Brain and Antiaging Medicine: Age-Related Changes in Cognitive Function

Cognitive function is defined as “the ability to know the higher properties of events based on reasoning and thinking, not on sensibility” (Kojien seventh Edition) and is divided into memory, orientation (time, place), executive function (social activities, housework), and activities of daily living (personal affairs). Age-related changes in cognitive function can be broadly divided into physiological and pathological (dementia). Dementia includes Alzheimer’s disease (AD), Lewy body dementia, frontotemporal lobar degeneration, vascular dementia, neurofibrillary tangle dementia, argyrophilic grain dementia, and limbic-predominant age-related TDP-43 encephalopathy (LATE). Among these, AD is one of the most common types of dementia. In studies that accurately counted the number of neurons using AD autopsy brains, there is not much decrease in the number of neurons due to physiological aging in the olfactory cortex and hippocampus in the medial temporal lobe, but a significant decrease in neurons is observed in AD [1]. In fact, in brain imaging tests such as MRI, hippocampal atrophy due to aging is about 1% per year, but it rises to 5% in typical AD. An epidemiological survey targeting a wide age range of Japanese people reported that the score of the Mini-Mental State Examination (MMSE), a cognitive function test, begins to decline around the age of 55–64 [2]. Although rigorous studies using human autopsy brains are difficult, studies using primates have reported a decrease in the number of dendritic spine of neurons and changes in synapse morphology due to aging, suggesting that similar morphological and functional changes in synapses may occur in humans due to aging. Physiological cognitive decline includes a known decrease in logical memory (immediate and delayed reproduction of long sentences) due to normal aging. In AD, senile plaques, neurofibrillary changes, and neuronal death are the three major pathologies. Senile plaques are accumulations of beta-amyloid outside the cell. Neurofibrillary changes are accumulations of excessively phosphorylated tau inside neurons. Neuronal death in AD is observed mainly in the temporal and parietal lobes and is associated with neurofibrillary changes and dystrophic “Neuritic plaques” associated with neurites, that is, “accumulation of phosphorylated tau” correlates with diffuse senile plaques and “total senile plaques,” that is, “accumulation of β-amyloid” does not correlate. This suggests that neuronal cell death in Alzheimer’s disease (AD) correlates with tau and not directly with β-amyloid. APOE genotype is a strong risk gene for AD, and β-amyloid accumulation is influenced by the APOE genotype. On the other hand, tau accumulation correlates with aging. Recently, it has been reported that the APOE genotype also affects neuronal cell death due to tau accumulation. In addition to AD, there are dementia with Lewy bodies (accumulation of α-synuclein), frontotemporal dementia (accumulation of tau and TDP-43), vascular dementia, and neurofibrillary tangle dementia and argyrophilic grain dementia, which are seen in older age, and in the latter two, it is known that tau accumulates [primary age-related tauopathy (PART)]. Furthermore, limbic-predominant TDP-43 encephalopathy (LATE), in which TDP-43 accumulates in the cerebral limbic system, is attracting attention in relation to hippocampal sclerosis (neuronal cell death in the hippocampus with hippocampal atrophy), and the pathological significance of TDP-43, which was originally found in frontotemporal dementia and amyotrophic lateral sclerosis, is expected to be elucidated. The combination of these proteins is also important in considering cognitive decline due to aging. In fact, the more you age, the more the combination of β-amyloid, tau, α-synuclein, and TDP-43 pathology increases. Even at the stage of mild cognitive impairment, which is a precursor to dementia, only β-amyloid + tau (2 types) is 40%, and β-amyloid + tau + α-synuclein (3 types) is 20%. Cognitive function is “the ability to know the higher properties of events based on reasoning and thinking, not on sensibility” (Kojien seventh edition) and is divided into memory, orientation (time, place), executive function (social activities, housework), and activities of daily living (personal matters). Changes in cognitive function due to aging are broadly divided into physiological and pathological (dementia). Dementia includes Alzheimer’s disease (AD), dementia with Lewy bodies, frontotemporal dementia, vascular dementia, neurofibrillary tangle dementia, argyrophilic grain dementia, and limbic-predominant age-related TDP-43 (TAR DNA-binding protein-43) encephalopathy (Limbic-predominant age-related TDP-43). Among dementia, one of the most common types is Alzheimer’s disease (AD). In studies that meticulously counted the number of neurons using AD autopsy brains, it was found that there is not much decrease in the number of neurons due to physiological aging in the olfactory cortex and hippocampus within the temporal lobe, but a significant decrease in neurons is observed in AD. In fact, in brain imaging tests such as MRI, hippocampal atrophy due to aging is about 1% per year, but it rises to 5% in typical AD. In an epidemiological survey targeting a wide age range of Japanese people, it has been reported that the score of the Mini-Mental State Examination (MMSE), a cognitive function test, begins to decline around the age of 55–64. Although rigorous studies using human autopsy brains are difficult, studies using primates have reported a decrease in the number of dendritic spines of neurons and changes in synapse morphology due to aging, suggesting that similar morphological and functional changes in synapses may occur in humans due to aging. As a physiological cognitive decline, it is known that logical memory (logical memory: immediate and delayed reproduction of long sentences) decreases due to normal aging. In AD, senile plaques, neurofibrillary changes, and neuronal death are the three major pathologies. Senile plaques are accumulations of beta-amyloid outside the cell. Neurofibrillary changes are accumulations of excessively phosphorylated tau inside neurons. Neuronal death in AD is observed mainly in the temporal and parietal lobes and correlates with neurofibrillary changes and “senile plaques with dystrophic neurites (neuritic plaques)”, that is, “accumulation of phosphorylated tau”, but not with diffuse senile plaques or “total senile plaques”, that is, “accumulation of beta-amyloid”. This suggests that neuronal death in AD correlates with tau and not so much directly with beta-amyloid. APOE genotype is a strong risk gene for AD, and beta-amyloid accumulation is affected by the APOE genotype. On the other hand, tau accumulation correlates with aging. In recent years, there have been reports that the APOE genotype also affects neuronal death due to tau accumulation. In addition to AD, as mentioned above, there are Lewy body dementia (accumulation of alpha-synuclein), frontotemporal lobar dementia (accumulation of tau and TDP-43), vascular dementia, and dementia observed in older age such as neurofibrillary tangle dementia and argyrophilic grain dementia, in the latter two of which it is known that tau accumulates, such as primary age-related tauopathy (primary Age-related tauopathy (PART)) is also drawing attention in relation to hippocampal sclerosis (characterized by neuronal cell death accompanied by hippocampal atrophy) where TDP-43 accumulates in the cerebral limbic system, known as Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). In addition to the originally discovered frontotemporal dementia and amyotrophic lateral sclerosis, the pathological significance of TDP-43 is expected to be clarified. The combined pathology of these proteins is also important in considering age-related cognitive decline. In fact, the older one gets, the more the pathology of β-amyloid, tau, α-synuclein, and TDP-43 increases. Even at the stage of mild cognitive impairment, which is a precursor to dementia, 40% have only β-amyloid + tau (2 types), 20% have β-amyloid + tau + α-synuclein (3 types), and 10% have β-amyloid + tau + TDP-43 (3 types). In dementia, it has been reported that 20% have all four types: β-amyloid + tau + α-synuclein + TDP-43. In addition to the accumulation of these proteins, the increase in vascular lesions with age has a significant impact on cognitive function. Diabetes, hypertension, and dyslipidemia, known as vascular risk factors, each affects cognitive function. Interestingly, it has been reported that the impact of diabetes on cognitive decline depends on the APOE genotype, i.e., it is observed in APOE2 and APOE3 types, but not in APOE4 type. The elucidation of this mechanism is awaited. Also, although the causal relationship is unclear, BMI (body mass... It has been reported that there is an inverse correlation between the index and brain amyloid. There is still much we do not know about the decline in cognitive function due to aging, but from what has been mentioned above, it is thought that the following equation can be established for “changes in cognitive function due to aging”. That is, “changes in cognitive function due to aging” = “physiological aging changes + pathological changes in the brain + vascular damage + effects from the whole body (peripheral) tissues (including vascular risk factors) (including interactions with genetic factors)”. Recently, it has been shown that cognitive functions such as execution function and processing speed improve by multi-domain (multifactor) interventions such as exercise, diet, cognitive training, and vascular risk management for people at risk of dementia (FINGER study). This research is spreading worldwide. Disease-modifying drugs such as antibody therapy against β-amyloid are still being developed for AD, and recently, the success of the phase III trial of Lecanemab was reported. It is expected that disease-modifying drugs targeting abnormally accumulating proteins will continue to be developed not only for AD, but also for dementia as a whole. Since the development of disease-modifying drugs is expected to take time, a combination of “non-drug therapies such as multi-domain interventions” and “development of disease-modifying drugs targeting key molecules of etiology including accumulating proteins” is expected for dementia (Fig. 36.1).