The Contribution of Cerebral Vascular Neuropathology to Mild Stage of Alzheimer’s Dementia Using the NACC Database
Authors: Liu Yue , Chan Daniel K. , Crawford John D. , Sachdev Perminder S. , Braidy Nady 
Published: February 2021

Background:
The interaction between cerebral vessel disease (CVD) pathology and Alzheimer’s
disease (AD) pathology in the development of dementia is controversial. We examined the
association of cerebral vascular neuropathology and cerebrovascular risk factors with the mild stage of
Alzheimer's dementia and cognitive function.

Methods:
This cross-sectional study included men and women aged 60 years or over who had yearly
clinical assessments and had agreed to brain autopsy at the time of death, and who contributed to data
stored at the National Alzheimer's Coordinating Center (NACC) in the USA. Cognitively normal and
impaired subjects with presumptive aetiology of AD, including mild cognitive impairment (ADMCI)
and dementia (Alzheimer’s dementia), and with complete neuropathological data, were included in our
analyses. We used neuropsychological data proximate to death to create summary measures of global
cognition and cognitive domains. Systematic neuropathological assessments documenting the severity
of cerebral vascular pathology were included. Logistic and linear regression analyses corrected for age
at death, sex and Lewy body pathology were used to examine associations of vessel disease with the
severity of Alzheimer's disease dementia, and cognitive function, respectively.

Results:
No significant relationship was observed between late-life risk factors and Alzheimer’s
dementia. The severity of arteriosclerosis and presence of global infarcts/lacunes were related to mild
Alzheimer’s dementia (B=0.423, p<0.001; B=0.366, p=0.026), and the effects were significant after
adjusting for neuritic plaques and neurofibrillary tangles (B=0.385, p<0.001; B=0.63, p=0.001). When
vascular brain injuries were subdivided into old and acute/subacute types, we found that old microinfarcts
and old microbleeds were associated with mild Alzheimer’s dementia (B=0.754, p=0.007;
B=2.331, p=0.032). The old microinfarcts remained significantly associated with mild Alzheimer’s
dementia after correcting AD pathologies (B=1.31, p<0.001). In addition, the number of microinfarcts
in the cerebral cortex had a significant relation with mild Alzheimer’s dementia, whether or not the
data were corrected for AD pathologies (B=0.616, p=0.016; B=0.884, p=0.005). Atherosclerosis, arteriosclerosis
and white matter rarefaction were found to be significantly associated with faster progression
of Alzheimer’s dementia (B=0.068, p=0.001; B=0.046, p=0.016, B=0.081, p=0.037), but white
matter rarefaction no longer had a significant effect after adjusting for AD pathologies. We also found
that the severity of atherosclerosis was related to impairment in processing speed (β=-0.112, p=0.006)
and executive function (β=-0.092, p=0.023). Arteriosclerosis was significantly associated with language
(β=-0.103, p=0.011) and global cognition (β=-0.098, p=0.016) deficits.

Conclusion:
Our study found the significant relation of global, old, acute/subacute and regional cerebral
vascular pathologies, but not white matter rarefaction, to the onset and severity of Alzheimer’s
dementia. We also showed that late-life risk factors were found to have no relation with Alzheimer’s
dementia, and the increased risk of dementia with APOE ε4 is not mediated by CVD. The best interpretation
of these findings is that CVD has a potential additive effect with AD pathologies in the development
and progression of what is clinically diagnosed as Alzheimer's dementia.