Patients with early onset AD were diagnosed using NINCDS-ADRA criteria and supported by structural and functional imaging (FDG PET) and neuropsychometry.^{3 5 6} Patients were diagnosed with FTD using existing published criteria⁷ and refined as new technology (such as FDG PET) became available⁶ and at annual review using contemporary international guidelines.^{3 8} With this approach, no patients have been excluded and our neuropathological sensitivity and specificity for the diagnosis of AD and FTD=100%.

The FTD group comprised only patients with the behavioural variant of FTD for uniformity of analysis; patients identified with semantic dementia (n=1), primary progressive aphasia (n=8) and motor neuron disease–FTD complex (n=2) were not included.

A detailed history was recorded from the patient at baseline, including education, family history and medical history. This information was then corroborated with the spouse or primary carer, and the general practitioner. Additionally, during follow-up this information was updated if the patient characteristics changed; for example, if a patient developed cancer.

Age at onset was determined from self and carer/spouse report of the onset of symptoms. Education is defined as self-reported years of formal education. Family history is defined as a self-reported family history of dementia in first-degree and second-degree relatives. Cerebrovascular risk factors are hypertension, hypercholesterolaemia, increased girth, obesity, diabetes, smoking, excessive alcohol consumption, coronary heart disease and peripheral vascular disease, the measurement of which has been described elsewhere.⁹ The presence of at least one of these risk factors was determined from self-report and medical notes. The presence of mental illness (depression or psychosis) or other comorbidities was also determined through self-report, carer information and medical notes.

Mini mental state exam (MMSE) was performed at each visit as a measure of cognition.¹⁰ Global Deterioration Scale (GDS) and Total Functional Capacity (TFC) staging were determined for each visit as markers of the severity of the dementia and abilities to perform acts of daily living.^{11 12} The ratings were performed by the same trained team of cognitive assessors.

DNA screening was performed on our patients with an autosomal-dominant pattern of inheritance—nucleotide changes in the coding sequences of the amyloid precursor protein, progranulin gene, presenilin-1 and presenilin-2 genes, Tau and SIGMAR 1 gene were performed by direct sequencing of polymerosechoid reaction (PCR) products derived from genomic DNA. Nucleotide sequence information from each PCR product was obtained from both strands and possible mutations were verified by an independent amplification of the PCR product and resequenced. ApoE genotypes were determined by restriction fragment polymorphism analysis of PCR amplified products. Individuals identified with presenilin-1 mutation (Q222H), progranulin mutations and SIGMAR 1 mutations are not included in this study and will be reported elsewhere.

The mean MMSE was consistently lower in those with FTD compared with those with AD over a decade of follow-up (figure 2). At baseline the MMSE, TFC and GDS did not show any significant difference between AD and FTD, providing further evidence for a worse progression of early onset FTD in comparison to AD. The boxplot shows that spread of MMSE scores is more condensed in those with FTD compared with AD across follow-up time. Similar results were seen with TFC. A greater range of GDS scores was seen in FTD patients compared with AD patients at baseline; however, a more condensed range of scores was seen across follow-up time. Mean GDS was consistently higher in those with FTD over the follow-up period. Some of the boxplots are missing (eg, year 11 for early onset Alzheimer's disease (EOAD) and years 9 and 10 for FTD): this is because median value is 0, min=0, max=0 so there is no box; for year 12 there are no data, hence no box. The unusual distribution beyond 9 years is likely due to small sample size, which would also be affecting the boxplots. It is possible there is a survival effect; those few who survive to that point and with longer follow-up may have a slower disease progression. The boxplots may also be affected by a clustering of scores at zero (figure 2).

The majority of patients had a GDS score of four at baseline with a mean 4.02 years of follow-up (table 3).

The difference in depression between those with FTD and those with AD is a complex issue. It may be that those with a history of depression are more at risk of FTD, or that patients with FTD are more likely to develop depression.

We found a difference in the MMSE, GDS and TFC between AD and FTD patients during the progress of the study, but not at the commencement of the study. The greater decline in MMSE in FTD patients might be attributable to the more aggressive nature of the dementia in FTD: findings supported by the changes in the functional scales and the differences in survival.

We sought to describe the natural history of early-onset dementia, particularly AD and FTD. We found that survival is significantly reduced in those with FTD compared with those with AD, as seen by Koedam et al.⁴ In contrast, Pasquier et al¹³ found survival to be similar between patients with AD and FTD after controlling for sex, age, age at onset and education level, although they did find sudden death to be more frequent in FTD. These differences may be related to the inclusion of older onset dementia patients in this study. There was approximately a decade difference in mean age between Pasquier's AD and FTD patients while mean average was the same in our population. We speculate that the difference in survival between AD and FTD in our cohort might relate to the greater presence of one or more cerebrovascular risk factors in FTD patients—an unexpected finding. While our previous research had identified hypertension to be a risk factor in the development of AD, it does not appear to affect survival. Other elements of cardiovascular risk including smoking, increased alcohol consumption and obesity may develop in FTD as part of the frontal disinhibition syndrome and these factors may impact on survival. We need to be mindful of the risk profile in individuals with early onset AD as management of cerebrovascular risk factors will affect progress (figure 3).

Our experience of different rates of progression in AD appears to be similar to the results of Thalhauser and Komarova.¹⁴ They used a different staging system, the functional assessment staging (FAST) procedure and found that if a patient progressed rapidly through a FAST stage he or she was likely to experience rapid progression through the remaining stages (similar to the patient described in figure 3). It has been found that comorbidity can be associated with an increased disease progression,¹⁵ and this reflects our experiences with patients like patient 2 (figure 3). Additionally, poor physical health in those with AD is linked to poorer survival.¹⁶ Work by Paradise and colleagues modelled survival time from age, constructional and gait apraxia in a much older cohort (mean age 81 years). These patients experienced shorter survival (approximately 3 years), likely due to the age of the population studied, while others found a median survival of 6.7 years in a younger group of AD patients aged 60–69 years.^{17 18} While determining the predictors of survival in older age groups, Wolfson et al¹⁹ were unable to determine the estimated probability of survival in early-onset AD after adjustment for rapid progression (length bias) because of a small early-onset sample size. Rapid versus slow progression may be related to structural and functional changes in the brain. Kim et al²⁰ suggested that a greater degree of glucose hypometabolism in the brain at the same level of dementia severity in early-onset versus late-onset AD patients might reflect rapid disease progression. Sluimer et al²¹ identified that more generalised whole-brain atrophy may reflect rapid disease progression in comparison with more localised hippocampal atrophy in slow progressing AD; Karas et al²² suggested the precuneus as a marker for progression of early-onset AD.