A strategy to prevent a disease is to determine the primary cause of that disease. In the case of Alzheimer’s disease (AD), there are two main types: familial AD (FAD) and sporadic AD (SAD). It is mainly assumed that the primary cause for FAD is the presence of mutations in some genes like presenilin 1 (PSEN1), presenilin 2 (PSEN2) , precursor of beta amyloid peptide (APP) [1] and, probably, sortilin related receptor 1 (SORL1) [2, 3] that could favor the presence of beta amyloid (Aβ) peptide aggregates, being that presence the first step for AD development. In this way, FAD could be similar to other neurodegenerative disorders, like Huntington’s disease (HD), that results from a genetic mutation [4]. However, even assuming that it was the primary cause, there is not suitable therapies for FAD or HD.

For FAD, the great majority of the cases are the consequences of PSEN1 gene mutations and it has been described that those PSEN1 mutations may produce alterations appearing in the brain previously to Aβ over-production, in a mouse FAD model [5]. Thus, the presence of Aβ could not be the first step in FAD due to mutated PSEN1. Nevertheless, the prevalent view is that in FAD, the increase in Aβ is a very early factor in the development of the disease and that it could be, also, for SAD (amyloid hypothesis) [6].

However, in SAD, there are other additional hypotheses suggesting primary causes for the disease [7]. Examples of those hypotheses are: cholinergic [8], calcium [9], oxidative stress [10], neuron inflammation [11], microbial (viral) infections [12], glucose hypometabolism [13] or the presence of an excess of tau aggregates [14], among others.

On the other hand, the main risk factor for SAD is aging [15] and healthy longevity could prevent the appearance of SAD.

Aging can be observed at different levels: the whole organism, organs (or tissues), cellular, and molecular levels. At cellular level, after the cells become old could be an additional step, senescence, with the senescence-associated secretion phenotype (SASP) [16] in which senescent cells could secrete toxic substances to the surrounding cells, with or without the same origin. Thus, the presence of a tissue with senescent cells could facilitate the toxicity and aging of neighboring tissues. Recently, it has been described an example, showing that skin cell aging drives age related bone loss via secreted cystatin A [17], or that knee osteoarthritis (OA), in old people, may accelerate Aβ deposition and neurodegeneration in the central nervous system (CNS) [18], although the presence of the brain blood barrier (BBB) may difficult the crossing of secreted compounds from the periphery to CNS. In any way, it has been proposed that AD may be a multiorgan disorder [19].

In addition to being a neurodegenerative disorder, AD pathology may include immune system dysfunction [20], inflammation, dysbiosis, insulin resistance, heart problems, kidney, and hepatic dysfunction, among others [19].

However, the main pathology is related to CNS disorders and the disorders in other tissues and organs may be used, or not, as putative biomarkers of the disease, although further work should be done to know if those peripheral disorders are cause or consequence of the CNS.

The most well-known neuronal hallmarks in AD are senile plaques [21] and neurofibrillary tangles [22], coming from two proteins, APP and tau protein, mainly expressed in neurons [23–25]. In addition, glia cells, present in CNS, may play an important role in the development of AD. In this way, microglia can have harmful actions in AD [26]. Activated microglia or disease associated microglia (DAM) with the new nomenclature [27] may be one of the key factors involved in the neuroinflammation found in AD [28]. Also, the activation of microglia could be the consequence of a change in the cross-talking neuron-resting microglia [29] and could be the consequence of microglia change of status specific features found in AD mouse models. Parabiosis experiments in mouse models indicate that microglia account for the increased myeloid cell number observed in brains with plaque pathology [30]. Additionally, astrocytes may also play a role in neuroinflammation [31].

AD is a CNS disorder but it could correlate with some changes in the peripheral nervous system (PNS) that could be used as biomarkers of the disease. An example is the lower degree of pain observed in AD patients [32].

About peripheral biomarkers, in human fluids, in addition to looking at the levels of Aβ or tau protein in cerebral spinal fluid (CSF) [33, 34], other peripheral fluids, like plasma, saliva, or urine, have been used as possible markers of compounds, like proinflammatory cytokines, or others, that could be altered in AD patients [35]. The kinetics for the appearance of these markers could be important since earlier markers could facilitate the earlier prevention of the disease [35].

Briefly, it will be described some peripheral features that are present in AD patients or in models for the disease, although, probably, in many cases the features could be more the consequence than the cause, that facilitate the development of the disorders. On the other hand, the use of palliative pharmacological treatments, for the disease, could result in damage to organs like kidney or liver.

Here, it is commented on the possible relation of AD development with seven different organs: heart, blood, gut, muscle, bone, kidney, and liver (Figure 1). Although other organs like lungs have been suggested to get a link with dementia [36], little is known about molecular factors involved in that interaction and they are not mentioned here.

Actually, the main targets for AD therapies are the components of senile plaques, Aβ peptide aggregates; or the component of neurofibrillary tangles, tau protein, since the amyloid [6] and tau protein [14] hypothesis are now the most popular hypothesis for AD development. Mainly, antibodies against Aβ aggregates have been tested, as a possible therapy for amyloid pathology. Although some of those antibodies like aducanumab or lecanemab have been raised some good expectations, no suitable results were obtained and, in addition, some side effects, like cerebral hemorrhages, were found in some treated patients [87]. More recently, it has been also indicated an accelerated brain volume loss is caused by these anti Aβ drugs [88]. Indeed, almost all of clinical trials for AD have failed to show positive results as indicated in the commentary “The long road to a cure for AD is paved with failures” recently published in Nature Medicine [89], discussing the last data in clinical trials for multiple targets like Aβ, tau, inflammation components, and other ones, see also [90]. Also, Aβ and tau have been mainly used as early biomarkers for AD, looking at fluids like CSF, or blood, see for example [91]. Also, from glia (microglia) cells, triggering receptor expressed on myeloid cells 2 (TREM2) level could be associated with the transition from mild cognitive impairment to dementia, during the development of the AD continuum process [92].

On the other hand, it has been discussed why successful results have been obtained in animal models but not in humans [93]. Also, some compounds that could result in a neurodegeneration or cognitive improvement have been proposed as possible palliative therapies [94].

The use of other compounds related to some features found in AD has been reported. For example, the small compound “simufilam”, a stabilizer of filamin A [95], has been proposed as a possible therapy for AD, although that use is under discussion [96].

Now, new targets or new early biomarkers for AD are being looked for. About new possible biomarkers for AD, from the periphery, some examples related to blood are included. A possible link between platelet biomarkers and cognitive functions has been proposed [97] and between plasma β₂ microglobulin and N-methyl-D-aspartate (NMDA) receptors, since β₂ microglobulin could act as an antagonist for NMDA receptors, resulting in cognitive impairment [98]. Also, related to blood, associations of plasma cluster of differentiation 22 (CD22) level with cognitive decline in AD have been reported [99].

Biomarkers in other fluids like saliva and urine, for AD diagnosis, have been also proposed. Since chronic stress is a risk factor for the disease, the level of cortisol (related to stress) could be used as a prodromic marker for the AD continuum process [100]. Additionally, as indicated in kidney section, the presence of formic acid in urine could be used as a possible marker for dementia [81].

This brief review is mainly focused on the contribution of peripheral tissues in AD development, although, in many cases, the observed peripheral pathology could be more the consequence than a possible cause for AD.

It is well-known that changes in life style, or improving the quality of nutrition, could result in a decrease in the incidence of AD development [101, 102]. Treatment of risk factors like hypertension or diabetes or playing physical exercise could retard the appearance of dementia, decreasing the fast progression of AD at world level [103]. Additionally, since aging is the main risk factor for neurodegenerative disorders, a possible therapy to reprogram (rejuvenate) old into young neurons has been proposed [104]. Also, the presence of senescent cells, like senescent astrocytes, with SASP, may contribute to an increase in Aβ aggregation or tau phosphorylation [105] and, in that way, the use of senolytic drugs has been proposed in clinical trials for AD [106]. Other possible therapeutical ways could be based on microbiota changes, since it has been suggested that the presence of some bacteria in the gut of aged people may contribute to AD progression [107, 108], affecting Aβ pathology. However, although Aβ accumulation is a factor for AD pathogenesis, in the absence of tau, its presence is insufficient for cognitive decline. Now, it has been described on microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy, being that effect modulated by ApoE4 isoform [60]. In that way, reshaping or eliminating gut microbiota may decrease the progression of neurodegeneration.

About new biomarkers, from the periphery, testing the level of formic acid in patients’ urine [81] or measuring the lower degree of pain, related to PNS, observed in subjects with mild cognitive decline, previous to dementia onset, could be suggested [32].

Thus, to get a whole picture of the clinical features of a patient, at the early phases of AD continuum, the suggested Alzheimer’s precision medicine initiative could be a good approach to retard the progression of AD [109]. Nevertheless, more work should be done to look for modifiers of the disease that may prevent, decrease or stop the development of the disease.