The main findings from our study of elderly Taiwanese people may be summarized in the following points: (1) Dementia patients have a more than 2-fold greater risk of developing stroke within 5 years of diagnosis compared to non-dementia age- and sex-matched subjects, after adjusting for other risk factors, and (2) antipsychotic usage increases the risk of stroke in dementia patients.
The association between dementia and stroke originated mainly from community-based studies of people with cognitive dysfunction rather than dementia. A large-scale community- based study in Italy indicated that elevated stroke risk is associated with cognitive impairment 
. However, cognitive impairment was indicated through a self-administered questionnaire; thus, their results may be different from clinical dementia and confounded by recall bias. Zhu et al 
showed a 2- to 3-fold greater risk of developing stroke among community-dwelling persons with dementia over a 3-year follow-up period. Their diagnoses of dementia were made according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition-revised (DSM III-R). However, the limited number of persons with dementia at baseline (n=
70) and short duration
of the follow
may have compromised their findings. This is a nationwide population-based epidemiologic study for examining the relationship between dementia and risk of incident stroke. The strength of this study originates from its nationwide population data set, which included nearly all cases of dementia and stroke in Taiwan during the study period because all practices of psychiatrists and neurologists were covered by the LHID. The large sample size and cohort study design with controls provide considerable statistical power for detecting real and even subtle differences between the 2 cohorts.
Several explanations are plausible for the increased risk of stroke in dementia patients. First, dementia patients have an increased burden of cerebrovascular disease. Several studies have suggested that a significant number of dementia patients suffer from a combination of both degenerative and vascular pathology; thus, a combination of cerebral hypoperfusion, culmination of vascular pathology, and senescence leads to a neuroglial energy crisis, neuronal injury, cognitive impairment, and ultimately, dementia 
. The cerebrovascular insults may begin numerous years before the manifestation of a clinical stroke. The decline in intellectual level may be correlated with the degree of neurological impairments caused by cerebrovascular insults. Therefore, older people with sufficient deterioration of cognitive function that meet the diagnostic criteria of dementia have a higher probability of suffering an acute stroke.
Second, patients with dementia may be more vulnerable to the complications that are associated with cardiovascular diseases 
. Furthermore, they may be less likely to recover if affected by these complications compared to non-dementia patients, either because of general frailty, under-diagnosis, under-treatment, and/or noncompliance. Physicians may be hesitant in prescribing several effective drugs such as anticoagulants, even when indicated otherwise because of their potential adverse effects and by regarding that intervention in dementia patients is futile. For example, dementia is generally believed to be a relative contraindication for warfarin treatment in patients with atrial fibrillation 
. The manner in which physicians behave toward such patients can be affected by the presence of cardiovascular risk factors. Studies have shown that vascular risk factors are treated less often in patients with dementia 
, which may increase the susceptibility to stroke in dementia patients.
On the other hand, we identified that stroke risk with antipsychotic usage was higher among dementia patients compared to patients who did not receive antipsychotics. This finding was consistent with previous reports 
, and provides strong evidence for supporting the US Food and Drug Administration’s warnings of increased stroke risk in elderly dementia patients with exposure to antipsychotics. A crossover study recently using the data of 14 584 patients with incident stroke from the insurance database in Taiwan showed similar findings, indicating that elderly patients treated with antipsychotics had a 1.6-fold greater risk of stroke than patients without prior antipsychotic use 
. Potential mechanisms for antipsychotic use-related stroke may include orthostatic hypotension in patients with pre-existing cerebrovascular disease, which may lead to “watershed” strokes and antipsychotic-induced tachycardia, causing unstable hemodynamic conditions 
. Furthermore, over-sedation induced by antipsychotic use may result in dehydration and hemoconcentration, which may be potential mechanisms for increased stroke risk 
. The association of antipsychotics with stroke may be partially explained by their hyperprolactinemia effect, which may promote platelet aggregation 
. However, several studies have reported that antipsychotics may inhibit platelet aggregation through serotonin receptor antagonism rather than promote it 
. Certain observational data have shown that antipsychotics may be associated with an increased risk of venous thromboembolic disease 
; arterial thrombosis such as stroke shares few risk factors with venous thrombosis. A clear biological mechanism has not been identified for the antipsychotic use-associated increased risk of stroke.
Our study has several limitations. First, all administrative databases are subject to possible coding errors and under- or over-coding problems. The definitions of dementia and stroke relied solely on the coding of hospital diagnoses, but the accuracy of the diagnosis and coding were not verified. Second, information regarding the degree or stage of dementia was unavailable in this database, and the subtypes of dementia were not considered in the analyses of this study. All of these factors may affect the degree of stroke risk. Third, stroke is a heterogeneous disease that includes large-artery atherosclerosis, cardioembolism, small-artery occlusion, and other subtypes 
. However, patients were only divided into groups of developed stroke or did not develop stroke; thus, we were unable to examine the associations between dementia and stroke subtypes. Fourth, we did not record the duration of treatment (eg, cumulative days of antipsychotic use after initial diagnosis of dementia) for antipsychotics analysis. Moreover, we did not analyze the risk of stroke by the characteristics of antipsychotic use based on average daily dose, classification of antipsychotics, and grouping of the binding affinity for various neurotransmitters; all of these factors may contribute to stroke susceptibility 
. Finally, individual information regarding dietary habits, cigarette smoking, and body mass index can contribute to stroke, but were not available in the data set. These limitations may have compromised our findings.
We identified dementia as an independent risk factor for stroke using a large-scale population-based study. The use of antipsychotic agents in dementia patients may increase the risk of stroke. Further studies are required to replicate these findings and examine whether preventing cognition decline or discontinuing antipsychotic usage can modify the risk of stroke in dementia patients.