ABSTRACT & COMMENTARY
Clinical Differences Between Early- and Late-Onset Alzheimer’s Disease
By Michael Lin, MD, PhD
Assistant Professor of Neurology and Neurosciences, Weill Cornell Medical College
Dr. Lin reports no financial relationships relevant to this field of study.
SYNOPSIS: In a large pooled database from seven AD clinical trials, the clinical features of early and late-onset AD were compared and contrasted.
SOURCE: Panegyres PK, et al. Early-onset Alzheimer’s disease: A global cross-sectional analysis. Eur J Neurol 2014;21:1149-1154.
Although the majority of cases of Alzheimer’s disease (AD) have initial symptoms at age > 65 (late-onset AD, LOAD), the index case described in 1906 was in a 50-year-old woman; for much of the 20th century, the term AD was reserved for cases beginning at age < 65 (now called early-onset AD, EOAD). Despite this history, there have been relatively few large-scale studies of EOAD.
To compare clinical and demographic characteristics of EOAD vs LOAD, an Australian group queried a large global database containing information on more than 3000 subjects who were in the placebo arms of 10 clinical trials on AD from seven major pharmaceutical companies. The companies agreed to rework their trial data into a uniform format specified by the Coalition Against Major Diseases and the Clinical Data Interchange Standards Consortium.
Of the 3747 AD subjects extracted from the database, 614 (16.4%) were EOAD cases. The mean ages of EOAD and LOAD were 59.3 (SD = 3.76) and 76.2 (SD = 5.98), and there was no difference in sex distribution. The key differences between EOAD and LOAD were:
- A higher proportion of EOAD cases consisted of ethnicities other than white, black, or Asian compared to LOAD (3.4% vs 1.3%, P = 0.002),
- LOAD cases were more likely to have vascular risk factors such as hypertension, stroke, and atrial fibrillation (P < 0.01) as well as hypothyroidism
(P = 0.006), - A higher proportion of LOAD cases had a first-degree relative with AD compared to EOAD cases (68.9% vs 57.5%, P < 0.0001),
- A higher proportion of EOAD cases had anxiety or depression than LOAD cases (30.9% vs 23.2%, P < 0.0001), and
- LOAD cases were more likely to be on donepezil (48.8% vs 39.7%, P < 0.0001) or risperidone (6.2% vs 3.4%, P = 0.008).
COMMENTARY
Although this was a large study, several cautions should be kept in mind. First, it consisted solely of participants in clinical trials, a rather select group. For example, the proportion of EOAD cases in this study (16.4%) is larger than estimates in the general population (~5% according to the Alzheimer Association), perhaps because EOAD cases may be more motivated to participate in studies. Second, because age was the defining feature separating EOAD and LOAD, and because vascular risk factors are age-related, it is unclear whether the association between vascular risk factors and LOAD is due to age alone, or whether there is more pathophysiologic significance. The cross-sectional design also precludes conclusions about causation, but the results are consistent with growing consensus that vascular risk factors are involved in AD. Third, data such as education, socioeconomic status, and genotype were unavailable. These data would be particularly important in trying to understand the role of ethnicity, which clearly interacts with both socioeconomic and genetic factors, and the association with family history. It is puzzling that family history was more strongly associated with LOAD, considering that the known autosomal dominant causes of AD (mutations in APP, PS1, and PS2) and the strongest genetic risk factor for AD (apoE4) are all associated with earlier onset.
Other findings are also puzzling. EOAD cases were less likely to be treated with donepezil, even though the same authors had previously found that EOAD cases had lower mini-mental state scores at baseline and that the difference enlarged over time. Given greater cognitive impairment and neuropsychiatric symptomatology in EOAD, it is also puzzling that there was less use of neuropsychiatric medications in EOAD. Finally, it would be very interesting to consider whether biomarkers such as CSF Abeta and tau or amyloid PET imaging were different between EOAD and LOAD.
These cautions aside, the collaboration involved in voluntary pooling of data from multiple studies, reworked to have a uniform consensus format, is to be strongly encouraged.
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