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- Early-onset dementia
- Alzheimer's disease
- cerebrovascular disease
- cerebrovascular risk factors
- fronto temporal dementia
Introduction
Alzheimer's disease (AD) is the leading cause of dementia. Research into environmental factors is currently focused on cerebrovascular risk factors.1 Treatment of vascular risk factors has been associated with slower cognitive decline and reduced risk of AD in older populations.2 Genetics are important in rare genetically determined autosomal dominant familial patients with AD or frontotemporal dementia (FTD).3 Apolipoprotein E (APOE) is a risk factor for familial late-onset sporadic AD, but its role as a risk factor in younger populations is unclear. The role of APOE as a risk factor for FTD is controversial.
Early-onset dementia is dementia that develops in individuals prior to the age of 65 years, and some studies suggest it is associated with a higher mortality. AD and FTD are the most common causes of dementia in this population.4 The onset of FTD may be characterised by behavioural change and speech disturbance, whereas AD is usually characterised by defective episodic memory. It is hypothesised that cerebrovascular risk factors, such as hypertension and diabetes, are associated with the development of early-onset Alzheimer's disease (EOAD) but not early-onset FTD. We set out to investigate this hypothesis in a cohort of early-onset AD and FTD patients.
The participants in this study are a cohort of 123 consecutive prospectively analysed early-onset dementia patients with clinically confirmed AD or FTD who gave informed consent. They are a subset of patients in a larger longitudinal study. Sixty-two patients had AD, and 61 had FTD. Patients were diagnosed using published criteria augmented by modern research criteria utilising MRI and functional imaging (brain SPECT, PET) combined with genetic analysis. Appropriate ethics approval was obtained.
Methods
At first contact, patients self reported education, family history of dementia, head injury, hypertension, hypercholesterolaemia, diabetes, smoking, alcohol use, cardiovascular disease, peripheral vascular disease, statin and hormone-replacement therapy use. These histories were confirmed by the spouse or carer and supported by information collated from the primary physicians. The neurologist measured blood pressure, height, weight and abdominal girth (table 1). All measurements were made using the same equipment.
Cerebrovascular risk factors in patients with Alzheimer's disease and frontotemporal dementia
DNA was extracted from lymphocytes using established methods. APOE genotypes were determined using the restriction isotyping technique with HhaI.
Measurement definitions
Body mass index (BMI) was calculated from height and weight data and grouped into underweight (BMI<18.5), normal (18.5–24.9), overweight (25–29.9), obese (30+). Abdominal girth was grouped into normal (≤80 cm for women, ≤94 cm for men) and increased (>80 cm for women, >94 cm for men) based on guidelines from the National Health and Medical Research Council.
Head injury, hypertension, high cholesterol, diabetes, cardiovascular disease, peripheral vascular disease, statin and hormone-replacement therapy use were grouped dichotomously into ‘yes’ or ‘no.’ Education was grouped into completing year 10 or less, completing year 11–12 and completing tertiary education. Family history of dementia was grouped into ‘yes,’ ‘no’ and ‘unsure.’ Smoking was grouped into ‘never,’ ‘ex,’ or ‘current,’ as self-reported by the participants.
Univariate and multivariate analyses were conducted using logistic regression models, ORs and 95% CIs as reported to explain dementia type by vascular risk factors. All statistical analyses was carried out using Stata VII (Stata, College Station, Texas).
Results
Information was collected from 62 EOAD patients and 61 FTD patients. The mean age of dementia onset for both groups was 56 years, and there were more males than females (51% male in EOAD and 64% in FTD). The groups were matched for education level, family history of dementia and head injuries.
Univariate analysis found that patients with EOAD reported almost three times more hypertension (OR=2.68, 95% CI 1.02 to 7.09) and also experienced a 3% higher systolic blood pressure (OR=1.03, 95% CI 1.01 to 1.05) than those with FTD. Those with FTD were more likely to be current smokers (OR=3.12, 95% CI 1.04 to 9.09) and were also heavier (OR=1.03, 95% CI 1.01 to 1.06) than the patients with AD. Other measures did not differ significantly between the two groups.
Multivariate modelling revealed systolic blood pressure (OR=1.04, 95% CI 1.01 to 1.07), weight (OR=0.96, 95% CI 0.93 to 0.99) and being an APOE ε4 heterozygote (OR=4.25, 95% CI 1.67 to 10.86) as being significant. Systolic blood pressure was almost 4% higher in those with EOAD compared with those with FTD. Weight was 4% higher in FTD patients than in EOAD patients. Those with EOAD were four times more likely than patients with FTD to have only one copy of APOE ε4. Having two copies of the gene was not significant (OR=7.72, 95% CI 0.90 to 66.27).
Discussion
The significance of systolic blood pressure in the multivariate analysis contributes to a growing body of evidence implicating vascular changes in the development of AD. The univariate results are similar to those found in an older population, in identifying hypertension as a significant risk factor for AD, but we did not replicate the observations of an association between diabetes and stroke.1 This may be due to differences in study design, the age of the study population and the power of the study. Treatment of hypertension has been shown to slow cognitive decline.5 Hypertension and other cerebrovascular risk factors have not been identified as risk factors for FTD, suggesting that FTD develops independent of cerebrovascular pathology.
The significance of weight in the FTD group may be a reflection of their disease, as hyperphagia can become problematic in this patient group. Univariate analysis revealed that FTD patients were more likely to be current smokers than those with EOAD, which might also have a behavioural explanation. In the ARIC cohort, smoking was strongly associated with risk of hospitalisation for dementia.1 While that study did not specify the type of dementia, it did implicate mid-life smoking as a risk factor.
The APOE ε4 genotype was found to be a risk factor for EOAD but not FTD in univariate analysis. The multivariate analysis revealed that EOAD patients were four times more likely to be heterozygotic for APOE ε4. Our findings confirm: (1) observations in older populations that APOE is the most important genetic marker for sporadic AD and (2) implicate APOE as a genetic risk factor in those patients whose AD has its onset prior to age 65 years.3
Conclusion
These findings suggest that an elevated systolic blood pressure and having one copy of an APOE ε4 allele may be important risk factors in the development of EOAD but not FTD.
Footnotes
Funding York Neuroscience Discovery.
Competing interests None.
Ethics approval Ethics approval was provided by the governing body of Neurodegenerative Disorders Research.
Provenance and peer review Not commissioned; externally peer reviewed.