16 Jan 2020

Three new studies add to growing evidence that damaged blood vessels wreak havoc on the brain, but not by exacerbating Aβ deposition. One, published in JAMA Neurology on December 20, found no correlation between intracerebral atherosclerosis and overall amyloid plaque burden in cognitively normal older adults. Another, in the January issue of Annals of Neurology, reported that midlife atherosclerosis in the carotid artery upped future risk of vascular dementia, but not AD. A third, published in Neurology on December 30, found that white-matter hyperintensities—a proxy for damage to small vessels in the brain—had no bearing on future changes in AD biomarkers.

Atherosclerosis in the brain does not correlate with amyloid burden.

Midlife atherosclerosis boosts risk of vascular dementia, but not AD.

White-matter pathology does not predict abnormal AD biomarkers.

“These studies can all be interpreted to support the hypothesis that vascular risk influences the risk for development of cognitive impairment and dementia principally via non-amyloidogenic pathways,” wrote Jonathan Schott of University College London. “They provide further evidence for, and are compatible with, the growing body of evidence that the timing of vascular risk also matters, with midlife being the most sensitive period.”

To Anja Soldan, Johns Hopkins University, Baltimore, who led one of the studies, all three converge on a similar conclusion. “They all suggest that cerebrovascular disease and AD affect cognitive decline through distinct pathways,” she said.

On their own, faulty blood vessels in the brain can cause cognitive impairment and dementia. Blood-vessel disease is also thought to contribute to the clinical symptoms of AD, since people with Alzheimer’s often have vascular pathology along with amyloid plaques and neurofibrillary tangles (Honig et al., 2005; Yarchoan et al., 2012; Toledo et al., 2013). However, if, and at what disease stage, vascular dysfunction contributes to the amyloid deposition is unclear.

While the Atherosclerosis Risk in Communities (ARIC) study tied midlife vascular risk to subsequent Aβ accumulation, recent data from the British birth cohort indicated no such relationship (Apr 2017 news; Aug 2019 news; Nov 2019 news).

Now, as reported in JAMA Neurology, researchers led by Rebecca Gottesman at Johns Hopkins looked for cross-sectional correlations in ARIC between Aβ load and intracerebral atherosclerotic disease (ICAD)—a manifestation of vascular disease in the brain that has been tied to stroke and cognitive decline. They used black-blood MRI, which detects atherosclerotic plaques, to measure ICAD throughout the brains of 300 cognitively normal ARIC participants in their 70s. Each of them also had an amyloid PET scan in the same year. MRI indicated that 105 people had at least one vessel containing an atherosclerotic plaque. Though the global Aβ burden generally trended higher in people with ICAD, this association disappeared once the researchers adjusted for age, sex, and other demographic factors.

Gottesman did pick up some associations in specific regions of the brain. Among 22 people with at least one ICAD plaque who also had narrowing, aka stenosis, of the middle or anterior cerebral arteries, chances of Aβ deposition in regions directly supplied by those vessels more than doubled. However, Gottesman cautioned that this intriguing hint came from a small subset of people in the cohort, and needs to be tested in a larger sample.

If midlife vascular risk correlated with future Aβ deposition in ARIC, why didn’t late-life ICAD? Gottesman thinks that the midlife vascular risk factors that influence ICAD and Aβ may be different. Costantino Iadecola of Weill Cornell Medical College in New York noted that because the study excluded people with cognitive impairment, it likely excluded those with more advanced ICAD—especially people with stenosis. Perhaps an association with Aβ would be detected in advanced ICAD, he said.

In contrast, researchers led by Katarina Nägga and Oskar Hansson of Lund University in Mälmo, Sweden, found no relationship between midlife atherosclerosis in the carotid artery and future AD diagnoses. As they reported in Annals of Neurology 6,103 participants in the Mälmo Diet and Cancer Study had baseline ultrasound to measure the thickness of their intima media—the innermost layers of the carotid artery—in midlife. Over the following 20 years, 462 developed dementia. Of those, 138 were classified as pure AD, 147 as AD with cerebrovascular pathology, and 109 as vascular dementia. The researchers found that neither midlife intima media thickness nor the number of carotid atherosclerotic plaques associated with AD or mixed dementia. However, a thicker intima media in midlife did associate with all-cause and with vascular dementia. People with the most carotid plaques in midlife also had higher chances of vascular dementia later on.

What about CSF biomarkers? Among 330 participants in the Swedish BIOFINDER cohort—a cognitively normal subgroup of the Mälmo study whose members had CSF biomarker measurements—the researchers found no connection between midlife carotid atherosclerosis and CSF Aβ42 or Aβ42/p-tau measured 20 years later. Iadecola noted that, similar to the ARIC study, the BIOFINDER cohort was subject to selection bias, as people with dementia were excluded.

The third study, published in Neurology and led by Soldan, investigated in the BIOCARD study whether the size of a person’s white-matter hyperintensities—a gauge of small-vessel disease in the brain—correlated with cognitive impairment or CSF biomarkers of AD. WMH volume and CSF biomarkers were measured at baseline in 274 participants, when they were in their late 50s and cognitively normal. Over the next decade, 37 had developed MCI and 23 dementia. Clinical records indicated that 24 had vascular disease. Those 60 people had larger WMHs, less CSF Aβ42, and more CSF t-tau and p-tau at baseline than the 214 who did not go on to develop MCI.

However, WMH volume did not sway a person’s time to MCI independently of baseline Aβ or p-tau. Hence, the data suggest that small-vessel pathology did not influence subsequent cognitive decline in people who had AD, Soldan said. In people with low baseline total tau, and hence a lesser degree of neurodegeneration, baseline WMH volume did correlate with earlier symptom onset. However, overall, people with low t-tau at baseline had lower odds of future cognitive impairment, regardless of their WMH burden, than did people with high t-tau or other AD biomarkers.

Soldan followed a subset of 132 participants who donated at least two CSF samples over the next two to four years. Their baseline WMH volume did not correlate with any fluid biomarker changes. Essentially, this study suggests that damage to small vessels in the brain exacerbates neither AD pathology nor cognitive decline in people who tested positive for AD biomarkers.

Anna-Märta Gustavsson, first author of the Mälmo study, also thinks cerebrovascular disease and AD work through different pathways. “My interpretation of these joint findings is that vasculopathy may contribute to cognitive decline in AD dementia by cerebrovascular alterations, rather than influencing Aβ pathology directly,” she wrote. Gustavsson added that further studies should examine relationships between midlife vascular risk and subsequent AD biomarkers in more diverse cohorts, and include people who have MCI and dementia.

Prashanthi Vemuri of the Mayo Clinic in Rochester, Minnesota, said that findings from the three studies dovetail with those from her group, which cast good vascular health not as a protector against amyloid, but as shield against synaptic damage and neurodegeneration, regardless of its cause (Vemuri et al., 2017; Vemuri et al., 2017; Vemuri et al., 2019). “Good vascular health may not stop Ab deposition, but it likely delays the onset of clinical symptoms in people with AD,” she said.

Iadecola thinks that regardless of whether vascular dysfunction has an additive or synergistic relationship with AD pathology in influencing cognitive decline, the crucial point is that good blood vessel health benefits the brain. A person’s vascular risk is highly modifiable by way of lifestyle choices or, if need be, medication.—Jessica Shugart