A burgeoning global health concern, obesity has nearly tripled since 1975 (Gerontological Society of America, 2021; WHO, 2021). Adults with obesity are at increased risk for numerous comorbidities, including cardiovascular diseases, stroke, type 2 diabetes, hypertension, and some cancers (CDC, 2021). Further, obesity is linked to increased Alzheimer’s disease (AD) risk, another growing public health crisis. Several studies highlight that obesity, independent of cardiovascular disease comorbidities, is a risk factor for later-life dementia (Whitmer et al., 2008). However, these findings mainly apply to obesity in midlife (Whitmer et al., 2008; Anstey et al., 2011; Xu et al., 2011; Meng et al., 2014), with relatively few studies demonstrating that late-life obesity is associated with increased AD risk (Gustafson et al., 2003). Conversely, several studies demonstrate that in later-life, obesity is associated with a lower risk of dementia (Atti et al., 2008; Fitzpatrick et al., 2009). Overall, while midlife obesity appears to be a risk factor for AD, later-life obesity may be neutral or even protective with respect to AD (Bischof and Park, 2015).

Similarly, whether late-life obesity is related to better or worse cognitive function remains equivocal. For example, while some studies indicate that late-life obesity is associated with poorer executive function, verbal abilities, and processing speed (Ihle et al., 2016; Yang et al., 2018), there is also evidence that late-life obesity may be associated with better cognitive function (Tolppanen et al., 2014). One study suggests that obesity in late life is positively associated with reasoning and speed of processing (Kuo et al., 2006). In a longitudinal study, late-life obesity was associated with attenuated decline in global cognition, perceptual speed, visuospatial ability, as well as episodic, semantic, and working memory (Aiken-Morgan et al., 2020). Thus, obesity may confer detrimental or protective effects to cognition as measured by standardized neuropsychological tests in later life.

Another area of consideration linking obesity and cognitive function or AD risk is related to brain atrophy and structural changes. In fact, some studies report higher body weight is associated with lower whole brain volume in middle-age (Enzinger et al., 2005; Ward et al., 2005; Taki et al., 2008). A 24-year follow-up study among older females reported that higher body mass index was related to greater temporal atrophy but there were no associations with frontal, parietal or occipital atrophy (Gustafson et al., 2004). However, most studies have examined whole brain or hippocampal volume, and more recent research suggests fine-scale subregional analysis of the hippocampus may have advantages over overall volume (e.g., see Apostolova et al., 2010; Younes et al., 2014). While the mechanisms linking obesity and brain atrophy are not fully understood, obesity is related to other risk factors associated with brain atrophy including reduced aerobic fitness (Colcombe et al., 2003), hyperlipidemia (Bruce-Keller et al., 2009), increased inflammation (Arnoldussen et al., 2014), and impaired respiratory function (Zammit et al., 2010).

Alarmingly, African Americans bear a disproportionate burden of both obesity and AD (US Department of Health and Human Services, 2020). Across the lifespan, African Americans are 1.4 times more likely to have obesity relative to non-Hispanic white Americans (US Department of Health and Human Services, 2020), and more than 80% of African American females are overweight or obese (National Center for Health Statistics, 2019). Notably, the prevalence of obesity in midlife is higher in African Americans (46.2%) than in non-Hispanic white Americans (34.9%) (Nianogo et al., 2022). In parallel, the lifetime prevalence of AD is two to three times higher among older African Americans than in older non-Hispanic whites (Rajan et al., 2019). Importantly, 21.7% of dementia cases among African Americans are attributable to mid-life obesity as compared to 17.3% of dementia cases in non-Hispanic whites (Nianogo et al., 2022). Although mid-life obesity increases risk for AD, we still know too little about the relationship between late-life obesity and AD, especially in older African Americans.

Previous research demonstrates that the relationship between cognitive function and BMI in older adults varies by race/ethnicity (Bryant et al., 2014). Both non-Hispanic whites and African Americans showed better cognitive function as BMI increased, but African Americans showed poorer cognition at extreme BMI levels (i.e., very low and very high). Notably, BMI standards may be too crude a measure to accurately classify older African Americans and other non-white samples, especially since body composition indices were derived from predominantly non-Hispanic white samples (Smalley et al., 1990; Wagner and Heyward, 2000). For example, recent research demonstrates that whereas black women have the highest levels of subcutaneous abdominal fat, Hispanic women have the highest levels of visceral abdominal fat (Banack et al., 2023); but BMI does not differentiate types of fat nor where they accumulate. Further research is necessary to determine how cognitive function associated with standard BMI cutoffs, particularly in the high or low BMI ranges, may vary within high-risk populations, such as older African Americans. In addition, other factors that vary by race/ethnicity may influence the obesity-cognition and obesity-brain structure relationships.

One possible factor confounding these relationships is AD genetic predisposition. The apolipoprotein (APOE) ε4 allele located on chromosome 19 is the most prevalent and well-studied genetic risk factor for late-onset AD (Rajan et al., 2014). Although African Americans are 1.4 times more likely to carry the APOE-ε4 allele than European Americans (Rajan et al., 2014), its effect on AD development is diminished in African ancestry groups (Hendrie et al., 2014; Rajabli et al., 2018). Still, African Americans with at least one copy of the APOE-ε4 allele are almost three times more likely to develop AD than their noncarrier counterparts (Farrer et al., 1997). Recent research, however, suggests environmental or health factors, such as obesity, may modify the influence of APOE-ε4 in some racial and ethnic groups (Rajabli et al., 2018). Indeed, in several studies among homozygotic twin pairs, environmental factors account for up to 20% in vulnerability to AD development, suggesting a gene-environment interaction (for a review, see Plassman and Breitner, 1996). Further, genetic factors account for about 50% of AD risk (Gatz et al., 2006, for a review, see Tang and Gershon, 2022). However, no work, to date, has systematically examined the interactions of obesity and AD risk via APOE-ε4 in older African American adults.

Therefore, the purpose of this study was to examine: (1) the influence of body mass index (BMI) groups (normal; overweight; class 1 obese; ≥ class 2 obese) on cognitive and structural MRI measures of AD risk; and (2) the interaction between BMI and APOE-ε4 in older African Americans. The current analyses focused on a novel cognitive outcome, generalization, the ability to apply previously learned rules to new situations and contexts (Myers et al., 2002). Previous studies have shown that generalization is a cognitive marker of AD risk with deficits preceding explicit memory declines (Myers et al., 2002, 2008; Myers and Ahmed, 2019). For structural neuroimaging, we examined the medial temporal lobe (MTL), including the hippocampus, given its particular vulnerability to AD in preclinical stages (Jagust et al., 2006). Further, both higher body weight and APOE-ε4 allele presence individually have been associated with smaller MTL region volumes among non-Hispanic white American and European older adult samples (Reiman et al., 1998; Gustafson et al., 2004; Cacciaglia et al., 2018).

Descriptive statistics for the 70 participants are included in Table 1. Participants were ages 60 to 90 years and completed, on average, an associate’s degree or some college coursework. The vast majority of the participants were female (86%). Almost half (47%) of the participants’ BMI fell in the obese category and 39% were APOE-ε4 allele carriers. See Table 2 for volumes and SAs by BMI group. See Supplementary Data Sheet 1, 2 for complete dataset and statistical coding, respectively.

We examined the independent effects of BMI group and the interactive effects of BMI group and APOE-ε4 status on MTL/hippocampal cognitive function and structure among older African Americans. There were two main findings: (1) older African Americans in the overweight range demonstrate better ability to apply previously learned rules to novel situations (i.e., generalization performance) than individuals in the normal BMI range; and (2) among older African Americans who are APOE-ε4 non-carriers, obesity is associated with larger CA1 volumes. In contrast, among APOE-ε4 carriers, obesity is associated with smaller CA1 volumes. Overall, these data suggest being overweight by BMI standards may preserve hippocampal function, but obesity reduces hippocampal structure and function in older African Americans with the APOE- ε4 Alzheimer’s disease risk allele.

Among older adults, conflicting studies have reported overweight or obesity in late life to be both detrimental and beneficial to cognitive function (Han et al., 2009, Walther et al., 2010). Our study findings support being overweight but not obese in late life may be beneficial to hippocampal-dependent cognitive performance. This is consistent with prior work across older white, African, and Hispanic Americans showing these BMI ranges to be protective for global cognitive function (Kuo et al., 2006; Yoon et al., 2012; Bryant et al., 2014) as well as for reasoning, processing speed, and memory (Kuo et al., 2006). Our study, though, is the first to identify that excess body weight is neuroprotective for generalization performance in older African Americans, independent of their demographics and other potential confounding variables (i.e., fitness levels, depressive symptomology). These findings suggest standard BMI cutoffs for being overweight may systematically overestimate adiposity and its negative effects on cognition and AD risk in this population. Some evidence suggests alternative anthropometric measures of central obesity (e.g., waist-to-hip ratio) may be better predictors of cardiovascular and cognitive outcomes than BMI (Luchsinger et al., 2012). Given reports that body morphology/composition differs by race and ethnicity, future studies should compare the relative contributions of BMI and measures of central obesity to cognitive function and AD development within at-risk populations such as older African Americans.

Importantly, while our study examined cross-sectional associations, longitudinal changes in BMI appear to contribute to dementia risk (Kadey et al., 2021; Guo et al., 2022). One study of a predominantly non-Hispanic white sample (84.2%) found that among only APOE-ε4 allele carriers, a decline in BMI over 5 years was associated with conversion to mild cognitive impairment or dementia (Kadey et al., 2021). Similarly, in another non-Hispanic white majority sample (85.6% white), individuals who went on to develop mild cognitive impairment had lower BMIs about 7 years preceding their diagnosis as compared to their cognitively unimpaired counterparts (Guo et al., 2022). The decreases in BMI as a risk factor for cognitive decline could be attributed to negative health consequences that accompany obesity such as chronic inflammation and muscle atrophy (as a result of reduced physical activity and/or aerobic fitness). Indeed, the current study cohort showed low overall estimated aerobic fitness levels (see Table 1; Mean overall VO₂max estimate = 15.04 mL/kg/min) which is a lower reported estimate than other groups that analyzed older adults samples (e.g., Mean VO2max estimates 19.1 and 22.8 mL/kg/min for women and men, respectively; Paterson et al., 1999). Lower BMIs preceding cognitive impairment may be attributed to alterations in appetite regulation that may influence hippocampal plasticity and hence cognitive performance and status (Fadel et al., 2013). Together, BMI declines in later life (and related maladaptive health behaviors) along with a genetic predisposition may increase risk for dementia. Future studies should examine how the interactions of late-life body weight changes and genetic risk factors (e.g., APOE-ε4) influence cognitive change and status over time within underrepresented populations in biomedical research, including older African Americans.

Our study also observed that obesity effects on hippocampal subfield volume may differ by APOE-ε4 carrier status. Specifically, APOE-ε4 non-carriers had larger left CA1 subfields if they were in the overweight or higher ranges of BMI relative to individuals in the normal BMI range. However, APOE-ε4 carriers had smaller CA1 subfields if they were in the obese range relative to individuals in the overweight range. The differential effect of AD genetic risk on CA1 volume suggests late-life obesity is neuroprotective for APOE-ε4 non-carriers while particularly detrimental to brain health for APOE-ε4 carriers.

Although a recent cross-sectional study found that older European American individuals with higher BMI and high genetic risk for AD had smaller hippocampal and entorhinal cortex volumes (Hayes et al., 2020), the present study is the first to identify, via fine-scale subregion structural analysis, that BMI and APOE-ε4 synergistically impact CA1 volume specifically. Indeed, the CA1 is particularly susceptible to Alzheimer’s pathology early in the disease course (Zarow et al., 2005; de Flores et al., 2015), and atrophy in this subfield is linked to poorer verbal memory and global cognition (Csernansky et al., 2005; Apostolova et al., 2006). That genetic and health risk factors (i.e., obesity) synergistically affect CA1 subfield volume may help explain why African Americans–who have higher prevalence of both the APOE-ε4 allele and obesity–are more likely to develop AD. The mechanism by which obesity interacts with genetic factors is beyond the scope of this work, but obesity has been suggested to be neuroprotective due to hormonal changes (e.g., leptin, estrogen), dietary factors (e.g., vitamin E and D levels), and less risk for fragility (Yaffe et al., 2000; Holden et al., 2009; Bove et al., 2013).

Being overweight (relative to normal weight by BMI standards) may be neuroprotective with respect to MTL/hippocampal-dependent cognitive function in older African Americans. However, in the obese BMI ranges (30 kg/m²), AD genetic susceptibility conferred by the APOE-ε4 allele may compound the risk for hippocampal atrophy in this population. Future studies should investigate the potential overlap between the metabolic sequelae of late-life obesity and genetic mechanisms underlying AD. The present data highlight the importance of examining the synergistic effects of health and genetic risk factors on markers for AD in diverse populations with the ultimate goal of developing ways to delay progression to AD.

The original contributions presented in this study are included in the article/Supplementary materials, further inquiries can be directed to the corresponding authors.

The studies involving humans were approved by the Rutgers University Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

ZO, BF, and MG contributed to conception and design of the study. ZO and BF organized the database, performed the statistical analysis, and wrote the first draft of the manuscript. NS, JG, SM, and MG wrote sections of the manuscript. All authors read and revised the manuscript and approved the submitted version.