Sejumlah patogenesis penyakit alzheimer yaitu:a. Faktor genetik

Beberapa peneliti mengungkapkan 50% prevalensi kasus alzheimer ini diturunkan melalui gen autosomal dominant. Individu keturunan garis pertama pada keluarga penderita alzheimer mempunyai resiko menderita demensia 6 kali lebih besar dibandingkan kelompok kontrol normal. Pemeriksaan genetika DNA pada penderita alzheimer dengan familial early onset terdapat kelainan lokus pada kromosom 21 diregio proximal log arm, sedangkan pada familial late onset didapatkan kelainan lokus pada kromosom 19. Begitu pula pada penderita down syndrome mempunyai kelainan gen kromosom 21, setelah berumur 40 tahun terdapat neurofibrillary tangles (NFT), ssenile plaque dan penurunan. Marker kolinergik pada jaringan otaknya yang menggambarkan kelainan histopatolgi pada penderita alzheimer.Hasil penelitian penyakit alzheimer terhadap anak kembar menunjukkan 40-50% adalah monozygote dan 50% adalah dizygote. Keadaan ini mendukung bahwa faktor genetik berperan dalam penyakit alzheimer. Pada sporadik non familial (50-70%), beberapa penderitanya ditemukan kelainan lokus kromosom 6, keadaan ini menunjukkan bahwa kemungkinan faktor lingkungan menentukan ekspresi genetika pada alzheimer.

b. Faktor infeksiAda hipotesa menunjukkan penyebab infeksi virus pada keluarga penderita alzheimer yang dilakukan secara immuno blot analisis, ternyata diketemukan adanya antibodi reaktif. Infeksi virus tersebut menyebabkan infeksi pada susunan saraf pusat yang bersipat lambat, kronik dan remisi. Beberapa penyakit infeksi seperti Creutzfeldt-Jacob disease dan kuru, diduga berhubungan dengan penyakit alzheimer.Hipotesa tersebut mempunyai beberapa persamaan antara lain:1) Manifestasi klinik yang sama2) Tidak adanya respon imun yang spesifik3) Adanya plak amyloid pada susunan saraf pusat4) Timbulnya gejala mioklonus5) Adanya gambaran spongioform

c. Faktor lingkunganEkmann (1988), mengatakan bahwa faktor lingkungan juga dapat berperan dalam patogenesa penyakit alzheimer. Faktor lingkungan antara lain, aluminium, silicon, mercury, zinc. Aluminium merupakan neurotoksik potensial pada susunan saraf pusat yang ditemukan neurofibrillary tangles (NFT) dan senile plaqueHal tersebut diatas belum dapat dijelaskan secara pasti, apakah keberadaan aluminum adalah penyebab degenerasi neurosal primer atau sesuatu hal yang tumpang tindih. Pada penderita alzheimer, juga ditemukan keadan ketidakseimbangan merkuri, nitrogen, fosfor, sodium, dengan patogenesa yang belum jelas.

Ada dugaan bahwa asam amino glutamat akan menyebabkan depolarisasi melalui reseptor N-methy D-aspartat sehingga kalsium akan masuk ke intraseluler (Cairan-influks) danmenyebabkan kerusakan metabolisma energi seluler dengan akibat kerusakan dan kematian neuron.

d. Faktor imunologisBehan dan Felman (1970) melaporkan 60% pasien yang menderita alzheimer didapatkan kelainan serum protein seperti penurunan albumin dan peningkatan alpha protein, anti trypsin alphamarcoglobuli dan haptoglobuli.Heyman (1984), melaporkan terdapat hubungan bermakna dan meningkat dari penderita alzheimer dengan penderita tiroid. Tiroid Hashimoto merupakan penyakit inflamasi kronik yang sering didapatkan pada wanita muda karena peranan faktor immunitas.

e. Faktor traumaBeberapa penelitian menunjukkan adanya hubungan penyakit alzheimer dengan trauma kepala. Hal ini dihubungkan dengan petinju yang menderita demensia pugilistik, dimana pada otopsinya ditemukan banyak neurofibrillary tangles.

f. Faktor neurotransmiterPerubahan neurotransmitter pada jaringan otak penderita Alzheimer mempunyai peranan yang sangat penting seperti:1) AsetilkolinBarties et al (1982) mengadakan penelitian terhadap aktivitas spesifik neurotransmiter dgncara biopsi sterotaktik dan otopsi jaringan otak pada penderita alzheimer didapatkan penurunan aktivitas kolinasetil transferase, asetikolinesterase dan transport kolin serta penurunan biosintesa asetilkolin.Adanya defisit presinaptik dan postsynaptic kolinergik ini bersifat simetris pada korteks frontalis, temporallis superior, nukleus basalis, hipokampus. Kelainan neurottansmiter asetilkoline merupakan kelainan yang selalu ada dibandingkan jenis neurottansmiter lainnya pada penyakit alzheimer, dimana pada jaringan otak/biopsinya selalu didapatkan kehilangan cholinergik Marker.Pada penelitian dengan pemberian scopolamine pada orang normal, akan menyebabkan berkurang atau hilangnya daya ingat. Hal ini sangat mendukung hipotesa kolinergik sebagai patogenesa penyakit Alzheimer.2) NoradrenalinKadar metabolisme norepinefrin dan dopamin didapatkan menurun pada jaringan otak penderita alzheimer. Hilangnya neuron bagian dorsal lokus seruleus yang merupakan tempat yang utama noradrenalin pada korteks serebri, berkorelasi dengan defisit kortikal noradrenergik. Bowen et al(1988), melaporkan hasil biopsi dan otopsi jaringan otak penderita alzheimer menunjukkan adanya defisit noradrenalin pada presinaptik neokorteks. Palmer et al(1987),

Reinikanen (1988), melaporkan konsentrasi noradrenalin menurun baik pada post dan ante-mortem penderita alzheimer.3) DopaminSparks et al (1988), melakukan pengukuran terhadap aktivitas neurottansmiter region hipothalamus, dimana tidak adanya gangguan perubahan aktivitas dopamin pada penderita alzheimer. Hasil ini masih kontroversial, kemungkinan disebabkan karena potongan histopatologi regio hipothalamus setia penelitian berbeda-beda.

4) SerotoninDidapatkan penurunan kadar serotonin dan hasil metabolisme 5 hidroxi-indolacetil acid pada biopsi korteks serebri penderita alzheimer. Penurunan juga didapatkan pada nukleus basalis dari meynert. Penurunan serotonin pada subregio hipotalamus sangat bervariasi, pengurangan maksimal pada anterior hipotalamus sedangkan pada posterior peraventrikuler hipotalamus berkurang sangat minimal. Perubahan kortikal serotonergik ini berhubungan dengan hilangnya neuron-neuron dan diisi oleh formasi NFT pada nukleus rephe dorsalis5) MAO (Monoamine Oksidase)

Enzim mitokondria MAO akan mengoksidasi transmitter mono amine. Aktivitas normal MAO terbagi 2 kelompok yaitu MAO A untuk deaminasi serotonin, norepineprin dan sebagian kecil dopamin, sedangkan MAO B untuk deaminasi terutama dopamin. Pada penderita alzheimer, didapatkan peningkatan MAO A pada hipothalamus dan frontais sedangkan MAO B meningkat pada daerah temporal dan menurun pada nukleus basalis dari meynert.

EtiologyThe cause of AD is unknown. Several investigators now believe that converging environmental and genetic risk factors trigger a pathophysiologic cascade that, over decades, leads to Alzheimer pathology and dementia.

The following risk factors for Alzheimer-type dementia have been identified[23, 24, 25, 26] :

Advancing age Family history APOE 4 genotype Obesity Insulin resistance Vascular factors Dyslipidemia Hypertension Inflammatory markers Down syndrome Traumatic brain injury

Midlife hypertension is an established risk factor for late-life dementia, of which AD is the most common type. A brain autopsy study evaluating the link between hypertension and AD found that patients using

beta-blockers to control blood pressure had fewer Alzheimer's-type brain lesions on autopsy compared to patients taking no drug therapy or those taking other medications.[27]

In addition, epidemiologic studies have suggested some possible risk factors (eg, aluminum,[28, 29] previous depression) and some protective factors (eg, education,[30, 31] long-term use of nonsteroidal anti-inflammatory drugs[32] ).

Genetic causes

Although most cases of AD are sporadic (ie, not inherited), familial forms of AD do exist. Autosomal dominant AD, which accounts for less than 5% of cases, is almost exclusively early onset AD; cases occur in at least 3 individuals in 2 or more generations, with 2 of the individuals being first-degree relatives.[33]

Familial clustering represents approximately 15–25% of late-onset AD cases and most often involves late-onset AD. In familial clustering, at least 2 of the affected individuals are third-degree relatives or closer.[33]

Mutations in the following genes unequivocally cause early-onset autosomal dominant AD:

The amyloid precursor protein (APP) gene on chromosome 21 The presenilin-1 (PS1) gene on chromosome 14 The presenilin-2 (PS2) gene on chromosome 1

All 3 of these genes lead to a relative excess in the production of the stickier 42-amino acid form of the Ab peptide over the less sticky 40-amino-acid form.

This beta-pleated peptide is postulated to have neurotoxic properties and to lead to a cascade of events (as yet incompletely understood) that results in neuronal death, synapse loss, and the formation of NFTs and SPs, among other lesions. Nonetheless, the mutations that have been found to date account for less than half of all cases of early-onset AD.

Other than the apolipoprotein E epsilon 4 (APOE E4) genotype, no polymorphisms in other genes have been consistently found to be associated with late-onset AD. However, genome-wide association studies have identified the following additional susceptibility loci[34] :

Clusterin (CLU) gene Phosphatidylinositol-binding clathrin assembly protein (PICALM) gene Complement receptor 1 (CR1) gene ATP-binding cassette sub-family A member 7 gene (ABCA7) Membrane-spanning gene cluster (MS4A6A/MS4A4E) Ephrin receptor A1 (EPHA1) CD33 CD2AP

APP mutations

The observation that patients with Down syndrome (trisomy 21) develop cognitive deterioration and typical pathological features of AD by middle age led to the discovery of the APP gene on chromosome 21. Simultaneously, a locus segregating with a minority of early-onset familial AD kindreds was mapped to this chromosome, in the same region as the APP gene. For more information, see the Medscape Reference article Alzheimer Disease in Down Syndrome.

Subsequently, several missense mutations within the APP gene that resulted in amino acid substitutions in APP were identified in these familial AD kindreds. Such mutations appear to alter the previously described proteolytic processing of APP, generating amyloidogenic forms of Ab.

Skin fibroblasts from individuals carrying APP mutations produce increased Ab 42/43. Increased plasma concentration of Ab 42/43 is also seen in these patients, regardless of age, sex, or clinical status. Interestingly, some patients with sporadic AD may exhibit similar elevations of plasma Ab 42/43.

PS1 and PS2 mutations

Approximately 50-70% of early-onset autosomal-dominant AD cases appear to be associated with a locus (AD3) mapped by genetic linkage to the long arm of chromosome 14 (14q24.3). Numerous missense mutations have been identified on a strong candidate gene, called PS1.

At the same time, another autosomal dominant locus responsible for early-onset AD was localized to chromosome 1. Two mutations were identified on the candidate gene, designated PS2. The physiological role of presenilins and the pathogenic effects of their mutations are not yet well understood.

APOE

The gene encoding the cholesterol-carrying apolipoprotein E (APOE) on chromosome 19 has been linked to increased risk for AD, principally late-onset but also some early-onset cases. The gene is inherited as an autosomal codominant trait with 3 alleles. The APOE E2 allele, the least prevalent of the 3 common APOE alleles, is associated with the lowest risk of developing AD,[35] with a lower rate of annual hippocampal atrophy and higher cerebrospinal fluid Aβ and lower phosphotau, suggesting less AD pathology.[36]

The E3 allele confers intermediate risk of developing AD, with less risk than the E4 allele. The E3 allele, which is more common than the E2 allele, may protect tau from hyperphosphorylation, and the E2 allele’s effect on tau phosphorylation is complex.

APOE E4 gene “dose” is correlated with increased risk and earlier onset of AD.[37]Individuals who are genetically predisposed to AD are advised to closely control their blood pressure closely. Hypertension has been shown to interact with APOE E4 genotype to increase amyloid deposition in cognitively healthy middle-aged and older adults; controlling hypertension may significantly decrease the risk of developing amyloid deposits, even in those with genetic risk.[38, 39]

Persons with 2 copies of the APOE E4 allele (4/4 genotype) have a significantly greater risk of developing AD than persons with other APOE subtypes. Mean age at onset is significantly lower in the presence of 2 APOE E4 copies. A collaborative study has suggested that APOE E4 exerts its maximal effect before the age of 70 years.

Many APOE E4 carriers do not develop AD, and many patients with AD do not have this allele. Therefore, the presence of an APOE E4 allele does not secure the diagnosis of AD, but instead, the APOE E4 allele acts as a biologic risk factor for the disease, especially in those younger than 70 years.

Insulin resistance

A small study by Baker et al implies that insulin resistance, as evidenced by decreased cerebral glucose metabolic rate measured by a specific type of positron emission tomography (PET) scan, may be useful as an early marker of AD risk, even before the onset of MCI.[40] The PET scan revealed a qualitatively different activation pattern in patients with prediabetes or type 2 diabetes mellitus during a memory encoding task, as compared with healthy individuals who were not insulin resistant.

Although the study by Baker et al had too few subjects (n=23) for the results to reach statistical significance, a study by Schrijvers et al in a much larger population (3,139 subjects) found a similar association between insulin resistance and AD over 3 years, which then disappeared after that time.[41] These researchers used a different measure of insulin resistance, the homeostasis model assessment. Disturbances in insulin metabolism may not cause neurological changes but may influence and accelerate these changes, leading to an earlier onset of AD.

Infection

An emerging field of research suggests a significant association between AD and chronic infection with various species of spirochetes, including the periodontal pathogen Treponemas and Borrelia burgdorferi, as well as pathogens such as herpes simplex virus type 1.[42] In vitro and animal studies support the concept of infection resulting in chronic inflammation and neuronal destruction. Ab has been shown to be an antimicrobial peptide, so its accumulation might represent a response to infection.

Depression

Depression has been identified as a risk factor for AD and other dementias. Recent Framingham data have helped bolster the epidemiological association. The study showed a 50% increase in AD and dementia in those who were depressed at baseline.[43] During a 17-year follow-up period, a total of 21.6% of participants who were depressed at baseline developed dementia, as compared with 16.6% of those who were not depressed.

In another related study, recurrent depression was noted to be particularly pernicious. One episode of depression conferred an 87–92% increase in dementia risk, while having 2 or more episodes nearly doubled the risk.[44]

According to the results of a meta-analysis of 23 population-based, prospective cohort studies, late-life depression is associated with an increased risk for all-cause dementia, vascular dementia, and AD.[45,

46] The risk for vascular dementia appeared to be significantly higher than the risk for AD. The analysis included data on patients 50 years and older who were free of dementia at baseline. The total sample included in the pooled analysis for all-cause dementia was 49,612 participants, 5116 of whom had late-life depression.

Head trauma

Moderate to severe head trauma has been documented as a risk factor for the development of AD as well as other forms of dementia later in life.[47] Chen et al have proposed that traumatic brain injury leads to accumulation of amyloid precursor protein with its proteolytic enzymes at sites of axonal injury, increased intracellular production of Ab, release of Ab from injured axons into the extracellular space, and deposition of Ab into extracellular plaques.[48]

A study that followed over 7,000 US veterans of World War II showed that those who had sustained head injuries had twice the risk of developing dementia later in life, with veterans who suffered more severe head trauma being at an even higher risk. The study also found that the presence of the APOE gene and sustaining head trauma seemed to act additively to increase the risk of developing AD, although there was no direct correlation.[49]

Epigenetics

Epigenetics is a change in gene expression that results from gene-environment interactions. This is mediated by DNA methylation, RNA editing, and RNA interference without changes in the DNA sequence. Epigenetic elements in AD are suggested by facts that the majority of cases of AD are sporadic, occur in patients without a family history of the disease, and have onset late in life.

One environmental factor that has shown damage in laboratory animals consistent with human AD is lead. Early exposure to lead in monkeys resulted in plaque formation as they aged.[50] One aspect of early lead exposure appears to be increased oxidative stress in brain cells. Oxidative stress is the accumulation of excess free radicals that alter methylation patterns in the cells.

Early oxidative stress other than lead has been postulated as one cause of sporadic AD. Brain cells in AD exhibit overexpression and repression of AD genes, suggesting hypomethylation and hypermethylation, which are associated with oxidative stress.[51]

Given that lead exposure to animals in early life does not produce manifestations until later in life, continued environmental stress may contribute to expression. Consequently, it is possible that the use of antioxidant supplements starting in childhood might decrease long-term oxidative stress and decrease the incidence of AD. The work of Harman indicates that antioxidants may decrease cell damage and aging by decreasing excess oxidative stress.[52]

The only major study of one antioxidant, vitamin E, yielded disappointing results. However, the study involved a very limited time usage. At present no other changes in environmental exposures have been studied for prevention of AD, but this area will be critical in future long-term studies.