Simple blood test reveals hidden changes of Alzheimer's disease

Simple blood test reveals hidden changes of Alzheimer's disease

A large community study shows that Alzheimer's-related brain changes with age are far more widespread than symptoms alone suggest, underscoring both the promise and complexity of blood-based screening.

In a study recently published in the journalNatureResearchers estimated the age- and cognition-stratified prevalence of Alzheimer's disease neuropathological changes (ADNCs) in adults aged 70 years and older using plasma phosphorylated tau at threonine 217 (pTau217) as a blood-based surrogate marker. The study also examined associations with demographic characteristics, apolipoprotein E (APOE) genotype and kidney function.

Alzheimer's disease and the role of blood biomarkers

Dementia represents a major public health challenge worldwide, with Alzheimer's disease (AD) being the most common cause. Until recently, verification of AD neuropathological changes, amyloid-β plaques, and tau tangles required cerebrospinal fluid analysis or positron emission tomography, which is impractical for population screening. Blood-based biomarkers now enable the detection of pTau217, a marker closely linked to downstream tau pathology following amyloid-β accumulation.

In this study, elevated plasma pTau217 was used to classify individuals as ADNC-positive, intermediate, or ADNC-negative, rather than directly confirming brain pathology at the individual level. Understanding how ADNC prevalence varies by age, cognitive status, and APOE-ε4 carrier status may inform eligibility for disease-modifying therapies, health service planning, and personal decision-making. Additional research is needed to guide follow-up strategies for intermediate biomarker results.

Population cohort and cognitive classification

Researchers analyzed 11,486 plasma samples from Trøndelag Health (HUNT) population studies in Norway. This included 2,537 participants aged 58–69.9 years from HUNT3 and 8,949 participants aged 70 years and older from HUNT4 70+.

Formal cognitive assessment was performed only in the HUNT4 70+ cohort using comprehensive clinical assessment and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) consensus. Participants were classified as cognitively normal, with mild cognitive impairment (MCI), or dementia. Cognitive status was not examined in participants under 70 years of age.

Biomarker measurement and statistical methods

Plasma pTau217 concentrations were measured using the Single Molecule Array (Simoa) HD-X platform with a validated commercial assay. A two-cutoff strategy categorized individuals as ADNC negative (less than 0.40 pg/mL), intermediate (0.40 to less than 0.63 pg/mL), or ADNC positive (0.63 pg/mL or higher) according to Global CEO Initiative recommendations. APOE genotyping identified the ε2, ε3 and ε4 alleles.

Inverse probability weighting accounted for participation bias, selection into the biomarker subgroup, and differential blood sampling. The associations were examined with regard to age, gender, education, cognitive status and kidney function. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration 2021 equation. Exploratory analyzes estimated positive and negative predictive values ​​by integrating age-specific prevalence with sensitivity and specificity estimates from external studies. Eligibility for disease-modifying therapies followed current clinical recommendations.

Age and cognitive status differences in ADNC prevalence

ADNC prevalence increased significantly with increasing age. Using the ADNC-positive threshold of 0.63 pg/mL or higher, the estimated prevalence was less than 8 percent in adults aged 58-69.9 years and approached 65 percent in those older than 90 years.

Of adults aged 70 years and older, approximately 10 percent were classified as having preclinical AD, which is defined as cognitively normal with ADNC positivity. An additional 10.4 percent were classified as prodromal AD, defined as MCI with ADNC positivity, and 9.8 percent met criteria for AD dementia.

Within cognitive strata, about 60 percent of people with dementia were ADNC positive, compared to 32.6 percent of people with MCI and 23.5 percent of cognitively unimpaired adults. Increasing age was associated with higher ADNC prevalence in all groups.

Genetic, educational and renal associations

Gender differences in ADNC prevalence were small. Men aged 80–89 years showed a slightly higher prevalence than women, reflecting preclinical and prodromal stages, while no sex difference was observed in AD dementia.

Education level was inversely associated with ADNC prevalence, particularly at older ages. Those with tertiary education had the lowest prevalence, those with primary school education had the highest prevalence, and those with secondary education had an intermediate level.

APOE-ε4 carrier status was strongly associated with ADNC positivity in a dose-dependent manner. The prevalence increased from 27.1 percent in non-carriers to 46.4 percent in people with one ε4 allele and 64.6 percent in people with two ε4 alleles.

Decreased renal function was associated with higher pTau217 concentrations, particularly below an eGFR of approximately 51 ml/min/1.73 m². After adjusting for demographic and clinical factors, self-reported comorbidities such as cardiovascular disease, diabetes, cancer, and chronic obstructive pulmonary disease were not significantly associated with ADNC positivity.

Clinical implications and conclusions at the population level

Based on current eligibility criteria, approximately 10 percent of the HUNT4 70+ cohort and approximately 11 percent of the age-weighted population aged 70 years and older could be eligible for disease-modifying anti-amyloid therapies. Predictive value analyzes showed that the positive predictive value increased with age while the negative predictive value decreased, reflecting underlying prevalence effects.

Overall, these results demonstrate a pronounced age-related increase in the estimated prevalence of neuropathological changes in Alzheimer's disease, with significant variation depending on cognitive status, genetic risk, educational level, and renal function. Because the classification was based on a blood-based surrogate marker and not on direct neuropathological confirmation, the results should be interpreted at a population level and not as individual diagnoses.

Sources: