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• Published: 09 May 2019

Alzheimer’s disease: risk factors and potentially protective measures

• Marcos Vinícius Ferreira Silva 1 ,
• Cristina de Mello Gomide Loures 1 ,
• Luan Carlos Vieira Alves 1 ,
• Leonardo Cruz de Souza 2 ,
• Karina Braga Gomes Borges 1 &
• Maria das Graças Carvalho 1  

Journal of Biomedical Science volume  26 , Article number:  33 ( 2019 ) Cite this article

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Alzheimer’s disease (AD) is the most common type of dementia and typically manifests through a progressive loss of episodic memory and cognitive function, subsequently causing language and visuospatial skills deficiencies, which are often accompanied by behavioral disorders such as apathy, aggressiveness and depression. The presence of extracellular plaques of insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein (P-tau) in the neuronal cytoplasm is a remarkable pathophysiological cause in patients’ brains. Approximately 70% of the risk of developing AD can be attributed to genetics. However, acquired factors such as cerebrovascular diseases, diabetes, hypertension, obesity and dyslipidemia increase the risk of AD development. The aim of the present minireview was to summarize the pathophysiological mechanism and the main risk factors for AD. As a complement, some protective factors associated with a lower risk of disease incidence, such as cognitive reserve, physical activity and diet will also be addressed.

Introduction

Alzheimer’s disease (AD) is the most common type of dementia [ 1 ], affecting at least 27 million people and corresponding from 60 to 70% of all dementias cases [ 2 ]. The occurrence of this disease also has a huge impact on life of patient’s family, in addition to a high financial cost to society [ 3 ]. From an anatomopathological point of view, AD is characterized by two prototypical lesions: 1) senile plaques, composed of a nucleus of β-amyloid protein accumulation (Aβ42), as extra-cellular lesions and 2) neurofibrillary tangles composed of phosphorylated tau protein (P-tau) and which are intraneuronal findings [ 4 ]. Deposition of β-amyloid protein can also occur in capillaries walls, arteries and arterioles causing amyloid cerebral angiopathy leading to degeneration of vascular wall componentes and worsening of blood flow, besides predisposing to intraparenchymal hemorrhages [ 5 ].

AD typically manifests through a progressive loss of episodic memory and cognitive function, with later deficiency of language and visuospatial abilities. Such changes are often accompanied by behavioral disorders such as apathy, aggressiveness and depression [ 6 ]. It should be noted that there is an important subgroup of AD patients who do not present a typically amnestic picture, manifesting non-amnestic deficits from the onset of symptoms [ 7 ]. Structural neuroimaging, with a pattern of hippocampal and parietal atrophy in typical cases reinforces the diagnosis [ 8 ]. Patients who meet typical disease characteristics, excluding other causes such as vascular and fronto-temporal dementias, have a probable diagnosis of AD [ 6 ]. Definitive diagnosis of the disease is usually carried out only through postmortem examination, whose purpose is to demonstrate histologically the neurofibrillary tangles and the senile plaques [ 9 ].

Pathophysiology of Alzheimer’s disease

The presence of extracellular plaques of insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFT) of P-tau in neuronal cytoplasm is the hallmark of AD [ 10 ]. Although the mechanisms by which these changes lead to cognitive decline are still debated, these deposits are believed to lead to atrophy and death of neurons resulting from excitotoxicity processes [excessive stimulation of neurotransmitter receptors in neuronal membranes], collapse in calcium homeostasis, inflammation and depletion of energy and neuronal factors. As a result of this process, damage to neurons and synapses involved in memory processes, learning and other cognitive functions lead to the aforementioned cognitive decline [ 11 ].

According to amyloid cascade theory (one of the most accepted theories about AD pathogenesis, although still debated), the cerebral accumulation of Aβ peptide, resulting from the imbalance between production and clearance of this protein, is the main event causing the disease, being other events observed (including the formation of NFT) resulting from this process [ 12 ].

The Aβ peptide, which has 36 to 43 aminoacids, is derived from amyloid precursor protein (APP) enzymatic proteolysis, a physiologically produced protein that plays important roles in brain homeostasis [ 13 , 14 ]. The APP gene is located on chromosome 21, which explains the higher incidence of early-onset AD in individuals with 21 trisomy (Down Syndrome) and in individuals with APP gene locus duplication [a rare form of early onset of familial origin]. It is believed that overexpression of APP results in an increase of cerebral Aβ peptide, and consequently, in its deposition [ 15 ].

Two main pathways for APP processing are now recognized: a non-amyloidogenic α-secretase-mediated pathway and an amyloidogenic β-and γ-secretase-mediated pathway. Cleavage of APP by α-secretase results in a soluble molecule, sAPPα, which has probable neuroprotective function, playing important roles in the plasticity and survival of neurons and protection against excitotoxicity [ 16 , 17 ]. The Aβ peptide is produced by APP cleavage by a β-secretase (mainly BACE1 enzyme). In this pathway, APP is cleaved by β-secretase to give a APP soluble fragment (sAPPβ, a mediator related to neuronal death), and a carboxy-terminal complex linked to cell membrane. The latter is cleaved by a γ-secretase complex composed by 4 proteins: presenilin 1 or 2, nicastrin, APH-1 (formerly pharynx-defective-1) and and PEN-2 (presenilin enhancer-2), to give rise to the Aβ peptide. Aβ peptides ranging in size from 38 to 43 aminoacids are generated with predominance of the 40 aminoacid form (Aβ 40), followed by 42 (Aβ 42) [ 17 , 18 ]. In physiological conditions, the amyloidogenic and non-amyloidogenic pathways coexist in equilibrium, the latter being favored preferentially [ 19 ].

The Aβ42 peptide is more prone to aggregation than Aβ40. Immunohistochemical analyses indicate that Aβ42 is initially deposited and found at higher concentrations in the amyloid plaques observed in AD patients [ 20 ]. Several studies showed that CSF Aβ42 levels are surrogate markers of underlying brain amyloidosis [ 21 , 22 ]. On the contrary, the correlation between serum Aβ42 levels and cerebral amyloidosis is not yet demonstrated. A decrease in Aβ42 levels is observed in cerebrospinal fluid of AD subjects, which can be explained in part by higher deposition of β-amyloid plaques [ 23 ]. As additional evidence of Aβ42 peptide and the AD pathophysiology, it is further noted that mutations in APP and presenilin genes, which give rise to early-onset familial AD forms, lead to a relative increase in Aβ42 levels [ 20 ].

Aβ peptides, under physiological conditions, are produced primarily in monomeric forms with synapses protective function. However, the accumulation of this protein leads to formation of fibrils that accumulate in senile plaques. High levels of Aβ may lead to oligomeric products formation (dimers, trimers, tetramers) leading to neuronal toxicity and degeneration (both by interaction with cell membranes and their receptors, and by direct interference in intracellular processes), interfering with the function and survival of cholinergic, serotonergic, noradrenergic and dopaminergic neurons, reducing their control over the amyloidogenic pathway and favoring the accumulation of insoluble Aβ peptide [ 19 , 24 ].

The exact mechanism by which deposition of Aβ peptide promotes NFT formation of hyperphosphorylated tau protein is not known. Blurton-Jones & Laferla (2006) [ 25 ] suggest four basic mechanisms:

The Aβ peptide promotes the activation of specific kinases (GSK3β, e.g.) that catalyze the hyperphosphorylation of tau protein, leading to its conformation change and formation of NFT;

Neuroinflammation promoted by the deposition of Aβ peptide leads to the production of proinflammatory cytokines that stimulate the phosphorylation of tau protein;

Reduced capacity of degradation of tau protein by the proteasome, in a process induced by Aβ peptide;

Defects in axonal transport promoted by Aβ peptide lead to inadequate localization of tau protein and its messenger RNA, which can lead to hyperphosphorylation and aggregation in NFT.

Tau protein is a microtubule-associated protein, produced by alternative splicing of the MAPT gene, located on chromosome 17 (17q21). Six isoforms of tau protein are produced by this process [ 26 ]. The main known physiological functions of this protein are the stimulation of tubulin polymerization, microtubules stabilization and intracellular organelles transport by microtubules. Once hyperphosphorylated, the protein loses its functions in the synthesis and stabilization of microtubules, leading to neuronal damage and promoting cytotoxicity [ 27 ]. Histological analyses demonstrate that both the load and the distribution of NFT in brain tissue correlate better with the severity of cognitive deficit than the Aβ peptide deposits [ 28 ].

• Genetic risk factors

AD can be classified by the age of onset of the first symptoms. Early-onset AD affects individuals under 65 years of age, accounting for about 4–6% of cases of AD, while the late form AD affects individuals aged 65 years or older. Besides the age of onset of symptoms, the early and late forms of AD differ in other clinical, neuropsychological, neuropathological and neuroimaging variables [ 29 ].

According to Ballard et al. (2011) [ 1 ] about 70% of the risk of developing AD can be attributed to genetics. Early AD usually occurs due to mutations in genes APP, PSEN1 and PSEN2 (genes of amyloid precursor protein, presenilin 1 and presenilin 2, respectively), whereas late-form AD is mainly associated with a polymorphism in APOE gene (apolipoprotein E gene), especially the presence of ε4 allele [ 30 , 31 ].

More than 30 dominant mutations have already been found in APP gene (located in chromosome 21q21) and are associated with about 15% of cases of early-onset autosomal dominant AD. Mutations in PSEN1 gene (located at 14q24.3) are associated with 80% of cases of early-onset AD, whereas 5% of cases are associated with PSEN2 mutations (located at 1q31-q42) [ 32 ]. Most of APP gene mutations, as well as PSEN1 mutations, lead to an increase in Aβ42: Aβ40 ratio, either by Aβ42 increased expression, reduction of Aβ40, or both. This deregulation favors early Aβ deposition in brain tissue favoring the amyloidogenic cascade [ 33 ]. It is believed that there are other genes besides APP, PSEN1 and PSEN2 involved in the pathogenesis of early-onset AD, as demonstrated by Campion et al. (1999) [ 34 ].

Apolipoprotein E (ApoE) is a protein involved in lipid metabolism encoded by APOE gene, located on chromosome 19. There are three APOE alleles described (ε2, ε3 and ε4, giving rise to apoE2, apoE3 and apoE4 isoforms), present in population at different frequencies (ε2: 5–10%, ε3: 65–70% and ε4: 15–20%). A study by Corbo and Scacchi (1999) [ 35 ] showed that there is a great variability in the APOE allele distribution among the different populations, with ε2 frequencies varying from 0.0 in some Native American populations up to 0.145 in Papuans. The ε 4 frequencies obtained by the authors range from 0.052 (Sardinians) to 0.407 (Pygmies). The ε4 allele is the main risk factor for late-onset AD. The presence of ε4 in heterozygosity increases 3-fold the risk of AD developing, whereas in homozygosis, the risk is increased 12-fold. Conversely, the presence of ε2 allele reduces the risk of AD developing [ 36 , 37 ].

The causes of the association between apoE are not yet fully understood, although some mechanisms have been proposed, and presented consistent results in clinical and in vitro studies. Among these studies, some show that apoE is able to bind to Aβ peptide. While the apoE4 isoform binds to Aβ peptide promoting its polymerization in fibrils and its deposition, apoE2 and apoE3 forms are more efficient in promoting the clearance of this peptide, reducing its deposition in brain tissue [ 38 ]. ApoE has neuroprotective effects and is able to act on neurons development, with apoE2 and apoE3 performing better than apoE4. Additionally, it is observed that protease-generated apoE fragments have toxic effects, which may lead to neuronal injury and favor Aβ peptide deposition [ 38 , 39 ].

More recently it was observed that rare alterations in the triggering receptor expressed on myeloid cells 2 ( TREM2 ) gene elevated the risk ratio by 2.9% for AD development [ 40 , 41 ]. The pathophysiological mechanism by which the deficiency in the gene increases the risk ratio for AD still needs to be better clarified. The gene is located on chromosome 6p21 [ 42 ] and the TREM2 protein is a highly expressed receptor on the surface of microglia, phagocytic cells of central nervous system, and has the function of modulating phagocytic and inflammatory responses in central nervous system [ 43 ]. Activation of microglia through the interaction of TREM2 and DAP12 stimulates the production of CCL19 and CCL21 chemokines and phagocytosis [ 44 ]. In knockout models for the TREM2 receptor it was observed that phagocytic capacity of apoptotic neuronal cell bodies was deficient [ 44 ]. Thus the accumulation of these cellular debris would promote a proinflammatory microenvironment [ 44 ]. Xiang et al. (2016) [ 45 ] observed that the removal capacity of Aβ peptide deposits is impaired in TREM2 receptor deficiency and would favor amyloid plaques accumulation.

• Acquired risk factors

A number of acquired factors increase the risk of developing AD. Among those factors are cerebrovascular diseases (most commonly reported risk factor), diabetes, hypertension, obesity and dyslipidemia [ 46 ]. The association of these risk factors to AD development will be described in the following subsections, as well as some protective factors associated with a lower risk of disease incidence, such as cognitive reserve, physical activity and diet as reported by Mayeux & Stern (2012) [ 46 ].

Cerebrovascular diseases

Cerebrovascular diseases and AD share many risk factors, which often overlap. Cerebrovascular changes such as hemorrhagic infarcts, small and large ischemic cortical infarcts, vasculopathies, and changes in cerebral white matter are known to increase the risk of dementia. Postmortem analyses of the brains of patients with AD indicate the presence of parenchymal vascular disease (amyloid angiopathy by Aβ peptide and small vessels arteriolosclerotic disease), with hemorrhagic outbreaks and infarcts being found in more than 50% of them [ 47 , 48 ]. According to Liu et al., (2015) [ 49 ], neuropathological findings indicate that between 6 and 47% of individuals with dementia have a simultaneous occurrence of cerebrovascular disease. These observations point to the potential role of homeostatic mechanisms in AD and lead to question whether the dementias in which vascular processes are involved are fundamentally different from those related to accumulation of Aβ42 and tau proteins or if both pathological processes produce synergistic effects on cognitive function [ 9 ].

According to the “double-stroke” theory of AD, vascular risk factors (“first stroke”) lead to dysfunction in blood-brain barrier and reduction in cerebral blood flow, with decreased blood supply to the region (oligoemia). This event leads to neuronal damage by non-amyloidogenic and amyloidogenic pathways. Firstly, the dysfunction of blood-brain barrier leads to oligoemia and the accumulation of neurotoxic molecules, events associated with the occurrence of multiple focal ischemic infarcts and micro-injuries resulting from hypoxia, causing neuronal damage. In the amyloidogenic pathway, vascular injury leads to increased expression and processing of APP, resulting in an increase in Aβ peptide. In addition, damage to blood-brain barrier leads to decreased clearance of Aβ peptide. The accumulation of amyloid in brain (“second stroke”) amplifies neuronal dysfunction and speeds up neurodegeneration process. Both Aβ peptide accumulation and hypoperfusion lead to hyperphosphorylation of tau protein, promoting the formation of NFT [ 50 ].

Hypertension

A longitudinal study carried out by Skoog et al. (1996) demonstrated that hypertension is capable of leading to increased risk of developing AD [ 51 ]. Other studies have confirmed this association, indicating that hypertension, especially when present in middle age, negatively affects cognitive performance at more advanced ages, and this association becomes weaker with age [ 52 ]. Hypertension is capable of causing changes in the vascular walls which can lead to hypoperfusion, ischemia and cerebral hypoxia, contributing to trigger the development of AD. Studies demonstrate that cerebral ischemia is capable of leading to the accumulation of APP and Aβ, in addition to stimulating the expression of presenilin, involved in Aβ synthesis. Hypertension may also lead to dysfunction in the blood-brain barrier, an event associated with the genesis of AD by previously discussed mechanisms [ 53 ].

Type 2 diabetes

Epidemiological studies indicate a clear association between type 2 diabetes mellitus and the increased risk of developing AD. Several mechanisms for this association are suggested, including insulin resistance and insulin deficiency, impaired insulin receptor, toxicity of hyperglycemia, adverse effects due to advanced glycation end products, cerebrovascular damage, vascular inflammation and others [ 54 ].

The use of animal models was able to demonstrate that deficiency or resistance to insulin are able to stimulate the action of β and γ-secretases, besides promoting reduction of Aβ clearance, leading to its accumulation in brain tissue. Insulin resistance or deficiency are still capable of inducing hyperphosphorylation of tau protein, leading to NFT formation. Insulin and insulin-like growth factor bind to insulin receptor, leading to its autophosphorylation and activation. Activation of this receptor leads to phosphorylation of phosphoinositide 3-kinase (PI3K) enzyme, which in turn phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β) enzyme, which is important for tau protein phosphorylation. Thus, insulin deficiency / resistance leads to GSK3β abnormal activation, and consequently, to an increase of p-tau formation [ 55 ].

In addition to the mechanisms discussed earlier, studies have reported that advanced glycation end products (AGEs) induce neuronal death through activation of cell death pathways, in addition to stimulating APP processing through increased expression of complexes β and γ-secretases (BACE and PSEN1), in a process involving reactive oxygen species generation [ 56 ]. In addition, Aβ peptide may undergo non-enzymatic glycation, making it an AGE more neurotoxic than its non-glycated form [ 57 ].

The role of obesity as a risk factor for AD development is still uncertain, with studies presenting rather heterogeneous results. According to a meta-analysis developed by Profenno, Porsteinsson, & Faraone (2010) [ 58 ], obesity (Body Mass Index - BMI ≥30 kg / m 2 ) is significantly and independently associated with AD developing risk. On the other hand, a meta-analysis conducted by Fitzpatrick et al. (2009) [ 59 ] indicated that obesity in middle age is a risk factor for dementia development (hazard ratio - HR: 1.39; 95% CI: 1.03–1.87), while in later stages of life, obesity is inversely correlated with the risk of dementia (HR: 0.63; 95% CI: 0.44–0.91). The same authors have also reported that below-ideal weight (BMI < 20 kg / m 2 ) is also associated with an increased risk of dementia (HR: 1.62, 95% CI: 1.02–2.64). Weight loss at more advanced ages occurs in concomitance to other comorbidities and is often indicative of poor health, and may even precede dementia onset within 10 years. Another meta-analysis conducted by Anstey et al. (2011) [ 60 ] indicated that both low weight and overweight as well as obesity in middle age are associated with a higher risk of developing AD in late life.

Dyslipidemia

Elevated cholesterol levels have been proposed as risk factors for the development of AD. Studies have already demonstrated 10% higher cholesterol levels in patients with AD, compared to healthy individuals [ 61 ]. Hypercholesterolemia is a risk factor both for atherosclerosis development and AD development as well as other neurodegenerative diseases [ 62 ].

Hypercholesterolemia increases AD risk primarily because of its effects on the blood-brain barrier. Studies have shown that elevated circulating cholesterol levels are capable of compromising integrity in blood-brain barrier [ 62 ], resulting in mechanisms previously discussed. In addition, experimental studies using animal models demonstrate that hypercholesterolemia is associated with increased Aβ peptide deposition, in addition to increased NFT formation, cognitive decline, neuroinflammation, dysfunction of cholinergic neurons and the presence of cerebral microhemorrhages compatible with AD [ 63 , 64 ].

In observational studies a beneficial effect was observed in the users of statins as the reduction in AD incidence or improvement in the disease progression [ 65 , 66 , 67 ]. However, clinical studies to date have not demonstrated benefit of statins treatment and protection against cognitive decline in AD patients at various stages of disease [ 68 , 69 , 70 , 71 , 72 ]. Contrary to meta-analysis findings conducted by Song et al. (2013) [ 73 ] who observed a lower risk of developing AD in statins users, a Cochrane meta-analysis [ 74 ] did not observe difference in disease outcome as well as alteration in mini-mental status examination (MMSE) in patients using or not statins. However, some important questions regarding the clinical studies are pointed out, i.e., whether treatment initiated in middle age prior disease onset would also have a beneficial effect in elderly, or whether in people with AD family history the treatment would be effective in comparison to those without this background.

Marital status, stress, depression and inadequate sleep

Widowhood status has been reported as an important risk factor AD. A cohort study by Håkansson et al. (2009) [ 75 ] shows that widowed individuals have an increased risk of developing AD compared to married or cohabiting individuals and that this effect is more pronounced in carriers of the APOE ε4 allele. Other studies, such as that by Fan et al. (2015) [ 76 ] demonstrated an association between the risk of all-cause dementia and widow status. A meta-analysis by Sommerlad et al. (2018) [ 77 ] reported an association between widowhood and all-cause dementia, but the same association was not found between widowhood and AD or vascular dementia.

Studies in animal models of AD have shown that stress, characterized as hyperactivation of the hypothalamic, pituitary and adrenal axis (HPA) leading to an increase in cortisol production, causes an increase in Aβ peptide deposition in regions of the brain such as hypothalamus and prefrontal cortex [ 78 , 79 , 80 ]. Carroll et al. (2011) [ 81 ] have observed that the prolonged stress caused by this hyperactivation also causes an increase in the accumulation of hyperphosphorylated tau and neurodegeneration in mice. In humans, increased levels of cortisol were observed in patients with AD compared to the control group [ 82 , 83 , 84 ]. Huang et al. (2009) [ 85 ] observed in a 2-year follow-up of patients with AD that the higher cortisol levels correlated with the faster progression of the disease, worsened in the MMSE and smaller volume of the hippocampus region when observed by resonance. The authors of this study argue that hippocampal atrophy causes a disinhibition effect on the HPA axis, which would cause elevation in cortisol levels as a consequence of the pathophysiological process of AD. Toledo et al. (2012) [ 86 ], observed in a sample of 26 patients with AD that the increase in cortisol levels is correlated with the deposition of the Aβ peptide observed by means of pittsburgh compound b-positron emission tomography (PiB-PET). Ennis et al. (2017) [ 87 ], in a 10-year longitudinal study with 1025 participants observed an increased risk of 1.31 for the development of AD and elevation in cortisol levels that were dosed in 24-h urine samples. However, this result contrasts with that observed in the Rotterdan study [ 88 ] in blood samples collected in the morning when there was no correlation between cortisol levels and AD or dementia in general.

Early adult depression is a risk factor for the development of dementia at more advanced age including AD [ 89 , 90 , 91 ]. Zverova et al. (2013) [ 83 ] observed a greater odds ratio for cognitive decline in the presence of cortisol levels and patients with AD and symptoms of depression. Wu et al. (2018) [ 92 ] observed in some patients with major depression in middle age hippocampal atrophy and Aβ peptide deposition observed by PET indicating that the protein metabolism may be altered in patients with depression.

According to a study published by Proserpio et al. (2018) [ 93 ], sleep disorders have a bidirectional relationship with AD: sleep disorders arise during the early stages of dementia and tend to worsen with the onset of dementia. Similarly, sleep disorders can lead to an increased risk of dementia. A meta-analysis by Shi et al. (2018) [ 94 ] demonstrated that individuals with sleep disorders have an increased risk of developing dementia. More specifically, individuals with insomnia are at high risk for developing AD but not for vascular dementia or other causes. Similarly, individuals with sleep disordered breathing had an increased risk of developing all-cause dementia, AD, and vascular dementia.

Smoking may affect the risk of developing AD by various mechanisms. It is known that it is able to raise the generation of free radicals, increasing oxidative stress, and to promote pro-inflammatory action in the immune system, leading to the activation of phagocytes and consequently, additional oxidative damage. In addition, smoking may lead to cerebrovascular diseases, which increase the risk of AD [ 95 , 96 ]. In a meta-analysis performed by Cataldo et al. (2010), an analysis of 8 case-control studies with affiliations with the tobacco industry suggested a protective effect of smoking in relation to AD (odds ratio (OR): 0.91, 95% CI 0.75–1, 10). In contrast, 14 cohort studies with no association with the tobacco industry demonstrated an increased relative risk for smokers (Relative Risk (RR): 1.45; 95% CI, 1.16–1.80) [ 97 ]. According to Durazzo et al. (2014), the sum of the evidence presented today in the literature is enough for the cessation of smoking to be recommended in order to reduce the incidence of dementia [ 96 ].

Protective factors

Cognitive reserve.

It has been observed in many cases a discrepancy between the degree of brain damage found in histopathological analyses and the severity of cognitive decline. To explain these findings, the theory of cognitive reserve was proposed, which postulates that the gap between brain injury and clinical manifestations is attributable to cognitive reserve capacity. This can be subdivided into two models: brain reserve model or threshold, and cognitive reserve model and / or compensation. The first is based on the amount of available neural substrate (eg, brain size, synapses density or dendritic branching), while the latter focuses on the more efficient ability to use the preexisting brain network in healthy individuals and on the recruitment of more resources to support normal functioning in presence of brain damage [ 98 ].

Several elements are associated with a greater cognitive reserve, such as educational level, occupational activities, leisure activities, physical activities and the integrity of relationships network [ 98 , 99 ]. A study conducted by Stern et al. (1994) [ 100 ] indicated that individuals with low level of schooling and low level of professional achievement had an approximately two-fold increased risk of developing dementia. Similarly, another study indicated that individuals with a higher level of leisure activities performance had a lower risk of developing dementia [ 101 ].

Physical activity

A meta-analysis developed by Hamer & Chida (2009) [ 102 ] indicated that physical activity practice is able to reduce AD risk by 45%. This protective effect is related to several mechanisms, such as reduction of blood pressure, obesity and proinflammatory activity besides the improvement in lipid profile and endothelial function. In addition, adaptations that occur in response to exercise can lead to a better cerebral blood flow and, consequently, better oxygenation of important areas for cognitive function [ 102 ]. It is also believed that physical activity is able to prevent AD by increasing neurotrophic factors such as BDNF (Brain Derived Neurotrophic Factor), IGF-1 (Insulin-Like Growth Factor), VEGF (Vascular Endothelial Growth Factor), stimulating neurogenesis and synaptic plasticity; and by the reduction of free radicals in the hippocampus, as well as increase of superoxide dismutase and eNOS (endothelial nitric oxide synthase) [ 103 ]. Studies have shown that the practice of physical activities is capable of promoting an increase in hippocampal volume, in addition to increasing plasma BDNF concentrations in healthy elderly, indicating a possible neuroprotective effect. It was also reported that in the AD elderly, practice of physical activities correlates positively with the levels of BDNF [ 104 ], which is a growth factor associated with the development and survival of neurons and synapses [ 105 ].

The relationship between the effects of diet and the risk of developing AD was based on certain patterns that were associated with lower or higher risk of developing AD [ 106 ]. As an example, Mediterranean diet is rich in unsaturated fats and antioxidants which confers a protection factor, as diets rich in saturated and trans fats and low levels of anti-oxidants are associated with higher risk of developing AD [ 106 , 107 ]. Some dietary components are essential for neurocognition protection such as dietary fatty acids, including fish oil; antioxidants, such as vitamins E and C; fruits and vegetables; vitamins B6, B12 (cobalamine) and folate, in addition to caloric restriction [ 108 ]. Antioxidants are able to prevent damage caused by reactive oxygen species in addition to stabilizing the membranes; docosahexaenoic acid (DHA) helps clear the Aβ peptide and, together with choline and uridine, aid in the synthesis of the neuronal membrane [ 106 ]. Phospholipid composition is essential in neuronal membrane function. Thus, adequate intake of DHA, eicosapentaenoic acid (EPA), uridine monophosphate, choline, folate, vitamins B6, B12, C, and E, and selenium contributes to a better synthesis of phospholipids and, consequently, to synaptic function preservation and against neurodegeneration [ 106 ]. Nerve synapses consist mainly of neuronal membranes, and neuronal and synaptic losses observed in AD have been related to degeneration and alteration in the composition of these membranes [ 109 ]. Brain aging associated with changes in lipid composition is well studied for treatment and prevention purposes with phospholipids such as phosphatidylcholine and phosphatidylserine that could favor cognitive improvement [ 110 ]. The OmegAD study (a set of double-blind, placebo-controlled clinical trials involving AD patients which evaluated the effects of omega-3 fatty acids (n − 3 FAs) daily supplementation in patients with mild to moderate AD) showed that after six months, DHA (1.7 g) and EPA (0.6 g) supplementation demonstrated benefits such as preservation of cognitive performance, increase in plasma and CSF (Cerebrospinal fluid) levels of n − 3 FAs, DHA and EPA (and negative correlation between DHA and total / phosphorylated tau levels in CSF), reduction in cytokine release pro-inflammatory by blood peripheral mononuclear cells (PBMC), modulation in the expression of genes involved in the regulation of inflammation in PBMC, elevation in transthyretin plasma levels (a protein that binds to AB and which may influence its deposition in the brain), and increase in body weight and BMI. However, the literature data do not support the benefits of 3-FA supplementation in preventing cognitive decline in elderly subjects [ 111 ].

Epidemiological studies have observed a relationship between serum levels of vitamin D reduction, especially 25-hydroxyvitamin D, and AD development [ 112 , 113 , 114 ]. Vitamin D is an important steroid hormone that acts on calcium metabolism and bone regulation, and has some functions in central nervous system, such as regulation of neurotrophic factors, calcium homeostasis, acts on oxidative stress mechanisms, immune system modulation and inflammation [ 115 ]. In the case of inflammation, vitamin D deficiency causes an increase in the amyloidogenic pathway due to elevation of BACE1 and APP cleavage and decrease of Aβ degradation [ 116 ]. Briones & Darwish (2012) [ 117 ] reported a BACE1 and Aβ peptide reduction after vitamin D supplementation in elderly rats. It has also been observed that vitamin D acts on macrophages in order to promote clearence of Aβ peptide [ 118 , 119 ]. In AD patients mutations were also observed in vitamin D receptor (VDR) gene, which would favor the onset of the disease [ 120 ]. To date, no large randomized clinical trial has been conducted on the effect of vitamin D supplementation on the cognition of AD patients. However, in smaller or cohort studies, the results of using high doses of vitamin D and cognitive improvement are divergent [ 121 , 122 , 123 , 124 ]. Vitamin D deficiency should be screened and supplemented in the elderly population due to its high prevalence, but this treatment is not specific for cognitive improvement.

Estrogen (hormone replacement therapy)

Estrogen roles in sex organs are well understood, but it has recently been observed that local production of estrogen plays specific roles in tissues in which it is produced, with or without dependence on circulating estrogen [ 125 ]. Estrogen, especially estradiol, is able to prevent mitochondrial dysfunction in nerve cells, neuroinflammation and assist in DNA repair mechanisms [ 126 ], thus presenting neuroprotective effect [ 126 , 127 ]. The results observed in epidemiological studies are inconsistent [ 128 , 129 ]. Some studies have not observed a beneficial effect of hormone replacement therapy, estrogen or combination therapy on the risk of developing AD [ 130 , 131 ]. Other studies reported a beneficial effect on cognition protection in women receiving hormone replacement therapy at different ages after the onset of menopause [ 132 , 133 , 134 , 135 ]. Inconsistent epidemiological findings, in addition to other factors such as increased risk of deep venous thrombosis, hormone replacement therapy is not recommended in order to prevent cognitive decline and AD development [ 136 ].

Other relevant factors and conclusion

The main pathophysiological mechanisms of AD are amyloidosis and tau-related neurodegeneration, and have specific topographical and chronological pathways. For instance, brain amyloidosis starts in neocortical regions and then affects subcortical structures [ 137 ]. On the other hand, neurodegeneration first appear on locus coeruleus and then spreads through transentorrinal area and neocortical regions [ 137 ]. Cognitive and behavioral features of AD are significantly correlated to the topographical distribution of neurofibrillary tangles.

There is great variability in topographical patterns of pathological findings in AD, causing great phenotypical variability [ 7 ], with atypical presentations of the disease [ 138 ]. It is not clear how risk and beneficial factors may modulate the topographical progression of amyloidosis and neurodegeneration.

The effects of modifiable risk factors on cross-sectional cognition have been the target of multiple WRAP (The Wisconsin Registry for Alzheimer’s Prevention) investigations. This study has investigated risk factors for AD in middle age, since this phase of life is less studied in relation to the later stages of aging. However, this is a critical time because it is when the Alzheimer’s pathology begins and thus, when its trajectory can be modified through pharmacological approaches and / or lifestyle changes. Within this context, the WRAP study, reported by Johnson et al. (2018), suggest that social engagement, physical and cognitive activities, glucose regulation, stress and sleep, in addition to cardiovascular and metabolic risks are interventional parameters that may improve brain health and reduce the likelihood and severity of AD pathology. These authors conclude that a good health and a salutary lifestyle are factors associated not only with better cognition and brain structure but also the lower AD pathophysiologic burden [ 139 ].

The studies of genetic risk factors are important to better elucidate the pathophysiological processes in the development of AD. However, such factors are not passible to any intervention until now. Faced to this scenario, modifiable risk factors such as diabetes, hypertension and dyslipidemia and others previously mentioned should be closely monitored to prevent complications favoring cognitive decline or even to improve the quality of life of patients with AD. In this context, it should also be emphasized that factors considered protective, such as physical exercise, diet and cognitive stimuli should be strongly and widely encouraged, so that such theoretically preventive measures can be adopted by the population contributing to reduce risk of this disease. Since no current drug intervention can modify the pathophysiological mechanisms related to the development of this devastating disease, adoption of these measures constitutes an important strategy for clinical management in order to prevent or postpone cognitive decline.

Abbreviations

• Alzheimer’s disease

Advanced glycation end products

Apolipoprotein E (ApoE)

Amyloid precursor protein

β-amyloid peptide

Brain Derived Neurotrophic Factor

Body Mass Index

Cerebrospinal fluid

Docosahexaenoic acid

Endothelial nitric oxide synthase

Eicosapentaenoic acid

Hypothalamic, pituitary and adrenal axis

Hazard Ratio

Insulin-Like Growth Factor

Omega-3 fatty acids

Neurofibrillary tangles

Peripheral blood mononuclear cells

Phosphorylated tau protein

Vitamin D receptor

Vascular Endothelial Growth Factor

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Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Presidente Antônio Carlos, 6627 – Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil

Marcos Vinícius Ferreira Silva, Cristina de Mello Gomide Loures, Luan Carlos Vieira Alves, Karina Braga Gomes Borges & Maria das Graças Carvalho

Faculdade de Medicina, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena, 190 - Santa Efigênia, Belo Horizonte, Minas Gerais, 30130-100, Brazil

Leonardo Cruz de Souza

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A comprehensive research setup for monitoring Alzheimer’s disease using EEG, fNIRS, and Gait analysis

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• Published: 09 August 2023
• Volume 14 , pages 13–21, ( 2024 )

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• Minhee Kim 1 ,
• Sehyeon Jang 2 ,
• Donjung Lee 3 ,
• Seungchan Lee 4 ,
• Jeonghwan Gwak 5 ,
• Sung Chan Jun 2 &
• Jae Gwan Kim   ORCID: orcid.org/0000-0002-1010-7712 1  

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Alzheimer’s disease (AD) has a detrimental impact on brain function, affecting various aspects such as cognition, memory, language, and motor skills. Previous research has dominantly used electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) to individually measure brain signals or combine the two methods to target specific brain functions. However, comprehending Alzheimer’s disease requires monitoring various brain functions rather than focusing on a single function. This paper presents a comprehensive research setup for a monitoring platform for AD. The platform incorporates a 32-channel dry electrode EEG, a custom-built four-channel fNIRS, and gait monitoring using a depth camera and pressure sensor. Various tasks are employed to target multiple brain functions. The paper introduced the detailed instrumentation of the fNIRS system, which measures the prefrontal cortex, outlines the experimental design targeting various brain functioning programmed in BCI2000 for visualizing EEG signals synchronized with experimental stimulation, and describes the gait monitoring hardware and software and protocol design. The ultimate goal of this platform is to develop an easy-to-perform brain and gait monitoring method for elderly individuals and patients with Alzheimer’s disease.

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Advancements in Measuring Cognition Using EEG and fNIRS

Emerging Non-invasive Brain–Computer Interface Technologies and Their Clinical Applications

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Acknowledgements

This work was supported by Brain Research Program, National Research Foundation of Korea (NRF-2016M3C7A1905475) and Healthcare AI Convergence Research & Development Program through the National IT Industry Promotion Agency of Korea (NIPA) funded by the Ministry of Science and ICT (No. S1601-20-1016)

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Minhee Kim & Jae Gwan Kim

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Sehyeon Jang & Sung Chan Jun

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Conceptualization: JGK, SCJ, JG; Methodology: MK, SJ, DL, SL; Formal analysis and investigation: MK, SJ; Writing–original draft preparation: MK; Writing—review and editing: MK, JGK; Funding acquisition: JGK, SCJ, JG; Supervision: JGK, SCJ.

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Kim, M., Jang, S., Lee, D. et al. A comprehensive research setup for monitoring Alzheimer’s disease using EEG, fNIRS, and Gait analysis. Biomed. Eng. Lett. 14 , 13–21 (2024). https://doi.org/10.1007/s13534-023-00306-7

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Masks Strongly Recommended but Not Required in Maryland, Starting Immediately

Due to the downward trend in respiratory viruses in Maryland, masking is no longer required but remains strongly recommended in Johns Hopkins Medicine clinical locations in Maryland. Read more .

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Research aims to uncover the mysteries of alzheimer’s disease.

Physicians often detect early warning signs of dementia in their aging patients from the stories shared by a patient’s family members. They learn about situations that are out of character, such as paying a bill multiple times, misplacing keys and repeating stories. Often a patient has become more irritable and anxious.

When the clinical examination also suggests that a longtime patient’s behavior or disposition has changed, the next step is to rule out possible causes such as medication issues, poor sleep or traumatic life events, according to Esther Oh , co-director of the Johns Hopkins Memory and Alzheimer’s Treatment Center.

“When there’s clearly some functional impairment going on, I try to figure out why,” she says. “How older patients experience cognitive problems is complex.”

If physicians suspect a patient may have mild cognitive impairment due to Alzheimer’s disease or a related brain disease, they can order a variety of labs including blood tests, MRIs and CT scans, and may refer the patient to Oh and her colleagues in psychiatry, geriatrics or neurology at the Memory and Alzheimer’s Treatment Center.

There, patients can receive individualized treatment based on their needs, including medications targeting memory and cognition and treatments for mood, behavioral and sleep changes. Additionally, patients, caregivers and family members can get guidance and support that helps improve their quality of life, plan for the future and manage inevitable crises.

Much is still unknown about the disease. At this time, there’s no cure for Alzheimer’s, no proven way of slowing down its progression and no treatment available to reverse the deterioration that occurs in the brain.

Best practices for managing the disease include physical and social activity, healthy lifestyle and diet, and a well-structured environment. Older adults who engage in these behaviors appear to have less risk of cognitive and functional decline.

While the diagnosis is grim, Johns Hopkins clinicians and researchers are broadening Alzheimer’s and dementia research and expanding treatment options in a number of ways: searching for biological markers (biomarkers) that could predict Alzheimer’s; determining how to target certain proteins that are present in the brains of patients with the disease; defining the different kinds of Alzheimer’s to tailor future treatment and research; developing new drugs; and piloting a home-based care program.

Defining and Refining

Dementia is a general term that refers to memory loss and decline of other cognitive abilities that limit independence in day-to-day function. Alzheimer’s is the most common brain disease that causes dementia among older adults, accounting for 60%–80% of cases. It affects an estimated one in nine people age 65 and older — 6.2 million Americans. This number is projected to grow to 12.7 million by 2050, according to the Alzheimer’s Association.

Almost two-thirds of the cases are in women, and people of color are at a higher risk of developing Alzheimer’s.

Alzheimer’s is a progressive, neurodegenerative disease that occurs when nerve cells in the brain die. It affects memory, thinking and behavior. But, unlike other forms of dementia, it does not affect patients’ motor function until late stages of the disease.

Alzheimer’s experts think individuals may experience different versions of the disease.

“It’s probably not one kind of Alzheimer’s disease, it’s probably many,” says psychiatrist Paul Rosenberg , co-director of the Johns Hopkins Memory and Alzheimer’s Treatment Center. “What we want to do is find the subtypes so we can find better treatments.”

Cancer treatment, for example, is specific to the kind and subtype of cancer. Breast cancer is treated differently from colon cancer, and within breast cancer, different subtypes mean different treatments. This is the direction in which Johns Hopkins researchers hope to move Alzheimer’s treatment.

Rosenberg and his colleagues, including Memory and Alzheimer’s Treatment Center director Kostas Lyketsos , are crunching data in the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease to do just that. The goal is to find characteristics that can allow physicians to predict which patients will develop Alzheimer’s, as well as determine what clinical data is necessary to differentiate subtypes of the disease.

The Precision Medicine Center’s patient registry includes more than 130,000 medical records that researchers hope can help define clinical subgroups of patients with dementia, determine when symptoms first develop and when diagnoses occur, among other factors. Additionally, center researchers are developing a collection of unique blood biomarkers that could help target future treatments to subgroups of patients.

Other projects include:

• Analyzing hundreds of MRIs from patients with dementia to look for variations in the size of different structures that could indicate subgroups.
• Studying changes in biomarkers over time to try to measure the progression of dementia.
• Using person-specific stem cells — which are made using a person’s own blood — to create different brain cells in the lab with the potential to predict response to specific medications that may have a role in improving cognitive decline.
• Treating brain vascular disease — an important contributor to dementia — by repurposing an existing drug, atorvastatin, which is typically used to lower cholesterol. Researchers are studying the drug’s effect on the brain’s circulatory system using a new MRI technique.

New Drugs in Development

Other Johns Hopkins researchers are testing a drug that has the potential to slow the progression of Alzheimer’s. Marilyn Albert , director of the Johns Hopkins Alzheimer’s Disease Research Center , Michela Gallagher , a professor of neuroscience at the Johns Hopkins University School of Medicine, and Arnold Bakker , director of the Johns Hopkins Psychiatric Neuroimaging Core , hope to receive FDA approval for the drug for patients in the earliest stages of the disease.

The drug targets two proteins: tau, which serves many functions in healthy neurons but can accumulate into tangles in cells, and amyloid, which forms plaques between cells. Gallagher theorized that periods of hyperactivity in the brain, such as seizures, push those proteins around the brain, spreading more tangles and plaques. She identified a compound, levetiracetam, that calms these hyperactive periods and is now approved by the FDA to treat seizures in patients with epilepsy when used with other medications. She and Albert are testing a time-release capsule version of levetiracetam taken at breakfast by patients in early stages of the disease.

The study , sponsored by AgeneBio , involves more than 164 people taking the drug for 78 weeks at 27 research sites across the country. Preliminary results are expected in fall 2022.

In addition to Albert and Gallagher’s drug, referred to as AGB101, there are more than 100 other Alzheimer’s drugs being tested at Johns Hopkins and elsewhere, according to the Alzheimer’s Association.

Universal Screening

As researchers wrestle with how to catch the disease in its early stages, the question of whether to do universal screening for cognitive impairment remains. Such screening is required as part of the Medicare Annual Wellness visit, initiated in 2011 as part of the Affordable Care Act. While primary care providers must perform this screening for Medicare patients, specialists at Johns Hopkins believe this kind of test can be useful in more targeted ways.

“There could be a place for targeted universal screening, but we have to be very careful,” Oh says. “The question remains, what are you going to do with that information?”

In some scenarios, screening may be appropriate, she says. For example, a patient undergoing surgery who has possible cognitive impairment could be screened in order to make sure they understand the procedure as well as post-op instructions. It could help providers manage possible complications, such as delirium after surgery, which occurs more commonly in individuals with dementia.

The Alzheimer’s Association recommends evaluation for people with memory concerns or cognitive complaints as well as for those with non-memory triggers, including personality change, depression, deterioration of chronic disease without explanation, and falls or balance issues. It is also recommended if a family member or loved one reports cognitive impairment.

Like Oh, Paul Rosenberg and Kostas Lyketsos don’t see a role for universal screening as there’s no demonstrated benefit from it.

“Until we have a safe and effective therapy that people can afford, it is just not ethical to do the tests,” Rosenberg says.

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Preventing and Treating Alzheimer's Disease and Related Dementias: Promising Research and Opportunities to Accelerate Progress: Proceedings of a Workshop—in Brief

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• Bookshelf ID: NBK603367
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In response to a request from Congress, the National Institutes of Health asked the National Academies to conduct a study to assess the current state of research on Alzheimers Disease and Related Dementias (AD/ADRD) prevention and treatment, recommend research priorities, and identify strategies for overcoming barriers that impede scientific advancement. The resulting committee held a public workshop in January 2024 to explore promising areas of research that could catalyze scientific breakthroughs or accelerate the translation of discoveries into effective prevention and treatment strategies, as well as to discuss barriers to the advancement of research. The committee final report will be released in December 2024.

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Study Suggests Genetics as a Cause, Not Just a Risk, for Some Alzheimer’s

People with two copies of the gene variant APOE4 are almost certain to get Alzheimer’s, say researchers, who proposed a framework under which such patients could be diagnosed years before symptoms.

By Pam Belluck

Scientists are proposing a new way of understanding the genetics of Alzheimer’s that would mean that up to a fifth of patients would be considered to have a genetically caused form of the disease.

Currently, the vast majority of Alzheimer’s cases do not have a clearly identified cause. The new designation, proposed in a study published Monday, could broaden the scope of efforts to develop treatments, including gene therapy, and affect the design of clinical trials.

It could also mean that hundreds of thousands of people in the United States alone could, if they chose, receive a diagnosis of Alzheimer’s before developing any symptoms of cognitive decline, although there currently are no treatments for people at that stage.

The new classification would make this type of Alzheimer’s one of the most common genetic disorders in the world, medical experts said.

“This reconceptualization that we’re proposing affects not a small minority of people,” said Dr. Juan Fortea, an author of the study and the director of the Sant Pau Memory Unit in Barcelona, Spain. “Sometimes we say that we don’t know the cause of Alzheimer’s disease,” but, he said, this would mean that about 15 to 20 percent of cases “can be tracked back to a cause, and the cause is in the genes.”

The idea involves a gene variant called APOE4. Scientists have long known that inheriting one copy of the variant increases the risk of developing Alzheimer’s, and that people with two copies, inherited from each parent, have vastly increased risk.

The new study , published in the journal Nature Medicine, analyzed data from over 500 people with two copies of APOE4, a significantly larger pool than in previous studies. The researchers found that almost all of those patients developed the biological pathology of Alzheimer’s, and the authors say that two copies of APOE4 should now be considered a cause of Alzheimer’s — not simply a risk factor.

The patients also developed Alzheimer’s pathology relatively young, the study found. By age 55, over 95 percent had biological markers associated with the disease. By 65, almost all had abnormal levels of a protein called amyloid that forms plaques in the brain, a hallmark of Alzheimer’s. And many started developing symptoms of cognitive decline at age 65, younger than most people without the APOE4 variant.

“The critical thing is that these individuals are often symptomatic 10 years earlier than other forms of Alzheimer’s disease,” said Dr. Reisa Sperling, a neurologist at Mass General Brigham in Boston and an author of the study.

She added, “By the time they are picked up and clinically diagnosed, because they’re often younger, they have more pathology.”

People with two copies, known as APOE4 homozygotes, make up 2 to 3 percent of the general population, but are an estimated 15 to 20 percent of people with Alzheimer’s dementia, experts said. People with one copy make up about 15 to 25 percent of the general population, and about 50 percent of Alzheimer’s dementia patients.

The most common variant is called APOE3, which seems to have a neutral effect on Alzheimer’s risk. About 75 percent of the general population has one copy of APOE3, and more than half of the general population has two copies.

Alzheimer’s experts not involved in the study said classifying the two-copy condition as genetically determined Alzheimer’s could have significant implications, including encouraging drug development beyond the field’s recent major focus on treatments that target and reduce amyloid.

Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai in New York, who was not involved in the study, said that patients with two copies of APOE4 faced much higher safety risks from anti-amyloid drugs.

When the Food and Drug Administration approved the anti-amyloid drug Leqembi last year, it required a black-box warning on the label saying that the medication can cause “serious and life-threatening events” such as swelling and bleeding in the brain, especially for people with two copies of APOE4. Some treatment centers decided not to offer Leqembi, an intravenous infusion, to such patients.

Dr. Gandy and other experts said that classifying these patients as having a distinct genetic form of Alzheimer’s would galvanize interest in developing drugs that are safe and effective for them and add urgency to current efforts to prevent cognitive decline in people who do not yet have symptoms.

“Rather than say we have nothing for you, let’s look for a trial,” Dr. Gandy said, adding that such patients should be included in trials at younger ages, given how early their pathology starts.

Besides trying to develop drugs, some researchers are exploring gene editing to transform APOE4 into a variant called APOE2, which appears to protect against Alzheimer’s. Another gene-therapy approach being studied involves injecting APOE2 into patients’ brains.

The new study had some limitations, including a lack of diversity that might make the findings less generalizable. Most patients in the study had European ancestry. While two copies of APOE4 also greatly increase Alzheimer’s risk in other ethnicities, the risk levels differ, said Dr. Michael Greicius, a neurologist at Stanford University School of Medicine who was not involved in the research.

“One important argument against their interpretation is that the risk of Alzheimer’s disease in APOE4 homozygotes varies substantially across different genetic ancestries,” said Dr. Greicius, who cowrote a study that found that white people with two copies of APOE4 had 13 times the risk of white people with two copies of APOE3, while Black people with two copies of APOE4 had 6.5 times the risk of Black people with two copies of APOE3.

“This has critical implications when counseling patients about their ancestry-informed genetic risk for Alzheimer’s disease,” he said, “and it also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk.”

Under the current genetic understanding of Alzheimer’s, less than 2 percent of cases are considered genetically caused. Some of those patients inherited a mutation in one of three genes and can develop symptoms as early as their 30s or 40s. Others are people with Down syndrome, who have three copies of a chromosome containing a protein that often leads to what is called Down syndrome-associated Alzheimer’s disease .

Dr. Sperling said the genetic alterations in those cases are believed to fuel buildup of amyloid, while APOE4 is believed to interfere with clearing amyloid buildup.

Under the researchers’ proposal, having one copy of APOE4 would continue to be considered a risk factor, not enough to cause Alzheimer’s, Dr. Fortea said. It is unusual for diseases to follow that genetic pattern, called “semidominance,” with two copies of a variant causing the disease, but one copy only increasing risk, experts said.

The new recommendation will prompt questions about whether people should get tested to determine if they have the APOE4 variant.

Dr. Greicius said that until there were treatments for people with two copies of APOE4 or trials of therapies to prevent them from developing dementia, “My recommendation is if you don’t have symptoms, you should definitely not figure out your APOE status.”

He added, “It will only cause grief at this point.”

Finding ways to help these patients cannot come soon enough, Dr. Sperling said, adding, “These individuals are desperate, they’ve seen it in both of their parents often and really need therapies.”

Pam Belluck is a health and science reporter, covering a range of subjects, including reproductive health, long Covid, brain science, neurological disorders, mental health and genetics. More about Pam Belluck

The Fight Against Alzheimer’s Disease

Alzheimer’s is the most common form of dementia, but much remains unknown about this daunting disease..

How is Alzheimer’s diagnosed? What causes Alzheimer’s? We answered some common questions .

A study suggests that genetics can be a cause of Alzheimer’s , not just a risk, raising the prospect of diagnosis years before symptoms appear.

Determining whether someone has Alzheimer’s usually requires an extended diagnostic process . But new criteria could lead to a diagnosis on the basis of a simple blood test .

The F.D.A. has given full approval to the Alzheimer’s drug Leqembi. Here is what to know about i t.

Alzheimer’s can make communicating difficult. We asked experts for tips on how to talk to someone with the disease .

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May 14, 2024

How to Lower Your Risk for Alzheimer’s

Genes and age play a big role in susceptibility to the disease, but choices make a difference, too

Joelle Bolt

This article was produced in partnership with the Davos Alzheimer’s Collaborative by Scientific American Custom Media, a division separate from the magazine’s board of editors.

S cientists are still learning about the causes of Alzheimer’s, but most agree that many factors contribute to an individual’s risk of getting the disease. Some risk factors, such as age and genes, are inescapable. Others can be modified with lifestyle changes, such as exercise and nutrition—in one study, participants were able to reduce their risk of getting Alzheimer’s by 60 percent. Although most risk studies focus on dementia in general, here are important findings about the known risk factors as they apply to Alzheimer’s.

Katie Peek and Joelle Bolt; Sources: Risk factor relative importance: G. Livingston et al., The Lancet , 396, 413 (2020); normal brain aging: “Alzheimer’s Disease and Other Dementias,” Mayo Clinic, 2020

This article is part of The New Age of Alzheimer’s , a special report on the advances fueling hope for ending this devastating disease.

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Research Highlights

A magnetic liquid makes for an injectable sensor in living tissue.

Fluid studded with microscopic magnetic particles can be inserted into the body and later retrieved.

Pandemic lockdowns were less of a shock for people with fewer ties

During periods of enforced isolation, life satisfaction for older adults took less of a hit in those who were already socially isolated.

Not just truffles: dogs can sniff out surpassingly rare native fungus

Daisy, a member of a breed used to find fungal delicacies, detected a critically endangered Australian fungus faster than a trained human could.

Never mind little green men: life on other planets might be purple

Bacteria that make food using a compound other than chlorophyll could paint other planets in a wide range of colours.

News in Focus

What china’s mission to collect rocks from the moon’s far side could reveal.

The Chang’e-6 mission aims to land in the Moon’s oldest and largest crater, where it will collect rocks to bring back to Earth.

First fetus-to-fetus transplant demonstrated in rats

The tissue developed into functioning kidneys and produced urine.

• Smriti Mallapaty

Superconductivity hunt gets boost from China’s $220 million physics ‘playground’

From extreme cold to strong magnets and high pressures, the Synergetic Extreme Condition User Facility (SECUF) provides conditions for researching potential wonder materials.

• Gemma Conroy

Scientists tried to give people COVID — and failed

Researchers deliberately infect participants with SARS-CoV-2 in ‘challenge’ trials — but high levels of immunity complicate efforts to test vaccines and treatments.

• Ewen Callaway

Epic blazes threaten Arctic permafrost. Can firefighters save it?

Some scientists argue that it’s time to rethink the blanket policy of letting blazes burn themselves out in northern wildernesses.

• Jeff Tollefson

How reliable is this research? Tool flags papers discussed on PubPeer

Browser plug-in alerts users when studies — or their references — have been posted on a site known for raising integrity concerns.

• Dalmeet Singh Chawla

‘ChatGPT for CRISPR’ creates new gene-editing tools

Some of the AI-designed gene editors could be more versatile than those found in nature.

Dark energy is tearing the Universe apart. What if the force is weakening?

The first set of results from a pioneering cosmic-mapping project hints that the repulsive force known as dark energy has changed over 11 billion years, which would alter ideas about how the Universe has evolved and what its future will be.

• Davide Castelvecchi

Hacking the immune system could slow ageing — here’s how

Our immune system falters over time, which could explain the negative effects of ageing.

• Alison Abbott

Books & Arts

Book review, smarty plants controversial plant-intelligence studies explored in new book.

A deep dive into plant behaviour and consciousness asks why the topic has been taboo for so long, and whether botanists are changing their minds about plants’ cognitive abilities.

• Beronda L. Montgomery

How rich is too rich?

Where should society draw the line on extreme wealth? A fresh account sets out the logic and suggests how to redress inequality.

• Lucas Chancel

From multiverses to cities: Books in brief

Andrew Robinson reviews five of the best science picks.

• Andrew Robinson

Allen J. Bard obituary: electrochemist whose techniques underpin clinical diagnostics, materials discovery and more

Innovator who pioneered scanning electrochemical microscopy, bioassays and solar fuels.

• Michael Rose
• Henry S. White

Correspondence

Beware of graphene’s huge and hidden environmental costs.

• Qingyuan Ding

Japan can embrace open science — but flexible approaches are key

Countering extreme wildfires with prescribed burning can be counterproductive.

• David Lindenmayer
• Philip Zylstra

Finding millennia-old ‘monumental’ corals could unlock secrets of climate resilience

• Simone Montano
• Federica Siena
• Giovanni Strona

Hunger on campus: why US PhD students are fighting over food

Graduate students are relying on donated and discounted food in the struggle to make ends meet.

• Laurie Udesky

Technology Feature

Powerful ‘nanopore’ dna sequencing method tackles proteins too.

Latest methods bring the speed, portability, and long read lengths of nanopore sequencing to proteomics.

• Caroline Seydel

Collection:

Where I Work

I make 3d models of conifer needles to explore their climate effects.

Jan Pisek seeks a better understanding of how forests absorb sunlight, carbon and heat.

• Nic Fleming

News & Views

Ancient dna traces family lines and political shifts in the avar empire.

Genetic pedigrees spanning nine generations uncover the social organization of a nomadic empire that dominated much of central and eastern Europe from the sixth to the early ninth century.

• Lara M. Cassidy

Vibration isolation could boost performance of near-infrared organic LEDs

The development of high-performance organic LEDs and other devices that emit near-infrared light has been hindered by seemingly fundamental features of the light-emitting molecules. A potential solution has been identified.

• Margherita Maiuri

Streamlined skull helps foxes take a nosedive

Some fox species leap up and pounce head first into snow to capture prey that they hear below the surface. An analysis of the forces involved reveals how the shape of the skull has evolved to minimize damage from this behaviour.

• Mary Abraham

Coupled neural activity controls working memory in humans

How does the human brain temporarily store information without losing track of it? Neuroscientists have discovered that neurons in the frontal and temporal lobes work together to hold information in working memory.

• Ziv Williams

Bioengineered ‘mini-colons’ shed light on cancer progression

Cells grown on a 3D scaffold have generated a ‘mini-colon’ that mimics key features of the organ. Controlled expression of cancer-associated genes in the system offers a way to examine tumour formation over space and time.

• Nicolò Riggi
• Felipe de Sousa e Melo
• Cancer at Nature Portfolio

Perspective

The refinery of the future.

Efforts to find renewable alternatives to fossil fuels that might enable a carbon-neutral society by 2050 are described, as well as outlining a possible roadmap towards a refinery of the future and evaluating its requirements.

• Eelco T. C. Vogt
• Bert M. Weckhuysen

Venus water loss is dominated by HCO + dissociative recombination

Water loss to space late in Venus history is shown to be more active than previously thought, with unmeasured HCO + dissociative recombination dominating present-day H loss.

• M. S. Chaffin
• E. M. Cangi

An atomic boson sampler

Boson sampling using ultracold atoms in a two-dimensional, tunnel-coupled optical lattice is enabled by high-fidelity programmable control with optical tweezers of a large number of atoms trapped in an optical lattice.

• Aaron W. Young
• Shawn Geller
• Adam M. Kaufman

Observation of Nagaoka polarons in a Fermi–Hubbard quantum simulator

Emergence of Nagaoka polarons and kinetic magnetism is observed in a Hubbard system realized with strongly interacting fermions trapped in a triangular optical lattice.

• Martin Lebrat
• Markus Greiner

Directly imaging spin polarons in a kinetically frustrated Hubbard system

A triangular-lattice Hubbard system realized with ultracold atoms is used to directly image spin polarons, revealing ferromagnetic correlations around a charge dopant, a manifestation of the Nagaoka effect.

• Max L. Prichard
• Benjamin M. Spar
• Waseem S. Bakr

All-optical subcycle microscopy on atomic length scales

All-optical subcycle microscopy is achieved on atomic length scales, with picometric spatial and femtosecond temporal resolution.

Multi-project wafers for flexible thin-film electronics by independent foundries

The iconic 6502 microprocessor designed in two key thin-film transistor technologies by independent foundries is used to demonstrate and expand the multi-project wafer approach for flexible electronics.

• Hikmet Çeliker
• Wim Dehaene

Chemical short-range disorder in lithium oxide cathodes

The introduction of chemical short-range disorder substantially affects the crystal structure of layered lithium oxide cathodes, leading to improved charge transfer and structural stability.

• Zhenpeng Yao
• Chenglong Zhao

Growth of diamond in liquid metal at 1 atm pressure

Diamond crystals and polycrystalline diamond films can be grown using liquid metal at standard pressure and high temperature instead of conventional high pressure and high temperature.

• Rodney S. Ruoff

Decoupling excitons from high-frequency vibrations in organic molecules

A molecular design strategy for reducing the vibration-induced non-radiative losses in emissive organic semiconductors is realized by decoupling excitons from high-frequency vibrations.

• Pratyush Ghosh
• Antonios M. Alvertis

Copper-catalysed dehydrogenation or lactonization of C( sp 3 )–H bonds

Use of N -methoxyamides as oxidants enables controllable, redox-neutral, green catalysis of bimodal dehydrogenation/lactonization reactions with methanol as the only by-product.

• Shupeng Zhou
• Zi-Jun Zhang
• Jin-Quan Yu

Ghost roads and the destruction of Asia-Pacific tropical forests

An effort to map roads in the Asia-Pacific region finds that there are 3.0–6.6 times more roads than other sources suggest, and that unmapped ‘ghost roads’ are a major contributor to tropical forest loss.

• Jayden E. Engert
• Mason J. Campbell
• William F. Laurance

Network of large pedigrees reveals social practices of Avar communities

Analysis of ancient DNA from 424 individuals in the Avar period, from the sixth to the ninth century AD, reveals population movement from the steppe and the prolonged existence of a steppe nomadic descent system centred around patrilineality and female exogamy in central Europe.

• Guido Alberto Gnecchi-Ruscone
• Zsófia Rácz
• Zuzana Hofmanová

Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain

Using mosaic variant barcode analysis, clonal dynamics of specific cell types are deconvolved in the human forebrain.

• Changuk Chung
• Xiaoxu Yang
• Joseph G. Gleeson

Control of working memory by phase–amplitude coupling of human hippocampal neurons

Hippocampal theta–gamma phase–amplitude coupling integrates cognitive control and working memory storage across brain areas in humans.

• Jonathan Daume
• Jan Kamiński
• Ueli Rutishauser

Control of neuronal excitation–inhibition balance by BMP–SMAD1 signalling

Signalling by the developmental morphogen BMP2 through the transcription factor SMAD1 has a key role in controlling the glutamatergic innervation of parvalbumin-expressing interneurons and maintaining the balance between excitation and inhibition in the mammalian cortex.

• Zeynep Okur
• Nadia Schlauri
• Peter Scheiffele

DNA glycosylases provide antiviral defence in prokaryotes

A screen utilizing an environmental DNA library in Escherichia coli is used to identify Brig1, a previously unknown anti-phage defence system with homologues across distinct clades of bacteria.

• Amer A. Hossain
• Ying Z. Pigli
• Luciano A. Marraffini

PGE 2 limits effector expansion of tumour-infiltrating stem-like CD8 + T cells

Tumour-derived prostaglandin E 2 , signaling through its receptors EP 2 and EP 4 , is shown to restrain the responses of tumour-infiltrating stem-like TCF1 + CD8 + T lymphocytes, and modulation of T cell EP 2 and EP 4 can restore anticancer immunity.

• Sebastian B. Lacher
• Janina Dörr
• Jan P. Böttcher

PGE 2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function

Prostaglandin E2 from the tumour microenvironment impairs interleukin-2 sensing by tumour-infiltrating lymphocytes, restricting proliferative response and promoting T cell death via metabolic impairment and ferroptosis. 

• Matteo Morotti
• Alizee J. Grimm
• George Coukos

Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase

VVD-133214, a clinical-stage, covalent allosteric inhibitor of the helicase WRN, was well tolerated in mice and led to robust tumour regression in multiple microsatellite-instability-high colorectal cancer cell lines and patient-derived xenograft models.

• Kristen A. Baltgalvis
• Kelsey N. Lamb
• Todd M. Kinsella

Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers

HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation.

• Stephane Ferretti
• Jacques Hamon
• Marta Cortés-Cros

Spatiotemporally resolved colorectal oncogenesis in mini-colons ex vivo

Topobiologically complex mini-colons—which enable the faithful in vitro recapitulation of colorectal cancer tumorigenesis and its environmental determinants—offer the possibility to reduce animal use in a wide range of experimental applications.

• L. Francisco Lorenzo-Martín
• Tania Hübscher
• Matthias P. Lutolf

Single-cell analysis reveals context-dependent, cell-level selection of mtDNA

A new method for tracking single-cell heteroplasmy, called SCI-LITE, is combined with mitochondrial DNA base editing to reveal principles of heteroplasmy dynamics in dividing cells.

• Anna V. Kotrys
• Timothy J. Durham
• Vamsi K. Mootha

Structures and activation mechanism of the Gabija anti-phage system

Structures of complexes containing GajA and GajB proteins of the prokaryotic Gabija anti-phage defence system reveal the mechanism of its activation after DNA cleavage upon ATP depletion.

• Longfei Wang

Ligand efficacy modulates conformational dynamics of the µ-opioid receptor

Studies on the µ-opioid receptor using fluorescent labelling of intracellular residues and energy transfer experiments in the presence of different ligands with or without G-protein binding reveals conformational changes that correlate to ligand efficacy.

• Jiawei Zhao
• Matthias Elgeti
• Chunlai Chen

Promiscuous G-protein activation by the calcium-sensing receptor

Structures of the human calcium-sensing receptor can be bound into complex with G proteins from three different Gα subtypes while maintaining G-protein-binding specificity.

• Jinseo Park
• Qing R. Fan

Amendments & Corrections

Author correction: targeting swi/snf atpases in enhancer-addicted prostate cancer.

• Abhijit Parolia
• Arul M. Chinnaiyan

Author Correction: Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia

• Dwight Koeberl
• Andreas Schulze
• Stephanie Grunewald

Publisher Correction: FOXO1 is a master regulator of memory programming in CAR T cells

• Alexander E. Doan
• Katherine P. Mueller
• Evan W. Weber

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