May 27, 2011 — Patients with early-onset Alzheimer's disease (AD) may present initially with symptoms other than typical memory problems, which often leads to misdiagnosis, a new study confirms.

Albert Lladó, MD, PhD, of the Hospital Clínic and the Institute of Biomedical Investigation August Pi i Sunyer, in Barcelona, Spain, and colleagues report this observation in the May 17 issue ofNeurology.

"Several clinical series have shown that early-onset AD presents more frequently with atypical manifestations, such as visual, executive, behavioral, or language impairment, compared with the late-onset variant," Dr. Lladó told Medscape Medical News.

"However, clinical studies are made using clinical criteria lacking pathological confirmation. In our study, all patients have a pathological confirmed early-onset AD," he noted.

More Than Half Incorrectly Diagnosed

In this study, Dr. Lladó and colleagues reviewed clinical data and APOE genotype in 40 brain donors (25 male, 15 female) fulfilling neuropathologic criteria for AD. All of them developed AD early, between 46 and 60 years of age (mean age, 54.4 years). The average duration of AD in study subjects was 11 years; the average age at death was 65.5 years.

According to the investigators, 25 of the 40 cases (62.5%) presented with typical episodic memory dysfunction as the first symptom. In all but 1 (4%), the initial diagnosis was correct (early-onset AD).

The other 15 cases (37.5%) presented with symptoms other than memory loss, usually behavioral or executive dysfunction, and visual or language impairment.

This atypical presentation "led to an increased misdiagnosis compared with the typical clinical forms," Dr. Lladó said. More than half of the patients (53%) with atypical (nonmemory) presentations received an incorrect diagnosis at first. Seven patients (47%) still had incorrectly diagnosed conditions at the time of their death.

The incorrect diagnoses included behavioral variant frontotemporal lobar degeneration, normal pressure hydrocephalus, semantic dementia, primary progressive aphasia, corticobasal degeneration, pseudodementia with depression, and unclassifiable dementia.

Dr. Lladó and colleagues report that the average delay in diagnosis of AD was 3.1 years, with no difference between the typical and atypical cases. "The diagnostic delay in early-onset AD might have been caused by the young age itself because the family and attending physicians do not contemplate dementia in the initial differential diagnosis," the researchers note in their report.

"A better knowledge of the different clinical presentations of AD and the use of AD biomarkers would be needed to promote an earlier and more accurate diagnosis," Dr. Lladó told Medscape Medical News.

New diagnostic criteria for Alzheimer's disease were recently published.

Delay in Diagnosis Equals Delay in Treatment

Reached for comment, Gustavo C. Román, MD, medical director of the Nantz National Alzheimer Center at the Methodist Neurological Institute in Houston, Texas, who was not involved in the study, said, "The study is extremely important because it reminds physicians that early-onset behavioral problems are not always frontotemporal dementia but can be Alzheimer's disease."

Dr. Román made the point that "a delay in diagnosis of Alzheimer's disease also leads to a delay in treatment, and the treatments tend to stabilize and give you a little bit more time in the progression of the disease."

a delay in diagnosis of Alzheimer's disease, also leads to a delay in treatment and the treatments tend to stabilize and give you a little bit more time in the progression of the disease.

APOE e4 allele carriers were 3.3-fold more frequent in familial cases (76.9% vs 23.1%; 95% confidence interval, 1.5 – 7.1), "but that did not seem to influence the clinical phenotype," Dr. Lladó said. No significant differences were found in APOE genotype between typical and atypical presentations.

This study, Dr. Román commented, "also reminds us that APOE ε4 continues to be the most reliable genetic risk factor that we have.

"In a way," he added, "if you can't do a PET [positron emission tomography] scan or show the presence of amyloid with Pittsburgh compound B, 1 option in early-onset patients with atypical presentations would be APOE genotyping. If you find they are ε4 carriers, then the likelihood is that it is going to be early-onset Alzheimer's disease and it should be treated as such."

The study was supported by the Hospital Clinic-Emili Letang. Dr. Lladó has disclosed no relevant financial relationships. A complete list of author disclosures is available in the original article. Dr. Román has disclosed no relevant financial relationships.