In this exploratory study of AD patients in memory clinics, we had expected to find that AD patients with concomitant CVD also had symptoms typical for VCI, therefore cognitive test results and depression would differ between patients with and without CVD. Differences were shown in univariate analyses, but after adjusting for age and sex we found no difference in cognitive profiles or depressive symptoms between the two groups. Neuropathology studies have shown that AD patients with concomitant CVD get symptoms with less neurodegeneration than AD patients without. Therefore, as MTA is considered a biomarker of AD in diagnostic criteria, we had expected to find more MTA among patients without CVD. Contrary to this, we observed that patients with CVD had more pronounced atrophy of the medial temporal lobes than those without CVD.
According to diagnostic criteria, a diagnosis of AD requires evidence of a decline in memory and learning, whereas diagnostic criteria for (VCI) describe deterioration in complex attention and executive function. AD patients with concomitant CVD could thus be expected to show additional symptoms associated with the vascular pathology, but no such difference was demonstrated in our study. The literature shows conflicting results on whether concomitant CVD in AD leads to distinct cognitive deficits (18, 28, 29). Even in comparisons of AD with vascular dementia (VaD), the cognitive dysfunction has been shown to be similar, although VaD patients may have better memory and worse executive functioning (30). The cognitive effects of small vessel disease may be heterogeneous and not particularly distinct, and neuropsychological profiles have only modest ability to distinguish between AD and subcortical VaD (31, 32). Subcortical infarcts have been associated not only with reduced processing speed and impaired executive function but also with reduced episodic memory (33). These discrepancies could be related to individual differences in the distribution of pathology in the brain.
Threshold effects may be another reason why studies on cognition in AD with CVD show mixed results. There are indications that a certain amount of vascular pathology may be required to produce distinct symptoms (34). On the other hand, in the late stages of AD, the effect of AD pathology on symptoms may be so strong that it overwhelms the influence of other pathologies (2). Depending on disease stage in AD and cerebrovascular burden, different studies may thus lead to conflicting results. In our study, the group of AD patients not classified with CVD may also have had some CVD, as many of them had some degree of WMH on MRI (Fazekas score of 1) and most had vascular risk factors (35).
No statistically significant association between CVD and depressive symptoms was found. Studies on neuropsychiatric symptoms in VCI compared to AD have shown conflicting results (36). Some find that depression is more common in VCI than in AD, and WMH have been associated with depression (37, 38).
Interestingly, we found a statistically significant association between CVD and more pronounced MTA. We had anticipated the inverse association, as studies have shown that patients with concomitant CVD show less severity of AD pathology than do other AD patients at the same disease stage (39). Various mechanisms may explain this finding. The outcome may be due to the lack of specificity of MTA as a biomarker of AD and of WMH as a marker of small vessel disease. Studies also show that these biomarkers may be interlinked. WMH in white matter tracts connected with the medial temporal lobe may lead to MTA by inducing axonal loss and subsequent atrophy (40). The hippocampus is vulnerable not only to AD pathology but also to vascular damage, as suggested by its sensitivity to hypertension and to hypoxia (41, 42).
Although strongly associated with small vessel disease, WMH in the elderly may result from inflammation or other non-ischemic damage (43). Some of these mechanisms may simultaneously increase WMH and induce atrophy of the medial temporal lobe. In autosomal dominant AD, increased WMH volumes are found years before symptom onset, suggesting that WMH may be part of the pathogenetic processes in AD (44). The results of the present study align with studies where WMH were independently associated with entorhinal cortex volume in aMCI, an effect also observed in patients without significant CVD (45). Even in normal controls, WMH are associated with increased rates of hippocampal atrophy, also when controlling for CSF biomarkers, vascular risk factors, and concurrent brain atrophy (46).
WMH Fazekas 2 is a frequent finding in elderly people and often considered normal above the age of 70-75 years. However, omitting patients with Fazekas 2 from the CVD group in this study did not change the results.
Diagnostic criteria for AD and VCI describe typical symptoms and cognitive deficits for these conditions. However, as there was no observed difference in symptoms between AD patients with and without concomitant CVD after adjusting for age and sex, our findings do not support the idea that symptoms can be used to discern these groups. The patients in our study were well characterized clinically, with diagnoses assessed by a panel of experienced clinicians, and MRIs were systematically interpreted by a highly skilled neuroradiologist blinded to clinical data. Prospective studies with larger study sizes and assessments of CSF and PET biomarkers should be performed to better understand the relationships between symptom profile and underlying pathology in dementia.
As the cognitive profiles of different etiologies of dementia become less distinct with increasing disease severity, only patients with mild dementia and aMCI were included in these analyses
A strength of this study is that the patients were all in the early stages of AD, when cognitive profiles are more distinct than in later stages of the disease. However, the study has some limitations. Analyses were done post hoc, and we did not have clinical data on urinary incontinence and gait performance or CSF markers to quantify amyloid burden. MRI scans were done at several centers using different protocols. Multiple analyses have been performed, and the results should be regarded as exploratory. Lack of power in the study may explain the lack of statistically significant associations for some of the analyses.