Mechanistic insights into the pathogenesis of neurodegenerative diseases: towards the development of effective therapy

Abstract

Neurodegeneration is a prevalent and one of the emerging reasons for morbidity, mortality, and cognitive impairment in aging. Dementia is one of such conditions of neurodegeneration, partially manageable, irreversible, and worsens over time. This review is focused on biological and psychosocial risk factors associated with Alzheimer’s and Parkinson’s diseases, highlighting the value of cognitive decline. We further emphasized on current therapeutic strategies from pharmacological and non-pharmacological perspectives focusing on their effects on cognitive impairment, protein aggregation, tau pathology, and improving the quality of life. Deeper mechanistic insights into the multifactorial neurodegeneration could offer the design and development of promising diagnostic and therapeutic strategies.

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Molecular and Cellular Biochemistry
https://doi.org/10.1007/s11010-021-04120-6
Mechanistic insights intothepathogenesis ofneurodegenerative
diseases: towardsthedevelopment ofeffective therapy
FauziaNazam1· SibhghatullaShaikh2· NaziaNazam3· AbdulazizSaadAlshahrani4· GulamMustafaHasan5· Md.
ImtaiyazHassan6
Received: 19 December 2020 / Accepted: 23 February 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Abstract
Neurodegeneration is a prevalent and one of the emerging reasons for morbidity, mortality, and cognitive impairment in
aging. Dementia is one of such conditions of neurodegeneration, partially manageable, irreversible, and worsens over time.
This review is focused on biological and psychosocial risk factors associated with Alzheimer’s and Parkinson’s diseases,
highlighting the value of cognitive decline. We further emphasized on current therapeutic strategies from pharmacological
and non-pharmacological perspectives focusing on their effects on cognitive impairment, protein aggregation, tau pathol-
ogy, and improving the quality of life. Deeper mechanistic insights into the multifactorial neurodegeneration could offer the
design and development of promising diagnostic and therapeutic strategies.
Keywords Alzheimer’s disease; Parkinson’s disease· Therapeutic management· Neurodegenerative diseases·
Neurodegeneration
Introduction
Dementia is a chronic disorder of cognitive decline charac-
terized by deterioration of memory, thinking, behavior, and
normal physical activities [1]. It affects learning, memory,
comprehension, calculation, language, reasoning, and atten-
tion. Yet consciousness remains unaffected and the most
affected ones are elder people [2]. Undoubtedly, with the
progressive aging population of modern society, age-related
disorders have become predominant. Compelling evidence
of the aging population indicates that the number of demen-
tia cases would increase rapidly to over 150 million by 2050,
creating a major public health and social challenge (https ://
www.who.int/news-room/fact-sheet s/detai l/demen tia).
Neurodegenerative diseases (ND) comprise a range of
disorders mainly affecting the neurons in the human brain
[3, 4]. Alzheimer’s disease (AD) is the most familiar basis
of dementia, responsible for an estimated 60–80% of total
cases. Parkinson’s disease (PD) remains the second most
prevalent ND affecting over 6.1 million people [5]. Although
PD is principally a motor disorder, it is consistently associ-
ated with dementia. A significantly growing concern linked
with social and economic burden is imposed particularly by
these ND and their contribution to dementia.
Fauzia Nazam and Sibhghatulla Shaikh have contributed equally
to this work.
* Nazia Nazam
nazianazam@gmail.com
* Md.Imtaiyaz Hassan
mihassan@jmi.ac.in
1 Section ofPsychology, Women’s College, Aligarh Muslim
University, Aligarh, UP202002, India
2 Department ofMedical Biotechnology, Yeungnam
University, Gyeongsan38541, RepublicofKorea
3 Amity Institute ofMolecular Medicine andStem Cell
Research, Amity University, Noida, UttarPradesh201313,
India
4 Department ofMedicine, Najran University, P.O. Box- 1988,
Najran, SaudiArabia
5 Department ofBiochemistry, College ofMedicine,
Prince Sattam Bin Abdulaziz University, P.O. Box173,
Al-Kharj11942, KingdomofSaudiArabia
6 Centre forInterdisciplinary Research inBasic Sciences,
Jamia Millia Islamia, NewDelhi110025, India

Molecular and Cellular Biochemistry
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Tremendous efforts have been employed for the devel-
opment of effective treatments but still, no cure can fully
control, delay, or regress the conditions leading to dementia
[6, 7]. Elucidating the role played by crucial risk factors
in the progression of dementia is an attempt to restrain the
commencement by controlling various risk factors [8, 9].
Thus, identifying probable risk attributes could facilitate in
dropping off the burden in dementia patients.
Thus, the biological risk factors could be regarded as
attributes confirming the heterogeneity of AD or PD as well
as contributing to the etiology and pathogenesis with their
particular mechanisms. The psychosocial risk factors on
the contrary refer to aspects that may affect an individual’s
social and/or psychological response/traits. These biological
and psychosocial factors could be regarded as non-modifia-
ble and modifiable risks, respectively (Fig.1).
In the present review, we intend to elaborate on risk fac-
tors from biological, psychological, and social perspectives.
We further emphasized their management could reduce the
development and progression of NDs.
Non‑modiable biological risk factors
The biological risk factors can enhance the propensity of
dementia arising out of these neurodegenerative diseases and
are appropriately called non-modifiable. The major unmodi-
fiable factors are aging, genetics, and gender. The interplay
of these factors with the psychosocial attributes contributes
to the risk of AD and PD.
Aging
Older age though is not the cause, but it is the greatest
biological risk factor for AD and PD and linked with
dementia. Undoubtedly, with aging, the incidence of
dementia exponentially increases above 65years of age
(5). Although the majority of people with AD are aged 65
and beyond, yet younger individuals may also develop the
disease [10]. Dementia in persons younger than 65years,
arising irrespective of any neurodegenerative disease is
referred to as ‘‘younger-onset’’ or ‘‘early-onset’’ demen-
tia/AD/PD. Although advancing age is one of the greatest
risk factors for AD as well as a challenge to preserve the
cognitive function during the process of aging, it is not
a normal part of aging. With studies suggesting that loss
of neurons is an integral part of the aging brain, it has
become even more challenging. However, a vital ques-
tion is “why aging in some people proceed with normal
cognitive functions while in others there is a deterioration
and disease development?” Perhaps the answer lies in AD
being a multifactorial disease rather than a single cause.
Like AD, PD has the potential to influence well-being
and socio-economic status, and reveal escalating tenden-
cies together with the population longevity. Aging contin-
ues the main risk factor for developing idiopathic PD. In
the population with the age of over 60years, PD affects
more than 1 in 100 individuals, while this 1% rate shows
a whopping 5% prevalence in individuals above 85years
[11]. This underscores the impact of advancing age on
the risk of PD development. Commonly thought of as a
disease of the elderly, yet a small 5% of total cases show
symptoms below 60years of age too of which the majority
is attributed to gene mutations affecting protein metabo-
lism or mitochondrial dysfunction [12]. These hereditary
forms of PD with early-onset may show similar or different
phenotypes or neuropathology compared to sporadic PD.
Fig. 1 Classification of risk
factors for AD and PD. Crucial
risk factors in the development
and progression of dementia can
be “Biological” and “Psycho-
social” risk factors contributing
to pathogenesis, culminating in
dementia. The major biologi-
cal factors are aging, genetics,
and gender, while innumerable
psychosocial risk factors associ-
ated could be broadly catego-
rized into comorbidities and life
events, and lifestyle and mental
health. The interplay of biologi-
cal factors with psychosocial
factors contributes to the risk of
AD and PD

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Genetics
Genetic is one of the major risk factors that contribute
about 70% risk of AD development [13]. However, genetic
research in PD confirms the involvement of genetic risk
factors, including monogenic forms in 30% of the familial
and 3% to 5% of the sporadic cases [12]. To begin with, we
predominantly focus on the risk genes for AD and PD identi-
fied from genome-wide association studies. This progress in
genetic research has immensely improved our understanding
of pathogenesis and the molecular mechanism of dementia.
The presence of Lewy bodies (LB) is an important fea-
ture of PD [14]. LB comprised ubiquitinated α-synuclein,
synaptic vesicle protein, and parkin. These LBs induce
dysfunction of mitochondria, free radicals release, JNK
pathway-stimulated apoptosis, and microglia-triggered
inflammation in the brain [15]. The main genes reported for
causing PD are α-synuclein (SNCA), parkin, leucine-rich
repeat kinase 2 (LRRK2), PTEN-induced putative kinase
1 (PINK1), and DJ-1 [16]. Among 6 genes with a clear
association with heritable and single gene PD, mutations in
SNCA (PARK1 = 4) and LRRK2 (PARK8) are accounted for
autosomal-dominant PD forms, while mutations in Parkin
(PARK2), PINK1 (PARK6), DJ-1 (PARK7), and ATP13A2
(PARK9) are responsible for autosomal recessive PD forms
[17]. Figure2 illustrates the role of genetics and aging in the
development and progression of AD.
The first “PD gene- PARK1/SNCA” was the gene that
encodes the α-synuclein (presynaptic protein). PARK1-asso-
ciated PD is frequently of early commencement and gener-
ally advances promptly. PARK1/SNCA is the key element
in LB which is mostly phosphorylated at Ser129 leading to
its fibril uptake by neurons and intensifies the development
of PD [14]. α-synuclein restrains BDNF/TrkB signaling
pathway by binding to TrkB receptors, resulting in dopa-
minergic death of neurons [18]. Farrer and colleagues [19]
found a double enhancement of α-synuclein at both mRNA
and protein levels in PD; hence, decreasing the expression
of α-synuclein presents a possible curative approach. The
missense mutation in α-synuclein (A53T) was recognized as
a cause of familial PD [20]. A53T has been seen to inhibit
autophagy in the brain of animal models and lead to synucle-
inopathy [21]. A53T mutations along with A30P and E46K
in the α-synuclein gene cause rare familial PD forms, play-
ing a significant role in the neurodegeneration [22].
Mutation in the second “PD gene- PARK2” and gene
encoding parkin protein, result in an autosomal recessive
form of PD [23]. Parkin is a ubiquitin E3 ligase that mono
and/or polyubiquitinates proteins regulating numerous cel-
lular processes. Loss of parkin’s E3 ligase activity exhibits
a pathogenic role in both inherited and sporadic PD. The
third “PD gene- PARK7” results from mutations in the DJ-1
gene [24]. Inline, the fourth “PD gene PARK6” results from
mutations in PTEN kinase 1 (PINK1). A mitochondrial pro-
tein kinase (PTEN1) is linked with the PD pathogenesis. The
deficiency of PINK1 leads to an autosomal recessive form
of PD. Wild-type PINK1 is important for neuroprotection
against the dysfunction of mitochondria and proteasome-
stimulated apoptosis. However, the mutation in G309D
damages this protective effect, probably by interfering with
adenosine diphosphate binding, and thus reduces the activ-
ity of kinase [25]. PINK1 loss was linked with mitochon-
drial dysfunction causing deficient LETM1 phosphorylation
and damage to the mitochondrial Ca2+ transport [26]. In
addition, an interrupted mitochondrial membrane potential
under stressful conditions has been found in PINK1 mutant-
transfected cells.
The fifth “PD gene-PARK8” along with LRRK2 muta-
tions result in the highest risk of familial PD and causes
the autosomal dominant PD [27]. α-synuclein mobility and
its accumulation are enhanced by LRRK2 G2019S muta-
tion in cultured primary neurons and dopaminergic neu-
rons in substantia nigra pars compacta of PD brain [28].
Tau transmission in mouse brain neurons is promoted by
LRRK2 G2019S mutation, suggesting a need to understand
the tau protein progression and neuropathology in LRRK2-
associated PD [29]. The kinase activities of LRRK2 were
enhanced by mutations in LRRK2; thus, LRRK2 inhibitors
could be employed to block the activity of kinase to contrib-
ute neuroprotection in PD models [30]. The identification
of mutations in the above five PD genes provided deeper
insights into the mechanism of PD pathogenesis.
Amyloid precursor protein (APP) mutation or either of
the presenilin gene mutation (PSEN1 or PSEN2) accounts
for the early-onset AD [31]. The important genetic risk fac-
tor for the progression of late-onset AD is the E4 allele of
apolipoprotein E-APOE4 which is involved in fat metabo-
lism. Besides, CR1, CLU, and PICALM genes have been
recognized as risk factors for early-onset of the AD. In the
brain, APOE is the principal apolipoprotein of the high-
density lipoprotein complex. Pathologically, the E4 allele
of APOE is linked with enhanced deposition of Aβ peptide
in the brain. Although APOE has various functions in the
brain, its role in AD progression relates to its ability to bind
with the Aβ peptide [32].
APP is an integral transmembrane protein expressed in
the brain and metabolized by a series of sequential proteases
together with the γ-secretase complex. Sequential APP pro-
teolysis generates neurotoxic Aβ peptide and its aggregation
within the brain imparts a vital step in AD development
[33]. The common APP mutation (APPswe) changes the
amino acid adjacent to the BACE1 cleavage site, while the
mutations aggregate nearby the γ-secretase cleavage site in
NDs. Mutations in the presenilin (PS1 and PS2) result in
increased Aβ42 –the less soluble toxic contrasted to Aβ40
production [34].

Molecular and Cellular Biochemistry
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Processing of APP by β-secretase pursued by γ-secretase
resulting in the Aβ generation is termed as an amyloido-
genic pathway. The β-secretase first cuts the APP to pro-
duce the C-terminal fragment known as C99 subsequently
γ-secretase cleaves C99 to generate the Aβ peptides [33].
The α-secretase cuts APP in the center of the Aβ domain
and subsequently prevents its production. The member of
a disintegrin and metalloprotease domain (ADAM) family,
such as ADAM9, ADAM10, and ADAM17, has shown to
exhibit α-secretase activity, though the mechanism that con-
trols the activity of α-secretase is still uncertain. However,
it has been established that ADAM10 is the key α-secretase
and cleaves the APP in a non-amyloidogenic way [35]. As
the β- and γ-secretases are involved in Aβ generation, inhibi-
tion of these enzymes have been considered as the potential
target to control cerebral Aβ levels in AD. On the other hand,
α-secretase activation makes a possible therapeutic approach
in the reduction of Aβ [36].
Fig. 2 Role of risk factors—Genetics and Aging towards AD patho-
genesis. Cleavage of transmembrane amyloid precursor protein
(APP) by α-secretase results in the production of peptides required
for normal neuronal function (non-amyloidogenic pathway). How-
ever, the abnormal cleaving by β-secretase initially generates a mem-
brane-associated fragment and later γ-secretase releases neurotoxic
amyloid-beta (Aβ) peptide (amyloidogenic pathway). Aβ accumula-
tion in the extracellular space is influenced by the Aβ-binding mol-
ecules—APOE which tends to aggregate, giving rise to senile plaques
and other insoluble oligomeric protein forms. Aβ-induced elevated
GSK3β activity causes tau protein phosphorylation producing
increased levels of neurofibrillary tangles (NFT). Once Aβ aggregates
into oligomers and fibrils, it can induce cellular toxicity, neuronal
inflammation, and dysfunction, neurotrophic activity leading to AD
pathogenesis. Neurotoxic Aβ accumulation is the result of impaired
Aβ homeostasis, i.e., between its production and clearance. Defective
Aβ clearance contributes to pathological accumulations of cerebral
Aβ. Aging-related increased aggregation of Aβ in the brain function
as a link between aging and AD. It induces tissue inflammation and
organ dysfunction, together with being vital components of the amy-
loidogenic pathway

Molecular and Cellular Biochemistry
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Tau (microtubule-associated protein) is the principal
component in neurofibrillary tangles (NFTs), a major
player of neurodegeneration. It plays important roles in
the assembly and stabilization of microtubules, and helps
in linking the polymers with other cytoskeletal filaments
[37–41]. Hyperphosphorylated tau produces the NFTs in
AD [42]. Mutations in the tau gene causes frontotemporal
dementia FTDP-17 which impairs its binding to micro-
tubules moderately and subsequently induces neurode-
generation [43]. Tau causes induction of Aβ-stimulated
toxicity and hence shows a useful approach for treating
AD and related disorders [40, 44–46]. Proteolytic cleavage
of tau is appearing to be a potential marker in AD devel-
opment. Tau has several sites for proteolytic cleavage,
which subsequently result in the breakdown and release
of toxic fragments. For instance, tau cleavage by caspases
at Asp421 or Asp13 at its C-terminus produces a truncated
protein that is susceptible to the aggregation and conse-
quent progression of AD [47].
As the studies on AD and PD validate, however, the
genetic mapping and gene-isolation tools by the Human
Genome Project have aided in the gene identification to
unravel their role in the multifaceted forms of NDs. The
emergence of a consensus hypothesis that aggregates of
amyloid-beta and NFT, and α-synuclein are linked with
neurotoxicity in AD and PD respectively could explain the
pathogenesis of the hereditary forms and idiopathic variety
(Figs.2 and 3). Such insights into underlying mechanism of
Fig. 3 Role of risk factors—Genetics and aging towards Parkinson’s
pathogenesis. Gene PARK1/SNCA encodes the presynaptic and
soluble unfolded protein, α- synuclein. In PD, due to mutations and
overexpression of its wild type, these abnormally aggregate into fila-
ments, amyloid fibrils called Lewy pathology, becomes insoluble and
such toxic misfolded forms contribute to the neuronal death. Their
accumulation leads to loss of dopamine neurons impairing synaptic
dopamine release and consequently PD pathogenesis. Overexpression
of α-synuclein inhibits autophagy and increases the accumulation of
aggregate-prone proteins, hence a potent impetus for neurodegenera-
tion. Mutation in the gene PARK2 encoding parkin protein, a ubiq-
uitin E3 ligase inactivates, resulting in neurodegeneration via inter-
ference of adverse outcome pathway (AOP) for parkinsonian motor
deficits through mitochondrial dysfunction. PARK6 resulting from
mutations in PTEN Kinase 1 (PINK1), while PARK7 from mutations
in the DJ-1 gene are linked with mitochondrial dysfunction and pro-
teasome-stimulated apoptosis of neurons. Gene PARK8 due to muta-
tions in LRRK2 enhances α-synuclein mobility, its accumulation in
dopaminergic neurons and abnormal tau phosphorylation depositions
in the brainstem. Progressive mitochondrial dysfunction is a key hall-
mark of the aging process due to the accumulation of mitochondrial
DNA mutations and increased reactive oxygen species production
causing oxidative damage, thereby leading to perturbed respiratory
chain activity leading to neurodegeneration

Molecular and Cellular Biochemistry
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pathogenesis could benefit us to identify novel drug targets
for these diseases.
Gender
The study on the association between gender differences in
AD or PD is still in its infancy. The convergence of non-
modifiable attributes results in creating distinctive sex dif-
ferences risk profiles for AD. The sex-based prevalence in
AD patients is confirmed to be more than 60% for females
itself [48]. APOE4 risk in AD female sufferers is higher
in stark contrast to males, thereby apparent in women het-
erozygous for the APOE4 allele. Surprisingly, males with
homozygosity for APOE4 are seen to be a greater risk in
terms of AD as well as slight cognitive damage. Gender dif-
ferences in PD are evident from recent findings. Incidence
and prevalence data from epidemiological studies in PD con-
firm these figures to be approximately 1.5–twofold more in
men contrasted to women [49]. The delayed symptomatic
development in PD is seen in women on account of greater
physiological striatal dopamine levels, corroborating the epi-
demiological interpretations of poor incidence and higher
onset age in females [50].
The three major biological risk factors discussed above
are largely studied, yet they fail to explain a definite or
specific biological cause of ND. Rightly kept under the
non-modifiable category, the biological factors pose diffi-
culty to intervene. There is a need to focus on developing
interventions that enhance the overall well-being of elderly
people to physical and psycho-social health elements [51].
Since the risk factors could be cause and effect, their pre-
clinical intervention holds the potential to prevent the onset
and development of NDs. Several psychosocial aspects are
unexplored; thus, more attention needs to study the psycho-
social concerns which could be a novel approach towards the
therapeutic management of NDs.
Modiable psychosocial risk factors
Modifiable factors play a vital role in the development of
AD or PD. Numerous psychosocial risk factors are associ-
ated with the onset of dementia which could be discussed
broadly under categories as follows: (i) Comorbidities and
life events, and (ii) Lifestyle and mental health.
Comorbidities andlife events
Preventing the modifiable risk factors might serve as an
alternative approach to fight these debilitating NDs.
Cardiovascular diseases
Acquired factors such as vascular diseases, diabetes, high
blood pressure, and hyperlipidemia are the risk of AD pro-
gression [52]. Neuropathological studies show a massive 6%
to 47% of individuals with dementia to have coexistence of
cerebrovascular disease pathologies [53]. Cardiovascular
disease and AD have many common risk factors. Aβ and
amyloid accumulation in pial and intracerebral arteries lead
to cerebral amyloid angiopathy (CAA) in more than 80% AD
cases [54]. In AD patients with established cerebral amyloid
angiopathy in small arteries and arterioles, atrophy of vascu-
lar smooth muscle cells layer causes the vessel wall to rup-
ture and bleeding within the cerebra in these patients [55].
On the other hand, in PD patients, cardiovascular comor-
bidities are associated with the degeneration of neurons in
the elderly and this risk factor contributes to axial motor
features in PD [56].
Type 2 diabetes
The link between type 2 diabetes and enhanced AD risk has
illustrated in several epidemiological studies suggesting that
Aβ and tau protein phosphorylation are linked with insu-
lin resistance or deficiency and results in the onset of AD
development [57]. Insulin resistance or deficiency increases
the action of β- and γ-secretases and subsequently reduces
amyloid-beta clearance, leading to its deposition in brain tis-
sue. Besides, insulin resistance or deficiency stimulates the
tau protein hyperphosphorylation, resulting in the generation
the neurofibrillary tangles [58]. A contrasting association is
seen when a comparable evaluation is made between dia-
betes and the risk of PD. Meta-analysis from case–control
studies covering 14 studies, including 21,395 PD patients
and 84,579 control subjects, suggests that diabetes may exert
a lower risk despite significant heterogeneity [59].
Hypertension
Hypertension plays an important role in stroke, post-stroke
dementia, and the pathogenesis of vascular dementia. In a
longitudinal study, hypertension was found to increase the
risk of AD progression [60]. Hypertension, particularly
when exists in middle age, adversely affects cognitive func-
tion. Hypertension causes an alteration in vascular walls
which results in ischemia and cerebral hypoxia, thereby
prompting AD development. Cerebral ischemia stimulates
the presenilin expression, able to accumulate the APP and
Aβ and also caused the blood–brain barrier dysfunction [61].
Enhanced cholesterol levels have been considered as a
risk factor for AD development. About 10% higher cho-
lesterol level was found in the AD patients relative to the
healthy individuals [62]. Similarly, in PD, enhanced total

Molecular and Cellular Biochemistry
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cholesterol at baseline was linked with an enhanced risk
[63]. It is interesting to note that cholesterol-lowering
agents reduce α-synuclein level, while hypercholesterolemia
increases the risk of PD.
Environmental exposure
Exposure to pesticides is associated with the risk of PD and
the person with impaired metabolism of pesticides might
be more susceptible [64]. However, pesticide categories are
broad and comprise chemicals having diverse mechanism.
Only some reports have described specific chemicals or
classes of chemicals, such as organochlorines, insecticides,
wood preservatives, herbicides, dieldrin, and paraquat. Liv-
ing in rural areas, agriculture, and drinking water are con-
tributors to cause of PD [65].
Mood
Mood, particularly depression, is a moderate risk factor for
NDs. Studies have identified the chemical abnormality may
be responsible for a depressive mood and dementia. Folate
deficiency or low folic acid was found in depressed mood
and cognitive impairment in AD [66]. Although folic acid
plays a crucial role across all the life-span developmental
stages (neonate, infant, children, and adolescence), but in the
elderly population, its deficiency is reported in old age brain
which increases vulnerability to AD and vascular dementia.
In elderly Latin American, low folate status was associated
with dementia after control for confusing by the impact of
vitamin B-12, depressive symptoms, and other demographic
variables, such as age, sex, and some years of education.
Recent studies have explained the clinical mechanism of
increased folic acid intake and deterioration in symptoms
that reduces neuroinflammatory disturbances which have an
essential role in AD [67]. However, it is too early to con-
clude that a greater intake of folic acid supplements should
be encouraged in the elderly to reduce the risk of cognitive
impairment.
Social disengagement
The exponential increase in social disengagement among the
geriatric population is noteworthy [68]. Social engagement
is the most crucial social factor correlated with dementia,
and a lower social engagement generally leads to greater
chances of disease development [69]. Strikingly, high or
medium social engagement is associated with a lower risk
of dementia compared to low social engagement [70]. An
average hippocampus volume and high risk of dementia in
Japanese–American men at late-life between the ages of
71–92years are assessed by Hazard Ratio. The value of the
Hazard Ratio was found critically significant in later life
with low social engagement [71]. Thus, it could be inferred
that lower social engagement later in life could be linked to
the risk of dementia.
Lifestyle andmental health
Epidemiological studies fortify that various lifestyle factors
are accountable for varying degrees of Alzheimer’s and PD
risk [72]. Lifestyle interventions could improve or maintain
cognitive function in the absence of medications. Also, other
factors that could be modulated socially are diet, physical
activity and mental health, exposure to stress, and sleep
patterns, which are so far considered a major concern to
control cognitive decline and dementia [73]. Interference
in the insulinergic function by stress, inactive lifestyle, and
overconsumption could lower the peptide level and their
cognate receptors in the brain [74].
Diet
Diet is a leading risk factor in PD [74]. For instance, con-
sumption of lipids and fat-rich foods increases oxidative
stress which is associated with PD and AD risk [75]. Dairy
consumption is also associated with the increased risk of
PD, as shown in large prospective cohort studies [76]. Con-
sumption of milk is linked with PD risk as it might contain
organochlorine pesticides and tetrahydroisoquinoline which
can bypass the blood–brain barrier and stimulate Parkinson-
ism. Of the possible PD risk-reducing dietary components,
caffeine, nicotine, and antioxidants are the most examined
ones. Meta-analyses predict PD risk to 30 and 25% lower in
coffee drinkers and caffeine consumers, respectively, indica-
tive of neuroprotection linked with caffeine only and not
to another coffee constituent [77]. On the contrary, good
health and a salutary lifestyle are major factors correlated
with a better cognition and brain structure. Data supporting
a healthy diet as a preventive or delaying factor for AD are
largely based on cardio-metabolic status which maintains
a healthy tissue vasculature and intact insulin sensitivity,
indicates the protective actions of a balanced diet on brain
function.
Personality traits
The available literature indicates an association of personal-
ity traits and clinical markers of dementia. A positive cor-
relation between an increased neuroticism trait disposition
to experience negative effects, low extraversion, high social
introversion, and decreased conscientiousness [78]. Other
personality traits are associated with AD are paranoid, schiz-
oid, schizotypal, borderline, and narcissistic traits [79]. On
similar lines, PD is also accompanied by a characteristic par-
kinsonian personality, characterized by conscientiousness,

Molecular and Cellular Biochemistry
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punctuality, industriousness, and reduced novelty seeking,
in stark contrast to the elderly in the pink [80].
Education
Twin studies on the Swedish population examining the role
of education in the prognosis of AD and dementia demon-
strate a lower education as a risk factor for Alzheimer’s but
not for dementia [81]. However, other researchers have ques-
tioned the latent factor that could plausibly link low educa-
tion and dementia. An empirical investigation was carried
out in people with 5years or less, 6–8years, and those with
9years of formal education. The vulnerability to dementia
calculated by Odd ratio was found significantly higher in
the first group. The reason attributed is that persons with
higher education have more mental occupations and cogni-
tive reservation, thereby delaying the clinical manifestation
of AD and dementia [82]. Like AD, the higher educational
level, conversely, was allied with a lower risk of cognitive
decline. The hypotheses that education predicts the socio-
economic condition of the person and education improves
the reservation of the brain and increase cognitive capacity
proven and accepted. A school study has even shown gender-
specific findings, that is, risk of dementia is increased in
sisters being poorly educated and who did not receive any
vocational training [83]. It has been reported that below the
age of 80years the incidence is higher in males compared
to females but above this age, the incidence is high in males,
which shows an interaction effect on dementia of age and
gender.
Depression
Depression is directly correlated with poor cognition and
functional status in AD patients. A history of depression
sensitizes for enhanced risk of AD development [1, 69]. A
positive correlation between depression and PD develop-
ment has also been reported [84]. Depression could be a
warning for NDs. Hence, more research towards bringing out
the association between AD and depression hold clinical rel-
evance. Altogether, it can be inferred that psychosocial risk
factors sensitize the person to develop the disease towards
the risk imposed by biological factors. Therefore, the iden-
tification of potential risk factors may facilitate a reduction
in the burden of people afflicted by dementia. Preventing
the risk factors might not possibly influence completely the
disease development in the future. However, establishing the
association of modifiable factors with disease progression is
difficult to determine, primarily due to the absence of objec-
tive and sensitive markers.
Therapeutic andmanagement strategies
Both AD and PD equally demand better healthcare in addi-
tion to institutionalization costs [9]. In the subsequent sec-
tion, we explore how prevention and control over these
risk factors could impact ND development. To meet these
demands, numerous strategies have been developed [85, 86].
These options could broadly be categorized as pharmaco-
logical and psychosocial (non-pharmacological) approaches
(Fig.4).
Fig. 4 Potential preventive
strategies for dementia develop-
ment. Numerous strategies for
cognitive impairment treatment
arising out of NDs could be
pharmacological and psychoso-
cial approaches. Their combina-
tions have proven more effective
in retarding disease progression

Molecular and Cellular Biochemistry
1 3
Pharmacological approaches
Improving cognition and slowing the advancing symptoms
is the foremost aim in drug development for both condi-
tions. At present, various drugs received FDA approval since
they are a step ahead in the path of better treatment and due
course may lead to a cure.
Cholinesterase inhibitors (ChEIs)
Several pieces of evidence from neuropathological and
imaging studies have shown substantial cholinergic deficits
in NDs [87]. Deficits in cholinergic activity are associated
with cognitive deficits in either of the conditions which may
be addressed by the design and development of cholinester-
ase inhibitors (ChEIs). These inhibitors are considered safe
and effective in AD and PD patients. ChEI, such as Riv-
astigmine, is successful in cognitive improvement by inhib-
iting cortical AChE and butyrylcholinesterase (BuChE) in
affected brain regions—hippocampus and amygdala [88].
While rivastigmine and galantamine are efficacious in AD
patients with mild to moderate symptoms, donepezil benefits
are extended in alleviating severe AD symptoms [89].
In contrast to AD, a lesser number of clinical trials of
ChEI in PD patients are reported. Yet, studies focused on
ChEIs for PD treatment suggest an improved cognitive func-
tion [90]. Tacrine was the first studied ChEI in Parkinson’s
patients with significant improvements in cognition. It bears
dual inhibition of AChE and BuChE along with modula-
tion effect on the nicotinic receptor. In a placebo-controlled
study, rivastigmine adequately improved dementia con-
nected with PD but was associated with few side effects. The
efficacy together with the safety of AChI-donepezil hydro-
chloride in PD dementia was studied and found that done-
pezil could improve cognition and executive function [91].
N‑Methyl D‑Aspartate (NMDA) receptor antagonist
Although cholinergic drugs increase existing levels of acetyl-
choline in surviving brain cells, they are not successful in pre-
venting neuronal death as well as disease progression. Hence,
evaluating the potential AD and PD treatments and improv-
ing clinical management via different mechanisms is essential.
Substantial evidence favors the role of disrupted glutamate
in the pathophysiology of neurodegenerative disorders [92].
Various glutamate-gated channels, in addition to a group of
G-Protein Coupled Receptors (GPCRs), play crucial roles in
synaptic plasticity and the cellular processes underlying learn-
ing and memory. Among them, glutamate NMDA receptor
antagonists emerged as attractive therapeutic targets [93].
Memantine is one of such antagonists that modulate the flow
of glutamatergic neuronal transmission relying on glutamate
as the main excitatory neurotransmitter [94]. During normal
physiological functions, memantine ineffectively blocks the
low receptor activity levels. While enhanced glutamate con-
centrations is associated with increased activation of NMDA
receptors. Hence, blocks the lethal effects of overactive glu-
tamatergic activity such as compromised synaptic plasticity
and damage to neuron. Memantine—an accepted drug is
focused on the symptomatic treatment of adequate to severe
AD. Although insufficient evidence of the memantine efficacy
exists in PD, yet it is regarded as safe and well tolerated in such
patients [95]. Notably, memantine being is widely accepted in
both AD and PD, its combination with other therapies could
be an effective alternative.
Other treatment options
Altogether, the benefits out of symptomatic treatments
employed for Alzheimer’s patients are modest and do not
alter natural disease progression. Yet, disease-modifying
approaches are under the exploration of which many tar-
get the amyloid cascade. These agents are either aimed at
decreasing Aβ production, reducing aggregation, or enhanc-
ing its clearance. Inhibiting phosphorylation of tau protein
is also promising and is under exploration in animal models
as well as pilot human studies for AD patients. Similarly,
for PD, where the present pharmacological approaches
are mainly symptomatic rather than preventive and with
no cure to date, various dopaminergic (DAergic) drugs or
therapeutic candidates based on the novel mechanisms are
employed [96]. Levodopa and other DAergic drugs are effec-
tive pharmacological options for PD patients (141). DAergic
drugs, when combined with an inhibitor against monoam-
ine oxidase type B, catechol-O-methyl transferase, and cho-
linergic, hold potential for improved motor control or also
improve levodopa-mediated motor complications. Besides,
non-motor symptoms of PD, such as the cognitive deficit,
neuropsychiatric impairment, disturbed sleep pattern, and
dementia, caused by intrinsic PD pathology or drug-medi-
ated side effects, have gained attention. The involvement of
potential risks is highly recommended for modifying disease
progression or even improving clinical symptoms of NDs. A
better understanding of preclinical markers, neuroprotective
strategies are the silver lining for "at-risk" patients before the
clinical onset of the disease. In this context, non-pharmaco-
logical or psychosocial interventions will possibly offer both
symptomatic relief and disease modifications.
Psychosocial (non‑pharmacological)
interventions
Although a decrease in the cognitive impairment features in
NDs is evident from pharmacotherapies, the gain is minimal
and short term. Moreover, the prospective side effects out

Molecular and Cellular Biochemistry
1 3
of pharmacotherapies render the clinical management more
challenging as improving one symptom could end up dete-
riorating the other. Hence, non-pharmacological-based inter-
ventions are required to fight innumerable clinical aspects,
such as cognitive, functional, behavioral, and affective NDs.
Health professionals and scientists are now endorsing non-
pharmacological therapies for healing than just cure. Psy-
chosocial interventions refer to non-pharmacological tech-
niques, including cognitive training, cognitive stimulation
therapy, and cognitive rehabilitation, which aim to improve
cognition impairments.
Cognitive stimulation therapy (CST)
Limited evidence prevails supporting any significant positive
or negative impact of cognitive training (CT) and rehabili-
tation (CR) on cognitive outcomes in both AD and PD. In
comparison to CT and CR technique, the impact of the CS
approach in AD significantly improved [97]. A study based
on randomized controlled group design has shown the com-
bined efficacy of pharmacological and non-pharmacological
CST. The experimental group administered with AChEI
(Donepezil) along with 21h session of CST showed a slow
cognitive decline in comparison with the control group [98].
The impact of cognitive treatment with medication helps in
the improvement of language and cognition and stabilizes
routine activities in the patient with mild AD. Irrespective
of the fact that CS has proven efficacious, most of the studies
neglect to include it in the patients with PD. Many studies
investigated cognitive training in PD patients, yet most of
them deal with the non-demented population [99].
Motor therapy
Dance Movement Therapy (DMT) is one such motor thera-
pies, though underutilized but is preventive in cognitive deg-
radation [100]. DMT involves the use of sound and motor
movement for cognitive stimulation with the perspective
that declines in memory are a part of the aging process, but
mental and physical stimulation may prove preventive. This
therapy is based on the assumption of the body–mind con-
nection and neurophysiological mechanism works behind
DMT as it alters cognition through neurotransmitters. Motor
therapy improves functional abilities, social well-being, and
quality of life in patients with PD [101].
Music therapy
Music therapy has been found to reduce negative symptoms
(behavioral agitation) of AD particularly dementia [102].
Rhythmic sound is found to stimulate neural activity and
improve stages 1, 2, and 3 of AD. It improves memory
and orientation, reduces depression and anxiety, alleviates
delirium, agitation, hallucination, irritability, and language
disorder in the group of moderate AD. Music therapy
improves movement-related symptoms; however, group
music therapy has a substantial impact on the speech qual-
ity and voice range of a person with PD [103].
Dyadic exercise intervention
Studies with randomized control group design have shown a
positive impact of home-based group exercise on the execu-
tive function of patients with AD measured by Clock Draw-
ing Test [104]. The exercise would help increase the vascular
biomarkers of patients with AD. Although non-pharmaco-
logical treatments in AD have been studied substantially
and proven efficacious, limited research are undertaken for
Parkinson’s patients.
Other interventions
The psychosocial interventions combined with pharmaco-
logical interventions have produced better results [105]. A
combination of psychosocial interventions (CST, cognitive
training) and AChEI was found to be more effective than
inhibitor alone. It may well be inferred that pharmacological
treatments offset the symptoms but lack stable and effica-
cious results. Moreover, they are associated with various
side effects and are expensive. This could be overcome to
an appreciable extent by cost-effective non-pharmacological
interventions and their extensive use to improve cognition
or retard progression of cognitive impairment. The direct
impact of this approach would be delayed hospitalization and
a reduction in the costs of national healthcare. This would
improve both well-being of patients as well as caregivers.
Conclusions
Although AD and PD are having a distinct difference in their
clinical and pathological landscapes, both share several com-
mon features. The situation is worsening since no effective
cure for this multifactorial disease is in practice. A detailed
knowledge and better understanding of the risk factors
linked with the onset and advancement of these disorders
are critical for discovering novel targets and new therapeu-
tic approaches. Besides, early diagnosis could reduce the
incidence and pathophysiological advances of NDs. ChEIs
alter the clinical indicators of AD and the therapy results in
a modest but significant improvement. However, in the PD
pharmacological interventions by ChEIs are the first choice
since they have a positive effect on cognition, neuropsychi-
atric symptoms, and functions. Nevertheless, a large number
of randomized trials of ChEIs are needed to evaluate their
precise role. Future investigations should be focused on the

Molecular and Cellular Biochemistry
1 3
design and development of effective treatment options, based
on clinically vital outcomes. Moreover, high-quality rand-
omized control trials are needed to reach a strong conclusion
with powerful evidence.
The pharmacological therapies are successful in improv-
ing the symptoms of dementia and/or slowing the disease
progression. Nevertheless, the biological risk factors lack
explanation to the exact mechanism behind neurodegen-
eration. Focusing on the development of interventions that
improve cognition would be beneficial. It is believed that
the efficacy of treatment could be optimized if interven-
tions are initiated in the early or prodromal disease stage. In
this context, screening and treatment for psychosocial risk
factors would certainly decrease the threat. The available
interventions from pharmacological and psychosocial per-
spective would not only benefit health risk but also benefit
the healthcare cost.
Acknowledgements M.I.H. extends sincere thanks to the National
Medicinal Plants Board, Ministry of AYUSH, Government of India
for financial support (Grant No. Z. 18017/187/CSS/R&D/DL-01/2019-
20-NMPB-IVA). F.N. is thankful for the records of the manuscript
available in Social Science Cyber Library, Aligarh Muslim University,
Aligarh, India.
Author contributions F.N., N.N., and S.S. contributed to conceptual-
ization; F.N., N.N., G.M.H., and A.S.A. were involved in writing—
original draft; G. M. H. and M.I.H contributed to writing—review and
editing. All the authors have read and agreed to the published version
of the manuscript.
Data availability All data generated or analyzed during this study are
included in this published article.
Declarations
Conflict of interest The authors declare no conflict of interest.
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