Memory loss occurs in most people with aging. It is challenging to determine whether symptoms are normal or indicative of something more sinister, like Alzheimer’s disease (AD), the most common neurodegenerative disorder affecting cognition.
Answering this question is more important than ever since new therapeutic advancements likely work best when started as soon as memory symptoms are first recognized. Fortunately, comprehensive evaluations and diagnostic testing help define the underlying cause of memory loss, including AD. This brief article will provide a summary of how to approach patients with cognitive symptoms with specific focus on diagnosing AD.
Cognition changes are typically recognized by the patient, a close contact or the primary care provider (PCP). In some cases, the patient may be less aware of the symptoms than those around them. These symptoms are often discussed with a PCP at a yearly visit or with a specialist. Many times, these cognitive symptoms are blamed on other conditions, including aging.
A good cognitive screening tool or neuropsychological testing at this stage can help the provider determine if cognitive symptoms are secondary to normal aging or if performance is lower than would be expected for age and education. Without this additional screen or testing, the provider may not be able to confidently differentiate between normal aging or something more concerning.
The differential diagnosis of memory loss is broad but can be refined with a good clinical history of the symptoms, a thorough neurological exam, and examining how other medical conditions could impact cognition (ex: sleep or mood disturbance, medications, substance use, recent illness). Understanding level of functional capacity is also helpful in providing context for cognitive symptoms. Is the patient independent with all activities of daily living, suggesting either normal cognition or mild cognitive impairment (MCI), or is the patient starting to have trouble with independent activities of daily living and transitioning into dementia? There are multiple questionnaires to help assess functional status, such as the functional activities questionnaire: FAQ7 and the Quick Dementia Rating Scale (QDRS8) among others.
Once cognitive symptoms are considered more than just aging, additional diagnostic workup may help clarify the underlying etiology. Basic blood work including complete blood count, comprehensive metabolic panel, thyroid stimulating hormone (TSH) and vitamin B12 level can help identify metabolic contributors. This can be expanded to other studies including RPR and HIV depending on risk factors.
An MRI of the brain without contrast can help identify underlying structural changes, including patterns of atrophy that correlate with clinical symptoms or other findings like microvascular ischemic changes. Enlarged lateral ventricles are sometimes present and most often due to cortical atrophy rather than disrupted cerebrospinal fluid dynamics like normal pressure hydrocephalus (NPH), where clinical correlation of classic symptoms is needed. Contrasted MRI should be considered if there is concern about inflammatory, infectious or neoplastic contributors. Importantly, gradient echo (GRE) or preferably, susceptibility weighted imaging (SWI) sequences, are important to review for prior microhemorrhage or siderosis, especially in context with considering newer AD therapies. If there is contraindication for MRI brain, a non-contrast head CT could be considered but has limitations.
Other studies such as a dopamine transporter (DaT) scan or alpha-synuclein assays (skin, spinal fluid) could be used if there is concern for a Lewy body process. A metabolic brain PET scan is also available to assess for patterns of hypometabolism to support frontotemporal dementia or other cognitive dysfunction but only rarely in select cases.
The above history, cognitive testing and imaging could provide support for underlying AD, suggesting that additional confirmatory biomarker testing is needed. There are three important caveats. The first is that brain imaging without clear patterns of atrophy, also known as a “normal appearing brain,” is not exclusionary for underlying AD. The amount of atrophy does not always correlate with the severity of symptoms. The second caveat is that AD has multiple clinical phenotypes. The most common is the classic amnestic or “short-term memory” presentation where patients have trouble encoding new pieces of information and are repetitive, however, patients can present with predominant language, executive or visual symptoms.
The third caveat is that other pathologies can cause memory loss and cerebral atrophy, specifically in the hippocampus, that looks like AD, but is not AD. A younger patient with clear family history across multiple generations could have a mutation in microtubule associated protein tau (MAPT-R406W10,11) whereas an older patient (80s-90s) could have limbic predominant age-related TDP-43 encephalopathy (LATE12) or primary age-related tauopathy (PART13). Confirmatory AD biomarker testing can provide the additional clarity on underlying etiology.
Currently, two forms of AD biomarker testing are recognized as confirmatory: amyloid brain PET imaging and cerebrospinal fluid AD profile testing for abeta-42, total tau and phospho-tau. There are several amyloid PET radiotracers on the market, however, these require specialized technique with image acquisition and neuroradiology interpretation.
Suboptimal scans or lower expertise with image interpretation can lead to diagnostic misclassification. Amyloid PET can also be confused with metabolic brain PET causing diagnostic errors.
For spinal fluid profiles, there are two main platforms, each with their own reference ranges, so it is important to review the full report for interpretation. Although each platform provides an automated interpretation of the values and amyloid to tau indices, it is important to examine the absolute values abeta42, total tau and phospho-tau levels in context with the patient.
Studies have shown that African Americans can have lower tau values than whites, which could lead a provider to exclude AD as a diagnosis. There are other spinal fluid assays, including abeta ratios, however, these are not recommended as a confirmatory study.
AD blood test utilization is also increasing and considered as a supportive AD biomarker, at least for now. Plasma phospho-tau 217 (ptau217) is showing the most promise. Several commercial products offer ptau217 in context with apolipoprotein E genotype (APOE) or abeta ratios, however the sensitivity and specificity using ptau217 alone remains very high and sufficient.
Ptau217 assays with dual cutoff values can also improve sensitivity and specificity. Ptau217 is a useful screening tool to look for AD in patients presenting with cognitive concerns and with objective evidence for cognitive impairment that classifies the patient as mild cognitive impairment or dementia. It should not be used in patients without cognitive symptoms or in patients just presenting with a family history of AD or known APOE genotype.
Guidance on the use of ptau217 or other AD biomarker testing in asymptomatic patient populations could change as we move into the future. APOE E4 confers strong risk susceptibility for AD but is not confirmatory for AD. APOE testing has increased recently to help assess risk for side effects in patients considering amyloid monoclonal antibodies.
In conclusion, it is important to consider additional cognitive screening and more comprehensive evaluation in patients presenting with even subtle memory symptoms. We have excellent tools to help refine diagnoses, and in some cases, to confirm underlying AD in symptomatic patients.
The use of plasma ptau217 in the clinic is evolving and may eventually be recognized as a confirmatory AD biomarker. Disease-modifying therapies for AD are available and there are likely more on the way, but these therapies likely work best when started soon after symptom onset. Ongoing trials may provide evidence that disease modifying therapies work even before symptoms start, but we are not yet at the point of screening patients with plasma, CSF or amyloid PET for asymptomatic AD changes.
Dr. Hales is an Associate Professor of Neurology at Emory University School of Medicine. He is an investigator for AD and FTD clinical research trials and is Co-Lead of the Goizueta ADRC clinical core. As assistant director for the Georgia Memory Net, Clinical Director of the Emory Cognitive Neurology Program and Goizueta Brain Health Institute clinical lead, he is working on new models of care to improve patient access and personalized brain health.
