Biomarkers for Alzheimer's disease may aid diagnosis, predict dementia, studies find
A Swedish study found that blood biomarkers for Alzheimer's disease had high diagnostic accuracy in primary and secondary care, while a U.S. study found that the biomarkers' association with dementia may begin in midlife.
Two recent studies looked at the use of blood biomarkers to diagnose Alzheimer's disease and predict risk for dementia.
In the first study, published July 28 by JAMA, researchers in Sweden evaluated whether a commercially available blood test for Alzheimer's disease could help accurately diagnose the condition in primary and secondary care. The blood test was based on the ratio of plasma phosphorylated tau 217 (p-tau217) to non-p-tau217, expressed as percentage of p-tau217. Its performance was evaluated alone and together with the amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) plasma ratio. The combination is known as the Amyloid Probability Score 2 (APS2). The study included patients who were evaluated for cognitive symptoms between February 2020 and January 2024. The primary outcome was Alzheimer's disease pathology, and the secondary outcome was clinical Alzheimer's disease.
A total of 1,213 patients, 515 from primary care and 698 from secondary care, participated in the study. Overall, patients' mean age was 74.2 years and 48% were women. Twenty-three percent had subjective cognitive decline, 44% had mild cognitive impairment, and 33% had dementia, with Alzheimer's disease pathology noted in 50% of those who underwent both the primary and secondary care assessments. In the primary care cohort, when samples were analyzed in a single batch, the area under the curve (AUC) for the APS2 was 0.97 (95% CI, 0.95 to 0.99), the positive predictive value (PPV) was 91% (95% CI, 87% to 96%), and the negative predictive value (NPV) was 92% (95% CI, 87% to 96%); in the secondary care cohort, these values were 0.96 (95% CI, 0.94 to 0.98), 88% (95% CI, 83% to 93%), and 87% (95% CI, 82% to 93%), respectively.
When samples were analyzed prospectively biweekly in the primary and secondary care cohorts, the AUC of the APS2 was 0.96 (95% CI, 0.94 to 0.98) and 0.97 (95% CI, 0.95 to 0.98), the PPV was 88% (95% CI, 81% to 94%) and 91% (95% CI, 87% to 95%), and the NPV was 90% (95% CI, 84% to 96%) and 91% (95% CI, 87% to 95%), respectively. In all four cohorts, it had high diagnostic accuracy, ranging from 88% to 92%. Primary care physicians' diagnostic accuracy for clinical Alzheimer's disease was 61% (95% CI, 53% to 69%) after clinical examination, cognitive testing, and a CT scan versus 91% (95% CI, 86% to 96%) using the APS2, while diagnostic accuracy among dementia specialists was 73% (95% CI, 68% to 79%) versus 91% (95% CI, 88% to 95%). Diagnostic accuracy for the APS2 and the percentage of p-tau217 alone did not differ in the overall population.
The authors noted that their study was done in only one country using only one type of immunoassay. “The APS2 and percentage of p-tau217 alone had high diagnostic accuracy for identifying Alzheimer disease among individuals with cognitive symptoms in primary and secondary care using predefined cutoff values,” they wrote. “Future studies should evaluate how the use of blood tests for these biomarkers influences clinical care.”
The second study, also published July 28 by JAMA, used data from the Atherosclerosis Risk in Communities (ARIC) study to determine whether changes in plasma biomarkers over time were associated with all-cause dementia. Plasma biomarkers were measured using stored specimens from 1,525 ARIC participants collected in midlife (1993-1995), at a mean age of 58.3 years, and late life (2011-2013), at a mean age of 76.0 years. Patients were followed until 2016 to 2019, when the mean age was 80.7 years. The researchers assessed midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) and any association with change in plasma biomarkers over time. The association between biomarkers and incident all-cause dementia was evaluated in a subpopulation of 1,339 patients who did not have dementia in 2011-2013 and had biomarkers measured in 1993-1995 and 2011-2013. The study's main outcome measure was incident all-cause dementia, as determined from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance.
Participants' mean age was 58.3 years, 59.9% were women, and 25.8% were Black. Overall, 252 participants (16.5%) developed dementia. Decreasing Aβ42:Aβ40 and increasing p-tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) occurred from midlife to late life, more rapidly in those who carried the apolipoprotein E epsilon 4 (APOEε4) allele. The only biomarkers in midlife that were associated over the long term with late-life dementia were those specific to Alzheimer's disease (hazard ratios, 1.11 per SD lower Aβ42:Aβ40 ratio [95% CI, 1.02 to 1.21] and 1.15 per SD higher p-tau181 [95% CI, 1.06 to 1.25]). In late life, all plasma biomarkers, especially Nfl (1.92; 95% CI, 1.72 to 2.14), had statistically significant associations with dementia.
The researchers noted that plasma biomarkers were measured at only three time points and that only all-cause dementia, not Alzheimer's disease specifically, was assessed, among other limitations. “Plasma biomarkers of AD [Alzheimer's disease] neuropathology, neuronal injury, and astrogliosis rise with age and are associated with known dementia risk factors,” they concluded. “The association of AD-specific biomarkers with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.”
An editorial accompanying both studies said the second study's finding that biomarkers can be detected earlier in life was important but noted that their predictive power was low. Meanwhile, the first study convincingly argued that highly sensitive blood measures of Alzheimer's disease can be used in the clinical decision-making process, including in primary care, the editorialists said.
“Current practice should focus on using these blood biomarkers in individuals with cognitive impairment rather than in those with normal cognition or subjective cognitive decline until further research demonstrates effective interventions for individuals considered cognitively normal with elevated levels of amyloid,” the editorialists said.