Alzheimer’s disease (AD; named after the German psychiatric Alois Alzheimer) is a type of dementia which can be defined as a gradual progressive neurodegenerative disease characterized by neuritic plaques and neurofibrillary tangles (NFTs) which results in the accumulation of amyloid-beta peptide’s (Aβ’s) in the most affected area of the brain, the medial temporal lobe and neocortical structures [1]. It is a neurodegenerative condition that arises in two forms: an early-onset familial form and a sporadic late-onset form called late-onset AD (LOAD). In the familial early-onset form of the disease, patients at first display minor memory loss but then progress to major cognitive dysfunction, which is prevalent among adults aged 45–64. The late-onset form includes motor difficulties, language problems, behavioral disorders, severe memory loss, and paranoia and occurs in elderly more than 65 years of age [2–6]. Genetic influence plays an important role in the early-onset form of AD and rarely occurs (5% of cases). The most common form is the late-onset form which has been identified in more than 95% of all AD cases, and its genetic determination remains questionable, however, the research is going on, unraveling the genetic networks underlying LOAD. It has a multifactorial etiology with no obvious simple (mendelian) genetic determinants, yet, the risk of developing LOAD could be, in some cases, significantly influenced by genetics [7]. The well-accepted risk factor for disease development in the LOAD is the possession of the ɛ4 allele at the apolipoprotein E (APOE) locus on human chromosome 19. Not all individuals possessing the ɛ4 allele at the APOE locus will develop LOAD, but its presence increases the risk for disease development, promotes the earlier onset of symptoms, and facilitates rapid progression. In particular, individuals homozygous for the ɛ4 allele type are at high risk for disease development [8, 9]. As AD is characterized by neuritic senile plaques (NSP) and NFT, the diagnosis of LOAD comes from post-mortem examination of the density of NSP and NFT, and the overall neuronal death in the affected brain regions including the frontal and temporal lobes [10].

Advanced age and female sex are the two major risk factors for LOAD [11]. Aging comes with natural cellular senescence, decreasing the neuronal and glial cell populations, and leading to the neurodegenerative condition. Aging-associated cellular senescence is the consequence of the activation of apoptotic molecular machinery due to oxidative stress or mitochondrial dysfunction [12]. Oxidative stress generates reactive oxygen species from the oxidation of biomolecules and is considered the major cause of progressive aging, including both physical and mental aging [13]. Mitochondrial dysfunction is associated with the disruption in ATP production and apoptosis regulation, and these defects in mitochondrial dynamics can lead to irreversible damage to neuronal cells [14]. Hence, multiple pathways are involved in cell death during natural aging, and another phenomenon that impacts natural aging is epigenetic alterations while aging. Very few studies have been conducted considering how natural aging shapes the epigenome and vice versa. The epigenetic changes associated with aging have gained much attention in the aging biomarker research field [15]. Alterations of the epigenetic mechanisms (including DNA methylation, histone modifications, and non-coding RNAs) affect most nuclear processes, such as gene transcription and silencing, DNA replication and repair, and cell cycle progression, affecting natural aging. Recent studies have shown rapid, dynamic, and persistent epigenetic modifications in neurons and in neurodegenerative diseases [16–18]. DNA methylation patterns are largely remodeled during aging [16], where a trend toward global loss of DNA methylation with hypermethylation at specific loci is observed [17]. Although with some differences among brain regions, age-associated epigenetic changes interest the brain also, likely contributing to the structural and functional alterations that can result in progressive cognitive decline and increased susceptibility to neurodegenerative disorders including LOAD [18]. Non-epigenetic mechanisms including telomere shortening and immunosenescence are also involved in accelerated cellular aging and contribute to the LOAD development in the elderly [19].

Aging is the irreversible physiological process linked to the lifespan of cells and the body and is the primary cause of age-related diseases. Several biological mechanisms mediate aging and its primary feature is the accumulation of cellular senescence driven on by harmful stimuli from both inside and outside the cell [20, 21]. When determining the aging phenotype, nine criteria and associated potential markers are typically taken into account, including genomic instability, reduced telomere length, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, cellular senescence, stem cell exhaustion, mitochondrial dysfunction, and altered intercellular communication. These factors are based on the research of many different types of species, particularly mammals [21]. One of the most accepted factors of aging is the genomic instability that occurs due to the accumulation of genetic damage from time to time and causes interference with cellular homeostasis [22]. Another factor i.e. shortening of telomere length observed in naturally aging cells, however, due to detrimental external or internal stimulus, cells might undergo accelerated telomere shortening, which gives rise to cellular senescence [23–25]. Cellular senescence is a critical aging factor and is characterized by cell cycle arrest. The senescent cells are presented with senescence-related secreted phenotype and result from DNA damage [20, 26]. Another factor i.e. epigenetic mechanisms are the key regulators of cellular functioning; however, with aging the epigenetic machinery might lose its control giving rise to age-related defects [27]. The disturbance in protein homeostasis is linked to the onset of aging and the majority of aging-related illnesses. Aging is characterized by altered post-translational modification, and protein aggregation [28]. The disruption in the endoplasmic reticulum (ER) homeostasis leads to protein aggregation and causes ER stress. The ER stress response can be seen to increase with aging due to several factors like hyperhomocysteinemia, lack of glucose or energy, redox changes, disruption of calcium homeostasis, and others [29]. The protein degradation machinery in the cells i.e. autophagy and proteasome mediated degradation is widely hampered with aging [30, 31]. Nutrient sensing is the cell’s ability to identify and respond to the nutrient in the body, insulin/insulin growth factor-1 (IGF-1) signaling is one of the pathways involved in this process and is known to regulate aging and aging-related disease [32]. Another crucial aspect of aging is the decline in the capacity of tissues and organs to regenerate [33]. A number of age-related disorders are caused by inflammation, that occurs due to mitochondrial dysfunction, which also increases the formation of reactive oxygen species, lowers ATP levels, promotes apoptosis, and causes defects in the respiratory chain [34, 35]. The regulation of neuroendocrine, endocrine, and neuronal levels via cellular communication is another significant factor in the aging process [36]. Renin-angiotensin, adrenergic, and insulin/IGF1 signaling are the neurohormonal signaling that mediates aging when inflammatory responses rise and the immunosurveillance environment changes in the cell [37]. The molecular mechanisms can be targeted to reduce the risk of age related diseases including LOAD.

A naturally aging brain undergoes significant changes in activity, however, the evident structural changes are near to negligible, and the LOAD and AD brain shows significant atrophy in different brain regions with aging [38, 39]. Neuronal loss is significant in AD, while the number of neurons does not change in healthy aging brains [40]. Brain atrophy in LOAD is positively correlated with cognitive impairment in LOAD patients, which is attributed to neuronal cell death, shrinkage of neurons, and axonal damage [38, 39]. Another factor that is commonly observed even in the natural aging and cognitive fit brain is NFTs [41], however, in LOAD patients the abundance and localization of NFTs are strongly correlated with neurodegeneration [42, 43]. Although significant structural changes like NFTs deposition in the brain with aging could cause LOAD’s development, other factors might also play a significant role in initiating the neurodegenerative process. One such factor is declining neurotransmission, which is affected by altered dendritic morphology, reduced spine density, and spine volume with natural aging and in LOAD. These complications are associated with age-related deficits in learning and memory formation commonly seen in elderly people [42, 43]. The cholinergic system is most commonly studied in classical AD and cognition impairment is also associated with cholinergic degeneration with aging. LOAD is also associated with cholinergic degeneration presented with reduced choline acetyltransferase (CHAT) activity, total acetylcholine levels, and reduced receptor binding [42, 43]. CHAT activity can be influenced by gene polymorphisms and is majorly associated with AD etiopathogenesis [44]. Hence the neurotransmission is vividly affected in natural aging but intensely deteriorated in LOAD.

Oxidative damage in cells is another driving force of aging. The free radical theory of aging states that the constant buildup of reactive oxygen species for an organism’s life results in cellular senescence and aging of the organism [45]. Increased oxidative stress in the brain is another factor that may act as the critical threshold for LOAD development in the naturally aging brain. Increased oxidative stress and lipid peroxidation is observed in LOAD patients [46, 47]. Oxidative damage can also give rise to DNA damage leading to mutations. Mitochondrial mutations are well reported with aging and aging-related diseases [46, 47], but an increased number of nuclear mutations and mitochondrial mutations have been reported in LOAD [48]. One such mutation identified is CD36 gene mutations that are linked with delaying the onset of AD by eight years. CD36 is involved in Aβ clearance by phagocytosing microglia and is involved in reactive oxygen species production and cytokine production [49]. Therefore, alterations in brain morphology, functioning, and oxidative damage are increased extensively in LOAD brain giving rise to mutations and epimutations.

Epigenetics is the study of heritable changes in the genome environment leading to variations in gene expression without altering the DNA sequence, hence inducing a phenotypic change in organisms [50]. Three major epigenetic mechanisms involved in cellular regulation include DNA methylation, histone modifications, and non-coding RNA-mediated regulation. These epigenetic mechanisms following random occurrences and environmental influence have been identified as contributors to the aging phenotype. Numerous studies have suggested that due to the higher occurrence of epigenetic alterations compared to genetic mutations, epigenetic alterations might be predominantly associated with age-related phenotypes [51, 52]. Epigenetic alterations might be tolerated to a certain degree, however, after a certain threshold these might lead to organ dysfunction and accelerated cellular aging, as illustrated in Figure 1. It is suggested by Wang et al. [53] suggested that every individual is predisposed to have AD at a certain time point after crossing the threshold of epigenetic deregulation and that LOAD can be presented as the extreme form of aging with epigenetic alterations in the brain. Epigenetic markers, including DNA methylation, histone modifications, and non-coding RNAs served as the critical factors in regulating brain physiology and pathology of several neurodegenerative diseases, including AD as well as aging [54].

The impact of epigenetic alterations can become more prominent with aging due to the progressive weakening of epigenetic control on several physiological processes. Despite the old age, the epigenetic machinery can also be affected from as early as an embryonic stage or from the transgenerational effects i.e. the epigenetic events experienced by the parents. One study reported that the lead exposure to rat pups and cynomolgus monkeys during the early postnatal period resulted in the overexpression of Aβ precursor protein (APP) and overproduction of amyloidogenic Aβ in older life, proving that the environmental conditions during the early age might impact the disease pathology later in the life [112]. Another factor that significantly influences epigenetics is the lifestyle and dietary habits of the individual. The diet composition and inclusion of essential vitamins and omega-3 fatty acid helps regulate epigenetic mechanisms, while the sedentary lifestyle hampers the same [51].

Another common epigenetic alteration seen in LOAD patients is an aberrant one-carbon methylation metabolism, which is indicated by increased total Hcy and low folate concentrations. Studies have demonstrated that an increase in plasma Hcy levels occurs before dementia develops and that there is an inverse linear relationship between plasma Hcy concentrations and cognitive function in elderly individuals [113]. The reduction in the levels of S-adenosylmethionine, which plays a critical role in the methylation of DNA and histones, was also reported in AD patients [114]. Altogether these findings suggest a disruption in epigenetic pathways before the manifestation of major LOAD phenotypes. Another factor i.e. MTHFR polymorphism has been reported in a large number of AD patients, including LOAD cases and ultimately resulting in severe MTHFR deficiency and hyperhomocysteinemia. Elevated total Hcy levels (> 14 μmol/L) in elderly individuals is a well-established risk factor of LOAD and cognitive deficit [115]. Low folate levels and vitamin B₁₂ deficiency throughout life reportedly have a direct correlation with increasing incidence of cognitive impairment in the elderly population and have been considered as the major contributors to the development of LOAD [113].

The occurrence of aberrant chromatin and altered histone regulation in AD is a further poorly understood phenomenon. AD patients reportedly had reduced condensation of constitutive heterochromatin region of chromosomes 1, 9, and 16 compared to the healthy subjects [116]. This study also suggested age-dependent chromosomal anomalies selectively in the region of APOE in AD patients. In addition to the genetic and environmental effects, the epigenetic variability among individuals is also a strong determinant or the risk factor in the occurrence of LOAD as suggested by Wang et al. [53]. An array of epigenetic markers and interindividual variations can affect LOAD predisposition and disease severity.

LOAD is extensively associated with aging-related dementia, and the lack of biomarkers makes it challenging to find selective targets to reduce the disease burden in the elderly. However, the advanced technologies in the field of genetics and bioinformatics in the past decade have made it easier to linearize the pathophysiology of LOAD. Epigenome being affected by a sedentary lifestyle is associated with cellular stress and accelerated cellular aging, a well-established risk factor in LOAD development. Research findings confirm the significant disruption in epigenetic regulation with age progression and can certainly be used as early biomarkers to identify individuals at higher risk of having LOAD. As discussed in earlier sections, every individual can develop LOAD, as it is the aggravated form of aging associated with cognition deficit and epigenomic alterations, however maintaining a proper lifestyle with healthy dietary habit can make one less susceptible to LOAD and associated comorbidities. The lack of animal models selectively for LOAD to study the molecular pathways and the link of aging with cognition decline is another major setback to tackle, however, the advancements in three-dimensional (3D) organoid models can easily overcome this research gap.