Alzheimer's disease (AD), which affects approximately 6.9 million people in the United States, is a progressive neurodegenerative disorder marked by cognitive and behavioral impairment that significantly affects social and occupational functioning. AD typically occurs in patients over age 65 years, but research has uncovered a subtype of AD, early-onset Alzheimer's disease (EOAD), that affects people younger than age 65 years.
Because EOAD (also referred to as younger- or earlier-onset AD) represents only about 200,000 AD cases in the United States, it poses unique diagnostic challenges. Symptoms are frequently misattributed to other medical conditions more common in younger individuals (eg, depression, menopause, stress). It is also often misdiagnosed as frontotemporal dementia. Consequently, patients with EOAD often must endure an arduous and frustrating testing process before receiving an accurate diagnosis. Current research is making strides to better define the clinical characteristics of this AD variant, laying the groundwork for promising improvements in diagnostic accuracy.
Understanding Early-Onset Alzheimer's Disease
Although both late-onset AD (LOAD) and EOAD are marked by beta-amyloid plaques, neurofibrillary tangles (abnormal accumulations of tau protein), and progressive neuronal damage, there are several substantial key distinctions between the two types. Like LOAD, EOAD includes a wide range of symptoms, with memory loss being one of the most prominent. EOAD, however, often presents with atypical nonamnestic cognitive deficits, including language difficulties, visual and spatial deficits, impaired motor skills, and behavioral changes.
Several small-scale studies suggest that EOAD progression may be more aggressive compared with LOAD. One retrospective cohort study, which compared neuropsychological assessments of participants with EOAD or LOAD vs those of healthy controls, found that the EOAD group exhibited more pronounced deficits in visual perception, praxis, and executive tasks. Another cohort study, involving 1538 LOAD patients and 387 EOAD patients assessed at specific intervals post-diagnosis, revealed a higher prevalence of behavioral and psychological symptoms of dementia in the EOAD group.
Challenges in Diagnosis
In addition to nonamnestic presenting symptoms and a more aggressive disease course, a significant difference exists in the time to diagnosis between EOAD and LOAD. On average, EOAD has a longer delay in diagnosis — approximately 1.6 years. This delay can be attributed to several factors, including atypical presenting symptoms, the absence of cognitive screening tests to detect symptoms, and the frequent misdiagnosis of AD symptoms as psychiatric illness.
The extended time to diagnosis often results in substantial losses, including time and financial resources, which can be devastating for patients. Other risks associated with delayed diagnosis include treatment delays, anxiety related to prolonged uncertainty, and increased caregiver burden. Additionally, the psychological impact of an EOAD diagnosis is significant. Patients with EOAD have a higher likelihood of developing depression compared with patients with LOAD, according to a recent case study. Although an AD diagnosis is devastating at any age, individuals diagnosed with EOAD are often in their prime, which may lead to an unexpected sense of loss personally and professionally. Patients with EOAD also appear to experience a more rapid cognitive decline.
Multidisciplinary Approach to Diagnosis
Primary care physicians (PCPs) are often the first clinicians to identify cognitive deficits that require further assessment and follow-up. Numerous barriers to cognitive screening exist within the primary care setting, however, including lack of specialized training and time constraints. A special report released by the Alzheimer's Association in 2020, based on a national survey of PCPs, highlighted the challenges they face in diagnosing dementia. Survey findings revealed that 53% of PCPs receive questions from patients about AD or other forms of dementia every few days, and 27% are "only sometimes or never comfortable" answering their questions. Consequently, 32% of PCPs refer patients to specialists for diagnosis and follow-up care at least once a month.
The importance of a multidisciplinary care team in the diagnostic process cannot be overstated. A prospective study involving 439 patients with suspected AD compared independent diagnostic evaluations by a single clinician vs a multidisciplinary team of dementia experts, including physicians and nurses. The study showed that the multidisciplinary team achieved higher accuracy in etiologic diagnosis compared with the single clinician. Moreover, a series of international working group meetings with diverse dementia experts underscored the necessity of a patient-centered multidisciplinary approach to AD diagnosis. Specifically, the group advocated the development of a subspecialty of "dementia-trained" healthcare professionals who would serve as experts, contributing to accurate and timely diagnoses.
Diagnostic Tools and Techniques
Current diagnostic recommendations for AD encompass a combination of cognitive, functional, and behavioral assessments, supplemented by imaging and cerebrospinal fluid (CSF) and plasma biomarker assays. While these tools are beneficial, they have notable limitations. Commonly used cognitive assessment tools, such as the Mini-Mental State Examination (MMSE), can accurately identify memory and language deficits but are limited in detecting executive functioning impairments, which are often present in EOAD. Amyloid PET scans can confirm the presence of beta-amyloid plaques in the brain. CSF biomarkers serve as an alternative to amyloid PET scans, but lumbar puncture is invasive and may lead to postprocedure complications.
Patients with EOAD are frequently excluded from studies and clinical trials owing to their atypical symptoms and younger age. The Longitudinal EOAD Study (LEADS) is a prospective longitudinal study following 400 participants with EOAD and 100 age-matched controls. The goals of LEADS are to define the clinical and biological characteristics of EOAD, develop specific biomarkers for future research, and establish a trial-ready network. This study is among the first to focus specifically on EOAD, representing a significant step toward achieving more timely and accurate diagnoses for this particular subgroup.
Promising Advances in Diagnosis
Research has increasingly focused on identifying blood-based biomarkers that can detect AD before clinical symptoms appear. One particularly promising biomarker is phosphorylated tau 217 (p-tau217). In March 2024, the US Food and Drug Administration granted breakthrough device designation for the Simoa phospho-Tau 217 blood test, which is designed for earlier detection of AD. While further research is warranted, especially regarding EOAD diagnosis, the development of an accurate blood biomarker is a significant advance toward more timely and precise AD diagnosis.
Additionally, the development of smartphone and mobile applications capable of administering cognitive tests is a promising tool for early AD detection. Although still in early development, a small cohort study involving 360 participants with a family history of frontotemporal lobal degeneration utilized mobile devices for cognitive testing. The findings suggest that smartphone-based assessments could become reliable tools for early dementia diagnosis.
Although EOAD poses distinct diagnostic challenges owing to its atypical presentation and age of onset, these advances in diagnostic techniques offer hope for early detection in the future. Furthermore, a multidisciplinary approach to diagnosis, involving healthcare practitioners who specialize in dementia, can enhance diagnostic accuracy and patient care.