Healthy weight help preserve brain structure in people with mild Alzheimer’s disease dementia

New research from the University of Sheffield has found being overweight is an additional burden on brain health and it may exacerbate Alzheimer’s disease.

The pioneering multimodal neuroimaging study revealed obesity may contribute toward neural tissue vulnerability, whilst maintaining a healthy weight in mild Alzheimer’s disease dementia could help to preserve brain structure.

The findings, published in The Journal of Alzheimer’s Disease Reports, also highlight the impact being overweight in mid-life could have on brain health in older age.

Lead author of the study, Professor Annalena Venneri from the University of Sheffield’s Neuroscience Institute and NIHR Sheffield Biomedical Research Centre, said: “More than 50 million people are thought to be living with Alzheimer’s disease and despite decades of ground breaking studies and a huge global research effort we still don’t have a cure for this cruel disease.

“Prevention plays such an important role in the fight against the disease. It is important to stress this study does not show that obesity causes Alzheimer’s, but what it does show is that being overweight is an additional burden on brain health and it may exacerbate the disease.”

She added:”The diseases that cause dementia such as Alzheimer’s and vascular dementia lurk in the background for many years, so waiting until your 60s to lose weight is too late.

We need to start thinking about brain health and preventing these diseases much earlier. Educating children and adolescents about the burden being overweight has on multimorbidities including neurodegenerative diseases is vital.”

Researchers from the University of Sheffield and the University of Eastern Finland examined MRI brain scans from 47 patients clinically diagnosed with mild Alzheimer’s disease dementia, 68 patients with mild cognitive impairment, and 57 cognitively healthy individuals.

The novel study used three complementary, computational techniques to look at the anatomy of the brain, blood flow and also the fibres of the brain.

The international team compared multiple brain images and measured differences in local concentrations of brain tissues to assess grey matter volume – which degenerates during the onset of Alzheimers – white matter integrity, cerebral blood flow and obesity.

In mild dementia patients, a positive association was found between obesity and grey matter volume around the right temporoparietal junction. This suggests obesity might contribute toward neural vulnerability in cognitively healthy individuals and those with mild cognitive impairment.

The study also found that maintaining a healthy weight in mild Alzheimer’s disease dementia could help preserve brain structure in the presence of age and disease-related weight loss.

Joint author of the study, Dr. Matteo De Marco from the University of Sheffield’s Neuroscience Institute, said: “Weight-loss is commonly one of the first symptoms in the early stages of Alzheimer’s disease as people forget to eat or begin to snack on easy-to-grab foods like biscuits or crisps, in place of more nutritional meals.

“We found that maintaining a healthy weight could help preserve brain structure in people who are already experiencing mild Alzheimer’s disease dementia.

Unlike other diseases such as cardiovascular disease or diabetes, people don’t often think about the importance of nutrition in relation to neurological conditions, but these findings show it can help to preserve brain structure.”

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Obesity: A Health Problem
Obesity, defined by accumulation of excess adipose tis- sue has now become a worldwide epidemic. In fact, in 1997 the World Health Organization (WHO) stated that ‘‘obesity should now be regarded as one of the great- est neglected public health problems of our time ’’ A numerous studies have indicated obesity per se as an independent cardiovascular risk factor, as well as predisposing to type 2 diabetes, induction of insulin resistance, hypertension, and dyslipidaemia.1,2

The origins of adult obesity stems from child- hood lifestyle behavior with numerous longitudinal studies indicating a positive correlation between high body weight and obese adults.3-5 Although certain proportions of cardiovascular disorders are attrib- uted to the secondary complications of obesity (eg, hypertension, atherosclerosis, type 2 diabetes, and aging), a direct deleterious effect of obesity on the cardiovascular system is now clearly evident.

For example, patients with morbid obesity have higher rates of sudden unexpected cardiac-related death,6 implicating the importance of obesity as an indepen- dent risk factor for cardiovascular dysfunction, both at arterial and at cardiac myocyte levels.

There is no comprehensive information on the role of obesity on vascular morphology and function. However, almost all animal and clinical studies examining vascular function in obesity have shown some degree of vascular abnormalities that occur at both endothelial and smooth muscle levels.7-10

Therefore, it is plausible to hypothesis that increased vascular disease at the level of the brain may in turn affect memory function. Obesity results in insulin resistance.4,5,8,9 Insulin has a significant role on modulation of synaptic plasticity and learning memory.11

Insulin receptors and insulin-sensitive glucose transporters are densely expressed in the medial temporal region of the brain that supports memory formation,12 indicating that insulin may have a role in maintaining normal cognitive function. Hence, abnormalities in the insulin signaling pathway may contribute to impairment of memory function, similar to those seen in patients with Alzheimer’s disease (AD). In fact animal studies have shown that intranasal administration of insulin improves cognitive behavior in mice13 perhaps by modulating neuronal communication within the brain.

Alzheimer’s Disease
Alzheimer’s disease is a progressive neurodegenerative disease that is mainly diagnosed by its clinical fea- tures. The clinical characteristics of AD involve pro- gressive impairment of cognitive function, impaired orientation, impaired attention, language disturbance (aphasia), difficulty in recognizing or identifying objects (agnosia), disturbance in executive functioning, and impaired motor activity (apraxia).

Histopathologically, development of what is known as senile plaques and neurofibrillary tangles and deposits of aggregated amyloid b (Ab) in neuritic plaques and cerebral vessels are characteristic hallmarks of AD.14 The association between apolipoprotein E4 (ApoE4) alleles and cognitive dysfunction has also been exten- sively indicated.15,16

Overweight participants exhibit an inverse association with ApoE4 and associated with decreased non-ApoE4 AD onset age. Pathogenic mechanisms associated with diabetes and overweight are enriched in AD cases without an ApoE4 allele.17

Obesity and Cognitive Function
Emerging reports from various clinical studies sup- port the idea of negative correlation between adiposity per se and cognitive function. From published litera- ture, it appears that deterioration of cognitive and motor function accelerates with increasing total body fat irrespective of body fat distribution pattern. In fact, a cohort study of obese women has shown that irrespective of body fat distribution, overall body weight is associated with derangement of motor function.18

Similar observations from the Framingham heart study have also reported a marked impairment of cognitive function in patients with obese compared with nonobese counterparts.19 These reports indicate an inverse correlation between higher body weight and memory function in adult human participants.

In a prospective study of 2798 adults without dementia, over an average follow-up period of 5.4 year, 480 people were diagnosed with incident of dementia of which 245 with AD (no vascular dementia [VD]) and 213 with VD (with or without AD). An increased risk of dementia was found for obese (BMI >30) versus normal weight (BMI 20-25) participants with midlife (age 50 years) obesity.

Interestingly, this study reported reversal of risk estimates in assessments of late-life (>65 years of age) BMI. Underweight persons (BMI <20) had an increased risk of dementia, whereas being over- weight (BMI >25-30) was not associated and being obese reduced the risk of dementia compared with those with normal BMI.20

A similar finding is also reported in another large scale study. In a population-based prospective cohort study of 1836 with a mean age of >71 years at base line who were followed up for further 7 years reported that the higher baseline BMI was significantly associated with a reduced risk of AD. More importantly, slower rate of decline in BMI was associated with a reduced risk of dementia,21 indicating protective effects of higher late life adiposity in retaining cognitive func- tion.

Furthermore, another prospective study of 10 136 participants (40-45 years of age) examining association between midlife BMI and dementia over an average of 36 years follow-up reported that obese participants (BMI 30) at midlife had more than 3-fold increase in risk of AD compared to those with a normal BMI (>18.5-<25) at midlife. What is important to note is that the increase in AD risk was significant even after adjustments for age, education, race, sex, marital status, smoking, hyperlipidaemia, hypertension, diabetes, ischemic heart disease, and stroke.

The risk of VD was also increased by 5-fold, while those overweight at midlife (BMI 25 and <30) had a 2-fold increase in risk of AD and VD.22 These data strongly implicate midlife BMI as a marker for prediction of AD and VD in later life. Moreover, it strongly suggests that obesity per se has significant negative impact on cognitive function irrespective of secondary complications of obesity.

Data from the above studies suggest a ‘‘bimodal’’ effect of total adiposity on cognitive function in later life—a negative effect if the participant is obese at midlife and a positive effect if the participant is obese in later life. Interestingly, in a study of healthy adults (20-82 years), BMI was also inversely related to performance on all cognitive tests such that over- weight and obese adults (BMI > 25) exhibited poorer executive function test performance than normal weight adults (BMI 18.5-24.9).23

This study may suggest that obesity-induced cognitive impairment can set in at an early age if total adiposity is increased. A similar retrospective study with 18 year follow-up on women with dementia reported higher BMI for participants with AD compared with non-AD participants with similar age. In fact for every 1.0 increase in BMI at age 70 years, AD risk increased by 36%,24 further highlighting the importance of overall adiposity on cognitive function at any given age.

Noninvasive studies using magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopic indicate higher BMI is strongly corre- lated with lower concentrations of N-acetylaspartate (spectroscopic marker of neuronal viability) in fron- tal, parietal, and temporal white matter as well as lower N-acetylaspartate levels in frontal gray matter.

There were also lower concentrations of choline- containing metabolites (associated with membrane metabolism) in frontal white matter.25 Furthermore, these differences were irrespective of age or sex, stressing negative impact of increased BMI per se on central nervous system (CNS) neuronal viability.

Moreover, these results suggest that higher BMI at midlife (midlife 40-50 years of age) is associated with neuronal and/or myelin abnormalities, which may in turn reflect accelerated aging and subsequently the development of age-related cognitive impairment. Furthermore, in older adult participants without sig- nificant neurological or psychiatric history, plasma levels of Ab were correlated directly with adiposity and inversely with cognitive function26,27 suggestive of role of obesity in deposition of Ab and ultimately deterioration of cognitive function.

Histological examination of autopsied brain has indicated frequent Alzheimer-type neurological changes in hippocampal structure of morbidly obese participants. Obese (BMI > 45) patients >65 years showed higher levels of Ab (4G8), t (AT8), or Ab PP protein deposits in brain compared with none- obese participants.

More interestingly, these indices in some cases were comparable to those seen in patients with established AD. Furthermore, the dif- ferences in t and Ab PP expression were significantly higher in obese non-AD patients than non-obese non-AD controls.28 What is important to note is that Alzheimer-type neuropathological changes in mor- bidly obese elderly individuals but not younger obese patients were observed without any clinical history of cognitive impairment.

Contrary to human studies, animal histopathological studies were equivocal fail- ing to show a clear association between diet-induced obesity and development of AD. High-fat diet feed- ing of animal model of obesity and type II diabetes mellitus (C57BL/6 mice) doubled mean body weight, caused type II diabetes mellitus, and marginally reduced mean brain weight. Moreover, these effects were associated with significantly increased levels of t, insulin-like growth factor (IGF)-I receptor, insulin receptor substrate-1 (IRS-1), IRS-4, ubiquitin, glial fibrillary acidic protein, and 4-hydroxynonenol, and decreased expression of b-actin.

High-fat diet feed- ing also caused brain insulin resistance manifested by reduced BMAX (baseline standard expected to yield the highest possible bound response) for insulin receptor binding and modestly increased brain insu- lin gene expression. Despite such alteration in above indices high-fat diet-fed mouse brains did not exhibit AD histopathology, increases in amyloid-b or phos- pho-t, or impairments in IGF signaling or acetylcholine homeostasis.29

Therefore, in animal models, although diet-induced obesity and subsequent devel- opment of type II diabetes causes brain atrophy, it does not produce characteristics histological changes seen in AD. A similar increased atrophic change has also been reported in obese human compared with lean counterparts. Overweight and obese women present with increased temporal but not frontal, parietal, or occipital atrophy compared with lean controls.30

Therefore, it is plausible to consider obesity and overall adiposity as an important independent factor in the genesis and progression of cognitive impairment. This hypothesis is further strengthened by an important ani- mal study where addition of sucrose-sweetened water to normal rodent diet daily intake of animal model of AD induced obesity, glucose intolerance, hyperinsulinaemia, and hypercholesterolaemia. What is signifi- cant in this study to note is that these metabolic changes were associated with increased exacerbation of memory impairment and a 2- to 3-fold rise in insoluble Ab protein levels and its deposition in the brain of these animals compared with nonobese transgenic AD mice.31 This study provides direct evidence that obesity not only induces cognitive decline but it in fact can exacerbate memory impairment in those who already show sign of cognitive dysfunction.

References

1. Wing RR, Mathews KA, Kuller LH, Meilahn EN, Plantinga P. Waist to hip ratio in middle-aged women. Associations with behavioral and psychological factors and with changes in cardiovascular risk factors. Arterios- cler Thromb. 1991;11(5):1250-1257.
2. Wellman NS, Friedberg B. Causes and consequences of adult obesity: health, social and economic impacts in the United States. Asia Pac J Clin Nutr. 2002;11(suppl 8): S705-S709.
3. Law CM, Shiell AW, Newsome CA, et al. Fetal, infant and childhood growth and adult blood pressure: a longi- tudinal study from birth to 22 years of age. Circulation. 2002;105(9):1088-1092.
4. Lloyd LJ, Langley-Evans SC, McMullen S. Childhood obe- sity andadult cardiovascular disease risk: a systematic review. Int J Obes. (Lond). 2009May 12. [Epub ahead of print].
5. Whitaker RC, Wright  JA,  Pepe  MS,  Seidel  KD,  Dietz WH. Predicting obesity in young adulthood from childhood and parental obesity. N Engl J Med. 1997;337(13):869-873.
6. Duflou J, Virmani R, Robin I, Burke A, Farb A, Smialek J. Sudden death as a result of heart disease in morbid obe- sity. Am J Heart. 1995;130(2):306-313.
7. Creager MA, Cooke JP, Mendelsohn ME, et al. Impaired vasodilation of forearm resistance vessels in hypercholes- terolemic humans. J Clin Invest. 1990;86(1):228-234.
8. Fatani S, Pickavance LC, Sadler CJ, et al. Differential vascular dysfunction in response to diets of differing macronutrient composition: a phenomenonological study. Nutr Metab. (Lond). 2007;4:15.
9. Naderali EK, Fatani S. The effects of fenofibrate on metabolic and vascular changes induced by chocolate- supplemented diet in the rat. Eur J Pharmacol. 2005;521(1-3):99-104.
10. Steinberg HO, Chacker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance isassociated with endothelial dysfunction: implications for the syndrome of insulin resistance. J Clin Invest. 1996; 97(11):2601-2610.
11. Watson GS, Craft S. Modulation of memory by insulin and glucose: neuropsychological observations in Alzhei- mer’s disease. Eur J Pharmacol. 2004;490(1-3):97-113.
12. Watson GS, Craft S. The role of insulin resistance in the pathogenesis of Alzheimer’s disease: implications for treatment. CNS Drugs. 2003;17(1):27-45.
13. Marks DR, Tucker K,  Cavallin  MA,  Mast  TG,  Fadool DA. Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfac- tory behaviors. J Neurosci. 2009;29(20):6734-6751.
14. Selkoe DJ. The genetics and molecular pathology of Alz- heimer’s disease: roles of amyloid and the presenilins. Neurol Clin. 2000;18(4):903-922.
15. Jellinger KA, Attems J. Neurofibrillary tangle- predominant dementia: comparison with classical Alzhei- mer disease. Acta Neuropathol. 2007;113(2):107-117.
16. Premkumar DR, Cohen DL, Hedera P, Friedland RP, Kalaria RN. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology asso- ciated with Alzheimer’s disease. Am J Pathol. 1996;148(6):2083-2095.
17. Profenno LA, Faraone SV. Diabetes and overweight associate with non-APOE4 genotype in an Alzheimer’s disease population. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(6):822-829.
18. Lafortuna CL, Agosti F, Proietti M, Adorni F, Sartorio A. The combined effect of adiposity, fat distribution and age on cardiovascular risk factors and motor disability in a cohort of obese women (aged 18-83). J Endocrinol Invest. 2006;29(10):905-912.
19. Elias MF, Elias PK, Sullivan  LM,  Wolf  PA, D’Agostino RB. Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study. Int J Obes Relat Metab Disord. 2003;27(2):260-268.
20. Fitzpatrick AL, Kuller LH, Lopez OL, et al. Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol. 2009;66(3):336-342.
21. Hughes TF, Borenstein AR, Schofield E,  Wu  Y, Larson EB. Association between late-life body mass index and dementia: the Kame Project. Neurology. 2009;72(20):1741-1746.
22. Whitmer RA, Gunderson EP, Quesenberry CP Jr,  Zhou J, Yaffe K. Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzhei- mer Res. 2007;4(2):103-109.
23. Gunstad J,  Paul  RH,  Cohen  RA,  Tate  DF,  Spitznagel MB, Gordon E. Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. Compr Psychiatry. 2007;48(1):57-61.
24. Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med. 2003;163(13):1524-1528.
25. Gazdzinski S, Kornak J, Weiner MW, Meyerhoff DJ. Body mass index and magnetic resonance markers of brain integrity in adults. Ann Neurol. 2008;63(5): 652-657.
26. Gunstad J, Spitznagel MB, Glickman E, et al. beta- Amyloid is associated with reduced cognitive function in healthy older adults. J Neuropsychiatry Clin Neurosci. 2008;20(3):327-330.
27. Leahey TM, Myers TA, Gunstad J, et al. Abeta40 is associated with cognitive function, body fat and physical fitness in healthy older adults. Nutr Neurosci. 2007;10(5-6): 205-209.
28. Mrak RE. Alzheimer-type neuropathological changes in morbidly obese elderly individuals. Clin Neuropathol. 2009;28(1):40-45.
29. Moroz N, Tong M, Longato L, Xu H, de la Monte SM. Limited Alzheimer-type neurodegeneration in experi- mental obesity and type 2 diabetes mellitus. J Alzhei- mers Dis. 2008;15(1):29-44.
30. Gustafson D, Lissner L, Bengtsson C, Bjo¨ rkelund C, Skoog I. A 24-year follow-up of body mass index and cerebral atrophy. Neurology. 2004;63(10): 1876-1881.
31. Cao D, Lu H, Lewis TL, Li L. Intake of sucrose- sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J Biol Chem. 2007;282(50):36275-36282.

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More information: Manmohi D. Dake et al, Obesity and Brain Vulnerability in Normal and Abnormal Aging: A Multimodal MRI Study, Journal of Alzheimer’s Disease Reports (2021). DOI: 10.3233/ADR-200267