The findings of height-, age-, and sex-independent increases in intracranial, hippocampal, and white-matter volumes and in cortical surface area in members of the Framingham Heart Study born over successive decades are fascinating and suggest that changing exposures in early life might specifically influence brain development. Whether these changes contribute to the decreased incidence of dementia seen in Western countries is, at this stage, less clear. Pathological studies in other cohorts have shown significant reductions in cerebrovascular pathology over the years, likely related to improved management of vascular risk factors in prior decades, which would seem likely to be a major influence on changing dementia rates (Grodstein et al., 2023). It is of course possible that increased brain volumes over the decades might improve reserve/resilience to AD and neurodegenerative pathologies—which, in contrast to cerebrovascular disease, do not seem to be changing over time (Grodstein et al., 2023).
Given the relatively young age of this cohort, 45 to 74 years, further follow-up to capture cognitive outcomes and dementia diagnosis rates, ideally with autopsy confirmation of diagnosis, is required to address this idea. More broadly, studies such as this demonstrate the power of combining cohorts studied prospectively over many years with brain imaging and other biomarkers of brain health to determine potentially modifiable early life risk/protective factors for cognition and dementia in later life.
References:
Grodstein F, Leurgans SE, Capuano AW, Schneider JA, Bennett DA.
Trends in Postmortem Neurodegenerative and Cerebrovascular Neuropathologies Over 25 Years.
JAMA Neurol. 2023 Apr 1;80(4):370-376.
PubMed.
DeCarli et al. provide evidence for secular trends in intracranial volume, white- and gray-matter volume, hippocampal volume, and cortical surface area for birth cohorts from 1930 to 1970. Although ICV is established fairly early in life and does not change over the remainder of the lifespan, other volumes, including hippocampal volume, decrease with age. The authors of this report address this issue by adjusting for age at the MRI scan as well as comparing two groups of participants from adjacent birth cohorts of similar mean age. They note that the increases in brain volume parallel earlier findings of declining incidence of dementia over time in the Framingham Study.
Although the observations of decreased dementia incidence and increased brain size over time are important, data from studies measuring the association of head size with dementia in individuals provide additional support for this relationship. Beginning with Schofield et al. (1995), numerous studies have shown associations between measures of larger brain size and lower risk of dementia in individual participants (Borenstein and Mortimer, 2016).
In 2001, in a prospective study we showed that among individuals who carried one APOE4 allele, those with smaller head circumferences had a 12-fold higher risk of incident probable AD compared to those with larger head circumferences (Borenstein Graves et al., 2001). A later analysis from the Nun Study (Mortimer et al., 2003) demonstrated that among nuns with less than a college education, smaller head circumference was associated with a higher prevalence of dementia. In 2009, this finding in the Nun Study was extended to incident dementia, with both smaller head circumference and lower education increasing the risk of dementia independent of the severity of AD neuropathology at autopsy (Mortimer et al. 2009). Finally in a large prospective community study in China, we reported that smaller head circumference combined with lower education predicted a higher risk of incident dementia (Wang et al., 2019).
Among other factors, the presence of small strokes greatly increases the risk of dementia (Snowdon et al., 1996). It is likely that all three factors (brain size, education, and cerebrovascular disease) play a role in mitigating the effects of AD pathology on the expression of dementia. Therefore, it might be expected that secular effects in all three variables would result in declines in dementia and AD incidence over time.
References:
Schofield PW, Mosesson RE, Stern Y, Mayeux R.
The age at onset of Alzheimer's disease and an intracranial area measurement. A relationship.
Arch Neurol. 1995 Jan;52(1):95-8.
PubMed.
Borenstein AR, Mortimer JA.
Alzheimer’s Disease, from Life Course Perspectives on Risk Reduction.
Elsevier: London, 2016.
Borenstein Graves A, Mortimer JA, Bowen JD, McCormick WC, McCurry SM, Schellenberg GD, Larson EB.
Head circumference and incident Alzheimer's disease: modification by apolipoprotein E.
Neurology. 2001 Oct 23;57(8):1453-60.
PubMed.
Mortimer JA, Snowdon DA, Markesbery WR.
Head circumference, education and risk of dementia: findings from the Nun Study.
J Clin Exp Neuropsychol. 2003 Aug;25(5):671-9.
PubMed.
Mortimer JA, Snowdon DA, Markesbery, WR.
Larger head circumference and greater education provide protection against incident dementia independent of the severity of Alzheimer pathology: The Nun Study.
Alzheimer’s & Dementia 2009; 5:379.
Wang F, Mortimer JA, Ding D, Luo J, Zhao Q, Liang X, Wu W, Zheng L, Guo Q, Borenstein AR, Hong Z.
Smaller Head Circumference Combined with Lower Education Predicts High Risk of Incident Dementia: The Shanghai Aging Study.
Neuroepidemiology. 2019;53(3-4):152-161. Epub 2019 Jul 15
PubMed.
Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR.
Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.
JAMA. 1997 Mar 12;277(10):813-7.
PubMed.
Comments
University College London
The findings of height-, age-, and sex-independent increases in intracranial, hippocampal, and white-matter volumes and in cortical surface area in members of the Framingham Heart Study born over successive decades are fascinating and suggest that changing exposures in early life might specifically influence brain development. Whether these changes contribute to the decreased incidence of dementia seen in Western countries is, at this stage, less clear. Pathological studies in other cohorts have shown significant reductions in cerebrovascular pathology over the years, likely related to improved management of vascular risk factors in prior decades, which would seem likely to be a major influence on changing dementia rates (Grodstein et al., 2023). It is of course possible that increased brain volumes over the decades might improve reserve/resilience to AD and neurodegenerative pathologies—which, in contrast to cerebrovascular disease, do not seem to be changing over time (Grodstein et al., 2023).
Given the relatively young age of this cohort, 45 to 74 years, further follow-up to capture cognitive outcomes and dementia diagnosis rates, ideally with autopsy confirmation of diagnosis, is required to address this idea. More broadly, studies such as this demonstrate the power of combining cohorts studied prospectively over many years with brain imaging and other biomarkers of brain health to determine potentially modifiable early life risk/protective factors for cognition and dementia in later life.
References:
Grodstein F, Leurgans SE, Capuano AW, Schneider JA, Bennett DA. Trends in Postmortem Neurodegenerative and Cerebrovascular Neuropathologies Over 25 Years. JAMA Neurol. 2023 Apr 1;80(4):370-376. PubMed.
View all comments by Jonathan SchottUniversity of South Florida
DeCarli et al. provide evidence for secular trends in intracranial volume, white- and gray-matter volume, hippocampal volume, and cortical surface area for birth cohorts from 1930 to 1970. Although ICV is established fairly early in life and does not change over the remainder of the lifespan, other volumes, including hippocampal volume, decrease with age. The authors of this report address this issue by adjusting for age at the MRI scan as well as comparing two groups of participants from adjacent birth cohorts of similar mean age. They note that the increases in brain volume parallel earlier findings of declining incidence of dementia over time in the Framingham Study.
Although the observations of decreased dementia incidence and increased brain size over time are important, data from studies measuring the association of head size with dementia in individuals provide additional support for this relationship. Beginning with Schofield et al. (1995), numerous studies have shown associations between measures of larger brain size and lower risk of dementia in individual participants (Borenstein and Mortimer, 2016).
In 2001, in a prospective study we showed that among individuals who carried one APOE4 allele, those with smaller head circumferences had a 12-fold higher risk of incident probable AD compared to those with larger head circumferences (Borenstein Graves et al., 2001). A later analysis from the Nun Study (Mortimer et al., 2003) demonstrated that among nuns with less than a college education, smaller head circumference was associated with a higher prevalence of dementia. In 2009, this finding in the Nun Study was extended to incident dementia, with both smaller head circumference and lower education increasing the risk of dementia independent of the severity of AD neuropathology at autopsy (Mortimer et al. 2009). Finally in a large prospective community study in China, we reported that smaller head circumference combined with lower education predicted a higher risk of incident dementia (Wang et al., 2019).
Among other factors, the presence of small strokes greatly increases the risk of dementia (Snowdon et al., 1996). It is likely that all three factors (brain size, education, and cerebrovascular disease) play a role in mitigating the effects of AD pathology on the expression of dementia. Therefore, it might be expected that secular effects in all three variables would result in declines in dementia and AD incidence over time.
References:
Schofield PW, Mosesson RE, Stern Y, Mayeux R. The age at onset of Alzheimer's disease and an intracranial area measurement. A relationship. Arch Neurol. 1995 Jan;52(1):95-8. PubMed.
Borenstein AR, Mortimer JA. Alzheimer’s Disease, from Life Course Perspectives on Risk Reduction. Elsevier: London, 2016.
Borenstein Graves A, Mortimer JA, Bowen JD, McCormick WC, McCurry SM, Schellenberg GD, Larson EB. Head circumference and incident Alzheimer's disease: modification by apolipoprotein E. Neurology. 2001 Oct 23;57(8):1453-60. PubMed.
Mortimer JA, Snowdon DA, Markesbery WR. Head circumference, education and risk of dementia: findings from the Nun Study. J Clin Exp Neuropsychol. 2003 Aug;25(5):671-9. PubMed.
Mortimer JA, Snowdon DA, Markesbery, WR. Larger head circumference and greater education provide protection against incident dementia independent of the severity of Alzheimer pathology: The Nun Study. Alzheimer’s & Dementia 2009; 5:379.
Wang F, Mortimer JA, Ding D, Luo J, Zhao Q, Liang X, Wu W, Zheng L, Guo Q, Borenstein AR, Hong Z. Smaller Head Circumference Combined with Lower Education Predicts High Risk of Incident Dementia: The Shanghai Aging Study. Neuroepidemiology. 2019;53(3-4):152-161. Epub 2019 Jul 15 PubMed.
Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997 Mar 12;277(10):813-7. PubMed.
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