Blood Test May Predict Dementia Up To 25 Years Before Symptom Onset In Women

The diagnosis of Alzheimer’s disease is based on assessing cognitive and neuropsychological function, followed by examining structural changes in the brain, and increasingly, measuring Alzheimer’s biomarkers.

Hallmarks of Alzheimer’s disease include the aberrant accumulation of the beta-amyloid and phosphorylated tau proteins into amyloid plaques and tau neurofibrillary tangles, respectively. Core Alzheimer’s disease biomarkers include those that reflect the accumulation of the amyloid or tau proteins and damage to brain cells.

Until recently, these biomarkers of Alzheimer’s disease have been evaluated using brain imaging scans or by measuring changes in the composition of amyloid beta or tau proteins in cerebrospinal fluid that bathes the brain.

Brain imaging scans are expensive and require specialized equipment, whereas collecting cerebrospinal fluid samples is invasive. Blood-based biomarkers have emerged as a promising, cost-effective, and minimally invasive alternative to these techniques.

These Alzheimer’s biomarkers indicate the deposition of amyloid-beta plaques and neurofibrillary tangles in the brain rather than clinical symptoms of Alzheimer’s disease, with their appearance preceding cognitive decline by years. Thus, these biomarkers can be used to assess the future risk of cognitive decline due to Alzheimer’s disease, and potentially facilitate the use of interventions before symptom onset.

p-tau217, a newer biomarker

One such blood-based biomarker is p-tau217, one of several phosphorylated tau species that has emerged as one of the most accurate plasma biomarkers for Alzheimer’s disease.

Plasma p-tau217 is an accurate indicator of the extent of amyloid-beta and neurofibrillary tangle accumulation in the brain and can reliably track cognitive decline due to Alzheimer’s disease. Additionally, plasma p-tau217 is as reliable as cerebrospinal fluid biomarkers.

Most data on plasma p-tau217 accuracy have been obtained from clinical trials conducted under standardized conditions, and there is insufficient evidence on its performance in the general population. An increasing number of studies have been conducted in community settings to better understand the association between plasma p-tau 217 and the risk of mild cognitive impairment (MCI), a precursor to dementia, or dementia.

The present study further examined the association between baseline plasma p-tau217 and the future risk of mild cognitive impairment or dementia over a follow-up period of up to 25 years in community-dwelling participants enrolled in the Women’s Health Initiative Memory Study (WHIMS).

The researchers also assessed whether the association between plasma p-217 levels and dementia risk was influenced by factors such as age, race, and genetic predisposition for Alzheimer’s disease.

The study included 2,766 cognitively healthy women ages 65 to 79 years at its onset in the late 1990s. These women were originally a part of two clinical trials to examine the impact of hormone therapy in the form of either oral estrogen or a combination of estrogen and progesterone on dementia risk.

Among the 2,766 women, 1,311 participants developed either mild cognitive impairment (MCI) or dementia during the follow-up period, ranging from 1 to 25 years. Consistent with previous research, the present study found that women with higher p-tau217 at baseline were more likely to develop dementia or MCI during the follow-up period.

Notably, the researchers also found that Alzheimer’s disease risk factors, such as advanced age and genetic predisposition, interacted with the plasma p-tau217 levels to result in elevated risk of MCI or dementia during the follow-up period.

Specifically, the association between p-tau217 levels and the risk of dementia or mild cognitive impairment was stronger in participants older than 70 years than in those younger than 70 years and in women carrying the APOE ε4 gene variant, which is associated with increased Alzheimer’s disease risk, than in non-carriers. In other words, the risk of MCI or dementia associated with p-tau217 levels was influenced by age and genetic predisposition.

Although Black Americans are at a higher risk of dementia, the present study found that white women with higher plasma p-tau217 levels were more likely to develop dementia or MCI than their Black counterparts.

Plasma p-tau217 levels in combination with age were a better predictor of the risk of MCI or dementia than p-tau217 levels alone. Furthermore, plasma p-tau217 levels in combination with age were similarly reliable in predicting dementia risk in Black and White women, but were less accurate in predicting MCI in Black women.

“These results suggest that plasma biomarkers are not going to be a one-size-fits-all forecasting solution. We need to better identify subgroups of older adults (as well as middle-aged adults) for whom these plasma markers might be most predictive and those for whom they could even be misleading (like Black Americans) because they might suggest a low risk for dementia, when in fact they are at high risk,” said McDonough.

The study also reported a stronger association between dementia or MCI risk and higher p-tau217 levels among women treated with estrogen combined with progesterone than placebo. These results are consistent with the WHIMS clinical trials, which show a greater risk of dementia in women using estrogen combined with progesterone.

It must be noted that the levels of p-tau217 are associated with the levels of amyloid-beta plaques and tau tangles, and not all individuals with elevated Alzheimer’s biomarkers develop Alzheimer’s disease in their lifetime.

Moreover, other hurdles remain to the integration of blood-based biomarkers in clinical practice, including the interpretation of results and the standardization of procedures.