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BMI and Cognitive Health

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We've talked quite a bit around here lately about the optimal BMI for longevity, most notably in this thread about the Optimal Late-Life BMI for Longevity, and this one called Will Serious CR Beat a Healthy Obesity-Avoiding Diet & Lifestyle , and this one called Relationship between BMI and Disease, Longevity, and finally this one called Body Mass Index and All-Cause Mortality.


In general, it appears (to my interpretation) that it doesn't pay to be very thin when it comes to longevity, and may in fact be counterproductive, particularly as someone gets into their senior years. Being average weight or even overweight does not appear to adversely impact longevity in older folks, in fact if anything the evidence points the other way - being a heavy senior appears associated with increased longevity.


But what about cognitive health? It would be pretty tragic to live an especially long time, but lose your marbles along the way. Three recent studies that came across my radar shed some light on the issue of BMI and cognitive health. 


The first [1] looks pretty bad for chubby folks. It found being overweight was associated with a reduction in the volume of several important brain areas.


The researchers did structural MRI scans of the brains of 203 relatively young men and women (mean age 32, range 18-50). They ranged in BMI from 18.5 to 46.4. They all self-reported being healthy, and were not receiving any pharmacological treatments. They processed the MRI scans to estimate cortical thickness and surface area, both globally and on a per-region basis.


Overall they didn't find a correlation between any of the global brain anatomy measures and BMI:


There was no association between BMI and global measures of average cortical thickness, total surface area or average LGI [Local gyrification index - a measure of how folded the cortex is. DP].


But in two brain areas there was a difference between obese folks and people who were either thin or simply overweight:


Post-hoc contrasts revealed that while lean (BMI < 25) and overweight subjects (25 ≤ BMI < 30) did not significantly differ in the thickness of the right vmPFC or left LOC (p = 0.29 and p = 0.34, respectively), obese subjects (BMI ≥ 30) had significantly thinner cortices in these clusters, compared to both lean (p < 0.0001 in both clusters) and overweight subjects (p < 0.0001 in both clusters).


The ventromedial prefrontal cortex (vmPFC) is at the front of the brain, above the eyebrows and is involved in executive function and decision-making. The LOC (lateral occipital cortex) is at the back of the brain, and is involved in vision processing and object recognition.


The scatter plots for the cortical thickness in those two brain areas as a function of BMI look pretty scattered to me. It seems difficult to put too much stock in their results, especially below a BMI of 30, where the plots look pretty random, at least to my eyes:




My dubiousness about the result is bolstered by the fact that this cortical thinning effect was discovered in post-hoc analysis. In other words, the researchers were fishing for differences in brain anatomy as a function of BMI, after the main effect they were looking for (cortical changes across the whole brain varying with BMI) didn't pan out. After undoubtedly looking at many regions, these two showed up with statistically significant variations as a function of BMI. There is always the danger with this sort of post-hoc approach of finding spurious correlations if you look hard enough at enough different variables.


But other studies have found variations in the vmPFC related to obesity. In fact, these authors and others have speculated that the direction of causality may be reserved for the vmPFC. Rather than obesity causing brain shrinking in the vmPFC, having a smaller vmPFC may predispose someone to gaining weight. Why? Because the vmPFC is critical for good decision-making, and the thought is that a smaller vmPFC may result in poor impulse control, and therefore overeating and weight gain.


In a separate new study by the same authors [2] (popular press coverage), this time looking at white matter (axons between brain areas) rather than grey matter (neuronal cell bodies and dendrites), the authors did find a more widespread difference between the brains of obese/overweight people and thin people.


This time they scanned the brains of over 500 people aged 20 to 87. Basically, when it came to white matter volume, the brains of overweight (avg BMI 27.1) or obese (avg BMI 33.5) folks looked about 10 years older than the lean (normal weight) folks (avg BMI 22.7). Here are the curves for white matter volume as a function of age:




As you can see, everyone's white matter volume declines past age 40, but the overweight/obese folks appear to never reach the same peak volume as the normal weight folks and start to decline earlier than the normal weight folks as well. As a result, past middle age the overweight/obese folks' brains looked about 10 years older than the thin folks in terms of white matter volume. The impact of BMI on white matter volume appeared to be independent of exercise, income or education. 


Interestingly, the authors also found that "a previous diagnosis of elevated cholesterol" was associated with reduced white matter volume, independent of age and BMI.


But perhaps most surprisingly, despite the reduced white matter volume in obese/overweight folks relative to lean folks, they saw no difference in cognitive scores (on the Cattell test - "used to capture fluid intelligence by measuring abstract reasoning ability") between the chubby and the lean folks:




The authors say:


Although previous studies have linked white matter integrity, processing speed and fluid intelligence (Kievit et al., 2016) our results suggest that BMI does not additional influence the age and brain structure relationship with cognition.


In other words, despite having less white matter, the heavier folks didn't suffer any faster cognitive decline than the thin folks, at least as measured by this test of "fluid intelligence" in a snapshot of people at various ages. 


The authors again point to the possibility of reverse causality (less white matter → weight gain), but it seems harder to argue in this case, where the white matter shrinkage/deficit was global rather than confined to decision-making parts of the brain like they saw in [1].


Despite minor doubts about the arrow of causality, and despite a lack of cognitive deficits in the heavier folks, it seems to me like a no-brainer to prefer potentially preserving white matter by staying lean (avg BMI ~23) relative to becoming overweight (BMI >25) or obese (BMI > 30).


So these two studies (weakly) suggest it's better to be lean than overweight/obese for brain health. But what about the other end of the scale? That's where study [3] comes in.


In this one, a different set of researchers did PET brain imaging on 280 healthy older people (mean age 73, range 62-90) with normal cognitive function. More on demographics:


Subjects were roughly average for the American population in terms of prevalence for antihypertensive use (58%) and statin use (44%), but had less diabetes mellitus type 2 (9%) and active smoking (4%).d


Here was the distribution of BMIs:


Body-Mass Index 26.9 (16–41)
- Underweight (BMI <18.5) 2.5% (n=7)
- Normal (BMI 18.5–24.9) 31.8% (n = 89)
- Overweight (BMI 25–29.9) 41.4% (n = 116)
- Obese (BMI >30) 24.3% (n = 68)



What they did was correlate BMI with PiB retention, which is a surrogate for brain amyloid concentration, an early marker for increased risk of cognitive impairment / alzheimer disease. 


What they found that was being on the thin end of the BMI spectrum (i.e. < 25) was associated with an increased PiB retention, i.e. increased risk of future cognitive decline. This association was seen across the board, but was only significant in APOE4 carriers (i.e. those with a genetic tendency to develop cognitive impairment / alzheimer's disease). Here are the scatter plots of data from APOE4 carriers (green) and non-carriers (blue):




As you can see, once again there was a pretty wide scatter, and the blue points have only a very modest downward slope (i.e. reduced risk of cognitive decline) with increasing BMI.


In short, it appears if you know you are an APOE4 carrier (or if you don't know that you aren't an APOE4 carrier) it looks like it may be a good idea to avoid being thin late in life. But once again it is hard to know if being thin causes cognitive decline in APOE4 carriers, or that being an APOE4 carrier causes weight loss later in life.


When taken together, the upshot of these three studies of BMI & cognitive health seems to point to a similar conclusion as we've seen for BMI & longevity. Namely that a middle-of-the-road BMI (i.e. 23-25) in one's elder years appears associated with the maximum chance of keeping one's marbles intact with age. 





[1] Int J Obes (Lond). 2016 Jul;40(7):1177-82. doi: 10.1038/ijo.2016.42. Epub 2016

Mar 22.
Increased body mass index is associated with specific regional alterations in
brain structure.
Medic N(1,)(2), Ziauddeen H(1,)(2,)(3), Ersche KD(1), Farooqi IS(2), Bullmore
ET(1,)(4), Nathan PJ(1,)(5), Ronan L(1), Fletcher PC(1,)(2,)(3).
Author information: 
(1)Department of Psychiatry, University of Cambridge, Cambridge, UK. (2)Wellcome 
Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
(3)Cambridgeshire and Peterborough NHS Foundation Trust, University of Cambridge,
Cambridge, UK. (4)Medicines Discovery and Development, GlaxoSmithKline, Clinical 
Unit Cambridge, Cambridge, UK. (5)School of Psychological Sciences, Monash
University, Melbourne, Victoria, Australia.
BACKGROUND: Although obesity is associated with structural changes in brain grey 
matter, findings have been inconsistent and the precise nature of these changes
is unclear. Inconsistencies may partly be due to the use of different volumetric 
morphometry methods, and the inclusion of participants with comorbidities that
exert independent effects on brain structure. The latter concern is particularly 
critical when sample sizes are modest. The purpose of the current study was to
examine the relationship between cortical grey matter and body mass index (BMI), 
in healthy participants, excluding confounding comorbidities and using a large
sample size.
SUBJECTS: A total of 202 self-reported healthy volunteers were studied using
surface-based morphometry, which permits the measurement of cortical thickness,
surface area and cortical folding, independent of each other.
RESULTS: Although increasing BMI was not associated with global cortical changes,
a more precise, region-based analysis revealed significant thinning of the cortex
in two areas: left lateral occipital cortex (LOC) and right ventromedial
prefrontal cortex (vmPFC). An analogous region-based analysis failed to find an
association between BMI and regional surface area or folding. Participants' age
was also found to be negatively associated with cortical thickness of several
brain regions; however, there was no overlap between the age- and BMI-related
effects on cortical thinning.
CONCLUSIONS: Our data suggest that the key effect of increasing BMI on cortical
grey matter is a focal thinning in the left LOC and right vmPFC. Consistent
implications of the latter region in reward valuation, and goal control of
decision and action suggest a possible shift in these processes with increasing
DOI: 10.1038/ijo.2016.42 
PMCID: PMC4936515 [Available on 2017-01-01]
PMID: 27089992
[2] Neurobiology of Aging (2016), 
Obesity associated with increased brain-age from mid-life
Ronan, L., Alexander-Bloch, A.F, Wagstyl, K., Farooqi, S., Brayne, C., Tyler, L.K, Cam-CAN, Fletcher, P.C,
Common mechanisms in aging and obesity are hypothesized to increase susceptibility to neurodegeneration, however direct evidence in support of this hypothesis is lacking. We therefore performed a cross-sectional analysis of MRI-based brain structure on a population-based cohort of healthy adults. Study participants were originally part of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) and included 527 individuals aged 20 – 87 years. Cortical reconstruction techniques were used to generate measures of whole brain cerebral white matter volume, cortical thickness and surface area. Results indicated that cerebral white matter volume in overweight and obese individuals was associated with a greater degree of atrophy, with maximal effects in middle-age corresponding to an estimated increase of brain-age of 10 years. There were no similar BMI-related changes in cortical parameters. This study suggests that at a population level, obesity may increase the risk of neurodegeneration. Keywords obesity; white matter volume; structural MRI; population-based
PMID: Not available
doi: 10.1016/j.neurobiolaging.2016.07.010.
[3] J Alzheimers Dis. 2016 Jun 18;53(3):1097-105. doi: 10.3233/JAD-150987.
Lower Late-Life Body-Mass Index is Associated with Higher Cortical Amyloid Burden
in Clinically Normal Elderly.
Hsu DC(1,)(2,)(3), Mormino EC(4), Schultz AP(4), Amariglio RE(4,)(2), Donovan
NJ(1,)(2,)(5), Rentz DM(4,)(2,)(5), Johnson KA(4,)(6,)(2), Sperling RA(4,)(2),
Marshall GA(4,)(2); Harvard Aging Brain Study.
Author information: 
(1)Department of Psychiatry, Massachusetts General Hospital, Harvard Medical
School, Boston, MA, USA. (2)Department of Neurology, Center for Alzheimer
Research and Treatment, Brigham and Women's Hospital, Harvard Medical School,
Boston, MA, USA. (3)Department of Psychiatry, Mercy Medical Group, Sacramento,
CA, USA. (4)Department of Neurology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA, USA. (5)Department of Psychiatry, Brigham and Women's
Hospital, Harvard Medical School, Boston, MA, USA. (6)Department of Radiology,
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Full text: available on request
BACKGROUND: Lower body-mass index (BMI) in late life has been associated with an 
increased risk of dementia, and weight loss has been associated with more rapid
decline in Alzheimer's disease (AD) dementia.
OBJECTIVE: To explore the association between BMI and cortical amyloid burden in 
clinically normal (CN) elderly at risk for AD dementia.
METHODS: Cross-sectional analyses were completed using baseline data from the
Harvard Aging Brain Study, consisting of 280 community-dwelling CN older adults
aged 62-90. Assessments included medical histories and physical exam, Pittsburgh 
compound B (PiB) positron emission tomography (PET) amyloid imaging, and
apolipoprotein E ɛ4 (APOE4) genotyping. For the primary analysis, a general
linear regression model was used to evaluate the association of BMI with PiB
retention. Covariates included age, sex, years of education, and APOE4 carrier
status. Secondary analyses were performed for BMI subdivisions (normal,
overweight, obese), APOE4 carriers, and BMI×APOE4 interaction.
RESULTS: In the primary analysis, greater PiB retention was associated with lower
BMI (β  =  -0.14, p = 0.02). In the secondary analyses, APOE4 carrier status
(β= -0.27, p = 0.02) and normal BMI (β= -0.25, p = 0.01), as opposed to
overweight or obese BMI, were associated with greater PiB retention. The
BMI×APOE4 interaction was also significant (β= -0.14, p = 0.04).
CONCLUSIONS: This finding offers new insight into the role of BMI at the
preclinical stage of AD, wherein lower BMI late in life is associated with
greater cortical amyloid burden. Future studies are needed to elucidate the
mechanism behind this association, especially in those with lower BMI who are
APOE4 carriers.
DOI: 10.3233/JAD-150987 
PMCID: PMC4976009
PMID: 27340843
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