Modeling the Relationships Among Late-Life Body Mass Index, Cerebrovascular Disease, and Alzheimer's Disease Neuropathology in an Autopsy Sample of 1,421 Subjects from the National Alzheimer's Coordinating Center Data Set

Abstract

The relationship between late-life body mass index (BMI) and Alzheimer's disease (AD) is poorly understood due to the lack of research in samples with autopsy-confirmed AD neuropathology (ADNP). The role of cerebrovascular disease (CVD) in the interplay between late-life BMI and ADNP is unclear. We conducted a retrospective longitudinal investigation and used joint modeling of linear mixed effects to investigate causal relationships among repeated antemortem BMI measurements, CVD (quantified neuropathologically), and ADNP in an autopsy sample of subjects across the AD clinical continuum. The sample included 1,421 subjects from the National Alzheimer's Coordinating Center's Uniform Data Set and Neuropathology Data Set with diagnoses of normal cognition (NC; n = 234), mild cognitive impairment (MCI; n = 201), or AD dementia (n = 986). ADNP was defined as moderate to frequent neuritic plaques and Braak stageIII-VI. Ischemic Injury Scale (IIS) operationalized CVD. Joint modeling examined relationships among BMI, IIS, and ADNP in the overall sample and stratified by initial visit Clinical Dementia Rating score. Subject-specific random intercept for BMI was the predictor for ADNP due to minimal BMI change (p = 0.3028). Analyses controlling for demographic variables and APOE ɛ4 showed lower late-life BMI predicted increased odds of ADNP in the overall sample (p < 0.001), and in subjects with CDR of 0 (p = 0.0021) and 0.5 (p = 0.0012), but not ≥1.0 (p = 0.2012). Although higher IIS predicted greater odds of ADNP (p < 0.0001), BMI did not predict IIS (p = 0.2814). The current findings confirm lower late-life BMI confers increased odds for ADNP. Lower late-life BMI may be a preclinical indicator of underlying ADNP.

Keywords: Alzheimer’s disease; body mass index; cerebrovascular disease; neuropathology; obesity.

Figure 1

Sample size flow chart Abbreviations: UDS = Uniform Data Set; ADNP = Alzheimer’s disease neuropathology; BMI = body mass index; NC = normal cognition; MCI = mild cognitive impairment; AD = Alzheimer’s disease * ADNP positive = moderate to frequent neuritic plaques and Braak stage III-VI; ADNP negative = none or sparse neuritic plaques and Braak stage 0-II

Figure 2

Joint Modeling of the Relationships Among BMI, Cerebrovascular Disease, and Alzheimer’s Disease Neuropathology in 1,421 Subject’s from the NACC Neuropathology Data Set. Figure shows that lower BMI significantly predicted higher odds of having Alzheimer’s disease neuropathology. BMI was not associated with the Ischemic Injury Scale, however, higher scores on the Ischemic Injury Scale (worse cerebrovascular disease) predicted greater odds of having Alzheimer’s disease neuropathology. All analyses were controlled for age at death, education, race, sex, and presence of the APOE ε4 allele.