Exciting New Potential Alzheimer’s Disease Biomarker

Lidia Glodzik, M.D., Ph.D.

Circle of Willis abnormalities may be linked to Alzheimer’s disease.


Hypertension (high blood pressure (BP)), affects more than 60% of us, and dramatically increases Alzheimer’s disease (AD) risk when present in mid-life. Increased pressure accomplishes this by creating and aggravating atherosclerotic plaque in blood vessels of the heart and brain. This agglomeration can result in vessel stiffening and narrowing, catastrophically reducing blood flow to the brain.

As noted by Weill Cornell Medicine (WCM) vascular disease expert Lidia Glodzik, M.D., Ph.D., since, under normal circumstances, 20% of the body’s oxygen (carried by blood) is consumed by the brain, which makes up 2% of body weight, any lack of blood flow is serious. It can lead to hypoxia (lack of oxygen) and inflammation, a milieu conducive to accumulation of AD-associated proteins amyloid beta (β) and tau. Positron emission tomography (PET) scans using amyloid tracers have revealed the former; cerebrospinal fluid (CSF) studies conducted by many groups including Dr. Glodzik’s have established the latter.

Both amyloid β and tau are normally present in the brain. Amyloid β is a membrane protein playing key roles in neuron growth/repair; tau is part of the cytoskeleton. However, hypertension may contribute to their impaired elimination from the brain, helping to drive AD.

Of course, if this were all that drove AD, the disease would be on the verge of a cure. It is not. The problem is far more nuanced. Among other things, bewilderingly, mid-life hypertension is a risk factor for later-life AD—if less so in later life hypertension. Hypertension can even be strangely protective of the brain with age—in terms of cognition, mortality, AD generally.

Happily, Dr. Glodzik’s lab is figuring out why. Her group, with the help of an earlier National Institutes of Health (NIH) R01 grant, suggested an optimal BP level after which hypertension can start to aid older brains. That is, in older, previously hypertensive brains, there can be a point of optimal BP, one that maximizes brain function while minimizing damage.

Now, in a recently awarded competitive renewal of that earlier R01, her group is poised to gather more evidence about other features of brain vessels that could impact optimal BP. The structure of the Circle of Willis (CoW)–a net of arteries supplying the brain–may be one of them, her team believes.

There is an incomplete CoW in more than 1/3 of subject brains in the WCM Stroke Repository, and this phenomenon is associated with worse stroke outcome, her team and others have discovered. Further, it is known that CoW abnormalities are associated with a higher incidence of neurologic events during procedures involving the carotid arteries. Moreover, in carotid stenosis patients, CoW abnormalities are associated with higher white matter lesion (WML) burden; poorer ischemic stroke outcome; future stroke in subjects with atherosclerosis; and cognitive impairment after carotid endarterectomy.

Given such “strong” evidence, Dr. Glodzik says, her team’s R01 may well lead to “fine tuning of hypertension management. It may be necessary to adjust antihypertensive treatment based on cerebrovascular anatomy. Moreover, by confirming that CoW variants are related to cerebral blood flow and AD biomarkers in subjects with hypertension, we may come closer to discovering a novel risk factor for AD.”

Dr. Glodzik heads the VAscular RIsk in Alzheimer’s (VARIA) lab in WCM’s Brain Health Imaging Institute (BHII). She trained and worked in the New York University Center for Brain Health with Dr. Mony de Leon, a pioneer in AD imaging and dementia prediction in the healthy. Dr. Glodzik employs magnetic resonance imaging (MRI) and PET imaging techniques, as well as biofluids, to investigate early indicators of cognitive decline. 



Research reported in this article was supported by the National Heart, Lung, and Blood Institute of the NIH under award number R01HL111724. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.





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