The findings of the present study show differences in the rate of cognitive decline between AD patients with and without WMLs. The mean MMSE scores of all patients decreased slightly from 19.1 ± 4.6 to 18.5 ± 5.9 during the approximately 1-year follow-up. A meta-analysis of the literature revealed that untreated AD patients lose at least 2.9 points on the MMSE per year [13
]. Therefore, AChE-I was effective against progressive cognitive impairment in our patients as a whole. The changes in the mean MMSE scores, however, differed between AD patients with and without WMLs. The mean MMSE scores remained above baseline values in the WMLs(-) group, whereas they decreased in the mild and moderate WMLs(+) groups. Moreover, the improvement tended to be higher in the WMLs(-) group than in the mild and moderate WMLs(+) groups. AD patients with WMLs showed a faster rate of change in MMSE scores during AChE-I treatment. These findings are consistent with those of previous studies suggesting baseline WMLs are associated with a more rapid cognitive decline in AD patients [11
]. Although the clinical response to AChE-I therapy and the rate of cognitive decline are considerably variable [14
], the reasons for this remain unclear. We suggest that baseline WMLs might be associated with the heterogeneous cognitive outcome and response to AChE-I in AD patients.
Neuropathological studies showed that AD patients with vascular lesions have less AD pathology, including neuritic plaques and neurofibrillary tangles, compared to those without vascular pathology, despite the same severity of cognitive impairment [16
]. Moreover, cerebrovascular disease may promote AΒ aggregation or plaque formation and cognitive decline in early or mild AD [17
]. These findings suggest that AD pathology and small vessel vascular disease act synergistically in the course of cognitive symptoms in AD [13
]. Moreover, neuroimaging data revealed a relationship between WMLs and regional cerebral blood flow or cerebral metabolism in AD patients. AD patients with WMLs have decreased metabolism in the frontal lobes on positron emission tomography and hypoperfusion in the hippocampal regions on brain perfusion SPECT [19
]. Similarly, we previously reported that AD patients with WMLs showed hypoperfusion in the limbic system compared to those without WMLs [7
]. These findings suggest that WMLs contribute to the decreased brain function in AD patients. Therefore, we propose that WMLs influence the progression of cognitive decline through neuropathological and brain functional mechanisms. Future studies are needed to investigate the effects of preventing WMLs on the progression of cognitive decline in AD.
The present study has several limitations. First, we selected late-onset AD patients with mild-to-moderate dementia because the severity of white matter involvement is associated with age and severity of cognitive impairment. Second, the dose of donepezil was 5 mg/day, which is lower than the international standard (10 mg/day). In Japan, donepezil at a dose of 5 mg/day is indicated for mild-to-moderate AD [21
]. Third, the follow-up MRI study was not performed to assess cerebrovascular disease and progression of WMLs. Although the incidence of cerebrovascular disease could not be completely excluded, especially in the patients with rapid cognitive decline, none of the patients showed focal neurological symptoms and signs. Moreover, our results could not demonstrate a correlation between the progression of WMLs and the rate of cognitive decline.
In conclusion, the present study reveals a difference in the rate of cognitive decline between AD patients with and without baseline WMLs. We suggest that baseline WMLs may be associated with a more rapid cognitive decline and the response to AChE-I in AD patients.