Frontotemporal dementia (FTD), the second most common cause of dementia under the age of 65 in many Western cohorts after Alzheimer’s disease (AD), appears to be relatively less common in Asian populations. It often ranks third or even fourth, behind AD, vascular dementia and Parkinson’s disease dementia respectively. With regards to familial FTD, the proportion of FTD patients with a positive family history in Asian cohorts range from 9.5% to 20%, far lower than the 30 to 50% seen in Western groups. Whether this is largely related to under-reporting or potential differences in biological underpinnings remains unknown.
Since the discovery of C9ORF72 repeat expansions as a major cause for inherited FTD and amyotrophic lateral sclerosis (ALS), many Asian groups have been screened for this hexanucleotide expansion. Cohorts comprising hundreds of patients with FTD and associated disorders were found to be negative for the abnormal repeat expansion. Overall, less than thirty Asian (Chinese, Taiwanese, Japanese and Singaporean Han Chinese) patients have been reported to be positive for C9ORF72 so far, comprising 8 familial ALS, 6 sporadic (in other words no family history) ALS, 5 familial FTD, 1 sporadic FTD, 3 FTD-ALS patients and 2 presymptomatic siblings.
This contrasts starkly with Western data where the frequency of C9ORF72 expansions is much higher (25% of familial FTD, 6% of sporadic FTD, 40% of familial ALS, 3-19% of sporadic ALS and 30% of FTD-ALS cases). The clinical presentations of Asian cases appear similar to that of Caucasian patients, but the numbers remain too small to determine if there truly are phenotypic differences. Asian C9 carriers have mostly been found to possess a genetic risk variant similar to that of the hypothesized Northern European founder, and the only reported pathological findings of Asian C9 carriers appear to be indistinguishable from those of Caucasian patients.
Looking at mutations in microtubule-associated protein tau (MAPT) and progranulin (GRN) genes that are the next most common cause of familial FTD, the prevalence appears to be relatively more comparable between Western and Asian cohorts. A review of Japanese familial dementias including FTD identified 16 MAPT mutations in 84 patients (19%), somewhat similar to Western data where both MAPT and GRN mutations each account for up to 20% of familial FTD cases. However, only 2 Japanese GRN carriers were reported in this analysis (one with primary progressive aphasia and the other with behavioural variant FTD). In this report, the mean age at onset of MAPT carriers in their 40s appeared similar to other ethnic groups. Japanese MAPT carriers displayed relatively typical symptoms of either impaired behaviour or episodic memory and six patients had a syndrome similar to progressive supranuclear palsy.
The reasons for this apparent lower incidence of FTD and positive family history in Asian patients are multifactorial. While a large part of it is thought to be due to under-diagnosis, given the relatively more recent recognition of FTD as a disease entity amongst physicians in many parts of Asia, the high incidence of vascular risk factors in Asian populations plays a significant role in driving vascular dementia and mixed dementia (AD plus vascular dementia) as the top causes for young-onset dementia in this part of the world. Cultural, social and economic factors play an important role as families often delay seeking medical help for affected individuals, only doing so when the disease has progressed to an advanced stage.
On a broader scale, greater multinational efforts are taking place to collaborate amongst Asian countries, particularly with regards to genetic screening in FTD and other young-onset dementias. Pathogenic mutations and genetic modifiers prevalent in Caucasian populations may play a weaker role in Asian cohorts. Whether this is related to lack of recognition, or due to the fact that Asian FTD patients have molecular and genetic underpinnings unique from those of Caucasians, remain to be determined.