Midlife central and general adiposity are modifiable risk factors for AD pathology and AD dementia, while late-life adiposity shows inverse associations with plasma p-tau217 and biomarker-verified AD dementia.
Key Findings
Results
Midlife waist-to-height ratio (WtHR) ≥0.60 was associated with significantly higher late-life plasma p-tau217 concentration compared with WtHR <0.50.
Midlife WtHR ≥0.60 was associated with 12.8% (95% CI 7.3–19.7) higher late-life p-tau217 concentration.
The association was adjusted for demographics, APOE ε4, lifestyle, and mental health.
The study sample comprised 8,797 participants (53.5% women, mean age at HUNT4 77.8 [SD 6.2]).
Of the total sample, 2,649 (30.1%) were p-tau217-positive using a threshold of ≥0.63 pg/mL.
Results
Midlife WtHR ≥0.60 was associated with higher risk of positive p-tau217 and biomarker-verified AD dementia compared with WtHR <0.50.
Midlife WtHR ≥0.60 was associated with relative risk ratio (RRR) of 1.55 (95% CI 1.21–1.99) for positive p-tau217.
Midlife WtHR ≥0.60 was associated with RRR of 1.84 (95% CI 1.27–2.65) for biomarker-verified AD dementia.
Biomarker-verified AD dementia was defined as positive p-tau217 (≥0.63 pg/mL) coupled with a clinical dementia diagnosis; 659 participants (7%) met this definition.
WtHR was measured three times across HUNT2–4 (1995–2019).
Results
Late-life WtHR ≥0.60 was associated with lower plasma p-tau217 concentration and decreased risk of positive p-tau217 and biomarker-verified AD dementia.
Late-life WtHR ≥0.60 was associated with 15.6% (95% CI −19.0 to −12.2) lower p-tau217 concentration compared with WtHR <0.50.
Late-life WtHR ≥0.60 was associated with RRR of 0.49 (95% CI 0.41–0.59) for positive p-tau217.
Late-life WtHR ≥0.60 was associated with RRR of 0.63 (95% CI 0.46–0.86) for biomarker-verified AD dementia.
This inverse association in late life contrasts directly with the positive associations observed in midlife, suggesting a time-dependent relationship between adiposity and AD pathology.
Results
BMI showed patterns similar to WtHR, with midlife obesity associated with higher p-tau217 and elevated AD dementia risk, and late-life overweight/obesity associated with lower p-tau217 and decreased AD dementia risk.
BMI was measured four times across HUNT1–4 (1984–2019), providing a longitudinal span of approximately 35 years.
The pattern of midlife obesity increasing and late-life overweight/obesity decreasing risk was consistent across both central (WtHR) and general (BMI) adiposity measures.
Analyses were adjusted for demographics, APOE ε4, lifestyle, and mental health factors.
Results
Among participants with positive p-tau217 or biomarker-verified AD dementia, mixed-effects regression showed higher midlife adiposity that reversed by late life.
Linear mixed-effects regression was used to examine trajectories of adiposity measures across the life course.
The reversal pattern — higher adiposity in midlife transitioning to lower adiposity in late life among those with AD pathology — was observed for both WtHR and BMI.
This trajectory pattern may partly explain the apparent protective effect of late-life higher adiposity, as individuals with dementia may lose weight as part of the disease process.
Methods
The study used a large, population-based cohort of older adults from the Norwegian Trøndelag Health Study (HUNT) with standardized clinical cognitive assessments and plasma p-tau217 biomarker data.
Data came from 8,797 participants aged 70 years or older from HUNT4 (2017–2019).
Plasma p-tau217 was collected and standardized clinical cognitive assessments were performed at HUNT4.
WtHR was measured three times (HUNT2–4; 1995–2019) and BMI was measured four times (HUNT1–4; 1984–2019).
Analyses used linear, logistic, and linear mixed-effects regression models adjusting for demographics, APOE ε4, lifestyle, and mental health.
What This Means
This research suggests that carrying excess weight around the middle (central adiposity) during middle age is linked to greater accumulation of Alzheimer's disease-related proteins in the blood and a higher likelihood of developing Alzheimer's disease dementia later in life. The study followed nearly 9,000 Norwegian adults over roughly 35 years, measuring waist size relative to height (waist-to-height ratio) and body mass index at multiple points. People who had a high waist-to-height ratio in midlife were about 55% more likely to show elevated levels of a key Alzheimer's biomarker (p-tau217) in late life, and were 84% more likely to have biomarker-confirmed Alzheimer's dementia, compared to people with lower midlife waist measurements.
Interestingly, the relationship between body size and Alzheimer's risk reversed in late life: older adults who were heavier in their 70s and beyond actually had lower levels of the Alzheimer's biomarker and lower rates of diagnosed Alzheimer's dementia. The researchers found that people who went on to develop Alzheimer's pathology tended to be heavier in midlife but lost weight by late life, which likely explains this apparent reversal — the late-life weight loss may be a consequence of the disease process itself rather than being protective.
This research suggests that central fat accumulation in midlife — the kind measured by waist-to-height ratio — is a modifiable risk factor for Alzheimer's disease pathology. The findings indicate that waist-to-height ratio could be a useful, low-cost tool for identifying people at higher risk of Alzheimer's disease at a stage when preventive interventions might still be effective, and that efforts to reduce abdominal fat in middle age may be relevant to brain health decades later.
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Zotcheva E, Strand B, Sunde A, Deckers K, Aarsland D, Ashton N, et al.. (2026). Associations of Anthropometry Measures Across 35 Years With Late-Life Plasma P-tau217 and Dementia: The HUNT Study.. Neurology. https://doi.org/10.1212/WNL.0000000000218093