Annals Neurology: Tau is a mediator of vascular risk and Aβ for cognitive decline

Despite recent advances in anti-amyloid therapy, there is still an urgent need for safe and effective treatments
that can meaningfully alter the course of Alzheimer's disease (AD).
It is increasingly believed that the increased burden of β-amyloid (Aβ) is necessary but not sufficient to cause AD
.
Therefore, it is critical to identify, characterize, and target those factors
that co-alter cognitive decline with Aβ pathology.

Figure 1: Paper cover image

Elevated vascular risk and cerebrovascular disease are very common with age, often coexisting with AD pathology, and are increasingly recognized as important factors in
AD-related cognitive decline.
Systemic vascular risk increases, particularly when combined with elevated Aβ burden, are associated with accelerated cognitive decline and an increased risk of dementia in individuals with cognitive impairment (CU).

This suggests that interventions to reduce vascular risk may be effective in delaying the onset or development
of cognitive decline.
However, this clinically meaningful mechanism of interaction between vascular risk and Aβ remains to be elucidated
.

Previous studies have shown a synergistic relationship
between higher baseline vascular risk and Aβ and increased tau burden in the inferior temporal cortex (ITC) in older CU adults.
These findings suggest that promoting the development of tau pathology associated with vascular risk is an underlying mechanism
connecting vascular risk with AD pathology and early AD-related cognitive decline.
Better elucidating the longitudinal relationship between vascular risk and AD pathology is essential
to confirm the findings of these cross-sections.
If vascular risk does have a synergistic effect with Aβ in promoting longitudinal tau accumulation, this would strongly support the goal of reducing vascular risk – alone or in combination with therapies focused on AD pathology – as a possible disease-modifying treatment strategy
for AD.
In addition, it supports the need to consider vascular risk factors in ongoing and future AD clinical trials, particularly those using tau PET or cognitive decline as a outcome
.

With this, Wai-Ying W.
Yau of Harvard University, et al.
, in a group of deeply characterized CU adults who participated in the Harvard University Aging Brain Study (HABS), tested the hypothesis that increased baseline vascular risk and Aβ burden were synergistic with increased longitudinal ITC tau accumulation
.
Further studies were conducted to determine whether and to what extent tau accumulation mediates the effect
of elevated vascular risk on prospective cognitive decline in individuals with an increased Aβ burden.

They included 175 older adults (aged 70.
5±8.
0 years) without cognitive impairment.

Baseline vascular risk was quantified
using the Framingham Heart Study General Cardiovascular Disease Risk Score (FHS-CVD).
The baseline Aβ burden was measured with Pittsburgh composite B-type PET
.
Tau burden was measured longitudinally with Flortaucipir PET (3.
6±1.
5 years), focusing on the inferior temporal cortex (ITC).

Cognitive performance was assessed longitudinally using preclinical Alzheimer's cognitive composite measures (7.
0±2.
0 years).

The linear mixed-effects model investigated the interaction effects
of baseline vascular risk and Aβ on longitudinal ITC tau.
In addition, regulatory mediation was used to determine whether tau accumulation mediates the effect
of FHS-CVD*Aβ on cognitive decline.

Figure 2: Graph of paper results

Elevated baseline FHS-CVD and Aβ had a significant interaction on the increase in ITC tau accumulation (P=0.
004), even in individuals with Aβ burden below the conventional threshold of amyloid positivity
.
When examining individual vascular risk factors, we found that elevated systolic blood pressure and body mass index showed independent interactions with Aβ on longitudinal tau (both P<0.
0001).

In the interaction between FHS-CVD and Aβ on cognitive decline, the accumulation of ITC tau played a 33% mediating role
.

The significance of the study lies in the fact that vascular risk interacts with subthreshold levels of Aβ, promoting cognitive decline, in part by accelerating the accumulation
of early neocortical tau.
The findings support a reduction in vascular risk, particularly in the treatment of hypertension and obesity, to attenuate tau pathology associated with Aβ and reduce cognitive decline
in later life.

Yau WW, Shirzadi Z, Yang H, et al.
Tau mediates synergistic influence of vascular risk and Aβ on cognitive decline.
_Annals of Neurology_.
Published online July 26, 2022:ana.
26460.
doi:[10.
1002/ana.
26460](https://doi.
org/10.
1002/ana.
26460)