https://doi.org/10.62909/pcjmhs.2025.004 Pioneer College Journal for Medical and Health Sciences (PCJMHS)

Article

Alzheimer disease categorization and fundamental anatomy

Mariam Hussian Hameed 1,

1 Cosmetic and Laser Department, Collage of Health and Medical Technology, Imam Ja’afar Al-Sadiq Univer-

sity, Baghdad, Iraq; mariam_hussian@ijsu.edu.iq

Abstract: The pathological features of Alzheimer’s disease include protein buildup, neuronal and

synaptic loss, and changes associated with reactive processes. Extracellular antibody buildup man-

ifests in the parenchyma as diffuse, localized, or stellate deposits. It may pertain to the vascular

walls of arteries, veins, and capillaries. Instances where the capillary vessel walls are compromised

show an elevated likelihood of possessing one or two apoe 4 alleles. Parenchymal and vascular an-

tibody deposition occurs in a sequential manner. Tau accumulation, likely the most significant his-

tological correlate of clinical symptoms, manifests in three forms: inside the neuronal cell body as

neurofibrillary tangles, in the dendrites as neuropil threads, and in the axons as the neuritic corona

of senile plaques. Tau disease advances in a sequential and predictable manner from the entorhinal

cortex, via the hippocampus, to the isocortex. The neuronal loss is variable and particular to certain

areas. The mechanism remains a subject of discussion. The timing of synapse loss, likely associated

with the Ab peptide, maybe in the form of oligomers, remains contentious. Multiple clinico-patho-

logical variants of Alzheimer disease have been characterized based on lesion type (plaque-only and

tangle-predominant), onset type (focal onset), etiology (genetic or spontaneous), and accompanying

lesions (Lewy bodies).

Keywords: basic pathology; Alzheimer disease; Classification

MSC:

1. Introduction

The pathogenesis of Alzheimer’s disease (AD) has been extensively researched dur-

ing the last two decades. Animal models have yielded significant insights into the patho-

genetic pathways. Reviewing this extensive material in a single piece has proven unfeasi-

ble. This is why we will not systematically evaluate the animal models; the reader is di-

rected to another review by the same authors.

The lesions associated with accumulation mostly consist of extracellular deposition

of Ab peptide and intracellular aggregation of tau protein. Both Ab peptides and tau pro-

tein are normal biological components that, in Alzheimer's disease, adopt an aberrant fi-

brillary form characterized by low solubility in aqueous solutions. Nonetheless, the cor-

relation between the two lesion types remains ambiguous [1].

The deposition of Ab pertains to a discrepancy between its synthesis and elimination.

The Ab peptide is derived from its precursor, the amyloid precursor protein (APP), a

transmembrane protein, through two successive enzymatic processes: b-secretase cleaves

APP in its extracellular domain, resulting in a fragment known as C99, which is subse-

quently cleaved by the transmembrane gamma-secretase complex that comprises prese-

nilin. The subcellular compartmentalization of these sequential cleavages is still under

discussion. It is now widely acknowledged that the last stages occur inside the endoso-

mal-lysosomal pathway. The deposits include a combination of different Ab isoforms,

Citation: To be added by editorial

staff during production.

Academic Editor: Firstname Last-

name

Received: 10/5/2025

Revised: 27/5/2025

Accepted: 15/7/2025

Published: 20/7/2025

Submitted for possible open access

publication under the terms and

conditions of the Creative Commons

Attribution (CC BY) license

(https://creativecommons.org/license

s/by/4.0/).

PCJMHS 2025, Vol.1 21 of 25

with some starting at amino acid (AA) 11 (referred to as "N-truncated" isoforms) or con-

cluding at AA 39 to 42. A prevalent variant starts at position 3, with the first glutamine

residue having undergone cyclization into pyroglutamate [2]. The isoform terminating at

AA 42 has two more amino acids at the C-terminus of the peptide, resulting in an extended

section integrated inside the cell membrane; it exhibits increased hydrophobicity and a

tendency to precipitate in aqueous solution. Mutations in APP, presenilin 1, and prese-

nilin 2 are linked to an elevation in Ab production and an increased ratio of Ab42 to Ab40.

The Ab peptide has an inherent propensity to oligomerize; oligomers, often referred

to as ADLL (Ab-derived diffusible ligands), may represent the hazardous entities. Oligo-

mers likely develop intracellularly [3].

2. Materials and Methods

The Ab peptide is often undetectable by immunohistochemistry in the brains of

healthy young people. Ab deposition occurs in some elderly individuals deemed cogni-

tively normal (pathological aging), in patients with moderate cognitive impairment

(MCI), in those with advanced sporadic or familial Alzheimer's disease (AD), and in indi-

viduals with trisomy 21. The terminology about Ab peptide deposition is perplexing. The

word "senile plaque" has been used in several contexts, rendering it imprecise. We con-

sciously sought to restrict its use to the so-called mature neuritic plaque, particularly when

discussing the lesion without specifying the method employed for its revelation. In differ-

ent contexts and for clarity, all forms of extracellular accumulation are referred to as de-

posits, followed by a qualifying phrase that characterizes their mode of revelation, e.g.

Antibody deposits are identified by anti-antibody antibodies, whereas amyloid deposits

are detected using Congo red or thioflavin S staining (Figure 1). A further qualifying

phrase may indicate their morphology: diffuse, localized, or stellate Ab deposits [4]. The

neuritic element of the plaque forms its corona (Figure 1).

Localized deposits Alongside diffuse deposits, immunohistochemistry reveals dense,

spherical accumulations of Ab peptide, referred to as focal deposits. The focused deposits

are visible on slides stained with hematein and eosin (Figure 2), but the diffuse deposits

remain unstained. Focal deposits may be amyloid or non-amyloid, with or without an

accompanying neuritic corona.

Figure 1. Terms used to describe Ab deposits and se-

nile plaques.

Various aspects of Ab deposition, as seen with Ab

and tau

immunohistochemistry

Figure 2. Aspects of the senile plaque, the senile

plaque as seen after

hematein–eosin stain.

PCJMHS 2025, Vol.1 22 of 25

Amyloid or otherwise Certain localized deposits lack amyloid tinctorial properties

yet may be readily identified using antibody immunohistochemistry. It is reported that

they mostly comprise the Ab-40 peptide. Additional focal deposits consist of amyloid,

identifiable by Congo red or thioflavin S staining. CD-68 positive, active microglia are

almost always associated with the amyloid focal deposits [5]. This discovery may be elu-

cidated by two distinct scenarios: either the microglial cell is essential for the conversion

of diffuse amyloid deposits into amyloid, or it is the structure of amyloid that triggers

microglial activation. A multitude of microglial receptors, outside the purview of this

study, have been shown to participate in this response. Microglial cells release cytokines

that initiate and maintain persistent non-immune inflammation.

The astrocytic element Neuritic plaques are encircled by astrocytic processes; in con-

trast to microglial cells that interact with the amyloid core, the fibrous astrocytes are situ-

ated in the plaque's perimeter. Evidence suggests that the astrocytic component emerges

later in the development of the senile plaque; the prevalence of astrocytic processes infil-

trating the plaque's core may be associated with a regressive phase of the lesion [6].

The predominant quantity of Ab deposits is situated in the gray matter; however,

streaks of diffuse deposits may be seen in the white matter. Neuritic plaques are mostly

located in layers II and III. The areal architecture of Ab deposition is contingent upon the

illness stage and is not arbitrary. Two methods for staging this process have been docu-

mented. In the Braak system, just the cerebral cortex is considered. In stage A, amyloid

deposits are located in the basal sections of the cortex; in stage B, the whole isocortex is

affected, except the primary cortices, with moderate involvement of the hippocampus; in

stage C, deposits are present across all regions of the isocortex, including sensory and

motor core fields.

The microscopic alterations discussed in the previous paragraphs explain the macro-

scopic observations. The atrophy typical of Alzheimer's disease encompasses regions

where tau pathology is predominant, with neuronal loss, including in the entorhinal cor-

tex, hippocampus, and amygdala. The inferior temporal and superior and middle frontal

gyri are significantly impacted, although the inferior frontal and orbitofrontal gyri remain

unaffected. The causative relationship between synaptic loss or process loss and atrophy,

independent of neuronal loss, remains uncertain; nonetheless, a robust association has

been shown between neuronal loss and atrophy in Alzheimer's disease [7]. Atrophy is not

associated with the amyloid load.

The oldest-old population has a weaker clinico-pathological connection. Three sub-

groups were created within the 317-case population by Haroutunian et al.: young-old,

middle-old, and oldest-old. The oldest-old category did not show any relationships with

NFT and neuritic plaque density, which rose more than tenfold with disease severity,

mostly due to the reduced lesion density at that age.

identified neurofibrillary tangle density in the medial temporal lobe as the most ef-

fective indicator for differentiating between normal and MCI (amnestic type) individuals.

This region includes the entorhinal cortex, subiculum, CA1, and amygdala. According to

neuropathologists, "from a neuropathologic perspective, it appears that amnestic MCI is,

in reality, early Alzheimer disease" since the density of neurofibrillary tangles and neuritic

plaques was often greater in early AD cases compared to MCI patients. Similarly, Bennett

et al. discovered AD cases in their "normal" population that met the criteria for the disease.

However, after conducting more thorough tests, they came to the conclusion that AD le-

sions (in the intermediate or high probability range of the NIA Reagan criteria, see later)

were linked to subtle changes in memory even in the so-called pre-symptomatic phase [8].

Notably, the diffuse deposits (sometimes called "diffuse plaques") do not serve as a dis-

criminative variable in either the Knopman et al. or Markesbery et al. trials. As we will

show in the next section, the accompanying changes, particularly those involving the

blood vessels, and in the oldest of the lesions reduce the threshold at which symptoms

begin to manifest [9].

PCJMHS 2025, Vol.1 23 of 25

3. Results

Those published under the name of Khachaturian were the first formal neuropatho-

logical criteria that were accepted globally. The researchers leaned heavily toward the idea

that senile plaques, not neurofibrillary tangles, were the hallmark lesions of Alzheimer's

disease. Neurofibrillary tangles were originally considered to be nonspecific since they

were seen in a wide variety of diseases. This led to the development of this idea. The Kha-

chaturian criteria outlined a method for sampling and recommended quantitative cutoff

values for the density of senile plaques; these values would be affected by the patient's

age and would lead to a "black and white" diagnosis of Alzheimer's disease. Looking back,

it's possible that these criteria weren't stringent enough. For example, the senile plaque

number threshold wasn't grounded in theory or epidemiological evidence; it was deter-

mined conventionally. In addition, the "threshold" method required a level of measure-

ment accuracy that was not feasible back then.

The relationship between clinically determined dementia and the density of amyloid

and tau pathology was formalized by the NIA Reagan criteria [349], which were based on

the findings that tau pathology was the best predictor of dementia and that plaque counts

could be high in subjects with minimal cognitive impairment. Lesions having a "high,"

"intermediate," or "low likelihood" were associated with dementia. Additional research

has to be conducted to determine if lesions may have been detected even when no clinical

symptoms were present. Because Alzheimer's disease lesions do not always affect adja-

cent areas, seemingly healthy nerve tissue borders regions with significant damage; this

has led some to question if the emphasis on diagnosis was deceptive for a number of rea-

sons.

Therefore, a scientist may sometimes get a "normal" or at least a "minimal" sample

from a brain that is supposedly affected by AD. However, lesions-free entorhinal cortex

or hippocampi in elderly individuals is very unusual, suggesting that Alzheimer's disease

pathology is much more common than previously believed. At long last

One characteristic in the established course of AD is the presence of amyloid deposits

in the neocortex and neurofibrillary tangles restricted to the hippocampus (Braak III-IV;

Thal phase 1), as previously discussed. When there is no accompanying disease, these

instances often progress to later stages. Poor prognosis of even these early lesions when

accompanied with Lewy pathology is connected to the plaque-only phenotype, according

to this theory.

Although severe astrogliosis and neuronal loss in the CA1 sector and subiculum may

be seen in elderly people on their own, they can also be seen in AD, the most frequent

disease involving sclerosis of the hippocampus, and other forms of the disease. Among

650 instances of Alzheimer's disease confirmed by autopsy, 3.1% had hippocampal scle-

rosis, according to a Viennese study. Cases with hippocampus sclerosis were older on

average and more likely to have coronary heart disease, which raises the possibility that

hypoxic-ischemic events were a contributing cause. Pathology involving TDP-43 may po-

tentially increase the likelihood of developing hippocampal sclerosis.

In severe instances of Alzheimer's disease (AD), the argyrophilic grain disease (AGD)

lesions could be hard to tell apart. To differentiate between neurofibrillary lesions (4R and

3R tau positive) and grains (only 4R tau positive), Fujino et al. used a particular 4 repeats

(4R) tau antibody. There was a 26% prevalence of AGD in AD. AGD was associated with

a somewhat older age group, an overrepresentation of the H1 tau haplotype, and a lack

of the Apoe4 allele in AD patients. Given the prevalence of both conditions, it is unclear

from the available research if AGD is indeed more common in the AD population or

whether the correlation between the two is coincidental.

Dentate gyrus localization of TDP-43, a phosphorylated, ubiquitinated protein that

abnormally accumulates in the cytoplasm of neurons in some forms of frontotemporal

dementia, has been seen in up to 34% of AD patients. Compared to patients devoid of

TDP-43 inclusions, they were in a more advanced clinical stage. Both hippocampus scle-

rosis and medial temporal atrophy were more common. In several amyotrophic lateral

PCJMHS 2025, Vol.1 24 of 25

sclerosis (AD) lesions, including tangles, reactive astrocytes, and neuritic plaques,

caspase-cleaved TDP-43 was found. While tau buildup is not associated with TDP-43, a-

synuclein pathology is in instances of AD and Lewy body disease.

5. Conclusions

Important strides in our knowledge of AD pathology have been achieved in the past

20 years, including the identification of lesion components, the description of pathology

progression, and the clinical correlates of changes in patient or community cohorts. The

progression and underlying causes of the lesions may now be better understood thanks

to cutting-edge imaging methods and robust animal models. But there are still some fun-

damental mysteries: how sporadic AD occurs is still up for discussion, and how Ab

buildup relates to tau pathology is still poorly known. We need fresh postmortem and in

vivo neuropathological evidence to confirm the following theories: an increase in Ab pep-

tide synthesis, a failure in its clearance, or an initial disruption of tau metabolism.

PCJMHS 2025, Vol.1 25 of 25

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