This study is one of the first to compare relatively large cohorts of patients with the clinical diagnoses of familial (PSEN1
mutations) and early onset AD patients without a family history of the disorder. This study corroborates the finding that FAD occurs earlier, on average 14 years earlier, than the average age of onset among non-familial patients. There were several FAD patients, however, with onset in their 50s reflecting an overlap in the age-of-onset distribution (see ). By the time of presentation, the FAD patients were more advanced with longer disease duration and lower MMSE scores [15
]. In addition, the two groups varied significantly in their presenting symptoms. PSEN1
-related FAD patients, by and large, presented with memory deficits [26
], whereas those with presumed sporadic EAD were more likely to present with visuospatial or language deficits [25
Scatter plot of ages of onset of the two patient groups
When demographic variability (age of onset, education, and MMSE scores) were controlled in a logistical regression model, the PSEN
-related FAD patients had significantly more headaches, myoclonus, gait abnormalities, and pseudobulbar affect than the NF-EAD patients. Previous reviews have found a correlation between age, disease severity, and seizures in AD patients [27
]. In this study, it is surprising that seizures did not distinguish between the familial and non-familial EAD patients. This clinical data seems to indicate that seizures occur somewhat later (5–12 years after onset) than other neurological traits in FAD, and may have required a longer period of follow-up in order to detect them.
Clinicians who evaluate and manage patients with early onset dementias benefit from information regarding when to pursue genetic testing for PSEN1
and other mutations causing young-onset AD. The current guidelines and practice are to suspect an autosomal dominant mutation in those patients with EAD and at least two first-degree relatives [7
]. These guidelines may be insufficient as there are patients who lack a known or reliable family history for early onset dementia. Certain symptoms such as headaches and other neurological abnormalities are frequently associated with FAD, especially those cases due to PSEN1
mutations, and may reflect other neuropathology such as cerebrospinal fluid involvement [13
]. Though it is possible that the apparent increased frequency of headaches in persons with FAD is due to differential medication use (e.g., acetylcholinesterase inhibitors), most persons with NF-EAD were also on such medications. Furthermore, in a previous report [16
] we observed an increased frequency of headaches in FAD mutation carriers who were in the preclinical stage of the disease and therefore none of them were on such medications. The current study corroborates the observation that FAD is of particularly young onset, often in the 40s, has an aggressive course, and is frequently associated with neurological abnormalities.
These clinical features can guide clinicians towards consideration of FAD, particularly in the presence of a progressive neurodegenerative disorder presenting in the early 50s or younger. The presentation is typically with memory impairment; presentations with other cognitive or behavioral deficits are more consistent with sporadic EAD, including early language impairment, visuospatial deficits, apraxia, and behavioral/executive dysfunction [3
]. Although visuospatial deficits suggest the non-familial form, it is noteworthy that one FAD patient in the current study with a relatively late age of onset (55 years; R269H mutation) presented with visuospatial difficulties, suggesting that such deficits may more related to a patient’s age rather than to genetic etiology.
The current study expands on the literature regarding clinical characteristics of FAD and NF-EAD. Prior studies have examined biological and neuroimaging markers (MRI, PET scans) to diagnose EAD [33
]. Such studies have shown an association of temporo-parietal neocortical atrophy with EAD and hippocampal atrophy with late-onset AD [35
], suggesting that neuroimaging can be helpful in distinguishing EAD from the typical late-onset AD [36
]. Imaging with Pittsburgh Compound B has revealed an atypical pattern of amyloid distribution in PSEN1
-related FAD, namely early and severe deposition in the striatum [37
] and sometimes in the cerebellum [38
], apparently reflecting a distinct pattern of the progression of amyloid pathology. Our group has identified a distinct pattern of Aβ peptides in the cerebrospinal fluid of carriers of the A431E PSEN1
mutation compared to late-onset AD [39
], again suggesting different pathogenetic mechanisms in the causes of FAD and NF-AD. Relating the clinical characteristics of FAD to pathological and biomarker changes can help us understand how the pathophysiological cascade of FAD is similar to or distinct from NF-AD and late-onset AD.
There are several limitations to this study. First of all, it is clinical and retrospective, based on recorded differences on clinical assessments and with variable follow-ups. Using such an approach, it is possible that the presence of certain symptoms may have been underestimated. However, there is no reason to suspect any systematic differences in ascertainment of symptoms or signs between the FAD and NF-EAD populations. The observed differences corroborate previous observations regarding differences between FAD and NF-EAD. Second, the two groups are significantly different in ethnic backgrounds, age of onset, and disease progression and severity. Although this study could not eliminate the effects of ethnicity on a genetic disease such as PSEN1
-related FAD, the subsequent logistical regression helped control for the other factors. As the majority of subjects with FAD (22/32) in this cohort had the common A431E substitution representing a founder effect [18
], the findings may not entirely generalize to persons with other PSEN1
mutations or to persons with APP
mutations. Finally, the use of MMSE scores for disease severity can be influenced by language abilities and lower education level among the FAD patients. However, the fact that subjects with FAD were seen later in the course of their symptoms than those with NF-EAD (mean of 5.1 vs. 3.3 years after symptom onset) provides support for FAD subjects being in a more severe stage of the disease. Taking age, MMSE score, and severity into account in logistic regression analyses helped reduce their influence on the occurrence of neurological abnormalities in that analysis.
In conclusion, in addition to a much younger age of onset, clinicians can recognize FAD patients with PSEN1 by abnormalities on the neurological history and examination. In the absence of a reliable family history, an early and progressive age of onset with a history of headaches, myoclonus, gait abnormalities and pseudobulbar affect suggests that genetic testing of EAD patients might be informative. These findings should lead to genetic counseling and related recommendations for these patients. Further studies with different populations and larger sample sizes could corroborate the current findings and, particularly when related to imaging, pathological, and biochemical differences, shed light on distinct or common mechanisms between FAD and NF-EAD.