amyloid correlated closely in individuals who had florbetapir-PET imaging within 99 days before death and then upon autopsy. [91] Patients with probably Alzheimer disease, mild cognitive impairment, or older healthy controls showed significantly different mean cortical florbetapir uptake value ratios in a study by Fleisher et al. [92]

In October 2013, the FDA approved a second 18F-labeled Pittsburgh compound B (PIB) derivative, flutemetamol F18 injection (Vizamyl), for use with PET brain imaging in adults undergoing evaluation for Alzheimer disease and dementia. Like florbetapir F18, flutemetamol F18 attaches to beta-amyloid in the brain and produces a PET image that can be used to assess its presence. A positive scan indicates there is likely a moderate or greater amount of amyloid in the brain, but it does not establish a diagnosis of Alzheimer disease or other dementia. The effectiveness of flutemetamol F18 was established in 2 clinical studies with 384 participants who had a range of cognitive function. [93]

A third agent, florbetaben F18 (Neuraceq), was approved by the FDA in March 2014. Images may be obtained between 45-130 minutes following the injected dose. FDA approval was based on safety data from 872 patients who participated in global clinical trials as well as 3 studies that examined images from adults with a range of cognitive function, including 205 end-of-life patients who had agreed to participate in a post-mortem brain donation program. Images were analyzed from 82 subjects with post-mortem confirmation of the presence or absence of beta-amyloid neuritic plaques. [94]

A study of 129 cognitively normal adults aged 65-87 years (mean, 73.7 years) indicated that a combination of memory tests and brain imaging may help to identify the earliest stages of AD, before symptoms appear. [95] The investigators found that poor episodic memory in the context of synaptic dysfunction and elevated amyloid identified subjects who were at high risk for progression to AD dementia.

Subjects in this study underwent testing of memory and executive function along with fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scanning and amyloid deposition with C 11 Pittsburgh Compound B (PiB PET). [95] The researchers found that amyloid burden and lower FDG metabolism (synaptic dysfunction) independently predicted episodic memory performance. Subjects with worse memory performance had higher PiB deposition and lower FDG metabolism in regions of the brain commonly affected in AD.

For more information, see the Medscape Reference article Imaging of Alzheimer Disease.



Electroencephalography (EEG) is valuable when Creutzfeldt-Jakob disease or other prion-related disease is a likely diagnosis (see EEG in Dementia and Encephalopathy). Periodic high-amplitude sharp waves can eventually be detected in most cases of Creutzfeldt-Jakob disease.

EEG is also useful if pseudodementia is a realistic consideration when a normal EEG in a patient who appears profoundly demented would support that diagnosis. Multiple unwitnessed seizures rarely can present as dementia, and an EEG would be valuable for evaluating such a possibility.


Lumbar Puncture

Perform lumbar puncture in select cases to rule out conditions such as normal-pressure hydrocephalus or central nervous system infection (eg, neurosyphilis, neuroborreliosis, cryptococcosis).

CSF levels of tau and phosphorylated tau are often elevated in Alzheimer disease (AD), whereas amyloid levels are usually low. The reason for this is not known, but perhaps amyloid levels are low because the amyloid is deposited in the brain rather than the CSF. By measuring both proteins, sensitivity and specificity of at least 80%—and more often 90%—can be achieved.

In May 2022, the FDA approved the first in vitro diagnostic test for early detection of AD. The test measures the ratio of β-amyloid 1-42 and β-amyloid 1-40 concentrations in CSF. A positive test result is consistent with the presence of amyloid plaques, similar to that revealed in a PET scan. A negative result is consistent with a negative amyloid PET scan result. [96]

At present, however, routine measurement of CSF tau and amyloid is not recommended except in research settings. Lumbar puncture for measurement of tau and amyloid may become part of the diagnostic workup when effective therapies that slow the rate of progression of AD are developed, particularly if the therapies are specific for AD and carry significant morbidity.




Genotyping for apolipoprotein E (APOE) alleles is a research tool that has been helpful in determining the risk of AD in populations, but until recently it was of little, if any, value in making a clinical diagnosis and developing a management plan in individual patients. Numerous consensus statements have recommended against using APOE genotyping for predicting AD risk. [39]

Investigators from the Copenhagen General Population Study and the Copenhagen City Heart Study have reported that plasma levels of APOE epsilon 4 (APOE ε4) are associated with the risk of dementia, independent of the APOE genotype. [97, 98] The risk of Alzheimer disease increased with decreasing levels of APOE levels, with a highly significant 3-fold increased risk for the lowest tertile of APOE levels relative to the highest tertile—an association that remained even after adjusting for the APOE genotype. [97, 98] The APOE genotypes with highest risks of Alzheimer disease were ε43 and ε44, whereas those with the lowest risks were ε22, ε32, ε42, and ε33. [98]

Concern has previously been expressed that in asymptomatic individuals, genetic testing that identifies increased risk may trigger an untoward psychological response. However, in a trial of the effect of disclosing APOE genotyping results to 162 asymptomatic adults who had a parent with AD, Green et al found that follow-up testing over the course of a year showed no significant differences with disclosure versus nondisclosure on time-averaged measures of anxiety, depression, or test-related distress. [99] Test-related distress was reduced in those who learned that they did not carry the APOE E4) allele. Persons who had high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure. [99]

Genetic testing for APP and presenilin mutations

According to guidelines from the American College of Medical Genetics and the National Society of Genetic Counselors, testing for the APP and presenilin genes associated with early-onset autosomal dominant AD should be offered in the following situations [39] :

  • In symptomatic patients with early-onset AD who have a family history of dementia or an unknown family history (eg, because of adoption)

  • In persons with a family history of autosomal dominant dementia with one or more cases of early-onset AD

  • In relatives with a mutation consistent with early-onset AD (ie, PS-1, PS-2,APP)

Before undergoing testing, patients should receive appropriate counseling on the predictive value of genetic testing for AD. Afterward, patients should receive counseling on the implications of the results. Recommendations on pre- and post-test counseling are detailed in the guidelines from the American College of Medical Genetics and the National Society of Genetic Counselors. [39]